Novel Heteroaromatic Inhibitors of Fructose 1,6-Bisphosphatase

专利摘要:
The novel FBPase inhibitors of formulas (I) and (X) are useful for the treatment of diabetes and other diseases associated with elevated blood glucose. (I) (X)
公开号:KR20010085776A
申请号:KR1020017003079
申请日:1999-09-03
公开日:2001-09-07
发明作者:쿤 당；스리니바스 라오 카시브하트라；케이 라쟈 레디；마크 디. 에리온；엠.라미 레디；아툴 아가르왈
申请人:마크 디. 에리온；메타베이시스 테라퓨틱스, 인크.；
IPC主号:

专利说明:

Novel Heteroaromatic Inhibitors of Fructose 1,6-Bisphosphatase < RTI ID = 0.0 >
[1] <Related application>
[2] This application is a continuation of application Serial No. 60 / 135,504 (filed September 9, 1998) and 60 / 111,077 (filed December 7, 1998), the full text of which is incorporated herein by reference Respectively.
[3] The present invention relates to a novel heteroaromatic compound having a phosphonate group which is an inhibitor of fructose-1,6-bisphosphatase. The invention also relates to the use of the compounds in the manufacture of and to the treatment of diabetes and other diseases in which inhibition of gluconeogenesis, regulation of blood glucose levels, reduction of glycogen accumulation, or reduction of insulin levels are useful.
[4] The following description of the background of the present invention is intended to aid in understanding the invention and is not intended to be embracing or describing the prior art of the present invention. All cited publications are incorporated herein by reference in their entirety.
[5] Diabetes mellitus (or diabetes) is one of the most widespread diseases in the world today. Diabetic patients have been divided into two groups: type I or insulin dependent diabetes mellitus and type II or non-insulin dependent diabetes mellitus (NIDDM). NIDDM accounts for about 90% of all diabetics and is estimated to be between 1.2 and 14 million adults in the United States alone (6.6% of the population). NIDDM is characterized by both rapid hyperglycemia and excessive postprandial increases in plasma glucose levels. NIDDM is associated with various long-term complications including microvascular diseases such as retinopathy, nephritis and neuropathy, and macular vascular diseases such as coronary heart disease. Many studies in animal models suggest a causal relationship between long-term hyperglycemia and complications. The results of the Diabetes Control and Complications Trial (DCCT) and the Stockholm Prospective Study show that insulin-dependent diabetes mellitus, due to more thorough blood glucose control, is substantially associated with the development and progression of these complications By demonstrating that there is considerably less risk. More thorough control is also expected to be useful for NIDDM patients.
[6] Current therapies used to treat NIDDM patients specify regulating both lifestyle risk factors and the intervention of the constraints. Because top priority treatment for NIDDM is typically overweight or obese (67%) in the majority of NIDDM patients, and because weight loss can improve insulin secretion, insulin sensitivity and induce normal blood glucose, And exercise therapy. Normalization of blood glucose occurs in less than 30% of these patients because of poor compliance and low response. Patients with hyperglycemia not controlled by diet alone are treated with oral diabetes medications or insulin. Until recently, sulfonylureas were the only class of oral diabetic drugs available for NIDDM. Sulfonylurea therapy is effective in reducing blood glucose in only 70% of patients and only 40% after 10 years of treatment. Patients who fail to respond to dietary and sulfonylurea receive daily injections of insulin to achieve adequate blood glucose control.
[7] Despite the fact that sulfonylurea is the primary treatment for patients with NIDDM, four factors limit his overall success. First, as mentioned above, the majority of NIDDM populations do not respond adequately to sulfonylurea therapy (e. G., The first impairment) or develop resistance (e. G., Second impairment). This is especially true for patients with NIDDM who are progressive NIDDM because they have significantly reduced insulin secretion. Second, sulfonylurea therapy is associated with an increased risk of developing severe hypoglycemia. Third, chronic hyperinsulinemia has been associated with increased cerebrovascular disease, although their relevance is debatable and unproven. Finally, sulfonylureas are associated with weight gain that can aggravate peripheral insulin sensitivity and thereby accelerate disease progression.
[8] In addition, the results from the UK Daiabetsu prospective study show that patients treated with the maximum of sulfonylurea, metformin, or a combination of both, could not maintain normal fast-blood glucose during the six-year study period [ UK Prospective Diabetes Study 16. Diabetes, 44: 1249-158 (1995)]. These results are also presented as the greatest need for alternative therapies.
[9] Glucogenesis from pyruvate and other 3-carbon precursors is a highly regulated biosynthetic pathway that requires eleven enzymes. Seven enzymes are used as catalysts for reversible reactions, and are common to both glucose synthesis and glycosylation. Four enzymes, namely pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase, are used as catalysts for a unique reaction to glucose synthesis. The overall flow through the pathway is regulated by the specific activity and substrate availability of the enzymes that promote the corresponding step in the sugar degradation direction. Dietary factors (glucose, fat) and hormones (insulin, glucagon, glucocorticoid, and epinephrine) coordinate the enzymatic activity of glucose synthase and glycosylation pathways through gene expression and post-translocation mechanisms.
[10] Among the four enzymes specific for gluconeogenesis, fructose-1,6-bisphosphatase (hereinafter "FBPase") is the most suitable target for glucose synthesis inhibitors based on efficiency and safety considerations. Studies indicate that the property uses the FBPase / PFK cycle as an important regulatory point (metabolic switch) capable of reacting to determine whether the metabolic flux proceeds in the direction of glycosylation or gluconeogenesis (Claus, et al., Mechanisms Biol., 11, 635-658 (1984), Pilkis, et al., Annu. Rev. Biol., pp. 305-321, Elsevier Science 1992, Regen, et al. FBPase is inhibited by fructose-2,6-bisphosphate in the cell. Fructose-2,6-bisphosphate is bound to the substrate region of the enzyme. Is bound to the allosteric site on the enzyme.
[11] Inhibitors of FBpase synthesis have also been reported. McNiel discloses that fructose-2,6-bisphosphate homologues inhibit FBPase by binding to substrate sites (J. Am. Chem. Soc., 106: 7851-7853 (1984) 4,968, 790 (1984)). However, these compounds are relatively weak and probably do not inhibit glucose production in hepatocytes due to poor cellular permeability.
[12] Gruber has disclosed that several nucleosides can degrade blood glucose in whole animals through the inhibition of FBPase. These compounds exhibit their activity by first performing phosphorylation on the corresponding monophosphate (EP 0 427 799 B1).
[13] U.S. Patent No. 5,658,889 to Gruber et al. Discloses the use of FBPase as an inhibitor of the AMP site for treating diabetes. WO 98/39344, EP 39343, and EP 98/39342 disclose inhibitors of certain FBPases that treat diabetes.
[14] SUMMARY OF THE INVENTION [
[15] The present invention relates to a novel heteroaromatic compound containing a phosphate group and being a strong FBPase inhibitor. In another aspect, the present invention relates to the preparation of compounds of this type of compounds and the FBPase inhibitory activity of such compounds in vitro and in vivo. Another aspect of the invention relates to the clinical use of such FBPase inhibitors as a method for the treatment or prevention of diseases responsive to inhibition of glucose nephropathy and diseases responsive to degraded blood glucose levels.
[16] The compounds may also be used for the treatment of diseases such as hyperglycogen accumulation diseases and diseases such as atherosclerosis, cerebrovascular diseases including myocardial ischemic injury, and metabolic disorders such as hypercholesterolemia and hyperlipidemia, which are exacerbated by hyperinsulinemia and hyperglycemia .
[17] The present invention also includes novel compounds and methods of using them as specified in Formulas I and X below. Also included within the scope of the present invention are compounds of formula I and X.
[18]
[19]
[20] Since the compound may have an asymmetric center, the present invention relates to each stereoisomer as well as the racemic mixture of the compound. The invention also encompasses pharmaceutically acceptable (or useful) salts of compounds of formulas I and X, including acid addition salts. In addition, the present invention includes all of the compounds of formula (I) and (X).
[21] <Definition>
[22] In accordance with the present invention and as used herein, the following terms are defined with the following meanings unless otherwise indicated.
[23] The X and X ² group designations used in formulas I and X herein describe the groups attached to the phosphonate, with the group attached to the heteroaromatic ring at the end. For example, when X is alkylamino, it has the following structure.
[24] (Heteroaromatic ring) -NR-Alk-P (O) (OR &^lt; ¹ &gt;) ₂
[25] As such, the A, B, C, D, E, A ", B", C ", D", E ", A ² , L ² , E ² and J ² groups of the heteroaromatic rings and Other substituents are described as being terminated by a group attached to a heteroaromatic ring. Generally, substituents refer to that the term is terminated at the point of attachment.
[26] The term " aryl " refers to an aromatic group having one or more rings having 5 to 14 ring atoms and a conjugated pi electron system, which includes carbocyclic aryl, heterocyclic aryl and biaryl groups, . Suitable aryl groups include phenyl and furan-2,5-diyl.
[27] The carbocyclic aryl group is a group in which the ring atom on the aromatic ring is a carbon atom. Carbocyclic aryl groups include fused compounds such as monocyclic carbocyclic aryl groups and polycyclic or optionally substituted naphthyl groups.
[28] The heterocyclic aryl or heteroaryl group is a group in which one or two heteroatoms as the residue of the ring atom in the aromatic ring and the rest of the ring atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen and selenium. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkylpyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl and the like, all optionally substituted.
[29] The term " ring " or " cyclic " refers to the formation of additional cyclic moieties in an existing aryl or heteroaryl group. The newly formed ring is carbocyclic or heterocyclic and may be saturated or unsaturated and includes from 2 to 9 new atoms, from 0 to 3, which may be a heteroatom selected from the group of N, O and S. The ring can introduce atoms from group X as part of the newly formed ring. For example, the phrase " L ² and E ² together form a cyclic cyclic group " includes the following formula.
[30]
[31] The term " biaryl " refers to an aryl group containing more than one aromatic ring, including both fused ring systems and aryl groups substituted with other aryl groups. The group may be optionally substituted. Suitable biaryl groups include naphthyl and biphenyl.
[32] The term " alicyclic " refers to a compound that combines the properties of aliphatic and cyclic compounds. Such cyclic compounds include, but are not limited to, aromatic, cycloalkyl, and bridged cycloalkyl compounds. Cyclic compounds include heterocycles. Cyclohexenylethyl and cyclohexylethyl are suitable alicyclic groups. Such groups may be optionally substituted.
[33] The term "optionally substituted" or "substituted" includes groups substituted with 1 to 4 substituents independently selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, lower alicyclic, hydroxy, lower alkoxy, Lower alkoxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino, guanidino, amidino, halo, lower alkylthio, oxo, acylalkyl, carboxy Wherein the alkyl moiety is selected from the group consisting of alkyl, alkenyl, alkynyl, alkynyl, aryl, heteroaryl, ester, carboxyl, -carboxamido, nitro, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, Lower alkoxyalkyl, lower perhaloalkyl, and aryl &lt; RTI ID = 0.0 &gt; Alkyloxyalkyl. &Lt; / RTI &gt;&Quot; Substituted aryl " and &quot; substituted heteroaryl &quot; preferably refer to aryl and heteroaryl groups substituted with one to three substituents. Preferably, such substituents are selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halo, hydroxy, and amino. When describing the R &lt; ⁵ &gt; group, &quot; substituted &quot; does not include a ring.
[34] The term " aralkyl " refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted. The term "-aralkyl" refers to a divalent group of -aryl-alkylene-. &Quot; Heteroarylalkyl " refers to an alkylene group substituted with a heteroaryl group.
[35] The term "-alkylaryl-" refers to an -alk-aryl-group in which "alk" is an alkylene group. &Quot; Lower-alkylaryl- " refers to a group wherein the alkylene is lower alkylene.
[36] The term " lower ", as used herein, refers to definitions such as not more than 10, preferably not more than 6, and advantageously 1 to 4 carbon atoms, respectively, with respect to the organic radical or compound. The group may be linear, branched or cyclic.
[37] The term "arylamino" (a) and "aralkylamino" (b) in each case (a), R is aryl and R 'is hydrogen, alkyl, aralkyl or aryl, R 'is hydrogen or an alkyl, aryl, alkyl, -NRR' group.
[38] The term " acyl " refers to -C (O) R wherein R is alkyl and aryl.
[39] The term " carboxy ester " refers to -C (O) OR wherein R is alkyl, aryl, aralkyl and alicyclic, all optionally substituted.
[40] The term " carboxyl " refers to -C (O) OH.
[41] The term "oxo" refers to ═O in an alkyl group.
[42] The term " amino " means that R and R 'are independently selected from hydrogen, alkyl, aryl, aralkyl and alicyclic, all but H are optionally substituted and R and R' Quot; -NRR &quot;.
[43] The terms " carbonylamino " and " -carbonylamino- " refer to RCONR- and -CONR-, wherein each R is independently hydrogen or alkyl.
[44] The term " halogen " or " halo " refers to -F, -Cl, -Br and -I.
[45] The term "-oxyalkylamino-" refers to -O-Alk-NR-where "Alk" is an alkylene group and R is H or alkyl.
[46] The term "-alkylaminoalkylcarboxy-" refers to the -aralkyl-NR-Alk-C (O) -O- group in which "Alk" is an alkylene group and R is H or lower alkyl.
[47] The term "-alkylaminocarbonyl-" refers to a -aralkyl-NR-C (O) - group in which "Alk" is an alkylene group and R is H or lower alkyl.
[48] The term " -oxyalkyl- " refers to an -O-alk-group wherein " alk " is an alkylene group.
[49] The term " -alkylcarboxyalkyl- " refers to -alk-C (O) -O-alkyl groups wherein each of the alkes is independently an alkylene group.
[50] The term " alkyl " refers to saturated aliphatic groups including straight chain, branched chain and cyclic groups. The alkyl group may be optionally substituted. Suitable alkyl groups include methyl, isopropyl and cyclopropyl.
[51] The term " cyclic alkyl " or " cycloalkyl " refers to a cyclic alkyl group. Suitable cyclic groups include norbonyl and cyclopropyl. Such groups may be substituted.
[52] The terms " heterocyclic " and " heterocyclic alkyl " refer to a cyclic group of 3 to 10 atoms, more preferably 3 to 6 atoms, containing at least one, preferably from 1 to 3 heteroatoms . Suitable heteroatoms include oxygen, sulfur, and nitrogen. The heterocyclic group may be bonded through the nitrogen atom at the ring or through a carbon atom. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl.
[53] The term " phosphono " refers to -PO ₃ R _{2 wherein} R is selected from the group consisting of -H, alkyl, aryl, aralkyl, and alicyclic.
[54] The term "sulfonyl" or "sulfonyl" refers to -SO ₃ R R is a H, alkyl, aryl, aralkyl, and alicyclic.
[55] The term " alkenyl " refers to an unsaturated group containing one or more carbon-carbon double bonds and including straight chain, branched chain and cyclic groups. The alkenyl group may be optionally substituted. Suitable alkenyl groups include allyl. &Quot; 1-Alkenyl " refers to an alkenyl group in which the double bond is between the first and second carbon atom. When a 1-alkenyl group is bonded to another group, for example, when the W substituent is bonded to a cyclic phosph (ortho) urethane, it is attached to the first carbon.
[56] The term " alkynyl " refers to an unsaturated group containing one or more carbon-carbon triple bonds, including straight chain, branched chain and cyclic groups. The alkynyl group may be optionally substituted. Suitable alkynyl groups include ethynyl. &Quot; 1-Alkynyl " refers to an alkynyl group wherein the triple bond is between the first and second carbon atom. When the 1-alkynyl group is bonded to another group, for example, when the W substituent is bonded to the cyclic phosph (ortho) -ate, it is bonded to the first carbon.
[57] The term " alkylene " refers to a divalent linear, branched or cyclic saturated aliphatic group.
[58] The term "-cycloalkylene-COOR ³ " refers to a divalent cyclic alkyl group or a heterocyclic group comprising 4 or 6 atoms in a ring having 0 to 1 heteroatoms selected from O, N and S. The cyclic alkyl or heterocyclic group is substituted with -COOR &lt; ^{3 &} gt ;.
[59] The term " acyloxy " refers to the ester group of -O-C (O) R where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl or alicyclic.
[60] The term "aminoalkyl" is "alk" is an alkylene group, which NR ₂ R is selected from H, alkyl, aryl, aralkyl, and alicyclic-alk means a group.
[61] The term " -alkyl (hydroxy) - " refers to -OH coming out of the alkyl chain. When the term is X, -OH is in the alpha position relative to the phosphorus atom.
[62] The term " alkylaminoalkyl- " refers to alkyl-NR-alk-groups in which each " alk " is independently selected alkylene and R is H or lower alkyl. &Quot; Lower alkylaminoalkyl- " refers to a group wherein each alkylene group is lower alkylene.
[63] The term " arylaminoalkyl- " refers to an aryl-NR-alkyl- group wherein " alk " is an alkylene group and R is H, alkyl, aryl, aralkyl and alicyclic. In " lower arylaminoalkyl- ", the alkylene group is lower alkylene.
[64] The term "alkylaminoaryl-" refers to an alkyl-NR-aryl-group in which "aryl" is a divalent group and R is H, alkyl, aralkyl and alicyclic. In " lower acylaminoaryl- ", the alkylene group is lower alkyl.
[65] The term " alkyloxyaryl- " refers to an aryl group substituted with an alkyloxy group. In " lower alkyloxyaryl- ", the alkyl group is lower alkyl.
[66] The term " aryloxyalkyl- " refers to an alkyl group substituted with an aryloxy group.
[67] The term " aralkyloxyalkyl- " refers to an aryl-alk-O-alkyl group wherein the " alk " The term " lower aralkyloxyalkyl- " refers to a group in which the alkylene group is lower alkylene.
[68] The term " -alkoxy- " or " -alkyloxy- " refers to an -alk-O- group in which " alk " The term " alkoxy- " refers to an alkyl-O- group.
[69] The term " -alkoxyalkyl- " or " -alkyloxyalkyl- " refers to an -alk-O-alkyl group wherein each "alk" is an independently selected alkylene group. In " lower-alkoxyalkyl- ", each alkylene is lower alkylene.
[70] The terms "alkylthio-" and "-alkylthio-" refer to alkyl-S- and -aralkyl-S- groups, respectively, when "alk" is an alkylene group.
[71] The term " -alkylthioalkyl- " refers to an -alk-S-alkyl- group in which each " alk " is an independently selected alkylene group. In " lower-alkylthioalkyl- ", each alkylene is lower alkylene.
[72] The term " alkoxycarbonyloxy- " refers to alkyl-O-C (O) -O-.
[73] The term " aryloxycarbonyloxy- " refers to aryl-O-C (O) -O-.
[74] The term " alkylthiocarbonyloxy- " refers to alkyl-S-C (O) -O-.
[75] The term "-alkoxycarbonylamino-" refers to -alk-OC (O) -NR ¹ , where "alk" is alkylene and R ¹ is -H, alkyl, aryl, alicyclic and aralkyl.
[76] The term "alkyl-amino-carbonyl-amino" is an "alk" is alkylene, R ¹ is independently selected of H, alkyl, aryl, aralkyl, and alicyclic in-alk -NR ¹ -C (O) - refers to -NR ¹ .
[77] The term " amido " or " carboxamido " refers to the group -NR ₂ --C (O) - and RC (O) - NR ¹ - where R and R ¹ are H, alkyl, aryl, aralkyl, It says. The term does not include urea, -NR-C (O) -NR-.
[78] The terms " carboxamidoalkylaryl " and " carboxamidoaryl " are intended to include those wherein "Ar" is aryl, "Alk" is alkylene, R ¹ and R are H, alkyl, aryl, click an aryl-alk -NR ¹ -C (O) - and -NR ¹ -C (O) - refers to-alk.
[79] The term "-alkylcarboxamido-" or "-alkylcarbonylamino-" refers to -alk-C (O) N (R) - where "Alk" is an alkylene group and R is H or lower alkyl .
[80] The term "-alkylaminocarbonyl-" refers to -alk-NR-C (O) - wherein "alk" is an alkylene group and R is H or lower alkyl.
[81] The term "amino-carboxamido-alkyl" wherein R is an alkyl group or H, "alk" is an alkylene group _{NR 2 -C (O) -N (} R) - refers to a group alk. &Quot; Lower aminocarboxamidoalkyl- " refers to a group in which " alk " is lower alkylene.
[82] The term " thiocarbonate " refers to -O-C (S) -O- in the chain or cyclic group.
[83] The term " hydroxyalkyl " refers to an alkyl group substituted with one -OH.
[84] The term " haloalkyl " refers to an alkyl group substituted with one halo selected from the group I, Cl, Br,
[85] The term "cyano" refers to -C≡N.
[86] The term " nitro " refers to -NO ₂ .
[87] The term " acylalkyl " refers to alkyl-C (O) -alk- wherein " alk " is alkylene.
[88] The term " heteroarylalkyl " refers to an alkyl group substituted with a heteroaryl group.
[89] The term " -1,1-dihaloalkyl- " refers to the group X bonded at one position to the halogen atom phosphorus atom.
[90] The term " perhalo " refers to a group in which each CH bond can be replaced by a C-halo bond on an aliphatic or aryl group. Suitable perhaloalkyl groups include -CF ₃ and -CFCl ₂ .
[91] The term " guanidino " means that each R group is independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl and alicyclic, and all but -H are optionally substituted = C (NR _{2) 2} as well refers to both _{-NR-C (NR) -NR 2} .
[92] The term " amidino " refers to the group -C (NR) -NR ₂ where the R groups are each independently selected from -H, alkyl, alkenyl, alkynyl, aryl and alicyclic and all but- It says.
[93] The term " pharmaceutically acceptable salts " embraces salts of the compounds of formula I derived from the compounds of the invention and combinations of organic or inorganic acids or bases, and their precursors. Suitable acids include HCl.
[94] As used herein, the term " medicinal product " when administered to a biological system produces a " drug " substance (physiologically active compound) as a result of spontaneous chemical reactions, enzyme catalytic chemical reactions and / or metabolic chemical reactions &Lt; / RTI &gt; Standard Agonists are formed using groups associated with functional groups associated with FBPase inhibitors, such as HO-, HS-, HOOC-, and R ₂ N-, which are degraded in vivo. Standard analytes are selected from the group consisting of alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, as well as esters of hydroxyl, thiol and amine (the attached group is an acyl group, an alkoxycarbonyl, an aminocarbonyl, a phosphate or a sulfate ), But is not limited thereto. In addition, the standard salt of phosphonic acid may be represented by R ¹ in formulas I and X. The depicted reagents are illustrative and not exhaustive, and those skilled in the art are able to make a variety of other known oral preparations. The abovementioned formulas of compounds of formulas I and X are within the scope of the present invention. The entire Old Testament undergoes any form of chemical modification to produce compounds that are precursors to biologically active or biologically active compounds. In certain instances, the Agrochemical is typically less biologically active than the drug itself, and improves efficacy and safety through improved oral bioavailability, pharmacodynamic half-life, and the like.
[95] As used herein, the term " whole-ester ester " is intended to include the following groups and combinations of these groups.
[96] [1] Acyloxyalkyl esters are well described in Farquhar et al., J. Pharm. Sci. 72, 324-325 (1983) and are represented by Formula A.
[97]
[98] Wherein R, R 'and R "are independently H, alkyl, aryl, alkylaryl and alicyclic (see WO 90/08155 and WO 90/10636).
[99] [2] Other acyloxyalkyl esters are possible in which the alicyclic ring is formed as shown in formula (B). Such esters appear to produce phosphorus-containing nucleotides in the cells, beginning with de-esterification followed by a pre-determined sequence of subsequent elimination reactions (see, for example, Freed et al., Biochem. Pharm. 38: 3193-3198 1989).
[100]
[101] Wherein R is -H, alkyl, aryl, alkylaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, cycloalkyl, or alicyclic.
[102] [3] Another class of such double esters, known as alkyloxycarbonyloxymethyl esters, as shown in formula A, wherein R is alkoxy, aryloxy, alkylthio, arylthio, alkylamino, and arylamino, R And R "are independently H, alkyl, aryl, alkylaryl, and alicyclic) have been studied as regions of the -lactam antibody (Tatsuo Nishimura et al. J. Antibiotics, 1987, 40 Ferres, H., Drugs of Today, 1983, 19, 499). More recently, Cathy, M. S et al. (Summary of AAPS Western Regional Meeting, April, 1997) reported that such alkyloxy groups on (9 - [(R) -2-phosphonomethoxy] propyl) adenine Carbonyloxymethyl esters have shown to have less than 30% bioavailability in dogs.
[103] [4] Also, aryl esters have been used as phosphonate precursors (see, for example, Erion, DeLambert et al., J. Med. Chem. 37: 498, 1994, Serafinowska et al., J. Med. Chem. 38: 1372, 1995). Phenyl as well as single and multi-substituted phenyl propoes produce mophosphonic acid in studies carried out in animals and humans (Formula C). Another approach has been described wherein Y is an ortho carboxylic ester to the phosphonate (Khamnei and Torrence, J. Med. Chem; 39: 4109-4115 (1996)).
[104]
[105] Wherein Y is H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, halogen, amino, alkoxycarbonyl, hydroxy, cyano, and alicyclic.
[106] [5] It is also disclosed that the benzyl ester produces mophosphonic acid. In any case, substituents used in the para-position can accelerate the hydrolysis. A benzyl homologue having a 4-acyloxy or 4-hydroxy group [Formula D, X = H, OR or O (CO) R or O (CO) OR] can be prepared by the action of an enzyme, 4-hydroxy compound can be more easily produced through the reaction. Examples of this class of medicinal products are described in Mitchell et al., J. Chem. Soc. Perkin Trans. I 2345 (1992), Brook et al. International Patent Publication No. 91/19721.
[107]
[108] Wherein X and Y are independently H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, hydroxy, cyano, nitro, perhaloalkyl, halo, or alkyloxycarbonyl,
[109] R 'and R &quot; are independently H, alkyl, aryl, alkylaryl, halogen and alicyclic.
[110] [6] Thio-containing phosphonate pro-ester is disclosed as useful for delivering FBPase inhibitor to hepatocytes. Such pro-esters contain a protected thioethyl moiety as shown in formula (E). One or more of the oxygen of the phosphonate can be esterified. A variety of thiol protecting groups are possible because the mechanism of de-esterification requires the formation of free thiols. For example, disulfides are reduced in a reducing enzyme-mediated manner (Puech et al., Antiviral Res., 22: 155-174 (1993)). In addition, thioesters can generate free thiols after esterase-mediated hydrolysis (Benzaria, et al., J. Med. Chem., 39: 4958 (1996)). In addition, cyclic homologs are possible and are known to release phosphonates into isolated rat hepatocytes. The cyclic disulfide groups shown below are not described above and are novel.
[111]
[112] Wherein Z is alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, or alkylthio.
[113] Other examples of suitable full-form medicaments are described in U.S. Pat. No. 5,301,504 to Biller and Magnin (US Patent No. 5,157,027), Serafinowska et al. (J. Med. Chem. Starrett et al., J. Med. Chem., 37, 1857 (1994), Martin et al., J. Pharm. , 59, 1853 (1994), European Patent Application Publication No. 0 632 048 A1. Some of the structural classes described are optionally substituted and the fused lactone bonded at the omega position (E- 1 and E-2), optionally substituted 2-oxo-1, 3-dioxolane (Formula E-3) bonded via methylene to the phosphorus oxygen as follows.
[114]
[115]
[116]
[117] Wherein R is -H, alkyl, cycloalkyl, or alicyclic,
[118] Y is -H, alkyl, aryl, alkylaryl, cyano, alkoxy, acyloxy, halogen, amino, alicyclic, and alkoxycarbonyl.
[119] The general formula of formula E-3 is an example of " optionally substituted alicyclic wherein the cyclic moiety contains a carbonate or thiocarbonate ".
[120] [7] Propylphosphonate proester can also be used to deliver FBPase inhibitors to hepatocytes. Such pro-ester may contain hydroxyl and hydroxyl group derivatives at the 3-position of the propyl group as shown in formula (F). The R and X groups may form a cyclic ring system as shown in formula (F). More than one of the oxygen of the phosphonate can be esterified.
[121]
[122] Wherein R is alkyl, aryl, heteroaryl,
[123] X is hydrogen, alkylcarbonyloxy, alkyloxycarbonyloxy,
[124] Y is alkyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, halogen, hydrogen, hydroxy, acyloxy, amino.
[125] [8] Phosphoramidate derivatives have been exemplified as phosphonate precursors as shown in Formula G (see, for example, McGuigan et al., J. Med. Chem., 1999, 42; 393, references).
[126]
[127] In addition, cyclophosphoramidates have been studied as phosphonates because they have very high stability compared to non-cyclic phosphoramidates (see, for example, Starrett et al., J. Med. Chem , &Lt; / RTI &gt; 1994, 37: 1857).
[128] Other types of nucleotide agonists have been reported in combination with S-acyl-2-thioethyl ester and phosphoramidate as shown in Formula H (Egron et al., Nucleosides & Nucleotides, 1999, 18, 981).
[129]
[130] Other full-texts are described, for example, in McGuigan et al., Bioorg Med. Chem. (Trichloroethyl) esters and phenyls and mesylates as described in Meier, C. et al., J. Chem. Lett., 3: 1207-1210 (1993) Bioorg. Med. Chem. Lett,. 7: 99-104 (1997)). &Lt; / RTI &gt;
[131] constitutional formula Is a symmetric plane through the phosphorus-oxygen double bonds when R ⁶ = R ⁶ , V = W, W '= H and both V and W are either above the dotted line or below the dotted line. Each -NR ⁶ is the same as the structural formula substituted with -O-.
[132] The term "cyclic 1", 3'-propane ester "," cyclic 1,3-propane ester "," cyclic 1 ', 3'- propanyl ester " Means the following.
[133]
[134] The phrase " V and Z are taken together through an additional three to five atoms to form a hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarb which is attached to a carbon atom which is three atoms from all of the Y- To form a cyclic group containing 5 to 7 atoms optionally containing one heteroatom, substituted with &lt; RTI ID = 0.0 &gt; fluoro, &lt; / RTI &gt;
[135] And
[136] The structural formula shown above (left) has an additional three carbon atoms forming a five-membered cyclic group. The cyclic group must have the enumerated substitution to be oxidized.
[137] The phrase " V and Z together are joined through an additional three to five atoms to form a cyclic group optionally containing one heteroatom fused with an aryl group at the beta and gamma positions for Y bonded to phosphorus "Lt; / RTI &gt;
[138]
[139] Quot; V and W are taken together through an additional three carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms, said cyclic group being selected from the group consisting of the carbon Substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bonded to one of the atoms " includes the following.
[140]
[141] The structure has the three atoms of acyloxy substituents and any substituent -CH ₃ from Y on the new 6-membered ring. It should have a respective at least one hydrogen in position: Z the carbon, alpha carbon both sides for the carbon labeled "3" in combination, and the carbon bonded to the _{"OC (O) CH 3"} .
[142] W and W 'are taken together to form a cyclic group optionally containing from 0 to 2 heteroatoms, wherein V is selected from the group consisting of aryl, substituted aryl, heteroaryl, or substituted Quot; must be heteroaryl &quot; includes the following.
[143]
[144] The structure has a cyclopropyl group spirally fused to V = aryl and W and W '.
[145] The term " cyclic phospho (ortho) "
[146]
[147] Wherein Y is independently -O- or -NR &lt; ⁶ &gt; -. The carbon bonded to V must have a CH bond. The carbon bonded to Z must also have a CH bond.
[148] The term " liver " refers to liver and similar tissues and cells containing a CYP3A4 homozygote or any other P450 isoenzymes known to oxidize the phospho (oramido) ester of the present invention. Based on Example F, the present inventors have found that the full-length drugs of Formulas VI and VIII can be selectively oxidized by the cytochrome P450 isoenzymes CYP3A4. According to DeWaziers et al. (J. Pharm. Exp. Ther., 253, 387-394 (1990)), CYP3A4 is located in human sub-tissues (determined by immunoblotting and enzyme assay).
[149] group % Of liver activity liver 100 Duodenum 50 factory 30 Chairman 10 colon Less than 5 (only P450 isoenzymes found) top Less than 5 esophagus Less than 5 kidney Not detected
[150] Thus, " liver " relates more preferably to liver, duodenum, plant, ileum, colon, stomach, esophagus and kidney. Most preferably, the liver relates to liver organs.
[151] The term " reinforcement " refers to increasing or improving a particular ability.
[152] The term " liver-specificity " is referred to in the following ratios, as measured in an animal treated with a drug or whole drug.
[153]
[154] The ratio can be determined by measuring the tissue value at a particular time, or can be expressed as an AUC based on a value measured at three or more time points.
[155] The term " increased or augmented liver specificity " refers to an increase in the liver specificity ratio of an animal treated with a full-length medication as compared to an animal treated with the parent drug.
[156] The term " augmented oral bioavailability " refers to an increase in absorption from the digestive tract by more than 50% of the parent drug or the total (not of the invention) administration. More preferably, it is 100% or more. Oral bioavailability measurement generally refers to the measurement of analgesic, drug or drug metabolites in blood, tissue, or urine following oral administration, as compared to measurements taken by systemic administration.
[157] The term " parent drug " refers to any compound that delivers the same biologically active compound. The form of the parent drug is a standard drug such as R ⁵ -XP (O) (OH) ₂ and esters.
[158] The term " drug metabolite " refers to any compound that is produced in vivo or in vitro from a parent drug, which may include a biologically active drug.
[159] The term " pharmacodynamic half-life " refers to the time at which a half of the pharmacological response measured after administration of a drug or a global drug is measured. The pharmacokinetic half-life is preferably increased by more than 50% when the half-life is increased.
[160] The term " pharmacokinetic half-life " refers to the time at which half of the drug concentration in a plasma or tissue is reduced after administration of the drug or whole drug.
[161] The term " therapeutic index " refers to a dose or amount of a drug or analgesic that exhibits a therapeutically useful response to a dose that produces an undesired response, such as death, expression of a marker that exhibits toxicity, and / or pharmacological adverse effects Ratio.
[162] The term " sustained delivery " refers to an increase in the time period in which the appropriate blood level of a biologically active drug has a therapeutic effect.
[163] The term " passing drug resistance " refers to the loss or partial loss of a therapeutically effective amount of a drug due to a biochemical pathway that is important in generating and maintaining a biologically active form of the drug at a desired site in the body, Tolerance) and refers to the ability of the drug to elicit such resistance by using alternative pathways and cellular activities.
[164] The term " biologically active drug or drug " refers to a chemical substance that produces a biological effect. Thus, the active drug or medicament comprises a compound that is biologically active as R ⁵ -XP (O) (OH) ₂ .
[165] The term " therapeutically effective amount " refers to an amount that has a beneficial effect in treating a disease or disorder.
[166] Preferred compounds of formula (I)
[167] Suitable alkyl groups include groups having from 1 to about 20 carbon atoms. Suitable aryl groups include groups having from 1 to about 20 carbon atoms. Suitable aralkyl groups include groups having from 2 to about 21 carbon atoms. Suitable acyloxy groups include groups having from 1 to about 20 carbon atoms. Suitable alkylene groups include groups having from 1 to about 20 carbon atoms. Suitable alicyclic groups include groups having from 3 to 20 carbon atoms. Suitable heteroaryl groups include groups having from 1 to about 20 carbon atoms and preferably from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. Suitable heteroalicyclic groups include groups having from 2 to about 20 carbon atoms, preferably from 1 to 5 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur.
[168] In the method claims, the compounds of formula (I) and their pharmaceutically acceptable salts and salts are preferred.
[169] And
[170] In the formula,
[171] G is each independently selected from the group consisting of C, N, O, S and Se, wherein only one G may be O, S or Se,
[172] G 'are each independently selected from the group consisting of C and N, wherein no more than two G' are N,
[173] A is _{^{-H, -NR 4 2, -CONR 4}} 2, -CO 2 R 3, ^{halo, -S (O) R 3,} -SO 2 R 3, alkyl, alkenyl, alkynyl, alkyl, perhaloalkyl, halo Alkyl, aryl, -CH ₂ OH, -CH ₂ NR ⁴ ₂ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , ⁴ ₂ , -NHAc, and a substituent group (null)
[174] B and D are each independently selected from -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, -SO 2 R ^{11, -S (O) R 3} , -CN, -NR 9 2, -OR 3, -SR 3, selected from the group consisting of alkyl, halo, -NO _2, and no substituent perhaloalkyl, and -H, - CN, perhaloalkyl, -NO ₂ , and halo are optionally substituted,
[175] E is -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, -C (O) OR ³ , -CONR ⁴ ₂ , -CN, -NR ⁹ ₂ , -NO ₂ , -OR ³ , -SR ³ , perhaloalkyl, halo and no substituent, and all but -H, -CN, perhaloalkyl and halo are optionally substituted,
[176] J is selected from the group consisting of -H and no substituent,
[177] X combines R &lt; ⁵ &gt; to a phosphorus atom through 2 to 4 atoms, including zero or one heteroatom selected from N, O or S, except when X is urea or carbamate with two heteroatoms Which is measured as the shortest path between R &lt; ⁵ &gt; and the phosphorus atom, where the phosphorus bonded atom is a carbon atom and is not directly bonded to the carbonyl group or to the ring of the heterocycle, And X is not two carbon atom-alkyl, or -alkenyl- groups,
[178] X is not substituted with -COOR ² , -SO ₃ R ¹ or PO ₃ R ¹ ₂ ,
[179] Y is independently selected from the group consisting of -O-, and -NR &lt; ⁶ &gt; -,
[180] When Y is -O-, R ¹ bonded to -O- is independently -H, alkyl, optionally substituted aryl, optionally substituted alicyclic wherein the cyclic moiety is a carbonate or thiocarbonate containing also), optionally substituted with a - _{^{alkylaryl, -C (R 2) 2 OC}} (O) NR 2 2, -NR 2 -C (O) -R 3, -C (R 2) 2 -OC (O ^{) R 3, -C (R 2} ) 2 -OC (O) OR 3, -C (R 2) 2 OC (O) SR 3, - alkyl, -SC (O) R ^3, - alkyl hydroxy alkyl -SS- Gt; is selected from the group consisting &lt; RTI ID = 0.0 &gt; of-
[181] When Y is -NR ⁶ -, R ¹ bonded to -NR ⁶ - is independently -H, - [C (R ² ) ₂ ] _q -COOR ³ , -C (R ⁴ ) ₂ COOR ³ , - [ C (R ² ) ₂ ] _q -C (O) SR and -cycloalkylene-COOR ³ , or
[182] When one of Y is independently selected from -O- and -NR ⁶ -, R ¹ and R ¹ together form an -alkyl-SS-alkyl-cyclic group, or R ¹ and R ¹ together
[183] Lt;
[184] here,
[185] V, W and W 'are independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl Or
[186] V and Z together are joined through an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 atoms optionally containing one heteroatom, Acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy bonded to a carbon atom which is three atoms from the alkyl group,
[187] V and Z together are joined through an additional three to five atoms to form a cyclic group optionally containing one heteroatom fused to the aryl group at the beta and gamma positions for Y bonded to the phosphorus,
[188] V and W are taken together through an additional three carbon atoms to form an optionally substituted cyclic group comprising 6 carbon atoms and said cyclic group is selected from the group consisting of the carbon atoms having 3 atoms from Y bonded to phosphorus Substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bound to one,
[189] Z and W are taken together through an additional 3 to 5 atoms to form a cyclic group optionally containing one heteroatom and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
[190] W and W 'are taken together through an additional two to five atoms to form a cyclic group optionally containing from 0 to 2 heteroatoms, wherein V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl Lt; / RTI &gt;
[191] Z is ^{-CHR 2 OH, -CHR 2 OC (} O) R 3, -CHR 2 OC (S) R 3, -CHR 2 OC (S) OR 3, -CHR 2 OC (O) SR 3, -CHR 2 (CH = CR ² ₂ ) OH, -CH (C≡CR ² ) OH, -CH (O) ₂ R ³ , -OR ² , -SR ² , -CHR ² N ₃ , -CH ₂ aryl, _{^{OH, -R 2, -NR 2 2}} , -OCOR 3, -OCO 2 R 3, -SCOR 3, -SCO 2 R 3, -NHCOR 2, -NHCO 2 R 3, -CH 2 NH aryl, - (CH ₂ ) _p -OR ² , and - (CH ₂ ) _p -SR ² ,
[192] p is an integer 2 or 3,
[193] q is an integer of 1 or 2,
[194] Provided that a) V, Z, W and W 'are not all -H,
[195] b) when Z is -R ² , at least one of V, W and W 'is not -H, alkyl, aralkyl, or alicyclic,
[196] R ² is selected from the group consisting of R ³ and -H,
[197] R &lt; ³ &gt; is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl,
[198] R ⁴ are each independently selected from the group consisting of -H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group,
[199] R ⁶ is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl,
[200] R ⁹ are each independently selected from the group consisting of -H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group,
[201] R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² ₂ , and -OR ² ,
[202] 1) when G 'is N, each A, B, D, or E has no substituent,
[203] 2) A and B or at least one of A, B, D and E is not selected from the group consisting of -H or no substituent,
[204] 3) when R ⁵ is 6-membered ring, X is a bond of any two atoms, an optionally substituted -alkyl-, an optionally substituted-alkenyl, optionally substituted-alkyl-oxy, or optionally substituted - an alkylthio No,
[205] 4) when G is N, each A or B is not a group directly bonded to G through a halogen or a heteroatom,
[206] 5) R &lt; ¹ &gt; is not unsubstituted C1-C10 alkyl,
[207] 6) when X is not an aryl group, R &lt; ⁵ &gt; is not substituted with two or more aryl groups.
[208] In the method of using such compounds, preferred R &lt; ⁵ &gt; groups include pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, pyrazolyl, isoxazolyl, , 3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3 Thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3,4-tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, and 1,3-selenazolyl, all of which contain one or more substituents.
[209] Most preferred are compounds wherein R &lt; ⁵ &gt;
[210]
[211]
[212]
[213]
[214]
[215] In the formula,
[216] A '' is _{^{-H, -NR 4 2, -CONR 4}} 2, -CO 2 R 3, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl alkyl, C1 -CH ₂ OH, -CH ₂ NR ⁴ ₂ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , -NHC S) NR &lt; ⁴ &gt; ₂ and -NHAc,
[217] B '' and D '' are each independently -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, -SO ₂ R ¹¹ , -S (O) R ³ , -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , perhaloalkyl and halo and is selected from the group consisting of -H, -CN, Alkyl, and halo, is optionally substituted,
[218] E '' is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, C4-C6 alicyclic, ^{alkoxyalkyl, -C (O) OR 3,} -CONR 4 2, - CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , C 1 -C 6 perhaloalkyl and halo, all but -H, -CN, perhaloalkyl and halo may be optionally substituted ,
[219] C "is selected from the group consisting of -H, alkyl, alkylalkenyl, alkylalkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, and alkoxyalkyl,
[220] R &lt; ⁴ &gt; are each independently selected from the group consisting of-H, and C1-C2 alkyl.
[221] Particularly preferred are compounds wherein R &lt; ⁵ &gt;
[222]
[223]
[224]
[225] In the formula,
[226] A '' is _{^{-H, -NR 4 2, -CONR 4}} 2, -CO 2 R 3, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl alkyl, C1 -CH ₂ OH, -CH ₂ NR ⁴ ₂ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , -NHC S) NR &lt; ⁴ &gt; ₂ and -NHAc,
[227] B '' and D '' are each independently -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, -SO ₂ R ¹¹ , -S (O) R ³ , -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , perhaloalkyl and halo and is selected from the group consisting of -H, -CN, Alkyl, and halo, is optionally substituted,
[228] E '' is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 alicyclic, ^{alkoxyalkyl, -C (O) OR 3,} -CONR 4 2, -CN, _{^{-NR 9 2, -OR 3, -SR}} 3, is selected from the group consisting of alkyl and halo by C1-C6 perhaloalkyl, halo, and alkyl, all except by -H, -CN, perhaloalkyl, and is optionally substituted,
[229] R &lt; ⁴ &gt; are each independently selected from the group consisting of-H and C1-C2 alkyl.
[230] In the process, the preferred X groups are -alkyl (hydroxy), -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -Alkylthio-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -allylic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, , -Carbonyloxyalkyl-, -alkoxycarbonylamino-, -alkylaminocarbonylamino-, -alkylamino- and -alkenyl- (all optionally substituted).
[231] Compounds and Methods In the claims, the novel compounds of formula (I) and their pharmaceutically acceptable salts and salts are preferred.
[232] (I)
[233]
[234] R ⁵ is And , &Lt; / RTI &gt;
[235] In the formula,
[236] G is each independently selected from the group consisting of C, N, O, S and Se wherein only one G may be O, S or Se, at most one G is N,
[237] G 'are each independently selected from the group consisting of C and N, wherein no more than two G' are N,
[238] A is _{^{-H, -NR 4 2, -CONR 4}} 2, -CO 2 R 3, ^{halo, -S (O) R 3,} -SO 2 R 3, alkyl, alkenyl, alkynyl, alkyl, perhaloalkyl, halo Alkyl, aryl, -CH ₂ OH, -CH ₂ NR ⁴ ₂ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , ⁴ ₂ , -NHAc, and a substituent group (null)
[239] B and D are each independently selected from -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, -SO 2 R ^{11, -S (O) R 3} , -CN, -NR 9 2, -OR 3, -SR 3, selected from the group consisting of alkyl, halo, -NO _2, and no substituent perhaloalkyl, and -H, - CN, perhaloalkyl, -NO ₂ , and halo are optionally substituted,
[240] E is -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, -C (O) OR ³ , -CONR ⁴ ₂ , -CN, -NR ⁹ ₂ , -NO ₂ , -OR ³ , -SR ³ , perhaloalkyl, halo and no substituent, and all but -H, -CN, perhaloalkyl and halo are optionally substituted,
[241] J is selected from the group consisting of -H and no substituent,
[242] X binds R &lt; ⁵ &gt; to a phosphorus atom through 2 to 4 atoms, including zero or one heteroatom selected from N, O and S, except when X is urea or carbamate with two heteroatoms Which is measured as the shortest path between R &lt; ⁵ &gt; and the phosphorus atom, where the phosphorus bonded atom is a carbon atom and is not directly bonded to the carbonyl group or to the ring of the heterocycle, And X is not two carbon atom-alkyl, or -alkenyl- groups,
[243] X is not substituted with -COOR ² , -SO ₃ R ¹ or PO ₃ R ¹ ₂ ,
[244] Y is independently selected from the group consisting of -O-, and -NR &lt; ⁶ &gt; -,
[245] When Y is -O-, R ¹ bonded to -O- is independently -H, alkyl, optionally substituted aryl, optionally substituted alicyclic wherein the cyclic moiety is a carbonate or thiocarbonate containing also), optionally substituted with a - _{^{alkylaryl, -C (R 2) 2 OC}} (O) NR 2 2, -NR 2 -C (O) -R 3, -C (R 2) 2 -OC (O ^{) R 3, -C (R 2} ) 2 -OC (O) OR 3, -C (R 2) 2 OC (O) SR 3, - alkyl, -SC (O) R ^3, - alkyl hydroxy alkyl -SS- Gt; is selected from the group consisting &lt; RTI ID = 0.0 &gt; of-
[246] When Y is -NR ⁶ -, R ¹ bonded to -NR ⁶ - is independently -H, - [C (R ² ) ₂ ] _q -COOR ³ , -C (R ⁴ ) ₂ COOR ³ , - [ C (R ² ) ₂ ] _q -C (O) SR and -cycloalkylene-COOR ³ , or
[247] When one of Y is independently selected from -O- and -NR ⁶ -, R ¹ and R ¹ together form an -alkyl-SS-alkyl-cyclic group, or R ¹ and R ¹ together
[248] Lt;
[249] here,
[250] V, W and W 'are independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl Or
[251] V and Z together are joined through an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 atoms optionally containing one heteroatom, Acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy bonded to a carbon atom which is three atoms from the alkyl group,
[252] V and Z together are joined through an additional three to five atoms to form a cyclic group optionally containing one heteroatom fused to the aryl group at the beta and gamma positions for Y bonded to the phosphorus,
[253] V and W are taken together through an additional three carbon atoms to form an optionally substituted cyclic group comprising 6 carbon atoms and said cyclic group is selected from the group consisting of the carbon atoms having 3 atoms from Y bonded to phosphorus Substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bound to one,
[254] Z and W are taken together through an additional 3 to 5 atoms to form a cyclic group optionally containing one heteroatom and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
[255] W and W 'are taken together through an additional two to five atoms to form a cyclic group optionally containing from 0 to 2 heteroatoms, wherein V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl Lt; / RTI &gt;
[256] Z is ^{-CHR 2 OH, -CHR 2 OC (} O) R 3, -CHR 2 OC (S) R 3, -CHR 2 OC (S) OR 3, -CHR 2 OC (O) SR 3, -CHR 2 (CH = CR ² ₂ ) OH, -CH (C≡CR ² ) OH, -CH (O) ₂ R ³ , -OR ² , -SR ² , -CHR ² N ₃ , -CH ₂ aryl, _{^{OH, -R 2, -NR 2 2}} , -OCOR 3, -OCO 2 R 3, -SCOR 3, -SCO 2 R 3, -NHCOR 2, -NHCO 2 R 3, -CH 2 NH aryl, - (CH ₂ ) _p -OR ² , and - (CH ₂ ) _p -SR ² ,
[257] p is an integer 2 or 3,
[258] q is an integer of 1 or 2,
[259] A) V, Z, W, W 'are not all -H,
[260] b) when Z is -R ² , at least one of V, W and W 'is not -H, alkyl, aralkyl, or alicyclic,
[261] R ² is selected from the group consisting of R ³ and -H,
[262] R &lt; ³ &gt; is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl,
[263] R ⁴ are each independently selected from the group consisting of -H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group,
[264] R ⁶ is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl,
[265] R ⁹ are each independently selected from the group consisting of -H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group,
[266] R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² ₂ , and -OR ² ,
[267] 1) when G 'is N, each A, B, D, or E has no substituent,
[268] 2) A and B, or at least one of A, B, D and E is not selected from the group consisting of -H or no substituent,
[269] 3) when R ⁵ is 6-membered ring, X is a bond of any two atoms of the group, an optionally substituted -alkyl-, an optionally substituted-alkenyl, optionally substituted-alkyl-oxy, or optionally substituted -alkylthio However,
[270] 4) when G is N, each A or B is not a group directly bonded to G through a halogen or a heteroatom,
[271] 5) R &lt; ¹ &gt; is not unsubstituted C1-C10 alkyl,
[272] 6) when X is not an aryl group, R &lt; ⁵ &gt; is not substituted with two or more aryl groups.
[273] Preferred R ⁵ groups are pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, pyrazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridinyl , Pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, and 1,3-selenazolyl, all of which contain one or more substituents, .
[274] In one aspect,
[275] A is _{^{-H, -NR 4 2, -CONR 4}} 2, -CO 2 R 3, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl alkyl, C1-C6 haloalkyl, _{aryl, -CH 2 OH, -CH 2 NR} 4 2, -CH 2 CN, -CN, -C (S) NH 2, -OR 4, -SR 4, -N 3, -NHC (S) NR &lt; ^{4 &} _gt ; ₂ , -NHAc, and no substituent,
[276] Each B and D are independently -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, -SO 2 R ^{11, -S (O) R 3} , -CN, -NR 22, -OR 3, -SR 3, is selected from alkyl, halo, and the group consisting of N substituents perhaloalkyl, -H, -CN, alkyl, perhaloalkyl, And halo are optionally substituted,
[277] E is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, C4-C6 alicyclic, ^{alkoxyalkyl, -C (O) OR 3,} -CONR 4 2, -CN, _{^{-NR 9 2, -OR 3, -SR}} 3, is selected from the group consisting of C1-C6 alkyl, halo and perhalo no substituent, except for both the alkyl and halo by -H, -CN, perhaloalkyl may be optionally substituted In addition,
[278] R &lt; ⁴ &gt; are each independently selected from the group consisting of-H, and C1-C2 alkyl.
[279] In another preferred aspect, R &lt; ⁵ &gt; is to be.
[280] In another preferred aspect, R &lt; ⁵ &gt; is to be.
[281] In another preferred aspect, R &lt; ⁵ &gt; is selected from the group consisting of:
[282]
[283]
[284] And
[285]
[286] In the formula,
[287] A "is -H, -NR ⁴ ₂ , -CONR ⁴ ₂ , -CO ₂ R ³ , halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perhaloalkyl, -CH ₂ OH, -CH ₂ NR ⁴ ₂ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , -NHC S) NR &lt; ⁴ &gt; ₂ and -NHAc,
[288] B '' and D '' are independently -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, - SO ₂ R ¹¹ , -S (O) R ³ , -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , perhaloalkyl, and halo, Alkyl, and halo, is optionally substituted,
[289] E '' is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 alicyclic, ^{alkoxyalkyl, -C (O) OR 3,} -CONR 4 2, -CN, _{^{-NR 9 2, -OR 3, -SR}} 3, is selected from the group consisting of alkyl and halo by C1-C6 perhaloalkyl, halo, and alkyl, all except by -H, -CN, perhaloalkyl, and is optionally substituted,
[290] R &lt; ⁴ &gt; are each independently selected from the group consisting of-H and C1-C2 alkyl.
[291] R ⁵ is
[292] And
[293] And most preferably selected from the group consisting of &lt; RTI ID = 0.0 &gt;
[294] Also, R &lt; ⁵ &gt;
[295] And And more preferably selected from the group consisting of
[296] Also, R &lt; ⁵ &gt; And
[297] And more preferably selected from the group consisting of
[298] Preferred X groups are -alkyl (hydroxy), -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -Alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -allylic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyl Alkoxycarbonylamino-, and -alkylaminocarbonylamino- (all optionally substituted).
[299] More preferred X groups include -heteroaryl-, -alkylcarbonylamino-, -alkylaminocarbonyl-, -alkoxycarbonyl-, and -alkoxyalkyl-.
[300] Particularly preferred X groups are -heteroaryl- and -alkoxycarbonyl-. Furan-3, 5-diyl, -methylaminocarbonyl- and methyloxycarbonyl- are particularly preferred.
[301] Also particularly preferred are compounds wherein X is as shown in formula (II), (III) or (IV).
[302]
[303]
[304]
[305] Compounds where X is as shown in formulas (II) and (IV) are particularly preferred.
[306] A preferred group is _{^{-H, -NR 4 2, -CONR 4}} 2, -COR 3, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl alkyl, C1-C6 haloalkyl Alkyl, aryl, -CH ₂ OH, -CH ₂ NR ⁴ ₂ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , ⁴ ₂ , no substituent and -NHAc. Include _{halo, -CN, -OCH 3, -SCH 3} , and -H no substituents A more preferred A group is -NH _2, -CONH _{2, halo, -CH 3, -CF 3, -CH} 2. Particularly preferred groups A include -NH ₂ , -Cl, -Br, substituent-free and -CH ₃ .
[307] Preferred A '' groups are _{^{-H, -NR 4 2, -CONR 4}} 2, -COR 3, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl alkyl, C1- C6 haloalkyl, _{aryl, -CH 2 OH, -CH 2 NR} 4 2, -CH 2 CN, -CN, -C (S) NH 2, -OR 3, -SR 3, -N 3, -NHC (S ) NR &lt; ⁴ &gt; ₂ and -NHAc. It includes _{halo, -CN, -OCH 3, -SCH 3} , and -H - more preferred A '' group is -NH _2, -CONH _{2, halo, -CH 3, -CF 3, -CH} 2. Particularly preferred A "groups include -Cl, -NH ₂ , -Br, and -CH ₃ .
[308] Preferred B groups are -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, -SO 2 R 11, -S (O) R ³ , -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , perhaloalkyl, halo and no substituent and is selected from the group consisting of -H, -CN, perhaloalkyl, -NO ₂ , All are optionally substituted. More preferred B groups are ^{-H, -C (O) R 11} , -C (O) include SR ^3, alkyl, aryl, alicyclic, halo, -NR ⁹ _2, -OR ^3, -SR ^3, and no substituent do. A particularly preferred B groups include ^{-H, -C (O) OR 3} , -C (O) SR 3, C1-C6 alkyl, alicyclic, halo, heteroaryl, no substituent, and -SR ^3.
[309] Preferred B "groups are -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, -C (O) R ¹¹ , -C (O) SR ³ , -SO ₂ R ¹¹ , -S (O) R ³ , -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , perhaloalkyl, and halo; all but -H, -CN, perhaloalkyl, do. More preferred B '' groups are ^{-H, -C (O) R 11} , -C (O) include SR ^3, alkyl, aryl, alicyclic, halo, -SR ^3, -NR ⁹ _2, and -OR ³ do. Particularly preferred B "groups include -H, -C (O) OR ³ , -C (O) SR ³ , C 1 -C 6 alkyl, alicyclic, halo, heteroaryl and -SR ³ .
[310] Preferred D groups are -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, -C (O) R ¹¹ , -C (O) SR ³ , -SO ₂ R ¹¹ , -S (O) R ³ , -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , perhaloalkyl, halo and no substituent and is selected from the group consisting of -H, -CN, perhaloalkyl, -NO ₂ , All are optionally substituted. More preferred D groups include -H, -C (O) R ¹¹ , -C (O) SR ³ , alkyl, aryl, alicyclic, halo, -NR ⁹ ₂ , unsubstituted and -SR ³ . Particularly preferred D groups include-H, -C (O) OR &lt; ³ &gt;, lower alkyl, alicyclic,
[311] Preferred D '' groups are -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, -SO 2 R 11, -S (O) R ³ , -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , perhaloalkyl, and halo; all but -H, -CN, perhaloalkyl, do. More preferred D 'groups include -H, -C (O) R ¹¹ , -C (O) SR ³ , alkyl, aryl, alicyclic, halo, -NR ⁹ ₂ , and -SR ³ . Particularly preferred D 'groups include -H, -C (O) OR &lt; ³ &gt;, lower alkyl, alicyclic and halo.
[312] A preferred E group is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, C4-C6 alicyclic, ^{alkoxyalkyl, -C (O) OR 3,} -CONR 4 2, -CN , -NR ⁹ ₂ , -OR ³ , -SR ³ , C 1 -C 6 perhaloalkyl, halo and no substituent, and all but -H, -CN, perhaloalkyl and halo may be optionally substituted. More preferred E groups include -H, C 1 -C 6 alkyl, lower alicyclic, halogen, -CN, -C (O) OR ³ , -SR ³ , -CONR ⁴ ₂ and no substituent. Particularly preferred E groups include -H, -Br, -Cl, and no substituent.
[313] Preferred E '' groups are -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, C4-C6 alicyclic, ^{alkoxyalkyl, -C (O) OR 3,} -CONR 4 2, -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , C 1 -C 6 perhaloalkyl and halo, and all but -H, -CN, perhaloalkyl and halo may be optionally substituted. More preferred E "groups include -H, C1-C6 alkyl, lower alicyclic, halogen, -CN, -C (O) OR ³ , -SR ³ and -CONR ⁴ ₂ . Particularly preferred E 'groups include -H, -Br, and -Cl.
[314] In one preferred aspect,
[315] A '' is -NH _2, -CONH _{2, halo, -CH 3, -CF 3, -CH} 2 - is selected from, halo, -CN, -OCH _3, -SCH _3, and the group consisting of -H,
[316] B "is selected from the group consisting of -H, -C (O) R ¹¹ , -C (O) SR ³ , alkyl, aryl, alicyclic, halo, -CN, -SR ³ , -OR ³ and -NR ⁹ ₂ Lt; / RTI &gt;
[317] D '' is selected from the group consisting of ^{-H, -C (O) R 11} , -C (O) SR 3, -NR 9 2, alkyl, aryl, alicyclic, halo, and -SR ^3,
[318] E "is selected from the group consisting of -H, -Ci-C6 alkyl, lower alicyclic, halo, -CN, -C (O) OR ³ and -SR ³ ,
[319] X is selected from the group consisting of -alkyl (hydroxy), -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -Alkylthio-alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -allylic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxy Alkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted, &lt; RTI ID = 0.0 &gt;
[320] When both Y groups are -O-, R ¹ is independently an aryl, optionally substituted benzyl, optionally _{^{substituted, -C (R 2) 2 OC}} (O) R 3, -C (R 2) 2 OC (O) OR ³ and-H, or &lt; RTI ID = 0.0 &gt;
[321] When one Y is -O-, R ¹ bonded to -O- is optionally substituted aryl and the other Y is -NR ⁶ - R ¹ bonded to -NR ⁶ - is -C (R ⁴ ) ₂ COOR ³ and -C (R ² ) ₂ C (O) OR ³ , or
[322] When Y is -O- or -NR ⁶ -, R ¹ and R ¹ together
[323] Lt;
[324] In the formula,
[325] V, W and W 'are independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl Or
[326] V and W are taken together through an additional three carbon atoms to form an optionally substituted cyclic group comprising 6 carbon atoms and said cyclic group is selected from the group consisting of the carbon atoms having 3 atoms from Y bonded to phosphorus Substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bound to one,
[327] Z and W are taken together through an additional 3 to 5 atoms to form a cyclic group optionally containing one heteroatom and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
[328] W and W 'are taken together through an additional two to five atoms to form a cyclic group optionally containing from 0 to 2 heteroatoms, wherein V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl Lt; / RTI &gt;
[329] Z is ^{-CHR 2 OH, -CHR 2 OC (} O) R 3, -CHR 2 OC (S) R 3, -CHR 2 OC (S) OR 3, -CHR 2 OC (O) SR 3, -CHR 2 ^{_{OCO 2 R 3, -OR 2,}} -SR 2, -R 2, -NHCOR 2, -NHCO 2 R 3, - (CH 2) p -OR 2, and - the group consisting of (CH _{²⁾ p} -SR ₂ / RTI &gt;
[330] p is an integer 2 or 3,
[331] a) V, Z, W, W 'are not both -H,
[332] b) when Z is -R ² , at least one of V, W and W 'is not -H, alkyl, aralkyl, or alicyclic,
[333] c) Y is not all -NR &lt; ⁶ &gt; -,
[334] R ² is selected from the group consisting of R ³ and -H,
[335] R &lt; ³ &gt; is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl,
[336] R &lt; ⁶ &gt; is selected from the group consisting of-H and lower alkyl.
[337] In one particularly preferred aspect, R &lt; ⁵ &gt; is ego,
[338] X is selected from the group consisting of methylene oxycarbonyl and furan-2,5-diyl,
[339] At least one Y group is -O-, and pharmaceutically acceptable salts and solvates thereof.
[340] When Y is -O-, R ¹ bonded to -O- is independently -H, optionally substituted phenyl, -CH ₂ OC (O) -tBu, -CH ₂ OC (O) Et, and -CH ₂ OC (O) -iPr, &lt; / RTI &gt;
[341] When Y is -NR ⁶ -, R ¹ bonded to -NR ⁶ - is independently selected from the group consisting of -C (R ² ) ₂ COOR ³ , -C (R ⁴ ) ₂ COOR ³ , or
[342] When Y is -O- or -NR ⁶ -, at least one Y is -O-, R ¹ and R ¹ together
[343] Lt;
[344] V is selected from optionally substituted aryl, and optionally substituted heteroaryl, Z, W 'and W are H,
[345] R &lt; ⁶ &gt; is selected from the group consisting of-H and lower alkyl
[346] Compounds are more preferable.
[347] The following compounds and salts thereof are most preferred.
[348] 1) A "is -NH ₂ , X is furan-2,5-diyl, and B" is -CH ₂ -CH (CH ₃ ) ₂ .
[349] 2) A "is -NH ₂ , X is furan-2,5-diyl, and B" is -COOEt.
[350] 3) A "is -NH ₂ , X is furan-2,5-diyl, and B" is -SMe.
[351] 4) A "is -NH ₂ , X is furan-2,5-diyl, and B" is -SCH ₂ CH ₂ SCH ₃ .
[352] 5) A "is -NH ₂ , X is methyleneoxycarbonyl, and B" is -CH (CH ₃ ) ₂ .
[353] In another particularly preferred aspect, R &lt; ⁵ &gt; is ego,
[354] X is furan-2,5-diyl and methyleneoxycarbonyl, A "is -NH ₂ , and at least one or more Y groups are -O-, and pharmaceutically acceptable salts and solvates thereof.
[355] When Y is -O-, R ¹ is each independently -H, optionally substituted phenyl, -CH ₂ OC (O) -tBu, -CH ₂ OC (O) Et and -CH ₂ OC (O) &Lt; RTI ID = 0.0 &gt;
[356] When Y is -NR ⁶ -, each R ¹ is independently selected from the group consisting of -C (R ² ) ₂ COOR ³ , -C (R ⁴ ) ₂ COOR ³ , or
[357] When Y is selected from -O- and -NR ⁶ -, R ¹ and R ¹ together Lt;
[358] here,
[359] V is selected from optionally substituted aryl, and optionally substituted heteroaryl, with Z, W 'and W being especially preferred. Also particularly preferred are compounds wherein B &quot; is -SCH ₂ CH ₂ CH ₃ .
[360] In another particularly preferred aspect, R &lt; ⁵ &gt; is Lt;
[361] A "is -NH ₂ , E" and D "are -H, B" is n-propyl and cyclopropyl, X is furan-2,5-diyl and methyleneoxycarbonyl, One Y group is -O-, and pharmaceutically acceptable salts and solvates thereof. Wherein R ¹ is selected from the group consisting of -H, optionally substituted phenyl, -CH ₂ OC (O) -tBu, -CH ₂ OC (O) Et and -CH ₂ OC (O)
[362] When Y is -NR ⁶ -, R ¹ is each independently selected from the group consisting of -C (R ² ) ₂ C (O) OR ³ and -C (R ⁴ ) ₂ COOR ³ , or
[363] When Y is selected from -O- and -NR ⁶ -, R ¹ and R ¹ together Lt;
[364] here,
[365] V is selected from optionally substituted aryl and optionally substituted heteroaryl, and Z, W 'and W are especially preferred.
[366] In another particularly preferred aspect, R &lt; ⁵ &gt; is Lt;
[367] A "is -NH ₂ , D" is -H, B "is n-propyl and cyclopropyl, X is furan-2,5-diyl and methyleneoxycarbonyl, and at least one Y group is -O-, and pharmaceutically acceptable salts and solvates thereof.
[368] When Y is -O-, R ¹ is each independently -H, optionally substituted phenyl, -CH ₂ OC (O) -tBu, -CH ₂ OC (O) Et and -CH ₂ OC (O) Or &lt; RTI ID = 0.0 &gt;
[369] Y is -O-, and the other hand to the corresponding R ¹ is phenyl, and the other Y is -NH-, R ¹ corresponding thereto is -CH (Me) C (O) OEt thereto, or
[370] At least one Y is -O- when, R ¹ and R ¹ together are Lt;
[371] here,
[372] V is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl, with Z, W 'and W being especially preferred.
[373] Compounds of formula X and their pharmaceutically acceptable salts and salts are preferred.
[374] (X)
[375]
[376] In this formula,
[377] G "is selected from the group consisting of -O- and -S-,
[378] A ^2, L ^2, E ² and J ² is _{^{-NR 4 2, -NO 2, -H}} , -OR 2, -SR 2, -C (O) NR 4 2, halo, -COR ^11, -SO ₂ R ^3, guanidyl pyridinyl, amidinyl, aryl, aralkyl, ^{_{alkyloxy-alkyl, -SCN, -NHSO 2 R 9,}} -SO 2 NR 4 2, -CN, -S (O) R 3, acyl perhalo , Perhaloalkyl, perhaloalkoxy, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, and lower alicyclic, or
[379] L ² and E ² or E ² and J ² together form a cyclic cyclic group,
[380] X ² is an optionally substituted bonding group through which R ⁵ is bonded to the phosphorus atom through 1 to 3 atoms comprising 0 or 1 heteroatom selected from N, O and S, wherein the atom bonded to the phosphorus is a carbon atom However,
[381] However, X ² is not substituted with -COOR ^2, -SO ₃ R ¹ or PO ₃ R ¹ _2,
[382] Y is independently selected from the group consisting of -O-, and -NR &lt; ⁶ &gt; -,
[383] When Y is -O, R ¹ bonded to -O- is independently -H, alkyl, optionally substituted aryl, optionally substituted alicyclic wherein the cyclic moiety comprises a carbonate or thiocarbonate hereinafter), optionally _{^{substituted-alkylaryl, -C (R 2) 2 OC}} (O) NR 2 2, -NR 2 -C (O) -R 3, -C (R 2) 2 -OC (O) R _{^{3, -C (R 2) 2}} -OC (O) OR 3, -C (R 2) 2 OC (O) SR 3, - alkyl, -SC (O) R ^3, - alkyl -SS- alkyl hydroxy, And-alkyl-SSS-alkylhydroxy,
[384] When Y is -NR ⁶ -, R ¹ bonded to -NR ⁶ - is independently -H, - [C (R ² ) ₂ ] _q -COOR ³ , -C (R ⁴ ) ₂ COOR ³ , - [ C (R ² ) ₂ ] _q -C (O) SR and -cycloalkylene-COOR ³ , or
[385] When one of Y is independently selected from -O- and -NR ⁶ -, R ¹ and R ¹ together form a cyclic group as -alkyl-SS-alkyl-, or R ¹ and R ¹ together Lt;
[386] V, W and W 'are independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl Or
[387] V and Z together are joined through an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 atoms optionally containing one heteroatom, Acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy bonded to a carbon atom which is three atoms from the alkyl group,
[388] V and Z together are joined through an additional three to five atoms to form a cyclic group optionally containing one heteroatom fused to the aryl group at the beta and gamma positions for Y bonded to the phosphorus,
[389] V and W are taken together through an additional three carbon atoms to form an optionally substituted cyclic group comprising 6 carbon atoms and said cyclic group is selected from the group consisting of the carbon atoms having 3 atoms from Y bonded to phosphorus Substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bound to one,
[390] Z and W are taken together through an additional 3 to 5 atoms to form a cyclic group optionally containing one heteroatom and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
[391] W and W 'are taken together through an additional two to five atoms to form a cyclic group optionally containing from 0 to 2 heteroatoms, wherein V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl Lt; / RTI &gt;
[392] Z is ^{-CHR 2 OH, -CHR 2 OC (} O) R 3, -CHR 2 OC (S) R 3, -CHR 2 OC (S) OR 3, -CHR 2 OC (O) SR 3, -CHR 2 (CH = CR ² ₂ ) OH, -CH (C≡CR ² ) OH, -CH (O) ₂ R ³ , -OR ² , -SR ² , -CHR ² N ₃ , -CH ₂ aryl, _{^{OH, -R 2, -NR 2 2}} , -OCOR 3, -OCO 2 R 3, -SCOR 3, -SCO 2 R 3, -NHCOR 2, -NHCO 2 R 3, -CH 2 NH aryl, - (CH ₂ ) _p -OR ² , and - (CH ₂ ) _p -SR ² ,
[393] p is an integer 2 or 3,
[394] q is an integer of 1 or 2,
[395] Provided that a) V, Z, W and W 'are not all -H,
[396] b) when Z is -R ² , at least one of V, W and W 'is not -H, alkyl, aralkyl, or alicyclic
[397] R ² is selected from the group consisting of R ³ and -H,
[398] R &lt; ³ &gt; is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl,
[399] R ⁴ are each independently selected from the group consisting of -H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group,
[400] R ⁶ is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl,
[401] R ⁹ are each independently selected from the group consisting of -H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group,
[402] R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² ₂ , and -OR ² .
[403] The preferred G &quot; group is -S-.
[404] Preferred A ² , L ² , E ² and J ² groups are selected from -H, -NR ⁴ ₂ , -SC≡N, halogen, -OR ³ , hydroxy, -alkyl (OH), aryl, alkyloxycarbonyl, -SR ^3, or by lower perhalo alkyl, and C1-C5 alkyl, and forms an L ² and E ² is the cyclic cyclic together. More preferred A ² , L ² , E ² and J ² groups are -H, -NR ⁴ ₂ , -SC≡N, halogen, lower alkoxy, hydroxy, lower alkyl (hydroxy), lower aryl and C 1 -C 5 alkyl , L ² and E ² together form a cyclic cyclic group. Particularly preferred J &lt; ² &gt; groups are-H and lower alkyl. Particularly preferred A ² is -NH ₂ , -H, halo and C 1 -C 5 alkyl.
[405] A particularly preferred compound is L ² and E ² are independently -H, -SC≡N, lower alkoxy, C1-C5 alkyl, lower alkyl (hydroxy), or selected from the group consisting of lower aryl and halogen, L ² and E ² together form a cyclic cyclic group containing an additional four carbon atoms.
[406] Preferred X ² is selected from the group consisting of -alkyl, -alkenyl, -alkynyl, -alkylene-NR ⁴ -alkylene-O-, alkylene-S-, -C (O) (O) -. More preferred X ² is -alkylene-O-, -alkylene-S-, and -alkyl-. Particularly preferred X &lt; ² &gt; is -methyleneoxy-.
[407] In one aspect, A ² is selected from the group consisting of _{-H, -NH 2, -CH 3,} -Cl, and Br,
[408] L ² is -H, lower alkyl, halogen, lower alkyloxy, hydroxy, -alkylene-OH, or together with E ² form a cyclic group comprising aryl, cyclic alkyl, heteroaryl, heterocyclic alkyl and,
[409] E ² is selected from the group consisting of H, lower alkyl, halogen, SCN, lower alkyloxycarbonyl, lower alkyloxy, or a group including L ¹ together with aryl, cyclic alkyl, heteroaryl, or heterocyclic alkyl Forming a clicker,
[410] J ² is selected from the group consisting of H, halogen and lower alkyl,
[411] G &quot; is -S-,
[412] X ² is -CH ₂ O-,
[413] Preference is given to compounds of formula X wherein at least one Y group is -O-, and pharmaceutically acceptable salts and esters thereof. Especially preferred are compounds wherein A ² is NH ₂ , G "is -S-, L ² is -Et, E ² is -SCN and J ² is -H. One Y group is -O-, the corresponding R ¹ is -phenyl, while the other Y is -NH-, and the corresponding R ¹ is -C (R ² ) ₂ -COOR ³ . When R ¹ is -CHR ³ COOR ³ and the corresponding -NR ⁶ - ^* CHR ³ COOR ³ , it preferably has an L-configuration.
[414] In addition, one Y group is -O-, and R ¹ is equivalent to -phenyl, while the other Y is -NH-, and the corresponding R ¹ is more preferably a compound of -CH (Me) CO ₂ Et, which Do.
[415] In the compounds of formulas I and X, preferably all of the groups Y are -O-, or one group Y is -O- and one group Y is -NR ⁶ -. When only one Y group is -NR ⁶ -, Y, which is closest to W and W ', is preferably -O-. Most preferably, all Y groups are -O-.
[416] In another especially preferred aspect, Y is a group both -O-, R ¹ and R ¹ together are
[417] And V is phenyl substituted with one to three halogens. 3-bromo-4-fluorophenyl, 3-chlorophenyl, 3-bromophenyl and 3,5-dichlorophenyl are particularly preferred.
[418] In another especially preferred aspect, Y is -O- and one group, corresponding to R ¹ is either _{phenyl, -NHC (O) CH 3,} -F, -Cl, -Br, -C (O) OCH 2 CH ₃ , and -CH ₃ , the other Y is -NR ⁶ -, the corresponding R ¹ is -C (R ² ) COOR ³ , and R ² Are each independently selected from -H, -CH ₃ , and -CH ₂ CH ₃ More preferred R ⁶ is -H and R ¹ attached to -NH- is -CH (Me) CO ₂ Et.
