Azoles As Malonyl-CoA Decarboxylase Inhibitors Useful As Metabolic Modulators

专利摘要:
The present invention relates to methods of treating certain metabolic diseases, novel compounds, and their prodrugs, and / or pharmaceutically acceptable salts, pharmaceutical compositions comprising said compounds useful for the treatment of said diseases. In particular, the present invention relates to the use of novel compounds and compositions for the treatment of cardiovascular disease, diabetes, cancer, acidosis, and obesity, through the inhibition of malonyl-CoA decarboxylase (MCD). These compounds have the following general formulas: In the above formula, Y, C, R 1 , R 2 , R 6 , and R 7 are defined herein.
公开号:KR20030077015A
申请号:KR10-2003-7010409
申请日:2002-02-19
公开日:2003-09-29
发明作者:토마스 아르헤니우스；지에페이 쳉；마크 윌슨；로시 세라피모브
申请人:추가이 세이야쿠 가부시키가이샤；
IPC主号:

专利说明:

Azoles as Malonyl-CoA Decarboxylase Inhibitors Useful As Metabolic Modulators
[2] Malonyl-CoA is an important metabolic intermediate produced by the acetyl-CoA carboxylase enzymes in the body. In liver, adipocytes, and other tissues, malonyl-CoA is a substrate of fatty acid synthase (FAS). ACC and malonyl-CoA are found in skeletal and cardiomyocyte tissues with low levels of fatty acid synthase. Malonyl-CoA decarboxylase enzyme (MCD, EC 4.1.1.9) catalyzes the conversion of malonyl-CoA to acetyl-CoA to regulate malonyl-CoA levels. MCD activity has been described in a wide range of living organisms, including prokaryotes, birds, and mammals. It is found in the bacterium Rhizobium trifolii (An et al., J. Biochem. Biol. Mol. 32: 414-418 (1999)), uropygial glands (Buckner, et al., Arch. Biochem. Biophys 177: 539 (1976); Kim and Kolattukudy Arch.Biochem.Biophys 190: 585 (1978), mitochondria between rats (Kim and Kolattukudy, Arch.Biochem. (Kim and Kolattukudy, Biochem. Biophys, Acta 531: 187 (1978)), β-cells of rat pancreas (Voilley et al., Biochem. J. 340: 213 (1999)) and Anser anser (Jang) et al., J. Biol. Chem. 264: 3500 (1989). Patients with MCD deficiency could be identified to clone human gene homologues for MCD genes in goose and rats (Gao et al., J. Lipid. Res. 40: 178 (1999); Sacksteder et al. , J. Biol. Chem. 274: 24461 (1999); FitzPatrick et al., Am. J. Hum. Genet 65: 318 (1999) A single human MCD mRNA was observed in northern blot analysis. The highest mRNA expression levels were found in muscle and heart tissue, followed by liver, kidney and pancreas, and at detectable levels in all other tissues examined.
[3] Malonyl-CoA is a potent endogenous inhibitor of carnitine palmitoyltransferase-I (CPT-I), an enzyme essential for the metabolism of long-chain fatty acids. CPT-I is a rate-limiting enzyme in fatty acid oxidation and catalyzes the formation of acyl-carnitine transported from the cytoplasm through the mitochondrial membrane by an acyl carnitine translocase. Inside the mitochondria, long-chain fatty acids are returned to the CoA form by the complementary enzyme CPT-II, and in mitochondria, acyl-CoA enters the β-oxidation pathway, producing acetyl-CoA. In the liver, high levels of acetyl-CoA occur, for example, after meals, which elevate malonyl-CoA levels that inhibit CPT-I, which interferes with fat metabolism and favors fat synthesis. In contrast, low malonyl-CoA levels favor fatty acid metabolism by allowing long chain fatty acids to be transferred into the mitochondria. Therefore, malonyl-CoA is a central metabolite that plays an important role in balancing fatty acid synthesis and fatty acid oxidation (Zammit, Biochem. J. 343: 5050-515 (1990). Recent studies have shown that MCD is the term for mitochondria). It can be shown that it can regulate not only the level of nile-CoA but also the level of cytosolic malonyl-CoA (Alam and Saggerson, Biochem J. 334: 233-241 (1998); Dyck et al. 1998).
[4] Malonyl-CoA is present in muscle and heart tissues, but only low levels of FAS have been detected in these tissues. The role of malonyl-CoA and MCD in these tissues is believed to regulate fatty acid metabolism. This is done through malonyl-CoA inhibition by muscle (M) and liver (L) isoforms of CPT-I, encoded by separate genes (McGarry and Brown, Eur. J. Biochem 244: 1 -14 (1997). Muscle isoforms (IC ₅₀ 0.03 μM) are more sensitive to malonyl-CoA inhibition than hepatic isoforms (IC ₅₀ 2.5 μM). Malonyl-CoA regulation of CPT-I has been observed in liver, heart, skeletal muscle, and pancreatic β-cells. In addition, malonyl-CoA sensitive acyl-CoA transferase activity present in microsomes, which may be part of a system that carries acyl groups to the endoplasmic reticulum (ER), is also described (Fraser et al., FEBS Lett. 446: 69). -74 (1999).
[5] Cardiovascular Diseases:
[6] The heart of a healthy person uses available metabolic substrates. When blood glucose levels are high, glucose uptake and metabolism provide a major source of fuel for the heart. In the fasting state, lipids are provided by adipose tissue, and fatty acid uptake and metabolism in the heart inhibit and regulate glucose metabolism. Regulation of intermediate metabolism by levels of fatty acids and glucose in serum includes the glucose-fatty acid cycle (Randle et al., Lancet, 1: 785-789 (1963)). Under the condition of ischemic, limited oxygen supply reduces both the oxidation of fatty acids and glucose and also reduces the amount of ATP produced by oxidative phosphorylation in heart tissue. In the absence of sufficient oxygen, glycolysis increases to maintain ATP levels, leading to accumulation of lactic acid and a drop in intracellular pH. Energy is consumed to maintain ionic homeastasis and myocyte death occurs as a result of abnormally low ATP levels and osmotic destruction of cells. Secondly, activated AMPK is phosphorylated during ischemia to inactivate ACC. Malonyl-CoA levels in the overall heart are lowered, resulting in increased CPT-I activity and favoring fatty acid oxidation compared to the oxidation of glucose. The beneficial effects of metabolic regulators in cardiac tissues include increased efficiency of ATP per mole of oxygen to glucose compared to fatty acids and, more importantly, increased coupling to glucose oxidation in glycolysis, resulting in quantum loading in ischemic tissues. it causes an overall reduction in the burden of protons.
[7] Many clinical and experimental studies have shown that shifting energy metabolism in the heart for glucose oxidation is an effective approach to reducing conditions associated with cardiovascular diseases such as, but not limited to, myocardial ischemia (Hearse, "Metabolic apporoaches to ischemic heart disease and its management " , Science Press). Several clinically proven anti-angina drugs, including perhexiline and amiodarone, inhibit fatty acid oxidation through inhibition of CPT-I (Kennedy et al., Biochem. Pharmacology, 52: 273 (1996). Recently, anti-anginal agents, ranolazine and trimetazidine, in Phase III clinical trials, have been shown to inhibit fatty acid β-oxidation (McCormack et al., Genet.Pharmac. 30: 639 ( 1998), Pepine et al., Am. J. Cardiology 84:46 (1999). Trimetazidine has been shown to inhibit long chain 3-ketoacyl CoA thiolase, which is an essential step in fatty acid oxidation in particular (Kantor et al., Circ.Res. 86: 580-588 (2000)). Dichloroacetate increases glucose oxidation by stimulating pyruvate dehydrogenase complex and improves cardiac function in patients with coronary artery disease (Wargovich et al., Am. J. Cardiol. 61: 65-70 (1996)). Inhibiting CPT-I activity through increased malonyl-CoA levels as an MCD inhibitor is not only novel, but much more than other small molecule CPT-I inhibitors known for the prevention and treatment of cardiovascular diseases. It will be a safe way.
[8] Most of the steps involved in glycerol-lipid synthesis occur on the cytoplasmic side of the liver ER membrane. Synthesis of triacylglycerol (TAG), which is to be secreted into the ER from diacylglycerol (DAG) and acyl CoA, depends on acyl-CoA transfer through the ER membrane. This transfer is dependent on malonyl-CoA sensitive acyl-CoA transferase activity (Zammit, Biochem. J. 343: 505 (1999) Abo-Hashema, Biochem. 38: 15840 (1999) and Abo-Hashema, J. Biol Chem. 274: 35577 (1999). Inhibition of TAG biosynthesis by MCD inhibitors improves the blood lipid profile, thus reducing risk factors in patients with coronary artery disease.