[419] In general, the preferred substituents of formulas I and X, V, Z, W and W ', are chosen to appear as one or more of the following characteristics.
[420] (1) this reaction may be a rate determining step and therefore increases the oxidation reaction because it must be completed with the drug removal process;
[421] (2) increase stability in aqueous solution and in the presence of other non-p450 enzymes;
[422] (3) increase the cellular permeability of, for example, the absence of substituents or of high molecular weight substances, because of their ability to limit cellular permeability as well as oral bioavailability;
[423] (4) after the [beta] -removing reaction, the ring with one or more of the following characteristics promotes the [beta] -removal following initial oxidation by producing an open product;
[424] (a) not recast;
[425] (b) perform limited shared signatures;
[426] (c) promoting beta-elimination by assisting in proton elimination;
[427] (d) interfering with an addition reaction to form a stable adduct, e. g. a thiol, as an initial hydroxylated product, or a nucleophilic addition to the carbonyl produced after the ring is opened;
[428] (e) limiting the metabolism of the reaction intermediates (e. g., ring open ketones);
[429] (5) produce non-toxic and non-mutagenic by-products with one or more of the following characteristics. All properties include substituents that limit the Michael addition reaction, for example
[430] a) an electron donating Z group which reduces double bond polarization,
[431] b) a W group that sterically blocks the nucleophilic addition to the -carbon,
[432] c) a group Z which removes the double bonds through a rearrangement isomerization reaction (enol-> keto) or hydrolysis (for example, enamin) after the elimination reaction,
[433] d) a V group containing a group which is added to the , - unsaturated ketone to form a ring,
[434] e) a Z group which forms a stable ring through addition of Michael to the double bond, and
[435] f) one or more of the following characteristics
[436] (i) limited to
[437] (ii) sensitive to deoxygenation (e. g., ketone reduction)
[438] Which increases the deoxygenation of by-products
[439] . &Lt; / RTI &gt;
[440] (6) a pharmacologically active product.
[441] In another aspect, when Y is -O-, R ¹ bonded to -O- is independently -H, alkyl, optionally substituted aryl, optionally substituted alicyclic wherein the cyclic moiety is a carbonate or thio carbonate containing from carbonate), optionally _{^{substituted-alkylaryl, -C (R 2) 2 -OC}} (O) R 3, -C (R 2) 2 -OC (O) OR 3, -C (R ² ) ₂ OC (O) SR ³ , -alkyl-SC (O) R ³ , -alkyl-SS-alkylhydroxy,
[442] When Y is -NR ⁶ -, R ¹ bonded to -NR ⁶ - is independently -H, - [C (R ² ) ₂ ] _q -COOR ³ , -C (R ⁴ ) ₂ COOR ³ , - [ C (R ² ) ₂ ] _q -C (O) SR and -cycloalkylene-COOR ³ , or
[443] When one of Y is independently selected from -O- and -NR ⁶ -, R ¹ and R ¹ together
[444] Lt;
[445] here,
[446] V, W and W 'are independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl Or
[447] V and W are taken together through an additional three carbon atoms to form an optionally substituted cyclic group comprising 6 carbon atoms and said cyclic group is selected from the group consisting of the carbon atoms having 3 atoms from Y bonded to phosphorus Substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bound to one,
[448] Z and W are taken together through an additional 3 to 5 atoms to form a cyclic group optionally containing one heteroatom and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
[449] W and W 'are taken together through an additional two to five atoms to form a cyclic group optionally containing from 0 to 2 heteroatoms, wherein V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl Lt; / RTI &gt;
[450] Z is ^{-CHR 2 OH, -CHR 2 OC (} O) R 3, -CHR 2 OC (S) R 3, -CHR 2 OC (S) OR 3, -CHR 2 OC (O) SR 3, -CHR 2 ^{_{OCO 2 R 3, -OR 2,}} -SR 2, -R 2, -NHCOR 2, -NHCO 2 R 3, - (CH 2) p -OR 2, and - the group consisting of (CH _{²⁾ p} -SR ₂ / RTI &gt;
[451] p is an integer 2 or 3,
[452] q is an integer of 1 or 2,
[453] Provided that a) V, Z, W and W 'are not both -H,
[454] b) when Z is -R ² , at least one of V, W and W 'is not -H, alkyl, aralkyl, or alicyclic,
[455] c) Y is not all -NR ⁶ -
[456] R ² is selected from the group consisting of R ³ and -H,
[457] R &lt; ³ &gt; is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl,
[458] R ⁶ is preferably selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl.
[459] Y group when both -O-, R ¹ is an independently an optionally substituted aryl, optionally substituted _{^{benzyl, -C (R 2) 2 OC}} (O) R 3, -C (R 2) 2 OC (O) OR &lt; ³ &gt;, and -H,
[460] When Y is -NR ⁶ -, R ¹ bonded to the -NR ⁶ - group is selected from the group consisting of -C (R ⁴ ) ₂ -COOR ³ , and -C (R ² ) ₂ COOR ³ , and the other Y -O- groups in one time, the R ¹ bonded to the -O- is optionally substituted _{^{aryl, -C (R 2) 2 OC}} (O) R 3 and _{^{-C (R 2) 2 OC (}} O) OR 3 substituted Are more preferred.
[461] In another aspect, one Y group is -O-, the corresponding R ¹ is phenyl, the other Y is -NH-, and the corresponding R ¹ is -CH ₂ CO ₂ Et.
[462] In another preferred aspect, one Y group is -O-, the corresponding R ¹ is phenyl, the other Y is -NH-, and the corresponding R ¹ is -C (Me) ₂ CO ₂ Et.
[463] In another preferred aspect, one Y group is -O-, the corresponding R ¹ is 4-NHC (O) CH ₃ -phenyl and the other Y is -NH-, and the corresponding R ¹ is - CH ₂ COOEt.
[464] In another preferred aspect, one Y group is -O-, the corresponding R ¹ is 2-CO ₂ Et-phenyl and the other Y is -NH-, and the corresponding R ¹ is -CH ₂ CO ₂ It's Et.
[465] In another preferred aspect, one Y group is -O-, the corresponding R ¹ is 2-CH ₃ -phenyl and the other Y is -NH-, and the corresponding R ¹ is -CH ₂ CO ₂ Et to be.
[466] In another aspect, compounds wherein all of the groups Y are -O- and R &lt; ¹ &gt; is aryl or - (CR &lt; ² &gt;) ₂ -aryl are preferred.
[467] Wherein all Y groups are O- and at least one R ¹ is selected from the group consisting of -C (R ² ) ₂ -OC (O) R ³ and -C (R ² ) ₂ -OC (O) OR ³ Is also preferable.
[468] In yet another aspect, all Y groups are -O-, and one or more of R ¹ is -alkyl-SS-alkylhydroxyl, -alkyl-SC (O) R ³ and -alkyl-SSS-alkylhydroxy, or R Lt; ¹ &gt; and R &lt; ² &gt; together form a cyclic group are preferred.
[469] In one aspect, compounds wherein all of the groups Y are -O- and R &lt; ¹ &gt; is H are particularly preferred.
[470] In another aspect, Y groups are both an -O-, R = is preferred in particular is a -CH ₂ OC (O) OEt compound.
[471] More preferred are compounds wherein at least one Y is -O- and R &lt; ¹ &gt; and R &lt; ^{2 &}
[472]
[473] V, W and W 'are independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl Selected,
[474] V and W are joined together through an additional three carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms wherein the optionally substituted cyclic group is selected from the group consisting of 3 atoms from Y bonded to phosphorus Acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bonded to one of the above carbon atoms, which is unsubstituted or substituted with one substituent selected from the group consisting of halogen,
[475] Z and W are taken together through an additional 3 to 5 atoms to form a cyclic group optionally containing one heteroatom, V is aryl, substituted aryl, heteroaryl or substituted heteroaryl,
[476] W and W 'are taken together through an additional 2 to 5 atoms to form a cyclic group optionally containing 0 to 2 heteroatoms, V is aryl, substituted aryl, heteroaryl or substituted heteroaryl,
[477] Z is ^{-CHR 2 OH, -CHR 2 OC (} O) R 3, -CHR 2 OC (S) R 3, -CHR 2 OC (S) OR 3, -CHR 2 OC (O) SR 3, -CHR 2 from (CH ₂₎ group consisting of _{^{p -SR 2 - OCO 2 R 3}} , -OR 2, -SR 2, -R 2, -NHCOR 2, -NHCO 2 R 3, - (CH 2) p -OR 2 , and Selected,
[478] p is an integer of 2 or 3,
[479] A) V, Z, W and W 'are not both -H,
[480] b) when Z is -R ² , at least one of V, W and W 'is not -H, alkyl, aralkyl or alicyclic,
[481] c) Y is not -NR ⁶ -
[482] R ² is selected from the group consisting of R ³ and -H,
[483] R ³ is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl,
[484] R &lt; ⁶ &gt; is selected from the group consisting of-H and lower alkyl.
[485] In another aspect, one Y is -O-, R ¹ is optionally substituted aryl, the other is-NR ⁶ -, and R ¹ on -NR ⁶ - is -C (R ⁴ ) ₂ COOR ³ and -C (R ² ) ₂ C (O) OR ³ . Particularly preferred are compounds wherein R ¹ bonded to -O- is phenyl and R ¹ bonded to -NH- is -CH (Me) CO ₂ Et and -NH ^* CH (Me) CO ₂ Et is in the L configuration.
[486] Wherein R ¹ bonded to -O- is phenyl and phenyl substituted with 1 to 2 substituents selected from the group consisting of -NHAc-, -F, -Cl, -Br, -COOEt and -CH ₃ , -NR Particularly preferred are those compounds wherein R ¹ bonded to ⁶ is -C (R ² ) ₂ COOR ³ , wherein R ² and R ³ are independently -H, -CH ₃ or -Et. Among such compounds, when R ¹ bonded to -O- is phenyl substituted by -NHAc or -COOEt, preferably any -NHAc is in the 4-position and any -COOEt is in the 2-position. This is the substituent on the substituted phenyl _{4-NHC (O) CH 3} , -Cl, -Br, 2-C (O) OCH 3 CH 3 or -CH ₃ compound is more preferred.
[487] More preferred V groups of formula (VI) are aryl, substituted aryl, heteroaryl and substituted heteroaryl. Preferably, Y is -O-. Particularly preferred aryl and substituted aryl groups include phenyl, and phenyl substituted with one to three halogens. Particularly preferred are 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl and 3-bromophenyl.
[488] It is also particularly preferred that V is selected from the group consisting of monocyclic heteroaryl and monocyclic substituted heteroaryl containing at least one nitrogen atom. Most preferably, the heteroaryl and the substituted heteroaryl are 4-pyridyl and 3-bromopyridyl, respectively.
[489] It is also preferred that V and Z are joined together through an additional 3 to 5 atoms to optionally contain one heteroatom and to form a cyclic group fused to the beta and gamma position aryl groups of the Y bonded to the phosphorus Do. In such compounds, preferably the aryl group is an optionally substituted monocyclic aryl group and the linking group between Z and the gamma position of the aryl group is selected from the group consisting of O, CH ₂ , CH ₂ CH ₂ , OCH ₂ and CH ₂ O .
[490] In yet another aspect, V and W are joined together through an additional three carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms, wherein the optionally substituted cyclic group is selected from the group consisting of Y Acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy bound to one of the abovementioned additional carbon atoms which are three atoms from the group consisting of hydrogen, &lt; RTI ID = 0.0 &gt; . During such compounds, -CH ₂ V and the W -CH ₂ -CH (OH) with ^{_{-, -CH 2 -CH (OCOR 3}} ) -CH 2 - and _{-CH 2 -CH (OCO 2) R} 3) -CH ₂ -. &Lt; / RTI &gt;
[491] Another preferred group V is a 1-alkene. Oxidation by the p450 enzyme is known to occur in benzyl and allyl carbon.
[492] In one aspect, when Z is selected from the group consisting of -CHR ² OH, -CHR ² OCOR ^3, and -CHR ² OCO ₂ R ³ , the preferred V group is -H.
[493] In another aspect, when V is aryl, substituted aryl, heteroaryl or substituted heteroaryl, the preferred Z group is -OR ² , -SR ² , -CHR ² N ₃ , -R ² , -NR ² ₂ , - _{^{OCOR 2, -OCO 2 R 3,}} -SCOR 3, -SCO 2 R 3, -NHCOR 2, -NHCO 2 R 3, -CH 2 NH _{aryl, - (CH 2) p OR} 2 , and - (CH _{2) p} -SR &lt; ^{2 &} gt ;. More preferred Z groups are -OR ² , -R ² , -OCOR ² , -OCO ₂ R ³ , -CH ₃ , -NHCOR ² , -NHCO ₂ R ³ , - (CH ₂ ) _p OR ² and - (CH ₂ ) _p- SR ² . Most preferred Z groups include -OR ² , -H, -OCOR ² , -OCO ₂ R ^3, and -NHCOR ² .
[494] Preferred W and W 'groups include H, R ³ , aryl, substituted aryl, heteroaryl and substituted heteroaryl. Preferably, W and W 'are the same group. More preferably, W and W 'are H.
[495] In one aspect, the formula (VI) is preferred.
[496]
[497] V is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl, 1-alkenyl and 1-alkynyl. More preferred V groups of formula (VI) are aryl, substituted aryl, heteroaryl and substituted heteroaryl. Preferably Y is -O-. Particularly preferred aryl and substituted aryl groups include phenyl and substituted phenyl. Particularly preferred heteroaryl groups include monocyclic substituted and unsubstituted heteroaryl groups. Particularly preferred groups are 4-pyridyl and 3-bromopyridyl.
[498] In one aspect, the compound of formula (VI) has Z groups that are preferably H, alkyl, alicyclic, hydroxy, alkoxy, or OC (= O) R, OC (= O) OR, or NHCOR. Preferably, Z is a group that reduces the tendency of vinyl aryl ketone, which is a by-product of progressing Michael addition reaction. The preferred Z group is a group which donates electrons to a known vinyl group to reduce the tendency of an alpha, beta -unsaturated carbonyl compound to proceed the Michael addition reaction. For example, the methyl groups on acrylamide at similar positions do not cause mutagenic activity whereas the unsubstituted vinyl analogues are highly mutagenic. Other groups, for example, Z = OR, NHAc, etc., may perform similar functions. Further, groups in which the double bond is completely removed, such as Z = OH, -OC (O) R, -OCO ₂ R and NH ₂ , in which the remainder isomerization reaction can proceed rapidly after the elimination reaction, Can be prevented. Certain W and W ' groups are also advantageous in this role because they interfere with or make the addition reaction to the [beta] -carbon difficult. Another preferred group Z is a group containing a nucleophilic group that can be added to the , - unsaturated double bond after the elimination reaction, ie, (CH ₂ ) _p SH or - (CH ₂ ) _n OH wherein p is 2 or 3). Another preferred group is a group attached to V which may be attached to an alpha, beta-unsaturated double bond after the elimination reaction.
[499]
[500] In yet another aspect, the following formula (VII) is preferred:
[501]
[502] Wherein, Z is ^{-CHR 2 OH, -CHR 2 OCOR 3} , -CHR 2 OC (S) R 3, -CHR 2 OCO 2 R 3, -CHR 2 OC (O) SR 3 , and -CHR ² OC (S) OR &lt; ^{3 &} gt ;. More preferred groups include -CHR ² OH, -CHR ² OC (O) R ^3, and -CHR ² OCO ₂ R ³ .
[503] In another aspect, preferred are those of formula VIII: &lt; RTI ID = 0.0 &gt;
[504]
[505] Wherein Z 'is selected from the group consisting of -OH, -OC (O) R ³ , -OCO ₂ R ³ and -OC (O) SR ³ ,
[506] D ⁴ and D ³ are independently selected from the group consisting of -H, alkyl, OR ² , -OH, and -OC (O) R ³ , with the proviso that at least one of D ⁴ and D ³ is -H. Preferably Y is -O-.
[507] In one preferred embodiment, W ' and Z are-H, and both W and V are phosphonate precursor residue: Are the same aryl, substituted aryl, heteroaryl or substituted heteroaryl which have a symmetrical plane.
[508] Preferably Y is -O-.
[509] In another preferred embodiment, W and W 'are H and V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, and Z is selected from the group consisting of -H, OR ^2, and -NHCOR ² Lt; / RTI &gt; More preferred is a compound wherein Z is -H.
[510] Preferably, the oral bioavailability is at least 5%. More preferably, the oral bioavailability is at least 10%.
[511] The p450 oxidation reaction may be susceptible to stereochemistry that may occur in carbon bearing phosphorus or aromatic groups. The present invention has two isomeric forms around phosphorus. Preferred is a stereochemistry capable of both oxidation and elimination reactions. Preferred is cis-stereochemistry.
[512] The preferred compounds _{^{R 5 -X-PO 3 2-,}} R 5 -XP (O) corresponding with the elimination of the formula VIII (NHR ⁶⁾ _2, or ^{R 5 -XP (O) (O} -) (NHR 6) Lt; RTI ID = 0.0 &gt; Z &lt; / RTI &gt; A particularly preferred Z 'group is OH. D ⁴ and D ³ groups are preferably hydrogen, alkyl, -OR ² and -OC (O) R ³ , and at least one of D ⁴ and D ³ groups is H.
[513] Of the preferred compounds, the following are preferred:
[514] Acyloxyalkyl esters;
[515] Alkoxycarbonyloxyalkyl esters;
[516] Aryl esters;
[517] Benzyl and substituted benzyl esters;
[518] Disulfide-containing esters;
[519] Substituted (1, 3-dioxolen-2-one) methyl esters;
[520] Substituted 3-phthalidyl esters;
[521] Cyclic- [5-hydroxycyclohexane-1,3-diyl] diester and hydroxy protected form;
[522] Cyclic- [2-hydroxymethylpropane-1,3-diyl] diester and hydroxy protected form;
[523] Cyclic- (1-arylpropane-1,3-diyl);
[524] Monoaryl esters N-substituted monophosphoramidates;
[525] Bis-omega-substituted lactone esters; And all the mixed esters obtained from possible combinations of the esters.
[526] The following compounds are more preferred:
[527] Bis-pivaloyloxymethyl esters;
[528] Bis-isobutyryloxymethyl ester;
[529] Cyclic- [1- (3-chlorophenyl) propane-1,3-diyl] diester;
[530] Cyclic- [1- (3,5-dichlorophenyl) propane-1,3-diyl] diester;
[531] Cyclic- [1- (3-bromo-4-fluorophenyl) propane-1,3-diyl] diester;
[532] Cyclic- [2-hydroxymethylpropane-1,3-diyl] diester;
[533] Cyclic- [2-acetoxymethylpropane-1,3-diyl] diester;
[534] Cyclic- [2-methyloxycarbonyloxymethylpropane-1,3-diyl] diester;
[535] Cyclic- [1-phenylpropane-1,3-diyl] diester;
[536] Cyclic- [1- (2-pyridyl) propane-1,3-diyl] diester;
[537] Cyclic- [1- (3-pyridyl) propane-1,3-diyl] diester;
[538] Cyclic- [1- (4-pyridyl) propane-1,3-diyl] diester;
[539] Cyclic- [5-hydroxycyclohexane-1,3-diyl] diester and hydroxy protected form;
[540] Bis-benzoyl thiomethyl ester;
[541] Bis-benzoyl thioethyl ester;
[542] Bis-benzoyloxymethyl esters;
[543] Bis-p-fluorobenzoyloxymethyl ester;
[544] Bis-6-chloronicotinoyloxymethyl ester;
[545] Bis-5-bromonocotinoyloxymethyl ester;
[546] Bis-thiophenecarbonyloxymethyl esters;
[547] Bis-2-furoyloxymethyl ester;
[548] Bis-3-furoyloxymethyl ester;
[549] Diphenyl esters;
[550] Bis- (4-methoxyphenyl) ester;
[551] Bis- (2-methoxyphenyl) ester;
[552] Bis- (2-ethoxyphenyl) esters;
[553] Mono- (2-ethoxyphenyl) ester;
[554] Bis- (4-acetamidophenyl) ester;
[555] Bis- (4-acetoxyphenyl) ester;
[556] Bis- (4-hydroxyphenyl) ester;
[557] Bis- (2-acetoxyphenyl) esters;
[558] Bis- (3-acetoxyphenyl) ester;
[559] Bis- (4-morpholinophenyl) esters;
[560] Bis- [4- (1-triazolophenyl)] ester;
[561] Bis- (3-N, N-dimethylaminophenyl) ester;
[562] Bis- (1,2,3,4-tetrahydronaphthalen-2-yl) ester;
[563] Bis- (3-chloro-4-methoxy) benzyl ester;
[564] Bis- (3-bromo-4-methoxy) benzyl ester;
[565] Bis- (3-cyano-4-methoxy) benzyl ester;
[566] Bis- (3-chloro-4-acetoxy) benzyl ester;
[567] Bis- (3-bromo-4-acetoxy) benzyl ester;
[568] Bis- (3-cyano-4-acetoxy) benzyl ester;
[569] Bis- (4-chloro) benzyl ester;
[570] Bis- (4-acetoxy) benzyl ester;
[571] Bis- (3,5-dimethoxy-4-acetoxy) benzyl ester;
[572] Bis- (3-methyl-4-acetoxy) benzyl ester;
[573] Bis- (benzyl) esters;
[574] Bis- (3-methoxy-4-acetoxy) benzyl ester;
[575] Bis- (6'-hydroxy-3 ', 4'-dithia) hexyl ester;
[576] Bis- (6'-acetoxy-3 ', 4'-dithia) hexyl ester;
[577] (3,4-dithiahexane-1,6-diyl) ester;
[578] Bis- (5-methyl-1,3-dioxolen-2-one-4-yl) methyl ester;
[579] Bis- (5-ethyl-1,3-dioxolen-2-one-4-yl) methyl ester;
[580] Bis- (5-tert-butyl-1,3-dioxolen-2-one-4-yl) methyl ester;
[581] Bis-3- (5,6,7-trimethoxy) phthalidyl ester;
[582] Bis- (cyclohexyloxycarbonyloxymethyl) ester;
[583] Bis- (isopropyloxycarbonyloxymethyl) esters;
[584] Bis- (ethyloxycarbonyloxymethyl) esters;
[585] Bis- (methyloxycarbonyloxymethyl) ester;
[586] Bis- (isopropylthiocarbonyloxymethyl) ester;
[587] Bis- (phenyloxycarbonyloxymethyl) esters;
[588] Bis- (benzyloxycarbonyloxymethyl) esters;
[589] Bis- (phenylthiocarbonyloxymethyl) esters;
[590] Bis- (p-methoxyphenoxycarbonyloxymethyl) ester;
[591] Bis- (m-methoxyphenoxycarbonyloxymethyl) ester;
[592] Bis- (o-methoxyphenoxycarbonyloxymethyl) ester;
[593] Bis- (o-methylphenoxycarbonyloxymethyl) ester;
[594] Bis- (p-chlorophenoxycarbonyloxymethyl) ester;
[595] Bis- (1,4-biphenoxycarbonyloxymethyl) ester;
[596] Bis - [(2-phthalimidoethyl) oxycarbonyloxymethyl] ester;
[597] Bis- (N-phenyl-N-methylcarbamoyloxymethyl) ester;
[598] Bis- (2,2,2-trichloroethyl) esters;
[599] Bis- (2-bromoethyl) ester;
[600] Bis- (2-iodoethyl) esters;
[601] Bis- (2-azidethyl) ester;
[602] Bis- (2-acetoxyethyl) ester;
[603] Bis- (2-aminoethyl) ester;
[604] Bis- (2-N, N-dimethylaminoethyl) ester;
[605] Bis- (2-aminoethyl) ester;
[606] Bis- (methoxycarbonylmethyl) esters;
[607] Bis- (2-aminoethyl) ester;
[608] Bis- [N, N-di (2-hydroxyethyl)] carbamoyl methyl ester;
[609] Bis- (2-aminoethyl) ester;
[610] Bis- (2-methyl-5-thiazolomethyl) ester;
[611] Bis- (bis-2-hydroxyethylcarbamoylmethyl) ester,
[612] (O) (N (H) -CH (Me) CO ₂ Et), O-phenyl- [N- (1- ethoxycarbonyl) ethyl] phosphoramidate
[613] (N (H) -CH (Me) CO ₂ Me), O-phenyl- [N- (1-methoxycarbonyl) ethyl] phosphoramidate
[614] O- (3- chlorophenyl) - [N- ethyl (1-ethoxycarbonyl)] phosphoramidate (-P (O) (OPh- 3-Cl) (NH-CH (Me) CO 2 Et) ,
[615] O- (2- chlorophenyl) - [N- ethyl (1-ethoxycarbonyl)] phosphoramidate (-P (O) (OPh- 2-Cl) (NH-CH (Me) CO 2 Et) ,
[616] O- (4- chlorophenyl) - [N- ethyl (1-ethoxycarbonyl)] phosphoramidate (-P (O) (OPh- 4-Cl) (NH-CH (Me) CO 2 Et) ,
[617] (OP-4-NHAc) (NH-CH (Me) CO ₂ (-P (O) Et),
[618] (OP-2-CO ₂ Et) (NH-CH (Me (2-ethoxycarbonylphenyl) - [N- (1- ethoxycarbonyl) ethyl] phosphoramidate ) CO ₂ Et),
[619] O- phenyl - [N- (1-ethoxycarbonyl-1-methyl) ethyl] phosphoramidate (-P (O) (OPh) (NH-C (Me) 2 CO 2 Et),
[620] O- phenyl - [N- (1- methoxycarbonyl-1-methyl) ethyl] phosphoramidate (-P (O) (OPh) (NH-C (Me) 2 CO 2 Me),
[621] (OP-3-Cl) (NH-C (Me)) (O-P (O) ₂ CO ₂ Et),
[622] (OP-2-Cl) (NH-C (Me) 2), and the like. ₂ CO ₂ Et),
[623] (OPh-4-Cl) (NH-C (Me)) (- P (O) ₂ CO ₂ Et),
[624] (OP-4-NHAc) (NH-C (O) - (4-acetamidophenyl) - [N- (1-ethoxycarbonyl- Me) ₂ CO ₂ Et),
[625] (OPh-2-CO ₂ Et) (NH (CH3) 2) in the presence of a catalyst such as N, N-dimethylaminopyridine, O- (2-ethoxycarbonylphenyl) - [N- (1-ethoxycarbonyl- -C (Me) ₂ CO ₂ Et),
[626] O-phenyl- [N- (ethoxycarbonyl) methyl] phosphoramidate (-P (O) (OPh) (NH-CH ₂ CO ₂ Et)
[627] O-phenyl- [N- (methoxycarbonyl) methyl] phosphoramidate (-P (O) (OPh) (NH-CH ₂ CO ₂ Me)
[628] (OP-3-Cl) (NH-CH ₂ CO ₂ Et), (O-P (O)
[629] (OP-2-Cl) (NH-CH ₂ CO ₂ Et), (O-P (O)
[630] (OP-4-Cl) (NH-CH ₂ CO ₂ Et), (O-P (O)
[631] (OP-4-NHAc) (NH-CH ₂ CO ₂ Et), - (4-acetamidophenyl) - [N- (ethoxycarbonyl) methyl] phosphoramidate
[632] (OP-2-CO ₂ Et) (NH-CH ₂ CO ₂ Et (-P (O) ).
[633] The following compounds are most preferred:
[634] Bis-pivaloyloxymethyl esters;
[635] Bis-isobutyryloxymethyl ester;
[636] Cyclic- [1- (3-chlorophenyl) propane-1,3-diyl] diester;
[637] Cyclic- [1- (3,5-dichlorophenyl) propane-1,3-diyl] diester;
[638] Cyclic- [1- (3-bromo-4-fluorophenyl) propane-1,3-diyl] diester;
[639] Cyclic- (2-hydroxymethylpropane-1,3-diyl) ester;
[640] Cyclic- (2-acetoxymethylpropane-1,3-diyl) ester;
[641] Cyclic- (2-methyloxycarbonyloxymethylpropane-1,3-diyl) ester;
[642] Cyclic- (2-cyclohexylcarbonyloxymethylpropane-1,3-diyl) ester;
[643] Cyclic- [henylpropane-1,3-diyl] diester;
[644] Cyclic- [1- (2-pyridyl) propane-1,3-diyl] diester;
[645] Cyclic- [1- (3-pyridyl) propane-1,3-diyl] diester;
[646] Cyclic- [1- (4-pyridyl) propane-1,3-diyl] diester;
[647] Cyclic- [5-hydroxycyclohexane-1,3-diyl] diester and hydroxy protected form;
[648] Bis-benzoyl thiomethyl ester;
[649] Bis-benzoyl thioethyl ester;
[650] Bis-benzoyloxymethyl esters;
[651] Bis-p-fluorobenzoyloxymethyl ester;
[652] Bis-6-chloronicotinoyloxymethyl ester;
[653] Bis-5-bromonocotinoyloxymethyl ester;
[654] Bis-thiophenecarbonyloxymethyl esters;
[655] Bis-2-furoyloxymethyl ester;
[656] Bis-3-furoyloxymethyl ester;
[657] Diphenyl esters;
[658] Bis- (2-methylphenyl) esters;
[659] Bis- (2-methoxyphenyl) ester;
[660] Bis- (2-ethoxyphenyl) esters;
[661] Bis- (4-methoxyphenyl) ester;
[662] Bis- (3-bromo-4-methoxybenzyl) ester;
[663] Bis- (4-acetoxybenzyl) ester;
[664] Bis- (3,5-dimethoxy-4-acetoxybenzyl) ester;
[665] Bis- (3-methyl-4-acetoxybenzyl) ester;
[666] Bis- (3-methoxy-4-acetoxybenzyl) ester;
[667] Bis- (3-chloro-4-acetoxybenzyl) ester;
[668] Bis- (cyclohexyloxycarbonyloxymethyl) ester;
[669] Bis- (isopropyloxycarbonyloxymethyl) esters;
[670] Bis- (ethyloxycarbonyloxymethyl) esters;
[671] Bis- (methyloxycarbonyloxymethyl) ester;
[672] Bis- (isopropylthiocarbonyloxymethyl) ester;
[673] Bis- (phenyloxycarbonyloxymethyl) esters;
[674] Bis- (benzyloxycarbonyloxymethyl) esters;
[675] Bis- (phenylthiocarbonyloxymethyl) esters;
[676] Bis- (p-methoxyphenoxycarbonyloxymethyl) ester;
[677] Bis- (m-methoxyphenoxycarbonyloxymethyl) ester;
[678] Bis- (o-methoxyphenoxycarbonyloxymethyl) ester;
[679] Bis- (o-methylphenoxycarbonyloxymethyl) ester;
[680] Bis- (p-chlorophenoxycarbonyloxymethyl) ester;
[681] Bis- (1,4-biphenoxycarbonyloxymethyl) ester;
[682] Bis - [(2-phthalimidoethyl) oxycarbonyloxymethyl] ester;
[683] Bis- (6-hydroxy-3,4-dithia) hexyl ester;
[684] Cyclic- (3,4-dithiahexane-1,6-diyl) ester;
[685] Bis- (2-bromoethyl) ester;
[686] Bis- (2-aminoethyl) ester;
[687] Bis- (2-N, N-diaminoethyl) esters;
[688] O- phenyl - [N- ethyl (1-ethoxycarbonyl)] phosphoramidate (-P (O) (OPh) (NH- * CH (Me) CO 2 Et),
[689] O- phenyl - [N- (1- methoxycarbonyl) ethyl] phosphoramidate (-P (O) (OPh) (NH- * CH (Me) CO 2 Me),
[690] O- (3- chlorophenyl) - [N- ethyl (1-ethoxycarbonyl)] phosphoramidate (-P (O) (OPh- 3-Cl) (NH- * CH (Me) CO 2 Et ),
[691] (OP-2-Cl) (NH- ^* CH (Me) CO ₂ Et (-P (O) ),
[692] (OP-4-Cl) (NH- ^* CH (Me) CO ₂ Et (-P (O) ),
[693] O- (4- acetamido-phenyl) - [N- ethyl (1-ethoxycarbonyl)] phosphoramidate (-P (O) (OPh- 4-NHAc) (NH- * CH (Me) CO ₂ Et),
[694] (OP-2-CO ₂ Et) (NH- ^* CH ((O) - (2-ethoxycarbonylphenyl) - [N- (1- ethoxycarbonyl) ethyl] phosphoramidate Me) CO ₂ Et),
[695] O- phenyl - [N- (1-ethoxycarbonyl-1-methyl) ethyl] phosphoramidate (-P (O) (OPh) (NH-C (Me) 2 CO 2 Et),
[696] O- phenyl - [N- (1- methoxycarbonyl-1-methyl) ethyl] phosphoramidate (-P (O) (OPh) (NH-C (Me) 2 CO 2 Me),
[697] (OP-3-Cl) (NH-C (Me)) (O-P (O) ₂ CO ₂ Et),
[698] (OP-2-Cl) (NH-C (Me) 2), and the like. ₂ CO ₂ Et),
[699] (OPh-4-Cl) (NH-C (Me)) (- P (O) ₂ CO ₂ Et),
[700] (OP-4-NHAc) (NH-C (O) - (4-acetamidophenyl) - [N- (1-ethoxycarbonyl- Me) ₂ CO ₂ Et),
[701] (OPh-2-CO ₂ Et) (NH (CH3) 2) in the presence of a catalyst such as N, N-dimethylaminopyridine, O- (2-ethoxycarbonylphenyl) - [N- (1-ethoxycarbonyl- _{-C (Me) 2 CO 2 Et} ).
[702] In the above text, an asterisk ( ^* ) on the carbon indicates the L-configuration.
[703] O-phenyl- [N- (ethoxycarbonyl) methyl] phosphoramidate (-P (O) (OPh) (NH-CH ₂ CO ₂ Et)
[704] O-phenyl- [N- (methoxycarbonyl) methyl] phosphoramidate (-P (O) (OPh) (NH-CH ₂ CO ₂ Me)
[705] (OP-3-Cl) (NH-CH ₂ CO ₂ Et), (O-P (O)
[706] (OP-2-Cl) (NH-CH ₂ CO ₂ Et), (O-P (O)
[707] (OP-4-Cl) (NH-CH ₂ CO ₂ Et), (O-P (O)
[708] (OP-4-NHAc) (NH-CH ₂ CO ₂ Et), - (4-acetamidophenyl) - [N- (ethoxycarbonyl) methyl] phosphoramidate
[709] (OP-2-CO ₂ Et) (NH-CH ₂ CO ₂ Et (-P (O) ).
[710] R ⁵ is thiazolyl, oxazolyl, Selena pyridazinyl, pyrazolyl, imidazolyl, isoxazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazole Compounds of formula (I) wherein Z is aryl, pharmaceutically acceptable salts thereof and all clauses thereof are preferred. These preferred compounds are of the formulas (i) to (iv):
[711]
[712]
[713]
[714]
[715] Preferred compounds are shown in Table 1 according to the following scheme by the number given to the A, B, X and Y 'residues of the above formulas (i) - (iv). For each residue, the structural formula is given to the numbers shown in the following table for A, B, X, and Y '. The following terms are used: Pr-c is cyclopropyl, Pr-n is n-propyl, Pr-i is isopropyl, Bu-n is n-butyl, Bu- c is cyclobutyl, Bu-s is sec-butyl, Bu-t is tert-butyl and hexyl-c is cyclohexyl.
[716] The variable A is selected from seven different substituents:
[717] A period is given by the following number.
[718]
[719] Variable B is divided into four groups each containing nine different substituents.
[720] Group 1 substituents for variable B are given the following numbers:
[721]
[722] Group 2 substituents for variable B are given the following numbers:
[723]
[724] Group 3 substituents for variable B are given in the following numbers:
[725]
[726] Group 4 substituents for variable B are given in the following numbers:
[727]
[728] The variable X is selected from 9 different substituents.
[729] X groups are assigned the following numbers:
[730]
[731] The direction of the X group is defined to be from the heterocycle to the phosphorus atom in formulas (i), (ii), (iii) and (iv).
[732] The variable Y 'is selected from six different substituents.
[733] Y 'groups are assigned the following numbers:
[734]
[735]
[736]
[737]
[738]
[739]
[740]
[741]
[742]
[743] Thus, the compounds named in Table 1 of formula (i) having -S- as Y 'are compounds having thiazolyl as R ⁵ in formula (I). For example, a compound named as 2.6.1.1 using group 1 for variable B can be prepared by reacting -NH ₂ as A, -Pr-c as B, furan-2,5-diyl as X and Y ' S-, and this compound is 2-amino-5-cyclopropyl-4- [2- (5-phosphono) furanyl] thiazole prepared in Example 3 as compound 3.27. Similarly, the compounds named in Table 1 of formula (i) having -O- as Y 'are compounds having oxazolyl as R ⁵ in formula (I). For example, the compound named as 2.4.1.2 in Table 1 of formula (i) using group 1 for variable B is 2-amino-5-propyl-4- [2 - (phosphono) furanyl] oxazole. Similarly, a compound named in Table 1 of formula (i) having -Se- as Y 'is a compound having selenazolyl as R ⁵ in formula (I). Thus, the compound named as 2.3.1.3 in Table 1 of formula (i) using group 1 for variable B is 2-amino-5-ethyl-4- [2- 5-phosphono) furanyl] selenazole.
[744] Likewise, the compound named as 2.8.1.1 in Table 1 of formula (i) using Group 2 for Variant B was prepared from 2-amino-5-methylthio-4- [2- (5-phosphono) furanyl] thiazole. The compound named as 2.9.1.1 in Table 1 of formula (i) using Group 3 for Variable B was prepared from 2-amino-5-isobutyl-4- [2- (5 -Phosphono) furanyl] thiazole. &Lt; / RTI &gt;
[745] The compound named as 2.6.1.1 in Table 1 of formula (i) using Group 4 for Variable B was prepared from 2-amino-5- (2-thienyl) -4- [ 2- (5-phosphono) furanyl] thiazole.
[746] Some exemplary embodiments of compounds named in Table 1 using groups 1-4 for variable B in the compounds of formulas (i), (ii), (iii) and (iv) .
[747]
[748]
[749] Preferred are the compounds of formula I, wherein R &lt; ⁵ &gt; is pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, a pharmaceutically acceptable salt thereof and a precursor thereof. These preferred compounds are of the formulas (v) to (ix) below.
[750]
[751]
[752]
[753]
[754]
[755] Preferred compounds are listed in Table 3 by the numbering given in A, B, X, D and E of the above formulas (v) to (ix) according to the scheme (A.B.X.D.E). For compounds of formula (vi), D is absent and represented as number 0, for compounds of formula (vii), E is absent and represented as number 0, and for compounds of formula (viii) Does not exist and is indicated as the number 0. For example, all compounds named in Table 3 of formula (vi) are assigned as ABX0.E, and all compounds named in table 3 of formula (vii) are given as ABXD0 and the formula (viii) All compounds named in Table 3 are assigned as A.0.XDE and all compounds named in Table 3 of formula (ix) are assigned as 0.BXDE. For each residue, the structural formula is given to the numbers shown in the following table for A, B, X, D and E.
[756] The variable A is selected from eight different substituents.
[757] The A group is assigned the following number:
[758]
[759] Variable B is divided into four groups each containing eight different substituents.
[760] Group 1 substituents for variable B are given the following numbers:
[761]
[762] Group 2 substituents for variable B are given the following numbers:
[763]
[764] Group 3 substituents for variable B are given in the following numbers:
[765]
[766] Group 4 substituents for variable B are given in the following numbers:
[767]
[768] The variable X is divided into two groups each representing four different substituents.
[769] Group 1 substituents for variable X are given in the following numbers:
[770]
[771] The direction of the X group is defined as from the heterocycle to the phosphorus atom in the formulas (v), (vi), (vii), (viii) and (ix).
[772] Group 2 substituents for variable X are given in the following numbers:
[773]
[774] Variable D is divided into two groups, each containing eight different substituents.
[775] D groups are assigned the following numbers:
[776]
[777] Group 2 substituents for variable D are given in the following numbers:
[778]
[779] The variable E is divided into three groups, each of which describes four different substituents.
[780] Group 1 substituents for variable E are given in the following numbers:
[781]
[782] Group 2 substituents for variable E are given in the following numbers:
[783]
[784] Group 3 substituents for variable E are given the following numbers:
[785]
[786]
[787]
[788]
[789]
[790]
[791]
[792]
[793]
[794]
[795]
[796]
[797]
[798]
[799]
[800]
[801]
[802]
[803]
[804]
[805]
[806]
[807]
[808]
[809]
[810] Thus, each of the variables A, B, X, the compound named in Table 3 of formula (v) having the substituents named as 2.4.1.1.1 from Group 1 of D and E is -NH ₂ as A, a B - 5-diyl as X, -H as D, and -H as E, which compounds are prepared by reacting 2-amino-5-propyl-6- [2- (5-phosphono) furanyl] pyridine. The compounds named in Table 3 of formula (v) are compounds having pyridinyl as R ⁵ in formula (I). Similarly, the compounds named as 2.1.1.1.3 in Table 3 of formula (v) using a group of substituents of each of the variables A, B, X, D and E are 2-amino- 6- [2- (5-Phosphono) furanyl] pyridine and was prepared as compound 15.12 in Example 15.
[811] The compounds named in Table 3 of formula (vi) are compounds having pyrazinyl as R &lt; ⁵ &gt; in formula (I). One of the preferred pyrazinyl compounds named in Table 3 of formula (vi) is 2.1.1.0.4. 2.1.1.0.4 using a group of each variable has the structure of 2-amino-3-propyl-6- [2- (phosphono) furanyl] pyrazine and was prepared as compound 17.3 in Example 17. Similarly, the compounds named in Table 3 of formula (vii) are compounds having pyrimidinyl as R ⁵ in formula (I). The compound of formula (vii), designated as 2.4.1.1.0 in Table 3, using all the first group of variables, has the structure of 2-amino-5-propyl-6- [2- (phosphono) furanyl] pyrimidine And was prepared as compound 16.1 in Example 16. Similarly, the compounds named in Table 3 of formula (viii) are compounds having pyrimidinyl as R ⁵ in formula (I). Thus, using the first group of variables, the compound named as 1.0.1.1.1 in Table 3 had the structure of 2- [2- (5-phosphono) furanyl] pyrimidine and was prepared as compound 16.5 in Example 16 .
[812] In the compounds of formulas (v), (vi), (vii), (viii) and (ix), groups 1 to 4 for variable B, groups 1 to 2 for variable X, groups 1 to 2 for variable D, Some exemplary embodiments of the compounds named in Table 3 using groups 1 to 3 for variable E are set forth in Table 4 below.
[813]
[814]
[815]
[816]
[817] In addition, the numbers shown in Table 3 refer to the preferred benzothiazole and benzoxazole compounds of formula (X). These preferred compounds are of the formulas (x) and (xi).
[818]
[819]
[820] Preferred compounds of formulas (x) and (xi) are shown in Table 3 by the number given in B, X, A, D and E of formulas (x) to (xi) above according to scheme (BXADE) . For each residue, the structural formula is given to the numbers shown in the following table for B, X, A, D and E.
[821] Variable B is divided into two groups each containing eight different substituents.
[822] In Table 3, the substituents for the variable B of the formulas (x) and (xi) are given the following numbers:
[823] For groups (x) and (xi), a group of substituents for variable B in Table 3 are given the following numbers:
[824]
[825] Group 2 substituents for variable B are given the following numbers:
[826]
[827] The variable X is selected from eight different substituents attached by the numbers below.
[828]
[829] The orientation of the X group is defined to be from the heterocycle to the phosphorus atom in formulas (x) and (xi).
[830] Variable A is selected from four different substituents attached by the numbers below.
[831]
[832] Variable D is selected from eight different substituents appended by the numbers below.
[833]
[834] Variable E is selected from four different substituents assigned the following numbers.
[835]
[836] Thus, the compounds of formula (x) named 1.1.2.1.1 in Table 3 using group 1 for variable B include -H as B, -OCH ₂ - as X, -NH ₂ as A, H and E, and this compound is 2-amino-4-phosphonomethoxybenzothiazole, which is prepared as compound 34.2 in Example 34. Similarly, the compounds of using the group 1 for variable B of formula (x) named in Table 3 as 1.2.2.1.1 B is a -SCH ₂ as -H, X - a, A -NH _2, D And -H as E, which compound is 2-amino-4-phosphonomethylthiobenzothiazole, prepared as compound 46.1 in Example 46.
[837] Likewise, using group 2 for variable B, the compound of formula (x) named 8.1.2.1.1 in Table 3 was prepared from 2-amino-7-ethoxycarbonyl-4 -Phosphonomethoxybenzothiazole. &Lt; / RTI &gt;
[838] Examples of preferred compounds of formula X include, but are not limited to, the pharmaceutically acceptable salts of compounds named in Table 5 and the precursors.
[839]
[840]
[841]
[842]
[843]
[844] In addition, the numbers shown in Table 1 represent preferred compounds of the compounds of formula (I) represented by the following formulas (xii) and (xiii).
[845]
[846]
[847] In the above formulas (xii) and (xiii), Ar represents aryl including heteroaryl and is substituted with R ²⁵ . Preferred compounds of formulas (xii) and (xiii) are those represented by the numbers given to X, R ⁵ , R ²⁵ and Ar in formulas (xii) and (xiii) according to scheme (XR ⁵ R ²⁵ .Ar) 1 &lt; / RTI &gt;
[848] The variable X is selected from seven different substituents given by the following numbers:
[849]
[850] The variable R &lt; ⁵ &gt; is selected from 9 different substituents attached with the following numbers:
[851]
[852]
[853] The variable R &lt; ²⁵ &gt; is selected from 9 different substituents attached with the following numbers:
[854]
[855] The variable Ar is selected from six different substituents given by the following numbers:
[856]
[857] The compounds named in Table 1 of the formula (xii) or (xiii) in each of which the numbers are in Table 1 of the formula (xii) or (xiii) are stereochemically expressed as stereoisomeric mixtures or single stereoisomers since they are biologically active. .
[858] X, R ^5, R ^25, and using the parameters for the Ar The compound of formula (xii) named 1.2.2.2 in Table 1 as a furan-2,5-diyl, 4- (2-amino as R ⁵ as X -5-isobutyl) thiazolyl, chloro as R ²⁵ and 3-chlorophenyl as Ar, which compounds are prepared from 2-amino (2-aminoethyl) -5-isobutyl-4- {2- [5- (1- (3-chlorophenyl) -1,3-propyl) phosphono] furanyl} thiazole.
[859] In addition, the numbers shown in Table 3 represent preferred compounds of the compounds of formula (I) shown below in formulas (xiv) and (xv).
[860]
[861]
[862] In the compounds of formulas (xiv) and (xv) above, Ar represents aryl and heteroaryl and is substituted by R ²⁵ . Formula (xiv) and (xv) a preferred compound is the way ^{(R 5 .R 23 .Ar.R 25 .X} ) the formula (xiv) and (xv) R ^5, R ^23, Ar, R in accordance with the ²⁵ and the Lt; RTI ID = 0.0 &gt; X &lt; / RTI &gt; For each of the residues, the structural formula is given to the numbers shown in the following table for R ⁵ , R ²³ , Ar, R ²⁵ and X.
[863] The variable R &lt; ⁵ &gt; is selected from eight different substituents attached with the following numbers:
[864]
[865]
[866] The variable R &lt; ²³ &gt; is selected from eight different substituents attached with the following numbers:
[867]
[868]
[869] The variable Ar is selected from four different substituents assigned the following numbers.
[870]
[871] The variable R &lt; ²⁵ &gt; is selected from eight different substituents attached by the numbers below.
[872]
[873] The variable X is selected from four different substituents attached by the numbers below.
[874]
[875] ^{Thus, R 5, R 23, Ar} , R 25 and using a variable X for the compound of formula (viv) named in Table 3 as 2.7.2.2.1 as R ⁵ 4- (2- amino-5 Isobutyl) thiazolyl, -CH (Me) CO ₂ Me as R ²³ , 3-chlorophenyl as Ar, chloro as R ²⁵ and furan-2,5-diyl as X, Amino-5-isobutyl-4- {2- [5- (O-phenyl-N- (1- (1-methoxycarbonyl) ethyl) phosphono] furanyl} thia boil down.
[876] In addition, the numbers shown in Table 3 represent preferred compounds of the compounds of formula (I) shown in the following formulas (xvi) and (xvii).
[877]
[878]
[879] In the compounds of formulas (xvi) and (xvii), Ar represents aryl containing heteroaryl and is substituted by R ²⁴ and R ²⁵ . Preferred compounds of formulas (xvi) and (xvii) are the compounds given in R ²⁴ , R ²⁵ , Ar, R ⁵ and R ²³ in the above formula according to the scheme (R ²⁴ .R ²⁵ .Ar.R ⁵ .R ²³ ) Lt; / RTI &gt; For each of the residues, the structural formula is given to the numbers shown in the following table for R ²⁴ , R ²⁵ , Ar, R ^5, and R ²³ .
[880] The variable R &lt; ²⁴ &gt; is selected from eight different substituents attached with the following numbers:
[881]
[882] The variable R &lt; ²⁵ &gt; is selected from eight different substituents attached with the following numbers:
[883]
[884] The variable Ar is divided into two groups each representing four different substituents. Group 1 substituents for the variable Ar are given in the following numbers:
[885]
[886] Group 2 substituents for the variable Ar are given in the following numbers:
[887]
[888] The variable R &lt; ⁵ &gt; is selected from eight different substituents attached by the numbers below.
[889]
[890]
[891] The variable R &lt; ²³ &gt; is subdivided into two groups, each with four different substituents listed. A group of substituents for the variable R &lt; ²³ &gt;
[892]
[893] Group 2 substituents for the variable R &lt; ²³ &gt; are given the following numbers:
[894]
[895] The variable R &lt; ⁵ &gt; is selected from eight different substituents attached by the numbers below.
[896]
[897]
[898] The variable X is selected from four different substituents attached by the numbers below.
[899]
[900] In addition, preferred examples of compounds of the formula (I) shown in the formula (xi) are shown in Table 6 below.
[901] R &lt; ⁵ &gt; -X-P &
[902] Preferred compounds of formula (xix) are described in Table 6, numbered P ', R ⁵ and X in formula (xix) above according to scheme (P'.R ⁵ .X.). For each residue, the structural formula is given to the numbers shown in the following table for P ', R ^5, and X.
[903] The variable P 'is divided into two groups, each of which describes seven different substituents. Group 1 substituents for the variable P 'are given by the following numbers:
[904]
[905]
[906] Group 2 substituents for the variable P 'are given the following numbers:
[907]
[908]
[909] The variable R &lt; ⁵ &gt; is selected from the nine different substituents appended below.
[910]
[911]
[912] The variable X is selected from six different substituents assigned the following numbers.
[913]
[914]
[915] In addition, the numbers shown in Table 1 represent preferred compounds of the compounds of formula X shown in formula (xx) below.
[916]
[917] In the above formula (xx), Ar represents aryl containing heteroaryl and is substituted with R ²⁵ . Preferred compounds of formula (xx) are shown in Table 1, numbered Ar ', R ²⁵ , R ²³ and Ar according to scheme (Ar'.R ²⁵ .R ²³ .Ar). For each residue, the structural formulas are given in the numbers given in the following table for Ar ', R ²⁵ , R ²³ and Ar, wherein R ²⁵ is a substituent bonded to Ar.
[918] The variable Ar ' is selected from 7 different substituents attached with the following numbers:
[919]
[920]
[921] The variable R &lt; ²⁵ &gt; is selected from 9 different substituents attached by the numbers below.
[922]
[923] The variable R &lt; ²³ &gt; is selected from six different substituents assigned the following numbers.
[924]
[925]
[926] The variable Ar is selected from 9 different substituents attached by the numbers below.
[927]
[928] In addition, the numbers shown in Table 6 represent preferred compounds of the compounds of formula X shown in the following formula (xxi).
[929]
[930] In the above formula (xxi), Ar represents aryl containing heteroaryl and is substituted by R ²⁵ . Preferred compounds of formula (xxi) are listed in Table 6 according to the indicated method (Ar'.R ²⁵ .Ar) to the numbers assigned to Ar ', R ²⁵ and Ar. For each of the residues, the structural formula is given to the numbers shown in the following table for Ar ', R ²⁵ and Ar.
[931] The variable Ar ' is selected from 7 different substituents attached with the following numbers:
[932]
[933]
[934] The variable R &lt; ²⁵ &gt; is selected from 9 different substituents attached by the numbers below.
[935]
[936] The variable Ar is selected from six different substituents given by the numbers below.
[937]
[938]
[939]
[940] In addition, the numbers shown in Table 6 represent preferred compounds of the compounds of formula X shown in formula (xxii) below.
[941]
[942] Preferred compounds of formula (xxii) are depicted in Table 6, numbered according to scheme (P'.R'.R ") assigned to P ', R' and R". For each residue, a structural formula is given to the numbers shown in the following table for P ', R' and R ".
[943] The variable P 'is divided into two groups, each of which describes seven different substituents. Group 1 substituents for the variable P 'are given by the following numbers.
[944] Group 2 substituents for the variable P 'are given the following numbers:
[945]
[946]
[947] The variable R ' is selected from the nine different substituents appended below.
[948]
[949] The variable R " is selected from six different substituents given the numbers below.
[950]
[951] Section 1
[952] Synthesis of Compounds of Formula I
[953] The synthesis of the compounds according to the invention typically involves some or all of the following general steps: (1) Preparation of phosphonate precursor; (2) deprotection of phosphonate esters; (3) modification of the heterocycle; (4) Coupling of the heterocycle with the phosphonate component; (5) construction of a heterocycle; (6) cyclization for the formation of a heterocycle by an existing phosphonate group and (7) preparation of useful intermediates. These steps are illustrated by the following scheme for a compound of formula I wherein R &lt; ⁵ &gt; is a 5-membered heteroaromatic ring. Compounds of formula (I) wherein R &lt; ⁵ &gt; is a 6-membered heteroaromatic ring or other heteroaromatic ring are prepared in a similar manner. The present methods are also generally applicable to compounds of formula I wherein all of the groups Y are not -O.
[954]
[955]
[956] (1) Preparation of phosphonate derivatives
[957] The entire Old Testament can be introduced at different stages of synthesis. Most of these full-texts are made mainly from the phosphonic acids of formula (2) because of their tendency. Advantageously, these agrochemicals can be derived in the initial stage, provided that they can withstand the reaction conditions in the next step.
[958] The compound of formula (2) may be alkylated with an electrophilic group (e.g., alkyl halide, alkyl sulfonate, etc.) under nucleophilic substitution reaction conditions to yield a phosphonate ester. For example, compounds of formula (I) wherein R &lt; ¹ &gt; is an acyloxyalkyl group may be prepared by reacting a compound of formula I with a suitable base such as, for example, 1,1-dimethylformamide ("DMF") (Starrett, et al, J. Med. 1857) in the presence of a suitable base (e.g., N, N'-dicyclohexyl-4-morpholinecarboximidine, triethylamine, Hunig's base, etc.) in the presence of a suitable acyloxyalkyl halide Can be synthesized by direct alkylation of the compound of formula (2) with Cl, Br, I; Elhaddadi, et al Phosphorus Sulfur, 1990, 54 (1-4): 143; Hoffmann, Synthesis, 1988,62. The carboxylate components of these acyloxyalkyl halides include, but are not limited to, acetate, propionate, isobutyrate, pivalate, benzoate, and other carboxylates. Suitably, further modifications, for example oxidation of the nitro group, can be effected after the formation of these acyloxyalkylphosphonate esters. For example, a compound of formula 3 wherein A is a NO ₂ group can be converted to the corresponding compound of formula 3 by appropriate reduction conditions (Dickson, et al., J. Med. Chem., 1996, 39: 661; Iyer, et al., Tetrahedron Lett. ; Srivastva, et al., Bioorg. Chem., 1984, 12: 118) can be converted to compounds of formula 3 wherein A is a H ₂ N group. These methods include the preparation of compounds of formula I wherein R &lt; ^{1 &gt;} is 3-phthalidyl, 2-oxo-4,5-didehydro- It is possible to develop another form of synthesis of the Old Testament (Biller et al., US 5,157,027; Serafinowska et al., J. Med. Chem. 1995 , 38: 1372; Starrett, et al., J. Med. Alexander et al., Collect. Czech. Chem. Commun., 1994, 59: 1853; EPO 0632048A1). N, N-dimethylformamide dialkyl acetals may also be used in the alkylate phosphonic acid (Alexander et al., Collect. Czech. Chem. Commun., 1994, 59: 1853). Compounds of formula I wherein R &lt; ¹ &gt; is a cyclic carbonate, lactone or phthalidyl group may also be treated with a suitable base such as NaH or diisopropylethylamine, Biller et al., US 5,157,027; Serafinowska et al., J Martin et al., J. Pharm. Sci . 1987, 76: 180; Alexander et al., J. Med. Chem . 1995, 38: 1372; , Collect. Czech. Chem. Commun., 1994, 59: 1853; EPO 0632048A1).
[959] Alternatively, these phosphonates may also be synthesized by the reaction of an alcohol (Alexander et al., Collect. Czech. Chem. Commun., 1994, 59: 1853) with the corresponding dichlorophosphonate. For example, base (e.g., pyridine, triethylamine, etc.) reaction of the phenols and aralkyl alcohols substituted with dichloro-phosphonate in the presence of the R ¹ is an aryl group (Khamnei et al., J. Med. Chem. , 1994, 37: 498) or an arylalkyl group (Mitchell et al., &Lt; RTI ID = 0.0 &gt; , J. Chem. Soc. Perkin Trans. 1, 1992, 38: 2345). Disulfide containing agrochemicals (Puech et al., Antiviral Res., 1993, 22: 155) can also be prepared from dichlorophosphonate and 2-hydroxyethyl disulfide under normal conditions. Dichlorophosphonate is also useful as a whole in the preparation of various phosphoramides. For example, treatment of dichlorophosphonate with ammonia yields both monophosphonamide and diphosphonamide; Treatment of dichlorophosphonate with 1-amino-3-propanol affords cyclic 1,3-propylphosphonamide; Treatment of the chlorophosphonate monophenyl ester with an amino acid ester in the presence of a suitable base yields a substituted monophenyl monophosphonamidate.
[960] The reactive dichlorophosphonate is prepared by reacting the corresponding phosphonic acid with a chlorinating agent (thionyl chloride: Starrett, et al., J. Med. Chem., 1994, 1857, Oxalyl chloride: Stowell et al., Tetrahedron Lett., 1990 , 31: 3261, and fouling phosphor: Quast et al., Synthesis, 1974, 490). Alternatively, the dichlorophosphonate can also be reacted with the corresponding disilylphosphonate esters (Bhongle et al., Synth. Commun., 1987, 17, 1071) or dialkylphosphonate esters (Still et al., Tetrahedron Lett. , 1983, 24: 4405; Patois et al., Bull. Soc. Chim. Fr., 1993, 130: 485).
[961] Chlorophosphonate Monophenyl esters can be prepared from monophenyl phosphonate esters using the dichlorophosphonate synthesis described above, and monophenyl phosphonate esters can be prepared from the corresponding phosphonate esters by reaction with a base such as sodium hydroxide ) Hydrolysis. &Lt; / RTI &gt; Alternatively, by treatment of the dichlorophosphonate with one equivalent of phenol followed by the addition of an amine (e.g., alanine ethyl ester) in the presence of a suitable base such as pyridine or triethylamine, the monophenyl monophosphonamidate Can be obtained. When substituted phenols or other aryl-OH are used in place of phenol, these methods are useful for the synthesis of various monoaryl monophosphonamidates as a medicament for compounds of formula (I).
[962] Also, these Agents are described in Mitsunobu, Synthesis, 1981, 1 (Campbell, J. Org. Chem., 1992, 52, 6331), and other coupling reactions such as the use of carbodiimides: Alexander et al ..., Collect Czech Chem Commun , 1994, 59: 1853; Casara et al, Bioorg Med Chem Lett, 1992, 2:. 145; Ohashi et al, Tetrahedron Lett, 1988, 29:....... 1189 , And benzotriazolyloxytris (dimethylamino) phosphonium salts: Campagne et al., Tetrahedron Lett., 1993, 34: 6743).
[963] R &lt; ¹ &gt; can also be introduced into the initial stage of synthesis as long as it is compatible with the next reaction step. For example, a compound of formula (I) wherein R ¹ is an aryl group can be prepared by metallating a 2-furanyl heterocycle (eg, using LDA) followed by trapping the anion with a diarylchlorophosphate.
[964] Compounds of formula (I) may be mixed phosphonate esters (e.g., phenyl and benzyl esters, or phenyl and acyloxyalkyl esters) including chemically bound mixed esters, such as those described in Meier et al. Bioorg. Med. Chem. Lett. , 1997, 7: 99].
[965] Cyclic propylphosphonate esters can be prepared by reaction of a substituted 1,3-propanediol with the corresponding dichlorophosphonate or coupling using a suitable coupling agent (e.g. DCC, EDCI, pyBOP: Hoffmann, Synthesis , 1988, 62) Lt; / RTI &gt; can be synthesized by one of the reactions. Some of these methods useful for 1,3-propanediol are discussed below.
[966] Synthesis of 1,3-propanediol
[967] Various methods have been proposed for the preparation of 1,3-propanediol, such as (i) 1-substituted, (ii) 2-substituted, (iii) 1,2- or 1,3- Can be used. Substituents on the proton portion of the compound of Formula I (e.g., substituents on the 1,3-propanediol group) may be introduced or modified during synthesis of these diols or after synthesis of the compound of Formula 2.
[968] (I) 1-substituted 1,3-propanediol
[969] 1,3-Propanediol useful for the synthesis of the compounds of the present invention can be prepared using various synthetic methods. 1-Hydroxypropan-3-allyl aryl Grignard is added to give a 1-aryl-substituted 1,3-propanediol (Route a). This method is suitable for conversion to various aryl halides of 1-aryl substituted -1,3-propanediol (Coppi et al., J. Org. Chem., 1988, 53, 911). Conversion of the aryl halide to the 1-substituted 1,3-propanediol can also be accomplished by a nuclear reaction (e. G. Coupling with 1,3-diox-4-ene) followed by a reduction and sequential hydrolysis reaction (Sakamoto et al ., Tetrahedron Lett., 1992, 33, 6845). A variety of aromatic aldehydes can also be converted to 1-substituted-l, 3-propanediol using a borohydride-oxidation reaction after an alkenyl Grignard addition (path b).
[970]
[971] The aldol reaction between a carboxylic acid derivative (e.g., tert-butyl acetate) and an enolate of an aldehyde (e.g., lithium, boron, tin enolate), and these reactions (such as the Evans aldol reaction) Lt; / RTI &gt; For example, after the reaction of t-butyl acetate with a metal enolate of an aromatic aldehyde, the reduction of the ester (path e) yields 1,3-propanediol (Turner, J. Org. 4744). Alternatively, the epoxidation of cinnamyl alcohol using known methods (e.g., chaperis epoxidation and other asymmetric epoxidation reactions) followed by a reduction reaction (e. G., Using Red-Al) (Path c). Mirror isomerically pure 1,3-propanediol can be obtained via an asymmetric reduction reaction of 3-hydroxy-ketone (e.g., chiral reduction of borane) (Ramachandran et al., Tetrahedron Lett., 1997, 38, 761 ). Alternatively, the resolution of racemic 1,3-propanediol using a variety of methods (e. G., Enzymatic or chemical methods) can also yield enantiomerically pure 1,3-propanediol. The 1-heteroaryl substituent (e.g., pyridyl, quinolinyl, or isoquinolinyl) and propan-3-ol are oxygenated using an rearrangement reaction under acetone anhydride conditions after the N- A substituted 1,3-propanediol can be obtained (route d) (Yamamoto et al., Tetrahedron, 1981, 37, 1871).
[972] (Ii) 2-substituted 1,3-propanediol:
[973] Various 1,3-propanediol useful for the synthesis of the compound of formula (I) can be prepared from a variety of other 1,3-propanediol (e.g., 2-propanediol) using conventional chemical methods (Larock, Comprehensive Organic Transformations, VCH, New York, 1989) (Hydroxymethyl) -1,3-propanediol).
[974] For example, the reduction of the trialkoxycarbonylmethane under known conditions can be accomplished by complete reduction (path a) followed by reduction of the triol, or one optional hydrolysis of the ester group, (Hydroxymethyl) acetic acid. Nitrotriol is also known to obtain a triol via reduction elimination (path b) (Latour et al., Synthesis, 1987, 8, 742). In addition, 2- (hydroxymethyl) -1,3-propanediol can be converted to acyl chloride or alkyl chlorophores using a known chemical method (Greene et al., Protective Groups In Organic Synthesis; Wiley, New York, 1990) Can be converted to monoacylated derivatives (e. G., Acetyl, methoxycarbonyl) using mates (e. G., Acetyl chloride or methyl chloroformate) (path d). Other functional group manipulations can also be carried out by oxidation of one hydroxylmethyl group of 2- (hydroxymethyl) -1,3-propanediol with an aldehyde followed by addition of aryl Grignard (path c) to produce 1,3-propanediol Can be used. The aldehyde can also be converted to an alkylamine via a reductive amination reaction (path e).
[975]
[976] (Iii) Cyclic 1,3-propanediol:
[977] V and Z, or V and W are bonded through four carbons to form a ring, can be prepared from 1,3-cyclohexanediol. For example, cis, cis-1,3,5-cyclohexanetriol may be modified (as described in section (ii)) such that R ¹ and R ¹ together (Wherein V and W are bonded through three atoms to form a cyclic group containing 6 carbon atoms substituted by a hydroxy group), which is useful for the preparation of compounds of formula (I) Triol can be obtained. This modification can be carried out before or after the formation of the cyclic phosphonate 1,3-propanediol ester. A variety of 1,3-cyclohexanediol can also be prepared using a Diels-Alder reaction (e.g., using pyrone as the diene: Posner et al., Tetrahedron Lett., 1991, 32, 5295). 2-hydroxymethylcyclohexanol and 2-hydroxymethylcyclopentanol are preferred when R ¹ and R ¹ together Wherein V and Z are linked via 2 or 3 atoms to form a cyclic group containing 5 or 6 carbon atoms. 1,3-Cyclohexanediol derivatives can also be prepared via other methods of cyclic addition reaction. For example, the cyclic adducts from the cycloaddition of nitrile oxides and olefins can be separated into 1, 2, 3, 4, 5, 6, 7, 8, Can be converted into 2-ketoethanol derivatives which can be further converted into 3-propanediol (including 1,3-cyclohexanediol, 2-hydroxymethylcyclohexanol and 2-hydroxymethylcyclopentanol). Alternatively, precursors to 1,3-cyclohexanediol can be prepared from quinic acid (Rao et al., Tetrahedron Lett., 1991, 32, 547).
[978] (2) Deprotection of phosphonate ester
[979] Compounds of formula (I) wherein R &lt; ¹ &gt; is H may be prepared from the phosphonate esters under known phosphate and phosphonate ester cleavage conditions. Silyl halides are generally used in the cleavage of various phosphonate esters and the continuous intermediate hydrolysis of the resulting silyl phosphonate esters yields the desired phosphonic acid. If necessary, acid scavengers (e.g., 1,1,1,3,3,3-hexamethyldisilazane, 2,6-lutidine, etc.) can be used in the synthesis of acid labile compounds. The above silyl halides include chlorotrimethylsilane (Rabinowitz, J. Org. Chem., 1963, 28: 2975) and bromotrimethylsilane (McKenna, et al., Tetrahedron Lett., 1977, 155) and iodotrimethylsilane Blackburn, et al., J. Chem. Soc., Chem. Commun., 1978, 870). Alternatively, the phosphonate ester can be cleaved under strong acidic conditions (e.g., Hbr or HCl: Moffatt et al., US Pat. No. 3,524,846, 1970). These esters can also be prepared by treating the ester with a halogenating agent (e.g., phosphorus pentachloride, thionyl chloride, BBr ₃ : Pelchowicz et al., J. Chem. Soc. , 1961, 238), followed by aqueous hydrolysis The phosphonic acid is obtained by cleavage via a phenate. Aryl and benzylphosphonate esters can be prepared according to the hydrocracking conditions (Lejczak et al., Synthesis, 1982, 412, Elliott et al., J. Med. Chem., 1985, 28: 1208; Baddiley et al. , 171: 76) or under metal reduction conditions (Shafer et al., J. Am. Chem. Soc., 1977, 99: 5118). Conditions for pyrolysis (Gupta et al., Synth. Commun., 1980, 10: 299) were also used for various phosphonate ester cleavage Has come.
[980] (3) modification of the existing heterocycle
[981] The synthesis of the heterocycles contained in the disclosed compounds has been studied and described in various reviews (see section 4). It is advantageous to have the desired substituents present in these heterocycles prior to the synthesis of the compound of formula (4), but in some cases the desired substituents are incompatible with the continuous reaction and thus the modification of the existing heterocycle is carried out according to the usual chemistry (Larock, Comprehensive Organic Transformations, VCH, New York, 1989; Trost, Comprehensive organic synthesis; Pergamon Press, New York, 1991). For example, a compound of formula (I) wherein A, A "or B is a halo or cyano group is converted into a diazonium group by reaction with various copper (I) salts (eg CuI, CuBr, CuCl, CuCN) For example, 5-substituted-2-aminothiazole is reacted with a variety of reagents (e.g., NIS, NBS, NCS) and the like. Amino-5-halothiazole. Heteroaryl halides are also useful intermediates and can be prepared by Suzuki, nuclear or steel reactions (Farina et al., Organic Reactions, Vol.50; Wiley, New York, 1997 With the aid of a coupling reaction such as, for example, the reaction of a transition metal with a transition metal such as palladium, palladium, palladium, palladium, palladium, or palladium on a palladium catalyst; Mitchell, Synthesis, 1992, 808; Suzuki, Pure App. Chem. , 1991, 63, 419; Heck, Palladium Reagents in Organic Synthesis; Can easily be converted to other substituents (e.g., A, A ", B, B", C ", D, D", E and E " All. A is a conventional ester functional group transformation of the carbamoyl group can be made from their corresponding alkyl carboxylate esters via aminolysis with various amines also compounds of formula Ⅰ, alkyl carboxylate A is -CH ₂ OH group or a -CH ₂ - group halo are useful for the synthesis of compounds of formula ⅰ. A substitution reaction by various nucleophilic groups (e.g., HSMe, HOMe, etc.) of a heterocycle (e.g., 2-bromothiazole, 5-bromothiazole) introduces a substituent such as A, A ", B and B" It shows another method. For example, the replacement of 2-chlorothiazole with methanethiol gives the corresponding 2-methylthiothiazole.
[982] If necessary, alkylation of the nitrogen atom in a heterocycle (e.g. imidazole, 1,2,4-triazole and 1,2,3,4-tetrazole) can be carried out, for example, by standard alkylation reactions (alkyl halide, (Using an alkyl halide, an aralkyl halide, an alkyl sulfonate or an aralkyl sulfonate) or a Mitsunobu reaction (using an alcohol).
[983] (4) Coupling of the heterocycle with the phosphonate component
[984] The executable compounds disclosed herein can be advantageously prepared via a convergent synthetic route involving heterocycle coupling with a phosphonate diester component.
[985] Transition metal catalyzed coupling reactions such as steel or Suzuki reactions are particularly suitable for the synthesis of compounds of formula (I). Under the conditions of palladium catalysed reaction (Farina et al., Organic Reactions, Vol. 50; Wiley, New York, 1997; Mitchell, Synthesis, 1992, 808; Suzuki, Pure App. Chem . , 1991, 63, 419) Aryl halide or triflate such as 2-bromopyridine and M-PO ₃ R 'wherein M is 2- (5-tributylstannyl) furanyl or 2- (5-boronyl) To give a compound of formula (I) wherein X is a furan-2,5-diyl group. It is also contemplated that the coupling pair characteristics of these reactions can also be reversed (e.g., coupling of trialkylstannyl or boronyl heterocycle with halo-XP (O) (O-alkyl) ₂ ). Other coupling reactions between organostannes and alkenyl halides or alkenyl triflates have also been reported to be useful in the preparation of compounds of formula I wherein X is an alkenyl group. Nuclear reactions can be used to prepare compounds of formula I wherein X is an alkynyl group (Heck, Palladium Reagents in Organic Synthesis, Academic Press: San Diego, 1985). These reactions are particularly suitable for the synthesis of a variety of heteroaromatics as R &lt; ⁵ &gt; of the compounds of formula (I) provided with the availability of a plurality of halogenated heterocycles and these reactions are particularly suitable for the parallel reactions (e.g. Bunin, BA, The Combinatorial Index In a solution phase (Flynn, DL et al., Curr. Op. Drug. Disc. Dev., 1998, 1, 1367) . For example, ethyl 5-iodo-2-furanyl phosphonate can be coupled to the Wang resin under suitable coupling reaction conditions. The resin-linked 5-iodo-2- [5- (O-ethyl-O-Wile resin) phosphono] furan was prepared in a parallel manner using transition metal catalyzed by organotin and organotin Suzuki and steel reactions can be performed to provide a library of compounds of formula 3 wherein X is furan-2,5-diyl.
[986] The substitution reaction is useful for the coupling of the heterocycle with the phosphonate diester component. For example, cyanuric chloride may be substituted with a dialkyl mercaptoalkylphosphonate or a dialkylaminoalkylphosphonate, so that R &lt; ⁵ &gt; is 1,3,5-triazine and X is an alkylthio or alkylamino group To obtain a compound of formula (I). The alkylation reaction is also used for the coupling of the heterocycle with the phosphonate diester component. For example, a heteroaromatic thiol (e.g., 1,3,4-thiadiazole-2-thiol) is reacted with a dialkyl methylphosphonate derivative (e.g., ICH ₂ P (O) (OEt) ₂ , TsOCH ₂ P O) (OEt) _2, TfOCH can be alkylated with _{2 P (O) (OEt)} 2), X is an alkylthio group to give the compound of formula ⅰ. In another embodiment, a dialkyl methylphosphonate derivative of a heteroaromatic carboxylic acid (e.g., thiazole-4-carboxylic acid) (e.g., ICH ₂ P (O) (OEt) ₂ , TsOCH ₂ P (OEt) ₂ , TfOCH ₂ P (O) (OEt) ₂ ) produces a compound of formula (I) wherein X is an alkoxycarbonyl group, while a heteroaromatic thiocarboxylic acid according to the carboxylic acid) of a dialkyl methyl phosphonate derivatives (such _{as, ICH 2 P (O) (} OEt) 2, TsOCH 2 P (O) (OEt) 2, TfOCH 2 P (O) (OEt) 2) Alkylation produces a compound of formula (I) wherein X is an alkylthiocarbonyl group. Substitution by a nucleophilic group containing a phosphonate group (diethylhydroxymethylphosphonate) of a haloalkyl heterocycle (e.g., a 4-haloalkylthiazole) may be carried out by reacting a compound of formula I wherein X is an alkoxyalkyl or an alkylthioalkyl group And is useful for preparing compounds. For example, compounds of formula (I) wherein X is a -CH ₂ OCH ₂ - group may be prepared by the reaction of a 2-chloromethylpyridine or 4-chloromethylthiazole with a dialkyl hydroxymethylphosphonate and a suitable base such as sodium hydride &Lt; / RTI &gt; It is possible to reverse the properties of the nucleophilic group and the electrophilic group for the substitution reaction, that is, the haloalkyl- and / or sulfonylalkylphosphonate ester is a nucleophilic group (e.g., 2-hydroxyalkylpyridine, 2- Lt; RTI ID = 0.0 &gt; 4-hydroxyalkyloxazole). &Lt; / RTI &gt;
[987] Coupling of a heteroaromatic carboxylic acid with a phosphonate diester component leads to a known amide bond forming reaction (e.g., acyl halide method, mixed anhydride method, carbodiimide method), wherein X is an alkylaminocarbonyl or alkoxycarbonyl group Lt; RTI ID = 0.0 &gt; I &lt; / RTI &gt; For example, coupling of a thiazole-4-carboxylic acid with a dialkylaminoalkylphosphonate or a dialkylhydroxyalkylphosphonate is such that R ⁵ is thiazole and X is an alkylaminocarbonyl or alkoxycarbonyl group To obtain a compound of formula (I). Alternatively, the properties of the coupling pair can be reversed to yield a compound of formula (I) wherein X is an alkylcarbonylamino group. For example, 2-aminothiazole is coupled under these reaction conditions with (RO) ₂ P (O) -alkyl-CO ₂ H (such as diethylphosphonoacetic acid) to give R ⁵ as thiazole and X Lt; / RTI &gt; is an alkylcarbonylamino group. These reactions are also useful for parallel synthesis of compound libraries via combinatorial chemistry in solid or solution phase. For _{example, HOCH 2 P (O) (} OEt) (O- _{resin), H 2 NCH 2 P (} O) (OEt) (O- resin) and _{HOOCCH 2 P (O) (OEt} ) (O- resin) (prepared according to known methods) by using the above-described reaction, the various heterocycloalkyl ring couples X is -C (O) OCH ₂ - or -C (O) NHCH ₂ - or -NHC (O) CH ₂ - Lt; RTI ID = 0.0 &gt; (3) &lt; / RTI &gt;
[988] Rearrangement reactions can also be used in the preparation of compounds protected in the present invention. For example, the rearrangement reaction of thiazole-4-carboxylic acid in the presence of a dialkylhydroxyalkylphosphonate or a dialkylaminoalkylphosphonate can be carried out by reacting X with an alkylaminocarbonylamino or alkoxycarbonylamino group Lt; RTI ID = 0.0 &gt; I &lt; / RTI &gt; These reactions can also be applied to the combined synthesis of various libraries of compounds of formula (3). For example, the rearrangement reaction of the heterocyclic carboxylic acid with HOCH ₂ P (O) (OEt) (O-resin) or H ₂ NCH ₂ P (O) (OEt) -NHC (O) OCH ₂ - or -NHC (O) NHCH ₂ - it is possible to generate a library of compounds of formula ⅰ.
[989] (Bhattacharya et al., Chem. Rev., 1981, 81: 415), the Michaelis-Becker reaction (Blackburn et al. Such as the addition of phosphorus to an electrophilic group (e.g., aldehydes, ketones, acyl halides, imines and other carbonyl derivatives), as described in J. Organomet. Chem., 1988,348: . &Lt; / RTI &gt;
[990] The phosphonate component can also be introduced via the lithiation reaction. For example, after the lithiated pyridine-2-ethynyl with a suitable base, by wrapping the anion thus generated with a dialkyl chloro phosphonate agent, wherein R ⁵ is pyridyl, X is 1- (2-phosphonic Pheno) ethynyl group. &Lt; / RTI &gt;
[991] (5) Construction of Heterocycles
[992] While the present heterocycle is useful in the synthesis of formula I, the heterocycle can be constructed to produce the compounds of the present invention, if desired, and in some cases, preferred for the preparation of certain compounds. The construction of the heterocycle can be carried out using various reaction conditions (Joule et al., Heterocyclic Chemistry; Chapman Hall, London, 1995; Boger, Weinreb, Hetero Diels-Alder Methode In Organic Synthesis; Academic Press, San Diego, , 1,3-Dipolar Cycloaddition Chemistry, Wiley, New York, 1984; Katritzsky et al., Comprehensive Heterocyclic Chemistry; Pergamon press, Oxford; Newkome et al., Contemporary Heterocyclic Chemistry; Syntheses, Reaction and Applications, Wiley, 1982; Syntheses of Heterocyclic Compounds; Consultants Bureau, New York). Some methods useful for preparing compounds of the present invention are given as examples discussed below.
[993] (I) Construction of thiazole ring system
[994] Thiazoles useful in the present invention can be readily prepared using variously described ring forming reactions (Metzger, Thiazole and its derivatives, part 1 and part 2; Wiley & Sons, New York, 1979). The cyclisation of thioamides (e.g., thioacetamide, thiourea) and a-halocarbonyl compounds (e.g., -Haloketone, -Haloaldehyde) is particularly useful for thiazole ring systems. For example, the cyclization reaction between thiourea and 5-diethylphosphono-2 - [(2- bromo-1-oxo) alkyl] furan is such that R ⁵ is thiazole, A is an amino group, Lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt; The cyclisation reaction between thiourea and the bromopurylate alkyl ester is useful for preparing a compound of formula I wherein R &lt; ⁵ &gt; is a thiazole and X is an alkylaminocarbonyl, alkoxycarbonyl, alkylaminocarbonylamino or alkoxyacarbonylamino group 2-amino-4-alkoxycarbonylthiazole is obtained. Thioamide can be prepared using the reaction reported in Trost, Comprehensive organic synthesis, Vol. 6, Pergamon press, New York, 1991, pp 419-434, (Larock, Comprehensive Organic Tranformations, VCH, New York, 1989). For example, an amide can be converted to a thioamide using a Lavesson reagent or P ₂ S ₅ and the ketone can be halogenated using a variety of halogenating reagents (eg, NBS, CuBr ₂ ).
[995] (Ii) Construction of oxazole ring system
[996] Oxazoles useful in the present invention can be prepared using various methods of the literature (Turchi, Oxazoles; Wiley & Sons, New York, 1986). The reaction of isocyanide (eg, tosylmethylisocyanide) with carbonyl compounds (eg, aldehydes and acyl chlorides) can be used to construct the oxazole ring system (van Leusen et al., Tetrahedron Lett., 1972, 2369). Alternatively, cyclisation of amides (e. G. Urea, carboxamide) and a-halocarbonyl compounds is commonly used in the construction of oxazole ring systems. For example, the reaction of urea and 5-diethylphosphono-2 - [(- 2-bromo-1-oxo) alkyl] furan is such that R ⁵ is oxazole, A is an amino group, X is furan- Lt; / RTI &gt; is a 5-diyl group. The reaction of amines with imidates is also used in the formation of oxazole rings (Meyers et al., J. Org. Chem., 1986, 51 (26), 5111).
[997] (Iii) Construction of pyridine ring system