[9] Diabetes :
[10] Two metabolic complications most commonly associated with diabetes are hepatic overproduction of ketone bodies (in NIDDM), and organ toxicity associated with sustained increased glucose levels. Inhibition of fatty acid oxidation can regulate blood glucose levels and improve some conditions of type II diabetes. Malonyl-CoA inhibition of CPT-I is the most important regulatory mechanism that regulates the rate of fatty acid oxidation during the onset of the hypoinsulinemia-hyperglucagonism state. Several irreversible and reversible CPT-I inhibitors have been evaluated for their ability to control blood glucose levels, all of which are invariably hypoglycemic (Anderson, Current Pharmaceutical Design 4: 1 (1998)). The liver-specific and reversible CPT-I inhibitor, SDZ-CPI-975, did not induce cardiac hypertrophy and markedly lowered glucose levels in normal non-human primates and rats 18 hours fasted (Deems et al., Am. J. Physiology 274: R524 (1998). Malonyl-CoA plays an important role as a sensor for the relative utility of glucose and fatty acids in pancreatic β-cells, thus linking glucose metabolism to the energy state and insulin secretion of cells. Insulin secretagogues have been shown to elevate malonyl-CoA concentrations in β-cells (Prentki et al., Diabetes 45: 273 (1996)). However, direct treatment of diabetes with CPT-I inhibitors resulted in metabolic-based hepatic and myocardial toxicity. Thus, its endogenous inhibitor, MCD inhibitor, which inhibits CPT-I through an increase in malonyl-CoA, is safer and better when compared to the CPT-I inhibitor of diabetes treatment.
[11] Cancer :
[12] Malonyl-CoA has been suggested to be an effective modulator of cytotoxicity induced by inhibiting fatty acid synthase in human breast cancer cells and xenograft (Pizer et al., Cancer Res. 60: 213 (2000). Inhibition of fatty acid synthase with the antitumor antibiotic serurenin or synthetic analog C75 has been found to significantly increase malonyl-CoA levels in breast cancer tumor cells. In contrast, the fatty acid synthesis inhibitor, TOFA (5- (tetradecyloxy) -2-furoic acid), which only inhibits acetyl-CoA decarboxylase (ACC) levels, did not show any antitumor activity, but on the other hand At the same time malonyl-CoA levels were reduced to 60% of the control. Increased levels of malonyl-CoA are believed to be responsible for the antitumor activity of these fatty acid synthase inhibitors. Thus, regulating malonyl-CoA levels using MCD inhibitors constitutes a valuable therapeutic strategy for treating cancer diseases.
[13] Obesity :
[14] Malonyl-CoA has been suggested to play an important role in appetite signaling in the brain through inhibition of the neuropeptide Y pathway (Loftus et al., Science 288: 2379 (2000)). Systemic or intracerebroventrcular treatment of mice with fatty acid synthase (FAS) inhibitors, cerurenin or C75 results in inhibition of feeding and dramatic weight loss. It has been found that C75 inhibits the expression of signal neuropeptide Y in the hypothalamus and acts in a manner that does not depend on leptin, which appears to be modulated by malonyl-CoA. Thus, regulation of malonyl-CoA levels through inhibition of MCD provides a novel approach to the prevention and treatment of obesity.
[15] The design of MCD inhibitors for the treatment of cardiovascular disease, diabetes, cancer, or obesity has not been reported in the literature. We have now discovered a new series of compounds, including thiazoles and oxazoles, potent inhibitors of MCD. Compounds tested both in vitro and in vivo inhibit malonyl-CoA decarboxylase activity and raise malonyl-CoA concentrations in the body. In addition, compounds selected by way of example cause a significant increase in glucose oxidation compared to controls in an isolated perfused rat heart assay (McNeill, Measurement of Cardiovascular Function, CRC Press, 1997). . Advantageously, preferred compounds such as Table 3, Entry 16 and Table 8, Entry 7 of the present invention, metabolism shift over known metabolic modulators such as ranolazine or trimetazidine. Has a more important impact. Accordingly, the compounds of the present invention and pharmaceutical compositions comprising these compounds are useful in medicine, in particular for the prevention, treatment, and treatment of various cardiovascular diseases, diabetes, cancer, and obesity.
[16] In addition, these compounds are also useful as diagnostic tools for diseases associated with MCD deficiency or dysfunction.
[1] The present invention relates to methods of treating certain metabolic diseases, and novel compounds useful for treating such diseases, and prodrugs thereof, and / or pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds. In particular, the present invention provides novel compounds for the prevention, treatment or treatment of cardiovascular disease, diabetes, cancer, and obesity through the inhibition of malonyl-coenzyme A decarboxylase (malonyl-CoA decarboxylase, MCD) and It relates to the use of the composition.
[17] The present invention provides a novel compound represented by the following general formulas (I) and (II), a novel pharmaceutical composition containing the compound, and a method for the prevention, treatment, and treatment of diseases controlled by metabolic diseases and MCD inhibition. To provide. The compounds of the present invention are useful for the prevention, treatment and treatment of diseases related to glucose / fatty acid metabolism regulated by malonyl-CoA. In particular, these compounds and pharmaceutical compositions containing such compounds are applied in the prevention, treatment and treatment of cardiovascular disease, diabetes, cancer, and obesity. In addition to the novel compounds and compositions of the present invention, intermediates and methods useful in the preparation of the compounds of the present invention are included within the scope of the present invention.
[18] The invention also encompasses within its scope diagnostic methods for detecting diseases associated with MCD deficiency or dysfunction.
[19] Compounds of the invention are represented by the general formula:
[20]
[21] In the above formula, Y, C, R ₁ , R ₂ , R ₆ , and R ₇ are defined below. Corresponding enantiomers, diastereoisomers, prodrugs, and pharmaceutically acceptable salts of these compounds are also included within the scope of the present invention. Other aspects of the invention will become apparent as the description of the invention continues. Accordingly, the foregoing is only a summary of certain aspects of the invention and should not be intended or interpreted in any way as limiting the invention.
[22] The following detailed description of the invention is not intended to be exhaustive or to limit the obvious items that describe the invention. It is chosen and described to best explain the substance of the invention to those skilled in the art.
[23] The compounds of the present invention are compounds represented by the following general formulas (I) and (II), their corresponding enantiomers, diastereomers or tautomers, or pharmaceutically acceptable salts, or pharmaceutically acceptable In their carriers.
[24] Wherein Y is selected from S or O; C is a monocyclic monocyclic 5-7 membered ring containing 1 to 3 heteroatoms (wherein these heteroatoms are selected from O, N, or S, wherein these substituents are from R ₁ and R ₂ is independently selected), R ₁ and R ₂ are different from each other, and each is hydrogen, halogen, hydroxy, nitro, cyano, C ₁ -C ₁₂ alkyl, substituted C _1- C ₁₂ alkyl, alkylamino, alkylsulfanyl, Aryl, C ₁ -C ₁₂ alkoxy, substituted C ₁ -C ₁₂ alkoxy, C (X) R ₃ , -CR ₁₁ (V) R ₁₂ , -CH ₂ CR ₁₁ (V) R ₁₂ , -S (O) _n R _3- , -NR ₄ P (O) (R ₅ ) _2- , -P (O) (R ₅ ) ₂ , or a substituted or unsubstituted monocyclic 3-7 membered ring containing 0 to 3 heteroatoms Wherein the heteroatoms are selected from O, N, or S, wherein the substituents are independently selected from R ₉ , or R ₁ or R ₂ may be a group of the following structural formulas: ,
[25]
[26] Wherein the D ring is a substituted or unsubstituted monocyclic 3-7 membered ring containing 0-3 heteroatoms (wherein said heteroatom is selected from O, N, or S, these substituents are R ₉ And R ₃ and R ₄ together may form a substituted or unsubstituted monocyclic 3-7 membered ring containing 0 to 3 heteroatoms (wherein the heteroatoms are O, N, Or S are independently selected from R ₉ ), or R ₁ and R ₂ may together form a substituted or unsubstituted monocyclic 5-7 membered ring containing 0 to 3 heteroatoms. Wherein the heteroatom is selected from O, N, or S and these substituents are selected from R ₉ ;
[27] R ₃ is hydrogen, hydroxy, amino, C ₁ -C ₁₂ alkyl, substituted C ₁ -C ₁₂ alkyl, alkylamino, aryl, C ₁ -C ₁₂ alkoxy, substituted C ₁ -C ₁₂ alkoxy, or 0-3 Monocyclic 3-7 membered ring comprising a heteroatom, wherein said heteroatom is selected from O, N, or S and these substituents are independently selected from R ₉ ;