[998] Pyridines useful for the synthesis of compounds of Formula I can be prepared using a variety of known synthetic methods (Klingsberg, Pyridine and Its Derivatives; Interscience Publishers, New York, 1960-1984). 1,5-dicarbonyl compounds or their equivalents can be reacted with compounds capable of producing ammonia or ammonia to produce 1,4-dihydropyridine which is easily dehydrogenated with pyridine. When an unsaturated 1,5-dicarbonyl compound or an equivalent thereof (e.g., a pyrylium ion) is used in the reaction with ammonia, pyridine can be directly produced. 1,5-dicarbonyl compounds or their equivalents can be prepared using conventional chemical methods. For example, it has been found that 1,5-diketones are involved in a number of pathways, such as enones (or precursor mannich bases (Gill et al., J. Am. Chem. Soc., 1952, 74, 4923) , Ozone decomposition of the cyclopentene precursor, or reaction of 3-methoxyallyl alcohol with silylenol ethers (Duhamel et al., Tetrahedron, 1986, 42, 4777). If one of the carbonyl carbons is in an acidic oxidation state, this kind of reaction can be carried out using 2-halopyridine (Isler et al., Helv. Chim. Acta, 1955, 38, 1033) or 2-aminopyridine (Vorbruggen et al., Chem Ber., 1984, 117, 1523). Alternatively, pyridine can be prepared from aldehydes, 1,3-dicarbonyl compounds and ammonia via a typical one-step reaction (Bossart et al., Angew. Chem. Int. Ed. Engl., 1981, 20, 762) have. The reaction of 1,3-dicarbonyl compounds (or their equivalents) with 3-aminoenon or 3-amino-nitrile may also be used in the preparation of pyridine (see, for example, Guareschi synthesis, Mariella, Org. Synth. Coll. Vol. IV, 1963, 210). The 1,3-dicarbonyl compound can be prepared through an oxidation reaction to the corresponding 1,3-diol or aldol reaction product (Mukaiyama, Org. Reactions, 1982, 28, 203). The cycloaddition reaction may also be carried out by pyridine synthesis, for example the oxazole and alkene cycloaddition reactions (Naito et al., Chem. Pharm. Bull., 1965, 13, 869) and 1,2,4- (Borger et al., J. Org. Chem., 1981, 46, 2179).
[999] (Iv) Construction of the pyrimidine ring system
[1000] The pyrimidine ring systems useful for the synthesis of compounds of Formula I are readily available (Brown, The pyrimidines; Wiely, New York, 1994). One method of pyrimidine synthesis involves the coupling of a 1,3-dicarbonyl component (or an equivalent thereof) with an N-C-N fragment. 1943, 247), amidine (Kenner et al., J. Chem. Soc., 1943, 125) or guanidine (Burgess et al. The choice of - determines the substitution at C-2 in the pyrimidine product. [0154] &lt; EMI ID = 19.1 &gt; This method is particularly useful for the synthesis of compounds of formula I having various A groups. In another method, the pyrimidines can be prepared via cyclodeposition reactions such as the Aza-Diels-Alder reaction between 1,3,5-triazine and an enamine or an amine (Borger et al., J. Org. Chem , 1992, 57, 4331 and the literature cited herein).
[1001] (V) Construction of imidazole ring system
[1002] Imidazoles useful in the synthesis of compounds of formula (I) can be readily prepared using a variety of different synthetic methods. The various cyclisation reactions are generally carried out in the presence of amidine and -Haloketone (Mallick et al., J. Am. Chem. Soc., 1984, 106 (23), 7252) or -Hydroxy ketone (Shi et al. (U.S. Pat. No. 5,984,502, Synthetic Comm., 1993, 23 (18), 2623), the reaction between urea and an -Haloketone, and the reaction of aldehydes and 1,2-dicarbonyl compounds in the presence of amines do.
[1003] (Vi) Establishment of the Constitutional System
[1004] The isoxazoles useful for the synthesis of compounds of formula (I) may be prepared by a variety of methods (for example, the cyclization of nitrile oxides with alkynes or active methylene compounds, 1,3-dicarbonyl compounds or , -Acetylene carbonyl compounds or , β-dihalocarbonyl compounds, etc.) and can be used to synthesize an isoxazole ring system (Grunanger et al., Isoxazoles; Wiley & Sons, New York, 1991). For example, the reaction in the presence of an alkyne and a base of 5-diethylphosphono-2-chlorooxyimidofuran (e.g. triethylamine, Hünig's base, pyridine) allows R ⁵ to be isoxazole, Is a 2,5-diyl group.
[1005] (Ⅶ) Construction of pyrazole ring system
[1006] Pyrazoles useful in the synthesis of compounds of Formula I can be prepared by a variety of methods (Wiley, Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles, and Condensed Rings; Interscience Publishers, New York, 1967), such as hydrazine and 1,3- Reaction between 1,3-dicarbonyl equivalents (e.g., one of the carbonyl groups is masked with enamine or ketal or acetal), and cyclization after addition of hydrazine to acrylonitrile (Dorn et al., Org. Synth. 1973, Coll., Vol. V, 39). The reaction of 2- (2-alkyl-3-N, N-dimethylamino) acryloyl-5-diethylphosphonofuran with hydrazine is such that R ⁵ is pyrazole, X is a furan- &Quot; is an alkyl group.
[1007] (Ⅷ) Construction of 1,2,4-triazole ring system
[1008] 1,2,4-triazoles useful in the synthesis of compounds of formula (I) are readily available via various methodologies (Montgomery, 1,2,4-Triazoles; Wiley, New York, 1981). For example, the reaction between hydrazine and imidate or thioimidate (Sui et al., Bioorg. Med. Chem. Lett., 1998, 8, 1929; Catarzi et al., J. Med. (2), 2196), the reaction between 1,3,5-triazine and hydrazine (Grundmann et al., J. Org. Chem., 1956, 21, 1037), and the reaction between aminoguanidines and carboxyl esters al., Chem. Ber., 1968, 101, 2117) are used in 1,2,4-triazole synthesis.
[1009] (6) Closed ring reaction for heterocycle formation by phosphonate
[1010] The compound of formula (IV) can also be prepared using a ring-closing reaction for the formation of heterocycle from a precursor containing a phosphonate component. For example, the cyclization reaction of thiourea with 5-diethylphosphono-2 - [(2-bromo-1-oxo) alkyl] furan is such that R ⁵ is thiazole, A is an amino group, Lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt; The oxazoles of the present invention can also be prepared using a ring-closing reaction. In this case, the reaction of the urea and 5-diethylphosphono-2 - [(2- bromo-1-oxo) alkyl] furan is such that R ⁵ is oxazole, A is an amino group, X is furan- Lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt; The reaction between 5-diethylphosphono-2-furaldehyde, alkylamine, 1,2-diketone and ammonium acetate is such that the compound of formula I wherein R ⁵ is imidazole and X is a furan-2,5- . This type of cyclization reaction can also be used in pyridine or pyrimidine synthesis useful in the present invention. For example, the reaction of 5-diethylphosphono-2- [3-dimethylamino-2-alkyl) acryloyl] furan and cyanoacetamide in the presence of a base gives 5-alkyl- 6- [2- (5-diethylphosphono) furanyl] -2-pyridone (Jain et al., Tetrahedron Lett., 1995, 36, 3307). Subsequent conversions of these 2-pyridones to the corresponding 2-halopyridines (see literature cited in Section 3 for the modification of the heterocycle) indicate that R ⁵ is pyridine, A is halo, X is furan-2 , 5-diyl group, and B is an alkyl group. The reaction of 5-diethylphosphino-2- [3-dimethylamino-2-alkyl) acryloyl] furan and amidine in the presence of a base gives 5-alkyl-6- [2- (5-diethylphosphino ) -Furanyl] pyrimidine, which is a compound of formula I, wherein R ⁵ is pyrimidine, X is a furan-2,5-diyl group and B is an alkyl group.
[1011] (7) Preparation of various precursors useful for the cyclization reaction
[1012] The intermediates required for the synthesis of the compounds of the present invention are generally prepared using methods existing in literature or modifications of existing methods. Synthesis of some intermediates useful in the synthesis of compounds of the present invention is described herein.
[1013] Various aryl phosphonate dialkyl esters are particularly useful in the synthesis of compounds of formula (I). For example, compounds of formula I wherein X is a furan-2,5-diyl group can be prepared from various furanyl precursors. It is contemplated that the synthesis of other precursors may follow some or all of these reaction steps and that some modification of these reactions may require different precursors. 2-furancarbonyl compound (e.g., 5-diethylphosphono-2-furaldehyde, 5-diethylphosphono-2-acetylfuran) Lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt; These intermediates are prepared from furan or furan derivatives using conventional chemical methods, such as lithiation reactions, protection of the carbonyl group, and deprotection of the carbonyl group. For example, after lithiation of furan using the known method (Gschwend Org. React. 1979, 26: 1), the addition of a phosphorylating agent (eg CiPO ₃ R ₂ ) leads to the formation of 2-dialkylphosphono-furan For example, 2-diethylphosphonofuran). This method can be provided in a 2-substituted furan (e.g., 2-furoic acid) to give a 5-dialkylphosphono 2-substituted furan (e.g., 5-diethylphosphono-2-furoic acid) . Other arylphosphonate esters can also be prepared using these approaches or variations of this approach. Alternatively, other methods, such as the transition metal catalyzed reaction of aryl halides or triflates (Balthazar et al., J. Org. Chem., 1980, 45: 5425; Petrakis et al., J. Am. Chem. Soc., 1987, 109: 2831; Lu et al., Synthesis, 1987, 726) are used in the preparation of arylphosphonates. Arylphosphonate esters can also be prepared from aryl phosphates under anionic rearrangement conditions (Melvin, Tetrahedron Lett., 1981, 22: 3375; Casteel et al., Synthesis, 1991, 691). N-alkoxyaryl salts with alkali metal derivatives of dialkyl phosphonates provide another common synthetic method for heteroaryl-2-phosphonate esters (Redmore J. Org. Chem., 1970, 35: 4114) .
[1014] Although other known methods of producing these functional groups (e.g., aldehydes) may be well-adapted (e.g., the Vilsmeier-Hack reaction for aldehyde synthesis, or the Reimer-Teimann reaction), the second lithiation step may be an arylphosphonate di In the second lithiation step, the lithiated aromatic ring is reacted with the desired functional group (e.g., aldehyde using DMF, HCO ₂ R, etc.) (Such as alcohols, esters, nitriles, alkenes, which can be transformed into aldehydes) using a reagent that directly produces the desired functional group (s), or a reagent that produces a group that is continuously modified to the desired functional group using known chemistry. For example, after lithiation of 2-dialkylphosphonofuran (e.g., 2-diethylphosphonofuran) under normal conditions (e.g., LDA in THF), the anion thus generated is converted into an electrophilic group Butyltin chloride or iodine) to form 5-functionalized 2-dialkylphosphonofuran (e.g., 5-tributylstannyl-2-diethylphosphonofuran or 5-iodo-2-di Ethylphosphonofuran). Also, these sequential reactions can be reversed, i. E., After the aldehyde group is first incorporated, a phosphorylation reaction can take place. The order of the reactions depends on the reaction conditions and the protecting groups. Prior to phosphorylation, it may be advantageous to protect some of these functional groups using a number of known methods (e.g., acetal, protection of aldehydes as aminals, protection of ketones as ketals). The protected functional groups are then phosphorylated and then demasked (Protective groups in Organic Synthesis, Greene, TW, 1991, Wiley, New York). For example, after protection as the 1,3-propanediol acetal of 2-furaldehyde, trapping of the anion using a lithiation step (e.g. using LDA) and a dialkyl chlorophosphate (e.g. diethylchlorophosphate) , And successive deprotection of the acetal functionality under normal deprotection conditions yields 5-dialkylphosphono-2-furaldehyde (e.g., 5-diethylphosphono-2-furaldehyde). Another embodiment is the preparation of 5-keto-2-dialkylphosphonofuran comprising the steps of: obtaining 2-furan ketone by acylation of furan under Friedel-Craft reaction conditions, ketal (e.g., 1,3-propane Dialkylphosphono-2-furan ketone protected with a ketone as the 1,3-propanediol cyclic ketal in the lithiation step as described above after the continuous protection of the ketone, , The final deprotection of the ketal under acidic conditions yields 2-keto-5-dialkylphosphonofuran (e.g., 2-acetyl-5-diethylphosphonofuran). Alternatively, 2-ketofuran can be synthesized by palladium catalysed reaction between 2-trialkylstannylfuran (e.g., 2-tributylstannylfuran) and acyl chloride (e.g., acetyl chloride, isobutyryl chloride) have. It is advantageous to have a phosphonate group present in 2-trialkylstannylfuran (e.g., 2-tributylstannyl-5-diethylphosphonofuran). 2-Keto-5-dialkylphosphonofuran can also be obtained by conversion of the acid to the corresponding acyl chloride from 5-dialkylphosphono-2-furoic acid (e.g., 5-diethylphosphono-2-furoic acid) , &Lt; / RTI &gt; Grignard reagent.
[1015] Some of the intermediates described above may also be used in the synthesis of other useful intermediates. For example, 2-ketone-5-dialkylphosphonofuran can be additionally converted into 1,3-dicarbonyl derivatives useful for preparing pyrazole, pyridine or pyrimidine. The reaction of 2-keto-5-dialkylphosphonofuran (for example, 2-acetyl-5-diethylphosphonofuran) with a dialkylformamide dialkyl acetal such as dimethylformamide dimethylacetal, -Dialkylamino-2-alkyl-acryloyl) -5-dialkylphosphonofuran (e.g., 2- (3-dimethylaminoacryloyl) -5-diethylphosphonofuran) To obtain a levonyl equivalent.
[1016] The above-described methods for the synthesis of furan derivatives may be used directly or in the synthesis of various other useful intermediates such as arylphosphonate esters (e.g., thienylphosphonate esters, phenylphosphonate esters or pyridylphosphonate esters) Some modifications are applicable.
[1017] Where applicable, the synthetic methods described above are applicable to parallel synthesis in solid phase or solution to provide a rapid SAR (structural activity relationship) investigation of the FBPase inhibitors included in the present invention, and the provided method development of these reactions is successful.
[1018] Section 2
[1019] Synthesis of Compounds of Formula X
[1020] The synthesis of the compounds included in the present invention is typically carried out using (1) the preparation of a phosphonate precursor; (2) deprotection of phosphonate esters; (3) construction of a heterocycle; (4) introduction of a phosphonate component; (5) General steps of synthesis of aniline derivatives. Steps (1) and (2) were discussed in Section 1, and discussion of Step (3), Step (4) and Step (5) is as given below. These methods are also generally applicable to the preparation of compounds of formula (X) in which not all Y groups are -O-.
[1021]
[1022] (3) Construction of Heterocycles
[1023] I. Benzothiazole ring system:
[1024] The compounds of formula 3 wherein G " is S, i.e., benzothiazole, can be prepared using various synthetic methods reported in the literature. Two of these methods are given as examples discussed below. Another method is to cyclize the aniline (e.g., the compound of Formula 4) to form the thiazole moiety of the benzothiazole ring. The benzothiazole ring For example, the compounds of formula G '= S, A = NH ₂ , L ² , E ² , J ² = H, X ² = CH ₂ O and R' = Et 3 are commercially available 4 -Methoxy-2-aminothiazole in the presence of a continuous two-step: thiol (e.g. EtSH) (McOmie, JFW; et al., Org. Synth., Vol. V, 412, 1973) ₃ or _{BBr 3 (Node M .; et al} ., J. Org. Chem. 45, 2243-2246, 1980) 4- by the reagent, such as methoxy-2-amino-benzothiazole After conversion to 4-hydroxy-2-aminobenzothiazole, diethylphosphonomethyltrifluoromethylsulfonate (Phillion, &lt; RTI ID = 0.0 &gt; DP, et al., Tetrahedron Lett., 27, 1477-1484, 1986).
[1025] Several methods can be used to convert various anilines to benzothiazoles (Sprague, JM; Land, AH Heterocycle, Compd. 5, 506-12, 1957). For example, 2-aminobenzothiazole (Formula 3 where A = NH ₂ ) can be prepared by cyclisation of a compound of Formula 4 where W ² = H using various conventional methods. One method is the preparation of substituted 2-aminobenzothiazole (Ismail, IA; Sharp, DE; Chedekel, MRJ Org. Chem. 45, 2243-2246, 1991) by treating aniline appropriately substituted with a mixture of KSCN and CuSO4 in methanol. 1980). Alternatively, 2-aminobenzothiazole can also be prepared by treatment of Br ₂ in the presence of KSCN in acetic acid (Patil, DG; Chedekel, MRJ Org. Chem. 49, 997-1000, 1984). This reaction can also be carried out in two successive stages. For example, treatment of a substituted phenylthiourea with Br ₂ in CHCl ₃ affords a substituted 2-aminobenzothiazole (Patil, DG; Chedekel, MRJ Org. Chem. 49, 997-1000, 1984) . 2-Aminobenzothiazole can also be prepared by condensing orthoiodoaniline with thiourea in the presence of a Ni catalyst (NiCl ₂ (PPh ₃ ) ₂ ) (Takagi, K. Chem. Lett. 265-266, 1986 ).
[1026] Benzothiazole can perform electrophilic aromatic substitution to give a 6-substituted benzothiazole (Spargue, JM; Land, AH Heterocycle, Compd. 5, 606-13, 1957). For example, in a polar solvent such as AcOH, a compound of formula (3) wherein G "= S, bromine, A = NH _2, L ² , E ² , J ² = H, X ² = CH ₂ O, Lt; ² &gt; = Br.
[1027] Compounds of formula 3 in which A is halo, H, alkoxy, alkylthio or alkyl may be prepared from the corresponding amino compounds (Larock, Comprehensive Organic Transformations, VCH, New York, 1989; Trost, Comprehensive organic synthesis; Pergamon Press, New York, 1991).
[1028] Ii. Benzoxazole:
[1029] G "= O, a compound of formula (3), that is, benzoxazole is suitable reagent (e. G., Cyanogen halide _{(A = NH 2; Alt,} LO;.. Et al, J. Heterocyclic Chem 12, 775, 1975) or acetic acid ( _{A = CH 3; Saa, JM} ;.. J. Org Chem 57, 589-594, 1992) or trialkyl orthoformate (A = H;... . Org Prep Proced Int, 22, 613, 1990)) &Lt; / RTI &gt; by cyclisation of ortho-aminophenols by known methods.
[1030] (4) Introduction of phosphonate components:
[1031] Compounds of formula 4 wherein X ² = CH ₂ O, R '= alkyl may be prepared by different methods (eg, using alkylation and nucleophilic substitution reactions). The compound of formula 5 wherein M ' = OH is treated with a suitable base (e.g., NaH) in a polar aprotic solvent (e.g., DMF, DMSO) and the resulting phenoxide anion is treated with a suitable electrophilic group, (E.g., diethyl iodomethylphosphonate, diethyltrifluoromethylsulfone methylphosphonate, diethyl p-methyltoluenesulfonomethylphosphonate) to form a reaction mixture. The alkylation process is also applicable to the precursor compound for the compound of formula 5 in which the phenolic group is present and may be alkylated with the phosphonate containing moiety. Alternatively, the compound of formula 4 may also be prepared by the nucleophilic substitution of a precursor compound for a compound of formula 5, wherein halo group, preferably fluoro or chloro, is in the ortho position of the nitro group. For example, a compound of formula 4 wherein X ² = CH ₂ O and R '= Et is prepared from 2-chloro-1-nitrobenzene derivative by treatment with NaOCH ₂ P (O) (OEt) ₂ in DMF . Similarly, compounds of formula 4 wherein X ² = -alkyl-S- or -alkyl-N- can also be prepared.
[1032] (5) Synthesis of aniline derivative:
[1033] Many synthetic methods have been reported for the synthesis of aniline derivatives, and these methods can be applied to the synthesis of useful intermediates capable of producing compounds of formula (X). For example, various alkenyl or aryl groups can be introduced via a transition metal catalyzed reaction into the benzene ring (Kasibhatla, SR, et al., WO98 / 39343 and references cited therein); Aniline can be reduced by a reduction reaction (eg, hydrogenation in the presence of 10% Pd / C, or reduction with SnCl ₂ in HCl (Patil, DG; Chedekel, MRJ Org. Chem. 49, 997-1000, 1984) / RTI &gt; can be prepared from the corresponding nitro derivatives of formula &lt; RTI ID = 0.0 &gt;
[1034] Section 3
[1035] Synthesis of substituted 1,3-hydroxyamine and 1,3-diamine:
[1036] Due to the ubiquitous nature of these functional groups of naturally occurring compounds, a number of synthetic methods are available for the preparation of substituted 1,3-hydroxyamines and 1,3-diamines. Some of these methods include: 1. synthesis of substituted 1,3-hydroxyamine; 2. Synthesis of substituted 1,3-diamines and 3. Synthesis of chiral substituted 1,3-hydroxyamine and 1,3-diamine.
[1037] I. Synthesis of Substituted 1,3-Hydroxyamine:
[1038] The 1,3-diol described in the above section can be selectively converted to a hydroxyamine or the corresponding diamine by converting the hydroxy functionality to the leaving group and treating with anhydrous ammonia or the required primary or secondary amine (Corey , et al., Tetrahedron Lett., 1989, 30, 5207: Gao, et al., J. Org. Chem., 1988, 53, 4081). Similar variations can also be obtained directly from alcohols in Mitsunobu reaction conditions (Hughes, D. L., Org. React., 1992, 42). General synthetic methods for the 3-aryl-3-hydroxy-propane-amines of the full-ortho moiety are the synthesis of substituted benzoyl acetonitrile (Shih et al., Heterocycles, 1986, 24 , &Lt; / RTI &gt; 1599). This procedure can also be applied to the formation of 2-substituted aminopropanol using substituted alkylnitriles. In another approach, the 3-aryl-3-amino-propan-1-ol form of the prodrug can be synthesized from aryl aldehyde by condensation of malonic acid in the presence of ammonium acetate followed by reduction of the resulting substituted amino acid. Both of these methods lead to a wide variety of substitutions of aryl groups (Shih, et al., Heterocycles., 1978, 9, 1277). In another approach, a-substituted aminoorganosilane compound of 1-amino-1-arylethyldianion generated from a styrenic compound of a compound is added to a carbonyl compound to convert various W, W ' (Barluenga, et al., J. Org. Chem., 1979, 44, 4798).
[1039] Ii. Synthesis of substituted 1,3-diamines:
[1040] Substituted 1,3-diamines are synthesized from various substrates. The arylglutaronitrile is hydrolyzed to amides and the Hoffman rearrangement conditions (Bertochio, et al., Bull. Soc. Chim. Fr, 1962, 1809). On the other hand, malonitrilyl substitution enables various Z substitutions by hydrogenation and reduction to the corresponding diamines after introduction of the electrophilic group. In another approach, cinnamaldehyde reacts with hydrazine or substituted hydrazine to afford the corresponding pyrazoline, which upon catalytic hydrogenation produces a substituted 1,3-diamine (Weinhardt, et al., J. Med. Chem., 1985, 28, 694). The high trans-dihedral selectivity of 1,3-substituted is also obtainable by reduction after addition of aryl Grignard on the pyrazoline (Alexakis et al., J. Org. Chem., 1992, 576, 4563). 1-aryl-1,3-diaminopropane is also prepared from diborane reduction of 3-amino-3-aryl acrylonitrile and then from nitrile-substituted aromatics (Dornow, et al., Chem. Ber., 1949, 82, 254). Reduction of the 1,3-diamines obtained from the corresponding 1,3-carbonyl compounds is another source of the 1,3-diamine precursor part which allows a wide part of the activating groups V and / or Z (Barluenga, et al., J. Org. Chem., 1983, 48, 2255).
[1041] Iii. Synthesis of chiral substituted 1,3-hydroxyamine and 1,3-diamine .
[1042] The enantiomerically pure 3-aryl-3-hydroxypropan-1-amine is synthesized by CBS enantioselective catalytic reaction of chloropropiophenes by arrangement of halo groups to produce the required secondary or primary amine (Corey, et al., Tetrahedron Lett., 1989, 30, 5207). The chiral 3-aryl-3-aminopropane-1-ol forms of the prodrug moiety can be obtained by reduction of the resulting isoxazolidine after 1,3-dipolar addition of chirally pure olefins and substituted nitrons of aryl aldehydes (Koizumi et al., J. Org. Chem., 1982, 47, 4005). The chiral introduction to the 1,3-polar additive to form the substituted isoxazolidine can also be obtained by a chiral phosphine palladium complex and can be prepared from aminoalcohols (Hori, et al., J. Org. Chem. 1999, 64, 5017). Alternatively, any pure 1-aryl substituted amino alcohol is obtained by selective ring opening reaction of the corresponding chiral epoxy alcohol with the desired amine (Canas et al., Tetrahedron Lett., 1991, 32, 6931).
[1043] Various methods for the method for the synthesis of diastereomers selectively of 1,3-disubstituted amino alcohols are known. For example, the treatment of (E) -N-cinnamyl trichloroacetamide with hippocrossus acid is a trans-dihydrooxazine which is readily hydrolyzed to erythro-chloro-hydroxy-phenylpropanamine with high diastereoselectivity (Commercom et al., Tetrahedron Lett., 1990, 31, 3871). The diastereomeric selective formation of 1,3-aminoalcohol is also obtained by the reductive amination of optically pure 3-hydroxy ketone (Haddad et al., Tetrahedron Lett., 1997, 38, 5981). In another approach, 3-aminoketones are converted to 1,3-disubstituted amino alcohols with high stereoselectivity by selective hydrogenation reduction (Barluenga et al. J. Org. Chem., 1992, 57, 1219).
[1044] All of the above-mentioned processes can be applied to the preparation of corresponding V-Z or V-W cyclized chiral amino alcohols. In addition, the optically pure amino alcohol is also a source of obtaining an optically pure diamine by the method previously described in the section above.
[1045] Formulation
[1046] The compounds of the invention are orally administered in a total daily dosage of about 0.01 mg / kg / dose to about 100 mg / kg / dose, preferably about 0.1 mg / kg / dose to about 10 mg / kg / dose. It may be desirable to use a slow release formulation to control the release rate of the active ingredient. The administration can be conveniently administered in a variety of separate doses. Where other methods are used (e.g., intravenous administration), the compound is administered to the subject at a rate of 0.05 to 10 mg / kg / hr, preferably 0.1 to 10 mg / kg / hr. This rate can easily be maintained when these compounds are administered intravenously as follows.
[1047] For purposes of the present invention, the compounds may be administered by any of a variety of methods including oral, parenteral, aspirate, topical, or rectal, into a formulation containing a pharmaceutically acceptable carrier, adjuvant and vehicle. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, and intraarterial injections by various injection techniques. Intraarterial and intravenous injection as used herein includes administration via a catheter. Oral administration is generally preferred.
[1048] The pharmaceutical composition containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art of manufacturing pharmaceutical compositions, which may include one or more formulations including sweeteners, flavoring agents, coloring agents and preservatives to provide a good-tasting formulation Can be used. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets are also acceptable. These excipients include, for example, inert diluents, for example, calcium carbonate or sodium, lactose, calcium phosphate or sodium; Granulating and disintegrating agents, for example corn starch or alginic acid; Binders, for example starch, gelatin or acacia; And lubricants, such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated with known techniques, including microencapsulation to delay disintegration and absorption within the gastrointestinal tract to provide a sustained action over a prolonged period of time. For example, time delay materials such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with the wax.
[1049] Oral formulations may also be presented as soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium phosphate or kaolin, or soft gelatin capsules wherein the active ingredient is mixed with water or an oily medium, such as peanut oil, liquid paraffin or olive oil Gelatin capsules.
[1050] The aqueous suspensions of the present invention contain the active substance in admixture with excipients suitable for the manufacture of aqueous suspensions. The excipient may be a suspending agent such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum, and dispersing or wetting agents such as natural Condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), ethylene Oxides and condensation products of partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspensions may contain one or more preservatives, for example ethyl or n-propyl-p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, for example sucrose or saccharin.
[1051] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil, for example liquid paraffin. Oral suspensions may contain thickening agents, for example wax, hard paraffin or cetyl alcohol. The sweeteners and flavoring agents as described above may be added to provide a mouth-feelable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.
[1052] Dispersible powders and granules of the present invention suitable for the manufacture of aqueous suspensions by water addition provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents, and suspending agents are those exemplified above. Additional excipients, such as sweeteners, flavoring agents and coloring agents, may also be present.
[1053] The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, for example olive oil or arachis oil, mineral oil, for example liquid paraffin or a mixture thereof. Suitable emulsifiers include natural rubbers such as acacia gums and tragacanth gum, esters or partial esters derived from natural phosphatides, for example soy lecithin, fatty acids and hexitol anhydrides, for example sorbitan monooleate , And condensation products of ethylene oxide with these partial esters, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.
[1054] Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, sorbitol or sucrose. The formulations may also contain a scoop, preservative, flavoring or coloring agent.
[1055] The pharmaceutical composition of the present invention may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a injectable solution or suspension in a nontoxic, parenterally acceptable diluent or solvent such as a solution such as 1,3-butanediol, or may be a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils may conventionally be used as a solvent or suspending medium. For this purpose, any refreshing stationary oil may be used, including synthetic mono- or diglycerides. Likewise, fatty acids, such as oleic acid, can also be used in injectable preparations.
[1056] The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, sustained release formulations for oral administration to humans may contain from about 1 to 1000 mg of the active compound formulated with an appropriate and convenient amount of carrier material, which may be from about 5 to about 95% of the total composition . It is also desirable to prepare the pharmaceutical composition to provide an easily measurable amount for administration. For example, an aqueous solution for intravenous infusion should contain about 3 to 330 [mu] g of active ingredient per ml of solution, so that an appropriate volume of infusion can occur at a rate of about 30 ml / hr.
[1057] As known in the art, formulations of the present invention suitable for oral administration may be presented as separate units, for example capsules, shashers or tablets containing a predetermined amount of the active ingredient, respectively; Powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; Or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a pill, soft or paste.
[1058] The tablets may optionally be made by compression or molding with one or more accessory ingredients. Compressed tablets may be prepared by compressing the active ingredient in a suitable machine in a free-flowing form such as a powder or granules and may optionally be mixed with a binder such as povidone, gelatin, hydroxypropyl methylcellulose, a lubricant, an inert diluent, For example, sodium starch glycolate, crosslinked povidone, crosslinked sodium carboxymethyl cellulose), a surfactant or a dispersing agent. Molded tablets may be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be used in varying proportions, for example, hydroxypropylmethylcellulose to provide the desired release profile, to provide for the release of the slow or controlled active ingredient. The tablets may optionally be provided as enteric coatings, thus providing release in a portion of the gastrointestinal tract outside the stomach. When the compound is sensitive to acid hydrolysis, the compounds of the formulas I and X are particularly advantageous.
[1059] Formulations suitable for topical administration via the mouth include lozenges containing the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; Pasteil containing the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia; And an oral care agent containing the active ingredient in a suitable liquid carrier.
[1060] Formulations for rectal administration may be presented as suppositories, for example, with a suitable base comprising cocoa butter or salicylate.
[1061] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations, suitably containing carriers known in the art in addition to the active ingredient.
[1062] Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which are formulated with the blood of the intended recipient; And aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. Formulations may be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and may be stored in a freeze-dried condition just prior to use, simply by adding a sterile liquid carrier, for example, have. Injection solutions and suspensions may be provided from the sterile powders, granules and tablets described above.
[1063] Preferred unit dosage forms are those containing a single daily dose or unit of fructose 1,6-naphosphatase inhibitor compound, one day sub-dose or a suitable fraction thereof.
[1064] However, the specific dose for any particular patient will depend upon a variety of factors including the activity of the particular compound employed; The age, weight, general health, sex and diet of the patient to be treated; Time and route of administration; Excretion rate; Other drugs previously administered; And the severity of the particular disease under which the treatment is being performed, as well as is well known to those skilled in the art.
[1065] Use
[1066] FBPase inhibitors can be used to treat diabetes, hypoglycemia, or can be used to inhibit glucose synthesis.
[1067] FBPase inhibitors can also be used to treat excess glycogen storage disease. Excessive hepatic glycogen stores are found in patients with some glycogen storage diseases. Indirect pathway inhibition (glucose synaptic reflux) reduces glycogen and production because the indirect pathway has a significant effect on glycogen synthesis (Shulman, G. I. Phys. Rec. 72: 1019-1035 (1992)).
[1068] FBPase inhibitors can also be used to treat or prevent diseases associated with increased insulin levels. Increased insulin levels are associated with an increased risk of cardiovascular complications and atherosclerosis (Folsom et al., Stroke , 25: 66-73 (1994); Howard, G. et al., Circulation 93: 1809-1817 (1996) ). FBPase inhibitors are expected to reduce postprandial glucose levels due to hepatic glucose uptake. This effect occurs later in individuals who are non-diabetic (or pre-diabetic, i.e., do not increase hepatic glucose production (hereinafter HGO), or promote blood glucose levels). Increased hepatic glucose uptake reduces insulin secretion, thereby reducing the risk of disease or complications resulting from increased insulin levels.
[1069] One aspect of the present invention is the novel method for the cyclic 1,3-propanyl ester methodological use which leads to an effective conversion of cyclic phospho (orthamid) aate. Phosphonates containing compounds by the p450 enzyme are found in large amounts in the liver and other tissues containing these specific enzymes.
[1070] In another embodiment of the present invention, this global methodology also teaches that cyclic phosphates (oramides) of the present invention can inhibit the action of the enzyme that degrades the parent drug and therefore can be used to prolong the pharmacokinetic half life .
[1071] In another embodiment of the present invention, this global methodology can be used to achieve sustained delivery of the parent drug, since it is slowly oxidized in the liver at different rates of various new drugs.
[1072] The novel cyclic &lt; RTI ID = 0.0 &gt; 1, 3-propanyl &lt; / RTI &gt; ester methodology of the present invention also provides for the distribution of certain drugs in the liver, which contain abundant amounts of p450 isozymes that tend to oxidize the cyclic 1,3- , Thereby producing a free phospho (oramid) octaate.
[1073] In another embodiment of the present invention, the cyclic phosph (orthamido) agrochemical can increase the oral bioavailability of the drug.
[1074] These aspects are described in further detail below.
[1075] Evidence of liver specificity can be seen in vivo in both oral and intravenous administration of the full-length oral preparation described in Example E.
[1076] The drug may also be detected in the liver after administration of the drug of the formulas VI to VIII shown below.
[1077] &Lt; EMI ID =
[1078]
[1079] (VII)
[1080]
[1081] <Formula (VIII)
[1082]
[1083] Particular preference is given to the formulas VI, VII and VIII.
[1084] The cutting mechanism can be proceeded by the following mechanism. In addition, evidence of these mechanisms is indicated by breakdown byproduct analysis. The general formula of formula VI wherein Y is -O-, generates phenyl vinyl ketone while the Formula I compound is shown to generate phenol (Example H).
[1085]
[1086] Although the ester of the present invention is not limited to the above mechanism, generally, each ester contains a group or molecule (for example, an alcohol, a benzylmethyl proton) sensitive to micro-body oxidation, - Removal produces an intermediate which breaks down the parent compound in aqueous solution.
[1087] 1. Synthesis of compounds of formula (I)
[1088] &Lt; Example 1 >
[1089] Preparation of 5-diethylphosphono-2-furaldehyde (1)
[1090] Step A. A solution of 2-furaldehyde diethyl acetal (1 mmole) in THF (tetrahydrofuran) was treated with nBuLi (1 mmole) at -79 ° C. After 1 h, diethylchlorophosphate (1.2 mmole) was added and the reaction was stirred for 40 min. Extraction and evaporation gave a brown oil.
[1091] Step B. The resulting brown oil was treated with 80% acetic acid at 90 &lt; 0 &gt; C for 4 h. Extraction and chromatography gave Compound 1 as a clear yellow oil. Alternatively, the aldehyde can be prepared from furan as described below.
[1092] Step C. A solution of furan (1 mmole) in diethyl ether was treated with TMEDA (N, N, N'N'-tetramethylethylenediamine) (1 mmole) and nBuLi (2 mmole) at -78 ° C for 0.5 hour Respectively. Diethylchlorophosphate (1.2 mmole) was added to the reaction mixture and stirred for an additional 1 hour. Extraction and distillation yielded diethyl 2-furanphosphonate as a clear oil.
[1093] Step D. A solution of diethyl 2-furan phosphonate (1 mmole) in THF was treated with LDA (1.12 mmole, lithium NN-diisopropylamide) at -78 <0> C for 20 min. Methyl formate (1.5 mmole) was added and the reaction was stirred for 1 hour. Extraction and chromatography gave Compound 1 as a clear yellow oil. Preferably, the aldehyde can be prepared from 2-furaldehyde as described below.
[1094] Step E. A solution of 2-furaldehyde (1 mmole) and N, N'-dimethylethylenediamine (1 mmole) in toluene was refluxed and the resulting water was collected on a Dean-Stark trap. After 2 hours, the solvent was removed in vacuo and the residue was distilled to give furan-2- (N, N'-dimethylimidazolidine) as a clear colorless oil. mp 59-61 [deg.] C (3 mm Hg).
[1095] Step F. A solution of furan-2- (N, N'-dimethylimidazolidine) (1 mmole) and TMEDA (1 mmole) in THF was treated with nBuLi (1.3 mmole) at -40 to -48 占 폚. The reaction was stirred at 0 &lt; 0 &gt; C for 1.5 h, then cooled to -55 &lt; 0 &gt; C and treated with a solution of diethylchlorophosphate (1.1 mmole) in THF. After stirring at 25 ° C for 12 hours, the reaction mixture was evaporated and extracted to give 5-diethylphosphonofuran-2- (N, N'-dimethylimidazolidine) as a brown oil.
[1096] Step G. A solution of 5-diethylphosphonofuran-2- (N, N'-dimethyl-imidazolidine) (1 mmole) in water was treated with concentrated sulfuric acid until pH = 1. Extraction and chromatography gave Compound 1 as a clear yellow oil.
[1097] &Lt; Example 2 >
[1098] Preparation of 5-diethylphosphono-2 - [(1-oxo) alkyl] furan and 6-diethylphosphono-2 - [(1-oxo) alkyl] pyridine.
[1099] Step A. A solution of furan (1.3 mmole) in toluene was added to a solution of 4-methylpentanoic acid (1 mmole), trifluoroacetic anhydride (1.2 mmole) and boron trifluoride etherate Respectively. The cooled reaction mixture was quenched with aqueous sodium bicarbonate (1.9 mmole) and filtered through a pad of celite. Extraction, evaporation and distillation gave 2 - [(4-methyl-1-oxo) pentyl] furan as a brown oil (bp 65-77 ° C, 0.1 mmHg).
[1100] Step B. A solution of 2 - [(4-methyl-1-oxo) pentyl) furan (1 mmole) in benzene was treated with ethylene glycol (2.1 mmole) and p-toluenesulfonic acid (0.05 mmole) And the water was removed through a Dean-Stark trap. Triethylorthoformate (0.6 mmole) was added and the resulting mixture was heated at reflux for an additional hour. Extracted and evaporated to give 2- (2-furanyl) -2 - [(3-methyl) butyl] -1,3-dioxolane as an orange liquid.
[1101] Step C. A solution of 2- (2-furanyl) -2 - [(3-methyl) butyl] -1,3-dioxolane (1 mmole) in THF was added to TMEDA (1 mmole) and nBuLi 1.1 mmole) and the resulting reaction mixture was stirred at -5 to 0 &lt; 0 &gt; C for 1 hour. The resulting reaction mixture was cooled to -45 ° C and was cannulated with a solution of diethylchlorophosphate in THF at -45 ° C. The reaction mixture was slowly warmed to ambient temperature over a period of 1.25 hours. Extraction and evaporation yielded 2- [2- (5-diethylphosphono) furanyl] -2 - [(3-methyl) butyl] -1,3-dioxolane as a black oil.
[1102] Step D. A solution of 2- [2- (5-diethylphosphino) furanyl] -2 - [(3-methyl) butyl] -1,3-dioxolane (1 mmole) in methanol &Lt; / RTI &gt; for 1 hour with 1 N hydrochloric acid (0.2 mmole). Extraction and distillation yielded 5-diethylphosphono-2 - [(4-methyl-1-oxo) pentyl] furan (2.1) as a light orange oil (bp 152-156 ° C, 0.1 mmHg).
[1103] The following compounds were prepared by this method:
[1104] (2.2) 5-diethylphosphono-2-acetylfuran: bp 125-136 ° C, 0.1 mmHg.
[1105] (2.3) 5-Diethylphosphono-2 - [(1-oxo) butyl] furan: bp 130-145 DEG C, 0.08 mmHg.
[1106] Alternatively, the compound can be prepared using the following method:
[1107] Step E. A solution of 2 - [(4-methyl-1-oxo) pentyl] furan (1 mmole, prepared as in Step A) in benzene was treated with N, N-dimethylhydrazine (2.1 mmole) And trifluoroacetic acid (0.05 mmole). Extraction and evaporation gave 2 - [(4-methyl-1-oxo) pentyl] furan N, N-dimethylhydrazone as a brown liquid.
[1108] Step F. 2 - [(4-Methyl-1-oxo) pentyl] furan N, N-Dimethylhydrazone Treatment of 2- [ Ethylphosphonofuran N, N-dimethylhydrazone as a brown liquid which was treated with copper (II) chloride (1.1 eq.) In ethanol-water at 25 ° C for 6 h. Extraction and distillation gave compound 2.1 as a light orange oil.
[1109] Any 5-diethylphosphono-2 - [(1-oxo) alkyl] furan is prepared using the following method:
[1110] Step G. A solution of compound 1 (1 mmole) and 1,3-propanedithiol (1.1 mmole) in chloroform was treated with boron trifluoride etherate (0.1 mmole) at 25 占 폚 for 24 hours. Evaporation and chromatography afforded 2- (2- (5-diethylphosphono) furanyl) -1,3-dithiane as a light yellow oil. .
[1111] A solution of 2- (2- (5-diethylphosphino) furanyl) -1,3-dithiane in THF was cooled to -78 ° C and treated with nBuLi (1.2 mmole). After 1 h at -78 [deg.] C, the reaction mixture was treated with cyclopropanemethyl bromide and stirred at -78 [deg.] C for additional 1 h. Extraction and chromatography afforded 2- (2- (5-diethylphosphino) furanyl) 2-cyclopropanemethyl-1,3-dithiane as an oil.
[1112] A solution of 2- (2- (5-diethylphosphino) furanyl) -2-cyclopropanemethyl-l, 3 dithiane (1 mmole) in acetonitrile-water was added at 25 [ Fluoroacetoxy) iodo] benzene (2 mmole). Extraction and chromatography afforded 5-diethylphosphono-2- (2-cyclopropylethy l) furan as a light orange oil.
[1113] The following compounds were prepared by this method:
[1114] (2.4) 5-Diethylphosphono-2- (2-ethoxycarbonylacetyl) furan
[1115] (2.5) 5-Diethylphosphono-2- (2-methylthioacetyl) furan
[1116] (2.6) 6-diethylphosphono-2-acetylpyridine
[1117] &Lt; Example 3 >
[1118] Thiazole, 4- [2- (5-phosphono) furanyl] thiazole, 4- [2- (6-phosphono) .
[1119] Step A. A solution of compound 2.1 (1 mmole) in ethanol was treated with copper (II) bromide (2.2 mmole) at reflux temperature for 3 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The resulting black oil was purified by chromatography to give 5-diethylphosphono-2 - [(2-bromo-4-methyl-1-oxo) pentyl] furan as an orange oil.
[1120] Step B. A solution of 5-diethylphosphono-2 - [(2-bromo-4-methyl-1-oxo) pentyl] furan (1 mmole) and thiourea (2 mmole) / RTI &gt; The cooled reaction mixture was evaporated to dryness and the resulting yellow foam was suspended in saturated sodium bicarbonate and water (pH = 8). The resulting yellow solid was collected via filtration to give 2-amino-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole.
[1121] Step C. A solution of 2-amino-5-isobutyl-4- [2- (5-diethylphosphino) -furanyl] thiazole (1 mmole) in methylene chloride was treated with bromotrimethyl Silane (1 mmole). The reaction mixture was evaporated to dryness and the residue was suspended in water. The resulting solid was collected by filtration to give 2-amino-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole (3.1) as an off-white solid. Melting point exceeded 250 캜. C ₁₁ H ₁₅ N ₂ 0 ₄ PS + 1.25 Calculated for HBr: C: 32.75; H: 4.06; N: 6.94. Found: C: 32.39; H: 4.33; N: 7.18.
[1122] The following compounds were prepared according to the above method or, in some cases, with minor modifications to these methods using conventional chemical methods:
[1123] (3.2) 2-Methyl-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole. Calculated for C ₁₂ H ₁₆ NO ₄ PS + HBr + 0.1 CH ₂ Cl ₂ : C: 37.20; H: 4.44; N: 3.58. Found: C: 37.24; H: 4.56; N: 3.30.
[1124] (3.3) 4- [2- (5-Phosphono) furanyl] thiazole. C ₇ H ₆ NO ₄ PS + 0.65 Calculated for HBr: C: 29.63; H: 2.36; N: 4.94. Found: C: 29.92; H: 2.66; N, 4.57.
[1125] (3.4) 2-Methyl-4- [2- (5-phosphono) furanyl] thiazole. mp 235-236 [deg.] C. Calcd for C ₈ H ₈ NO ₄ PS + 0.25 H ₂ O: C: 38.48; H: 3.43; N: 5.61. Found: C: 38.68; H: 3.33; N: 5.36.
[1126] (3.5) 2-Phenyl-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole. Calcd for C ₁₇ H ₁₈ NO ₄ PS + HBr: C: 45.96; H: 4.31; N: 3.15. Found: C: 45.56; H: 4.26; N: 2.76.
[1127] (3.6) 2-Isopropyl-4- [2- (5-phosphono) furanyl] thiazole. mp 194-197 [deg.] C. Calcd for _{C 1O H 12 NO 4 PS:} C: 43.96; H: 4.43; N: 5.13. Found: C: 43.70; H: 4.35; N: 4.75.
[1128] (3.7) 5-Isobutyl-4- [2- (5-phosphono) furanyl] thiazole. mp 164-166 [deg.] C. Calcd for C ₁₁ H ₁₄ NO ₄ PS: C: 45.99; H: 4.91; N: 4.88. Found: C: 45.63; H: 5.01; N: 4.73.
[1129] (3.8) 2-Aminothiocarbonyl-4- [2- (5-phosphono) furanyl] thiazole. mp 189-191 [deg.] C. C ₈ H ₇ N ₂ 0 ₄ Calculated for PS ₂ : C: 33.10; H: 2.43; N: 9.65. Found: C: 33.14; H: 2.50; N: 9.32.
[1130] (3.9) Calculated for 2- (1-piperidyl) -5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole C ₁₆ H ₂₃ N ₂ 0 ₄ PS + 1.3 HBr : C: 40.41; H: 5.15; N: 5.89. Found: C: 40.46; H; 5.36; N: 5.53.
[1131] (3.10) 2- (2-thienyl) -5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole. C ₁₅ H ₁₆ NO ₄ Calculated for PS ₂ + 0.75 H ₂ O: C: 47.05; H: 4.61; N: 3.66. Found: C: 47.39; H: 4.36; N: 3.28.
[1132] (3.11) 2- (3-pyridyl) -5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole. C ₁₆ H ₁₇ N ₂ 0 ₄ PS + 3.75 Calculated for HBr: C: 28.78; H: 3.13; N: 4.20. Found: C: 28.73; H: 2.73; N, 4.53.
[1133] (3.12) 2-Acetamido-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole. mp 179-181 [deg.] C. Calcd for C ₁₃ H ₁₇ N ₂ O ₅ PS + 0.25 H ₂ O: C: 44.76; H: 5.06; N 8.03. Found: C: 44.73; H: 5.07; N: 7.89.
[1134] (3.13) 2-Amino-4- [2- (5-phosphono) furanyl] thiazole. Calcd for C ₇ H ₇ N ₂ 0 ₄ PS: C: 34.15; H: 2.87; N: 11.38. Found: C: 33.88; H: 2.83; N: 11.17.
[1135] (3.14) 2-Methylamino-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole. mp 202-205 ° C. Calcd for C ₁₂ H ₁₇ N ₂ 0 ₄ PS + 0.5 H ₂ O: C: 44.30; H: 5.58; N: 8.60. Found: C: 44.67; H: 5.27; N: 8.43.
[1136] (3.15) 2- (N-Amino-N-methyl) amino-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole. mp 179-181 [deg.] C. C ₁₂ H ₁₈ N ₃ 0 ₄ PS + 1.25 Calculated for HBr: C: 33.33; H: 4.49; N: 9.72. Found: C: 33.46; H: 4.81; N: 9.72.
[1137] (3.16) 2-Amino-5-methyl-4- [2- (5-phosphono) furanyl] thiazole. mp 200-220 C. C ₈ H ₉ N ₂ 0 ₄ PS + 0.65 Calculated for HBr: C: 30.72; H: 3.11; N: 8.96. Found: C: 30.86; H: 3.33; N: 8.85.
[1138] (3.17) 2,5-dimethyl-4- [2- (5-phosphono) furanyl] thiazole. mp 195 [deg.] C (decomposition). Calcd for _{C 9 H 1O N0 4 PS +} 0.7 HBr: C: 34.22; H: 3.41; N: 4.43. Found: C: 34.06; H: 3.54; N: 4.12.
[1139] (3.18) 2-Aminothiocarbonyl-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole. C ₁₂ H ₁₅ N ₂ 0 ₄ PS ₂ + 0.1 HBR + 0.3 Calculated for EtOAc: C: 41.62; H: 4.63; N: 7.35. Found: C: 41.72; H: 4.30; N: 7.17.
[1140] (3.19) 2-Ethoxycarbonyl-4- [2- (5-phosphono) furanyl] thiazole. mp 163-165 [deg.] C. Calcd for _{C 1O H 1O N0 6 PS +} 0.5 H 2 0: C: 38.47; H: 3.55; N: 4.49. Found: C: 38.35; H: 3.30; N: 4.42.
[1141] (3.20) 2-Amino-5-isopropyl-4- [2- (5-phosphono) furanyl] thiazole .. Anal.Caled. forCl3H3N2O4PS + 1HBr: C: 32.53; H: 3.82; N: 7.59. Found: C: 32.90; H: 3.78; N: 7.65.
[1142] (3.21) 2-Amino-5-ethyl-4- [2- (5-phosphono) furanyl] thiazole. mp> 250 [deg.] C. C ₉ H ₁₁ N ₂ 0 ₄ Calculated for PS: C: 39.42; H: 4.04; N: 10.22. Found: C: 39.02; H: 4.15; N: 9.92.
[1143] (3.22) 2-Cyanomethyl-4- [2- (5-phosphono) furanyl] thiazole. mp 204 - 206 ℃ .C calculated for _{9 H 7 N 2 0 4 PS} : C: 40.01; H; 2.61; N: 10.37. Found: C: 39.69; H: 2.64; N: 10.03.
[1144] (3.23) 2-Aminothiocarbonylamino-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole. mp 177-182 [deg.] C. C ₁₂ H ₁₆ N ₃ 0 ₄ PS ₂ + 0.2 Hexane + 0.3 Calculated for HBr: C: 39.35; H: 4.78; N: 10.43. Found: C: 39.61; H: 4.48; N: 10,24.
[1145] (3.24) 2-Amino-5-propyl-4- [2- (5-phosphono) furanyl] thiazole. mp 235-237 [deg.] C. Calculated for C ₁₀ H ₁₃ N ₂ 0 ₄ PS + 0.3 H ₂ O: C: 40.90; H: 4.67; N: 9.54. Found: C: 40.91; H: 4.44; N: 9.37.
[1146] (3.25) 2-Amino-5-ethoxycarbonyl-4- [2- (5-phosphono) furanyl] thiazole. mp 248-250 [deg.] C. C ₁₀ H ₁₁ N ₂ 0 ₆ PS + 0.1 Calculated for HBr: C: 36.81; H: 3.43; N: 8.58. Found: C: 36.99; H: 3.35; N: 8.84.
[1147] (3.26) 2-Amino-5-methylthio-4- [2- (5-phosphono) furanyl] thiazole. mp 181-184 [deg.] C. C ₈ H ₉ N ₂ 0 ₄ Calculated for PS ₂ + 0.4 H ₂ O: C: 32.08; H: 3.30; N: 9.35. Found: C: 32.09; H: 3.31; N: 9.15.
[1148] (3.27) 2-Amino-5-cyclopropyl-4- [2- (5-phosphono) furanyl] thiazole. C ₁₀ H ₁₁ N ₂ 0 ₄ PS + 1 H ₂ 0 + 0.7 Calculated for HBr: C: 32.91; H: 3.80; N: 7.68. Found: C: 33.10; H: 3.80; N: 7.34.
[1149] (3.28) 2-Amino-5-methanesulfinyl-4- [2- (5-phosphono) furanyl] thiazole. mp > 250 C. C ₈ H ₉ N ₂ 0 ₅ PS ₂ + 0.35 NaCl: C: 29.23; H: 2.76; N: 8.52. Found: C: 29.37; H: 2.52; N: 8.44,
[1150] (3.29) 2-Amino-5-benzyloxycarbonyl-4- [2- (5-phosphono) furanyl] thiazole. Calcd for C ₁₅ H ₁₃ N ₂ O ₆ PS + 0.2 H ₂ O: C: 46.93; H: 3.52; N: 7.30. Found: C: 46.64; H: 3.18; N: 7.20.
[1151] (3.30) 2-Amino-5-cyclobutyl-4- [2- (5-phosphono) furanyl] thiazole. C ₁₁ H ₁₃ N ₂ O ₄ PS + 0.15 HBr + 0.15 Calculated for H ₂ O: C: 41.93; H: 4.30; N: 8.89. Found: C: 42.18; H: 4.49; N: 8.53.
[1152] (3.31) 2-Amino-5-cyclopropyl-4- [2- (5-phosphono) furanyl] thiazole hydrobromide. C ₁₀ H ₁₁ N ₂ 0 ₄ PSBr + 0.73 HBr + 0.15 MeOH + 0.5 H ₂ O: C: 33.95; H: 3.74; N: 7.80; S: 8.93; Br: 16.24. Found: C: 33.72; H: 3.79; N: 7.65; S: 9.26; Br: 16.03.
[1153] (3.32) 2-Amino-5 - [(N, N-dimethyl) aminomethyl] -4- [2- (5-phosphono) furanyl] thiazole dihydrobromide. C ₁₀ H ₁₆ N ₃ O ₄ Br ₂ PS + 0.8 CH ₂ Cl ₂ : C: 24.34; H: 3.33; N: 1.88. Found: C: 24.23; H: 3.35; N: 7.64.
[1154] (3.33) 2- amino-5-methoxycarbonyl-4- [2- (5-phosphono) furanyl] thiazole. Mp 227 캜 (decomposition). C ₉ H ₉ N ₂ O ₆ PS + 0.1 H ₂ O + 0.2 HBr: C: 33.55; H: 2.94; N: 8.69. Found: C: 33.46; H: 3.02; N: 8.49.
[1155] (3.34) 2-Amino-5-ethylthiocarbonyl-4- [2- (5-phosphono) furanyl] thiazole. Mp 245 DEG C (decomposition). C ₁₀ H ₁₁ N ₂ 0 ₅ Calculated for PS ₂ : C: 35.93; H: 3.32; N: 8.38. Found: C: 35.98; H: 3.13; N: 8.17.
[1156] (3.35) 2-Amino-5-propyloxycarbonyl-4- [2- (5-phosphono) furanyl] thiazole. Mp 245 DEG C (decomposition). C ₁₁ H ₁₃ N ₂ O ₆ PS: C: 39.76; H: 3.94; N: 8.43. Found: C: 39.77; H: 3.72; N: 8.19.
[1157] (3.36) 2-Amino-5-benzyl-4- [2- (5-phosphono) furanyl] thiazole. Calcd for C ₁₄ H ₁₃ N ₂ 0 ₄ PS + H ₂ O: C: 47.46; H: 4.27; N: 7.91. Found: C: 47.24; H: 4.08; N: 7.85.
[1158] (3.37) 2-Amino-5 - [(N, N-diethyl) aminomethyl] -4- [2- (5-phosphono) furanyl] thiazole dihydrobromide. C ₁₂ H ₂₀ N ₃ 0 ₄ Br ₂ PS + 0.1 HBr + 1.4 MeOH: C; 29.47; H: 4.74; N: 7.69. Found: C: 29.41; H: 4.60; N: 7.32.
[1159] (3.38) 2-Amino-5 - [(N, N-dimethyl) carbamoyl) -4- [2- (5-phosphono) furanyl] thiazole. C ₁₀ H ₁₂ N ₃ 0 ₅ PS + 1.3 HBr + 1.OH ₂ 0 + 0.3 Calcd for acetone: C: 28.59; H: 3.76; N: 9.18. Found: C: 28.40; H: 3.88; N 9.01.
[1160] (3.39) 2-Amino-5-carboxy-4- [2- (5-phosphono) furanyl] thiazole. C ₈ H ₇ N ₂ 0 ₆ PS + 0.2 HBr + 0.1 H ₂ O: C: 31, 18; H: 2.42; N, 9.09. Found: C: 31.11; H: 2.42; N: 8.83.
[1161] (3.40) 2-Amino-5-isopropyloxycarbonyl-4- [2- (5-phosphono) furanyl] thiazole. Mp 240 캜 (decomposition). C ₁₁ H ₁₃ N ₂ O ₆ Calculated for PS: C: 39.76; H: 3.94; N: 8.43. Found: C: 39.42; H: 3.67; N 8.09.
[1162] (3.41) 2-Methyl-5-ethyl-4- [2- (5-phosphono) furanyl] thiazole. C ₁₀ H ₁₂ 0 ₄ PNS + 0.75 HBr + 0.35 H ₂ O: C: 36.02; H: 4.13; N, 4.06. Found: C: 36.34; H: 3.86; N: 3.69.
[1163] (3.42) 2-Methyl-5-cyclopropyl-4- [2- (5-phosphono) furanyl] thiazole. C ₁₁ H ₁₂ NO ₄ PS + 0.3 HBr + 0.5 CHCl ₃ : C: 37.41; H: 3.49; N: 3.79. Found: C: 37.61; H: 3.29; N: 3.41.
[1164] (3.43) 2-Methyl-5-ethoxycarbonyl-4- [2- (5-phosphono) furanyl] thiazole. Calcd for C ₁₁ H ₁₃ N ₂ O ₆ PS: C: 41, 64; H: 3.81; N: 4.40. Found: C: 41.61; H: 3.78; N: 4.39.
[1165] (3.44) 2 - [(N-acetyl) amino l-5-methoxymethyl-4- [2- (5-phosphono) furanyl] thiazole. C ₁₁ H ₁₃ N ₂ O ₆ PS + 0.15 HBr: C: 38.36; H: 3.85; N: 8.13, found: C: 38.74; H: 3.44; N: 8.13.
[1166] (3.45) 2-Amino-5- (4-morpholinyl) methyl-4- [2- (5-phosphono) furanyl] thiazole dihydrobromide. C ₁₂ H ₁₈ Br ₂ N ₃ 0 ₅ PS + 0.25 Calculated for HBr: C: 27.33; H: 3.49; N: 7.97. Found: C: 27.55; H: 3.75; N: 7.62.
[1167] (3.46) 2-Amino-5-cyclopropylmethoxycarbonyl-4- [2- (5-phosphono) furanyl] thiazole Mp 238 C (decomposition). Calcd for C ₁₂ H ₁₃ N ₂ O ₆ PS: C: 41.86; H: 3.81; N: 8.14. Found: C: 41.69; H: 3.70; N 8.01.
[1168] (3.47) 2-Amino-5-methylthio-4- [2- (5-phosphono) furanyl] thiazole N, N-dicyclohexylammonium salt. Mp > C ₈ H ₉ N ₂ 0 ₄ PS ₂ + 1.15 Calculated for C ₁₂ H ₂₃ N: C: 52.28; H: 7.13; N: 8.81. Found: C: 52.12; H: 7.17; N: 8.81.
[1169] (3.48) 2 - [(N-diryl) amino] -5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole. C ₂₃ H ₂₆ N ₃ O ₆ PS ₂ + 0.5 HBr: C: 47.96; H: 4.64; N: 7.29. Found: C: 48.23; H: 4.67; N: 7.22.
[1170] (3.49) 2-Amino-5- (2,2,2-trifluoroethyl) -4- [2- (5-phosphono) furanyl] thiazole. C ₉ H ₈ N ₂ F ₃ OPS: C: 32.94, H: 2.46, N: 8.54. Found: C: 32.57, H: 2.64, N: 8.14.
[1171] (3.50) 2-Methyl-5-methylthio-4- [2- (5-phosphono) furanyl] thiazole. Calcd for C ₉ H ₁₀ N 0 ₄ PS ₂ : C: 37.11; H: 3.46; N: 4.81. Found: C: 36.72; H: 3.23; N: 4.60.
[1172] (3.51) 2-Amino-5-methylthio-4- [2- (5-phosphono) furanyl] thiazole ammonium salt. C ₈ H ₁₂ N ₃ 0 ₄ Calculated for PS ₂ : C: 31.07; H: 3.91; N: 13.59. Found: C: 31.28; H: 3.75; N: 13.60.
[1173] (3.52) 2-Cyano-5-ethyl-4- [2- (5-phosphono) furanyl] thiazole. Calcd for C ₁₀ H ₉ N ₂ 0 ₄ PS: 42.26; H 3.19; N: 9.86. Found: C: 41.96; H: 2.95; N: 9.76.
[1174] (3.53) 2-Amino-5-hydroxymethyl-4- [2- (5-phosphono) furanyl] thiazole. C ₈ H ₉ N ₂ 0 ₅ Calculated for PS: C: 34.79; H: 3.28; N: 10.14. Found: C: 34.57; H: 3.00; N: 10.04.
[1175] (3.54) 2-Cyano-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole. C ₁₂ H ₁₃ N ₂ 0 ₄ SP + 0.09 Calculated for HBr: C: 46.15; H: 4.20; N: 8.97. Found: C: 44.81; H: 3.91; N: 8.51.
[1176] (3.55) 2-Amino-5-isopropylthio-4- [2- (5-phosphono) furanyl] thiazole hydrobromide. C ₁₀ H ₁₄ BrN ₂ O ₄ Calculated for PS ₂ : C: 29.94; H: 3.52; N: 6.98. Found: C: 30.10; H: 3.20; N, 6.70.
[1177] (3.56) 2-Amino-5-phenylthio-4- [2- (5-phosphono) furanyl] thiazole. C ₁₃ H ₁₁ N ₂ 0 ₄ Calculated for PS ₂ : C: 44.07; H: 3.13; N: .91. Found: C: 43.83; H: 3.07; N: 7.74.
[1178] (3.57) 2-Amino-5-tert-butylthio-4- [2- (5-phosphono) furanyl] thiazole. C ₁₁ H ₁₅ N ₂ 0 ₄ PS ₂ + 0.6CH ₂ CH ₂ : C: 36.16; H: 4.24; N: 7.27. Found: C: 36.39; H: 3.86; N: 7.21.
[1179] (3.58) 2-Amino-5-propylthio-4- [2- (5-phosphono) furanyl] thiazole hydrobromide. C ₁₀ H ₁₄ BrN ₂ O ₄ Calculated for PS ₂ : C: 29.94; H: 3.52; N: 6.98. Found: C: 29.58; H: 3.50; N: 6.84.
[1180] (3.59) 2-Amino-5-ethylthio-4- [2- (5-phosphono) furanyl] thiazole. C ₉ H ₁₁ N ₂ 0 ₄ PS ₂ + 0.25 Calculated for HBr: C: 33.11; H: 3.47; N: 8.58. Found: C: 33.30; H: 3.42; N: 8.60.
[1181] (3.60) 2 - [(N-tert-butyloxycarbonyl) amino] -5-methoxymethyl-4- [2- (5-phosphono) furanyl] thiazole. Calcd for C ₁₄ H ₁₉ NO ₂ PS: C: 43.08; H: 4.91; N: 7.18. Found: C: 42.69; H: 4.58; N: 7.39.
[1182] (3.61) 2-Hydroxyl-4- [2- (5-phosphono) furanyl] thiazole. Calcd for C ₇ H ₆ NO ₅ PS: C: 34.02; H: 2.45; N: 5.67. Found: C: 33.69; H: 2.42; N: 5.39.
[1183] (3.62) 2-Hydroxy-5-ethyl-4- [2- (5-phosphono) furanyl] thiazole. Calcd for C ₉ H ₁₀ NO ₅ PS: C: 39.28; H: 3.66; N, 5.09. Found: C: 39.04; H: 3.44; N: 4.93.
[1184] (3.63) 2-Hydroxy-5-isopropyl-4- [2- (5-phosphono) furanyl] thiazole. Calcd for _{C 1O H 12 NO 5 PS +} O.1 HBr: C: 40.39; H: 4.10; N: 4.71. Found: C: 40.44; H: 4.11; N: 4.68.
[1185] (3.64) 2-Hydroxyl-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole. Calcd for C ₁₁ H ₁₄ NO ₅ PS: C: 43.57; H; 4.65; N: 4.62. Found: C: 43.45; H: 4.66; N: 4.46.
[1186] (3.65) 5-Ethoxycarbonyl-4- [2- (5-phosphono) furanyl] thiazole. C ₁₀ H ₁₀ NO ₆ Calculated for PS: C: 39.61; H: 3.32; N: 4.62. Found: C: 39.60; H: 3.24; N: 4.47.
[1187] (3.66) 2-Amino-5-vinyl-4- [2- (5-phosphono) furanyl] thiazole. Calcd for C ₉ HN ₂ O ₄ PS + 0.28 HCl: C: 37.66; H: 3.26; N: 9.46. Found: C: 37.96; H: 3.37; N: 9.10.
[1188] (3.67) 2-Amino-4- [2- (6-phosphono) pyridyl] thiazole hydrobromide.
[1189] (3.68) 2-Methylthio-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole. Calcd for C ₁₂ H ₁₆ NO ₄ PS ₂ : C: 43.24; H: 4.84; N: 4.20. Found: C: 43.55; H: 4.63; N: 4.46.
[1190] (3.69) 2-Amino-5-isobutyl-4- [2- (3-phosphono) furanyl] thiazole. Calcd for C ₁₁ H ₁₅ N ₂ 0 ₄ PS + 0.1 H ₂ O: C: 43.45; H: 5.04; N: 9.21. Found: C: 43.68; H: 5.38; N: 8.98.
[1191] (3.70) 2-Amino-5-isobutyl-4- [2- (5-phosphono) furanyl] selenazole. C ₁₀ H ₁₅ N ₂ 0 ₄ PSe + 0.14 HBr + 0.6 Calculated for EtOAc: C: 38.93; H: 4.86; N: 6.78. Found: C: 39.18; H: 4.53; N: 6.61.
[1192] (3.71) 2-Amino-5-methylthio-4- [2- (5-phosphono) furanyl] selenazole. C ₈ H ₉ N ₂ O ₄ PSSe + 0.7 HBr + 0.2 Calculated for EtOAc: C: 25.57; H: 2.75; N: 6.78. Found: C: 25.46; H: 2.49; N: 6.74.
[1193] (3.72) 2-Amino-5-ethyl-4- [2- (5-phosphono) furanyl) selenazole. Calcd for C ₉ H ₁₁ N ₂ 0 ₄ PSe + HBr: C: 26.89; H: 3.01; N: 6.97. Found: C: 26.60; H: 3.16; N: 6.81.
[1194] <Example 4>
[1195] Preparation of 5-halo-4- [2- (5-phosphono) furanyl] thiazole.
[1196] Step A. A solution of 2-amino-4- [2- (5-diethylphosphino) furanyl] thiazole (prepared as in Step B of Example 3) (1 mmole) in chloroform was treated with 1 (NBS) &lt; / RTI &gt; (1.5 mmole). Extraction and chromatography afforded 2-amino-5-bromo-4- [2- (5-diethylphosphono) furanyl] -thiazole as a brown solid.
[1197] Amino-5-bromo-4- [2- (5-diethylphosphono) furanyl] thiazole was treated in analogy to step 3 of Example 3 to give 2-amino- 4- [2- (5-phosphono) -furanyl] thiazole (4.1) as a yellow solid. mp> 230 [deg.] C. Calculated for C ₇ H ₆ N ₂ 0 ₄ PSBr: C: 25.86; H: 1.86; N: 8.62. Found: C: 25.93; H: 1.64; N: 8.53.
[1198] The following compounds were prepared by this method:
[1199] (4.2) 2-Amino-5-chloro-4- [2- (5-phosphono) furanyl] thiazole. Calcd for C ₇ H ₆ N ₂ 0 ₄ PSCl: C: 29.96; H: 2.16; N: 9.98. Found: C: 29.99; H: 1.97; N: 9.75.
[1200] (4.3) 2-Amino-5-iodo-4- [2- (5-phosphono) furanyl] thiazole. Calcd for C ₇ H ₆ N ₂ 0 ₄ PSI: C: 22.42; H: 2.28; N, 6.70. Found: C: 22.32; H: 2.10; N: 6.31.
[1201] (4.4) 2,5-Dibromo-4- [2- (5-phosphono) furanyl] thiazole. Calcd for C ₇ H ₄ NO ₄ PSBr ₂ : C: 21.62; H: 1.04; N: 3.60. Found: C: 21.88; H: 0.83; N: 3.66.
[1202] &Lt; Example 5 >
[1203] Preparation of 2-halo-4- [2- (5-phosphono) furanyl] thiazole.
[1204] Step A. A solution of 2-amino-5-isobutyl-4- [2- (5-diethylphosphono) -furanyl] thiazole (prepared as in Example 3, Step B) (1 mmole) Was treated with copper (II) bromide bromide (1.2 mmole) and isoamyl nitrite (1.2 mmole) at 0 &lt; 0 &gt; C for 1 hour. Extraction and chromatography afforded 2-bromo-5-isobutyl-4- [2- (5 diethylphosphono) furanyl] thiazole as a brown solid.
[1205] Step B. Treatment of 2-bromo-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole Prepared similarly to step 3 of Example 3 to give 2-bromo- -4- [2- (5-phosphono) furanyl] thiazole (5.1) was obtained as yellow hygroscopic solid. Calcd for C ₁₁ H ₁₃ NO ₄ PSBr: C: 36.08; H: 3.58; N: 3.83. Found: C: 36.47; H: 3.66; N: 3.69.
[1206] The following compounds were prepared by this method:
[1207] (5.2) 2-Chloro-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole: Calculated for C ₁₁ H ₁₃ NO ₄ PSCl: C: 41,07; H: 4.07; N: 4.35. Found: C: 40.77; H: 4.31; N: 4.05.
[1208] Calcd for _{C 8 H 7 NO 4 PS 2} Br:: (5.3) 2- Bromo-5-methylthio-4- [2- (5-phosphono) furanyl] thiazole C: 26.98; H: 1.98; N: 3.93. Found: C: 27.21; H: 1.82; N: 3.84.
[1209] &Lt; Example 6 >
[1210] Preparation of various 2- and 5-substituted 4- [2- (5-phosphono) furanyl] thiazoles
[1211] Step A. To a solution of 2-bromo-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole (1 mmole, prepared as in Step A of Example 5) Was treated with tributyl (vinyl) tin (5 mmole) and palladium bis (triphenylphosphine) dichloride (0.05 mmole) at 100 &lt; 0 &gt; C under a nitrogen atmosphere. The cooled reaction mixture was evaporated after 5 hours and the residue was chromatographed to give 2-vinyl-5-isobutyl-4- [2- (5 diethylphosphono) furanyl] thiazole as a yellow solid.
[1212] Step B. Treatment of 2-vinyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole as in step C of Example 3 afforded 2-vinyl- 4- [2- (5-phosphono) furanyl) thiazole (6.1) as a yellow solid. C ₁₃ H ₁₆ NO ₄ PS + 1 Calculated for HBR + 1 H ₂ O: C: 39.43; H: 4.38; N: 3.54. Found: C: 39.18; H: 4.38; N: 3.56.
[1213] In addition, this method can be used to prepare various 5-substituted 4- [2- (5-phosphono) furanyl] thiazoles from their corresponding halides.
[1214] Step C. Treatment of 2-amino-5-bromo-4- [2- (5-diethylphosphono) furanyl] thiazole as in step A using 2-tributylstannylfuran as a coupling pair Amino-5- (2-furanyl) -4- [2- (5-diethylphosphino) furanyl] thiazole.
[1215] Step D. Treatment of 2-amino-5- (2-furanyl) -4- [2- (5-diethylphosphono) furanyl] thiazole Prepared similarly to step 3 of Example 3 to give 2-amino- (2-furanyl) -4- [2- (5-phosphono) furanyl] thiazole (6.2). mp 190-210 [deg.] C. C ₁₁ H ₉ N ₂ O ₅ PS + 0.25 Calculated for HBr: C: 39.74; H: 2.80; N: 8.43. Found: C: 39.83; H: 2.92; N: 8.46.
[1216] The following compounds were prepared by this method:
[1217] (6.3) 2-Amino-5- (2-thienyl) -4- [2- (5-diethylphosphono) furanyl] thiazole. Calcd for C ₁₁ H ₉ N ₂ O ₄ PS ₂ +0.3 EtOAc + 0.11 HBr: C: 40.77; H: 3.40; N: 7.79. Found: C: 40.87; H: 3.04; N: 7.45.
[1218] &Lt; Example 7 >
[1219] Preparation of 2-ethyl-4- [2- (5-phosphono) furanyl] thiazole.
[1220] Step A. A solution of 2-vinyl-5-isobutyl-4- [2- (5-diethylphosphino) furanyl] thiazole (1 mmole, prepared as in Step A of Example 6) in ethanol Was treated with palladium on carbon (0.05 mmole) for 12 hours under 1 atmosphere of hydrogen. The reaction mixture was filtered and the filtrate was evaporated and the residue was purified by chromatography to give 2-ethyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole as yellow foam .
[1221] Step B. Treatment of 2-ethyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole as in step C of Example 3 afforded 2-ethyl- 4- [2- (5-phosphono) furanyl] thiazole (7.1) as a yellow solid. C ₁₃ H ₁₈ NO ₄ PS + 1 Calculated for HBR: C: 39.41; H: 4.83; N: 3.53. Found: C: 39.65; H: 4.79; N: 3.61.
[1222] &Lt; Example 8 >
[1223] Preparation of 4-phosphonomethoxymethyl thiazole.
[1224] Step A. A solution of diethylhydroxymethylphosphonate (1 mmole) in DMF was treated with sodium hydride (1.2 mmole) at 0 ° C followed by treatment of 2-methyl-4-chloromethylthiazole (1 mmole) The mixture was stirred at 25 DEG C for 12 hours. Extraction and chromatography gave 2-methyl-4- (diethylphosphonomethoxymethyl) thiazole.
[1225] Step B. 2-Methyl-4-diethylphosphonomethoxymethylthiazole was treated as in Step C of Example 3 to give 2-methyl-4-phosphonomethoxymethylthiazole (8.1). C ₆ H ₁₀ N 0 ₄ PS + 0.5 Calculated for HBr + 0.5 H ₂ O: C: 26.43; H: 4.25; N: 5.14. Found: C: 26.52; H: 4.22; N: 4.84.
[1226] Step C. 2-Methyl-4-diethylphosphonomethoxymethylthiazole was treated as in step A of Example 4 and treated as in step C of Example 3 to give 5-bromo-2-methyl-4 -Phosphonomethoxymethyl thiazole (8.2). Calculation for C ₆ H ₉ NO ₄ PSBr + 0.5 HBr: C: 21.04; H: 2.80; N: 4.09, found: C: 21.13; H: 2.69; N, 4.01.
[1227] Step D. A solution of ethyl 2 - [(N-Boc) amino] -4- thiazole carboxylate (1 mmole) in CH ₂ Cl ₂ (10 mL) was cooled to -78 ° C and DIBAL- 5 mL). The reaction was stirred at -60 ℃ for 3 hours, quenched with a suspension of _{NaF / H 2 O (1 g} / 1 mL). The resulting mixture was filtered and the filtrate was concentrated to give 2 - [(NBoc) amino] -4-hydroxymethylthiazole as a solid.
[1228] Step E. A solution of 2 - [(N-Boc) amino] -4-hydroxymethylthiazole (1 mmole) in DMF (10 mL) was cooled to 0 C and treated with NaH (1.1 mmole). The mixture was stirred at room temperature for 30 minutes and then phosphomethyltrifluoromethane sulfonate (1.1 mmole) was added. After stirring at room temperature for 4 hours, the reaction was evaporated to dryness. The residue was chromatographed to give 2 - [(N-Boc) amino] -4-diethylphosphonomethoxymethyl thiazole as a solid.
[1229] Step F. 2 - [(N-Boc) amino] -4-diethylphosphonomethoxymethyl thiazole was treated as in Example 3, step C to give 2-amino-4-phosphonomethoxymethyl thiazole 8.3) as a solid. C ₅ H ₉ N ₂ 0 ₄ PS + 0.16 HBr + 0.1 Calculated for MeOH: C: 25.49; H: 4.01; N: 11.66. Found: C: 25.68; H: 3.84; N: 11.33.
[1230] &Lt; Example 9 >
[1231] Preparation of 2-carbamoyl- [4- [2- (5-phosphono) furanyl] thiazole.
[1232] Step A. Saturated methanol A solution of 2-ethoxycarbonyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole (1 mmole) in ammonia solution was stirred at 25 &Lt; / RTI &gt; Evaporation and chromatography afforded 2-carbamoyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole as a white solid.
[1233] Step B. Treatment of 2-carbamoyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole as in step 3 of Example 3 provided 2-carbamoyl- -Isobutyl-4- [2- (5-phosphono) furanyl] thiazole (9.1) as a solid. mp 185 - 186 ° C. Calcd for C ₁₂ H ₁₅ N ₂ 0 ₅ PS: C: 43.64; H: 4.58; N: 8.48. Found: C: 43.88; H: 4.70; N: 8.17.
[1234] The following compounds were prepared by this method:
[1235] (9.2) 2-Carbamoyl-4- [2- (5-phosphono) furanyl] thiazole. mp 195 - 200 [deg.] C. Calcd for C ₈ H ₇ N ₂ 0 ₅ PS + 0.25H ₂ O: C: 34.48; H: 2.71; N: 10.05. Found: C: 34.67; H: 2.44; N: 9.84.
[1236] Further conversion of 2-ethoxycarbonyl-4- [2- (5-diethylphosphono) furanyl] thiazole to other 2-substituted 4- [2- (5-phosphono) furanyl] thiazole can do.
[1237] Step C. A solution of 2-ethoxycarbonyl-4- [2- (5-diethylphosphono) furanyl] thiazole (1 mmole) in methanol was treated with sodium borohydride (1.2 mmole ). Extraction and chromatography afforded 2-hydroxymethyl-4- [2- (5-diethylphosphono) furanyl] thiazole.
[1238] Step D. Treatment of 2-hydroxymethyl-4- [2- (5-diethylphosphono) furanyl] -thiazole as in Step 3 of Example 3 provided 2-hydroxymethyl-4- [2- (5-phosphono) furanyl] thiazole (9.3). mp 205-207 [deg.] C. Calculated for C ₈ H ₈ NO ₅ PS + 0.25 H ₂ O: C: 36.16; H: 3.22; N: 5.27. Found: C: 35.98; H: 2.84; N: 5.15.
[1239] The following compounds were prepared by this method:
[1240] (9.4) 2-hydroxymethyl-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole. mp 160-170 [deg.] C. C ₁₂ H ₁₆ NO ₅ PS + 0.75 Calculated for HBr: C: 38.13; H: 4.47; N: 3.71. Found: C: 37.90; H: 4.08; N: 3.60.
[1241] Step E. To a solution of 2-hydroxymethyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole (1 mmole) in methylene chloride was added (1.2 mmole). Extraction and chromatography afforded 2-bromomethyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole.
[1242] Step F. 2-Bromomethyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] -thiazole By proceeding as in step 3 of Example 3, 2- - isobutyl-4- [2- (5-phosphono) furanyl] thiazole (9.5). mp 161-163 ° C. Calcd for C ₁₂ H ₁₅ BrNO ₄ PS + 0.25 HBr: C: 35.99; H: 3.84; N: 3.50. Found: C: 36.01; H: 3.52; N: 3.37.
[1243] The following compounds were prepared by this method:
[1244] (9.6) 2-Bromomethyl-4- [2- (5-phosphono) furanyl] thiazole. mp> 250 [deg.] C. Calcd for C ₈ H ₇ BrNO ₄ PS: C: 29.65; H: 2.18; N: 4.32. Found: C: 29.47; H: 1.99; N: 4.16.
[1245] Step G. A solution of 2-hydroxymethyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole (1 mmole) in methylene chloride was treated with thionyl Chloride (1.2 mmole). Extraction and chromatography afforded 2-chloromethyl-5-isobutyl-4- [2- (5-diethylphosphino) furanyl] thiazole.
[1246] Step H. Treatment of 2-chloromethyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] -thiazole In analogy to example 3 steps C there was obtained 2-chloromethyl- Butyl-4- [2- (5-phosphono) furanyl] thiazole (9.7). mp 160 - 162 캜. C ₁₂ H ₁₅ ClNO ₄ PS + 0.45 Calculated for HBr: C: 38.73; H: 4.18; N: 3.76. Found: C: 38.78; H: 4.14; N: 3.73.
[1247] Step I. A solution of 2-bromomethyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole (1 mmole) in DMF was treated with potassium phthalate (1.2 mmole). Extraction and chromatography gave 2-phthalimidomethyl-5-isobutyl-4- [2- (5-diethylphosphino) furanyl] thiazole.
[1248] (1.5 mmol) of 2-phthalimidomethyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole (1 mmole) in ethanol at 25 &lt;Lt; / RTI &gt; Filtration, evaporation and chromatography gave 2-aminomethyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] thiazole.
[1249] Step K. 2-Aminomethyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] -thiazole By proceeding as in step 3 of Example 3 2-Aminomethyl- Butyl-4- [2- (5-phosphono) furanyl] thiazole (9.8). mp 235-237 [deg.] C. C ₁₂ H ₁₇ N ₂ 0 ₄ PS + 0.205 Calculated for HBr: C: 43.30; H: 5.21; N: 8.41. Found: C: 43.66; H: 4.83; N 8.02.
[1250] The following compounds were prepared according to, or in some cases slightly modified, the above method:
[1251] (9.9) 2-Carbamoyl-5-cyclopropyl-4- [2- (5-phosphono) furanyl] thiazole. Calcd for C ₁₁ H ₁₁ N ₂ O ₅ PS + 0.15HBr: C: 40.48; H: 3.44; N: 8.58. Found: C: 40.28; H: 3.83; N: 8.34.
[1252] (9.10) 2-Carbamoyl-5-ethyl-4- [2- (5-phosphono) furanyl] thiazole. Calcd for _{C 10 H 11 N 2 O 5} PS + 0.75H 2 O: C: 38.04; H: 3.99; N: 8.87. Found: C: 37.65; H: 3.93; N: 8.76.
[1253] &Lt; Example 10 >
[1254] Preparation of 4- [2- (5-phosphono) furanyl] oxazole and 4- [2- (5-phosphono) furanyl] imidazole
[1255] Step A. To a solution of 5-diethylphosphono-2 - [(2-bromo-4-methyl-1-oxo) pentyl] furan (1 mmole) in t- Respectively. Filtration, evaporation and chromatography afforded 2-amino-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] oxazole and 2-hydroxy- (5-diethylphosphino) furanyl] imidazole.
[1256] Step B. Treatment of 2-amino-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] oxazole as in step C of Example 3 provided 2-amino- 4- [2- (5-phosphono) furanyl] oxazole (10.1). mp 250 [deg.] C (decomposition). Calcd for C ₁₁ H ₁₁ N ₂ O ₅ P: C: 46.16; H: 5.28; N: 9.79. Found: C: 45.80; H: 5.15; N: 9.55.
[1257] Step C. 2-Hydroxy-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] imidazole was treated as in Step 3 of Example 3 to give 2-hydroxy- Butyl-4- [2- (5-phosphono) furanyl] imidazole (10.14). mp 205 [deg.] C (decomposition). Calcd for C ₁₁ H ₁₁ N ₂ O ₅ P: C: 46.16; H: 5.28; N: 9.79. Found: C: 45.80; H: 4.90; N: 9.73.
[1258] Alternatively, 4- [2- (5-phosphono) furanyl] oxazole and 4- [2- (5-phosphono) furanyl] imidazole can be prepared as follows.
[1259] Step D. 4-Diethylphosphono-2 - [(2-bromo-4-methyl-1-oxo) pentyl] furan in acetic acid (1 mmole) Lt; / RTI &gt; and treated with ammonium acetate (2 mmole). Evaporation and chromatography afforded 2-methyl-5-isobutyl-4- [2- (5-diethylphosphono) furanyl] -Diethylphosphono) furanyl] oxazole and 2-methyl-5-isobutyl-4- [2- (5-diethylphosphino) furanyl] imidazole.
[1260] Step E. Preparation of 2-methyl-5-isobutyl-4- [2- (5-diethylphosphono) Methyl-5-isobutyl-4- [2- (5 diethylphosphono) furanyl] imidazole was treated as in step C of Example 3 to give the following compounds :
[1261] (10.18) 2-Methyl-4-isobutyl-5- [2- (5-phosphono) furanyl] oxazole hydrobromide. mp > 230 DEG C; Calcd for C ₁₂ H ₁₇ BrNO ₅ P + 0.4 H ₂ O: C: 38.60; H: 4.81; N: 3.75. Found: C: 38.29; H: 4.61; N: 3.67.
[1262] (10.19) 2-Methyl-5-isobutyl-4- [2- (5-phosphono) furanyl] oxazole hydrogen bromide. Calcd for C ₁₂ H ₁₇ BrNO ₅ P: C: 39.36; H: 4.68; N: 3.83. Found: C: 39.33; H: 4.56; N: 3.85.
[1263] (10.21) 2-Methyl-5-isobutyl-4- [2- (5-phosphono) furanyl] imidazole hydrogen bromide. Calcd for C ₁₂ H ₁₈ BrN ₂ O ₄ P + 0.2 NH ₄ Br: C: 37.46; H: 4.93; N 8.01. Found: C: 37.12; H: 5.11; N: 8.28,
[1264] Alternatively, 4- [2- (5-phosphono) furanyl] imidazole can be prepared as follows:
[1265] Step F. A solution of 5-diethylphosphono-2- (bromoacetyl) furan (1 mmole) in ethanol was treated with trifluoroacetamidine (2 mmole) at 80 <0> C for 4 hours. Evaporation and chromatography afforded 2-trifluoromethyl-4- [2- (5-diethylphosphono) furanyl] imidazole as an oil.