[28] R ₄ is hydrogen, C ₁ -C ₁₂ alkyl, substituted C ₁ -C ₁₂ alkyl, aryl, or a monocyclic 3-7 membered ring containing 0 to 3 heteroatoms, wherein the heteroatoms are O, N Or is selected from S, and these substituents are independently selected from R ₉ ;
[29] R ₅ is hydrogen, C ₁ -C ₁₂ alkyl, substituted C ₁ -C ₁₂ alkyl, alkylamino, alkoxy, aryl, or a monocyclic 3-7 membered ring containing 0 to 3 heteroatoms, wherein the hetero The atom is selected from O, N, or S, these substituents are independently selected from R ₉ ),
[30] As defined in formula (II), R ₆ located at the 5-position or the 6-position is selected from -NR ₈ P (O) (R ₅ ) ₂ , or a group of the formula
[31]
[32] Wherein the D ring is a substituted monocyclic 5-7 membered ring containing 1 to 3 heteroatoms, wherein the heteroatom is selected from O, N, or S, which substituents are independently from R ₉ And the E ring is a substituted 5 membered heteroaromatic ring containing 1 to 3 heteroatoms, or a monocyclic 3, 4, 6, or 7 membered heterocyclyl, wherein the heteroatoms are O, N, Or S, these substituents are independently selected from R ₉ ), and Q is selected from -NR _8- , -C (O)-, or -O-;
[33] R ₇ is selected from hydrogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy, halogen, cyano, SO ₂ R ₄ , SO ₂ NR ₄ R ₄ , or R ₇ and R ₆ are 1 to 3 A fused substituted 5-7 membered ring containing 3 heteroatoms, wherein the heteroatom is selected from O, N, or S, and these substituents are independently selected from R ₉ , and
[34] R ₈ is C ₂ -C ₁₂ substituted alkyl, C ₃ -C ₁₂ branched alkyl, C ₂ -C ₆ (alkylene) R ₁₄ , -CH (CF ₃ ) ₂ , -CH ((CF ₂ ) _n CF ₃ ) _n , -CH (CF ₃ ) R ₁₁ , -CHR ₁₂ (aryl), -CHR ₁₁ (heteroaryl), -CHR ₁₁ (heterocyclyl), cycloalkyl, or a group containing 0 to 3 heteroatoms A cyclic 3-7 membered ring, wherein the heteroatom is selected from O, N, or S, these substituents are independently selected from R ₉ , and
[35] R ₉ is hydrogen, halogen, -CN, -C (O) CF ₃ , -S (O) _n CF ₃ , -C (O) CH ₂ F, -CH (OH) CF ₃ , -N (CN) ₂ , -C (CN) ₃ , -CHR ₁₀ R ₁₁ , C ₁ -C ₁₂ alkyl, substituted C ₁ -C ₁₂ alkyl, -CF ₃ ,-(CF ₂ ) _m CF ₃ , -CH (CF ₃ ) ₂ , -CF (CF ₃ ) _2- , -SO ₃ H, alkylamino, alkylsulfanyl, aryl, C ₁ -C ₁₂ alkoxy, substituted C ₁ -C ₁₂ alkoxy, C (X) R ₁₀ , -CR ₁₁ (V ) R ₁₂ , -CH ₂ CR ₁₁ (V) R ₁₂ , -S (O) _n R ₁₂ , -S (O) ₂ NHMe (OH), -S (O) ₂ NH (2-thiazolyl),- (4-oxo-2-thioxo-thiazolidine-5-ylidene), tetrazolyl, CH ₂ (1,1-dioxo-1 lambda * 6 * -thiomorpholin-4-yl), -S (O) ₂ CH ₂ NO ₂ , -S (O) ₂ CH ₂ S (O) ₂ R ₁₂ , -P (O) (OR ₁₁ ) R ₁₂ , -NR ₁₁ P (O) OR ₁₂ , -P ( O) (NR ₁₁ R ₁₂ ), a substituted or unsubstituted monocyclic 3-7 membered ring containing 1 to 3 heteroatoms, wherein the heteroatom is selected from O, N, or S;
[36] R ₁₀ is selected from hydroxy, amino, NHCN, C ₁ -C ₁₂ alkyl, substituted C ₁ -C ₁₂ alkyl, cycloalkyl, alkylamino, C ₁ -C ₁₂ alkoxy, -CF ₃ , heterocyclyl, aryl Become;
[37] R ₁₁ is selected from hydrogen, C ₁ -C ₁₂ alkyl, substituted C ₁ -C ₁₂ alkyl, heterocyclyl, or aryl;
[38] R ₁₂ is selected from C ₁ -C ₁₂ alkyl, substituted C ₁ -C ₁₂ alkyl, heterocyclyl, or aryl;
[39] R ₁₃ is substituted C ₂ -C ₁₂ alkyl, substituted C ₂ -C ₁₂ alkenyl, substituted C ₂ -C ₁₂ alkynyl, heterocyclyl, alkylether, alkylamino, and unsubstituted or substituted heteroaryl or p − R ₉ -substituted phenyl;
[40] R ₁₄ is selected from -COR ₃ , R ₆ ;
[41] A is a bond, -NR _5- , or -CR ₄ R _5- ;
[42] B is a bond, -NR _4- , -CR ₄ H-, -CR ₄ (OH)-or -CR ₄ R _5- ;
[43] G is -CH (CH ₂ ) _m -,> C = CH-, -N (CH ₂ ) _m ;
[44] L is a bond, -O-, -C (O)-, -NR _5- , -CR ₄ H-, -CR ₄ (OH)-or -CR ₄ R _5- , -NHNR _5- ;
[45] Q is a bond, -NR _5- , -C (O)-, -O-, or -CR ₄ R _5- ;
[46] X is O, S, NR ₄ , NOR ₄ , NCN, NNO ₂ , CR ₁₁ NO ₂ , CR ₁₁ CN, C (CN) ₂ , CR ₁₁ R ₁₂ , or N-NR ₁₁ R ₁₂ ;
[47] V is -OH, -SH, -CN;
[48] m is 0, 1, 2, or 3;
[49] n is 1 or 2.
[50] As noted above, the compounds of the present invention may be provided as prodrugs, examples of which are as follows.
[51]
[52] The general formula (III) is represented by disulfide bonds, but is converted to an activated form, ie, general formula (I) in vivo. Formula (IV) is shown as ethyl ester, but is converted in vivo to its corresponding acid, ie -CO ₂ H form.
[53]
[54] Those skilled in the art for their arrangement indicates the arrangement of the substituents R _i and R _j at any position, the relative positions of R _i and R _j in the above structure is in the right ring for any position and each other with the above structure can be used in the ring It will be appreciated. This arrangement has been used to denote radicals that can be placed at any available valence throughout the specification of the present invention without further suggestion.
[55] In addition, with respect to the nomenclature of the present invention, while clearly named compounds have been generally named using IUPAC agreements, structurally described compounds are given the following ring numbering regardless of the heteroatoms present in the IUPAC agreements or rings. Use):
[56]
[57] Therefore, the compounds, for example, contain heteroatoms such as N at the six-membered site in the ring, the radicals attached to that part of the ring are described by the numbering indicated above. Thus, they represent the following heterocycles.
[58]
[59] Except where the compound is explicitly named, the above-mentioned numbering arrangement is applied to describe "structure (II)".
[60] There are some preferred embodiments of the invention. One such preferred embodiment is that in the general formulas (I) and (II) Y is a sulfur atom. In another preferred embodiment, ring C in formula (I) is pyridine or pyrimidine. Another preferred embodiment is that in the general formula (I) the substituents R ₁ and R ₂ are located in position 5 or 6, as represented by the following structures:
[61]
[62] In another preferred embodiment, the substituent R ₂ is hydrogen or absent and R ₁ is attached at the 6-position as indicated by the following structural formulas:
[63]
[64] In another preferred embodiment, ring C is pyrimidine and substituent R ₂ is hydrogen or absent and R ₁ is attached at the 6-position as shown by the following structural formula:
[65]
[66] Wherein the substituent R ₁ is a group of the following structural formulas:
[67]
[68] More preferred embodiments are those wherein R ₁ is selected from the following structural formulas:
[69]
[70] More preferred embodiments include, in the functional groups listed above, R _{5 ′} is hydrogen, R ₅ is C ₃ -C ₁₂ branched alkyl, C ₂ -C ₈ (alkylene) R ₁₄ , cycloalkyl, —CH ₂ ( Heterocyclyl), -CH ₂ (aryl), heterocyclyl, R ₄ is substituted C ₆ -C ₁₂ alkyl, C ₂ -C ₈ (alkylene) C ₁₄ , substituted heteroaryl, substituted heterocyclyl Or p- R ₉ -substituted phenyl. More preferably, R ₄ is substituted 5-6 membered heterocyclyl, R ₉ -substituted heteroaryl, or p -R ₉ -substituted phenyl.