[1266] Step G. 2-Trifluoromethyl-4- [2- (5-diethylphosphono) furanyl] imidazole The title compound was prepared from 2-trifluoromethyl-4- [2- (5-phosphono) furanyl] imidazole (10.22). mp 188 [deg.] C (decomposition); C ₈ H ₆ F ₃ N ₂ 0 ₄ P + 0.5 Calculated for HBr: C: 29.79; H: 2.03; N: 8.68. Found: C: 29.93; H: 2.27; N: 8.30.
[1267] Alternatively, 4,5-dimethyl-1-isobutyl-2- [2- (5-phosphono) furanyl] -imidazole can be prepared as follows:
[1268] Step H. A solution of 5-diethylphosphono-2-furaldehyde (1 mmole), ammonium acetate (1.4 mmole), 3,4-butanedione (3 mmole) and isobutylamine (3 mmole) Lt; 0 &gt; C for 24 hours. Evaporation and chromatography afforded 4,5-dimethyl-1-isobutyl-2- [2- (5-diethylphosphono) furanyl] imidazole as a yellow solid.
[1269] Step I. 4,5-Dimethyl-1-isobutyl-2- [2- (5-diethylphosphono) furanyl] -imidazoleThe procedure is carried out as in step C of Example 3 to give 4,5- - isobutyl-2- [2- (5-phosphono) furanyl] imidazole (10.23); C ₁₃ H ₁₉ N ₂ 0 ₄ P + 1.35 Calculated for HBr: C: 38.32; H: 5.03; N: 6.87. Found: C: 38.09; H: 5.04; N: 7.20.
[1270] The following compounds were prepared according to, or in some cases slightly modified, the above method:
[1271] (10.2) 2-Amino-5-propyl-4- [2- (5-phosphono) furanyl] oxazole. mp 250 [deg.] C (decomposition); Calcd for _{C 10 H 13 N 2 O 5} P: C: 44.13; H: 4.81; N: 10.29. Found: C: 43.74; H: 4.69; N: 9.92.
[1272] (10.3) 2-Amino-5-ethyl-4- [2- (5-phosphono) furanyl] oxazole. _{C 9 H 11 N 2 0 5} P + 0.4 calculated for H ₂ 0: C: 40.73; H: 4.48; N: 10.56. Found: C: 40.85; H: 4.10; N: 10.21.
[1273] (10.4) 2-Amino-5-methyl-4- [2- (5-phosphono) furanyl] oxazole. _{C 8 H 9 N 2 0 5} P + O.1 calculated for H ₂ 0: C: 39.07; H: 3.77; N: 11.39. Found: C: 38.96; H: 3.59; N: 11.18.
[1274] (10.5) 2-Amino-4- [2- (5-phosphono) furanyl] oxazole. _{C 7 H 7 N 2 0 5} P + 0.6 calculated for H ₂ 0: C: 34.90; H: 3.43; N: 11.63. Found: C: 34.72; H: 3.08; N: 11.35.
[1275] (10.6) 2-Amino-5-isobutyl-4- [2- (5-phosphono) furanyl] oxazole hydrogene bromide. Calcd for C ₁₁ H ₁₆ N ₂ O ₅ BrP + 0.4 H ₂ O: C: 35,29; H: 4.52; N: 7.48. Found: C: 35.09; H: 4.21; N: 7.34.
[1276] (10.7) 2-Amino-5-phenyl-4- [2- (5-phosphono) furanyl] oxazole. Calcd for _{C 13 H 11 N 2 0 5} P: C: 50.99; H: 3.62; N: 9.15. Found: C: 50.70; H: 3.43; N: 8.96.
[1277] (10.8) 2-Amino-5-benzyl-4- [2- (5-phosphono) furanyl] oxazole. _{C 14 H 13 N 2 0 5} P + 1.1 calculated for H ₂ 0: C: 49.45; H: 4.51; N: 8.24. Found: C: 49.35; H: 4.32; N, 8.04.
[1278] (10.9) 2-Amino-5-cyclohexylmethyl-4- [2- (5-phosphono) furanyl] oxazole. Calcd for _{C 14 H 19 N 2 0 5} P + O.3 H 2 0: C: 50.70; H: 5.96; N: 8.45. Found: C: 50.60; H: 5.93; N: 8.38.
[1279] (10.10) 2-Amino-5-allyl-4- [2- (5-phosphono) furanyl] oxazole. Calcd for _{C 10 H 11 N 2 0 5} P + 0.4 HBr + 0.3 H 2 0: C: 39.00; H: 3.93; N: 9.10. Found: C: 39.31; H: 3.83; N: 8.76.
[1280] (10.11) 5-Isobutyl-4- [2- (5-phosphono) furanyl] oxazole. Calcd for C ₁₁ H ₁₄ NO ₅ P: C: 48.72; H: 5.20; N: 5.16. Found: C: 48.67; H: 5.02; N: 5.10.
[1281] (10.12) 2-Amino-5-butyl-4- [2- (5-phosphono) furanyl] oxazole. Calcd for C ₁₁ H ₁₅ N ₂ O ₅ P + 0.2 H ₂ O: C: 45.59; H: 5.36; N: 9.67. Found: C: 45.32; H: 5.29; N: 9.50.
[1282] (10.13) 5-Isobutyl-4- [2- (5-phosphono) furanyl] oxazol-2-one. C ₁₁ H ₁₄ NO ₆ P + 0.39 Calculated for HBr: C: 41.45; H: 4.55; N: 4.39. Found: C: 41, 79; H: 4.22; N, 4.04.
[1283] (10.15) 5-Cyclohexylmethyl-2-hydroxy-4- [2- (5-phosphono) furanyl] imidazole. C ₁₄ H ₁₉ N ₂ 0 ₅ P + 0.05 Calculated for HBr: C: 50.90; H: 5.81; N: 8.48. Found: C: 51.06; H: 5.83; N: 8.25.
[1284] (10.16) 5-Butyl-2-hydroxy-4- [2- (5-phosphono) furanyl]. Calcd for C ₁₁ H ₁₅ N ₂ O ₅ P + 0.2 H ₂ O: C: 45.59; H: 5.36; N: 9.67. Found: C: 45.77; H: 5.34; N: 9.39.
[1285] (10.17) 5-Benzyl-2-hydroxy-4- [2- (5-phosphono) furanyl) imidazole. Calcd for _{C 14 H 13 N 2 0 5} P: C: 52.51; H: 4.09; N: 8.75. Found: C: 52.29; H: 4.15; N: 8.36.
[1286] (10.20) 2-Methyl-5-propyl-4- [2- (5-phosphono) furanyl] imidazole hydrogen bromide. Calcd for C ₁₁ H ₁₆ BrN ₂ O ₄ P + O ₅ H ₂ O: C: 36.69; H: 4.76; N: 7.78. Found: C: 36.81; H: 4.99; N: 7.42.
[1287] (10.24) 2-Amino-5- (2-thienylmethyl) -4- [2- (5-phosphono) furanyl] oxazole. C ₁₂ H ₁₁ N ₂ 0 ₅ PS + 0.9 Calculated for HBr: C: 36.12; H: 3.01; N: 7.02. Found: C: 36.37; H: 2.72; N: 7.01.
[1288] (10.25) 2-Dimethylamino-5-isobutyl-4- [2- (5-phosphono) furanyl] oxazole hydrobromide. C ₁₃ H ₂₀ BrN ₂ 0 ₅ P + 0.05 Calculated for HBr: C: 39.11; H: 5.06; N: 7.02. Found: C: 39.17; H: 4.83; N: 6.66.
[1289] (10.26) 2-Isopropyl-5-isobutyl-4- [2- (5-phosphono) furanyl] oxazole. Calcd for C ₁₄ H ₂₀ NO ₅ P + 0.8 HBr: C: 44.48; H: 5.55; N: 3.71. Found: C: 44.45; H: 5.57; N: 3.73.
[1290] (10.27) 2-Amino-5-ethoxycarbonyl-4- [2- (5-phosphono) furanyl] oxazole. mp 245 [deg.] C (decomposition). Calcd for _{C 10 H 11 N 2 0 7} P: C: 39.75; H: 3.67; N: 9.27. Found: C: 39.45; H: 3.71; N: 8.87.
[1291] (10.28) 2-Methylamino-5-isobutyl-4- [2- (5-phosphono) furanyl] oxazole hydrobromide. Calcd for C ₁₂ H ₁₈ BrN ₂ O ₅ P + 0.7 H ₂ O: C: 36.60; H: 4.97; N: 7.11. Found: C: 36.50; H: 5.09; N, 7.04.
[1292] (10.29) 2-Ethyl-5-isobutyl-4- [2- (5-phosphono) furanyl] oxazole hydrobromide. Calcd for _{C 13 H 19 BrNO 5 P:} C: 41.07; H: 5.04; N: 3.68. Found: C: 41.12; H: 4.84; N: 3.62.
[1293] (10.30) 2-ethylamino-5-isobutyl-4- [2- (5-phosphono) furanyl] oxazole hydrobromide. Calcd for C ₁₃ H ₂₀ BrN ₂ O ₅ P: C: 39.51; H: 5.10; N, 7.09. Found: C: 39.03; H: 5.48; N: 8.90.
[1294] (10.31) 2-vinyl-5-isobutyl-4- [2- (5-phosphono) furanyl] oxazole. C ₁₃ H ₁₆ NO ₅ P + 0.25 Calculated for HBr: C: 49.18; H: 5.16; N: 4.41. Found: C: 48.94; H: 5.15; N: 4.40.
[1295] (10.32) 2-Amino-5-pentyl-4- [2- (5-phosphono) furanyl] oxazole. Calcd for C ₁₂ H ₁₇ N ₂ O ₅ P + O.5 H ₂ O: C: 46.61; H: 5.87; N: 9.06, found: C: 46.38; H: 5.79; N 9.07.
[1296] (10.33) 5-Pentyl-2-hydroxy-4- [2- (5-phosphono) furanyl] imidazole. Calcd for C ₁₂ H ₁₇ N ₂ O ₅ P: C: 48.00; H: 5.71; N: 9.33. Found: C: 48.04; H: 5.58; N: 9.26.
[1297] (10.45) 2-Amino-5-methylthio-4- [2- (5-phosphono) furanyl] oxazole. mp 196 [deg.] C (decomposition). C ₈ H ₉ N ₂ 0 ₅ Calculated for PS: C: 34.79; H: 3.28; N: 10.14. Found: C: 34.60; H: 2.97; N: 10.00.
[1298] (10.35) 2-Amino-5-benzyloxycarbonyl-4- [2- (5-phosphono) furanyl] oxazole. mp 230 [deg.] C (decomposition). Calcd for _{C 15 H 13 N 2 0 7} P + O.7 H 2 0: C: 47.81; H: 3.85; N: 7.43. Found: C: 47.85; H: 3.88; N: 7.21.
[1299] (10.36) 2-Amino-5-isopropyloxycarbonyl-4- [2- (5-phosphono) furanyl] oxazole. mp 221 [deg.] C (decomposition). Calcd for C ₁₁ H ₁₃ N ₂ O ₇ P + 0.9 H ₂ O: C: 39.75; H: 4.49; N: 8.43. Found: C: 39.72; H: 4.25; N: 8.20.
[1300] (10.37) 2-Amino-5-methoxycarbonyl-4- [2- (5-phosphono) furanyl] oxazole. mp 240 [deg.] C (decomposition). _{C 9 H 9 N 2 0 7} P + 0.3 H 2 0 + O.1 acetone: C; 37.31; H: 3.43; N: 9.36. Found: C: 37.37; H 3.19; N 9.01.
[1301] (10.38) 2-Amino-5 - [(N-methyl) carbamoyl-4- [2- (5-phosphono) furanyl] oxazole. mp 235 ° C (decomposition). C ₉ H ₁₀ N ₃ 0 ₆ calculated for P: C: 37.64; H: 3.51; N: 14.63. Found: C: 37.37; H: 3.22; N: 14.44.
[1302] (10.39) 2-Amino-5-ethylthiocarbonyl-4- [2- (5-phosphono) furanyl] oxazole. mp 225 [deg.] C (decomposition). C ₁₀ H ₁₁ N ₂ O ₆ Calculated for PS: C: 37.74; H: 3.48; N: 8.80. Found: C: 37.67; H: 3.27; N: 8.46.
[1303] (10.40) 2-Amino-5-isopropylthio-4- [2- (5-phosphono) furanyl] oxazole. Calcd for _{C 1O H 13 N 2 0 5} PS + 0.2 HBr: C: 37.48; H: 4.15; N: 8.74. Found: C: 37.39; H: 4.11; N: 8.56.
[1304] (10.41) 2-Amino-5-phenylthio-4- [2- (5-phosphono) furanyl] oxazole. C ₁₃ H ₁₁ N ₂ O ₅ PS + 0.25 Calculated for HBr: C: 43.55; H: 3.16; N: 7.81. Found: C: 43.82 H: 3.28; N: 7.59.
[1305] (10.42) 2-Amino-5-ethylthio-4- [2- (5-phosphono) furanyl] oxazole. C ₉ H ₁₁ N ₂ 0 ₅ PS + 0.85 HBr: C: 30.11; H: 3.33; N: 7.80. Found: C: 30.18; H: 3.44; N: 7.60.
[1306] (10.43) 2-Amino-5-propylthio-4- [2- (5-phosphono) furanyl] oxazole. Calcd for _{C 10 H 13 N 2 0 5} + H 2 O: C: 37.27; H: 4.69; N: 8.69; H20: 5.59. Found: C: 37.27; H: 4.67; N: 8.60; H ₂ O: 5.66.
[1307] (10.44) 2-Amino-5-tert-butylthio-4- [2- (5-phosphono) furanyl] oxazole. C ₁₁ H ₁₅ N ₂ 0 ₅ PS + 0.25 Calculated for HBr: C: 39.03; H: 4.54; N: 8.28. Found: C: 39.04; H: 4.62; N: 8.06.
[1308] (10.34) 4,5-Dimethyl-2- [2- (5-phosphono) furanyl] imidazole. Calcd for _{C 9 H 11 N 2 0 4} P + 1.25 H 2 0: C: 40.84; H: 5.14; N: 10.58. Found: C: 41.02; H: 5.09; N: 10.27.
[1309] &Lt; Example 11 >
[1310] Preparation of N-alkylated 4- [2- (5-phosphono) furanyl] imidazole and 4- [2- (5-phosphono) furanyl] oxazole.
[1311] Step A. A suspension of cesium carbonate (1.5 mmole) and 2-methyl-5-isobutyl-4- (2- (5- diethylphosphono) furanyl] imidazole (1 mmole) in DMF (1.5 mmole) for 1 h. Extraction and chromatography gave 1,2-dimethyl-4-isobutyl-5- [2- (5-diethylphosphono) Dimethyl-5-isobutyl-4- [2- (5-diethylphosphino) -furanyl] imidazole.
[1312] Step B. Preparation of 1,2-dimethyl-4-isobutyl-5- [2- (5-diethylphosphono) furanyl] -imidazole and 1,2- (5-diethylphosphono) furanyl] -imidazole was treated as in step C of Example 3 to give the following compounds:
[1313] (11.1) 1,2-Dimethyl-5-isobutyl-4- [2- (5-phosphono) furanyl] imidazole hydrobromide. Calcd for C ₁₃ H ₂₀ N ₂ 0 ₄ PBr + 0.8 H ₂ O: C: 39.67; H: 5.53; N: 7.12. Found: C: 39.63; H: 5.48; N: 7.16.
[1314] &Lt; Example 12 >
[1315] Preparation of 2- [2- (6-phosphono) pyridyl] pyridine.
[1316] Step A. A solution of 2,2'-bipyridyl (1 mmole) in dichloromethane was treated with m-chloroperoxybenzoic acid (2 mmole) at 0 ° C and the reaction mixture was stirred at 25 ° C for 2 hours. Extraction and chromatography gave 2,2'-bipyridyl-N-oxide.
[1317] Bipyridyl-N-oxide methyl ether (1 mmole, dimethyl sulfate in diethyl phosphate and 2 &lt; RTI ID = 0.0 &gt; , 2'-bipyridyl-N-oxide) in 50 ml of DMF was added slowly to a solution of n-butyllithium (1 mmole) in diethylphosphate at -30 ° C at -30 ° C. The resulting reaction mixture was stirred at 25 &lt; 0 &gt; C for 12 hours. Extraction and chromatography gave 2- [2- (6-diethylphosphino) pyridyl] pyridine.
[1318] Step C. 2- [2- (6-Diethylphosphino) pyridyl] pyridine was treated as in Step C of Example 3 to give 2- [2- (6-phosphono) pyridyl] pyridine . mp 158 - 162 [deg.] C. C ₁₀ H ₉ N ₂ 0 ₃ P + 0.5 H ₂ O + 0.1 Calculated for HBr: C: 47.42; H: 4.02; N: 11.06. Found: C: 47.03; H: 3.67; N: 10.95.
[1319] &Lt; Example 13 >
[1320] Preparation of 4,6-dimethyl-2- (phosphonomethoxymethyl) pyridine.
[1321] Step A. A solution of 2,4,6-collidine (1 mmole) in carbon tetrachloride was treated with NBS (5 mmole) and dibenzoyl peroxide (0.25 mmole) at 80 ° C for 12 hours. The reaction mixture was cooled to 0 &lt; 0 &gt; C and the precipitate was filtered. The filtrate was concentrated in vacuo. Chromatography yielded 2-bromomethyl-4,6-dimethylpyridine.
[1322] Step B. A solution of diethylhydroxymethylphosphonate (1 mmole) in toluene was treated with sodium hydride (1.1 mmole) at 0 C and 15 minutes later 2-bromomethyl-4,6-dimethylpyridine ) Was added. After 3 hours, the reaction mixture was extracted and chromatographed to obtain 2-diethylphosphonomethyl-4,6-dimethylpyridine.
[1323] Step C. 2-Diethylphosphonomethyl-4,6-dimethylpyridine was treated as in Step C of Example 3 to give 4,6-dimethyl-2- (phosphonomethoxymethyl) pyridine (13.1). mp 109-112 [deg.] C. C ₉ H ₁₄ NO ₄ P + 1.OH ₂ 0 + 0.5 Calculated for HBr: C: 37.32; H: 5.74; N: 4.84. Found: C: 37.18; H: 5.38; N: 4.67.
[1324] The following compounds were prepared in a similar manner:
[1325] (13.2) 2-Amino-4-methyl-5-propyl-6-phosphonomethoxymethylpyrimidine. mp 153-156 [deg.] C. _{C 1O H 18 N 3 0 4} P + 1.25 H 2 calculated for 0 + 1.6 HBr: C: 28.11 ; H: 5.21; N: 9.84. Found: C: 28.25; H: 4.75; N: 9.74.
[1326] &Lt; Example 14 >
[1327] Preparation of diethyl 5-tributylstyrene-2-furanophosphonate (14).
[1328] A solution of diethyl 2-furan phosphonate (1 mmole, prepared as in Step C of Example 1) in THF was cooled to -78 ° C and a solution of lithium N-isopropyl-N-cyclohexylamide in THF C for 15 min at -78 &lt; 0 &gt; C. The resulting mixture was stirred at -78 &lt; 0 &gt; C for 2 hours and was then cannulated over 20 minutes at -78 [deg.] C in a solution of tributyltin chloride (1 mmole) in THF. The mixture was then stirred at-78 C for 1 hour. Extraction and chromatography afforded compound (14) as a light yellow oil.
[1329] &Lt; Example 15 >
[1330] Preparation of 6- [2- (5-phosphono) furanyl] pyridine.
[1331] Step A. A solution of 2,6-dichloropyridine (120 mmole) in ethanol was treated with aqueous ammonia solution (28%, excess) in a sealed tube at 160-165 캜 for 60 hours. Extraction and chromatography afforded 2-amino-6-chloropyridine as a white solid.
[1332] Step B. A solution of 2-amino-6-chloropyridine (1 mmole) and 14 (1 mmole) in p-xylene was treated with tetrakis (triphenylphosphine) palladium (0.05 mmole) Respectively. Extraction and chromatography afforded 2-amino-6- [2- (5 diethylphosphino) furanyl] pyridine as a light yellow solid.
[1333] Step C. Treatment of 2-amino-6- [2- (5-diethylphosphono) furanyl] pyridine as in step 3 of Example 3 provided 2-amino- Furanyl] pyridine (15.1). mp 186 - 187 [deg.] C. _{C 9 H 9 N 2 0 4} P + 0.4 calculated for HBr: C: 39.67; H: 3.48; N; 10.28. Found: C: 39.95; H: 3.36; N: 10.04.
[1334] Step D. A solution of 2-amino-6- [2- (5-diethylphosphino) furanyl] pyridine (1 mmole) in acetic acid was added to a solution of bromine (1N, 1 mmole) in acetic acid Lt; / RTI &gt; Evaporation and chromatography afforded 2-amino-5-bromo-6- [2- (5 diethylphosphono) furanyl] pyridine and 2-amino-3,5-dibromo-6- [2- Diethylphosphono) furanyl] pyridine.
[1335] Step E. Preparation of 2-amino-5-bromo-6- [2- (5-diethylphosphono) furanyl] pyridine and 2-amino- Diethylphosphono) furanyl] pyridine By proceeding as in step 3 of Example 3, the following compounds were obtained:
[1336] (15.2) 6-Amino-3-bromo-2- [2- (5-phosphono) furanyl] pyridine. C ₉ H ₈ BrN ₂ 0 ₄ P + 0.7 H ₂ 0 + 0.9 HBr + 0.12 Calculated for PhCH ₃ : C: 28.44; H: 2.73; N: 6.74. Found: C: 28.64; H: 2.79; N: 6.31.
[1337] (15.3) 6-Amine-3,5-dibromo-2- [2- (5-phosphono) furanyl] pyridine. mp 233-235 [deg.] C. C ₉ H ₇ Br ₂ N ₂ 0 ₄ P + 1.2 Calculated for HBr: C: 21.84; H: 1.67; N: 5.66. Found: C: 21.90; H: 1.52; N: 5.30.
[1338] Step F. A solution of 2-amino-3,5-dibromo-6- [2- (5-diethylphosphono) furanyl] pyridine (1 mmole) in DMF was added to tributyl Vinyl) tin (1.2 mmole) and tetrakis (triphenylphosphine) palladium (0.2 mmole). Evaporation and chromatography gave 2-amino-3,5-bis (vinyl) -6- [2- (5-diethylphosphono) furanyl] pyridine.
[1339] Step G. A solution of 2-amino-3,5-bis (vinyl) -6- [2- (5-diethylphosphono) furanyl] pyridine (1 mmole) in ethyl acetate was hydrogenated at 25 ° C Lt; / RTI &gt; for 12 hours with palladium on carbon (10%). Filtration, evaporation and chromatography gave 2-amino-3,5-diethyl-6- [2- (5-diethylphosphono) furanyl] pyridine.
[1340] Step H. Treatment of 2-amino-3,5-diethyl-6- [2- (5-diethylphosphono) furanyl] pyridine was performed in analogy to step 3 of Example 3 to give 2-amino- Diethyl-6- [2- (5-phosphono) furanyl] pyridine (15.4). mp 217-218 [deg.] C. _{C 13 H 17 N 2 0 4} P + 0.7 H 2 0 + 1.O calculated for HBr: C: 40.06; H: 5.02; N: 7.19. Found: C: 40.14; H: 4.70; N: 6.87.
[1341] Step I. A solution of 48% hydrobromic acid (4.4 mmole) 2-amino-6-picoline (1 mmole) was treated with bromine (3 mmole) at 0 C for 1 hour. An aqueous solution of sodium nitrite (2.5 mmole) was then added and the reaction mixture was stirred at 0 C for 0.5 hour. An aqueous solution of sodium hydroxide (9.4 mmole) was then added and the reaction mixture was stirred at 25 &lt; 0 &gt; C for 1 hour. Extraction and chromatography gave 2,3-dibromo-6-picoline and 2,3,5-tribromo-6-picoline.
[1342] Step J. 2,3-Dibromo-6-picoline Following the same procedure as in Step B of Example 15, Step C of Example 3 provided 5-bromo-2-methyl-6- [2- (5-phosphono) furanyl] pyridine (15.5). mp 207-208 [deg.] C. C ₁₀ H ₉ BrNO ₄ P + 0.6 Calculated for HBr: C: 32.76; H: 2.64; N: 3.88. Found: C: 32.62; H: 2.95; N: 3.55.
[1343] The following compounds were prepared according to the methods described above or using slight modifications of this method using conventional chemical methods.
[1344] (15.6) 2- [2- (5-Phosphono) furanyl] pyridine. mp 220-221 [deg.] C. C ₉ H ₈ NO ₄ P + 0.1 H ₂ O + 0.45 Calculated for HBr: C: 41.05; H: 3.31; N: 5.32. Found: C: 41.06; H: 3.10; N: 5.10.
[1345] (15.7) 2-Amino-3-nitro-6- [2- (5-phosphono) furanyl] pyridine. mp 221 - 222 캜. C ₉ H ₈ N ₃ O ₆ P + 0.55 HBr + 0.02 Calculated for PhCH ₃ : C: 33.12; H; 2.65; N: 12.68. Found: C: 33.22; H: 2.43; N: 12.26.
[1346] (15.8) 2,3-Diamino-6- [2- (5-phosphono) furanyl] pyridine. mp 150-153 [deg.] C. C ₉ H ₁₀ N ₃ 0 ₄ P + 1.5 HBr + 0.05 Calculated for PhCH ₃ : C: 29.46; H: 3.15; N: 11.02. Found: C: 29.50; H: 3.29; N: 10.60.
[1347] (15.9) 2-Chloro-6- [2- (5-phosphono) furanyl] pyridine. mp 94-96 [deg.] C. Calcd for C ₉ H ₇ ClNO ₄ P + 0.25 HBr: C: 38.63; H: 2.61; N: 5.01. Found: C: 38.91; H: 3.00; N: 5.07.
[1348] (15.10) 3,5-Dichloro-2- [2- (5-phosphono) furanyl] pyridine. mp 180-181 [deg.] C. Calcd for C ₉ H ₆ Cl ₂ NO ₄ P + 0.7 HBr: C: 31.61; H: 2.01; N: 3.94. Found: C: 31.69; H: 2.09; N: 3.89.
[1349] (15.11) 3-Chloro-5-trifluoromethyl-2- [2- (5-phosphono) furanyl] pyridine. mp 253 - 254 [deg.] C. Calcd for _{C 1O H 6 ClF 3 NO 4} P: C: 36.67; H: 1.85; N: 4.28. Found: C: 36.69; H: 1.89; N: 4.30.
[1350] (15.12) 2-Amino-3-ethyl-6- [2- (5-phosphono) furanyl] pyridine. mp 220-221 [deg.] C. C ₁₁ H ₁₃ N ₂ 0 ₄ P + 0.6 Calculated for HBr + 0.2 H ₂ O: C: 41.24; H: 4.40; N: 8.74. Found: C: 41.02; H: 4.57; N: 8.68.
[1351] (15.13) 6-Amino-3-ethyl-2- [2- (5-phosphono) furanyl] pyridine. C ₁₁ H ₁₃ N ₂ 0 ₄ P + 1.O Calculated for HBr +0.3H ₂ O: C: 37.27; H: 4.15; N: 7.90. Found: C: 37.27; H: 4.19; N: 7.51.
[1352] (15.14) 6-Amino-3-propyl-2- [2- (5-phosphono) furanyl] pyridine. mp 252 - 253 [deg.] C. C ₁₂ H ₁₅ N ₂ 0 ₄ P + 1.O HBr + 1.OH ₂ 0 + 0.32 Calculated for PhCH ₃ : C: 41.65; H: 5.05; N: 6.82. Found: C: 41.97; H: 5.19; N: 6.83.
[1353] (15.15) 2,4-Dimethyl-3-bromo-6- [2- (5-phosphono) furanyl] pyridine. mp 232 - 233 [deg.] C. C ₁₁ H ₁₁ BrNO ₄ P + 0.45 Calculated for HBr: C: 35.85; H: 3.13; N: 3.80. Found: C: 35.98; H: 3.10; N: 3.71.
[1354] (15.16) 2-Chloro-4-amino-6- [2- (5-phosphono) furanyl] pyridine. C ₉ H ₈ N ₂ O ₄ PCl + HBr + 0.5 H ₂ O + MeOH: C: 30.99; H: 3.38; N: 7.23. Found: C: 31.09; H: 3.21; N: 6.96.
[1355] (15.17) 3-Hydroxyl-2- [2- (5-phosphono) furanyl] pyridine. C ₉ H ₈ NO ₅ P + 1.1 HBr + 0.3 CH ₃ Calculated for Ph: C: 37.26; H: 3.24; N: 3.91. Found: C: 37.66; H: 3.55; N: 3.84.
[1356] (15.19) 2-Amino-3-cyclopropyl-6- [2- (5-phosphono) furanyl] pyridine. C ₁₂ H ₁₃ N ₂ 0 ₄ Calcd for PCl + HBr + 0.4 H ₂ O: C: 39.13; H: 4.05; N: 7.61. Found: C: 39.06; H: 3.85; N: 7.37,
[1357] (15.20) 2-Amino-5-cyclopropyl-6- [2- (5-phosphono) furanyl] pyridine. C ₁₂ H ₁₃ N ₂ 0 ₄ P + HBr + 0.7 Calculated for CH ₃ Ph: C: 47.69; H: 4.64; N: 6.58. Found: C: 47.99; H: 4.62; N: 6.91.
[1358] (15.21) 5-Amino-2-methoxy-6- [2- (5-phosphono) furanyl] pyridine. _{C 10 H 11 N 2 0 5} P + 0.2 calculated for H ₂ 0: C: 43.87; H: 4.20; N: 10.23. Found: C: 43.71; H: 3.77; N: 9.77.
[1359] (15.22) 2-Methyl-5-cyano-6- [2- (5-phosphono) furanyl] pyridine. C ₁₁ H ₉ N ₂ 0 ₄ P + 0.75 HBr + 0.5 H ₂ O + 0.5 Calculated for MePh: C: 45.84; H: 3.91; N: 7.37. Found: C: 45.93; H: 3.56; N: 7.36.
[1360] (15.23) 2-Amino-3,5-bis (cyano) -4-methyl-6- [2- (5-phosphono) furanyl] pyridine. Calcd for C ₁₂ H ₉ N ₄ 0 ₄ P + 0.7 H ₂ O: C: 45.49; H: 3.31; N: 17.68. Found: C: 45.48; H: 3.06; N: 17.51.
[1361] (15.24) 2-Chloro-4-cyano-6- [2- (5-phosphono) furanyl] pyridine. Calcd for _{C 1O H 6 N 2 0 4} PCl: C: 42.20; H: 2.13; N: 9.84. Found: C: 41.95; H: 2.10; N: 9.47.
[1362] &Lt; Example 16 >
[1363] Preparation of 2- [2- (5-phosphono) furanyl] pyrimidine and 4- [2- (5-phosphono) furanyl] pyrimidine.
[1364] Step A. A solution of 5-diethylphosphono-2 - [(1-oxo) pentyl] furan in N, N-dimethylformamide dimethylacetal was heated at reflux temperature for 12 hours. Evaporation and chromatography gave diethyl 5- (2-propyl-3-N, N-dimethylamino) acryloyl-2-furanphosphonate.
[1365] Step B. A solution of diethyl 5- (2-propyl-3-N, N-dimethylamino) acryloyl-2-furan phosphonate (1 mmole) in ethanol was added to a solution of guanidine hydrogen chloride (1.2 mmole) and sodium ethoxide (1 mmole). The reaction mixture was evaporated and the residue was dissolved in water. The aqueous solution was neutralized with HCl (2 N) and concentrated under reduced pressure. The residue was co-evaporated with toluene to give 2-amino-5-propyl-4- [2- (5-ethylphosphino) -furanyl] pyrimidine as a yellow solid.
[1366] Step C. 2-Amino-5-propyl-4- [2- (5-ethylphosphono) furanyl] pyrimidine (1 mmole) and thionyl chloride were heated to reflux for 2 hours. The reaction mixture was evaporated to dryness and the residue was dissolved in methylene chloride and treated with excess pyridine and ethanol at 25 &lt; 0 &gt; C for 12 h. Evaporation and chromatography afforded 2-amino-5-propyl-4- [2- (5-diethylphosphono) furanyl] pyrimidine.
[1367] Step D. 2-Amino-5-propyl-4- [2- (5-diethylphosphono) furanyl] pyrimidine was treated as in Step C of Example 3 to give 2-amino- [2- (5-phosphono) furanyl] pyrimidine (16.1) was obtained. mp 258 - 259 [deg.] C. _{C 11 H 14 N 3 0 4} P + 1.33 calculated for H ₂ 0: C: 43.01; H: 5.47; N: 13.68. Found: C: 43.18; H: 5.31; N: 13.30.
[1368] The following compounds were prepared by this method:
[1369] (16.2) 2-Amino-5-isobutyl-4- (2- (5-phosphono) furanyl] pyrimidine mp 218 -.. 220 ℃ C 12 H 16 N 3 0 4 P + 0.75 HBr + 0.3 PhCH Calculated for ₃ : C: 43.92; H: 5.01; N: 10.90. Found: C: 44.02; H: 4.62;
[1370] Alternatively, other 4- [2- (5-phosphono) furanyl] pyrimidines can be prepared according to the following method:
[1371] Step E. Compound 2.2 was treated as in Example 16, Step A to afford diethyl 5- (3-N, N-dimethylamino) acryloyl-2-furanphosphono as an orange solid.
[1372] Step F. A solution of diethyl 5- (3-N, N-dimethylamino) acryloyl-2-furan phosphonate (1 mmole), sodium ethoxide ethanol solution (2 mmole) and guanidine hydrochloride The solution was heated at 55 [deg.] C for 2 hours. The reaction mixture was cooled in an ice bath and neutralized with 1N HCl. Evaporation and chromatography afforded 2-amino-4- [2- (5-diethylphosphino) -furanyl] pyrimidine as a yellow solid.
[1373] Step G. 2-Amino-4- [2- (5-diethylphosphono) furanyl] pyrimidine was treated as in Step 3 of Example 3 to give 2-amino- ) Furanyl) -pyrimidine (16.3). mp> 230 [deg.] C. C ₈ H ₈ N ₃ 0 ₄ P + 0.75 H ₂ O + 0.2 Calculated for HBr: C: 35.48; H: 3.61; N: 15.51. Found: C: 35.42; H: 3.80; N: 15.30.
[1374] Step H. A solution of 2-amino-4- [2- (5-diethylphosphono) furanyl] pyrimidine (1 mmole) in methanol and chloroform was treated with NBS (1.5 mmole) at 25 < . Extraction and chromatography afforded 2-amino-5-bromo-4- [2- (5-diethylphosphino) furanyl] pyrimidine as a yellow solid.
[1375] Step I After treating 2-amino-5-bromo-4- [2- (5-diethylphosphono) furanyl] pyrimidine as in step F and G of Example 15, Amino-5-ethyl-4- [2- (5-phosphono) furanyl] pyrimidine (16.4). mp> 225 [deg.] C. Calcd for _{C 1O H 12 N 3 0 4} P + 1.4 H 2 0 + 0.2 HBr + 0.25 PhCH 3: C: 42.30; H: 5.14; N: 12.59. Found: C: 42.74; H: 4.94; N: 12.13.
[1376] The following compounds were prepared according to the above method or with slight modifications of this process using conventional chemical reactions:
[1377] (16.5) 2- [2- (5-Phosphono) furanyl] pyrimidine. mp 194-196 [deg.] C. Calcd for _{C 8 H 7 N 2 0 4} P + O.1 H 2 0 + 0.55 HBr: C: 35.27; H: 2.87; N: 10.28. Found: C: 35.26; H: 2.83; N: 9.89.
[1378] (16.6) 2-Amino-6-methyl-4- [2- (5-phosphono) furanyl] pyrimidine. mp 238-239 [deg.] C. Calcd for _{C 9 H 1O N 3 0 4} P + O.9 HBr: C: 32.96; H: 3.35; N: 12.81. Found: C: 33.25; H: 3.34; N: 12.46.
[1379] (16.7) 2-Methylthio-4- [2- (5-phosphono) furanyl] pyrimidine. mp 228-229 [deg.] C. Calcd for C ₉ H ₉ N ₂ 0 ₄ PS + 0.5 H ₂ O: C: 38.44; H: 3.58; N: 9.96. Found: C: 38.19; H: 3.25; N: 9.66.
[1380] (16.8) 2-Methyl-4- [2- (5-phosphono) furanyl] pyrimidine. mp 206-212 [deg.] C. C ₉ H ₉ N ₂ 0 ₄ P + 0.9 H ₂ O + 0.25 Calculated for HBr: C: 34.05; H: 3.30; N: 8.82. Found: C: 34.02; H: 3.06; N: 8.75.
[1381] (16.9) 4,6-Dimethyl-5-bromo-2- [2- (5-phosphono) furanyl] pyrimidine. mp 251 - 252 [deg.] C. Calcd for _{C 1O H 10 BrN 2 0 4} P: C: 36.06; H: 3.03; N: 8.41. Found: C: 35.89; H: 2.82; N: 8.11.
[1382] (16.10) 2-Amino-5-chloro-4- [2- (5-phosphono) furanyl] pyrimidine. Calcd for C ₈ H ₇ ClN ₃ 0 ₄ P + 0.5 H ₂ O: C: 33.76; H: 2.83; N: 14.76. Found: C: 33.91; H: 2.86; N: 14.20.
[1383] (16.11) 2-Amino-6-methylthio-4- [2- (5-phosphono) furanyl] pyrimidine. Calcd for C ₉ H ₉ N ₃ 0 ₄ PS + HBr: C: 29.36; H: 3.01; N: 11.41. Found: C: 29.63; H: 3.02; N: 11.27.
[1384] (16.12) 2-Amino-5-bromo-6-methylthio-4- [2- (5-phosphono) furanyl] pyrimidine. C ₉ H ₉ N ₃ O ₄ PSBR + 0.8 HBr + 0.2 Calculated for MePh: C: 27.80; H: 2.56; N: 9.35. Found: C: 27.74; H: 2.40; N: 8.94.
[1385] (16.13) 2-Amino- (4-morpholino) -4- [2- (5-phosphono) furanyl] pyrimidine. Mp > C ₁₂ H ₁₅ N ₄ 0 ₅ P + HBr + 0.05 Calculated for MePh: C: 36.02; H: 4.01; N: 13.61. Found: C: 35.98; H: 4.04; N: 13.33.
[1386] (16.14) 6-Amino-4-chloro-2- [2- (5-phosphono) furanyl] pyrimidine. Mp > _{C 9 H 7 N 3 0 4} PCl + 0.5 calculated for H ₂ 0: C: 33.76; H: 2.83; N: 14.76. Found: C: 33.83; H: 2.54; N: 14.48.
[1387] &Lt; Example 17 >
[1388] Preparation of 2- [2- (5-phosphono) furanyl] pyrazine and 2- [2- (5-phosphono) furanyl] triazine.
[1389] Step A. The procedure described in Example 16 was repeated for the synthesis of 2- [2- (5-phosphono) furanyl] pyrazine and 2- [2- (5-phosphono) furanyl] This method can be applied with a slight modification by using a conventional chemical method. Accordingly, the following compounds were prepared:
[1390] (17.1) 2,5-Dimethyl-3- [2- (5-phosphono) furanyl] pyrazine. mp 212-213 [deg.] C. C ₁₀ H ₁₁ N ₂ 0 ₄ P + 0.75 Calculated for HBr: C: 38.15; H: 3.76; N: 8.90. Found: C: 38.41; H: 3.93; N: 8.76.
[1391] (17.2) 2-Chloro-6- [2- (5-phosphono) furanyl] pyrazine. mp 204-205 [deg.] C. C ₈ H ₆ ClN ₂ 0 ₄ P + 0.3 HBr + 0.02 Calculated for PhCH ₃ : C: 34.10; H: 2.27; N: 9.77. Found: C: 34.36; H: 2.07; N: 9.39.
[1392] (17.3) 2-Amino-3-propyl-6- [2- (5-phosphono) furanyl] pyrazine. mp 227-228 [deg.] C. C ₁₁ H ₁₄ N ₃ 0 ₄ P + 0.7 Calculated for HBr: C: 38.87; H: 4.36; N: 12.36. Found: C: 39.19; H: 4.36; N: 11.92.
[1393] (17.4) 2-Amino-6- [2- (5-phosphono) furanyl] pyrazine. mp 235-236 [deg.] C. C ₈ H ₈ N ₃ 0 ₄ P + 1.15 H ₂ O + 0.03 Calcd for PhCH ₃ : C: 37.26; H: 4.01; N: 15.88. Found: C; 37.09; H: 3.67; N: 15.51.
[1394] (17.5) 2-Amino-3-bromo-6- [2- (5-phosphono) furanyl] pyrazine. C ₈ H ₇ N ₃ 0 ₄ PBr + 1.5 HBr: C: 23.97; H: 2.01; N: 10.48. Found: C: 24.00; H: 2.00; N: 10.13.
[1395] (17.6) 3-Methylthio-2- [2- (5-phosphono) furanyl] pyrazine. Calcd for C ₉ H ₉ N ₂ 0 ₄ PS + 0.3 H ₂ O: C: 38.94; H: 3.49; N: 10.09. Found: C: 38.99; H: 3.11; N: 9.67.
[1396] (17.7) 6-Amino-3-methylthio-2- [2- (5-phosphono) furanyl] pyrazine. C ₉ H ₁₀ N ₃ 0 ₄ PS + 1.5 H ₂ 0 + 1.7 HBr + 0.25 MePh: C: 27.19; H: 3.54; N: 8.85. Found: C: 27.10; H: 3.85; N: 8.49.
[1397] (17.8) Calculated for 6-amino-5-methylthio-2- [2- (5-phosphono) furanyl] pyrazine C ₉ H ₁₀ N ₃ 0 ₄ PS + 1.1 HBr + 0.05 MePh C: 29.49 ; H: 3.04; N: 11.03. Found: C: 29.23; H: 2.79; N: 10.87.
[1398] (17.9) 6-Amino-5-methoxycarbonyl-3-chloro-2- [2- (5-phosphono) furanyl] pyrazine. C ₁₀ H ₉ N ₃ O ₆ PCl + 0.3 HBr + 0.04 MePh: C: 34.15; H: 2.68; N: 11.62. Found: C: 34,20; H: 2.90; N: 11.21.
[1399] (17.10) 6-Amino-3-methylthio-2- [2- (5-phosphono) furanyl] pyrazine ammonium salt. C ₉ H ₁₃ N ₄ 0 ₄ PS + 0.8 Calculated for HBr: C: 29.30; H: 3.77; N: 15.18. Found: C: 29.03; H: 3.88; N: 15.08.
[1400] (17.11) 2-Amino-4-phenyl-6- [2- (5-phosphono) furanyl] triazine. C ₁₃ H ₁₁ N ₄ O ₄ P + HBr + 0.1 Calculated for EtOAc: C: 39.45; H: 3.16; N: 13.73. Found: C: 39.77; H: 3.26; N: 13.48.
[1401] &Lt; Example 18 >
[1402] Preparation of analogs wherein X is methoxycarbonyl, methylthiocarbonyl, methylaminocarbonyl and methylcarbonylamino.
[1403] Preparation of 4-phosphonomethoxycarbonylthiazole and 4-phosphonomethoxycarbonyloxazole.
[1404] Step A. A solution of 2-amino-4-ethoxycarbonylthiazole (1 mmole) in 1,4-dioxane (5 mL) was treated with di-tert-butyl dicarbonate (1.2 mmole), TMEDA ) And DMAP (0.1 mmole) at room temperature. The reaction was stirred for 20 hours and then evaporated to dryness. The residue was extracted to give 2- [N-Boc (amino)] - 4-ethoxycarbonylthiazole as a yellow solid.
[1405] Step B. A solution of 2- [N-Boc (amino)] - 4-ethoxycarbonylthiazole (1 mmole) in a 2: 1 mixture of EtOH: H2O (10 mL) 3N, 3 mmole) and the reaction was stirred for 4 hours. The reaction was cooled to 0 &lt; 0 &gt; C and neutralized to pH 5 using 3N HCl and the resulting solid was collected by filtration to give 2- [N-Boc (amino)] - 4-carboxythiazole as a white solid.
[1406] Step C. A suspension of 2- [N-Boc (amino)] - 4-carboxylothiazole (1 mmole) in CH ₂ Cl ₂ (5 mL) was treated with thionyl chloride (4 mmole) at room temperature. After stirring for 4 hours, the reaction was evaporated to dryness. The residue was taken up in a solution of diethyl (hydroxymethyl) phosphono benzoate (1.5 mmole) and pyridine (2 mmole) in CH ₂ Cl ₂ (5 mL) was dissolved, and 0 ℃ of CH ₂ Cl ₂ (5 mL) to . The reaction was warmed to room temperature and stirred for 4 hours. The reaction was quenched with water and the mixture was extracted to give 2- [N-Boc (amino)] - 4-diethylphosphonomethoxycarbonylthiazole as a dark yellow oil.
[1407] Alternatively, an ester linkage can be formed using a mixed anhydride method as illustrated in the following method.
[1408] A solution of 2- [N-Boc (amino)] - 4-carboxylate (1 mmole) in pyridine (5 mL) was treated with para-toluenesulfonyl chloride (2 mmole) Diethyl (hydroxymethyl) phosphonoate (2 mmole). Evaporation, extraction and chromatography gave 2- [N-Boc (amino)] - 4-diethylphosphonomethoxycarbonylthiazole as a dark yellow oil.
[1409] Step D. To a solution of 2- [N-Boc (amino)] - 4-diethylphosphonomethoxycarbonylthiazole (1 mmole) and anisole (5 mmol) in methylene chloride (5 mL) and trifluoroacetic acid 0.1 mmole) was stirred at 0 &lt; 0 &gt; C for 1 hour and at room temperature for 1 hour. Evaporation, extraction and chromatography afforded 2-amino-4-diethylphosphonomethoxycarbonylthiazole as a solid.
[1410] Step E. 2-Amino-4-diethylphosphonomethoxycarbonylthiazole was treated as in Step 3 of Example 3 to give 2-amino-4-phosphonomethoxycarbonylthiazole (18.1) as a solid . Mp > 240 DEG C (decomposition). Calcd for _{C 5 H 7 N 2 O 5} PS: C: 25.22; H: 2.96; N: 11.76. Found: C: 25.30; H: 2.86; N: 11.77.
[1411] Step F. A solution of 2- [N-Boc (amino)] - 4-diethylphosphonomethoxycarbonylthiazole (1 mmole) in CH ₂ Cl ₂ (5 mL) mmole). Evaporated and extracted to give 2- [N-Boc (amino)] - 5-bromo-4-diethylphosphonomethoxycarbonylthiazole as an orange oil which was treated as in Example 18, Step D 2-amino-5-bromo-4-phosphonomethoxycarbonylthiazole (18.2) was obtained as a solid by treatment in the same manner as in step C of Example 3. Mp > 230 DEG C (decomposition). Calculated for C ₅ H ₆ N ₂ 0 ₅ PSBr: C: 18.94; H: 1.91; N: 8.84. Found: C: 19,08; H: 1.76; N: 8.67.
[1412] Step G. To a solution of 2- [N-Boc (amino)] - 5-bromo-4-diethylphosphonomethoxycarbonylthiazole (1 mmole) and dichlorobis (triphenylphosphine) A solution of palladium (II) (0.1 mmole) was treated with tributyl (vinyl) tin (2.5 mmole) at 60 ° C for 2 hours and the reaction was stirred for 2 hours. The solvent was removed and the residue taken up in EtOAc and stirred with 2 mmole of NaF in 5 mL of water for 1 h. Extraction and chromatography gave 2- [N-Boc (amino)] - 5-vinyl-4-diethylphosphonomethoxycarbonylthiazole as a yellow solid.
[1413] Step H. Preparation of 2- [N-Boc (amino)] -5-vinyl-4-diethylphosphonomethoxycarbonylthiazole (1 mmole) and 10% Pd / C (0.5 mmole) Was stirred under H ₂ atmosphere (balloon) at room temperature for 15 hours. Filtration and evaporation gave 2- [N-Boc (amino)] - 5-ethyl-4-diethylphosphonomethoxycarbonylthiazole as a yellow solid which was treated as in Example 18, Step D, 2-amino-5-ethyl-4-phosphonomethoxycarbonylthiazole (18.3) was obtained as a solid by treatment as in Step 3 of Example 3. Mp > 230 DEG C (decomposition). Calcd for C ₇ H ₁₁ N ₂ O ₅ PS: 31.58; H: 4.16; N: 10.52. Found: C: 31.80; H: 4.04; N: 10.18.
[1414] Step I. A solution of N- [bis (methylthio) methylene] glycine methyl ester (1 mmole) in anhydrous THF (2 mL) was added to a solution of t-BuOH (1.4 mmole) in anhydrous TBF And the mixture was stirred for 30 minutes. A solution of ethyl isothiocyanate (1 mmole) in anhydrous TBF (2 mL) was then added and the reaction was stirred at -78 &lt; 0 &gt; C for 30 min and at room temperature for 2 h. The reaction was quenched with water. Extraction and chromatography afforded 2-methylthio-5- (N-ethylamino) -4-methoxycarbonylthiazole as a yellow solid which was treated as in Example 18, Steps B and C, 3, Step C, 2-methylthio-5- (N-ethylamino) -4-phosphonomethoxycarbonylthiazole (18.4) was obtained as a solid. Mp &gt; 200 DEG C (decomposition). C ₈ H ₁₃ N ₂ 0 ₅ PS ₂ + 0.1 HBr: C: 29.99; H: 4.12; N: 8.74. Found: C: 29.71; H: 4.10; N: 8.60.
[1415] II. Preparation of 4-phosphonomethylthiocarbonyl thiadiazole.
[1416] Step A solution of 2- [N-Boc (amino)] - 4-thiazolecarboxylate acid chloride (1 mmole) and 1 mmole of pyridine (2 mmole) in CH ₂ Cl ₂ (5 mL) Cooled and H ₂ S (g) was bubbled through the solution for 10 min. The reaction was stirred at -78 &lt; 0 &gt; C for 30 min, then allowed to warm to room temperature. The mixture was washed with 3N HCl. The organic phase was separated, dried and concentrated to give 2- [N-Boc (amino)] - 4-thiazolethiocarboxylic acid as a yellow solid.
[1417] Step K. A solution of 2- [N-Boc (amino)] - 4-thiazole thiocarboxylic acid (1 mmole) in DMF (5 mL) was cooled to -78 C and NaH (2 mmole) Respectively. After 10 min, the reaction was treated with diethylphosphonomethyltriflate solution in THF (5 mL). The reaction was stirred for 1 hour at -78 ℃, it was quenched with H ₂ 0. Extraction and chromatography to give 2- [N-Boc (amino)] - 4-diethylphosphonomethylthiocarbonylthiazole as a dark oil which was treated as in step D of Example 18, 2-amino-4-phosphonomethylthiocarbonylthiazole (18.5) as a solid. Mp > 230 DEG C (decomposition). C ₅ H ₇ N ₂ 0 ₄ Calculated for PS ₂ : C: 23.62; H: 2.78; N: 11.02. Found: C: 23.77; H: 2.61; N, 10.73.
[1418] The reaction of 4 - [(N-phosphonomethyl) carbamoyl] thiazole, 3- [N-phosphonomethyl] Produce.
[1419] Step L A solution of 2- [N-Boc (amino)] - 4-thiazolecarboxylic acid (1 mmole) in DMF (5 mL) was treated with 1- (3-dimethylaminopropyl) -3 (1.5 mmole) of ethyl carbodiimide hydrochloride (EDCI, 1.5 mmole) and 1-hydroxybenzotriazole hydrate (HOBt, 1.5 mmole). The reaction was evaporated, extracted and chromatographed to give 2- [N-Boc (amino)] - 4- [(N-diethylphosphonomethyl) carbamoyl] thiazole as a white solid, D and then treated in the same manner as in Step C of Example 3 to obtain 2-amino-4 - [(N-phosphonomethyl) carbamoyl] thiazole (18.6) as a light brown solid. Mp > 245 DEG C (decomposition). C ₅ H ₈ N ₃ 0 ₄ PS + 1.05 Calculated for HBr: C: 18.64; H: 2.83; N: 13.04. Found: C: 18.78; H: 2.43; N: 12.97.
[1420] Preparation of 2 - [(N-phosphonoacetyl) amino] thiazole and 2 - [(N-phosphonoacetyl) amino] pyridine.
[1421] A solution of 2-amino-4,5-dimethylthiazole hydrochloride (2 rmnoles) and phosphonoacetic acid (1 mmole) in DMF (5 mL) was treated with EDCI (1.5 mmole), HOBT 1.5 mmole) and triethylamine (2 mmole). The reaction product was evaporated, extracted and chromatographed to obtain 2 - [(N-diethylphosphonoacetyl) amino] -4,5-dimethylthiazole as a yellow solid, which was treated as in Step D of Example 18, 4,5-Dimethyl-2 - [(N-phosphonoacetyl) amino] thiazole (18.7) was obtained as a light brown solid by treatment as in Step 3 of Example 3. Mp > C ₇ H ₁₁ N ₂ 0 ₄ Calculated for PS: C: 33.60; H: 4.43; N: 11.20. Found: C: 33.62; H: 4.29; N: 10.99.
[1422] The following compounds were prepared according to the above method or, in some cases, with minor modifications to these methods using conventional chemical methods:
[1423] (18.8) 2 - [(N-phosphonomethyl) carbamoyl] pyridine. Calc. For C ₇ H ₉ N ₂ O ₄ P + HBr + 0.67 H ₂ O: C: 27.20; H: 3.70; N 9.06. Found: C; 27.02; H: 3.71; N: 8.92.
[1424] (18.9) 2 - [(N-phosphonoacetyl) amino] pyridine. C ₇ H ₉ N ₂ 0 ₄ P + HBr + 0.67 Calculated for H ₂ O: C: 21.20; H: 3.70; N 9.06. Found: C: 27.05; H: 3.59; N: 8.86.
[1425] (18.10) 4-Ethoxycarbonyl-2 - [(N-phosphonoacetyl) amino] thiazole. C ₈ H ₁₁ N ₂ O ₆ Calculated for PS: C: 32.66; H: 3.77; N: 9.52. Found: C: 32.83; H: 3.58; N: 9.20.
[1426] (18.11) 2-Amino-5-bromo-4 - [(N-phosphonomethyl) carbamoyl) thiazole. Mp 232 ° C (decomposition). C ₅ H ₇ N ₃ 0 ₄ PSBr + 0.15 HBr + 0.1 Calculated for hexane: C: 19.97; H: 2.56; N: 12.48. Found: C: 19.90; H: 2.29; N: 12.33.
[1427] (18.12) 2-Amino-5- (2-thienyl) -4 - [(N-phosphonomethyl) carbamoyl] thiazole. Mp 245 DEG C (decomposition). C ₉ H ₁₀ N ₃ O ₃ N ₄ PS ₂ + HBr + 0.1 Calculated for EtOAc: C: 27.60; H: 2.91; N: 10.27. Found: C: 27.20; H: 2.67; N: 9.98.
[1428] (18.13) 4,5-Dichloro-3 - [(N-phosphonomethyl) carbamoyl] isothiazole. Mp 189-191 ° C. Calcd for _{C 5 H 5 N 2 0 4} PSCl 2: C: 20.63; H: 1.73; N: 9.62. Found: C: 20.43; H: 1.54; N: 9.51.
[1429] (18.14) 2-Amino-5-bromo-4 - {[N- (1-phosphono-1-phenyl) methyl] carbamoyl} thiazole. Mp > C ₁₁ H ₁₁ N ₃ 0 ₄ Calculated for PSBr: C: 33.69; H: 2.83; N: 10.71. Found: C: 33.85; H: 2.63; N: 10.85.
[1430] (18.15) 2-Amino-5- (2-thienyl) -4-phosphonomethoxycarbonylthiazole. Mp > 230 DEG C (decomposition). C ₉ H ₉ N ₂ 0 ₅ Calculated for PS ₂ : C: 33.75; H: 2.83; N: 8.75. Found: C: 33.40; H: 2.74; N: 8.51.
[1431] (18.16) 2-Amino-5-benzyl-4-phosphonomethoxycarbonylthiazole. Mp > 230 DEG C (decomposition). Calcd for C ₁₂ H ₁₃ N ₂ 0 ₅ PS: C: 43.91; H: 3.99; N: 8.53. Found: C: 43.77; H: 4.03; N: 8.25.
[1432] (18.17) 2-Methylthio-5-methylamino-4-phosphonomethoxycarbonylthiazole. C ₇ H ₁₁ N ₂ 0 ₅ PS ₂ + 0.2 Calculated for HBr: C: 26.74; H: 3.59; N: 8.91. Found: C: 26.79; H: 3.89; N: 8.89.
[1433] (19.18) 2-Amino-5-ethyl-4 - [(N-phosphonomethyl) carbamoyl] thiazole. Mp 180 deg. C (decomposition). C ₇ H ₁₂ N ₃ 0 ₄ PS + HBr + 0.4 Calcd for C ₂ H ₂ Cl: C: 23.49; H: 3.67; N: 11.18. Found: C: 23.73; H: 3.29; N: 11.42.
[1434] (18.19) 2-Amino-5-isopropyl-4 - [(N-phosphonomethyl) carbamoyl] thiazole. Mp 247 - 250 ° C. C ₈ H ₁₄ N ₃ 0 ₄ Calculated for PS: C: 34.41; H: 5.05; N: 15.05. Found: C: 34.46; H: 4.80; N: 14.68.
[1435] (18.20) 2-Amino-5-isopropyl-4-phosphonomethoxycarbonylthiazole. Mp > Calcd for C ₈ H ₁₃ N ₂ O ₅ PS: C: 34.29; H: 4.68; N: 10.00. Found: C: 33.97; H: 4.49; N: 9.70.
[1436] (18.21) 2-Amino-5-phenyl-4-phosphonomethoxycarbonylthiazole. Mp > C ₁₁ H ₁₁ N ₂ 0 ₅ Calculated for PS: C: 42.04; H: 3.53; N: 8.91. Found: C: 42.04; H: 3.40; N: 8.72.
[1437] (18.22) 2-amino-4-phosphonomethoxycarbonyloxazole. C ₅ H ₇ N ₂ O ₆ P + 0.09 Calculated for HBr: C: 26.18; H: 3.12; N: 12.21. Found: C: 26.29; H: 3.04; N: 11.90.
[1438] (18.23) 2-Amino-6 - [(N-phosphonoacetyl) amino] pyridine. C ₇ H ₁₀ N ₃ 0 ₄ P + 1.1 HBr + 0.25 Calculated for MeOH: C: 26.54; H: 3.72; N: 12.80. Found: C: 26.79; H: 3.63; N: 12.44.
[1439] (18.24) 2-Amino-5-methyl-4 - [(N-phosphonomethyl) carbamoyl] thiazole. Mp > C ₆ H ₁₀ N ₃ 0 ₄ PS + 0.06 Calculated for EtOAc: C: 29.22; H: 4.12; N: 16.38. Found: C: 29.03; H: 3.84; N: 16.01.
[1440] (18.25) 2-Amino-3-bromo-6 - [(N-phosphonoacetyl) amino] pyridine. C ₇ H ₉ N ₃ O ₄ PBr + 1.25 HBr + 0.8 Calculated for EtOAc: C; 25.43; H: 3.48; N: 8.72. Found: C: 25.58; H: 3.71; N: 8.56.
[1441] (18.26) 2-Amino-3,5-dibromo-6 - [(N-phosphonoacetyl) amino] pyridine. C ₇ H ₈ N ₃ 0 ₄ Calculated for PBr ₂ + HBr + 0.5 EtOAc: C: 21.03; H: 2.55; N: 8.18. Found: C: 21.28; H: 2.55; N: 7.91.
[1442] (18.27) 2-Amino-5-methyl-4-phosphonomethoxycarbonylthiazole. Mp 230 deg. C (decomposition). C ₆ H ₉ N ₂ 0 ₅ Calculated for PS: C: 28.58; H: 3.60; N: 11.11. Found: C: 23.38; H: 3.49; N: 11.10.
[1443] (18.28) 2-Amino-3,5-diethyl-6 - [(N-phosphonoacetyl) amino] pyridine. _{C 11 H 18 N 3 0 4} P + calculated with respect to H MS: 288. Found: 288.
[1444] (18.29) 2-Amino-3,5-dibromo-6 - {[N- (2,2-dibromo-2-phosphono) acetyl] amino} pyridine. C ₇ H ₆ N ₃ 0 ₄ Calculated for PBr ₄ + 0.5 HBr + EtOAc: C: 19.56; H: 2.16; N: 6.22. Found: C: 19.26; H: 2.29; N: 5.91.
[1445] (18.30) 2-Amino-5-isopropyl-4-phosphonomethoxycarbonyloxazole. C ₈ H ₁₃ N ₂ 0 ₆ P + 0.2 Calculated for HBr: C: 34.27; H: 4.75: N: 9.99. Found: C: 34.47; H: 4.84; N: 9.83.
[1446] (18.31) 2-Amino-5- [1- (2-cyclohexylmethyl) ethynyl] -4-phosphonomethoxycarbonylthiazole. Mp 230 deg. C (decomposition). C ₁₄ H ₁₉ N ₂ 0 ₅ PS + 0.1 Calculated for HBr: C: 45.89; H: 5.25; N: 7.64. Found: C: 45.85; H: 4.96; N: 7.44.
[1447] (18.32) 2-Amino-5- [1- (4-cyano) butynyl] -4-phosphonomethoxycarbonylthiazole. Mp 230 deg. C (decomposition). C ₁₀ H ₁₀ N ₃ O ₅ PS + 0.25 Calculated for HBr: C: 35.80; H: 3.08; N: 12.53. Found: C: 35.92; H: 2.99; N: 12.20.
[1448] (18.33) 2-Amino-5-methyl-4-phosphonomethoxycarbonyloxazole. Calcd for C ₆ H ₉ N ₂ O ₆ P + 0.15 HBr: C: 29.03; H: 3.71; N: 11.28. Found: C: 28.98; H: 3.66; N: 11.21.
[1449] (18.34) 2-Amino-5- [1- (4-cyano) butyl] -4-phosphonomethoxycarbonylthiazole. Mp 230 deg. C (decomposition). C ₁₀ H ₁₄ N ₃ 0 ₅ Calculated for PS: C: 37.62; H: 4.42; N: 13.16. Found: C: 37.23; H: 4.18; N; 12.79.
[1450] (18.35) 2-Amino-5-pentyl-4-phosphonomethoxycarbonyloxazole. Calcd for _{C 10 H 17 N 2 0 6} P: C: 41.10; H: 5.86; N: 9.59. Found: C: 41.16; H: 5.75; N: 9.50.
[1451] (18.36) 2- [N-Boc (amino)] - 4 - [(2-phosphono) ethoxycarbonyl] thiazole. C ₁₀ H ₁₇ N ₂ 0 ₅ Calculated for PS: C: 37.50; H: 4.86; N: 7.95. Found: C: 37.10; H: 4.59; N: 7.84.
[1452] (18.37) 2-Amino-4 - [(2-phosphono) ethoxycarbonyl] thiazole hydrobromide. C ₆ H ₉ N ₂ O ₅ Calculated for PS + HBr: C: 21.63; H: 3.03; N: 8.41. Found: C: 22.01; H: 2.99; N: 8.15.
[1453] (18.38) 2-Amino-5-butyl-4-phosphonomethoxycarbonyloxazole. C ₉ H ₁₅ N ₂ calculated for 0 ₆ P: C: 38.86; H: 5.43; N: 10.07. Found: C: 38.59; H: 5.43; N: 9.96.
[1454] (18.39) 2-Amino-5- [1- (1-oxo-2,2-dimethyl) propyl] -4-phosphonomethoxycarbonylthiazole. Calcd for _{C 1O H 15 N 2 0 6} PS: C: 37.27; H: 4.69; N: 8.69. Found: C: 37.03; H: 4.69; N: 8.39.
[1455] (18.40) 2-Amino-5-propyl-4-phosphonomethoxycarbonyloxazole. C ₈ H ₁₃ N ₂ O ₆ P + 0.35 EtOAc + 0.05 Calculated for HBr: C: 37.75; H: 5.34; N: 9.37. Found: C: 37.69; H: 5.21; N 9.03.
[1456] (18.41) 2-Amino-5-propyl-4-phosphonomethoxycarbonylthiazole. Mp 134 ℃ (decomposition) Calcd .C _{8 H 13 N 2 0 5 PS} : C: 34.29; H: 4.68; N: 10.00. Found: C: 33.90; H: 4.30; N: 9.61.
[1457] (18.42) 2-Amino-5-pentyl-4-phosphonomethoxycarbonylthiazole. Mp 130 deg. C (decomposition). Calcd for _{C 10 H 17 N 2 O 5} PS: C: 38.96; H: 5.56; N, 9.09. Found: C: 38.69; H: 5.25; N: 8.85.
[1458] (18.43) 2-Amino-5-bromo-4-phosphonomethylthiocarbonylthiazole. Mp 230 deg. C (decomposition). C ₅ H ₆ N ₂ O ₅ PS ₂ Calcd for Br: C: 18.03; H: 1.82; N: 8.41. Found: C: 18.40; H: 1.93; N: 8.18.
[1459] (18.44) 2-Amino-5- (2-furanyl) -4-phosphonomethoxycarbonylthiazole. Mp 230 deg. C (decomposition). C ₉ H ₉ N ₂ O ₆ Calculated for PS: C: 35.53; H: 2.98; N: 9.21. Found: C: 35.78; H: 3.05; N: 8.11.
[1460] (18.45) 2-Amino-5-ethyl-4-phosphonomethoxycarbonyloxazole. Mp 141 [deg.] C (decomposition). Calcd for C _{7 H 11 N 2 0 6 P:} C: 33.61; H: 4.43; N: 11.20. Found: C: 33.79; H: 4.47; N: 11.09.
[1461] (18.46) 5-Methyl-4 - [(N-phosphonomethyl) carbamoyl] imidazole. Calcd for C ₆ H ₁₀ N ₃ O ₄ P: C: 32.89; H: 4.60; N: 19.18. Found: C: 33.04; H: 4.65; N: 18.84.
[1462] &Lt; Example 19 >
[1463] Preparation of various phosphonoate diesters as a whole.
[1464] A suspension of 2-methyl-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole (1 mmole) in thionyl chloride (5 mL) was warmed at reflux temperature for 4 hours. The cooled reaction mixture was evaporated to dryness and the resulting yellow residue was dissolved in methylene chloride and treated with a solution of the corresponding benzyl alcohol (4 mmole) and pyridine (2.5 mmole) in methylene chloride. After stirring at 25 [deg.] C for 24 hours, the reaction mixture was extracted and chromatographed to give the title compound. The following compounds were prepared by this method:
[1465] (19.1) 2-Methyl-5-isobutyl-4- (2- [5-bis (4-pivaloyloxybenzyl) phosphono] furanyl) thiazole. Calcd for C ₃₆ H ₄₄ NO ₈ PS + 0.4 H ₂ O: C: 62.76; H: 6.55; N 2.03. Found: C: 62.45; H: 6.44; N: 2.04,
[1466] (19.2) 2-Methyl-5-isobutyl-4- {2- [5-bis (3,4-diacetoxybenzyl) phosphono] furanyl] thiazole. Calcd for C ₃₄ H ₃₆ NO ₁₂ PS + 0.8 H ₂ O: C: 56.09; H: 5.21; N: 1.92. Found: C: 55.90; H: 4.98; N: 1.94.
[1467] (19.3) 2-Methyl-5-isobutyl-4- {2- [5-bis (4-acetoxy-3-methoxybenzyl) phosphono] furanyl} thiazole. Calcd for C ₃₂ H ₃₆ NO ₁₀ PS: C: 58.44; H: 5.52; N: 2.13. Found: C: 58.16; H: 5.34; N: 2.13.
[1468] (19.4) 2-Methyl-5-isobutyl-4- {2- [5-bis (4-acetoxy-3-methylbenzyl) phosphono] furanyl} thiazole. Calcd for C ₃₂ H ₃₆ NO ₈ PS: C: 61.43; H: 5.80; N: 2.24. Found: C: 61.34; H: 5.89; N: 2.25.
[1469] (19.5) 2-Amino-5-isobutyl 4- {2- [5-bis (3,4-diacetoxybenzyl) phosphono] furanyl} thiazole. C ₃₃ H ₃₅ N ₂ O ₁₂ Calculated for PS: C: 55.46; H: 4.94; N: 3.92. Found: C: 55.06; H: 4.96; N: 3.79.
[1470] (19.6) 2-Amino-5-isobutyl-4- {2- [5-bis (4-acetoxybenzyl) phosphono] furanyl} thiazole. C ₂₉ H ₃₁ N ₂ 0 ₈ Calculated for PS: C: 58.19; H: 5.22; N: 4.68. Found: C: 57.82; H: 4.83; N, 4.50.
[1471] This method is also useful in the preparation of phenylphosphonate esters as drug precursors, and the following compounds are prepared.
[1472] (19.7) 2-Methyl-5-isobutyl-4- [2- (5-diphenylphosphino) furanyl] thiazole. Calcd for C ₂₄ H ₂₄ NO ₄ PS + 0.1 H 2 O: C; 63.31; H: 5.36; N, 3.08. Found: C: 63.22; H: 5.34; N: 3.14.
[1473] (19.63) 2-Amino-5-isobutyl-4- [2- (5-diphenylphosphino) furanyl] thiazole. Mp 128 - 129 캜. Calcd for C ₂₃ H ₂₃ N ₂ 0 ₄ PS: C: 60.78; H: 5.10; N: 6.16. Found: C: 60.68; H: 4.83; N: 6.17.
[1474] (19.64) 2-Amino-5-isobutyl-4- [2- (5-phenylphosphino) furanyl] thiazole. Mp > C ₁₇ H ₁₉ N ₂ 0 ₄ Calculated for PS: C: 53.96, H: 5.06; N: 7.40. Found: C: 53.81; H: 4.87; N: 7.41.
[1475] (19.65) 2-Amino-5-isobutyl-4- [2- (5-bis (3-chlorophenyl) phosphono) furanyl] thiazole _{.C 23 H 21 N 2 0 4} PSCl 2 + 0.5 H 2 Calculation for 0: C: 51.89; H: 4.17; N: 5.26. Found: C: 51.55; H: 3.99; N: 5.22.
[1476] (19.67) 2-Amino-5-isobutyl-4- [2- (5-bis (4-methoxyphenyl) phosphono) furanyl] thiazole. Calcd for C ₂₅ H ₂₇ N ₂ O ₆ PS + 0.5 H ₂ O: C: 57.35; H: 5.39; N: 5.35. Found: C: 57.11; H: 5.36; N, 5.75.
[1477] This method is also useful for the preparation of some thio-containing phosphonoate esters as drug precursors, and the following compounds are prepared.
[1478] (19.8) 2-Methyl-5-isobutyl-4- {2- [5-bis (2-methylcarbonylthioethyl) phosphono] furanyl} thiazole. Calcd for C ₂₀ H ₂₈ NO ₆ PS ₃ : C: 47.51; H: 5.58; N: 2.77. Found: C: 47.32; H: 5.56; N: 2.77.
[1479] (19.9) 2-Methyl-5-isobutyl-4- {2- [5-bis (thiobenzoylmethyl) phosphono] furanyl} thiazole. Calcd for C ₂₈ H ₂₈ NO ₆ PS ₃ : C: 55.89; H: 4.69; N: 2.33. Found: C: 55.73; H: 4.72; N: 2.28.
[1480] In addition, the process can be carried out by coupling of phosphorous acid and various diols (see, for example, Example 21 for the synthesis of 1,3-propanediol, some 1,3-propanediol), cyclic phosphono (E. G., Cyclic 1,3-propanediol phosphonoate esters), and the following compounds are prepared.
[1481] (19.10) 5-Isobutyl-2-methyl-4- {2- [5- (1 -hydroxy-3,5cyclohexyl) phosphono] furanyl} thiazole (diisomer). Calcd for C ₁₈ H ₂₄ NO ₅ PS + 0.33 H ₂ O: C: 53.60; H: 6.16; N: 3.47. Found: C: 53.75; H: 6.53; N: 3.45.
[1482] (19.11) 5-Isobutyl-2-methyl-4- {2- [5- (1 -hydroxy-3,5-cyclohexyl) phosphono] furanyl} thiazole (main isomer). Calcd for C ₁₈ H ₂₄ NO ₅ PS: C: 54.40; H: 6.09; N: 3.52. Found: C: 54.44; H: 6.11; N: 3.63.
[1483] (19.12) 5-Isobutyl-2-methyl-4- {2- [5- (2-hydroxymethyl-1,3-propyl) phosphono] furanyl} thiazole. C ₁₆ H ₂₂ NO ₅ PS + 0.3 CH ₂ Cl ₂ + 0.5 H ₂ O: C: 48.24; H: 5.86; N: 3.45. Found: C: 47.94; H: 5.59; N: 3.57.
[1484] (19.13) 5-Isobutyl-2-methyl-4- {2- [5- (1-phenyl-1,3-propyl) phosphono] furanyl} thiazole, (diisomer). Calcd for C ₂₁ H ₂₄ NO ₄ PS + 0.25H ₂ O: C: 59.77; H: 5.85; N: 3.32. Found: C: 59.76; H: 5.69; N: 3.38.
[1485] (19.14) 5-Isobutyl-2-methyl-4- {2- [5- (1-phenyl-1,3-propyl) phosphono] furanyl} thiazole, (main isomer). Calcd for C ₂₁ H ₂₄ NO ₄ PS + 0.5 H ₂ O: C: 59.14; H: 5.91; N: 3.28. Found: C: 59.27; H: 5.85; N: 3.38.
[1486] (19.15) Synthesis of 2-amino-5-isobutyl-4- [2- (5- [2- (methoxycarbonyloxymethyl) -propan- 1, 3- yl) phosphono) furanyl] thiazole Isomer). mp 170-173 [deg.] C. C ₁₇ H ₂₃ N ₂ O ₇ Calculated for PS: C: 47.44; H; 5.39; N: 6.51. Found: C: 47.28; H: 5.27; N: 6.47.
[1487] (19.16) Synthesis of 2-amino-5-isobutyl-4- [2- (5- [2- (methoxycarbonyloxymethyl) -propan- 1,3- ylphosphino) furanyl] thiazole Isomer). Calcd for C ₁₇ H ₂₃ N ₂ 0 ₇ PS + 0.5 H ₂ O: C: 46.47; H: 5.51; N: 6.38. Found: C: 46.38; H: 5.29; N: 6.20.
[1488] (19.17) 5-Isobutyl-2-methyl-4- {2- [5- (1- (4-pyridyl) -1,3-propyl) phosphono] furanyl} -thiazole. Calcd for _{C 20 H 23 N 2 0 4} PS + 2 H 2 0 + 0.4 CH 2 Cl 2: C: 50.16; H: 5.74; N: 5.74. Found: C: 50.36; H: 5.36; N: 5.80.
[1489] (19.18) 2-Amino-5-isobutyl-4- (2- {5- [1- (4-pyridyl) -propane- 1,3- ylphosphono} furanyl) thiazole. mp 101-106 [deg.] C. Calcd for C ₁₉ H ₂₂ N ₃ 0 ₄ PS + 0.75 H ₂ O: C: 52.71; H: 5.47; N: 9.71. Found: C: 52.59; H: 5.49; N: 9.65.
[1490] (19.20) 2-Amino-5-isobutyl-4- {2- [5- (1-phenyl-1,3-propyl) phosphono] furanyl) thiazole (diisomer). Calcd for C ₂₀ H ₂₃ N ₂ 0 ₄ PS + 0.33 HCl: C: 55.80; H: 5.46; N: 6.51. Found: C: 55.95; H: 5.36; N: 6.46.
[1491] (19.21) 2-Amino-5-isobutyl-4- {2- [5- (1-phenyl-1,3-propyl) phosphono] furanyl} thiazole (master isomer). Calcd for C ₂₀ H ₂₃ N ₂ 0 ₄ PS + 0.33 HCl: C: 55.80; H: 5.46; N: 6.51. Found: C: 55.17; H: 5.19; N: 6.44.
[1492] (19.22) 2-Amino-5-ethyl-4- {2- [5- (l-phenyl-l, 3-propyl) phosphono] furanyl} thiazole (isomer with small polarity). Calcd for C ₁₈ H ₁₉ N ₂ O ₄ PS + 0.2 HCl + 0.25 H ₂ O: C: 53.75; H: 4.94; N: 6.97. Found: C: 53.86; H: 4.70; N: 6.87.
[1493] (19.23) 2-Amino-5-ethyl-4- {2- [5- (l-phenyl-l, 3-propyl) phosphono] furanyl} -thiazole (polar isomer). Calcd for C ₁₈ H ₁₉ N ₂ O ₄ PS + 0.2 HCl + 0.25 H ₂ O: C: 53.75; H: 4.94; N, 6.97. Found: C: 53.92; H: 4.82; N: 6.92.
[1494] (19.24) 2-Amino-5-ethyl-4- {2- [5- (1- {4-pyridyl} -1,3-propyl) phosphono] furanyl} thiazole. C ₁₇ H ₁₈ N ₃ O ₄ PS + 0.1 HCl + 0.5 H ₂ O: C: 50.54; H: 4.76; N: 10.40. Found: C: 50.38; H: 4.53; N, 10.25.
[1495] (19.25) 2-Methyl-4- {2- [5- (2-acetoxymethylpropane-1,3-diyl) phosphono] furanyl} thiazole. Calcd for C ₁₄ H ₁₆ NO ₆ PS + 0.5 H ₂ O: C: 45.90; H: 4.68; N: 3.82. Found: C: 45.50; H: 4.55; N: 3.45.
[1496] (19.26) 2-Methyl-4- (2- {5- [1- (4-pyridyl) propane-1,3-diyl] phosphono} furanyl) thiazole. Calcd for C ₁₆ H ₁₅ N ₂ 0 ₄ PS + 0.75 H ₂ O: C: 51.13; H: 4.42; N: 7.45. Found: C: 50.86; H: 4.72; N: 7.11.
[1497] (19.27) 2-Amino-5-methylthio-4- (2- {5- [1- (4-pyridyl) propane-1,3-diyl] phosphono} furanyl) thiazole. Calcd for C ₁₆ H ₁₆ N ₃ 0 ₄ PS ₂ +0.4 HCl: C: 45.32; H: 3.90; N: 9.91. Found: C: 45.29; H: 3.80; N: 9.83.
[1498] (19.28) 2-Amino-5-isobutyl-4- {2- [5- (1- (3-bromophenyl) propane-1,3-diyl) phosphono] furanyl} thiazole, diastereoisomer. Calcd for C ₂₀ H ₂₂ N ₂ O ₄ PBrS: C: 48.30; H: 4.46; N: 5.63. Found: C: 48.51; H: 4.21; N: 5.33.
[1499] (19.29) 2-Amino-5-methylthio-4- {2- [5- (1- (R) -phenyl-1,3-propyl) phosphono] furanyl} thiazole. Calcd for C ₁₇ H ₁₇ N ₂ 0 ₄ PS + HCl: C: 49.46; H: 4.39; N: 6.79. Found: C: 49.77; H: 4.13; N: 6.54.
[1500] (19.30) 2-Amino-5-isobutyl-4- {2- [5- (1- (3-bromophenyl) -1,3-propyl) phosphono] furanyl} thiazole, isomer. Calcd for C ₂₁ H ₂₂ N ₂ 0 ₄ PSBr + 0.25 HCl: C: 47.43; H: 4.43; N: 5.53. Found: C: 47.58; H: 4.16; N: 5.31.
[1501] (19.31) 2-Amino-5-isobutyl-4- {2- [5- (2-benzyl-1,3-propyl) phosphono] furanyl} thiazole. Calcd for C ₂₁ H ₂₅ N ₂ 0 ₄ PS: C: 58.32; H: 5.83; N: 6.48. Found: C: 57.98; H: 5.65; N: 6.47.
[1502] (19.32) 2-Amino-5-cyclopropyl-4- {2- [5- (1- (4-pyridyl) -1,3-propyl) phosphono] furanyl} thiazole. Calcd for C ₁₈ H ₁₈ N ₃ 0 ₄ PS + 0.5 H ₂ O: C: 52.42; H: 4.64; N: 10.19. Found: C: 52.62; H: 4.51; N: 9.89.
[1503] (19.33) 2-Methyl-5-isobutyl-4- {2- [5- (1- (S) -phenyl-1,3-propyl) phosphono] furanyl} thiazole, isomer. C ₂₁ H ₂₄ NO ₄ PS: C: 60.42; H: 5.9; N: 3.36. Found: C: 60.10; H: 5.58; N: 3.32.
[1504] (19.34) 2-Methyl-5-isobutyl-4- {2- [5- (1- (S) -phenyl-1,3-propyl) phosphono] furanyl} thiazole, diastereoisomer. Calcd for C ₂₁ H ₂₄ NO ₄ PS + 0.33 H ₂ O: C: 59.57; H: 5.87; N: 3.31. Found: C: 59.45; H: 5.83; N: 3.30.
[1505] (19.35) 2-azido-5-ethyl-4- {2- [5- (1-phenyl-1,3-propyl) phosphono] furanyl} thiazole, diastereoisomer. C ₁₈ H ₁₇ N ₄ O ₄ PS + 0.25 H ₂ O + 0.1 Calculated for isoamyl alcohol (C ₅ H ₁₂ O): C: 51.71; H: 4.39; N: 13.04. Found: C: 51.80; H: 4.20; N: 12.78.
[1506] (19.36) 2-azido-5-ethyl-4- {2- [5- (l-phenyl-l, 3-propyl) phosphono] furanyl} thiazole, diisomer. C ₁₈ H ₁₇ N ₄ 0 ₄ PS + 0.15 Calculated for isoamyl alcohol (C ₅ H ₁₂ O): C: 52.42; H: 4.41; N: 13.04. Found: C: 52.27; H: 4.47; N: 12.76.
[1507] (19.37) 2-Amino-5-isobutyl-4- {2- [5- (1- (1-naphthyl) -1,3-propyl) phosphono] furanyl} thiazole. C ₂₄ H ₂₅ N ₂ 0 ₄ Calculated for PS: C: 61.53; H: 5.38; N: 5.98. Found: C: 61.40; H: 5.12; N: 6.11.
[1508] (19.38) 2-Amino-5-isobutyl-4- {2- [5- (1- (2-bromophenyl) -1,3-propyl) phosphono] furanyl} thiazole. C _{2 O} H ₂₂ N ₂ 0 ₄ PSBr + 0.1 C ₅ H ₅ N: C: 48.73; H: 4.49; N: 5.82. Found: C: 48.63; H: 4.26; N, 5.70.
[1509] (19.39) 2-Amino-5-isobutyl-4- {2- [5- (1- (4-bromophenyl) -1,3-propyl) phosphono] furanyl} thiazole, isomer. Calcd for C ₂₀ H ₂₂ N ₂ 0 ₄ PSBr: C: 48.30; H: 4.46; N: 5.63. Found: C: 48.23; H: 4.30; N: 5.77,
[1510] (19.40) 2-Amino-5-isobutyl-4- {2- [5- (1- (4-bromophenyl) -1,3-propyl) phosphono] furanyl} thiazole, diastereoisomer. Calcd for C ₂₀ H ₂₂ N ₂ 0 ₄ PSBr: C: 48.30; H: 4.46; N: 5.63. Found: C: 48.20; H: 4.63; N: 5.41.
[1511] (19.41) Synthesis of 2-amino-5-isobutyl-4- {2- [5- (1- (4- fluoro-3- bromophenyl) -1,3-propyl) phosphono] furanyl} thiazole , A diastereomer. C ₂₀ H ₂₁ N ₂ 0 ₄ PSBrF + 0.1 Calculated for C ₅ H ₅ N: C: 47.06; H: 4.14; N: 5.62. Found: C: 47.00; H: 3.84; N: 5.48.
[1512] (19.42) Synthesis of 2-amino-5-isobutyl-4- {2- [5- (1- (4- fluoro-3- bromophenyl) -1,3-propyl) phosphono] furanyl} thiazole , The main isomer. Calcd for C ₂₀ H ₂₁ N ₂ 0 ₄ PSBrF: C: 46.61; H: 4.11; N: 5.44; P: 6.01. Found: C: 46.81; H: 4.23; N: 5.65; P: 5.65.
[1513] (19.43) 2-Amino-5-isobutyl-4- {2- [5- (1- (4-trifluoromethylphenyl) -1,3-propyl) phosphono] furanyl} thiazole, isomer. Calcd for C ₂₁ H ₂₂ N ₂ 0 ₄ PSF ₃ + 0.1 H ₂ O: C: 51.66; H: 4.58; N: 5.74. Found: C: 51.54; H: 4.28; N: 5.46.
[1514] (19.44) 2-Amino-5-isobutyl-4- {2- [5- (1- (4-trifluoromethylphenyl) -1,3-propyl) phosphono] furanyl} thiazole, isomer. Calcd for C ₂₁ H ₂₂ N ₂ OPSF ₃ + 0.1 H ₂ O: C: 51.66; H: 4.58; N: 5.74. Found: C: 51.48; H: 4.62; N: 5.81.
[1515] (19.45) 2-Amino-5-isobutyl-4- {2- [5- (1- (3-chlorophenyl) -1,3-propyl) phosphono] furanyl} thiazole, isomer. Calcd for C ₂₀ H ₂₂ N ₂ 0 ₄ PSCl + 0.5 H ₂ O: C: 52.01; H: 5.02; N, 6.06. Found: C: 52.10; H: 4.92; N: 5.82.
[1516] (19.46) 2-Amino-5-isobutyl-4- {2- [5- (1- (3-chlorophenyl) -1,3-propyl) phosphono] furanyl} thiazole, isomer. Calcd for _{C 2O H 22 N 2 0 4} PSCl + 0.25 H 2 0: C: 52.52; H: 4.96; N: 6.12. Found: C: 52.70; H: 4.79; N: 5.91.
[1517] (19.47) 2-Amino-5-isobutyl-4- {2- [5- (1- (3,5-dichlorophenyl) -1,3-propyl) phosphono] furanyl} thiazole, isomer. Calcd for C ₂₀ H ₂₁ N ₂ 0 ₄ PSCl ₂ : C: 49.29; H: 4.34; N: 5.75. Found: C: 49.47; H: 4.60; N: 5.89.
[1518] (19.48) 2-Amino-5-isobutyl-4- {2- [5- (1- (3,5-dichlorophenyl) -1,3-propyl) phosphono] furanyl} thiazole, diastereoisomer. Calcd for C ₂₀ H ₂₁ N ₂ 0 ₄ PSCl ₂ : C: 49.29; H: 4.34; N: 5.75; Cl: 14.55, found: C: 49.26; H: 4.36; N: 5.71; Cl: 14.66.
[1519] (19.49) 2-Amino-5-isobutyl-4- {2- [5- (2- (4-methoxybenzyl) -1,3-propyl) phosphono] furanyl} thiazole. Mp 185 - 188 ° C. Calcd for C ₂₂ H ₂₇ N ₂ O ₅ PS: C: 57.13; H: 5.88; N, 6.06. Found: C: 56.86; H: 5.71; N, 5.73.
[1520] (19.50) 2-Amino-5-isobutyl-4- {2- [5- (2-methanesulfonyloxymethyl-1,3-propyl) phosphono] furanyl} thiazole. Calcd for C ₁₆ H ₂₃ N ₂ O ₇ PS ₂ + 0.2 H ₂ O: C: 42.32; H: 5.19; N: 6.17, found: C: 42.15; H: 4.94; N: 5.95.
[1521] (19.51) 2-Amino-5-isobutyl-4- {2- [5- (2-azidomethyl-1,3-propyl) phosphono] furanyl} thiazole. Mp 187 - 189 ° C. Calcd for C ₁₅ H ₂₀ N ₅ O ₄ PS: C: 45.34; H: 5.07; N: 17.62. Found: C: 45.09; H: 4.82; N: 17.72.
[1522] (19.52) 2-Amino-5-isobutyl-4- {2- [5- (2-aminomethyl-1,3-propyl) phosphono] furanyl} thiazole. C ₁₅ H ₂₂ N ₃ 0 ₄ PS + 0.3 H ₂ O + 0.1 Calculated for HCl: C: 47.36; H: 6.01; N: 11.04. Found: C: 47.55; H: 5.62; N: 10.64.
[1523] (19.53) 2-Amino-5-isobutyl-4- {2- [5- (1- (4-tert-butylphenyl) -1,3-propyl) phosphono] furanyl} thiazole, isomer. Mp 141 - 143 ° C. Calcd for C ₂₄ H ₃₁ N ₂ 0 ₄ PS + 1.5 HCl: C: 54.47; H: 6.19; N: 5.29. Found: C: 54.44; H: 5.85; N: 4.92.
[1524] (19.54) 2-Amino-5-isobutyl-4- (2- [5- (1- (4-tert-butylphenyl) -1,3-propyl) phosphono] furanyl} thiazole, diastereoisomer. . Mp 178 ℃ _{(decomposition) C 24 H 31 N 2 0} 4 calculated for _{PS + H 2 0: C:} 58.52; H: 6.75; N:. 5.69 found: C: 58.20; H: 6.31 ; N: 5.29.
[1525] (19.55) 2-Amino-5-isobutyl-4- {2- [5- (1- (4-chlorophenyl) -1,3-propyl) phosphono] furanyl} thiazole, diastereoisomer. Mp 102-104 ° C. C ₂₀ H ₂₂ N ₂ O ₄ PSCl + H ₂ O + 0.2 Calcd for EtOAc: C: 51.14; H: 5.28; N, 5.73. Found: C: 50.86; H: 5.09; N: 5.34.
[1526] (19.56) 2-Amino-5-isobutyl-4- {2- [5- (1- (2,4-dichlorophenyl) -1,3-propyl) phosphono] furanyl} thiazole, isomer. Mp 173-174 ° C. Calcd for C ₂₀ H ₂₁ N ₂ 0 ₄ PSCl ₂ : C: 49.29; H: 4.34; N: 5.75. Found: C: 49.55; H: 4.32; N: 5.46.
[1527] (19.57) 2-Amino-5-isobutyl-4- {2- [5- (1,3- (S, S) -diphenyl) -1,3-propyl) phosphono] furanyl) thiazole. Mp 105 - 107 캜. C ₂₆ H ₂₇ N ₂ 0 ₄ PS + 0.5 H ₂ O + 0.5 HCl: C: 59.85; H: 5.51; N: 5.37. Found: C: 59.83; H: 5.18; N: 5.27.
[1528] (19.58) 2-Amino-5-isobutyl-4- {2- [5- (1- (4-chlorophenyl) -1,3-propyl) phosphono] furanyl} thiazole, isomer. Mp 102-104 ° C. Calcd for C ₂₀ H ₂₂ N ₂ 0 ₄ PSCl: C: 53.04; H: 4.90; N: 6.19. Found: C: 52.80; H: 4.70; N, 6.07.
[1529] (19.59) Synthesis of 2-amino-5-isobutyl-4- {2- [5- (1- (3,5- difluorophenyl) -1,3-propyl) phosphono] furanyl] thiazole, Isomer. Mp 152 - 154 캜. C ₂₀ H ₂₁ N ₂ O ₄ PSF ₂ + 0.5 H ₂ O + 0.3 Calcd for EtOAc: C: 51.98; H: 5.02; N: 5.72. Found: C: 51.67; H: 4.77; N: 5.42.
[1530] (19.60) Synthesis of 2-amino-5-isobutyl-4- {2- [5- (1- (3,5- difluorophenyl) -1,3-propyl) phosphono] Isomer. Mp 94 - 95 ° C. Calcd for C ₂₀ H ₂₁ N ₂ 0 ₄ PSF ₂ : C: 52.86; H: 4.66; N: 6.16. Found: C: 52.68; H: 4.73; N: 5.90,
[1531] (19.61) Synthesis of 2-amino-5-isobutyl-4- {2- [5- (1- (3,5- dibromophenyl) -1,3-propyl) phosphono] Isomer. Mp 113 - 115 캜. Calcd for _{C 20 H 21 N 2 0 4} PSBr 2 + 0.3 EtOAc: C: 42.25; H: 3.91; N: 4.65. Found: C: 42.52; H: 3.91; N; 4.96.
[1532] (19.62) Synthesis of 2-amino-5-isobutyl-4- {2- [5- (1- (3,5- dibromophenyl) -1,3-propyl) phosphono] furanyl) thiazole, Isomer. Mp 209 - 210 캜. Calcd for C ₂₀ H ₂₁ N ₂ 0 ₄ PSBr ₂ : C: 41.69; H: 3.67; N: 4.86. Found: C: 41.93; H: 3.71; N: 4.74.
[1533] (19.66) 2-Amino-5-isobutyl-4- {2- [5- (1- (3-pyridyl) -1,3-propyl) phosphono] furanyl} thiazole dihydrochloride. C ₁₉ H ₂₂ N ₃ O ₄ calculated for _{PS + 2 HCl + 2 H 2} 0: C: 43.19; H: 5.34; N: 7.95. Found: C: 43.10; H: 5.25; N: 7.85.
[1534] (19.68) Synthesis of 2-amino-5-isobutyl-4- {2- [5- (1-oxo-1-phospha-2,5,8-trioxa-3,4- benzo) Yl] furanyl} thiazole. C ₁₉ H ₂₁ N ₂ 0 ₅ Calculated for PS + 0.75 H ₂ O: C: 52.59; H: 5.23; N: 6.46. Found: C: 52.38; H: 4.85; N: 6.08
[1535] Preferably, cyclic 1,3-propanediol phosphonoate esters were prepared using 1,3-dicyclohexylcarbodiimide (DCC) coupling reaction conditions as follows.
[1536] A suspension of 2-amino-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole (1 mmole) in DMF: pyridine (5: 1, 10 mL) And treated with 3- (3,5-dichloro) phenyl-1,3-propanediol (1.1 mmole). The resulting mixture was heated at 80 &lt; 0 &gt; C for 8 hours. Evaporated and then subjected to column chromatography to obtain 2-amino-5-isobutyl-4- {2- [5- (1- (3,5-dichlorophenyl) -1,3-propyl) phosphono] , The main isomer. (19.48) as a solid.
[1537] In addition, this method is also useful for the production of polyphosphoric acid by reacting phosphorous acid with 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolane and 5-methyl-4-hydroxymethyl- (Prepared from 4,5-dimethyl-2-oxo-1,3-diosolene as described in Example 23) (5-substituted 2-oxo- -Yl) methyl and (5-substituted 2-thiocarbonyl-1,3-dioxolen-4-yl) methylphosphonate drug precursors. The following compounds were prepared using this method.
[1538] (19.19) Synthesis of 2-methyl-5-isobutyl-4- {2- [5- (bis (5-methyl-2-thioxo-1,3-dioxolen-4- yl) methyl) phosphono] ) Thiazole. Calcd for C ₂₂ H ₂₄ NO ₈ PS ₃ : C: 47.39; H: 4.34; N: 2.51. Found: C: 47.42; H: 4.30; N: 2.52.
[1539] Alternatively, this compound may be prepared by the method described in Chem. Pharm. Bull. 1984, 32 (6), 2241) by reaction of phosphorous acid with 5-methyl-4-bromomethyl-2-oxo-1,3-dioxolane in DMF in the presence of sodium hydride at 25 & .
[1540] In addition, 2-amino-5-isobutyl-4- {2- [5- bis (3-phthalidyl-2-ethyl) phosphono] (3-phthalidyl) ethanol prepared from acetic acid.
[1541] &Lt; Example 20 >
[1542] Preparation of acyloxyalkyl and alkyloxycarbonyloxyalkylphosphonate diesters as drug precursors.
[1543] A solution of 2-methyl-4- [2- (5-phosphono) furanyl] thiazole (1 mmole) in acetonitrile and N, N, N- diisopropylethylamine (5 mmole) &Lt; / RTI &gt; was treated with pivaloyloxymethyl iodide (4 mmole). Extraction and chromatography afforded 2-methyl-4- [2- (5-dipivaloyloxymethylphosphino) furanyl] -thiazole (20.1). Calcd for C ₂₀ H ₂₈ NO ₁₀ PS: C: 50.59; H: 6.03; N: 2.65. Found: C: 50.73; H: 5.96; N: 2.96.
[1544] The following compounds were prepared by this method:
[1545] (20.2) 2-Methyl-5-isobutyl-4- {2- [5- (O-isobutyryloxymethyl-0-pivaloyloxymethyl) phosphono] furanyl) thiazole. Calcd for C ₂₃ H ₃₄ NO ₈ PS: C: 53.58; H: 6.65; N: 2.72. Found: C: 53.81; H: 6.83; N: 2.60.
[1546] (20.3) 2-Methyl-5-isobutyl-4- {2- [5- (dipivaloyloxymethyl) phosphono] furanyl} thiazole. Calcd for C ₂₄ H ₃₆ NO ₈ PS: C: 54.43; H: 6.85; N: 2.64. Found: C: 54.46; H: 7.04; N: 2.55.
[1547] (20.4) 2-Amino-5-isobutyl-4- {2- [5- (dipyrrolo yloxymethyl) phosphono] furanyl] thiazole. C ₂₃ H ₃₅ N ₂ 0 ₈ Calculated for PS: C: 52.07; H: 6.65; N: 5.28. Found: C: 52.45; H: 6.78; N: 5.01.
[1548] (20.5) 2-Bromo-5-isobutyl-4- {2- [5- (dipyrrolo yloxymethyl) phosphono] furanyl} thiazole. Calcd for C ₂₃ H ₃₃ NO ₈ PSBr: C: 47.00; H: 5.75; N: 2.32. Found: C: 47.18; H: 5.46; N: 2.30.
[1549] Cyclic acyloxyalkylphosphonoate esters can also be prepared by analogous methods to the method of Farquhar's procedure {Farquhar, D., et al. (Tetrahedron Lett. 1995, 36, 655) have.
[1550] (20.13) 2-Amino-5-isobutyl-4- {2- [5- (1-benzoyloxypropane-1,3-diyl) phosphono] furanyl] thiazole, isomer with high polarity. C ₂₁ H ₂₃ N ₂ O ₆ MS calculated for PS + H: 463. Found: 463.
[1551] (20.14) 2-Amino-5-isobutyl-4- (2- [5- (1-benzoyloxypropane-1,3-diyl) phosphono] furanyl) thiazole, the less polar isomer. C ₂₁ H ₂₃ N ₂ O ₆ MS calculated for PS + H: 463. Found: 463.
[1552] In addition, alkyloxycarbonyloxyalkylphosphonoate esters were prepared according to the slightly modified method as described below:
[1553] A solution of 2-methyl-5-isobutyl-4- (2- (5-phosphono) furanyl] thiazole (1 mmole) in DMF was prepared by a known method [Nishimura et al., J Antibiotics, 1987 N, N'-dicyclohexyl-4-morpholinecarboximidine (5 mmole), prepared from chloromethyl chloroformate according to the procedure described in Example 1, 40 (1), 81-90) and ethyl propyloxycarbonyloxymethyl The reaction mixture was stirred at 25 &lt; 0 &gt; C for 24 h, evaporated and chromatographed to give 2-methyl-5-isobutyl-4- {2- [ Carbonyloxymethyl) phosphono] furanyl) thiazole (20.6). Calcd for C ₂₀ H ₂₈ NO ₁₀ PS: C: 47.52; H: 5.58; N: 2.77. Found: C: 47.52; H: 5.67; N: 2.80.
[1554] The following compounds were prepared by this method:
[1555] (20.7) 2-Methyl-5-isobutyl-4 - {- 2- [5-bis (isopropyloxycarbonyloxymethyl) phosphono] -furanyl} thiazole. Calcd for C ₂₂ H ₃₂ NO ₁₀ PS: C: 49.53; H: 6.05; N: 2.63. Found: C: 49.58; H: 6.14; N: 2.75.
[1556] (20.8) 2-Amino-5-isobutyl-4 - {- 2- [5-bis (phenoxycarbonyloxymethyl) phosphono] furanyl} thiazole. C ₂₇ H ₂₇ N ₂ O ₁₀ Calculated for PS: C: 53.82; H: 4.52; N: 4.65. Found: C: 54.03; H: 4.16; N: 4.30.
[1557] (20.9) 2-Amino-5-isobutyl-4 - {- 2- [5-bis (ethoxycarbonyloxymethyl) phosphono] furanyl} thiazole. C ₁₉ H ₂₇ N ₂ O ₁₀ Calculated for PS: C: 45.06; H: 5.37; N: 5.53. Found: C: 45.11; H: 5.30; N: 5.43.
[1558] (20.10) 2-Methyl-5-isobutyl-4 - {- 2- [5-bis (isopropylthiocarbonyloxymethyl) -phosphono] furanyl} thiazole. C ₂₂ H ₃₂ NO ₈ PS ₃ + 0.2 Calculated for EtOAc: C: 46.95; H: 5.81: N: 2.40. Found: C: 47.06; H: 5.86; N, 2.73.
[1559] (20.11) 2-Amino-5-isobutyl-4- {2- [5-bis (isopropyloxycarbonyloxymethyl) phosphono] furanyl} thiazole. C ₂₁ H ₃₁ N ₂ O ₁₀ Calculated for PS: C: 47.19; H: 5.85; N: 5.24. Found: C: 47.33; H: 5.66; N: 5.57.
[1560] (20.12) 2-Methyl-5-isobutyl-4- {2- [5-bis (benzoyloxymethyl) phosphono] furanyl} thiazole. Calcd for _{C 28 H 28 NO 8 PS +} 0.2 CH 2 Cl 2: C: 59.31; H: 5.40; N: 2.64. Found: C: 59.25; H: 5.27; N: 2.44.
[1561] (20.15) 2-Amino-5-isobutyl-4- {2- [5-bis (1- (1-ethoxycarbonyloxy) ethyl) phosphono] furanyl} thiazole. Mp 76 - 78 ° C. C ₂₁ H ₃₁ N ₂ 0 ₁₀ Calculated for PS: C: 47.19, H: 5.85; N: 5.42. Found: C: 48.06; H: 5.80; N: 5.16.
[1562] In addition, 2-amino-5-isobutyl-4- {2- [5- bis (3- (5,6,7-trimethoxy) phthalidyl) phosphono] furanyl} -Bromo-5,6,7-trimethoxyphthalide. &Lt; / RTI &gt;
[1563] &Lt; Example 21 >
[1564] Preparation of 3- (2-pyridyl) propane-1,3-diol
[1565] Step (A. Org. Chem., 1957, 22, 589) 3- (2-pyridyl) propanol in acetic acid was treated with 30% hydrogen peroxide for 16 hours at 80 ° C. The reaction was concentrated in vacuo and the residue was dissolved in acetic anhydride and heated at 110 &lt; 0 &gt; C for 12 h. Evaporation and chromatography afforded 3- (2-pyridyl) -1,3-propanediol diacetate.
[1566] Step B. A solution of 3- (2-pyridyl) -1,3-propanediol diacetate (1 mmole) in methanol-water (3: 1) was treated with potassium carbonate (5 mmole) at 25 & Respectively. Evaporation and chromatography afforded 3- (2-pyridyl) -1,3-propanediol as a solid.
[1567] &Lt; Example 22 >
[1568] Preparation of 3- (2-hydroxyethyl) phthalide.
[1569] A solution of phthalid-3-acetic acid (1 mmole) in THF was treated with boron dimethyl sulfide (1.5 mmole) at 0 &lt; 0 &gt; C for 1 hour and at 25 & Extraction and chromatography afforded 2- (3-phthalidyl) ethanol as a light yellow oil: Rf = 0.25, 50% EtOAc-hexane.
[1570] &Lt; Example 23 >
[1571] Preparation of 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolane.
[1572] 4,5-Dimethyl-2-oxo-1,3-dioxolane (1 mmole) and selenium dioxide (2.5 mmole) in dioxane were heated at reflux temperature for 1 hour. Evaporation, extraction and chromatography afforded 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolane as a yellow oil. TLC: Rf = 0.5, 5% MeOH-dichloromethane.
[1573] A solution of 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolane (1 mmole) in DMF was added to a solution of tert-butyldimethylsilane (1.2 mmole) and imidazole ). Extraction and chromatography afforded 5-methyl-4-tert-butyldimethylsilyloxymethyl-2-oxo-1,3-dioxolane.
[1574] A solution of 5-methyl-4-tert-butyldimethylsilyloxymethyl-2-oxo-1,3-dioxolane (1 mmole) and Lawesson's reagent (1.2 mmole) in toluene was heated to 120 &Lt; / RTI &gt; Extraction and chromatography gave 5-methyl-4-tert-butyldimethylsilyloxymethyl-2-thio-1,3-dioxolane.
[1575] A solution of 5-methyl-4-tert-butyldimethylsilyloxymethyl-2-thio-1,3-dioxolane in methanolic hydrogen chloride was stirred at 0 ° C for 1 hour and at 25 ° C for 12 hours. Extraction and chromatography afforded 5-methyl-4-hydroxymethyl-2-thio-1,3-dioxolane.
[1576] &Lt; Example 24 >
[1577] Preparation of hydroxyethyl disulfide ethyl phosphonate diester.
[1578] A suspension of 2-methyl-5-isobutyl-4- [2- (5-phosphono) furanyl] thiazole (1 mmole) in thionyl chloride (5 mL) was warmed at reflux temperature for 4 hours. The cooled reaction mixture was evaporated to dryness and the resulting yellow residue was treated with a solution of 2-hydroxyethyldisulfide (4 mmole), pyridine (2.5 mmole) in methylene chloride. After stirring at 25 &lt; 0 &gt; C for 4 h, the reaction was extracted and chromatographed to give two compounds: 2-methyl-5-isobutyl-4- {2- [5- bis (6'- -Disulfide) hexylphosphono] furanyl} thiazole and 2-methyl-5-isobutyl-4- {2- [5- (3 ', 4'-disulfide) nonaicylphosphono] ] Thiazole.
[1579] &Lt; Example 25 >
[1580] Preparation of 3- [2- (5-phosphono) furanyl] pyrazole.
[1581] Step A. To a solution of diethyl 5- (2-isobutyl-3-N, N-dimethylamino) acryloyl-2-furanphosphonate (1 mmole, prepared according to Step A of Example 17) The solution was treated with hydrazine (1.2 mmole) at 80 &lt; 0 &gt; C for 12 h. Evaporation and chromatography gave 4-isobutyl-3- [2- (5-diethylphosphino) furanyl] pyrazole.
[1582] Step B. 4-Isobutyl-3- [2- (5-diethylphosphono) furanyl] pyrazole The title compound was prepared from 4-isobutyl-3- [2- Trifluoromethyl-phenyl) -pyranyl] pyrazole (25.1). mp 210-215 [deg.] C. Calcd for C ₁₁ H ₁₅ N ₂ 0 ₄ P: C: 48.89; H: 5.60; N: 10.37. Found: C: 48.67; H: 5.55; N: 10.20.
[1583] Step C. 4-Isobutyl-3- [2- (5-diethylphosphono) furanyl] pyrazole was treated in analogy to step A of procedure 11 to give 1-methyl- (5-diethylphosphino) furanyl] pyrazole.
[1584] Step D. 1-Methyl-4-isobutyl-3- [2- (5-diethylphosphono) furanyl] pyrazole was treated as in Step C of Example 3 to give l- 3- {2- (5-phosphono) furanyl] pyrazole (25.2). C ₁₂ H ₁₇ N ₂ 0 ₄ P + 0.85 Calculated for HBr + 0.75 H ₂ O: C: 39.32; H: 5.32; N: 7.64. Found: C: 39.59; H: 5.30; N: 7.47.
[1585] &Lt; Example 26 >
[1586] Preparation of 3- [2- (5-phosphono) furanyl] isoxazole.
[1587] Step A. A solution of 5-diethylphosphono-2-furaldehyde (1 mmole) in ethanol was treated with hydroxylamine (1.1 mmole) and sodium acetate (2.2 mmole) at 25 ° C for 12 hours. Extraction and chromatography afforded 5-diethylphosphono-2-furaldehyde oxime.
[1588] Step B. A solution of 5-diethylphosphono-2-furaldehyde oxime (1 mmole) in DMF was treated with N-chlorosuccinimide (1.1 mmole) at 25 &lt; 0 &gt; C for 12 hours. To extract 5-diethylphosphono-2-chlorooximidofuran.
[1589] Step C. A solution of 5-diethylphosphono-2-chlorooximidofuran (1 mmole) and ethyl propionate (5 mmole) in diethyl ether was treated with triethylamine (2 mmole) at 25 ° C for 12 hours Respectively. Extraction and chromatography afforded 5-ethoxycarbonyl-3- {2- (5-diethylphosphono) furanyl} isoxazole.
[1590] Step D. 5-Ethoxycarbonyl-3- {2- (5-diethylphosphono) furanyl] isoxazole Following the procedure of Step A of Example 9, -Carbamoyl-3- [2- (5-phosphono) furanyl] isoxazole (26.1). mp 221-225 [deg.] C. Calcd for C ₈ H ₇ N ₂ O ₆ P + 0.25 EtOH: C: 37.86; H: 3.18; N: 10.39. Found: C: 37.90; H: 3.02; N: 10.05.
[1591] The following compounds were prepared by this method:
[1592] (26.2) 5-Ethoxycarbonyl-4-methyl-3- [2- (5-phosphono) furanyl] isoxazole. mp 150 - 152 [deg.] C. C ₁₁ H ₁₂ NO ₇ P + 0.25 H ₂ O + 0.15 Calculated for HBr: C: 41.57; H: 4.01; N: 4.41. Found: C: 41.57; H: 4.20; N, 4.54.
[1593] (26.3) 4,5-Bis (ethoxycarbonyl) -3- [2- (5-phosphono) furanyl] isoxazole. Calcd for C ₁₃ H ₁₄ NO ₉ P: C: 43.47; H: 3.93; N: 3.90, found: C: 43.26; H: 3.92; N: 3.97.
[1594] (26.4) 5-Amino-4-ethoxycarbonyl-3- [2- (5-phosphono) furanyl] isoxazole. mp 190 [deg.] C (decomposition). C ₁₀ H ₁₁ N ₂ 0 ₇ P + 0.2 Calculated for HBr: C: 37.25; H: 3.52; N: 8.69. Found: C: 37.56; H: 3.50; N: 8.85.
[1595] (26.5) 4,5-Bis (carbamoyl) -3- [2- (5-phosphono) furanyl] isoxazole. mp> 220 [deg.] C. C ₉ H ₈ N ₃ 0 ₇ calculated for P: C: 35.90; H: 2.68; N: 13.95. Found: C: 35.67; H: 2.55; N: 13.62.
[1596] (26.6) 4-Ethoxycarbonyl-5-trifluoromethyl-3- [2- (5-phosphono) furanyl] isoxazole. C ₁₁ H ₉ F ₃ NO ₇ P + 0.25 HBr: C: 35.20; H: 2.48; N: 3.73. Found: C: 35.25; H: 2.34; N: 3.98.
[1597] (26.7) 5-Amino-4- (2-furyl) -3- [2- (5-phosphono) furanyl] isoxazole. mp> 220 [deg.] C. Calcd for C ₁₂ H ₉ N ₂ O ₇ P + O.1 AcOEt: C: 44.73; H: 2.97; N: 8.41. Found: C: 45.10; H: 2.58; N, 8.73.
[1598] (26.8) 4-Amino-5-cyano-3- [2- (5-phosphono) furanyl] isoxazole. C ₈ H ₆ N ₃ 0 ₅ P + 0.1 H ₂ O + 0.2 Calculated for HBr: C: 35.18; H: 2.36; N: 15.39. Found: C: 35.34; H: 2.50; N: 15.08.
[1599] (26.9) 4-Cyano-5-phenyl-3- [2- (5-phosphono) furanyl] isoxazole. Calcd for C ₁₄ H ₉ N ₂ O ₅ P + 0.15 HBr: C: 51.21; H: 2.81; N: 8.53. Found: C: 51.24; H: 3.09; N; 8.33.
[1600] &Lt; Example 27 >
[1601] Preparation of 2- [2- (5-phosphono) furanyl] thiazole
[1602] Step A.
[1603] Diethyl 5-tributylstannyl-2-furanphosphonate (14) and 2-bromo-4-ethoxycarbonylthiazole were treated according to Step A of Example 6 to give 4-ethoxycarbonyl- 2- [2- (5-diethylphosphino) furanyl] thiazole.
[1604] Step B.
[1605] 2- (2- (5-Diethylphosphono) furanyl] thiazole was treated according to the method of Example 9, Step A followed by the procedure of Step C of Example 3 to give 4- Carbamoyl-2- [2- (5-phosphono) furanyl] thiazole (27.1). Calcd for melting point _{239-240 ℃, C 8 H 7 N} 2 O 5 PS + 0.2H 2 O C: 34.59; H: 2.68; N: 10.08, Found: C, 34.65; H: 2.69; N: 9.84.
[1606] &Lt; Example 28 >
[1607] Preparation of 4- (3,3-difluoro-3-phosphono-1-propyl) thiazole
[1608] Step A.
[1609] A solution of 3- (tert-butyl-diphenylsilyloxy) -1-propanol (1 mmole) in methylene chloride (7 mL) was added to the powdered molecular sieve (4A, 0.5 equivalent weight / weight) and pyridinium chlorochromate 1.5 mmole). The resulting mixture was stirred at room temperature for 2 hours, diluted with diethyl ether (7 mL) and further stirred at room temperature for 30 minutes. Filtration, evaporation and chromatography gave 3- (tert-butyldiphenylsilyloxy) -1-propanal as a colorless oil.
[1610] Step B.
[1611] The solution of LDA in THF (1.06 mmole) was treated with diethyl difluoromethylphosphonate (1 mmole) at -78 ° C for 45 minutes. The reaction was then treated with a THF solution of 3- (tert-butyldiphenylsilyloxy) -1-propane (1.07 mmole) and the resulting solution was further stirred at -78 ° C for 4 hours. The reaction was quenched with phenyl chloro thioformate (2.14 mmole) and the reaction mixture was purified by extraction and chromatography to give 4- (tert-butyldiphenylsilyloxy) -3-phenoxythiocarbonyloxy -2,2-difluorobutylphosphonate.
[1612] Step C.
[1613] To a solution of 4- (tert-butyldiphenylsilyloxy) -3-phenoxythiocarbonyloxy
[1614] -2-difluorobutylphosphonate (1 mmole) was treated with tri-n-butyltin hydride (1.5 mmole) and AIBN (0.1 mmole) and the resulting reaction mixture was heated for 2 hours Lt; / RTI &gt; Evaporation and chromatography were carried out to obtain diethyl 4- (tert-butyldiphenylsilyloxy) -2,2-difluorobutylphosphonate as a colorless oil.
[1615] Step D.
[1616] A solution of diethyl 4- (tert-butyldiphenylsilyloxy) -2,2-difluorobutylphosphonate (1 mmole) in methanol (1 mL) was treated with hydrochloric acid (4 N, 4 mmole) at 0 & And the resulting reaction was stirred at room temperature for 2 hours. Evaporation and chromatography were performed to give diethyl 4-hydroxy-2,2-difluorobutylphosphonate as a colorless oil.
[1617] Step E.
[1618] A solution of diethyl 4-hydroxy-2,2-difluorobutylphosphonate (1 mmole) in acetone (10 mL) was treated with Jones reagent (10 mmole) at 0 ° C for 30 minutes. The reaction was quenched with 2-propanol (10 mL) and the resulting mixture was filtered through a pad of celite. The filtrate was evaporated and extracted to give diethyl 3-carboxyl-2,3-difluoropropylphosphonate as an oil.
[1619] Step F.
[1620] A solution of diethyl 3-carboxyl-2,3-difluoropropylphosphonate (1 mmole) in thionyl chloride (3 mL) was heated to reflux for 2 hours. The reaction was evaporated to dryness and the residue, dissolved in diethyl ether (1 mL), was treated with an ether-based solution of diazomethane (10 mmoles) at 0 ° C for 30 minutes. HBr solution in acetic acid (30%, 1 mL) was added to the reaction and the resulting solution was stirred at room temperature for 1 hour. The reaction was evaporated to dryness and the residue was dissolved in THF-EtOH (1: 1.5 mL) and treated with thiourea (1 mmole). The resulting reaction mixture was heated to 75 &lt; 0 &gt; C for 1 hour. After evaporation, extraction and chromatography were carried out to obtain 2-amino-4- [1- (3-diethylphosphino-3,3-difluoro) propyl] thiazole as a solid, Was treated according to the method of Step C to obtain 2-amino-4- [1- (3-phosphono-3,3-difluoro) propyl] thiazole (28.1) as a solid. C ₆ H ₉ N ₂ O ₃ Calculation for PSF ₂ + HBr C: 21.25; H: 2.97; N: 8.26, found C: 21.24; H: 3.25; N: 8.21.
[1621] The following compounds were prepared in a similar manner.
[1622] 2-amino-5-methylthio-4- [1-phosphono-3,3-difluoro) propyl] thiazole (28.2). MS m / e 305 (M + H).
[1623] &Lt; Example 29 >
[1624] Preparation of 2-methylthio-5-phosphonomethylthio-1,3,4-thiadiazole and 2-phosphonomethylthiopyridine
[1625] Step A.
[1626] A solution of 2-methylthio-1,3,4-thiadiazol-5-thiol (1 mmole) in THF (5 mL) was treated with sodium hydride (60%, 1.1 mmole) at 0 C and the resulting reaction mixture Was stirred at room temperature for 30 minutes. The reaction was then cooled to 0 &lt; 0 &gt; C and treated with diethylphosphonomethyltrifluoromethanesulfonate (1.1 mmole). After stirring at room temperature for 12 hours, the reaction was quenched with saturated ammonium chloride. Extraction and chromatography were carried out to obtain 2-methylthio-5-diethylphosphonomethylthio-1,3,4-thiadiazole as an oil.
[1627] Step B.
[1628] 2-methylthio-5-diethylphosphonomethylthio-l, 3,4-thiadiazole was treated according to the procedure of Step C of Example 3 to give 2-methylthio-5-phosphonomethylthio -1,3,4-thiadiazole (29.1). Calcd for C ₄ H ₇ N ₂ O ₃ PS ₃ + 0.2HBr C: 17.50; H: 2.64; N: 10.21, Found: C, 17.64; H: 2.56; N: 10.00.
[1629] Alternatively, the heteroaromatics substituted with phosphonomethylthio were prepared using the following method, illustrated by the synthesis of 2-phosphonomethylthiopyridine.
[1630] Step C.
[1631] A solution of 2,2'-dipyridyl disulfide (1 mmole) in THF was treated with tri-n-butylphosphine (1 mmole) and diethylhydroxymethylphosphonate at 0 ° C. The resulting reaction solution was stirred at room temperature for 18 hours. Extraction and chromatography were performed to give 2-diethylphosphonomethylthiopyridine as a yellow oil.
[1632] Step D.
[1633] 2-Diethylphosphonomethylthiopyridine was treated according to the method of Step C of Example 3 to obtain 2-phosphonomethylthiopyridine (29.2) as a yellow solid. Calculation for C ₆ H ₈ NO ₃ PS + 0.62 HBr C: 28.22; H: 3.40; N: 5.49, Found C: 28.48; H: 3.75; N: 5.14.
[1634] &Lt; Example 30 >
[1635] Preparation of 2 - [(2-phosphono) ethynyl] pyridine
[1636] Step A.
[1637] A solution of 2-ethynylpyridine (1 mmole) in THF (5 mL) was treated with LDA (1.2 mmole) at 0 C for 40 minutes. Diethylchlorophosphate (1.2 mmole) was added to the reaction and the resulting reaction solution was stirred at room temperature for 16 hours. The reaction was quenched with saturated ammonium chloride, followed by extraction and chromatography to give 2 - [(2-diethylphosphino) ethynyl] pyridine as a yellow oil.
[1638] Step B.
[1639] 2- [(2-diethylphosphino) ethynyl] pyridine was treated according to the method of Example 3, Step C to give 2- [1- (2-phosphonoethynyl] pyridine (30.1) . Melting point 160 캜 (decomposition). MS m / e 184 (M + H).
[1640] &Lt; Example 31 >
[1641] A. Preparation of Various Phosphoramides as Formulas
[1642] Step A.
[1643] (1 mmole) solution of 2-methyl-5-isopropyl-4- [2- (5-phosphono) furanyl] thiazole dichloridate (produced as in Example 19) in dichloromethane Was cooled to 0 &lt; 0 &gt; C and treated with a solution of benzyl alcohol (0.9 mmole) in dichloromethane (0.5 mL) and pyridine (0.3 mL). The resulting reaction solution was stirred at 0 &lt; 0 &gt; C for 1 hour, and then an ammonia (excess) solution in THF was added. After stirring at room temperature for 16 h, the reaction was evaporated to dryness and the residue was purified by chromatography to give 2-methyl-5-isopropyl-4- [2- (5-phosphono monoamido ) Furanyl] thiazole (31.1), and 2-methyl-5-isopropyl-4- [2- (5-phosphorodiamido) furanyl] thiazole (31.2) was obtained as a yellowish hard rubber. (31.1) 2-Methyl-5-isopropyl-4- [2- (5-phosphono monoamido) furanyl] thiazole: MS m / e 299 (M-H). (31.2) 2-Methyl-5-isopropyl-4- [2- (5-phosphorodiamido) furanyl] thiazole: MS m / e 298 (M-H).
[1644] Alternatively, other methods were used to prepare other phosphoramides as illustrated in the methods below.
[1645] Step B.
[1646] (1 mmole) suspension of 2-amino-5-methylthio-4- [2- (5-phosphono) furanyl] thiazole dichloridate (produced as in Example 19) in dichloromethane Was cooled to 0 &lt; 0 &gt; C and ammonia (excess) was bubbled through the reaction for 10 minutes. After stirring at room temperature for 16 h, the reaction was evaporated to dryness and the residue was purified by chromatography to give 2-amino-5-methylthio-4- [2- (5- phosphorodiamido) ] Thiazole (31.3). C ₈ H ₁₁ N ₄ O ₂ PS ₂ + 1.5 HCl + 0.2 EtOH C: 28.48; H: 3.90; N: 15.82, found C: 28.32; H: 3.76; N: 14.21.
[1647] The following compounds were prepared according to the method described below, or, in some cases, by a modification of these methods.
[1648] (31.4) 2-Amino-5-isobutyl-4- [2- (5-phosphono monoamido) furanyl] thiazole. Melting point 77-81 [deg.] C. C ₁₁ H ₁₆ N ₃ O ₃ PS + H ₂ O + 0.8 Et ₃ N: C 47.41; H: 7.55; N: 13.30, found C: 47.04; H: 7.55; N: 13.67.
[1649] (31.5) 2-Amino-5-isobutyl-4- [2- (5-phosphorodiamido) furanyl] thiazole. C ₁₁ H ₁₇ N ₄ O ₂ PS + 0.5H ₂ O + 0.75 HCl C: 39.24; H: 5.61; N: 16.64. Found C: 39.05; H: 5.43; N: 15.82.
[1650] (31.28) 2-Amino-5-isobutyl-4- {2- [5- (N, N'-diisobutyl) phosphorodiamido] furanyl} thiazole. Melting point 182-183 [deg.] C. Calcd for C ₁₉ H ₃₃ N ₄ O ₂ PS C: 55.32; H: 8.06; N: 13.58, found C: 54.93; H: 7.75; N: 13.20.
[1651] (31.29) Synthesis of 2-amino-5-isobutyl-4- {2- [5- (N, N ' Yl} thiazole. Calcd for C ₂₉ H ₄₅ N ₄ O ₁₀ PS C: 51.78; H: 6.74; N: 8.33, found C: 51.70; H: 6.64; N: 8.15.
[1652] (31.30) 2-Amino-5-isobutyl-4- {2- [5- (N, N '- (1-benzyloxycarbonyl) -1-ethyl) phosphorodiamido] furanyl} thiazole. Calcd for C ₃₁ H ₃₇ N ₄ O ₆ PS C: 59.60; H: 5.97; N: 8.97, found C: 59.27; H: 5.63; N: 8.74.
[1653] (31.31) 2-Amino-5-isobutyl-4- {2- [5-bis (2-methoxycarbonyl-1-aziridinyl) phosphorodiamido] furanyl} thiazole. C ₁₉ H ₂₅ N ₄ O ₆ PS + 0.3CH ₂ Cl ₂ C: 46.93; H: 5.22; N: 11.34, found C: 58.20; H: 5.26; N: 9.25.
[1654] (31.39) 2-Amino-5-isobutyl-4- {2- [5- (N, N'-2- (1-ethoxycarbonyl) propyl) phosphorodiamido] furanyl} thiazole. C ₂₃ H ₃₇ N ₄ O ₆ PS + 0.6 EtOAc + 0.1 CH ₂ Cl ₂ C: 51.91; H: 7.18; N: 9.50, found C: 51.78; H: 7.17; N: 9.26.
[1655] Monophenyl-monophosphonamide derivatives of compounds of formula (I) may also be prepared according to the methods described above.
[1656] Step C.
[1657] Amino-5-isobutyl-4- [2- (5-diphenylphosphino) furanyl] thiazole (prepared according to the method of Example 19) in acetonitrile (9 mL) ) (1 mmole) was treated with lithium hydroxide (1N, 1.5 mmole) at room temperature for 4 hours. The reaction solution was evaporated to dryness and the residue was dissolved in water (10 mL), then cooled to 0 ° C and 6 N HCl was added to adjust the pH of the solution to 4. The resulting white solid was collected by filtration to give 2-amino-5-isobutyl-4- [2- (5-phenylphosphono) furanyl] thiazole (19.64).
[1658] Step D.
[1659] A suspension of 2-amino-5-isobutyl-4- [2- (5-phenylphosphono) furanyl] thiazole (1 mmole) in thionyl chloride (3 mL) was heated to reflux for 2 hours. The reaction solution was evaporated to dryness and the residue was dissolved in anhydrous dichloromethane (2 mL) and the resulting solution was treated at 0 ° C. with pyridine (0.8 mL) and L-alanine methyl ester hydrochloride in dichloromethane (3 mL) (1.2 mmole) solution. The resulting reaction solution was stirred at room temperature for 14 hours. Evaporation and chromatography afforded 2-amino-5-isobutyl-4- {2- [5- (O- phenyl-N- (1-methoxycarbonyl) ethyl) phosphonamido] } Thiazole (31.6). Calcd for C ₂₁ H ₂₆ N ₃ O ₅ PS C: 54.42; H: 5.65; N: 9.07, Found: C, 54.40; H: 6.02; N: 8.87.
[1660] The following compounds were prepared according to the method described below.
[1661] (31.7) 2-Amino-5-isobutyl-4- {2- [5- (O-phenylphosphonamido)] furanyl} thiazole. Melting point: 205 캜 (decomposition). C ₁₇ H ₂₀ N ₃ O ₃ PS + 0.3H ₂ O + 0.3HCl C: 51.86; H: 5.35; N: 10.67, Found C: 51.58; H: 4.93; N: 11.08.
[1662] (31.8) 2-Amino-5-isobutyl-4- {2- [5- (O-phenyl-N-ethoxycarbonylmethyl) phosphonamido] furanyl} thiazole. Calcd for C ₂₁ H ₂₆ N ₃ O ₅ PS C: 54.42; H: 5.65; N: 9.07, Found: C, 54.78; H: 5.83; N: 8.67.
[1663] (31.9) 2-Amino-5-isobutyl-4- {2- [5- (O-phenyl-N-isobutyl) phosphonamido] furanyl} thiazole. Melting point 151-152 [deg.] C. Calcd for C ₂₁ H ₂₈ N ₃ O ₃ PS C: 58.18; H: 6.51; N: 9.69, found C: 58.12; H: 6.54; N: 9.59.
[1664] (31.18) 2-amino-5-isobutyl-4- {2- [5- (O- phenyl- N- (1- (1- ethoxycarbonyl- Furanyl} thiazole. Calcd for _{C 28 H 32 N 3 O 5} PS C: 60.75; H: 5.83; N: 7.59, Found C: 60.35; H: 5.77; N: 7.37.
[1665] (31.19) Synthesis of 2-amino-5-isobutyl-4- {2- [5- (O- yl} thiazole-C ₂₃ H ₃₀ N ₃ O ₅ calculated for PS C:. 56.20; H: 6.15; N: 8.55, found C: 55.95; H: 5.80; N: 8.35.
[1666] (31.20) Synthesis of 2-amino-5-isobutyl-4- {2- [5- (O- Furanyl} thiazole C ₂₆ H ₃₄ N ₃ O ₇ PS + 0.2CH ₂ Cl ₂ C: 54.20, H: 5.97, N: 7.24, found C: 54.06, H: 5.68, N: 7.05.
[1667] (31.21) Synthesis of 2-amino-5-isobutyl-4- {2- [5- (O- (3- chlorophenyl) -N- (1- (1-methoxycarbonyl) ethyl) Yl] furanyl} thiazole. Calcd for C ₂₁ H ₂₅ N ₃ O ₅ PSCl C: 50.65; H: 5.06; N: 8.44, found C: 50.56; H: 4.78; N: 8.56.
[1668] (31.22) 2-Amino-5-isobutyl-4- {2- [5- (O- (4- chlorophenyl) -N- (1- (1-methoxycarbonyl) ethyl) phosphonamido) ] Furanyl} thiazole. C ₂₁ H ₂₅ N ₃ O ₅ Calcd for PSCl + 1 HCl + 0.2H ₂ O C: 46.88; H: 4.95; N: 7.81, Found C: 47.33; H: 4.71; N: 7.36.
[1669] (31.23) 2-Amino-5-isobutyl-4- {2- [5- (O-phenyl-N- (1- (1-bis (ethoxycarbonyl) methyl) phosphonamido)] furanyl } thiazol-C ₂₄ H ₃₀ N ₃ O ₇ calcd for PS C:. 53.83; H: 5.65; N: 7.85, found C: 53.54; H: 5.63; N: 7.77.
[1670] (31.24) 2-Amino-5-isobutyl-4- {2- [5- (O-phenyl-N- (1-morpholinyl) phosphonamido)] furanyl} thiazole. Calcd for C ₂₁ H ₂₆ N ₃ O ₄ PS C: 56.37; H: 5.86; N: 9.39, Found: C, 56.36; H: 5.80; N: 9.20.
[1671] (31.25) 2-Amino-5-isobutyl-4- {2- [5- (O- phenyl-N- (1- (1- benzyloxycarbonyl) ethyl) phosphonamido)] furanyl} thia Sol. C ₂₇ H ₃₀ N ₃ O ₅ Calculated for PS C: 60.10; H: 5.60; N: 7.79, Found C: 59.80; H: 5.23; N: 7.53.
[1672] (31.32) 2-Amino-5-isobutyl-4- {2- [5- (O-phenyl-N-benzyloxycarbonylmethyl) phosphonamido)] furanyl} thiazole. Calcd for C ₂₆ H ₂₈ N ₃ O ₅ PS C: 59.42; H: 5.37; N: 8.00, Found C: 59.60; H: 5.05; N: 7.91.
[1673] (31.36) Synthesis of 2-amino-5-isobutyl-4- {2- [5- (O- (4- methoxyphenyl) -N- (1- (1-methoxycarbonyl) ethyl) phosphonamido )] Furanyl} thiazole. C ₂₂ H ₂₈ N ₃ O ₆ PS + 0.1 CHCl ₃ + 0.1 MeCN C: 52.56; H: 5.62; N: 8.52, Found C: 52.77; H: 5.23; N: 8.87.
[1674] (31.37) 2-Amino-5-isobutyl-4- {2- [5- (O-phenyl-N-2-methoxycarbonyl) propyl) phosphonamido)] furanyl} thiazole. Calcd for C ₂₂ H ₂₈ N ₃ O ₅ PS + 0.6H ₂ O C: 54.11; H: 6.03; N: 8.60, found C: 53.86; H: 5.97; N: 8.61.
[1675] (31.38) Synthesis of 2-amino-5-isobutyl-4- {2- [5- (O- phenyl-N- (2- (1- ethoxycarbonyl) propyl) phosphonamido)] furanyl} Sol. Calcd for C ₂₃ H ₃₀ N ₃ O ₅ PS C: 56.20; H: 6.15; N: 8.55, Found C: 55.90; H: 6.29; N: 8.46.
[1676] The reaction of 1-amino-3-propanol with dichlorophosphonate in the presence of a suitable base (for example, pyridine, triethylamine) can be used to prepare cyclic phosphoramidate as a precursor of the phosphonate It is possible. The following compounds were prepared in this manner.
[1677] (31.10) 2-Methyl-5-isobutyl-4- {2- [5- (1-phenyl-1,3-propyl) phosphonamido] furanyl} thiazole isomer. Calcd for C ₂₁ H ₂₅ N ₂ O ₃ PS + 0.25H ₂ O + 0.1 HCl C: 59.40; H: 6.08; N: 6.60, found C: 59.42; H: 5.72; N: 6.44.
[1678] (31.11) 2-Methyl-5-isobutyl-4- {2- [5- (1-phenyl-1,3-propyl) phosphonamido] furanyl} thiazole isomer. Calcd for C ₂₁ H ₂₅ N ₂ O ₃ PS + 0.25H ₂ O C: 59.91; H: 6.11; N: 6.65, Found C: 60.17; H: 5.81; N: 6.52.
[1679] (31.12) 2-Amino-5-isobutyl-4- {2- [5- (1-phenyl-1,3-propyl) phosphonamido] furanyl} thiazole isomer. C ₂₀ H ₂₄ N ₃ O ₃ PS + 0.25H ₂ O + 0.1CH ₂ Cl ₂ C: 55.27; H: 5.72; N: 9.57, found C: 55.03; H: 5.42; N: 9.37.
[1680] (31.13) 2-Amino-5-isobutyl-4- {2- [5- (1-phenyl-1,3-propyl) phosphonamido] furanyl} thiazole isomer. C ₂₀ H ₂₄ N ₃ O ₃ PS + 0.15 CH ₂ Cl ₂ C: 56.26; H: 5.69; N: 9.77, found C: 56.36; H: 5.46; N: 9.59.
[1681] (31.14) 2-Amino-5-methylthio-4- {2- [5- (1-phenyl-1,3-propyl) phosphonamido] furanyl} thiazole. Calcd for C ₁₇ H ₁₈ N ₃ O ₃ PS ₂ +0.4 HCl C: 48.38; H: 4.39; N: 9.96, found C: 48.47; H: 4.21; N: 9.96.
[1682] (31.15) 2-Amino-5-methylthio-4- {2- [5- (1-phenyl-1,3-propyl) phosphonamido] furanyl} thiazole. Calcd for C ₁₇ H ₁₈ N ₃ O ₃ PS ₂ C: 50.11; H: 4.45; N: 10.31, Found: C, 49.84; H: 4.19; N: 10.13.
[1683] (31.16) 2-Amino-5-methylthio-4- {2- [5- (N-methyl-1-phenyl-1,3-propyl) phosphonamido] furanyl} thiazole. Calcd for C ₁₈ H ₂₀ N ₃ O ₃ PS ₂ + 0.25 HCl C: 50.21; H: 4.74; N: 9.76, found C: 50.31; H: 4.46; N: 9.79.
[1684] (31.17) 2-Amino-5-methylthio-4- {2- [5- (1-phenyl-1,3-propyl) -N-acetylphosphonamido] furanyl} thiazole. Calcd for _{C 22 H 26 N 3 O 4} PS + 1.25H 2 O C: 54.82; H: 5.96; N: 8.72, Found C: 55.09; H: 5.99; N: 8.39.
[1685] (31.26) 2-Amino-5-isobutyl-4- {2- [5- (1-oxo-1-phospha-2-oxa-7-aza-3,4-benzocycloheptan- ] Furanyl} thiazole, diastereomer. Melting point _{233-234 ℃ .C 21 H 24 N 3} O 5 calculated for PS + 0.2CHCl ₃ C: 52.46; H: 5.03; N: 8.66, found C: 52.08; H: 4.65; N: 8.58.
[1686] (31.27) Synthesis of 2-amino-5-isobutyl-4- {2- [5- (1-oxo-1-phospha-2-oxa-7-aza-3,4-benzocycloheptan- ] Furanyl} thiazole, &lt; / RTI &gt; MS calculated for C ₂₁ H ₂₄ N ₃ O ₅ PS + H: 462, found MS: 462.
[1687] (31.34) 2-Amino-5-isobutyl-4- {2- [5- (3- (3,5-dichlorophenyl) -1,3-propyl) phosphonamido] furanyl} thiazole. Calcd for C ₂₀ H ₂₂ N ₃ O ₃ PSCl ₂ C: 49.39; H: 4.56; N: 8.64, Found C: 49.04; H: 4.51; N: 8.37.
[1688] (31.35) 2-Amino-5-isobutyl-4- {2- [5- (4,5-benzo-1-oxo-1-phospha-2-oxa-6-aza) cyclohexan- ] Furanyl} thiazole. C ₁₈ H ₂₀ N ₃ O ₃ PS + 0.7H ₂ O C: 53.78; H: 5.37; N: 10.45, Found: C, 53.63; H: 5.13; N: 10.36.
[1689] Example 32: Preparation of 5- [2- (5-phosphono) furanyl] tetrazole
[1690] Step A.
[1691] Benzyl chloromethyl ether (1.2 mmole) was added to a mixture of tetrazole (1 mmole) and powder K ₂ CO ₃ (1.5 mmole) in 1 mL of DMF cooled to 0 ° C. and the resulting mixture was stirred at 0 ° C. for 30 minutes After stirring, the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and ether. Extraction and chromatography were performed to give 2-benzyloxymethyltetrazole as a colorless oil.
[1692] Step B.
[1693] To a solution of 2-benzyloxymethyltetrazole (1 mmole) and TMEDA (2 mmole) in 3 mL of diethyl ether at -78 [deg.] C was added n-BuLi (1 mmole) in hexane. The mixture was stirred at -78 &lt; 0 &gt; C for 5 min and then added to a (n-Bu) ₃ SnCl (1 mmole) precooled (-78 [deg.] C) solution in 2 mL of diethyl ether. The mixture was stirred at -78 &lt; 0 &gt; C for 30 min, then diluted with water and diethyl ether. Extraction and chromatography were performed to give 2-benzyloxymethyl-5- (tributylstannyl) tetrazole as a colorless oil.
[1694] Step C.
[1695] To a solution of 5-iodo-2-diethylphosphonofuran (1 mmole), 2-benzyloxymethyl-5- (tributylstannyl) tetrazole (1.05 mmole) in 3 mL of toluene, tetrakis ) Palladium (0) (0.03 mmole) and copper (I) iodide (0.07 mmole) was refluxed at 110 &lt; 0 &gt; C for 20 hours. Evaporation and chromatography were performed to give 2-benzyloxymethyl-5- [2- (5-diethylphosphono) furanyl] tetrazole as an oil.
[1696] Step D.
[1697] A mixture of 2-benzyloxymethyl-5- [2- (5-diethylphosphino) furanyl] tetrazole (1 mmole) and 6 M HCl (1 mL) in 10 mL of ethanol was stirred at 70 & After heating, the solvent was evaporated to dryness, basified with 1 N NaOH and extracted with EtOAc. The aqueous layer was acidified and extracted with EtOAc. This EtOAc extract was evaporated to give 5- [2- (5-diethylphosphono) furanyl] tetrazole as a solid and this solid was treated according to the procedure of Step C of Example 3 to give 5- [2 - (5-phosphono) furanyl] tetrazole (32.1). Melting point 186-188 占 폚. Calcd for _{C 5 H 5 N 4 O 4} P + 1.5H 2 O C, 24.70; H, 3.32; N, 23.05, Found C, 24.57; H, 2.57; N, 23.05.
[1698] Step E
[1699] Step 1: To a solution of 5- [2- (5-diethylphosphono) furanyl] tetrazole (1 mmole), 1-iodo-2-methylpropane (2 mmole) and powder K ₂ CO ₃ a mixture of (2 mmole) was then stirred at 80 ℃ for 48 h, diluted with CH ₂ Cl ₂ and water and the layers separated. The CH ₂ Cl ₂ layer was evaporated and mixed with the product of the following reaction for chromatography.
[1700] Step 2: The aqueous layer from step 1 was acidified with EtOAc and extracted. And evaporation of the extract and the residue 80 ℃, heated in 2 mL SOCl ₂ for 3 hours, the solvent was evaporated. The residue was dissolved in 5 mL of CH ₂ Cl ₂ and 0.3 mL of NEt ₃ and 0.5 mL of EtOH was added. After stirring for 1 hour at room temperature, the mixture was diluted with CH ₂ Cl ₂ and water. This organic extract was combined with the extract from step 1 and chromatographed to give 1-isobutyl-5- [2- (5-diethylphosphono) furanyl] tetrazole and 2-isobutyl- [2- (5-diethylphosphino) furanyl] tetrazole.
[1701] Step 3: 1-Isobutyl-5- [2- (5-diethylphosphono) furanyl] tetrazole was treated according to the procedure of Step 3 of Example 3 to give 1-isobutyl-5- [ - (5-phosphono) furanyl] tetrazole (32.2). Melting point 200-202 ° C. Calcd for C ₉ H ₁₃ N ₄ O ₄ P C: 39.71; H: 4.81; N: 20.58, found C: 39.64; H: 4.63; N: 20.21.
[1702] Step F.
[1703] A mixture of 2-isobutyl-5- [2- (5-diethylphosphino) furanyl] tetrazole (1 mmole) and TMSBr (10 mmole) in 10 mL of CH ₂ Cl ₂ was stirred at room temperature for 16 hours . The solvent was evaporated and the residue was dissolved in CH ₃ CN: water 10: 1, then the solvent was evaporated and dicyclohexylamine (2 mmole) was added to precipitate the residue from acetone to give 2-isobutyl- To obtain 5- [2- (5-phosphono) furanyl] tetrazole N, N-dicyclohexylammonium salt (32.3). Melting point 226-228 [deg.] C. C ₉ H ₁₃ N ₄ O ₄ Calcd for _{P + C 12 H 23 N C} : 55.62; H: 8.00; N: 15.44, found C: 55.55; H: 8.03; N: 15.07.
[1704] &Lt; Example 33 >
[1705] High-efficiency synthesis of various heteroaromatic compounds substituted with 2- (5-phosphono) furanyl
[1706] Step A.
[1707] A variety of heteroaromatic compounds substituted with 2- (5-diethylphosphono) furanyl were prepared in a similar manner to Example 15, Step B, and some of these compounds were subjected to high efficiency synthesis of compounds described in Tables 33.1 and 33.2 Respectively.
[1708] Step B.
[1709] A mixture of 2-chloro-6- [2- (5-diethylphosphino) furanyl] pyridine (0.01 mmole) and TMSBr (0.1 mL) in CH ₂ Cl ₂ (0.5 mL) was stirred at room temperature for 16 hours 0.5 mL was diluted with water: then evaporated and 9: 1 CH ₃ CN. Evaporation gave 2-chloro-6- [2- (5-phosphono) furanyl] pyridine.
[1710] Step C.
[1711] A mixture of 2-chloro-6- [2- (5-diethylphosphino) furanyl] pyridine (0.01 mmole) and freshly prepared sodium propoxide solution in propanol (0.25 M, 0.4 mL) Lt; / RTI &gt; The mixture was evaporated and the residue was treated according to Step B of Example 33 to give 2-propyloxy-6- [2- (5-phosphono) furanyl] pyridine.
[1712] Step D.
[1713] A mixture of 2-chloro-6- [2- (5-phosphono) furanyl] pyridine (0.01 mmole) and 1-methylpiperazine (0.2 mL) in ethylene glycol (0.2 mL) Respectively. This mixture was added to Dowex 12-100 formate resin of 150 mg was further diluted with water in 0.5 mL of CH ₃ CN and 0.1 mL. The mixture was stirred for 30 min, then filtered and the resin was washed with DMF (210 min), CH ₃ CN (210 min) followed by 9: 1 CH ₃ CN: water (110 min). Finally, the resin was stirred with 9: 1 TFA: water for 30 minutes, filtered and the filtrate was evaporated. The resulting residue was treated according to Step B of Example 15 to give 2- [1- (4-methyl) piperazinyl] -6- [2- (5-phosphono) furanyl] pyridine.
[1714] Step E.
[1715] In dioxane (0.5 mL) solution of 3-chloro-5- [2- (5-diethyl phosphono) furanyl] pyrazine (0.01 mmole), 5-tributyl star nilti thiophene (0.04 mmole), Pd (PPh 3) ₄ (0.001 mmole) and CuI (0.002 mmole) was heated at 85 &lt; 0 &gt; C for 16 hours and then the solvent was evaporated. The resulting residue in 0.5 mL of CH ₂ Cl ₂ and TMSBr (0.1 mL) were stirred at room temperature for 16 hours and then diluted with 0.5 mL of 9: 1 CH ₃ CN: water. Addition of Dowex 12-100 formate resin of 150 mg to this solution and after stirring for 30 minutes, filtration was followed by 9 of the resin in DMF (210 min), CH ₃ CN (210 min): CH ₃ CN for 1 : Water (110 min). Finally, the resin was stirred with 9: 1 TFA: water for 30 minutes and filtered, and the filtrate was evaporated to give 3- (2-thienyl) -5- [2- (5-phosphono) &Lt; / RTI &gt;
[1716] Step F.
[1717] (0.01 mmole), 1-hexyne (0.04 mmole), diisopropylethylamine (0.1 mmole) in dioxane (0.5 mL) , a mixture of _{Pd (PPh 3) 4 (0.001} mmole) and CuI (0.002 mmole) was on the 85 ℃ heating for 16 hours, the solvent was evaporated. The resulting residue was treated according to Step B to give 3- (l-hexyn-l-yl) -5- [2- (5-phosphono) furanyl] pyrazine.
[1718] Preparation of Carboxymethyl Phosphonate Resin
[1719] Step G.
[1720] A solution of trimethylphosphonoacetate (30.9 mmol), 2- (trimethylsilyl) ethanol (10.4 mmol) and DMAP (3.1 mmol) in toluene (25 mL) was refluxed under N ₂ for 48 h. After cooling, the solution was diluted with EtOAc, washed with 1 N HCl and then with water. The organic solution was dried over sodium sulfate and concentrated in vacuo to give an oil. The residue was treated with LiI (10.4 mmol) of 2-butanone (30 mL) and refluxed overnight under N _2. Dilute the solution with EtOAc and washed with 1 N HCl and concentrated under Na ₂ SO ₄ dried on vacuum to give a colorless oil by the SEM protected carboxy monomethyl obtain a phosphonate.
[1721] Step H.
[1722] Mixed with anhydrous THF (40 mL) for coupling and shaken briefly for 20 min, then excess solvent was removed with a cannula to produce 2.34 mmol of hydroxymethylpolystyrene. This process was repeated three times. The expanded resin was then suspended in THF (40 mL) and DIPEA (21.2 mmol). A solution of SEM protected carboxymonomethylphosphonate (7.1 mmol), DIAD (7.1 mmol) and tris (4-chlorophenyl) phosphine (7.1 mmol) in THF (15 mL) &Lt; / RTI &gt; and then added via cannula to the mixture. The mixture was shaken overnight under a blanket of N ₂ and then the resin was filtered and washed with THF (3 x 40 mL), DMF (3 x 40 mL) and THF (3 x 40 mL) before drying under vacuum 3.8 g of coupled phosphonate resin was obtained.
[1723] Step I.
[1724] 1 M TBAF in THF solution (12 mL) was added to the coupled phosphonate resin (2.41 mmol) in THF (100 mL). The mixture was shaken overnight before filtration and the resin was washed with THF (3 x 40 mL) to give the desired carboxymethylphosphonate resin as the tetrabutylammonium salt.
[1725] Coupling of the carboxymethylphosphonate resin to the heteroaromatic amine
[1726] Step J.
[1727] Heteroaromatic amine (0.14 mmol), resin (0.014 mmol), PyBOP (0.14 mmol) and TEA (0.36 mmol) in DMF (1.45 mL) were mixed in a 2 mL well and shaken at room temperature for 48 h. The treated resin was then filtered and washed with DMF (3 x) and CH ₂ Cl ₂ (3 x). The isolated resin was suspended in CH ₂ Cl ₂ (900 L) and combined with TMSBr (100 L) and mixed for 6 hours. The mixture was filtered and the resin was washed with anhydrous CH ₂ Cl ₂ (500 L) and the filtrate was concentrated in vacuo. _{CH 3 CN / H 2 O (} 9: 1, 300 L) was added to the the residue was isolated. After shaking for 30 minutes, the solvent was removed to obtain the desired heteroaromatic analogs substituted with [{N- (phosphono) acetyl] amino}. Compounds 33.97-33.119 and 33.146-33.164 were synthesized according to these methods and are listed in Tables 33.1 and 33.2.
[1728] Preparation of aminomethylphosphonate resin
[1729] Step K.
[1730] LiI (38.9 mmol) was added to a solution of dimethyl phthalimomethylphosphonate (37 mmole) in 2-butanone (150 mL). After refluxing under N ₂ overnight, the solution was diluted with EtOAc and washed with 1 N HCl, then dried over MgSO ₄ and concentrated in vacuo to give monomethylphthalimethylphosphonate as a white solid.
[1731] Step L.
[1732] As described above in Step H, monomethylphthalimethylphosphonate was coupled to hydroxymethylpolystyrene to obtain resin-coupled phthalimidomethylphosphonate monomethyl ester.
[1733] Step M: Anhydrous hydrazine (3 mL) was added to resin-coupled phthalimethylphosphonate monomethyl ester (6.8 mmol) in DMF (7 mL). After shaking at room temperature for 24 hours, the resin was filtered and washed with DMF (3 x 10 mL) and CH ₂ Cl ₂ (3 x 10 mL) and then dried under vacuum to afford the desired resin- 832 mg of nate monomethyl ester was obtained.
[1734] Coupling of various heteroaromatic carboxylic acids to resin-coupled aminomethylphosphonate monomethyl esters
[1735] Step N: The heteroaromatic carboxylic acid (0.2 mmol), resin (0.02 mmol), EDC (0.2 mmol) and HOBT (0.2 mmol) in DMF (0.5 mL) were pooled in a 2 mL well and shaken at room temperature for 24 h. The treated resin was then filtered and washed with DMF (3 x) and CH ₂ Cl ₂ (3 x). The isolated resin was suspended in CH ₂ Cl ₂ (500 L) and combined with TMSBr (50 L) and mixed for 6 hours. The mixture was filtered and the resin was washed with anhydrous CH ₂ Cl ₂ (500 L) and the filtrate was concentrated in vacuo. _{CH 3 CN / H 2 O (} 9: 1, 300 L) was added to the the residue was isolated. After shaking for 30 min, the solvent was evaporated to yield the desired heteroaromatic analogs substituted with (N-phosphonomethyl) carbamoyl. The compounds 33.120-33.145 are synthesized according to these methods and are listed in Table 33.2.
[1736] The following compounds were prepared according to some or all of the above methods. These compounds were characterized by HPLC (below) and mass spectrometer (APCI anion) and these characterization data are listed in Tables 33.1 and 33.2.
[1737] HPLC was carried out using a YMC ODS-Aq, Aq-303-5, 250 4.6 mm ID, S-5 占 퐉 and 120 占 column with a UV detector set at 280 nm.
[1738] HPLC recovery program: 1.5 mL / min Flow rate
[1739] Time (minutes)% Acetonitrile (A)% Buffer ^a (B) 01090 7.59010 12.49010 12.51090 151090
[1740] ^a buffer = 95: 5: 0.1 Water: methanol: acetic acid
[1741]
[1742]
[1743]
[1744]
[1745]
[1746] Section 2
[1747] Synthesis of compounds of formula (X)
[1748] &Lt; Example 34 >
[1749] Preparation of 2-amino-4-phosphonomethyloxy-6-bromobenzothiazole
[1750] Step A.
[1751] Cooling the AlCl ₃ (5 mmole) solution in EtSH (10 mL) to 0 ℃ and treated with 2-amino-4-methoxy-benzothiazole (1 mmole). The mixture was stirred at &lt; RTI ID = 0.0 &gt; 0-5 C &lt; / RTI &gt; Evaporation and extraction yielded 2-amino-4-hydroxybenzothiazole as a white solid.
[1752] Step B.
[1753] A mixture of 2-amino-4-hydroxybenzothiazole (1 mmole) and NaH (1.3 mmole) in DMF (5 mL) was stirred at 0 ° C for 10 minutes and then diethylphosphonomethyltrifluoromethylsulfone Nate (1.2 mmole). After stirring at room temperature for 8 hours, the reaction product was purified by extraction and chromatography to give 2-amino-4-diethylphosphonomethyloxybenzothiazole as an oil.
[1754] Step C.
[1755] A solution of 2-amino-4- (diethylphosphonomethyloxy) benzothiazole (1 mmole) in AcOH (6 mL) was cooled to 10 <0> C and treated with bromine (1.5 mmole) in AcOH (2 mL). After 5 minutes, the mixture was stirred at room temperature for 2.5 hours. The yellow precipitate was collected by filtration and washed with CH ₂ Cl ₂ to give 2-amino-4-diethylphosphonomethyloxy-6-bromobenzothiazole.
[1756] Step D.
[1757] A solution of 2-amino-4-diethylphosphonomethyloxy-6-bromobenzothiazole (1 mmole) in CH ₂ Cl ₂ (4 mL) was treated with TMSBr (10 mmole) at 0 ° C. After stirring at room temperature for 8 hours, the reaction was evaporated to dryness and the residue was dissolved in water (5 mL). The resulting precipitate was collected by filtration and washed with water to give 2-amino-4-phosphonomethyloxy-6-bromobenzothiazole (34.1) as a white solid. Melting point> 220 ° C (decomposition). Calculation for C ₈ H ₈ N ₂ O ₄ PSBr C: 28.34; H: 2.38; N: 8.26, found C: 28.32; H: 2.24; N: 8.06.
[1758] Similarly, the following compounds were prepared according to the above method.
[1759] (34.2) 2-Amino-4-phosphonomethyloxybenzothiazole. Melting point> 250 ° C. Calcd for C ₈ H ₉ N ₂ O ₄ PS + 0.4H ₂ O C: 35.93; H: 3.69; N: 10.48, found C: 35.90; H: 3.37; N: 10.37.
[1760] &Lt; Example 35 >
[1761] Preparation of 2-amino-4-phosphonomethyloxy-6-bromo-7-chlorobenzothiazole
[1762] Step A.
[1763] A solution of 1- (2-methoxy-5-chlorophenyl) -2-thiourea (1 mmole) in chloroform (10 mL) was cooled to 10 C and treated with bromine (2.2 mmole) in chloroform (10 mL). The reaction was stirred at 10 &lt; 0 &gt; C for 20 min and at room temperature for 0.5 h. The resulting suspension was heated to reflux for 0.5 h. The precipitate was collected by filtration (washed with CH ₂ Cl ₂ ) to afford 2-amino-4-methoxy-7-chlorobenzothiazole which was treated according to steps A, B, C and D of Example 34 to give 2 -Amino-4-phosphonomethoxy-6-bromo-7-chlorobenzothiazole (35.1). Melting point> 220 ° C (decomposition). Calcd for _{C 8 H 7 N 2 O 4} PSClBr C: 25.72; H: 1.89; N: 7.50, Found C: 25.66; H: 1.67; N: 7.23.
[1764] Similarly, the following compounds were prepared according to the above method.
[1765] (35.2) 2-Amino-4-phosphonomethoxy-6-bromo-7-methylbenzothiazole. Melting point> 220 ° C (decomposition). Calculation for C ₉ H ₁₀ N ₂ O ₄ PSBr C: 30.61; H: 2.85; N: 7.93, Found C: 30.25; H: 2.50; N: 7.77.
[1766] (35.3) 2-Amino-4-phosphonomethoxy-7-methylbenzothiazole. Melting point> 220 ° C (decomposition). C ₉ H ₁₁ N ₂ O ₄ PS + 1.0 H ₂ O C: 36.99; H: 4.48; N: 9.59, found C: 36.73; H: 4.23; N: 9.38.
[1767] (35.4) 2-Amino-4-phosphonomethoxy-7-chlorobenzothiazole. Melting point> 220 ° C (decomposition). C ₈ H ₈ N ₂ O ₄ Calculated for PSCl + 0.1 H ₂ O C: 32.41; H: 2.79; N: 9.45, found C: 32.21; H: 2.74; N: 9.22.
[1768] &Lt; Example 36 >
[1769] Preparation of 2-amino-4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole
[1770] Step A.
[1771] 3-Amino-2-hydroxy-5,6,7,8-tetrahydronaphthalene was treated according to Step B of Example 34 to give 3-amino-2-diethylphosphonomethyloxy- 8-tetrahydronaphthalene.
[1772] Step B.
[1773] A solution of KSCN (16 mmole) and CuSO ₄ (7.7 mmole) in MeOH (10 mL) was added to a solution of 3-amino-2-diethylphosphonomethyloxy-5,6,7,8-tetra Lt; / RTI &gt; (1 mmole) solution. The mixture was heated to reflux for 2 hours. Filtration, extraction and chromatography gave 2-amino-4-diethylphosphonomethyloxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole as a pale brown solid.
[1774] Step C.
[1775] Amino-4-diethylphosphonomethyloxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole was treated according to Step D of Example 34 to give 2-amino-4- -Phosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole (36.1). Melting point> 220 ° C (decomposition). Calcd for C ₁₂ H ₁₅ N ₂ O ₄ PS + 0.5H ₂ O C: 45.86; H: 4.81; N: 8.91, found C: 44.68; H: 4.77; N, 8.73.
[1776] The following compounds were also prepared according to the above method.
[1777] (36.2) 2-Amino-4-phosphonomethoxy- [1,2-d] naphthothiazole. Melting point> 240 ° C (decomposition). Calcd for C ₁₂ H ₁₁ N ₂ O ₄ PS + 0.2HBr C: 44.15; H: 3.46; N: 8.58, Found C: 44.13; H: 3.46; N: 8.59.
[1778] (36.3) 2-Amino-5,7-dimethyl-6-thiocyanato-4-phosphonomethoxybenzothiazole. Melting point> 240 ° C (decomposition). C ₁₁ H ₁₂ N ₃ O ₄ PS ₂ + 0.2CH ₂ Cl ₂ C: 37.13; H: 3.45; N: 11.60, found C: 37.03; H: 3.25; N: 11.65.
[1779] &Lt; Example 37 >
[1780] Preparation of 2-amino-7-methoxy-6-thiocyanato-4-phosphonomethoxybenzothiazole
[1781] Step A.
[1782] 2-hydroxy-5-methoxynitrobenzene was treated according to Step B of Example 34 to give 2-diethylphosphonomethyloxy-5-methoxynitrobenzene.
[1783] Step B.
[1784] A freshly prepared solution of SnCl ₂ (4 mmole) in methanolic HCl (10 mL) was added to a cooled (0 ° C.) solution of 2-diethylphosphonomethyloxy-5-methoxynitrobenzene (1 mmole) Solution. The mixture was warmed to room temperature and stirred for 3 hours. Evaporation, extraction and chromatography were carried out to obtain 2-diethylphosphonomethyloxy-5-methoxyaniline.
[1785] Step C.
[1786] Diethylphosphonomethyloxy-5-methoxyaniline was treated according to step B of Example 36 to give 2-amino-4-diethylphosphonomethyloxy-6-thiacyano-7-methoxybenzothiazole Sol which was treated according to Step D of Example 34 to give 2-amino-7-methoxy-6-thiocyanato-4-phosphonomethoxybenzothiazole (37.1). Melting point> 170 ° C (decomposition). C ₁₀ H ₁₀ N ₃ O ₅ Calculated for PS ₂ C: 34.58; H: 2.90; N: 12.10, found C: 34.23; H: 2.68; N: 11.77
[1787] Similarly, the following compounds were prepared according to the above method.
[1788] (37.2) 2-Amino-5,6-difluoro-4-phosphonomethoxybenzothiazole. Melting point> 240 ° C (decomposition). C ₈ H ₇ N ₂ O ₄ Calculation for PSF ₂ C: 32.44; H: 2.38; N: 9.46, found C: 32.30; H: 2.26; N: 9.17.
[1789] (37.3) 2-Amino-5-fluoro-7-bromo-4-phosphonomethoxybenzothiazole. Melting point > 190 DEG C (decomposition). Calculation for C ₈ H ₇ N ₂ O ₄ PSBrF C: 26.91; H: 1.98; N: 7.84, Found C: 27.25; H: 1.92; N: 7.54.
[1790] (37.4) 2-Amino-7-ethoxycarbonyl-4-phosphonomethoxybenzothiazole. Melting point> 240 ° C (decomposition). C ₁₁ H ₁₃ N ₂ O ₆ PS + 0.2 HBr + 0.1 DMF C: 38.15; H: 3.94; N: 8.27, found C: 38.51; H: 3.57; N: 8.66.
[1791] &Lt; Example 38 >
[1792] Preparation of 2-amino-7-bromo-6-thiocyanato-4-phosphonomethoxybenzothiazole
[1793] Step A.
[1794] A solution of 2-fluoro-5-bromonitrobenzene (1 mmole) in DMF (5 mL) was cooled to 0 C and a solution of diethylhydroxymethylphosphonate (1.2 mmole) in DMF Lt; / RTI &gt; sodium salt solution. The mixture was stirred at room temperature for 16 hours. Evaporation, extraction and chromatography were performed to obtain 2-diethylphosphonomethyloxy-5-bromonitrobenzene.
[1795] Step B.
[1796] Diethylphosphonomethyloxy-5-bromonitrobenzene was treated in accordance with Step B of Example 37, Step B of Example 36 and Step D of Example 34 to give 2-amino-7-bromo-6 -Thiocyanato-4-phosphonomethoxybenzothiazole (38.1). Melting point> 250 ° C (decomposition). C ₉ H ₇ N ₃ O ₄ PS ₂ Calcd for Br C: 27.79; H: 1.78; N: 10.61, Found C: 26.90; H: 1.58; N, 10.54.
[1797] Similarly, the following compounds were prepared according to the above method.
[1798] (38.2) 2-Amino-7-fluoro-6-thiocyanato-4-phosphonomethoxybenzothiazole. Melting point > 136 DEG C (decomposition). C ₉ H ₇ N ₃ O ₄ Calculation for PFS ₂ + 0.3 HBr C: 30.07; H: 2.05; N: 11.69, found C: 30.27; H: 2.01; N: 11.38.
[1799] &Lt; Example 39 >
[1800] Preparation of 2-amino-7-hydroxymethyl-6-thiocyano-4-phosphonomethoxybenzothiazole
[1801] Step A.
[1802] 2-Chloro-5-formylnitrobenzene was treated according to Step A of Example 38 to obtain 2-diethylphosphonomethyloxy-5-formylnitrobenzene.
[1803] Step B.
[1804] A solution of 2-diethylphosphonomethyloxy-5-formylnitrobenzene (1 mmole) in methanol (5 mL) was treated with 10% palladium on carbon (0.05 mmole) under 1 atmosphere of hydrogen at room temperature for 12 hours. Filtration followed by evaporation yielded 2-diethylphosphonomethyloxy-5-hydroxymethylaniline which was treated according to Step B of Example 36 followed by Step D of Example 34 to give 2-amino-7-hydroxymethyl -6-thiocyanato-4-phosphonomethoxybenzothiazole (39.1). Melting point 181-184 占 폚. C ₁₀ H ₁₀ N ₃ O ₅ Calculated for PS ₂ + 0.35H ₂ O C: 33.97; H: 3.05; N: 11.88, found C: 33.76; H: 2.66; N: 11.61.
[1805] &Lt; Example 40 >
[1806] Preparation of 2-amino-6-bromo-7-fluoro-4-phosphonomethoxybenzothiazole
[1807] Step A.
[1808] A solution of 2-diethylphosphonomethyloxy-4-bromo-5-fluoroaniline (1 mmole, prepared as in step B of Example 4) and KSCN (2 mmole) in AcOH (8 mL) , And treated with a solution of bromine (2 mmole) in AcOH (5 mL). After stirring at room temperature for 0.5 h, the reaction mixture was evaporated to dryness and the residue was purified by chromatography to give 2-amino-7-fluoro-6-bromo-4-diethylphosphonomethyloxybenzothiazole , Which was treated according to Step D of Example 34 to give 2-amino-6-bromo-7-fluoro-4-phosphonomethoxybenzothiazole (40.1). Calculation for C ₈ H ₇ N ₂ O ₄ PSBrF + 0.1HBr C: 26.31; H: 1.96; N: 7.67, found C: 25.96; H: 1.94; N: 7.37.
[1809] &Lt; Example 41 >
[1810] Preparation of 2-amino-7-ethyl-6-thiocyano-4-phosphonomethoxybenzothiazole
[1811] Step A.
[1812] A solution of 2-diethylphosphonomethyloxy-5-bromonitrobenzene (1 mmole, prepared as in Step A of Example 37) in DMF (5 mL) was treated with tributyl (vinyl) Was treated with palladium bis (triphenylphosphine) dichloride (0.1 mmole) and the mixture was heated at 60 ° C under nitrogen for 6 hours. Evaporation and chromatography were performed to give 2-diethylphosphonomethyloxy-5-vinylnitrobenzene as an oil which was purified by following Step B of Example 38, Step B of Example 36, and Step D of Example 34 To give 2-amino-7-ethyl-6-thiocyano-4-phosphonomethoxybenzothiazole (41.1). Melting point > 167 DEG C (decomposition). C ₁₁ H ₁₂ N ₃ O ₄ Calculated for PS ₂ C: 38.26; H: 3.50; N: 12.17, found C: 37.87; H: 3.47; N: 11.93.
[1813] &Lt; Example 42 >
[1814] Preparation of 2-amino-7-cyclopropyl-6-thiocyanato-4-phosphonomethoxybenzothiazole
[1815] Step A.
[1816] A suspension of 2-diethylphosphonomethyloxy-5-vinylnitrobenzene (1 mmole, prepared as in Step A of Example 40) and Pd (OAc) ₂ (0.1 mmole) in ether (8 mL) Was treated with a solution of diazomethane (generated from 3.0 g of 1-methyl-3-nitro-1-nitroguanidine in ether) in THF. After stirring at room temperature for 20 hours, the reaction was evaporated to dryness and the residue was purified by chromatography to give 2-diethylphosphonomethyloxy-5-cyclopropylnitrobenzene, which was obtained in step B of Example 37, Example 36, step B, and step D of Example 34 to yield 2-amino-7-cyclopropyl-6-thiocyanato-4-phosphonomethoxybenzothiazole hydrobromide (42.1). C ₁₂ H ₁₃ N ₃ O ₄ PS ₂ Br + 0.1HBr C: 27.76; H: 2.72; N: 8.09, Found C: 27.54; H: 3.05; N: 7.83.
[1817] &Lt; Example 43 >
[1818] Preparation of 2-amino-4-phosphonomethoxy-6-chloro-7-methylbenzothiazole
[1819] Step A.
[1820] Methoxy-4-chloro-5-methylaniline was treated according to steps A and B of Example 34, step B of example 36 and step D of example 34 to give 2-amino-4-phosphonom 6-chloro-7-methylbenzothiazole (43.1). Melting point> 250 ℃ _{(decomposition) .C 9 H 10 N 2 O} 4 PS 2 calculated for _{Cl + 0.3H 2 O + 0.4HBr C} : 31.20; H: 3.20; N: 8.09, Found: C, 31.37; H: 2.87; N: 7.89.
[1821] Similarly, the following compounds were prepared according to the above method.
[1822] (43.2) 2-Amino-7-phenyl-6-thiocyanato-4-phosphonomethoxybenzothiazole. Melting point> 250 ° C (decomposition). Calcd for C ₁₅ H ₁₂ N ₃ O ₄ PS ₂ +0.2H ₂ O C: 45.38; H: 3.15; N: 10.58, found C: 45.25; H: 3.21; N: 10.53.
[1823] &Lt; Example 44 >
[1824] Preparation of 2-bromo-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole
[1825] Step A.
[1826] CH ₃ CN (4 mL) solution of 2-amino-4-diethyl phosphono-methoxy-5,6,7,8-tetrahydro-naphtho [1,2-d] thiazole (1 mmole) solution 0 ℃ cooled, followed by CuBr ₂ (1.2 mmole) was added dropwise to a isoamyl nitrite (1.5 mmole). The resulting dark color mixture was stirred for 3.5 hours. Evaporation and chromatography were performed to give 2-bromo-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole as an oil.
[1827] Step B.
[1828] 2-Bromo-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole was treated according to Step D of Example 34 to give 2- Bromo-4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole (44.1). Melting point 220-230 [deg.] C. Calcd for C ₁₂ H ₁₃ NO ₄ PSBr C: 38.11; H: 3.46; N: 3.70, found C: 37.75; H: 3.26; N: 3.69.
[1829] &Lt; Example 45 >
[1830] Preparation of 4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole
[1831] Step A.
[1832] A solution of isoamyl nitrite (1.5 mmole) in DMF (1 mL) at 65 [deg.] C was added to a solution of 2-amino-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho [L, 2-d] thiazole (1 mmole). After 30 minutes, the cooled reaction solution was evaporated and purified by chromatography to give 4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole as an oil , Which was treated according to Step D of Example 34 to give 4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole (45.1) as a solid. Melting point 215-220 [deg.] C. Calculation for C ₁₂ H ₁₄ NO ₄ PS + 1.3 HBr C: 35.63; H: 3.81; N: 3.46, found C: 35.53; H: 3.46; N: 3.40.
[1833] &Lt; Example 46 >
[1834] Preparation of 2-amino-4-phosphonomethylthiobenzothiazole
[1835] Step A.
[1836] Diethylphosphonomethylthioaniline prepared according to Step B of Example 34 was treated according to Step B of Example 36 to give 2-amino-4-diethylphosphonomethylthiobenzothiazole.
[1837] Step B.
[1838] Amino-4-diethylphosphonomethylthiobenzothiazole was treated according to Step D of Example 34 to give 2-amino-4-phosphonomethylthiobenzothiazole (46.1) as a foam. Calcd for C ₈ H ₁₀ N ₂ O ₃ PS ₂ +0.4H ₂ O C: 35.63; H: 3.81; N: 3.46, found C: 35.53; H: 3.46; N: 3.40.
[1839] &Lt; Example 47 >
[1840] Manufacture of various oral preparations of benzothiazole
[1841] Step A.
[1842] To a solution of 2-amino-4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho
[1843] [1, 2-d] thiazole (1 mmole) suspension was treated with DCC (3 mmole) followed by 3- (3,5-dichloro) phenyl-1,3-propanediol (1.1 mmole). The resulting mixture was heated at 80 &lt; 0 &gt; C for 8 hours. After evaporation, column chromatography was performed to obtain 2-amino-4 - {[3- (3,5-dichlorophenyl) propane-1,3-diyl] phosphonomethoxy} Tetrahydronaphtho [1,2-d] thiazole (47.1) was obtained. Melting point> 230 ° C. Calcd for C ₂₁ H ₂₁ N ₂ O ₄ PSCl ₂ C: 50.51; H: 4.24; N: 5.61, Found C: 50.83; H: 4.34; N: 5.25.
[1844] Step B.
[1845] To a solution of 4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho [1, &lt; RTI ID = 0.0 &gt;
[1846] (1 mmole) in dichloromethane (0.5 mL) and pyridine (0.3 mL) was added dropwise to a solution of benzyl alcohol (0.9 mmol) in dichloromethane Lt; / RTI &gt; The resulting reaction solution was stirred at 0 &lt; 0 &gt; C for 1 hour, and then an ammonia (excess) solution in THF was added. After stirring at room temperature for 16 hours, the reaction was evaporated to dryness and the residue was purified by chromatography to give 4-phosphono monoamidomethoxy-5,6,7,8-tetrahydronaphtho [1,2- d] thiazole.
[1847] Alternatively, other methods are used to prepare other phosphoamides as illustrated in the following procedure.
[1848] Step C.
[1849] To a solution of 4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho [1, &lt; RTI ID = 0.0 &gt;
[1850] 2-d] thiazole dichloride (produced as in Example 19) (1 mmole) suspension was cooled to 0 &lt; 0 &gt; C and ammonia (excess) was bubbled into the reaction for 10 minutes. After stirring at room temperature for 16 h, the reaction was evaporated to dryness and the residue was purified by chromatography to give 4- (phosphorodiamido) methoxy-5,6,7,8-tetrahydronaphtho [1, 2-d] thiazole.
[1851] Monophenyl-monophosphonamide derivatives of compounds of formula (X) can also be prepared according to the above method.
[1852] Step D.
[1853] A solution of 4-diphenylphosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole (prepared according to the method of Example 19) in acetonitrile (9 mL) (1 mmole) was treated with lithium hydroxide for 24 hours at room temperature. The reaction solution was evaporated to dryness, the residue was dissolved in water, cooled to 0 ° C and 6 N HCl was added to adjust the pH of the solution to 4. The resulting white solid was collected by filtration to give 4-phenylphosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole.
[1854] Step E.
[1855] To a solution of 4-phenylphosphonomethoxy-5,6,7,8-tetrahydronaphtho (3 mL) in thionyl chloride
[1856] [1, 2-d] thiazole (1 mmole) in toluene was heated to reflux for 2 hours. The reaction solution was evaporated to dryness and the residue was dissolved in anhydrous dichloromethane (2 mL), and the resulting solution was treated with pyridine (0.8 mL) and L-alanine ethyl ester hydrochloride in dichloromethane (3 mL) (1.2 mmole) solution. The resulting reaction solution was stirred at room temperature for 14 hours. Evaporation and chromatography gave 4- [O-phenyl-N- (1-ethoxycarbonyl) ethylphosphonamido] methoxy-5,6,7,8-tetrahydronaphtho [ d] thiazole.
[1857] Step F.
[1858] A solution of 4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole (1 mmole) in DMF was treated with N, N'-dicyclohexyl- (5 mmole) and ethyl propyloxycarbonyloxymethyl iodide prepared from chloromethyl chloroformate according to the reported literature (Nishimura et al., J. Antibiotics, 1987, 40, 81) mmole). The reaction mixture was stirred at 25 &lt; 0 &gt; C for 24 hours. Evaporation and chromatography were performed to obtain 4-bis (ethoxycarbonyloxymethyl) phosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole.
[1859] (Dipyrroloxymethyl) phosphonomethoxy-5,6,7,8-tetrahydronaphtho [1,2-d] thiazole and 4-bis (isobutyryloxymethyl) phosphonomethoxy -5,6,7,8-tetrahydronaphtho
[1860] [1,2-d] thiazole is also prepared in a similar manner.
[1861] Examples using the method of the present invention include the following. It is to be understood that these examples are illustrative and that the method of the present invention is not limited to these examples.
[1862] For clarity and brevity, the chemical compounds are numbered in the synthetic examples in the biological examples below.
[1863] In addition to the following examples, assays that may be useful in identifying compounds that inhibit gluconeogenesis include the following diabetic animal models.
[1864] i. Animals (eg, streptozotocin-treated mice, rats, dogs, and monkeys) having pancreatic b-cells destroyed by specific chemical cytotoxins such as streptozotocin [Kodama, H., Fujita, M. et al. , Yamaguchi, I., Japanese Journal of Pharmacology 66, 331-336 (1994) (mouse); Youn, J. H., Kim, J. K., Buchanan, T. A., Diabetes 43, 564-571 (1994) (rat); Le Marchand, Y., Loten, E. G., Assimacopoulos-Jannet, F., et al., Diabetes 27, 1182-88 (1978); And Pitkin, R. M., Reynolds, W. A., Diabetes 19, 70-85 (1970) (monkeys)].
[1865] ii. Mutant mice such as C57BL / Ks db / db, C57BL / Ks ob / ob and C57BL / 6J ob / ob species from Jackson laboratory (Bar Harbor) and other species such as Yellow Ovess, T- Coleman, DL, Hummel, KP, Diabetologia 3, 238-248 (1967) (C57BL / Ks db / db); Coleman, D. L., Diabetologia 14, 141-148 (1978) (C57BL / 6J ob / ob); Wolff, G. L., Pitot, H. C., Genetics 73,109-123 (1973) (Yellow Obes); Dulin, W. E., Wyse, B. M., Diabetologia 6, 317-323 (1970) (T-KK); And Bielschowsky, M., Bielschowsky, F. Proceedings of the University of Otago Medical School 31, 29-31 (1953) (Obes, New Zealand)
[1866] iii. (Stolz, KJ, Martin, RJ, Journal of Nutrition 112, 997-1002 (1998)), such as diabetes mellitus, streptozotocin or dexamethasone-induced diabetic jurkat fa / fa rats, Zucker diabetic rats, and Wistar Kyoto rats 1982) (streptozotocin); Ogawa, A., Johnson, J. H., Ohnbeda, M., McAllister, C. T., Inman, L., Alam, T., Unger, R. H., The Journal of Clinical Investigation 90, 497-504 (1992) (dexamethasone); Clark, J. B., Palmer, C. J., Shaw, W. N., Proceedings of the Society for Experimental Biology and Medicine 173, 68-75 (1983) (Zucker diabetic rats); And Idida, H., Shino, A., Matsuo, T., et al., Diabetes 30, 1045-1050 (1981)
[1867] iv. (Gerritsen, GC, Connel, MA, Blanks, MC, Proceedings of the Nutrition Society 40, 237-245 (1981) (China hamster); Lang, C. M., Munger, B. L., Diabetes 25, 434-443 (1976) (guinea pig); Conaway, H. H., Brown, C. J., Sanders, L.L. et al., Journal of Heredity 71, 179-186 (1980) (New Zealand White rabbits); Hansen, B. C., Bodkin, M. L., Diabetologia 29, 713-719 (1986) (Lassus monkey); And Davidson, I. W., Lang, C. M., Blackwell, W. L., Diabetes 16, 395-401 (1976)
[1868] v. Diet-induced diabetic animals such as sand rats, spinel mice, Mongolian gerbils, and cohen sucrose-induced diabetic rats. [Schmidt-Nielsen, K., Hainess, HB, Hackel, DB, Science 143 , 689-690 (1964) (sand rats); Gonet, A. E., Stauffacher, W., Pictet, R., et al., Diabetologia 1, 162-171 (1965) (Spinel); Boquist, L., Diabetologia 8, 274-282 (1972) (Mongolian Gerville); And Cohen, A. M., Teitebaum, A., Saliternik, R., Metabolism 21, 235-240 (1972) (Cohen sucrose-induced diabetic rats)
[1869] vi. An individual suffering from one or more of impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, accelerated glucose synthesis, increased hepatic glucose output resulting from genetic engineering, genetic engineering, selective breeding, or chemical or nutritional induction Of other animals.
[1870] <Biological Example>
[1871] <Example A>
[1872] Inhibition of Human Interphase
[1873] E. coli strain BL21 transformed with the human interferon-beta plasmid was transformed into E. coli strain BL21. EI-Maghrabi (State University of New York at Stony Brook). Enzymes were typically purified from 10 liters of recombinant E. coli culture as described in M. Gidh-Jain et al., 1994, The Journal of Biological Chemistry 269, pp 27732-27738. Formation of the product (fructose 6-phosphate) via NADP ⁺ and phenazine phytosphate (PMS) using phosphoglucose isomerase and glucose 6-phosphate dihydrogenase as the coupling enzyme was carried out using dimethylthiazolidiphenyl The activity of the enzyme in the reaction coupled to the reduction of tetrazolium bromide (MTT) was measured with a spectrophotometer. The reaction mixture (200 μl) was created in a 96-well microplate, 50 mM Tris-HCl, pH 7.4, 100 mM KCl, 5 mM EGTA, 2 mM MgCl 2, 0.2 mM NADP, 1 mg / ml BSA, 1 mM MTT, 0.6 mM PMS, 1 unit / ml phosphoglucose isomerase, 2 units / ml glucose 6-phosphate dehydrogenase, and 0.150 mM substrate (fructose 1,6-bisphosphate). Inhibitor concentrations range from 0.01 μM to 10 μM. The reaction was initiated by adding 0.002 units of pure hlFBPase and observed for 7 minutes at 590 nm (Molecular Devices Plate Reader, 37 ° C).
[1874] The table below shows the IC ₅₀ values for the various compounds produced. The IC ₅₀ for AMP is 1 μM.
[1875] compound#IC ₅₀ (hlFBPase), μM 3.10.025 3.20.1 3.250.014 3.260.015 3.5882 3.672 3.69One 3.700.04 6.30.044 10.10.12 10.270.038 10.430.07 15.200.04 15.140.032 16.10.06 17.60.62 17.110.78 18.30.05 18.110.33 18.200.039 18.252 25.20.4 28.22.8 41.10.022
[1876] Inhibition of FBPase between rats
[1877] E. coli strain BL21 transformed with rat FBPase-coding plasmid was transformed into E. coli strain BL21. egg. Was obtained from Dr. MR EI-Maghrabi, State University of New York at Stony Brook. The recombinant FBPase was purified as described in EI-Maghrabi, MR, and Pilkis, SJ (1991) Biochem. Biophys. Res. Commun. 176, 137-144. Enzyme assays are the same as described above for human-to-human FBPase. The table below shows the IC ₅₀ values for the various compounds produced. The IC ₅₀ for AMP is 20 μM.
[1878] compound#IC ₅₀ (rlFBPase), μM 3.10.18 3.22.5 3.250.5 3.260.25 3.700.15 6.30.5 10.12 10.22.5 10.272.9 10.430.8 15.21.3 15.44.1 15.67 15.200.6 15.140.68 16.11.8 18.200.28 18.30.49 41.10.16
[1879] <Example B>
[1880] AMP site binding
[1881] To determine if the compound binds to the allosteric AMP binding site of hlFBPase, the enzyme was incubated with radiolabeled AMP in the presence of the test compound concentration range. The reaction mixture is composed of 25 mM Tris-HCl, pH 7.4 , 100 mM KCl and 1 mM MgCl ₂ A ^{25 mM 3 H-AMP (54} mCi / mmole) and 0-1000 mM test compound in buffer containing. Finally, 1.45 mg of homogenous FBPase (± 1 nmole) was added. After incubation for 1 minute, the AMP bound to FBPase was separated from the unbound AMP by centrifugal ultrafiltration unit ("Ultrafree-MC", Millipore) used according to the manufacturer's instructions. The radioactivity of the aliquots (100 μl) from the upper zone of the unit (residues containing enzymes and labels) and the lower zone (filtrate containing unbound label) was quantitated using a Beckman liquid scintillation counter. The amount of AMP bound to the enzyme was determined by comparing the total count of residues and the count of filtrate (unconjugated label).
[1882] &Lt; Example C >
[1883] AMP site / enzyme selectivity
[1884] To determine the selectivity of the compounds against FBPase, the effects of FBPase inhibitors on the five key AMP binding enzymes were determined using the assays described below.
[1885] Adenosine kinase : Spychala, J., Datta, NS, Takabayashi, K., Datta, M., Fox, IH, Gribbin, T., and Mitchell, BS (1996) Proc. Natl Acad Sci USA 93 , &Lt; / RTI &gt; 1232-1237). The human adenosine kinase was purified from E. coli expression system. Activity was measured essentially as described in Yamada, Y., Goto, H., Ogasawara, N. (1988) Biochim. Biophys. Acta 660, 36-43, but somewhat modified. The assay mixture contained 50 mM TRIS-Malate buffer, pH 7.0, 0.1% BSA, 1 mM ATP, 1 mM MgCl ₂ , 1.0 μM [U- ¹⁴ C] adenosine (400-600 mCi / mmol) . ^14C -AMP was adsorbed on anion exchange paper (Whatman) and separated from untreated ¹⁴ C-adenosine and quantified by scintillation counting.
[1886] Adenosine monophosphate diaminase: via the phosphocellulose step as described essentially in the literature (Smiley, KL, Jr. Berry, AJ, and Suelter, CH (1967) J. Biol. Chem. 242, 2502-2506) The pig heart AMPDA was purified. Inhibition of AMPDA activity was measured at 37 占 폚 in a 0.1 ml test mixture (containing inhibitor, ~ 0.005 U AMPDA, 0.1% bovine serum albumin, 10 mM ATP, 250 mM KCl and 50 mM MOPS at pH 6.5). The concentration of substrate AMP was 0.125 to 10.0 mM. The catalyst was initiated by addition of enzyme to the other complete reaction mixture and injected into the HPLC system and terminated after 5 minutes. Activity was determined from the amount of IMP formed for 5 minutes. IMP was isolated from AMP by HPLC using a Beckman Ultrasil-SAX anion exchange column (4.6 mm X 25 cm) with an isocratic buffer system (12.5 mM potassium phosphate, 30 mM KCl, pH 3.5) Absorbance was measured with a photometer.
[1887] The phosphofructokinase : enzyme (rabbit liver) was purchased from Sigma. Activity is measured at 30 占 폚 in which the formation of fructose 1,6-bisphosphate is coupled to the oxidation of NADH through the action of aldorase, trioctatephosphate isomerase and a-glycerophosphate dehydrogenase Respectively. The reaction mixture (200 μl) was made in 96-well microplates and read at 340 nm (Molecular Devices Plate Reader). The mixture was incubated overnight at 37 ° C in a buffer containing 200 mM Tris-HCl, pH 7.0, 2 mM DTT, 2 mM MgCl ₂ , 0.2 mM NADH, 0.2 mM ATP, 0.5 mM fructose 6-phosphate, And a 4 unit / ml a-glycerophosphate dehydrogenase. The concentration of the test compound ranged from 1 to 500 [mu] M. The reaction was initiated by the addition of 0.0025 units of phosphofructokinase and observed for 15 minutes.
[1888] Glycogen phosphorylase : Enzyme (rabbit muscle) was purchased from Sigma. Activity was measured at 37 [deg.] C, in which the formation of glucose 1-phosphate was coupled to the reduction of NADP via phosphoglucormycutase and glucose 6-phosphate dehydrogenase. Assays were performed on 96-well microplates and read at 340 nm (Molecular Devices Plate Reader). The reaction mixture was 20 mM imidazole, pH 7.4, 20 mM MgCl _2, 150 mM potassium acetate, 5 mM potassium phosphate, 1 mM DTT, 1 mg / ml BSA, 0.1 mM NADP, 1 unit / ml phosphoglucoisomerase mu hydratase, 1 unit / ml glucose 6-phosphate dehydrogenase, 0.5% glycogen. The concentration of the test compound ranged from 1 to 500 [mu] M. The reaction was started by adding 17 의 of enzyme and observed for 20 minutes.
[1889] Adenylate kinase: Enzyme (rabbit muscle) was purchased from Sigma. Activity was measured in the reaction mixture (100 占 퐇) at 37 占 폚 containing 100 mM HEPES, pH 7.4, 45 mM MgCl2, 1 mM EGTA, 100 mM KCl, 2 mg / ml BSA, 1 mM AMP and 2 mM ATP . 4.4 ng of enzyme was added to initiate the reaction and 17 ㎕ of perchloric acid was added and terminated after 5 minutes. The precipitated protein was removed by centrifugation and 33 [mu] l of 3 M KOH / 3 M KHCO ₃ was added to neutralize the supernatant. The neutralized solution was clarified by centrifugation and filtration and analyzed for ADP count (enzyme activity) by HPLC using a YMC ODS AQ column (25 x 4.6 cm). 0.1 M KH ₂ PO ₄ , pH 6, gradient from 8 mM tetrabutylammonium hydrogen sulphate to 75% acetonitrile. Absorbance was observed at 254 nm.
[1890] The table below shows the selectivity data for compounds 10.1 and 3.1.
[1891] 10.13.1(μM)(μM) FBPase (inhibition)0.10.025 Adenosine kinase (inhibition)>> 10>> 10 AMP diaminase (inhibition)>> 10>> 10 Adenylate kinase (inhibition)> 500> 500 Glycogen phosphorylase (activated)> 100> 100 Phosphofructokinase (activated)> 500> 500
[1892] <Example D>
[1893] Inhibition of Glucose Synthesis in Rat Hepatocytes
[1894] (Berry, MN, Friend, DS, 1969, J), which is modified by Groen, AK, Sips, HJ, Vervoorn, RC, Tager, JM, 1982, Eur. J. Biochem. Cells Biol., 43, 506-520) were obtained hepatocytes from Sprague-Dawaur rats (250-300 g) fasted overnight. Hepatocytes (75 mg wet weight / ml) were incubated in 1 ml Krebs-bicarbonate buffer containing 10 mM lactate, 1 mM pyruvate, 1 mg / ml BSA and test compounds at a concentration of 1 to 500 μM. Incubations were performed in a sealed 50-ml Falcon tube submerged in a rapidly shaking water bath (37 ° C) under a 95% oxygen, 5% carbon dioxide atmosphere. After 1 hour, the aliquots (0.25 ml) were transferred into Eppendorf tubes and centrifuged. Next, 50 μl of the supernatant was assayed for the glucose content using Sigma Glucose Oxidase Kit according to the manufacturer's instructions.
[1895] The IC ₅₀ for the selectivities in this assay is shown in the table below.
[1896] compoundIC ₅₀ glucose production, μM 3.12.5 3.226 3.2610 3.581.2 10.115 10.216 16.110 19.1810 19.486.5 20.92.2 31.62.3 31.83
[1897] <Example E>
[1898] Inhibition of glucose production and fructose 1,6-bisphosphate accumulation in rat hepatocytes
[1899] Rat hepatocytes isolated as described in Example D were prepared and cultured under the same conditions as described in Example D. An aliquot (250 μl) of the cell suspension was removed and the reaction was terminated by placing it in a 10% perchloric acid layer (100 μl) through an oil layer (0.8 ml silicone / mineral oil, 4/1). After removing the oil layer, 1/3 volume of 3 M KOH / 3 M KHCO ₃ was added to neutralize the acidic cell extract layer. After thorough mixing and centrifugation, the supernatant was analyzed for the glucose content as described in Example D, and the supernatant was also analyzed for fructose 1,6-bisphosphate. Fructose 1,6-bisphosphate was assayed by spectrophotometry by coupling the enzymatic conversion of glycerol 3-phosphate to the oxidation of NADH, which was observed at 340 nm. The reaction mixture (1 ml) consisted of 200 mM Tris-HCl, pH 7.4, 0.3 mM NADH, 2 units / ml glycerol 3-phosphate, 2 units / ml tinephosphate isomerase and 50-100 μl cell extract After preincubation for 30 minutes at 37 ° C, 1 unit / ml aldorase was added and the change in absorbance was measured until a stable value was obtained. In this reaction, 2 moles of NADH per 1 mole of fructose 1,6-bisphosphate present in the cell extract was oxidized.
[1900] The dose-dependent inhibition of glucose production accompanied by dose-dependent accumulation of fructose 1,6-bisphosphate (a substrate of FBPase) indicates that the target enzyme FBPase is inhibited in the glucose synthesis pathway.
[1901] &Lt; Example F >
[1902] Decreased blood glucose after intravenous administration to fasted rats
[1903] Sprague-Dawley rats (250-300 g) were fasted for 18 hours, followed by intravenous administration of physiological water or a 10 mg / kg FBPase inhibitor. The inhibitor was dissolved in water and the solution was neutralized with NaOH. Blood samples were obtained from the tail vein of conscious animals before and one hour after injection. Blood glucose was measured using a glucose analyzer from Hemocus Inc. according to the manufacturer's instructions.
[1904] The table below shows the% glucose depression exhibited by the compound compared to the control animals treated with the physiological water.
[1905] compound#Intravenous glucose lowering,% 3.165 3.255 (30 mg / kg) 3.2576 3.2673 3.5882 3.7172 6.324 10.151 10.4361 15.2024 18.280 18.375 35.365 41.480
[1906] Several compounds were also tested at doses less than 10 mg / kg. For example, compound 3.26 was tested at 3 mg / kg and was found to reduce blood glucose by 52%.
[1907] <Example G>
[1908] Analysis of drug concentration and liver accumulation in rats
[1909] Sprague-Dawley rats (250-300 g) were fasted for 18 hours, followed by intravenous administration of physiological water (n = 3) or 10.1 or 3.1 (n = 3 / group) of 10 mg / kg. The compound was dissolved in water and the solution was neutralized with NaOH. One hour after the injection, rats were anesthetized with halothane and liver biopsies (about 1 g) as well as blood samples (2 ml) were taken from the posterior veins. Heparinized needles and needles were used for blood collection. Liver samples were immediately homogenized in ice-cold 10% perchloric acid (3 ml) and centrifuged, and the supernatant was neutralized with 1/3 volume of 3 M KOH / 3 M KHCO ₃ . After centrifugation and filtration, 50 [mu] l of the neutralized extract for 10.1 content was analyzed by HPLC. YMC ODS AQ column (250 X 4.6 cm) was used and recovered by gradient from 10 mM sodium phosphate (pH 5.5) to 75% acetonitrile. Absorbance was observed at 310-325 nm. Plasma was obtained from blood samples by centrifugation and methanol was extracted by adding to 60% (v / v). The methanol extract was centrifuged and clarified by filtration and analyzed by HPLC as described above. The results are shown in the table below.
[1910] compound#Plasma concentration, μMLiver concentration, nmoles / g 10.118 ± 2.835.6 ± 4.2 10.222 ± 1.55.1100 ± 5.76.7 ± 0.7 3.2125 ± 115.2066.3 ± 3.913.1 ± 2.3 3.2656 ± 2
[1911] <Example H>
[1912] Glucose lowering after oral administration to fasted rats
[1913] The compounds were administered orally to Sprague Dawley rats (250-300 g, n = 3/4 / group) fasted for 18 hours. The phosphonic acid was prepared in deionized water and the solution was neutralized with sodium hydroxide. The whole globule was dissolved in polyethylene glycol (molecular weight 400). Blood glucose was measured immediately before and at 1 hour intervals after administration with a hemocyte glucose analyzer (HemoCue Inc., Mission Viejo, CA). The table below shows that maximal glucose depression is achieved compared to control animals administered with menstrual fluid.
[1914] compound#% Glucose loweringDose, mg / kgTime, time 3.2670302 3.2761603 10.155903 10.236903 19.4226303 19.4863302 19.4653302 20.967903 31.660103
[1915] &Lt; Example I >
[1916] Measurement of Oral Bioavailability of Phosphonic Acid and its Whole Forms
[1917] The phosphonic acid was dissolved in water and the solution was neutralized with sodium hydroxide. The whole globule was dissolved in 10% ethanol / 90% polyethylene glycol (molecular weight 400). The compounds were dosed orally in the Sprague Dawley rats (220-250 g) fasted for 18 hours at a dose ranging from 10-50 mg / kg. Thereafter, the rats were placed in a metabolic cage and urine was collected for 24 hours. The amount of phosphonic acid secreted into the urine was measured by HPLC as described in Example G. [ In a separate study, urine recovery was measured after intravenous (tail vein) administration of the compound (intravenous administration of the appropriate aminophosphonic acid in the case of whole blood). Oral bioavailability (%) was determined by comparing the recovery of the compound in the urine 24 hours after the oral administration with the recovery of the compound in the urine 24 hours after intravenous administration.
[1918] The oral bioavailability of the selected phosphonic acids and phosphonic acids is shown in the table below.
[1919] compound#% Oral bioavailability 3.14 3.2618 3.2732 10.121 10.222 19.4210 19.918.5 19.1716.2 19.4812 20.146 20.317.5 20.411 20.917.4 31.619 31.814
[1920] <Example J>
[1921] Zucker glucose lowering in diabetic rats (oral)
[1922] 8-week-old Zucker diabetic rats from the Genetics Model Inc. (Indiana, IN) were purchased and given the recommended Purina 5008 diet. At 12 weeks, 16 animals with blood glucose concentrations between 500 and 700 mg / dl were selected and divided into two groups (n = 8) with the same mean blood glucose levels statistically. 100 mg / kg dose of compound 3.26 was administered orally to one animal group at 1 pm. The drug solution for this treatment was prepared at 25 mg / ml in deionized water and neutralized by adding 5 N NaOH. The second rat group (n = 8) was orally administered the physiological saline. Blood glucose was measured in each rat just before administration of drug or physiological water and 6 hours after administration. For these measurements, a HemoChip blood glucose analyzer (HemoCue Inc., Mission Viejo, Calif.) Was used according to the manufacturer's instructions.
[1923] As shown in the table below, Compound 3.26 treatment resulted in a blood glucose lowering of 15.4% (p = 0.01) compared to the control group treated with physiological water.
[1924] Treated groupBlood sugar, mg / dl 1 pm7 pm Number of menstruation575 ± 28587 ± 26 3.26573 ± 26497 ± 14
[1925] The data indicate that compound 3.26 is an effective oral glucose lowering agent in a Zucker diabetic rat rat model with type II diabetes.
[1926] <Example K>
[1927] Decrease in blood glucose (intravenous) in Zucker diabetic rats
[1928] The 12-week-old Zucher diabetic rats (Genetics Model Inc., Indianapolis, Indiana), fed with the Purina 5008 diet, were equipped with a tail vein and a tail vein catheter at 8 am on the study day. I did not feed the animals for the rest of the day. Physiological water, or compound 3.26 at 1, 3 or 30 mg / kg / h, via the tail vein catheter from 12 pm, was maintained on the animals for 6 hours. Blood samples were obtained from the tail arterial catheter at the reference start point, and then every hour thereafter. Glucose was measured on the sample using HemoCue analyzer (HemoCue Inc., Mission Viejo, Calif.) According to the manufacturer's instructions.
[1929] At 6 hours, when 3 and 30 mg / kg / h of 3.26 were used, the blood glucose levels were significantly reduced to 29% and 39%, respectively, compared with the control group in which the physiological water was used. This study shows that 3.26 is an effective glucose lowering agent when administered intravenously to Zucker diabetic rats (a key rodent model of type II diabetes).
[1930] &Lt; Example L >
[1931] Inhibition of Glucose Synthesis by FBPase Inhibitors in Zucker Diabetic Rats
[1932] 3.26 or physiological water at 3 mg / kg / h was transplanted in zucerian diabetic rats (n = 3 / group) for 6 hours, as described in Example K, followed by the addition of a solution of ¹⁴ C- bicarbonate / 100 g body weight) was administered via a tail vein catheter. After 20 minutes, a blood sample (0.6 mL) was collected via the tail artery. Blood (0.5 mL) was diluted in 6 mL of deionized water and 1 mL of zinc sulfate (0.3 N) and 1 mL of barium hydroxide (0.3 N) was added to precipitate the protein. The mixture was centrifuged (20 min, 1000 x g) and 5 mL of the resulting supernatant was added to 1 g of a mixed bed ion exchange resin (1 part AG 50W-X8, 100-200 mesh, hydrogen form, AG 1-X8, 100-200 mesh, acetate form) were combined and were separated from the ¹⁴ C- ¹⁴ C- bicarbonate glucose. The slurry was shaken at room temperature for 4 hours and then allowed to stand. The aliquots (0.5 mL) of the supernatant were then counted in a 5 mL scintillation cocktail. Drug-% inhibition of gluconeogenesis in drug-treated rats is - the number of menstrual the average cpm of the ¹⁴ C- glucose from the sample obtained from the treated animals - as the average cpm of the ¹⁴ C- glucose from the sample obtained from the injected animals It was calculated by sharing.
[1933] It was confirmed that the production of ¹⁴ C-glucose was inhibited up to 75% in the rats subjected to 3.26. This result shows that the glucose-lowering activity of 3.26 in Zucker diabetic rats (Example K) is due to inhibition of glucose synthesis.
[1934] &Lt; Example M >
[1935] In the streptozotocin-treated rats,
[1936] Diabetes was induced in male Sprague-Dawaur rats (250-300 g) by intraperitoneal injection of 55 mg / kg of streptozotocin (Sigma Chemical Co.). After 6 days, blood glucose was measured as described in Example F. Animals with blood glucose levels between 850 and 600 mg / dl were selected and divided into two groups. One group was orally administered with compound (10-100 mg / kg) and the second group was orally administered with the same volume of physiological water. Stop feeding the animals with food. Blood glucose was measured again 2 and 4 hours after drug / physiological water administration.
[1937] &Lt; Example N >
[1938] Oral Absorption Measurements in Whole Forms in Rats
[1939] Whole-year 19.42, 19.48, 31.6 and 31.8 were administered by intraperitoneal injection and oral feeding (n = 3 rats / compound / administration route) to normal rats fed with 30 mg / kg. Thereafter, the rats were placed in a metabolic cage and urine was collected for 24 hours. The parent compound 3.1 was quantified on glass by reverse phase HPLC as described in Example G. [ The oral absorption rate (%) for each oral drug was calculated by comparing the amount of the endogenous compound secreted from the urine after oral administration and the amount of the endogenous compound secreted into the urine after intraperitoneal administration. The results are shown in the table below.
[1940] compoundPercent% (at oral administration)Percentage (in the case of intraperitoneal administration)% Water absorption 19.428.115.452 19.4811.611.3100 31.616.538.943 31.812.328.443
[1941] All four tested medications were easily absorbed after oral administration (43-100%).
[1942] &Lt; Embodiment O >
[1943] Treatment of db / db mice with FBPase inhibitor resulted in normalization of hepatic glycogen concentration
[1944] 8-week-old Db / db mice and their non-diabetic db / + offspring (Jackson Labs., Bar Harbor, Maine) were used for this study at week 11. Db / db mice were orally treated with physiological saline or compound 3.26 (100 mg / kg) at 8:00 am and 2:00 pm on the study day. Db / + mice were treated with physiological water according to the same schedule. At 6 pm, the mice were anesthetized with halothane and a small piece of liver (0.5 g) was cut with the freeze-cramping technique. Next, the liver sample was immersed in liquid nitrogen and completely frozen and homogenized in 5 volumes of cold 0.6 N perchloric acid. The glycogen content in the homogenate was determined enzymatically by the method of Keppler D and Decker K, Methods of Enzymatic Analysis, Bergmeyer, HU, Ed., Verlag Chemie international, Deerfield Beach, The results for pre-treatment (8 am) measured in individual groups of mice are shown in the table below.
[1945] Treated groupLiver glycogen, μmol glucose / g 8 in the morning6:00 pm db / db, control group102 ± 1.9 (n = 3)83.2 ± 22.5 (n = 7) db / db, 3.26 34.4 ± (n = 3) db / +, control group120.2 +/- 6.7 (n = 3)15.7 ± 7.2 (n = 3)
[1946] The above data indicate that significant glycogen changes were observed in the control non-diabetic db / + mice, while not significantly decreasing the hepatic glycogen stores in the control (physiological water-treated) diabetic db / db mice during the study day. At 3.26 db / db mice, acute treatment reduced glycogen storage to levels that reached glycogen storage in non-diabetic db / + mice.