[71] In another preferred embodiment, substituent R ₇ in formula (II) is hydrogen and R ₆ is attached at the 6-position as shown in the following structural formula:
[72]
[73] More preferred embodiments are those in which R ₆ is selected from the following structures:
[74]
[75] Particularly preferred embodiments include those in which R ₈ is C ₃ -C ₁₂ branched alkyl, C ₂ -C ₈ (alkylene) R ₁₄ , cycloalkyl, -CH ₂ (heteroaryl), -CH ₂ (heterocyclyl), Heterocyclyl and R ₁₃ is substituted C ₆ -C ₁₂ alkyl, C ₂ -C ₈ (alkylene) R ₁₄ , heterocyclyl, substituted heteroaryl, or p- R ₉ -substituted phenyl. More preferably, R ₁₃ in the functional group is R ₉ -substituted heteroaryl or p -R ₉ -substituted phenyl.
[76] Further preferred embodiments, in the above structures, R ₈ is C ₃ -C ₇ branched alkyl, in particular isopropyl and isobutyl, C ₃ -C ₇ cycloalkyl in particular cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, 5-6 membered heterocyclyl, especially terahydropyranyl, tetrahydrofuranyl, piperidinyl, and pyrrolininyl, -CH ₂ (heteroaryl), especially methylpyridinyl, methyl thiazolyl, and methyl isoxa Zolyl, -CH ₂ (heteroaryl), especially methyltetrahydropyranyl, methyltetrahydrofuranyl, methylpiperidinyl, and methylpyrrolininyl; And R ₁₃ is C ₂ -C ₈ (alkylene) R ₁₄ , more preferably — (CH ₂ ) _2-8 R ₁₄ , unsubstituted heteroaryl, or R ₉ -substituted heteroaryl, especially 5-6 membered hetero Aryl, for example pyridyl and oxazolinyl, thiophenyl, particularly preferably R ₁₃ is p- R ₉ -substituted phenyl.
[77] A very preferred embodiment is that in the above structures, R ₁₃ is p -R ₉ -substituted phenyl, most preferably wherein R ₉ is -CN-, -C (O) CF ₃ , -S (O) _n CF ₃ , -C (O) CH ₂ F, -CH (OH) CF ₃ , -N (CN) ₂ , -C (CN) ₃ , -CHR ₁₀ R ₁₁ , C ₁ -C ₁₂ alkyl, substituted C ₁ -C ₁₂ alkyl, -CF ₃ -,-(CF ₂ ) _m CF ₃ , -CH (CF ₃ ) ₂ , -CF (CF ₃ ) ₂ , -SO ₃ H, C ₂ -C ₁₂ alkoxy, substituted C ₂ -C ₁₂ alkoxy, -C (X) R ₁₀ , -CR ₁₁ (V) R ₁₂ , -CH ₂ CR ₁₁ (V) R ₁₂ , -S (O) _n R ₁₂ , -S (O) ₂ NHMe (OH), -S (O) ₂ NH (2-thiazolyl),-(4-oxo-2-thioxo-thiazolidine-5-ylidene), tetrazolyl, -CH ₂ (1,1- Dioxo-1 lambda * 6 * -thiomorpholin-4-yl), -S (O) ₂ CH ₂ NO ₂ , -S (O) ₂ CH ₂ S (O) ₂ R ₁₂ , -P (O) (OR ₁₁ ) R ₁₂ , -NR ₁₁ P (O) OR ₁₂ , -P (O) (NR ₁₁ R ₁₂ ), or a ring selected from the following structural formulas:
[78]
[79] Particularly preferred embodiments are of the following structural formula:
[80]
[81] In which R ₆ is
[82]
[83] Is selected from the formula
[84] Most preferred R ₈ is selected from C ₃ -C ₇ branched alkyl, C ₃ -C ₇ cycloalkyl, 5-6 membered heterocyclyl,-(CH ₂ ) _4-8 R ₁₄ , most preferred R ₁₃ is R ₉ -substituted 5-6 membered heteroaryl, or p -R ₉ -substituted phenyl, wherein the most preferred R ₉ is F, Cl, Br, I, OH, -CN, -N (CN) ₂ , -C (CN) ₃ , CF ₃ ,-(CF ₂ ) _m CF ₃ , -CH (CF ₃ ) ₂ , -CF (CF ₃ ) ₂ , -SO ₃ H, C ₂ -C ₁₂ alkylsulfanyl, C ₂ -C ₁₂ alkoxy, substituted C ₂ -C ₁₂ alkoxy, -C (X) R ₁₀ , tetrazolyl, 3-hydroxy-isoxazol-4-yl, 3-hydroxy-isoxazol-5-yl Most preferred R ₁₄ is —C (X) R ₁₀ wherein X is O, NH ₂ , NCN, NNO ₂ , and most preferred R ₁₀ is —OH, amino, alkylamino, CF ₃ , NHCN, And 5-6 membered heterocyclyl).