权利要求:
Claims (165)
[1" claim-type="Currently amended] Compounds of formula (I): &lt; EMI ID = 32.1 &gt;
(I)

In this formula,
R ⁵ is And , &Lt; / RTI &gt;
G is each independently selected from the group consisting of C, N, O, S and Se wherein only one G may be O, S or Se, at most one G is N,
G 'are each independently selected from the group consisting of C and N, wherein no more than two G' are N,
A is _{^{-H, -NR 4 2, -CONR 4}} 2, -CO 2 R 3, ^{halo, -S (O) R 3,} -SO 2 R 3, alkyl, alkenyl, alkynyl, alkyl, perhaloalkyl, halo Alkyl, aryl, -CH ₂ OH, -CH ₂ NR ⁴ ₂ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , ⁴ ₂ , -NHAc, and a substituent group (null)
B and D are each independently selected from -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, -SO 2 R ^{11, -S (O) R 3} , -CN, -NR 9 2, -OR 3, -SR 3, selected from the group consisting of alkyl, halo, -NO _2, and no substituent perhaloalkyl, and -H, - CN, perhaloalkyl, -NO ₂ , and halo are optionally substituted,
E is -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, -C (O) OR ³ , -CONR ⁴ ₂ , -CN, -NR ⁹ ₂ , -NO ₂ , -OR ³ , -SR ³ , perhaloalkyl, halo and no substituent, and all but -H, -CN, perhaloalkyl and halo are optionally substituted,
J is selected from the group consisting of -H and no substituent,
X binds R &lt; ⁵ &gt; to a phosphorus atom through 2 to 4 atoms, including zero or one heteroatom selected from N, O and S, except when X is urea or carbamate with two heteroatoms Which is measured as the shortest path between R &lt; ⁵ &gt; and the phosphorus atom, where the phosphorus bonded atom is a carbon atom and is not directly bonded to the carbonyl group or to the ring of the heterocycle, And X is not two carbon atom-alkyl, or -alkenyl- groups,
X is not substituted with -COOR ² , -SO ₃ R ¹ or PO ₃ R ¹ ₂ ,
Y is independently selected from the group consisting of -O-, and -NR &lt; ⁶ &gt; -,
When Y is -O-, R ¹ bonded to -O- is independently -H, alkyl, optionally substituted aryl, optionally substituted alicyclic wherein the cyclic moiety is a carbonate or thiocarbonate containing also), optionally substituted with a - _{^{alkylaryl, -C (R 2) 2 OC}} (O) NR 2 2, -NR 2 -C (O) -R 3, -C (R 2) 2 -OC (O ^{) R 3, -C (R 2} ) 2 -OC (O) OR 3, -C (R 2) 2 OC (O) SR 3, - alkyl, -SC (O) R ^3, - alkyl hydroxy alkyl -SS- Gt; is selected from the group consisting &lt; RTI ID = 0.0 &gt; of-
When Y is -NR ⁶ -, R ¹ bonded to -NR ⁶ - is independently -H, - [C (R ² ) ₂ ] _q -COOR ³ , -C (R ⁴ ) ₂ COOR ³ , - [ C (R ² ) ₂ ] _q -C (O) SR and -cycloalkylene-COOR ³ , or
When one of Y is independently selected from -O- and -NR ⁶ -, R ¹ and R ¹ together form an -alkyl-SS-alkyl-cyclic group, or R ¹ and R ¹ together
Lt;
here,
V, W and W 'are independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl Or
V and Z together are joined through an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 atoms optionally containing one heteroatom, Acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy bonded to the carbon atom which is three atoms from the nitrogen atom to which they are attached, or
V and Z together are joined through an additional three to five atoms to form a cyclic group optionally containing one heteroatom fused to the aryl group at the beta and gamma positions for Y bonded to the phosphorus,
V and W are joined together through an additional three carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and to bond to one of the carbon atoms having 3 atoms from Y bonded to phosphorus Alkyl, substituted alkoxy, hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, each of which is optionally substituted with one substituent selected from the group consisting of halogen,
Z and W are taken together through an additional 3 to 5 atoms to form a cyclic group optionally containing one heteroatom and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
W and W 'are taken together through an additional two to five atoms to form a cyclic group optionally containing from 0 to 2 heteroatoms, wherein V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl Lt; / RTI &gt;
Z is ^{-CHR 2 OH, -CHR 2 OC (} O) R 3, -CHR 2 OC (S) R 3, -CHR 2 OC (S) OR 3, -CHR 2 OC (O) SR 3, -CHR 2 (CH = CR ² ₂ ) OH, -CH (C≡CR ² ) OH, -CH (O) ₂ R ³ , -OR ² , -SR ² , -CHR ² N ₃ , -CH ₂ aryl, _{^{OH, -R 2, -NR 2 2}} , -OCOR 3, -OCO 2 R 3, -SCOR 3, -SCO 2 R 3, -NHCOR 2, -NHCO 2 R 3, -CH 2 NH aryl, - (CH ₂ ) _p -OR ² , and - (CH ₂ ) _p -SR ² ,
p is an integer 2 or 3,
q is an integer of 1 or 2,
Provided that a) V, Z, W and W 'are not all -H,
b) when Z is -R ² , at least one of V, W and W 'is not -H, alkyl, aralkyl, or alicyclic,
R ² is selected from the group consisting of R ³ and -H,
R &lt; ³ &gt; is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl,
R ⁴ are each independently selected from the group consisting of -H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group,
R ⁶ is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl,
R ⁹ are each independently selected from the group consisting of -H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group,
R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² ₂ , and -OR ² ,
1) when G 'is N, each A, B, D, or E has no substituent,
2) A and B, or at least one of A, B, D and E is not selected from the group consisting of -H or no substituent,
3) when R ⁵ is 6-membered ring, X is a bond of any two atoms of the group, an optionally substituted -alkyl-, an optionally substituted-alkenyl, optionally substituted-alkyl-oxy, or optionally substituted -alkylthio However,
4) when G is N, each A or B is not a group directly bonded to G through a halogen or a heteroatom,
5) R &lt; ¹ &gt; is not unsubstituted C1-C10 alkyl,
6) when X is not an aryl group, R &lt; ⁵ &gt; is not substituted with two or more aryl groups.
[2" claim-type="Currently amended] The compound of claim 1, wherein R ⁵ is selected from the group consisting of pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, pyrazolyl, isoxazolyl, Thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thia Thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, and 1,3-selenazolyl, all of which may be substituted with one or more substituents &Lt; / RTI &gt;
[3" claim-type="Currently amended] The method of claim 1 wherein, A is _{^{-H, -NR 4 2, -CONR 4}} 2, -COR 3, alkyl, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl , C1-C6 haloalkyl, _{aryl, -CH 2 OH, -CH 2 NR} 4 2, -CH 2 CN, -CN, -C (S) NH 2, -OR 4, -SR 4, -N 3, - is selected from the group consisting of _{^{NHC (S) NR 4 2,}} -NHAc, and no substituent,
Each B and D are independently -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, -SO 2 R ^{11, -S (O) R 3} , -CN, -NR 3 2, -OR 3, -SR 3, is selected from alkyl, halo, and the group consisting of perhalo no substituent, an alkyl with -H, -CN, perhaloalkyl , And halo are all optionally substituted,
E is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, C4-C6 alicyclic, ^{alkoxyalkyl, -C (O) OR 3,} -CONR 4 2, -CN, _{^{-NR 9 2, -OR 3, -SR}} 3, is selected from the group consisting of C1-C6 alkyl, halo and perhalo no substituent, except for both the alkyl and halo by -H, -CN, perhaloalkyl may be optionally substituted In addition,
R &lt; ⁴ &gt; are each independently selected from the group consisting of-H, and C1-C2 alkyl.
[4" claim-type="Currently amended] The compound according to claim 1, wherein R &lt; ⁵ &gt; / RTI &gt;
[5" claim-type="Currently amended] The compound according to claim 1, wherein R &lt; ⁵ &gt; / RTI &gt;
[6" claim-type="Currently amended] The compound according to claim 1, wherein R &lt; ⁵ &gt; is selected from the group consisting of the following formulas.


And

In the formula,
A "is -H, -NR ⁴ ₂ , -CONR ⁴ ₂ , -CO ₂ R ³ , halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perhaloalkyl, -CH ₂ OH, -CH ₂ NR ⁴ ₂ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , -NHC S) NR &lt; ⁴ &gt; ₂ and -NHAc,
B '' and D '' are independently -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, - SO ₂ R ¹¹ , -S (O) R ³ , -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , perhaloalkyl, and halo, Alkyl, and halo, is optionally substituted,
E '' is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 alicyclic, ^{alkoxyalkyl, -C (O) OR 3,} -CONR 4 2, -CN, _{^{-NR 9 2, -OR 3, -SR}} 3, is selected from the group consisting of alkyl and halo by C1-C6 perhaloalkyl, halo, and alkyl, all except by -H, -CN, perhaloalkyl, and is optionally substituted,
R &lt; ⁴ &gt; are each independently selected from the group consisting of-H and C1-C2 alkyl.
[7" claim-type="Currently amended] 7. The compound of claim 6 wherein R &lt; ⁵ &gt; is
And
&Lt; / RTI &gt;
[8" claim-type="Currently amended] 7. The compound of claim 6 wherein R &lt; ⁵ &gt; is And
&Lt; / RTI &gt;
[9" claim-type="Currently amended] 7. The compound of claim 6 wherein R &lt; ⁵ &gt; is And
&Lt; / RTI &gt;
[10" claim-type="Currently amended] 2. The compound of claim 1, wherein X is -alkyl (hydroxy), -alkyl, -alkynyl, -aryl, -carbonylalkyl, -Alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -allylic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl -, - carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino- (all optionally substituted).
[11" claim-type="Currently amended] 5. The compound according to claim 4, wherein X is -alkyl (hydroxy), -alkyl, -alkynyl, -aryl, -carbonylalkyl, -1,1- -Alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -allylic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl -, - carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino- (all optionally substituted).
[12" claim-type="Currently amended] 6. The compound according to claim 5, wherein X is -alkyl (hydroxy), -alkyl, -alkynyl, -aryl, -carbonylalkyl, -1,1- -Alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -allylic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl -, - carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino- (all optionally substituted).
[13" claim-type="Currently amended] The compound according to claim 3, wherein X is selected from the group consisting of -heteroaryl-, -alkylcarbonylamino-, -alkylaminocarbonyl-, alkoxycarbonyl-, and -alkoxyalkyl-.
[14" claim-type="Currently amended] 14. The compound of claim 13, wherein X is selected from the group consisting of -heteroaryl-, and -alkoxycarbonyl-.
[15" claim-type="Currently amended] 4. The compound according to claim 3, wherein said compound is a compound of formula (II), (III) or (IV).
&Lt;

(III)

(IV)

[16" claim-type="Currently amended] 7. The compound of claim 6 wherein X is selected from the group consisting of -alkyl (hydroxy), -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -Alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -allylic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl -, - carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino- (all optionally substituted).
[17" claim-type="Currently amended] 17. The compound of claim 16, wherein X is selected from the group consisting of -heteroaryl-, -alkylcarbonylamino-, -alkylaminocarbonyl-, -alkoxycarbonyl-, and -alkoxyalkyl-.
[18" claim-type="Currently amended] 18. The compound of claim 17, wherein said compound is a compound of formula II or IV.
&Lt;

(IV)

[19" claim-type="Currently amended] 18. The method of claim 17, A '' is -NH _2, -CONH _{2, halo, -CH 3, -CF 3, -CH} 2 - consisting of _{halo, -CN, -OCH 3, -SCH 3} , and -H Lt; / RTI &gt;
[20" claim-type="Currently amended] 20. The method of claim 19, A '' is a compound selected from the group consisting of -Cl, -NH _2, -Br, and -CH _3.
[21" claim-type="Currently amended] According to claim 17 wherein, B '' are each ^{-H, -C (O) R 11} , -C (O) SR 3, alkyl, aryl, alicyclic, halo, -CN, -SR ^3, -NR ⁹ ₂ , and -OR &lt; ³ &gt;.
[22" claim-type="Currently amended] 22. Compounds of formula I according to claim 21, wherein B &quot; is selected from the group consisting of-H, -C (O) OR ³ , -C (O) SR ³ , C 1 -C 6 alkyl, alicyclic, halo, heteroaryl and -SR ³ &Lt; / RTI &gt;
[23" claim-type="Currently amended] A compound according to claim 17, wherein D "is selected from the group consisting of -H, -C (O) R ¹¹ , -C (O) SR ³ , alkyl, aryl, alicyclic, halo, -NR ⁹ ₂ and -SR ³ &Lt; / RTI &gt;
[24" claim-type="Currently amended] 24. The method of claim 23 wherein, D '' is ^{-H, -C (O) OR 3} , lower alkyl, alicyclic, and a compound selected from the group consisting of halo.
[25" claim-type="Currently amended] 18. The compound of claim 17 wherein E &quot; is selected from the group consisting of -H, lower alkyl, lower alicyclic, halogen, -CN, -C (O) OR ³ , -SR ³ and -CONR ⁴ ₂ compound.
[26" claim-type="Currently amended] 26. The compound of claim 25, wherein E "is selected from the group consisting of -H, -Br, and -Cl.
[27" claim-type="Currently amended] The compound according to claim 1, wherein the group Y is all -O-.
[28" claim-type="Currently amended] The compound according to claim 4, wherein the group Y is all -O-.
[29" claim-type="Currently amended] 6. The compound according to claim 5, wherein the group Y is all -O-.
[30" claim-type="Currently amended] The compound according to claim 1, wherein one Y group is -NR &lt; ⁶ &gt; - and one Y group is -O-.
[31" claim-type="Currently amended] 5. The compound according to claim 4, wherein one Y group is -NR &lt; ⁶ &gt; - and one Y group is -O-.
[32" claim-type="Currently amended] ^{6. The} compound according to claim 5, wherein one Y group is -NR &lt; ⁶ &gt; - and one Y group is -O-.
[33" claim-type="Currently amended] 2. The compound of claim 1, wherein when Y is -O-, R ¹ bonded to -O- is independently -H, optionally substituted aryl, optionally substituted alicyclic wherein the cyclic moiety is a carbonate or thio carbonate containing from carbonate), optionally _{^{substituted-alkylaryl, -C (R 2) 2 OC}} (O) R 3, -C (R 2) 2 -OC (O) OR 3, -C (R 2 ) ₂ OC (O) SR ³ , -alkyl-SC (O) R ³ , and -alkyl-SS-alkylhydroxy,
When, -NR ⁶ - - Y is a -NR ⁶ R ¹ bonded to independently ^{-H, - [C (R 2} ) 2] q -COOR 3, - [C (R 2) 2] q -C ^{(O) SR 3, -C (} R 4) 2 COOR 3 , and-cycloalkylene selected from -COOR, or ^3, or
When one of Y is independently selected from -O- and -NR ⁶ -, R ¹ and R ¹ together
Lt;
here,
V, W and W 'are independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl Or
V and W are taken together through an additional three carbon atoms to form an optionally substituted cyclic group comprising 6 carbon atoms and said cyclic group is selected from the group consisting of the carbon atoms having 3 atoms from Y bonded to phosphorus Substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy,
Z and W are taken together through an additional 3 to 5 atoms to form a cyclic group optionally containing one heteroatom and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
W and W 'are taken together through an additional two to five atoms to form a cyclic group optionally containing from 0 to 2 heteroatoms, wherein V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl Lt; / RTI &gt;
Z is ^{-CHR 2 OH, -CHR 2 OC (} O) R 3, -CHR 2 OC (S) R 3, -CHR 2 OC (S) OR 3, -CHR 2 OC (O) SR 3, -CHR 2 ^{_{OCO 2 R 3, -OR 2,}} -SR 2, -R 2, -NHCOR 2, -NHCO 2 R 3, - (CH 2) p -OR 2, and - the group consisting of (CH _{²⁾ p} -SR ₂ / RTI &gt;
p is an integer 2 or 3,
q is an integer of 1 or 2,
Provided that a) V, Z, W and W 'are not all -H,
b) when Z is -R ² , at least one of V, W and W 'is not -H, alkyl, aralkyl, or alicyclic,
c) Y is not -NR ⁶ -
R ² is selected from the group consisting of R ³ and -H,
R &lt; ³ &gt; is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl,
R <^6> is selected from the group consisting of -H, and lower alkyl.
[34" claim-type="Currently amended] 34. The method of claim 33, wherein, when the group Y are both -O-, R ¹ is independently an optionally substituted aryl, optionally substituted _{^{benzyl, -C (R 2) 2 OC}} (O) R 3, -C (R 2 ) ₂ OC (O) OR &lt; ³ &gt;, and -H,
When Y is -NR ⁶ -, R ¹ bonded to the -NR ⁶ - group is selected from the group consisting of -C (R ⁴ ) ₂ -COOR ³ , and -C (R ² ) ₂ COOR ³ , and the other Y -O- groups in one time, the R ¹ bonded to the -O- is optionally substituted _{^{aryl, -C (R 2) 2 OC}} (O) R 3 and _{^{-C (R 2) 2 OC (}} O) OR 3 substituted &Lt; / RTI &gt;
[35" claim-type="Currently amended] 35. The compound of claim 34, wherein Y is all-O- and R &lt; ¹ &gt;
[36" claim-type="Currently amended] 18. The compound of claim 17, wherein the group Y is all -O- and R &lt; ¹ &gt; is aryl or -C (R &lt; ² &gt;) ₂ -aryl.
[37" claim-type="Currently amended] The method of claim 17 wherein when both Y groups are -O-, at least one R ¹ is _{^{-C (R 2) 2 -OC (}} O) R 3 and _{^{-C (R 2) 2 -OC (}} O) OR 3 &Lt; / RTI &gt;
[38" claim-type="Currently amended] 18. The compound of claim 17, wherein when the group Y is all -O-, it is preferred that at least one R ¹ is -alkyl-SS-alkylhydroxyl, -alkyl-SC (O) R ³ , Or R ¹ and R ¹ together form a cyclic group as -alkyl-SS-alkyl.
[39" claim-type="Currently amended] The method of claim 17 wherein at least one Y is -O-, R ¹ and R ¹ together are
Lt;
here,
V, W and W 'are independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl Or
V and W are taken together through an additional three carbon atoms to form an optionally substituted cyclic group comprising 6 carbon atoms and said cyclic group is selected from the group consisting of the carbon atoms having 3 atoms from Y bonded to phosphorus Substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy,
Z and W are taken together through an additional 3 to 5 atoms to form a cyclic group optionally containing one heteroatom and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
W and W 'are taken together through an additional two to five atoms to form a cyclic group optionally containing from 0 to 2 heteroatoms, wherein V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl Lt; / RTI &gt;
Z is ^{-CHR 2 OH, -CHR 2 OC (} O) R 3, -CHR 2 OC (S) R 3, -CHR 2 OC (S) OR 3, -CHR 2 OC (O) SR 3, -CHR 2 ^{_{OCO 2 R 3, -OR 2,}} -SR 2, -R 2, -NHCOR 2, -NHCO 2 R 3, - (CH 2) p -OR 2, and - the group consisting of (CH _{²⁾ p} -SR ₂ / RTI &gt;
p is an integer 2 or 3,
Provided that a) V, Z, W and W 'are not all -H,
b) when Z is -R ² , at least one of V, W and W 'is not -H, alkyl, aralkyl, or alicyclic,
c) Y is not -NR ⁶ -
R ² is selected from the group consisting of R ³ and -H,
R &lt; ³ &gt; is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl,
R <^6> is selected from the group consisting of -H, and lower alkyl.
[40" claim-type="Currently amended] 34. The compound of claim 34, wherein when one Y group is -O-, then R ¹ is optionally substituted aryl and when another Y group is -NR ⁶ -, R ¹ bonded to -NR ⁶ - is -C ⁴ ) ₂ COOR ³ and -C (R ² ) ₂ C (O) OR ³ .
[41" claim-type="Currently amended] 41. The method of claim 40 wherein in the R ¹ is phenyl, and _{-NHC (O) CH 3, -F} , -Cl, -Br, -C (O) OCH 2 CH 3, -CH ₃ and bonded to the -O- It is selected from the group consisting of phenyl substituted by 1 or 2 substituents selected from the group consisting of, -NR ⁶ - with R ¹ is bonded to -C (R ^{₂₎ 2} COOR ^3, and each R ² is independently -CH _3, -CH ₂ CH ₃ and a compound selected from the group consisting of -H.
[42" claim-type="Currently amended] The method of claim 41, wherein the compound is the substituent of the substituted phenyl is selected from _{4-NHC (O) CH 3} , -Cl, -Br, 2-C (O) OCH 2 CH 3, and the group consisting of -CH ₃ .
[43" claim-type="Currently amended] The method according to claim 6,
A '' is -NH _2, -CONH _{2, halo, -CH 3, -CF 3, -CH} 2 - is selected from, halo, -CN, -OCH _3, -SCH _3, and the group consisting of -H,
B "is selected from the group consisting of -H, -C (O) R ¹¹ , -C (O) SR ³ , alkyl, aryl, alicyclic, halo, -CN, -SR ³ , -OR ³ and -NR ⁹ ₂ Lt; / RTI &gt;
D '' is selected from the group consisting of ^{-H, -C (O) R 11} , -C (O) SR 3, -NR 9 2, alkyl, aryl, alicyclic, halo, and -SR ^3,
E "is selected from the group consisting of -H, -Ci-C6 alkyl, lower alicyclic, halo, -CN, -C (O) OR ³ and -SR ³ ,
X is selected from the group consisting of -alkyl (hydroxy), -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -Alkylthio-alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -allylic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxy Alkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino- (all optionally substituted)
When both Y groups are -O-, R ¹ is independently an aryl, optionally substituted benzyl, optionally _{^{substituted, -C (R 2) 2 OC}} (O) R 3, -C (R 2) 2 OC (O) OR ³ and-H, or &lt; RTI ID = 0.0 &gt;
When one Y is -O-, R ¹ bonded to -O- is optionally substituted aryl and the other Y is -NR ⁶ - R ¹ bonded to -NR ⁶ - is -C (R ⁴ ) ₂ COOR ³ and -C (R ² ) ₂ C (O) OR ³ , or
When Y is -O- or -NR ⁶ -, R ¹ and R ¹ together
Lt;
here,
V, W and W 'are independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl Or
V and W are taken together through an additional three carbon atoms to form an optionally substituted cyclic group comprising 6 carbon atoms and said cyclic group is selected from the group consisting of the carbon atoms having 3 atoms from Y bonded to phosphorus Substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bound to one,
Z and W are taken together through an additional 3 to 5 atoms to form a cyclic group optionally containing one heteroatom and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
W and W 'are taken together through an additional two to five atoms to form a cyclic group optionally containing from 0 to 2 heteroatoms, wherein V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl Lt; / RTI &gt;
Z is ^{-CHR 2 OH, -CHR 2 OC (} O) R 3, -CHR 2 OC (S) R 3, -CHR 2 OC (S) OR 3, -CHR 2 OC (O) SR 3, -CHR 2 ^{_{OCO 2 R 3, -OR 2,}} -SR 2, -R 2, -NHCOR 2, -NHCO 2 R 3, - (CH 2) p -OR 2, and - the group consisting of (CH _{²⁾ p} -SR ₂ / RTI &gt;
p is an integer 2 or 3,
Provided that a) V, Z, W and W 'are not all -H,
b) when Z is -R ² , at least one of V, W and W 'is not -H, alkyl, aralkyl, or alicyclic,
c) Y is not -NR ⁶ -
R ² is selected from the group consisting of R ³ and -H,
R &lt; ³ &gt; is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl,
R <^6> is selected from the group consisting of -H, and lower alkyl.
[44" claim-type="Currently amended] 7. The compound of claim 6 wherein R &lt; ⁵ &gt; is ego,
X is selected from the group consisting of methylene oxycarbonyl and furan-2,5-diyl,
At least one Y group is -O-, and the pharmaceutically acceptable salts and salts thereof.
[45" claim-type="Currently amended] 44. The compound of claim 44, wherein when Y is -O-, R ¹ bonded to -O- is independently -H, optionally substituted phenyl, -CH ₂ OC (O) -tBu, -CH ₂ OC Et and -CH ₂ OC (O) -iPr,
When Y is -NR ⁶ -, R ¹ bonded to -NR ⁶ - is independently selected from the group consisting of -C (R ² ) ₂ COOR ³ , -C (R ⁴ ) ₂ COOR ³ , or
When Y is -O- or -NR ⁶ - and at least one Y is -O-, R ¹ and R ¹ together
Lt;
here,
V is selected from optionally substituted aryl, and optionally substituted heteroaryl, Z, W 'and W are H,
R &lt; ⁶ &gt; is selected from the group consisting of-H and lower alkyl.
[46" claim-type="Currently amended] 46. The method of claim 45, A '' and is -NH _2, X is a furan-2,5-diyl, B '' is -CH ₂ -CH (CH _{3) 2} A compound.
[47" claim-type="Currently amended] 46. The method of claim 45, A '' and is -NH _2, X is a furan-2,5-diyl, B '' is a compound -COOEt.
[48" claim-type="Currently amended] 46. The method of claim 45, A '' and is -NH _2, X is a furan-2,5-diyl, B '' is a compound -SMe.
[49" claim-type="Currently amended] 47. The method of claim 46, A '' and is -NH _2, X is a methylene-oxy-carbonyl, B '' is -CH (CH _{3) 2} A compound.
[50" claim-type="Currently amended] 47. The compound of claim 46, wherein all the groups Y are -O- and R &lt; ¹ &gt; is -H.
[51" claim-type="Currently amended] 47. The method of claim 46, wherein both Y groups are -O-, R ¹ is -CH ₂ OC (O) OEt compounds.
[52" claim-type="Currently amended] 47. The method of claim 46, wherein both Y groups are -O-, R ¹ and R ¹ together are
Lt;
V is phenyl substituted with one to three halogens.
[53" claim-type="Currently amended] 48. The method of claim 47, wherein both Y groups are -O-, R ¹ and R ¹ together are
Lt;
V is phenyl substituted with one to three halogens.
[54" claim-type="Currently amended] 49. The method of claim 48, wherein both Y groups are -O-, R ¹ and R ¹ together are
Lt;
V is phenyl substituted with one to three halogens.
[55" claim-type="Currently amended] 50. The method of claim 49, wherein both Y groups are -O-, R ¹ and R ¹ together are
Lt;
V is phenyl substituted with one to three halogens.
[56" claim-type="Currently amended] 53. The compound of claim 52, wherein V is selected from the group consisting of 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl, and 3-bromophenyl.
[57" claim-type="Currently amended] The method of claim 46 wherein, Y is -O- and one group, the corresponding R ¹ is that - while the phenyl, and the other Y is -NH-, and corresponding to R ¹ is -CH (Me) CO ₂ Et and _{^{-NH- * CH (Me) CO 2}} Et is L- array of compounds.
[58" claim-type="Currently amended] 7. The compound of claim 6 wherein R &lt; ⁵ &gt; is ego,
X is furan-2,5-diyl and methyleneoxycarbonyl, A "is -NH ₂ , and at least one or more Y groups are -O-, and the pharmaceutically acceptable salts and salts thereof.
[59" claim-type="Currently amended] The method of claim 58, wherein when Y is -O-, R ¹ is independently -H, optionally substituted _{phenyl, -CH 2 OC (O) -tBu} , -CH 2 OC (O) Et and -CH ₂ respectively, OC (O) -iPr, or &lt; RTI ID = 0.0 &gt;
When Y is -NR ⁶ -, R ¹ is each independently selected from the group consisting of -C (R ² ) ₂ C (O) OR ³ and -C (R ⁴ ) ₂ COOR ³ , or
Y is independently selected from -O- and -NR ⁶ - when the chosen from, R ¹ and R ¹ together are
Lt;
V is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl, and Z, W 'and W are H.
[60" claim-type="Currently amended] 60. The method of claim 59, B '' is a -SCH ₂ CH ₂ CH _3, X is furan-2,5-yl.
[61" claim-type="Currently amended] The compound according to claim 60, wherein the group Y is all -O- and R ¹ is -H-.
[62" claim-type="Currently amended] 61. The method of claim 60, one Y group is -O-, and R ¹ is equivalent to - while the phenyl, and the other Y is -NH-, and corresponding to R ¹ is -CH (Me) CO ₂ Et and , -NH ^* CH (Me) CO ₂ Et is L-configuration.
[63" claim-type="Currently amended] 61. The method of claim 60, wherein both Y groups are -O-, R ¹ is -CH ₂ OC (O) OEt compounds.
[64" claim-type="Currently amended] 61. The method of claim 60, wherein both Y groups are -O-, R ¹ and R ¹ together are
ego,
And V is substituted with 1 to 3 halogens.
[65" claim-type="Currently amended] 66. The compound of claim 64, wherein V is selected from the group consisting of 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl, and 3-bromophenyl.
[66" claim-type="Currently amended] 7. The compound of claim 6 wherein R &lt; ⁵ &gt; is ego,
A "is -NH ₂ , E" and D "are -H, B" is n-propyl or cyclopropyl, X is furan-2,5-diyl or methyleneoxycarbonyl, And one Y group is -O-; and pharmaceutically acceptable salts thereof.
[67" claim-type="Currently amended] The method of claim 66 wherein when Y is -O-, R ¹ is independently -H, optionally substituted _{phenyl, -CH 2 OC (O) -tBu} , -CH 2 OC (O) Et and -CH ₂ respectively, OC (O) -iPr, or &lt; RTI ID = 0.0 &gt;
When Y is -NR ⁶ -, R ¹ is each independently selected from the group consisting of -C (R ² ) ₂ C (O) OR ³ and -C (R ⁴ ) ₂ COOR ³ , or
Y is independently selected from -O- and -NR ⁶ - when the chosen from, R ¹ and R ¹ together are
Lt;
V is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl, and Z, W 'and W are H.
[68" claim-type="Currently amended] 7. The compound of claim 6 wherein R &lt; ⁵ &gt; is ego,
A "is -NH ₂ , D" is -H, B "is n-propyl or cyclopropyl, X is furan-2,5-diyl or methyleneoxycarbonyl and at least one Y group is -O- &lt; / RTI &gt; and pharmaceutically acceptable salts thereof.
[69" claim-type="Currently amended] The method of claim 68 wherein when Y is -O-, R ¹ is independently -H, optionally substituted _{phenyl, -CH 2 OC (O) -tBu} , -CH 2 OC (O) Et and -CH ₂ respectively, OC (O) -iPr, or &lt; RTI ID = 0.0 &gt;
When Y is -NH ⁶ -, each R ¹ is independently selected from the group consisting of -C (R ² ) ₂ C (O) OR ³ and -C (R ⁴ ) ₂ COOR ³ , or
When Y is independently selected from -O- and -NR ⁶ -, R ¹ and R ¹ together
Lt;
V is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl, and Z, W 'and W are H.
[70" claim-type="Currently amended] Comprising administering to a mammal suffering from a fructose-1,6-bisphosphatase dependent disease or condition a pharmaceutically effective amount of a compound of formula (I): &lt; EMI ID = A method for treating a 1,6-bisphosphatase dependent disease or disease.
(I)

In this formula,
R ⁵ is And &Lt; / RTI &gt;
G is each independently selected from the group consisting of C, N, O, S and Se, wherein only one G may be O, S or Se,
G 'are each independently selected from the group consisting of C and N, wherein no more than two G' are N,
A is _{^{-H, -NR 4 2, -CONR 4}} 2, -CO 2 R 3, ^{halo, -S (O) R 3,} -SO 2 R 3, alkyl, alkenyl, alkynyl, alkyl, perhaloalkyl, halo Alkyl, aryl, -CH ₂ OH, -CH ₂ NR ⁴ ₂ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , ⁴ ₂ , -NHAc, and a substituent group (null)
B and D are each independently selected from -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, -SO 2 R ^{11, -S (O) R 3} , -CN, -NR 9 2, -OR 3, -SR 3, selected from the group consisting of alkyl, halo, -NO _2, and no substituent perhaloalkyl, and -H, - CN, perhaloalkyl, -NO ₂ , and halo are optionally substituted,
E is -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, -C (O) OR ³ , -CONR ⁴ ₂ , -CN, -NR ⁹ ₂ , -NO ₂ , -OR ³ , -SR ³ , perhaloalkyl, halo and no substituent, and all but -H, -CN, perhaloalkyl and halo are optionally substituted,
J is selected from the group consisting of -H and no substituent,
X binds R &lt; ⁵ &gt; to a phosphorus atom through 2 to 4 atoms, including zero or one heteroatom selected from N, O and S, except when X is urea or carbamate with two heteroatoms Which is measured as the shortest path between R &lt; ⁵ &gt; and the phosphorus atom, where the phosphorus bonded atom is a carbon atom and is not directly bonded to the carbonyl group or to the ring of the heterocycle, And X is not two carbon atom-alkyl, or -alkenyl- groups,
Y is independently selected from the group consisting of -O-, and -NR &lt; ⁶ &gt; -,
When Y is -O-, R ¹ bonded to -O- is independently -H, alkyl, optionally substituted aryl, optionally substituted alicyclic wherein the cyclic moiety is a carbonate or thiocarbonate containing also), optionally substituted with a - _{^{alkylaryl, -C (R 2) 2 OC}} (O) NR 2 2, -NR 2 -C (O) -R 3, -C (R 2) 2 -OC (O ^{) R 3, -C (R 2} ) 2 -OC (O) OR 3, -C (R 2) 2 OC (O) SR 3, - alkyl, -SC (O) R ^3, - alkyl hydroxy alkyl -SS- Gt; is selected from the group consisting &lt; RTI ID = 0.0 &gt; of-
When Y is -NR ⁶ -, R ¹ bonded to -NR ⁶ - is independently -H, - [C (R ² ) ₂ ] _q -COOR ³ , -C (R ⁴ ) ₂ COOR ³ , - [ C (R ² ) ₂ ] _q -C (O) SR and -cycloalkylene-COOR ³ , or
When one of Y is independently selected from -O- and -NR ⁶ -, R ¹ and R ¹ together form an -alkyl-SS-alkyl-cyclic group, or R ¹ and R ¹ together
Lt;
here,
V, W and W 'are independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl Or
V and Z together are joined through an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 atoms optionally containing one heteroatom, Acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy which is bonded to the carbon atom which is three atoms from the group consisting of
V and Z together are joined through an additional three to five atoms to form a cyclic group optionally containing one heteroatom fused to the aryl group at the beta and gamma positions for Y bonded to the phosphorus,
V and W are taken together through an additional three carbon atoms to form an optionally substituted cyclic group comprising 6 carbon atoms and said cyclic group is selected from the group consisting of the carbon atoms having 3 atoms from Y bonded to phosphorus Substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bound to one,
Z and W are taken together through an additional 3 to 5 atoms to form a cyclic group optionally containing one heteroatom and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
W and W 'are taken together through an additional two to five atoms to form a cyclic group optionally containing from 0 to 2 heteroatoms, wherein V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl Lt; / RTI &gt;
Z is ^{-CHR 2 OH, -CHR 2 OC (} O) R 3, -CHR 2 OC (S) R 3, -CHR 2 OC (S) OR 3, -CHR 2 OC (O) SR 3, -CHR 2 (CH = CR ² ₂ ) OH, -CH (C≡CR ² ) OH, -CH (O) ₂ R ³ , -OR ² , -SR ² , -CHR ² N ₃ , -CH ₂ aryl, _{^{OH, -R 2, -NR 2 2}} , -OCOR 3, -OCO 2 R 3, -SCOR 3, -SCO 2 R 3, -NHCOR 2, -NHCO 2 R 3, -CH 2 NH aryl, - (CH ₂ ) _p -OR ² , and - (CH ₂ ) _p -SR ² ,
p is an integer 2 or 3,
q is an integer of 1 or 2,
Provided that a) V, Z, W and W 'are not all -H,
b) when Z is -R ² , at least one of V, W and W 'is not -H, alkyl, aralkyl, or alicyclic,
R ² is selected from the group consisting of R ³ and -H,
R &lt; ³ &gt; is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl,
R ⁴ are each independently selected from the group consisting of -H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group,
R ⁶ is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl,
R ⁹ are each independently selected from the group consisting of -H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group,
R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² ₂ , and -OR ² ,
1) when G 'is N, each A, B, D, or E has no substituent,
2) A and B, or at least one of A, B, D and E is not selected from the group consisting of -H or no substituent,
3) when R ⁵ is 6-membered ring, X is a bond of any two atoms of the group, an optionally substituted -alkyl-, an optionally substituted-alkenyl, optionally substituted-alkyl-oxy, or optionally substituted -alkylthio However,
4) when G is N, each A or B is not a group directly bonded to G through a halogen or a heteroatom,
5) R &lt; ¹ &gt; is not unsubstituted C1-C10 alkyl,
6) when X is not an aryl group, R &lt; ⁵ &gt; is not substituted with two or more aryl groups.
[71" claim-type="Currently amended] The method of claim 70 wherein, R ⁵ is pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, pyrazolyl, isoxazolyl, 1,2,3-oxazole Thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thia 1,2,3-triazolyl, 1,2,3,4-tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3, Triazinyl, 1,2,4-triazinyl, and 1,3-selenazolyl, all of which contain one or more substituents.
[72" claim-type="Currently amended] The method of claim 70, wherein R ⁵ is selected from the group consisting of the following formula.





In the formula,
A '' is _{^{-H, -NR 4 2, -CONR 4}} 2, -CO 2 R 3, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl alkyl, C1 -CH ₂ OH, -CH ₂ NR ⁴ ₂ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , -NHC S) NR &lt; ⁴ &gt; ₂ and -NHAc,
B '' and D '' are each independently -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, -SO ₂ R ¹¹ , -S (O) R ³ , -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , perhaloalkyl and halo and is selected from the group consisting of -H, -CN, Alkyl, and halo, is optionally substituted,
E '' is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, C4-C6 alicyclic, ^{alkoxyalkyl, -C (O) OR 3,} -CONR 4 2, - CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , C 1 -C 6 perhaloalkyl and halo, all but -H, -CN, perhaloalkyl and halo may be optionally substituted ,
C "is selected from the group consisting of -H, alkyl, alkylalkenyl, alkylalkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, and alkoxyalkyl,
R &lt; ⁴ &gt; are each independently selected from the group consisting of-H, and C1-C2 alkyl,
R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² .
[73" claim-type="Currently amended] The method of claim 70, wherein the one to R ⁵ is selected from the group consisting of formulas.


And
In the formula,
A '' is _{^{-H, -NR 4 2, -CONR 4}} 2, -CO 2 R 3, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl alkyl, C1 -CH ₂ OH, -CH ₂ NR ⁴ ₂ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , -NHC S) NR &lt; ⁴ &gt; ₂ and -NHAc,
B '' and D '' are each independently -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, -SO ₂ R ¹¹ , -S (O) R ³ , -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , perhaloalkyl and halo and is selected from the group consisting of -H, -CN, Alkyl, and halo, is optionally substituted,
E '' is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 alicyclic, ^{alkoxyalkyl, -C (O) OR 3,} -CONR 4 2, -CN, _{^{-NR 9 2, -OR 3, -SR}} 3, is selected from the group consisting of alkyl and halo by C1-C6 perhaloalkyl, halo, and alkyl, all except by -H, -CN, perhaloalkyl, and is optionally substituted,
R &lt; ⁴ &gt; are each independently selected from the group consisting of-H and C1-C2 alkyl.
[74" claim-type="Currently amended] Wherein X is selected from the group consisting of -alkyl (hydroxy) -, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -Alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -allylic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl -Alkylcarbonyloxy-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, -alkylaminocarbonylamino-, -alkylamino-, and -alkenyl- (all optionally substituted).
[75" claim-type="Currently amended] 74. The method of claim 74, wherein X is selected from the group consisting of -heteroaryl-, -alkylcarbonylamino-, -alkylaminocarbonyl-, -alkoxycarbonyl-, and -alkoxyalkyl-.
[76" claim-type="Currently amended] 78. The compound of claim 75, wherein R &lt; ⁵ &gt; is Lt;
X is selected from the group consisting of methyleneoxycarbonyl, or furan-2,5-diyl, and at least one Y is -O-.
[77" claim-type="Currently amended] 78. The compound of claim 75, wherein R &lt; ⁵ &gt; is Lt;
Wherein X is furan-2,5-diyl or methyleneoxycarbonyl, A "is -NH ₂ - and at least one Y group is -O-.
[78" claim-type="Currently amended] 78. The compound of claim 75, wherein R &lt; ⁵ &gt; is Lt;
A "is -NH ₂ , E" and D "are -H, B" is n-propyl or cyclopropyl, X is furan-2,5-diyl or methyleneoxycarbonyl, And one Y group is -O-.
[79" claim-type="Currently amended] 78. The compound of claim 75, wherein R &lt; ⁵ &gt; is Lt;
A "is -NH ₂ , D" is -H, B "is n-propyl or cyclopropyl, X is furan-2,5-diyl or methyleneoxycarbonyl, and at least one Y group is -O-.
[80" claim-type="Currently amended] A method of treating diabetes by administering to a patient in need thereof a pharmaceutically effective amount of an FBPase inhibitor of Formula I and a pharmaceutically acceptable salt thereof.
(I)

In this formula,
R ⁵ is And &Lt; / RTI &gt;
G is each independently selected from the group consisting of C, N, O, S and Se, wherein only one G may be O, S or Se,
G 'are each independently selected from the group consisting of C and N, wherein no more than two G' are N,
A is _{^{-H, -NR 4 2, -CONR 4}} 2, -CO 2 R 3, ^{halo, -S (O) R 3,} -SO 2 R 3, alkyl, alkenyl, alkynyl, alkyl, perhaloalkyl, halo Alkyl, aryl, -CH ₂ OH, -CH ₂ NR ⁴ ₂ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , ⁴ ₂ , -NHAc, and a substituent group (null)
B and D are each independently selected from -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, -SO 2 R ^{11, -S (O) R 3} , -CN, -NR 9 2, -OR 3, -SR 3, selected from the group consisting of alkyl, halo, -NO _2, and no substituent perhaloalkyl, and -H, - CN, perhaloalkyl, -NO ₂ , and halo are optionally substituted,
E is -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, -C (O) OR ³ , -CONR ⁴ ₂ , -CN, -NR ⁹ ₂ , -NO ₂ , -OR ³ , -SR ³ , perhaloalkyl, halo and no substituent, and all but -H, -CN, perhaloalkyl and halo are optionally substituted,
J is selected from the group consisting of -H and no substituent,
X binds R &lt; ⁵ &gt; to a phosphorus atom through 2 to 4 atoms, including zero or one heteroatom selected from N, O and S, except when X is urea or carbamate with two heteroatoms Which is measured as the shortest path between R &lt; ⁵ &gt; and the phosphorus atom, where the phosphorus bonded atom is a carbon atom and is not directly bonded to the carbonyl group or to the ring of the heterocycle, And X is not two carbon atom-alkyl, or -alkenyl- groups,
Y is independently selected from the group consisting of -O-, and -NR &lt; ⁶ &gt; -,
When Y is -O-, R ¹ bonded to -O- is independently -H, alkyl, optionally substituted aryl, optionally substituted alicyclic wherein the cyclic moiety is a carbonate or thiocarbonate containing also), optionally substituted with a - _{^{alkylaryl, -C (R 2) 2 OC}} (O) NR 2 2, -NR 2 -C (O) -R 3, -C (R 2) 2 -OC (O ^{) R 3, -C (R 2} ) 2 -OC (O) OR 3, -C (R 2) 2 OC (O) SR 3, - alkyl, -SC (O) R ^3, - alkyl hydroxy alkyl -SS- Gt; is selected from the group consisting &lt; RTI ID = 0.0 &gt; of-
When Y is -NR ⁶ -, R ¹ bonded to -NR ⁶ - is independently -H, - [C (R ² ) ₂ ] _q -COOR ³ , -C (R ⁴ ) ₂ COOR ³ , - [ C (R ² ) ₂ ] _q -C (O) SR and -cycloalkylene-COOR ³ , or
When one of Y is independently selected from -O- and -NR ⁶ -, R ¹ and R ¹ together form an -alkyl-SS-alkyl-cyclic group, or R ¹ and R ¹ together
Lt;
here,
V, W and W 'are independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl Or
V and Z together are joined through an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 atoms optionally containing one heteroatom, Acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy which is bonded to the carbon atom which is three atoms from the group consisting of
V and Z together are joined through an additional three to five atoms to form a cyclic group optionally containing one heteroatom fused to the aryl group at the beta and gamma positions for Y bonded to the phosphorus,
V and W are taken together through an additional three carbon atoms to form an optionally substituted cyclic group comprising 6 carbon atoms and said cyclic group is selected from the group consisting of the carbon atoms having 3 atoms from Y bonded to phosphorus Substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bound to one,
Z and W are taken together through an additional 3 to 5 atoms to form a cyclic group optionally containing one heteroatom and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
W and W 'are taken together through an additional two to five atoms to form a cyclic group optionally containing from 0 to 2 heteroatoms, wherein V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl Lt; / RTI &gt;
Z is ^{-CHR 2 OH, -CHR 2 OC (} O) R 3, -CHR 2 OC (S) R 3, -CHR 2 OC (S) OR 3, -CHR 2 OC (O) SR 3, -CHR 2 (CH = CR ² ₂ ) OH, -CH (C≡CR ² ) OH, -CH (O) ₂ R ³ , -OR ² , -SR ² , -CHR ² N ₃ , -CH ₂ aryl, _{^{OH, -R 2, -NR 2 2}} , -OCOR 3, -OCO 2 R 3, -SCOR 3, -SCO 2 R 3, -NHCOR 2, -NHCO 2 R 3, -CH 2 NH aryl, - (CH ₂ ) _p -OR ² , and - (CH ₂ ) _p -SR ² ,
p is an integer 2 or 3,
q is an integer of 1 or 2,
Provided that a) V, Z, W and W 'are not all -H,
b) when Z is -R ² , at least one of V, W and W 'is not -H, alkyl, aralkyl, or alicyclic,
R ² is selected from the group consisting of R ³ and -H,
R &lt; ³ &gt; is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl,
R ⁴ are each independently selected from the group consisting of -H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group,
R ⁶ is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl,
R ⁹ are each independently selected from the group consisting of -H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group,
R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² ₂ , and -OR ² ,
1) when G 'is N, each A, B, D, or E has no substituent,
2) A and B, or at least one of A, B, D and E is not selected from the group consisting of -H or no substituent,
3) when R ⁵ is 6-membered ring, X is a bond of any two atoms of the group, an optionally substituted -alkyl-, an optionally substituted-alkenyl, optionally substituted-alkyl-oxy, or optionally substituted -alkylthio However,
4) when G is N, each A or B is not a group directly bonded to G through a halogen or a heteroatom,
5) R &lt; ¹ &gt; is not unsubstituted C1-C10 alkyl,
6) when X is not an aryl group, R &lt; ⁵ &gt; is not substituted with two or more aryl groups.
[81" claim-type="Currently amended] Wherein R &lt; ⁵ &gt; is pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, pyrazolyl, isoxazolyl, Thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thia 1,2,3-triazolyl, 1,2,3,4-tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3, Triazinyl, 1,2,4-triazinyl, and 1,3-selenazolyl, all of which contain one or more substituents.
[82" claim-type="Currently amended] The method of claim 80, wherein the one to R ⁵ is selected from the group consisting of formulas.





In the formula,
A '' is _{^{-H, -NR 4 2, -CONR 4}} 2, -CO 2 R 3, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl alkyl, C1 -CH ₂ OH, -CH ₂ NR ⁴ ₂ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , -NHC S) NR &lt; ⁴ &gt; ₂ and -NHAc,
B '' and D '' are each independently -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, -SO ₂ R ¹¹ , -S (O) R ³ , -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , perhaloalkyl and halo and is selected from the group consisting of -H, -CN, Alkyl, and halo, is optionally substituted,
E '' is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, C4-C6 alicyclic, ^{alkoxyalkyl, -C (O) OR 3,} -CONR 4 2, - CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , C 1 -C 6 perhaloalkyl and halo, all but -H, -CN, perhaloalkyl and halo may be optionally substituted ,
C "is selected from the group consisting of -H, alkyl, alkylalkenyl, alkylalkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, and alkoxyalkyl,
R &lt; ⁴ &gt; are each independently selected from the group consisting of-H, and C1-C2 alkyl,
R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² .
[83" claim-type="Currently amended] The method of claim 80, wherein the one to R ⁵ is selected from the group consisting of formulas.


And
In the formula,
A '' is _{^{-H, -NR 4 2, -CONR 4}} 2, -CO 2 R 3, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl alkyl, C1 -CH ₂ OH, -CH ₂ NR ⁴ ₂ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , -NHC S) NR &lt; ⁴ &gt; ₂ and -NHAc,
B '' and D '' are each independently -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, -SO ₂ R ¹¹ , -S (O) R ³ , -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , perhaloalkyl and halo and is selected from the group consisting of -H, -CN, Alkyl, and halo, is optionally substituted,
E '' is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 alicyclic, ^{alkoxyalkyl, -C (O) OR 3,} -CONR 4 2, -CN, _{^{-NR 9 2, -OR 3, -SR}} 3, is selected from the group consisting of alkyl and halo by C1-C6 perhaloalkyl, halo, and alkyl, all except by -H, -CN, perhaloalkyl, and is optionally substituted,
R &lt; ⁴ &gt; are each independently selected from the group consisting of-H and C1-C2 alkyl.
[84" claim-type="Currently amended] The method according to claim 83 wherein, R ⁵ -alkyl (hydroxy) -, - alkyl -, - alkynyl -, - aryl -, - carbonyl alkyl-, a 1,1-dihalo-alkyl -, - alkoxyalkyl - -Alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -allylic-, -aralkyl-, -alkylaryl-, -alkoxycar (All optionally substituted), which is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, alkoxy, alkoxy, alkoxy, / RTI &gt;
[85" claim-type="Currently amended] 84. The method of claim 84, wherein X is selected from the group consisting of -heteroaryl-, -alkylcarbonylamino-, -alkylaminocarbonyl-, -alkoxycarbonyl-, and -alkoxyalkyl-.
[86" claim-type="Currently amended] 86. The compound of claim 85, wherein R &lt; ⁵ &gt; is Lt;
X is selected from the group consisting of methyleneoxycarbonyl or furan-2,5-diyl, and at least one Y is -O-.
[87" claim-type="Currently amended] 86. The compound of claim 85, wherein R &lt; ⁵ &gt; is Lt;
Wherein X is furan-2,5-diyl or methyleneoxycarbonyl, A "is -NH ₂ - and at least one Y group is -O-.
[88" claim-type="Currently amended] 86. The compound of claim 85, wherein R &lt; ⁵ &gt; is Lt;
A "is -NH ₂ , E" and D "are -H, B" is n-propyl or cyclopropyl, X is furan-2,5-diyl or methyleneoxycarbonyl, And one Y group is -O-.
[89" claim-type="Currently amended] 86. The compound of claim 85, wherein R &lt; ⁵ &gt; is Lt;
A "is -NH ₂ , D" is -H, B "is n-propyl or cyclopropyl, X is furan-2,5-diyl or methyleneoxycarbonyl, and at least one Y group is -O-.
[90" claim-type="Currently amended] 86. The method of claim 85, wherein the patient is type I diabetes.
[91" claim-type="Currently amended] 86. The method of claim 85, wherein said patient is Type II diabetes.
[92" claim-type="Currently amended] A method of treating a glycogen accumulating disease by administering a pharmaceutically effective amount of an FBPase inhibitor of Formula I and a pharmaceutically acceptable salt thereof and a salt thereof to a patient in need thereof.
(I)

In this formula,
R ⁵ is And &Lt; / RTI &gt;
G is each independently selected from the group consisting of C, N, O, S and Se, wherein only one G may be O, S or Se,
G 'are each independently selected from the group consisting of C and N, wherein no more than two G' are N,
A is _{^{-H, -NR 4 2, -CONR 4}} 2, -CO 2 R 3, ^{halo, -S (O) R 3,} -SO 2 R 3, alkyl, alkenyl, alkynyl, alkyl, perhaloalkyl, halo Alkyl, aryl, -CH ₂ OH, -CH ₂ NR ⁴ ₂ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , ⁴ ₂ , -NHAc, and a substituent group (null)
B and D are each independently selected from -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, -SO 2 R ^{11, -S (O) R 3} , -CN, -NR 9 2, -OR 3, -SR 3, selected from the group consisting of alkyl, halo, -NO _2, and no substituent perhaloalkyl, and -H, - CN, perhaloalkyl, -NO ₂ , and halo are optionally substituted,
E is -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, -C (O) OR ³ , -CONR ⁴ ₂ , -CN, -NR ⁹ ₂ , -NO ₂ , -OR ³ , -SR ³ , perhaloalkyl, halo and no substituent, and all but -H, -CN, perhaloalkyl and halo are optionally substituted,
J is selected from the group consisting of -H and no substituent,
X binds R &lt; ⁵ &gt; to a phosphorus atom through 2 to 4 atoms, including zero or one heteroatom selected from N, O and S, except when X is urea or carbamate with two heteroatoms Which is measured as the shortest path between R &lt; ⁵ &gt; and the phosphorus atom, where the phosphorus bonded atom is a carbon atom and is not directly bonded to the carbonyl group or to the ring of the heterocycle, And X is not two carbon atom-alkyl, or -alkenyl- groups,
Y is independently selected from the group consisting of -O-, and -NR &lt; ⁶ &gt; -,
When Y is -O-, R ¹ bonded to -O- is independently -H, alkyl, optionally substituted aryl, optionally substituted alicyclic wherein the cyclic moiety is a carbonate or thiocarbonate containing also), optionally substituted with a - _{^{alkylaryl, -C (R 2) 2 OC}} (O) NR 2 2, -NR 2 -C (O) -R 3, -C (R 2) 2 -OC (O ^{) R 3, -C (R 2} ) 2 -OC (O) OR 3, -C (R 2) 2 OC (O) SR 3, - alkyl, -SC (O) R ^3, - alkyl hydroxy alkyl -SS- Gt; is selected from the group consisting &lt; RTI ID = 0.0 &gt; of-
When Y is -NR ⁶ -, R ¹ bonded to -NR ⁶ - is independently -H, - [C (R ² ) ₂ ] _q -COOR ³ , -C (R ⁴ ) ₂ COOR ³ , - [ C (R ² ) ₂ ] _q -C (O) SR and -cycloalkylene-COOR ³ , or
When one of Y is independently selected from -O- and -NR ⁶ -, R ¹ and R ¹ together form an -alkyl-SS-alkyl-cyclic group, or R ¹ and R ¹ together
Lt;
here,
V, W and W 'are independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl Or
V and Z together are joined through an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 atoms optionally containing one heteroatom, Acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy which is bonded to the carbon atom which is three atoms from the group consisting of
V and Z together are joined through an additional three to five atoms to form a cyclic group optionally containing one heteroatom fused to the aryl group at the beta and gamma positions for Y bonded to the phosphorus,
V and W are taken together through an additional three carbon atoms to form an optionally substituted cyclic group comprising 6 carbon atoms and said cyclic group is selected from the group consisting of the carbon atoms having 3 atoms from Y bonded to phosphorus Substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bound to one,
Z and W are taken together through an additional 3 to 5 atoms to form a cyclic group optionally containing one heteroatom and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
W and W 'are taken together through an additional two to five atoms to form a cyclic group optionally containing from 0 to 2 heteroatoms, wherein V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl Lt; / RTI &gt;
Z is ^{-CHR 2 OH, -CHR 2 OC (} O) R 3, -CHR 2 OC (S) R 3, -CHR 2 OC (S) OR 3, -CHR 2 OC (O) SR 3, -CHR 2 (CH = CR ² ₂ ) OH, -CH (C≡CR ² ) OH, -CH (O) ₂ R ³ , -OR ² , -SR ² , -CHR ² N ₃ , -CH ₂ aryl, _{^{OH, -R 2, -NR 2 2}} , -OCOR 3, -OCO 2 R 3, -SCOR 3, -SCO 2 R 3, -NHCOR 2, -NHCO 2 R 3, -CH 2 NH aryl, - (CH ₂ ) _p -OR ² , and - (CH ₂ ) _p -SR ² ,
p is an integer 2 or 3,
q is an integer of 1 or 2,
A) V, Z, W, W 'are not all -H,
b) when Z is -R ² , at least one of V, W and W 'is not -H, alkyl, aralkyl, or alicyclic,
R ² is selected from the group consisting of R ³ and -H,
R &lt; ³ &gt; is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl,
R ⁴ are each independently selected from the group consisting of -H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group,
R ⁶ is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl,
R ⁹ are each independently selected from the group consisting of -H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group,
R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² ₂ , and -OR ² ,
1) when G 'is N, each A, B, D, or E has no substituent,
2) A and B, or at least one of A, B, D and E is not selected from the group consisting of -H or no substituent,
3) when R ⁵ is 6-membered ring, X is a bond of any two atoms of the group, an optionally substituted -alkyl-, an optionally substituted-alkenyl, optionally substituted-alkyl-oxy, or optionally substituted -alkylthio However,
4) when G is N, each A or B is not a group directly bonded to G through a halogen or a heteroatom,
5) R &lt; ¹ &gt; is not unsubstituted C1-C10 alkyl,
6) when X is not an aryl group, R &lt; ⁵ &gt; is not substituted with two or more aryl groups.
[93" claim-type="Currently amended] The method of claim 92 wherein, R ⁵ is pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, pyrazolyl, isoxazolyl, 1,2,3-oxazole Thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thia 1,2,3-triazolyl, 1,2,3,4-tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3, Triazinyl, 1,2,4-triazinyl, and 1,3-selenazolyl, all of which contain one or more substituents.
[94" claim-type="Currently amended] The method of claim 92, wherein the one to R ⁵ is selected from the group consisting of formulas.



And

In the formula,
A '' is _{^{-H, -NR 4 2, -CONR 4}} 2, -CO 2 R 3, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl alkyl, C1 -CH ₂ OH, -CH ₂ NR ⁴ ₂ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , -NHC S) NR &lt; ⁴ &gt; ₂ and -NHAc,
B '' and D '' are each independently -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, -SO ₂ R ¹¹ , -S (O) R ³ , -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , perhaloalkyl and halo and is selected from the group consisting of -H, -CN, Alkyl, and halo, is optionally substituted,
E '' is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, C4-C6 alicyclic, ^{alkoxyalkyl, -C (O) OR 3,} -CONR 4 2, - CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , C 1 -C 6 perhaloalkyl and halo, all but -H, -CN, perhaloalkyl and halo may be optionally substituted ,
C "is selected from the group consisting of -H, alkyl, alkylalkenyl, alkylalkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, and alkoxyalkyl,
R &lt; ⁴ &gt; are each independently selected from the group consisting of-H, and C1-C2 alkyl,
R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² _2, and -OR ² .
[95" claim-type="Currently amended] The method of claim 92, wherein the one to R ⁵ is selected from the group consisting of formulas.


And
In the formula,
A '' is _{^{-H, -NR 4 2, -CONR 4}} 2, -CO 2 R 3, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl alkyl, C1 -CH ₂ OH, -CH ₂ NR ⁴ ₂ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , -NHC S) NR &lt; ⁴ &gt; ₂ and -NHAc,
B '' and D '' are each independently -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, ^{alkoxyalkyl, -C (O) R 11,} -C (O) SR 3, -SO ₂ R ¹¹ , -S (O) R ³ , -CN, -NR ⁹ ₂ , -OR ³ , -SR ³ , perhaloalkyl and halo and is selected from the group consisting of -H, -CN, Alkyl, and halo, is optionally substituted,
E '' is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 alicyclic, ^{alkoxyalkyl, -C (O) OR 3,} -CONR 4 2, -CN, _{^{-NR 9 2, -OR 3, -SR}} 3, is selected from the group consisting of alkyl and halo by C1-C6 perhaloalkyl, halo, and alkyl, all except by -H, -CN, perhaloalkyl, and is optionally substituted,
R &lt; ⁴ &gt; are each independently selected from the group consisting of-H and C1-C2 alkyl.
[96" claim-type="Currently amended] The method of claim 95, wherein X is selected from the group consisting of -alkyl (hydroxy), -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -Alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -allylic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl -Alkylcarbonyloxy-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, -alkylaminocarbonylamino-, -alkylamino-, and -alkenyl- (all optionally substituted). .
[97" claim-type="Currently amended] The method of claim 96, wherein X is selected from the group consisting of -heteroaryl-, -alkylcarbonylamino-, -alkylaminocarbonyl-, -alkoxycarbonyl-, and -alkoxyalkyl-.
[98" claim-type="Currently amended] 98. The compound of claim 97, wherein R &lt; ⁵ &gt; is Lt;
X is selected from the group consisting of methyleneoxycarbonyl or furan-2,5-diyl, and at least one Y is -O-.
[99" claim-type="Currently amended] 98. The compound of claim 97, wherein R &lt; ⁵ &gt; is Lt;
Wherein X is furan-2,5-diyl or methyleneoxycarbonyl, A "is -NH ₂ - and at least one Y group is -O-.
[100" claim-type="Currently amended] 98. The compound of claim 97, wherein R &lt; ⁵ &gt; is Lt;
A "is -NH ₂ , E" and D "are -H, B" is n-propyl or cyclopropyl, X is furan-2,5-diyl or methyleneoxycarbonyl, And one Y group is -O-.
[101" claim-type="Currently amended] 98. The compound of claim 97, wherein R &lt; ⁵ &gt; is Lt;
A "is -NH ₂ , D" is -H, B "is n-propyl or cyclopropyl, X is furan-2,5-diyl or methyleneoxycarbonyl, and at least one Y group is -O-.
[102" claim-type="Currently amended] 69. The method of claim 70, wherein the disease and condition is selected from the group consisting of atherosclerosis, hyperinsulinemia, hypercholesterolemia, and hyperlipidemia.
[103" claim-type="Currently amended] 70. The method of claim 70, wherein the FBPase inhibitor is administered to prevent myocardial ischemic damage.
[104" claim-type="Currently amended] Compounds of formula (X): &lt; EMI ID = 32.1 &gt;
(X)

In this formula,
G "is selected from the group consisting of -O- and -S-,
A ^2, L ^2, E ² and J ² is _{^{-NR 4 2, -NO 2, -H}} , -OR 2, -SR 2, -C (O) NR 4 2, halo, -COR ^11, -SO ₂ R ^3, guanidyl pyridinyl, amidinyl, aryl, aralkyl, ^{_{alkyloxy-alkyl, -SCN, -NHSO 2 R 9,}} -SO 2 NR 4 2, -CN, -S (O) R 3, acyl perhalo to, alkyl, perhaloalkyl perhalo alkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower or selected from the Ali when the group consisting of clicks, or L ² and E ² or E ² and J ² Together form a cyclic cyclic group,
X ² is an optionally substituted bonding group through which R ⁵ is bonded to the phosphorus atom through 1 to 3 atoms comprising 0 or 1 heteroatom selected from N, O and S, wherein the atom bonded to the phosphorus is a carbon atom However,
However, X ² is not substituted with -COOR ^2, -SO ₃ R ¹ or PO ₃ R ¹ _2,
Y is independently selected from the group consisting of -O-, and -NR &lt; ⁶ &gt; -,
When Y is -O, R ¹ bonded to -O- is independently -H, alkyl, optionally substituted aryl, optionally substituted alicyclic wherein the cyclic moiety comprises a carbonate or thiocarbonate hereinafter), optionally _{^{substituted-alkylaryl, -C (R 2) 2 OC}} (O) NR 2 2, -NR 2 -C (O) -R 3, -C (R 2) 2 -OC (O) R _{^{3, -C (R 2) 2}} -OC (O) OR 3, -C (R 2) 2 OC (O) SR 3, - alkyl, -SC (O) R ^3, - alkyl -SS- alkyl hydroxy, And-alkyl-SSS-alkylhydroxy,
When Y is -NR ⁶ -, R ¹ bonded to -NR ⁶ - is independently -H, - [C (R ² ) ₂ ] _q -COOR ³ , -C (R ⁴ ) ₂ COOR ³ , - [ C (R ² ) ₂ ] _q -C (O) SR and -cycloalkylene-COOR ³ , or
When one of Y is independently selected from -O- and -NR ⁶ -, R ¹ and R ¹ together form an -alkyl-SS-alkyl-cyclic group, or R ¹ and R ¹ together
Lt;
V, W and W 'are independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl Or
V and Z together are joined through an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 atoms optionally containing one heteroatom, Acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy bonded to a carbon atom having three atoms from the formula
V and Z together are joined through an additional three to five atoms to form a cyclic group optionally containing one heteroatom fused to the aryl group at the beta and gamma positions for Y bonded to the phosphorus,
V and W are taken together through an additional three carbon atoms to form an optionally substituted cyclic group comprising 6 carbon atoms and said cyclic group is selected from the group consisting of the carbon atoms having 3 atoms from Y bonded to phosphorus Substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bound to one,
Z and W are taken together through an additional 3 to 5 atoms to form a cyclic group optionally containing one heteroatom and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
W and W 'are taken together through an additional two to five atoms to form a cyclic group optionally containing from 0 to 2 heteroatoms, wherein V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl Lt; / RTI &gt;
Z is ^{-CHR 2 OH, -CHR 2 OC (} O) R 3, -CHR 2 OC (S) R 3, -CHR 2 OC (S) OR 3, -CHR 2 OC (O) SR 3, -CHR 2 (CH = CR ² ₂ ) OH, -CH (C≡CR ² ) OH, -CH (O) ₂ R ³ , -OR ² , -SR ² , -CHR ² N ₃ , -CH ₂ aryl, _{^{OH, -R 2, -NR 2 2}} , -OCOR 3, -OCO 2 R 3, -SCOR 3, -SCO 2 R 3, -NHCOR 2, -NHCO 2 R 3, -CH 2 NH aryl, - (CH ₂ ) _p -OR ² , and - (CH ₂ ) _p -SR ² ,
p is an integer 2 or 3,
q is an integer of 1 or 2,
A) V, Z, W, W 'are not all -H,
b) when Z is -R ² , at least one of V, W and W 'is not -H, alkyl, aralkyl, or alicyclic
R ² is selected from the group consisting of R ³ and -H,
R &lt; ³ &gt; is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl,
R ⁴ are each independently selected from the group consisting of -H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group,
R ⁶ is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl,
R ⁹ are each independently selected from the group consisting of -H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group,
R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² ₂ , and -OR ² .
[105" claim-type="Currently amended] RTI ID = 0.0 &gt; 104 &lt; / RTI &gt;
[106" claim-type="Currently amended] Wherein A ² , L ² , E ² and J ² are independently selected from the group consisting of -H, -NR ⁴ ₂ , -SC≡N, halogen, -OR ³ , hydroxy, Alkylcarbonyl, alkyloxycarbonyl, -SR ³ , lower perhaloalkyl, and C 1 -C 5 alkyl, or L ² and E ² together form a cyclic cyclic group.
[107" claim-type="Currently amended] 106. The method of claim 106, wherein A ² , L ² , E ² and J ² are independently selected from the group consisting of -H, -NR ⁴ ₂ , -SC≡N, halogen, lower alkoxy, hydroxy, lower alkyl (hydroxy) And C1-C5 alkyl, or L &lt; ² &gt; and E &lt; ² &gt; together form a cyclic cyclic group.
[108" claim-type="Currently amended] The method of claim 107, wherein, A ² is -NH _2, -H, halo and C1-C5 alkyl.
[109" claim-type="Currently amended] Wherein L ² and E ² are independently selected from the group consisting of -H, -SC≡N, lower alkoxy, C 1 -C 5 alkyl, lower alkyl (hydroxy), lower aryl and halogen, or L ² and E ² is the compound to form a cyclic cyclic containing an additional 4 carbon atoms together.
[110" claim-type="Currently amended] The method of claim 109, wherein, J ² is a compound selected from the group consisting of -H and C1-C5 alkyl.
[111" claim-type="Currently amended] Wherein X ² is selected from the group consisting of -alkyl, -alkenyl, -alkynyl, -alkylene-NR ⁴ , -alkylene-O-, alkylene-S-, -C (O) -Alkylene-C (O) -. &Lt; / RTI &gt;
[112" claim-type="Currently amended] The method of claim 111, wherein, X ² is-compound is selected from the group consisting of-alkylene -O-, - alkylene -S-, and - alkyl.
[113" claim-type="Currently amended] 112. The compound of claim 112, wherein X &lt; ² &gt; is -methyleneoxy-.
[114" claim-type="Currently amended] 105. The compound of claim 104, wherein the group Y is all-O-.
[115" claim-type="Currently amended] The compound according to claim 104, wherein one Y group is -NR ⁶ - and one Y group is -O-.
[116" claim-type="Currently amended] The method of claim 104, wherein when Y is -O-, with the R ¹ bonded to the -O- independently, -H, an optionally substituted aryl, optionally substituted alicyclic (where cyclic moieties carbonate or thio carbonate containing from carbonate), optionally _{^{substituted-alkylaryl, -C (R 2) 2 OC}} (O) R 3, -C (R 2) 2 -OC (O) OR 3, -C (R 2 ) ₂ OC (O) SR ³ , -alkyl-SC (O) R ³ , and -alkyl-SS-alkylhydroxy,
When, -NR ⁶ - - Y is a -NR ⁶ R ¹ bonded to are independently, -H, - [C (R 2) 2] q -COOR 3, - [C (R 2) 2] q - ^{C (O) SR 3, -C} (R 4) 2 COOR 3 , and-cycloalkylene selected from -COOR, or ^3, or
When one of Y is independently selected from -O- and -NR ⁶ -, R ¹ and R ¹ together
Lt;
V, W and W 'are independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl Or
V and W are taken together through an additional three carbon atoms to form an optionally substituted cyclic group comprising 6 carbon atoms and said cyclic group is selected from the group consisting of the carbon atoms having 3 atoms from Y bonded to phosphorus Substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bound to one,
Z and W are taken together through an additional 3 to 5 atoms to form a cyclic group optionally containing one heteroatom and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
W and W 'are taken together through an additional two to five atoms to form a cyclic group optionally containing from 0 to 2 heteroatoms, wherein V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl Lt; / RTI &gt;
Z is ^{-CHR 2 OH, -CHR 2 OC (} O) R 3, -CHR 2 OC (S) R 3, -CHR 2 OC (S) OR 3, -CHR 2 OC (O) SR 3, -CHR 2 ^{_{OCO 2 R 3, -OR 2,}} -SR 2, -R 2, -NHCOR 2, -NHCO 2 R 3, - (CH 2) p -OR 2, and - the group consisting of (CH _{²⁾ p} -SR ₂ / RTI &gt;
p is an integer 2 or 3,
q is an integer of 1 or 2,
A) V, Z, W, W 'are not all -H,
b) when Z is -R ² , at least one of V, W and W 'is not -H, alkyl, aralkyl, or alicyclic,
c) the group Y is not -NR ⁶ -
R ² is selected from the group consisting of R ³ and -H,
R &lt; ³ &gt; is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl,
R <^6> is selected from the group consisting of -H, lower alkyl.
[117" claim-type="Currently amended] The method of claim 116, wherein, when the group Y are both -O-, R ¹ is independently an optionally substituted aryl, optionally substituted _{^{benzyl, -C (R 2) 2 OC}} (O) R 3, -C (R 2 ) ₂ OC (O) OR &lt; ³ &gt;, and -H,
When Y is -NR ⁶ -, R ¹ bonded to the -NR ⁶ - group is selected from the group consisting of -C (R ⁴ ) ₂ -COOR ³ , -C (R ² ) ₂ COOR ³ , and H When Y is -O-, R ¹ bonded to -O- is optionally substituted aryl, -C (R ² ) ₂ OC (O) R ³ and -C (R ² ) ₂ OC (O) OR ³ &Lt; / RTI &gt;
[118" claim-type="Currently amended] 116. The compound of claim 116, wherein Y is all-O- and R &lt; ¹ &gt;
[119" claim-type="Currently amended] 116. The compound of claim 116, wherein the group Y is all -O- and R &lt; ¹ &gt; is aryl or -C (R &lt; ² &gt;) ₂ -aryl.
[120" claim-type="Currently amended] The method of claim 116, wherein both Y groups are -O-, with at least one R ¹ is _{^{-C (R 2) 2 -OC (}} O) R 3 and _{^{-C (R 2) 2 -OC (}} O) OR 3 &Lt; / RTI &gt;
[121" claim-type="Currently amended] The method of claim 116, wherein both Y groups are -O-, R is one or more ^1-alkyl -SS- alkyl hydroxyl, -alkyl -SC (O) R ^3, and - alkyl -SSS- alkyl, hydroxy, or R ¹ and R ¹ together form a cyclic group as -alkyl-SS-alkyl.
[122" claim-type="Currently amended] The method of claim 116, wherein at least one Y is -O-, R ¹ and R ¹ together are
Lt;
here,
V, W and W 'are independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl Or
V and W are taken together through an additional three carbon atoms to form an optionally substituted cyclic group comprising 6 carbon atoms and said cyclic group is selected from the group consisting of the carbon atoms having 3 atoms from Y bonded to phosphorus Substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bound to one,
Z and W are taken together through an additional 3 to 5 atoms to form a cyclic group optionally containing one heteroatom and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
W and W 'are taken together through an additional two to five atoms to form a cyclic group optionally containing from 0 to 2 heteroatoms, wherein V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl Lt; / RTI &gt;
Z is ^{-CHR 2 OH, -CHR 2 OC (} O) R 3, -CHR 2 OC (S) R 3, -CHR 2 OC (S) OR 3, -CHR 2 OC (O) SR 3, -CHR 2 ^{_{OCO 2 R 3, -OR 2,}} -SR 2, -R 2, -NHCOR 2, -NHCO 2 R 3, - (CH 2) p -OR 2, and - the group consisting of (CH _{²⁾ p} -SR ₂ / RTI &gt;
p is an integer 2 or 3,
A) V, Z, W, W 'are not all -H,
b) when Z is -R ² , at least one of V, W and W 'is not -H, alkyl, aralkyl, or alicyclic,
c) the group Y is not -NR ⁶ -
R ² is selected from the group consisting of R ³ and -H,
R &lt; ³ &gt; is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl,
R <^6> is selected from the group consisting of -H, and lower alkyl.
[123" claim-type="Currently amended] The method of claim 112, wherein, R ¹ is alicyclic where the cyclic moiety method contains carbonate or thiocarbonate.
[124" claim-type="Currently amended] Wherein R ¹ is optionally substituted aryl, the other Y is -NR ⁶ -, and R ¹ bonded to -NR ⁶ - is -C (R ⁴ ) -O-, ₂ COOR ³ , and -C (R ² ) ₂ C (O) OR ³ .
[125" claim-type="Currently amended] The method of claim 124, wherein the R ¹ bonded to the -O- from phenyl, and _{-NHC (O) CH 3, -Cl} , -Br, -C (O) OCH 2 CH 3, and the group consisting of -CH ₃ It is selected from the group consisting of phenyl substituted by one or two substituents selected, -NR ⁶ - with R ¹ is bonded to -C (R ^{₂₎ 2} COOR ^3, and, each R ² is independently selected from -CH _3, - CH ₂ CH ₃ and -H.
[126" claim-type="Currently amended] The method of claim 125, wherein the compound is the substituent of the substituted phenyl is selected from _{4-NHC (O) CH 3} , -Cl, -Br, 2-C (O) OCH 2 CH 3, and the group consisting of -CH ₃ .
[127" claim-type="Currently amended] 105. The method of claim 104,
A ² is selected from the group consisting of -H, -NH ₂ , -CH ₃ , -Cl, and Br,
L ² is -H, lower alkyl, halogen, lower alkyloxy, hydroxy, -alkylene-OH, or together with E ² form a cyclic group comprising aryl, cyclic alkyl, heteroaryl, heterocyclic alkyl and,
E ² is selected from the group consisting of H, lower alkyl, halogen, SCN, lower alkyloxycarbonyl, lower alkyloxy, or a group including L ¹ together with aryl, cyclic alkyl, heteroaryl, or heterocyclic alkyl Forming a clicker,
J ² is selected from the group consisting of H, halogen and lower alkyl,
G &quot; is -S-,
X ² is -CH ₂ O-,
At least one Y group is -O-
Compounds and their pharmaceutically acceptable salts and salts.
[128" claim-type="Currently amended] The method of claim 127, wherein, one Y group is -O- and, while this corresponds to R ¹ is optionally a substituted phenyl, and the other Y is -NH-, corresponding to R ¹ is -C (R ^{₂₎ 2} -COOR ³ in the compound.
[129" claim-type="Currently amended] The method of claim 128, wherein the other Y group is -NH-, the corresponding R ¹ is -CHR ² is ^{COOR 3, -NH * CHR 2 COOR} 3 has L- array of compounds.
[130" claim-type="Currently amended] 127. The compound of claim 127, wherein A ² is NH ₂ , L ² is -Et, E ² is -SCN, and J ² is -H.
[131" claim-type="Currently amended] 128. The compound of claim 130, wherein the group Y is all -O- and R &lt; ¹ &gt; is -H.
[132" claim-type="Currently amended] The method of claim 130, wherein both Y groups are -O-, R ¹ is -CH ₂ OC (O) OEt compounds.
[133" claim-type="Currently amended] The method of claim 130, wherein both Y groups are -O-, R ¹ and R ¹ together are
ego,
And V is substituted with 1 to 3 halogens.
[134" claim-type="Currently amended] 133. The compound of claim 133, wherein V is selected from the group consisting of 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl, and 3-bromophenyl.
[135" claim-type="Currently amended] The method of claim 130, wherein, one Y group is -O-, and R ¹ is equivalent to - while the phenyl, and the other Y is -NH-, and corresponding to R ¹ is -CH (Me) CO ₂ Et and , -NH ^* CH (Me) CO ₂ Et is an L-configuration.
[136" claim-type="Currently amended] Comprising administering a therapeutically effective amount of a compound of formula (X) and a pharmaceutically acceptable salt thereof and a salt thereof to an animal suffering from a fructose-1,6-bisphosphatase dependent disease or condition, , 6-bisphosphatase dependent disease or disease.
(X)

In this formula,
G "is selected from the group consisting of -O- and -S-,
A ^2, L ^2, E ² and J ² is _{^{-NR 4 2, -NO 2, -H}} , -OR 2, -SR 2, -C (O) NR 4 2, halo, -COR ^11, -SO ₂ R ^3, guanidyl pyridinyl, amidinyl, aryl, aralkyl, ^{_{alkyloxy-alkyl, -SCN, -NHSO 2 R 9,}} -SO 2 NR 4 2, -CN, -S (O) R 3, acyl perhalo to, alkyl, perhaloalkyl perhalo alkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower or selected from the Ali when the group consisting of clicks, or L ² and E ² or E ² and J ² Together form a cyclic cyclic group,
X ² is an optionally substituted bonding group through which R ⁵ is bonded to the phosphorus atom through 1 to 3 atoms comprising 0 or 1 heteroatom selected from N, O and S, wherein the atom bonded to the phosphorus is a carbon atom However,
However, X ² is not substituted with -COOR ^2, -SO ₃ R ¹ or PO ₃ R ¹ _2,
Y is independently selected from the group consisting of -O-, and -NR &lt; ⁶ &gt; -,
When Y is -O, R ¹ bonded to -O- is independently -H, alkyl, optionally substituted aryl, optionally substituted alicyclic wherein the cyclic moiety comprises a carbonate or thiocarbonate hereinafter), optionally _{^{substituted-alkylaryl, -C (R 2) 2 OC}} (O) NR 2 2, -NR 2 -C (O) -R 3, -C (R 2) 2 -OC (O) R _{^{3, -C (R 2) 2}} -OC (O) OR 3, -C (R 2) 2 OC (O) SR 3, - alkyl, -SC (O) R ^3, - alkyl -SS- alkyl hydroxy, And-alkyl-SSS-alkylhydroxy,
When Y is -NR ⁶ -, R ¹ bonded to -NR ⁶ - is independently -H, - [C (R ² ) ₂ ] _q -COOR ³ , -C (R ⁴ ) ₂ COOR ³ , - [ C (R ² ) ₂ ] _q -C (O) SR and -cycloalkylene-COOR ³ ,
Or when one of Y is independently selected from -O- and -NR ⁶ -, R ¹ and R ¹ together form a cyclic group as -alkyl-SS-alkyl-, or R ¹ and R ¹ together
Lt;
here,
V, W and W 'are independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl Or
V and Z together are joined through an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 atoms optionally containing one heteroatom, Acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy which is bonded to the carbon atom which is three atoms from the group consisting of
V and Z together are joined through an additional three to five atoms to form a cyclic group optionally containing one heteroatom fused to the aryl group at the beta and gamma positions for Y bonded to the phosphorus,
V and W are taken together through an additional three carbon atoms to form an optionally substituted cyclic group comprising 6 carbon atoms and said cyclic group is selected from the group consisting of the carbon atoms having 3 atoms from Y bonded to phosphorus Substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bound to one,
Z and W are taken together through an additional 3 to 5 atoms to form a cyclic group optionally containing one heteroatom and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
W and W 'are taken together through an additional two to five atoms to form a cyclic group optionally containing from 0 to 2 heteroatoms, wherein V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl Lt; / RTI &gt;
Z is ^{-CHR 2 OH, -CHR 2 OC (} O) R 3, -CHR 2 OC (S) R 3, -CHR 2 OC (S) OR 3, -CHR 2 OC (O) SR 3, -CHR 2 (CH = CR ² ₂ ) OH, -CH (C≡CR ² ) OH, -CH (O) ₂ R ³ , -OR ² , -SR ² , -CHR ² N ₃ , -CH ₂ aryl, _{^{OH, -R 2, -NR 2 2}} , -OCOR 3, -OCO 2 R 3, -SCOR 3, -SCO 2 R 3, -NHCOR 2, -NHCO 2 R 3, -CH 2 NH aryl, - (CH ₂ ) _p -OR ² , and - (CH ₂ ) _p -SR ² ,
p is an integer 2 or 3,
q is an integer of 1 or 2,
A) V, Z, W, W 'are not all -H,
b) when Z is -R ² , at least one of V, W and W 'is not -H, alkyl, aralkyl, or alicyclic,
R ² is selected from the group consisting of R ³ and -H,
R &lt; ³ &gt; is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl,
R ⁴ are each independently selected from the group consisting of -H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group,
R ⁶ is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl,
R ⁹ are each independently selected from the group consisting of -H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group,
R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² ₂ , and -OR ² .
[137" claim-type="Currently amended] A method of treating diabetes by administering a pharmaceutically effective amount of an FBPase inhibitor of formula (X) and a pharmaceutically acceptable salt thereof and a salt thereof to a patient in need thereof.
(X)

In this formula,
G "is selected from the group consisting of -O- and -S-,
A ^2, L ^2, E ² and J ² is _{^{-NR 4 2, -NO 2, -H}} , -OR 2, -SR 2, -C (O) NR 4 2, halo, -COR ^11, -SO ₂ R ^3, guanidyl pyridinyl, amidinyl, aryl, aralkyl, ^{_{alkyloxy-alkyl, -SCN, -NHSO 2 R 9,}} -SO 2 NR 4 2, -CN, -S (O) R 3, acyl perhalo to, alkyl, perhaloalkyl perhalo alkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower or selected from the Ali when the group consisting of clicks, or L ² and E ² or E ² and J ² Together form a cyclic cyclic group,
X ² is an optionally substituted bonding group through which R ⁵ is bonded to the phosphorus atom through 1 to 3 atoms comprising 0 or 1 heteroatom selected from N, O and S, wherein the atom bonded to the phosphorus is a carbon atom However,
However, X ² is not substituted with -COOR ^2, -SO ₃ R ¹ or PO ₃ R ¹ _2,
Y is independently selected from the group consisting of -O-, and -NR &lt; ⁶ &gt; -,
When Y is -O, R ¹ bonded to -O- is independently -H, alkyl, optionally substituted aryl, optionally substituted alicyclic wherein the cyclic moiety comprises a carbonate or thiocarbonate hereinafter), optionally _{^{substituted-alkylaryl, -C (R 2) 2 OC}} (O) NR 2 2, -NR 2 -C (O) -R 3, -C (R 2) 2 -OC (O) R _{^{3, -C (R 2) 2}} -OC (O) OR 3, -C (R 2) 2 OC (O) SR 3, - alkyl, -SC (O) R ^3, - alkyl -SS- alkyl hydroxy, And-alkyl-SSS-alkylhydroxy,
When Y is -NR ⁶ -, R ¹ bonded to -NR ⁶ - is independently -H, - [C (R ² ) ₂ ] _q -COOR ³ , -C (R ⁴ ) ₂ COOR ³ , - [ C (R ² ) ₂ ] _q -C (O) SR and -cycloalkylene-COOR ³ ,
Or when one of Y is independently selected from -O- and -NR ⁶ -, R ¹ and R ¹ together form a cyclic group as -alkyl-SS-alkyl-, or R ¹ and R ¹ together
Lt;
here,
V, W and W 'are independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl Or
V and Z together are joined through an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 atoms optionally containing one heteroatom, Acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy which is bonded to the carbon atom which is three atoms from the group consisting of
V and Z together are joined through an additional three to five atoms to form a cyclic group optionally containing one heteroatom fused to the aryl group at the beta and gamma positions for Y bonded to the phosphorus,
V and W are taken together through an additional three carbon atoms to form an optionally substituted cyclic group comprising 6 carbon atoms and said cyclic group is selected from the group consisting of the carbon atoms having 3 atoms from Y bonded to phosphorus Substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bound to one,
Z and W are taken together through an additional 3 to 5 atoms to form a cyclic group optionally containing one heteroatom and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
W and W 'are taken together through an additional two to five atoms to form a cyclic group optionally containing from 0 to 2 heteroatoms, wherein V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl Lt; / RTI &gt;
Z is ^{-CHR 2 OH, -CHR 2 OC (} O) R 3, -CHR 2 OC (S) R 3, -CHR 2 OC (S) OR 3, -CHR 2 OC (O) SR 3, -CHR 2 (CH = CR ² ₂ ) OH, -CH (C≡CR ² ) OH, -CH (O) ₂ R ³ , -OR ² , -SR ² , -CHR ² N ₃ , -CH ₂ aryl, _{^{OH, -R 2, -NR 2 2}} , -OCOR 3, -OCO 2 R 3, -SCOR 3, -SCO 2 R 3, -NHCOR 2, -NHCO 2 R 3, -CH 2 NH aryl, - (CH ₂ ) _p -OR ² , and - (CH ₂ ) _p -SR ² ,
p is an integer 2 or 3,
q is an integer of 1 or 2,
Provided that a) V, Z, W and W 'are not all -H,
b) when Z is -R ² , at least one of V, W and W 'is not -H, alkyl, aralkyl, or alicyclic,
R ² is selected from the group consisting of R ³ and -H,
R &lt; ³ &gt; is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl,
R ⁴ are each independently selected from the group consisting of -H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group,
R ⁶ is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl,
R ⁹ are each independently selected from the group consisting of -H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group,
R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² ₂ , and -OR ² .
[138" claim-type="Currently amended] A method of treating a glycogen accumulating disease by administering a pharmaceutically effective amount of an FBPase inhibitor of formula (X) and a pharmaceutically acceptable salt thereof and a salt thereof to a patient in need thereof.
(X)

In this formula,
G "is selected from the group consisting of -O- and -S-,
A ^2, L ^2, E ² and J ² is _{^{-NR 4 2, -NO 2, -H}} , -OR 2, -SR 2, -C (O) NR 4 2, halo, -COR ^11, -SO ₂ R ^3, guanidyl pyridinyl, amidinyl, aryl, aralkyl, ^{_{alkyloxy-alkyl, -SCN, -NHSO 2 R 9,}} -SO 2 NR 4 2, -CN, -S (O) R 3, acyl perhalo to, alkyl, perhaloalkyl perhalo alkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower or selected from the Ali when the group consisting of clicks, or L ² and E ² or E ² and J ² Together form a cyclic cyclic group,
X ² is an optionally substituted bonding group in which R ⁵ is bonded to the phosphorus atom through 1 to 3 atoms comprising 0 or 1 heteroatom selected from N, O or S, wherein the phosphorus- However,
However, X ² is not substituted with -COOR ^2, -SO ₃ R ¹ or PO ₃ R ¹ _2,
Y is independently selected from the group consisting of -O-, and -NR &lt; ⁶ &gt; -,
When Y is -O, R ¹ bonded to -O- is independently -H, alkyl, optionally substituted aryl, optionally substituted alicyclic wherein the cyclic moiety comprises a carbonate or thiocarbonate hereinafter), optionally _{^{substituted-alkylaryl, -C (R 2) 2 OC}} (O) NR 2 2, -NR 2 -C (O) -R 3, -C (R 2) 2 -OC (O) R _{^{3, -C (R 2) 2}} -OC (O) OR 3, -C (R 2) 2 OC (O) SR 3, - alkyl, -SC (O) R ^3, - alkyl -SS- alkyl hydroxy, And-alkyl-SSS-alkylhydroxy,
When Y is -NR ⁶ -, R ¹ bonded to -NR ⁶ - is independently -H, - [C (R ² ) ₂ ] _q -COOR ³ , -C (R ⁴ ) ₂ COOR ³ , - [ C (R ² ) ₂ ] _q -C (O) SR and -cycloalkylene-COOR ³ ,
Or when one of Y is independently selected from -O- and -NR ⁶ -, R ¹ and R ¹ together form a cyclic group as -alkyl-SS-alkyl-, or R ¹ and R ¹ together
Lt;
here,
V, W and W 'are independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl Or
V and Z together are joined through an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 atoms optionally containing one heteroatom, Acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy which is bonded to the carbon atom which is three atoms from the group consisting of
V and Z together are joined through an additional three to five atoms to form a cyclic group optionally containing one heteroatom fused to the aryl group at the beta and gamma positions for Y bonded to the phosphorus,
V and W are taken together through an additional three carbon atoms to form an optionally substituted cyclic group comprising 6 carbon atoms and said cyclic group is selected from the group consisting of the carbon atoms having 3 atoms from Y bonded to phosphorus Substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bound to one,
Z and W are taken together through an additional 3 to 5 atoms to form a cyclic group optionally containing one heteroatom and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
W and W 'are taken together through an additional two to five atoms to form a cyclic group optionally containing from 0 to 2 heteroatoms, wherein V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl Lt; / RTI &gt;
Z is ^{-CHR 2 OH, -CHR 2 OC (} O) R 3, -CHR 2 OC (S) R 3, -CHR 2 OC (S) OR 3, -CHR 2 OC (O) SR 3, -CHR 2 (CH = CR ² ₂ ) OH, -CH (C≡CR ² ) OH, -CH (O) ₂ R ³ , -OR ² , -SR ² , -CHR ² N ₃ , -CH ₂ aryl, _{^{OH, -R 2, -NR 2 2}} , -OCOR 3, -OCO 2 R 3, -SCOR 3, -SCO 2 R 3, -NHCOR 2, -NHCO 2 R 3, -CH 2 NH aryl, - (CH ₂ ) _p -OR ² , and - (CH ₂ ) _p -SR ² ,
p is an integer 2 or 3,
q is an integer of 1 or 2,
A) V, Z, W, W 'are not all -H,
b) when Z is -R ² , at least one of V, W and W 'is not -H, alkyl, aralkyl, or alicyclic,
R ² is selected from the group consisting of R ³ and -H,
R &lt; ³ &gt; is selected from the group consisting of alkyl, aryl, alicyclic and aralkyl,
R ⁴ are each independently selected from the group consisting of -H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group,
R ⁶ is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl,
R ⁹ are each independently selected from the group consisting of -H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group,
R ¹¹ is selected from the group consisting of alkyl, aryl, -NR ² ₂ , and -OR ² .
[139" claim-type="Currently amended] 46. The method of claim 45, A '' and is -NH _2, X is a furan-2,5-diyl, B '' is -SCH ₂ CH ₂ CH ₃ A compound.
[140" claim-type="Currently amended] 46. The method of claim 45 wherein, Y is -O- and one group, the corresponding R ¹ is a phenyl, whereas, the other Y is -NH-, the corresponding R ¹ is -CH ₂ CO ₂ Et the compound.
[141" claim-type="Currently amended] 46. The method of claim 45 wherein, Y is -O- and one group, the corresponding R ¹ is that - while the phenyl, and the other Y is -NH-, and corresponding to R ¹ is -C (Me) ₂ CO ₂ Et / RTI &gt;
[142" claim-type="Currently amended] 46. The method of claim 45 wherein, Y is -O- and one group, corresponding to R ¹ is - (phenyl _{-4-NHC (O) CH 3} ) , while the other Y is -NH-, and R corresponding to ¹ is -CH ₂ CO ₂ Et.
[143" claim-type="Currently amended] 46. The method of claim 45 wherein, Y is -O- and one group, corresponding to R ¹ is - (phenyl _{-4-NHC (O) CH 3} ) , while the other Y is -NH-, and R corresponding to ¹ is -C (Me) ₂ CO ₂ Et a compound.
[144" claim-type="Currently amended] 46. The method of claim 45 wherein, Y is -O- and one group, the corresponding R ¹ is a - (phenyl -2-CO ₂ Et), while the other Y is -NH-, and R ^1, which are equivalent - CH ₂ CO ₂ Et.
[145" claim-type="Currently amended] 46. The method of claim 45 wherein, Y is -O- and one group, corresponding to R ¹ is - (phenyl -2-CH _3), whereas, the other Y is -NH-, corresponding to R ¹ is -CH ₂ CO ₂ Et.
[146" claim-type="Currently amended] The method of claim 46 wherein, Y is -O- and one group, the corresponding R ¹ is a phenyl, whereas, the other Y is -NH-, the corresponding R ¹ is -CH ₂ CO ₂ Et the compound.
[147" claim-type="Currently amended] The method of claim 46 wherein, Y is -O- and one group, the corresponding R ¹ is that - while the phenyl, and the other Y is -NH-, and corresponding to R ¹ is -C (Me) ₂ CO ₂ Et / RTI &gt;
[148" claim-type="Currently amended] The method of claim 46 wherein, Y is -O- and one group, corresponding to R ¹ is - (phenyl _{-4-NHC (O) CH 3} ) , while the other Y is -NH-, and R corresponding to ¹ is -CH ₂ CO ₂ Et.
[149" claim-type="Currently amended] The method of claim 46 wherein, Y is -O- and one group, corresponding to R ¹ is - (phenyl _{-4-NHC (O) CH 3} ) , while the other Y is -NH-, and R corresponding to ¹ is -C (Me) ₂ CO ₂ Et a compound.
[150" claim-type="Currently amended] The method of claim 46 wherein, Y is -O- and one group, the corresponding R ¹ is a - (phenyl -2-CO ₂ Et), while the other Y is -NH-, and R ^1, which are equivalent - CH ₂ CO ₂ Et.
[151" claim-type="Currently amended] The method of claim 46 wherein, Y is -O- and one group, corresponding to R ¹ is - (phenyl -2-CH _3), whereas, the other Y is -NH-, corresponding to R ¹ is -CH ₂ CO ₂ Et.
[152" claim-type="Currently amended] 48. The compound of claim 47, wherein all the groups Y are -O- and R &lt; ¹ &gt; is -H.
[153" claim-type="Currently amended] The method of claim 47 wherein, Y groups are both -O-, R ¹ is -CH ₂ OC (O) OEt compounds.
[154" claim-type="Currently amended] 49. The compound of claim 48, wherein all of the groups Y are-O- and R &lt; ¹ &gt; is -H.
[155" claim-type="Currently amended] 49. The method of claim 48 wherein, Y groups are both -O-, R ¹ is -CH ₂ OC (O) OEt compounds.
[156" claim-type="Currently amended] 50. The compound of claim 49, wherein all the groups Y are -O- and R &lt; ¹ &gt; is -H.
[157" claim-type="Currently amended] 50. The method of claim 49 wherein, Y groups are both -O-, R ¹ is -CH ₂ OC (O) OEt compounds.
[158" claim-type="Currently amended] 54. The compound of claim 53, wherein V is selected from the group consisting of 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl, and 3-bromophenyl.
[159" claim-type="Currently amended] 48. The method of claim 47, one Y group is -O-, and R ¹ is equivalent to - while the phenyl, and the other Y is -NH-, and corresponding to R ¹ is -CH (Me) CO ₂ Et and _{^{-NH- * CH (Me) CO 2}} Et is L- array of compounds.
[160" claim-type="Currently amended] 58. The compound of claim 54, wherein V is selected from the group consisting of 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl, and 3-bromophenyl.
[161" claim-type="Currently amended] 49. The method of claim 48 wherein, Y is -O- and one group, the corresponding R ¹ is that - while the phenyl, and the other Y is -NH-, and corresponding to R ¹ is -CH (Me) CO ₂ Et and _{^{-NH- * CH (Me) CO 2}} Et is L- array of compounds.
[162" claim-type="Currently amended] 56. The compound of claim 55, wherein V is selected from the group consisting of 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl, and 3-bromophenyl.
[163" claim-type="Currently amended] 50. The method of claim 49, one Y group is -O-, and R ¹ is equivalent to - while the phenyl, and the other Y is -NH-, and corresponding to R ¹ is -CH (Me) CO ₂ Et and _{^{-NH- * CH (Me) CO 2}} Et is L- array of compounds.
[164" claim-type="Currently amended] 61. The method of claim 60, one Y group is -O-, and R ¹ is equivalent to -phenyl, while the other Y is -NH- and, the corresponding R ¹ is -CH ₂ CO ₂ Et the compound.
[165" claim-type="Currently amended] The method of claim 130, wherein, one Y group is -O-, and R ¹ is equivalent to -phenyl, while the other Y is -NH- and, the corresponding R ¹ is -CH ₂ CO ₂ Et the compound.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1998-09-09|Priority to US13550498P

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1998-09-09|Priority to US60/135,504

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1998-12-07|Priority to US11107798P

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1998-12-07|Priority to US60/111,077

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1999-09-03|Application filed by 마크 디. 에리온, 메타베이시스 테라퓨틱스, 인크.

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2001-09-07|Publication of KR20010085776A

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2008-04-01|Application granted

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2008-04-01|Publication of KR100818845B1

优先权:

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申请号 | 申请日 | 专利标题

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US13550498P| true| 1998-09-09|1998-09-09|

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US60/135,504|1998-09-09|

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US11107798P| true| 1998-12-07|1998-12-07|

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US60/111,077|1998-12-07|