[85] Composition
[86] The composition of the present invention,
[87] (a) a safe, therapeutically effective amount of an MCD inhibitory compound (I) or (II), a corresponding enantiomer, diastereomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, or prodrug thereof; And
[88] (b) a pharmaceutically acceptable carrier.
[89] As noted above, a number of diseases can be mediated by MCD related therapies. Thus, the compounds of the present invention are useful for the treatment of conditions involving this MCD activity.
[90] Accordingly, the compounds of the present invention can be prepared in pharmaceutical compositions for use in the prevention, treatment, and treatment of these conditions. Standard pharmaceutical pharmaceutical formulation techniques are used, such as those described in Remington's Pharmaceutical Sciences, published by Mac Publishing Company, Easton, Pennsylvania.
[91] A "safe, therapeutically effective amount" of a compound of the present invention, when used in the methods of the present invention, refers to a tissue to be tested, in reasonable ratios of benefit / risk, without excessive side effects (toxic, irritant or allergic reactions), or To the cell, preferably at an active site in an animal, more preferably in a mammal, an amount effective to inhibit MCD. The specific "safe and therapeutically effective amount" means the specific condition to be treated, the physical condition of the patient, the duration of the treatment, the nature of the accompanying therapy (if any), the specific formulation to be used, the carrier used, and the compound therein. The solubility, and the dosage regimen required for the composition, and the like vary clearly.
[92] In addition to the compounds of the present invention, the compositions of the present invention contain a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers, diluents or encapsulating materials, suitable for administration to a mammal. As used herein, the term "compatible" is used in admixture with a compound of the present invention in such a way that the components of the composition do not interact with substantially reducing the pharmaceutical efficacy of the composition under normal conditions of use. It can be. Pharmaceutically acceptable carriers must, of course, be sufficiently pure and of low toxicity to be suitable for administration to the animal to be treated, preferably a mammal.
[93] Some examples of substances that can act as pharmaceutically acceptable carriers or components thereof include sugars such as lactose, glucose, and sucrose; Starches such as corn starch and potato starch; Cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; Powdery tragacanth; malt; gelatin; Talc; Solid lubricants such as stearic acid and magnesium stearate; Calcium sulfate; Vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cacao oil; Polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; Arginine acid; Emulsifiers such as TWEENS; Wetting agents, such as sodium lauryl sulfate; coloring agent; Flavoring agents; Tableting agents; Stabilizer; Antioxidants; antiseptic; Pyrogen-free water; Isotonic saline; And phosphate buffers.
[94] The choice of pharmaceutically acceptable carrier used in connection with the compound of the present invention is basically determined by the manner in which the compound is administered.
[95] When the compound of the present invention is injected, a preferred pharmaceutically acceptable carrier is sterile saline solution containing a suspending agent compatible with blood and having a pH adjusted to about 7.4. In particular, pharmaceutically acceptable carriers for systemic administration include sugars, starches, cellulose and derivatives thereof, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffers, emulsifiers, isotonic saline, and Depyrogen water is included. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. In compositions for parenteral administration, the pharmaceutically-acceptable carrier preferably comprises at least about 90% by weight of the total composition.
[96] The composition of the present invention is preferably provided in unit dosage form. As used herein, a “unit dosage form” is a composition of the present invention which contains, in accordance with good medical practice, an amount of a compound suitable for administration to an animal, preferably a mammal, in a single dosage (but not in a single or unit). This does not mean that the formulation of the formulation is administered once per day or once per course of treatment, such formulations are intended to be administered once, twice, three times or more per day, with the exception of a single administration being specifically excluded. However, it is expected to be administered one or more times during the course of treatment The person skilled in the art will recognize that formulations do not specifically take into account the entire course of treatment, and that such decisions are left to those skilled in the therapeutic field rather than formulation). These compositions preferably contain at least about 5 mg (milligrams) of the selected compound, more preferably from about 10 mg to about 1000 mg more, more preferably about 500 mg, most preferably up to about 300 mg.
[97] The compositions of the present invention may be in any of a variety of forms suitable for oral, nasal, rectal, topical (including transdermal), ocular, intracranial, intravenous, intramuscular, or parenteral administration (for example). It will be appreciated that oral, nasal compositions consist of compositions administered by inhalation and prepared by available methodologies). Depending on the particular route of administration desired, various pharmaceutically acceptable carriers well known to those skilled in the art can be used. These include solid or liquid fillers, diluents, hydrotropy, surfactants, and encapsulating materials. Any pharmaceutically active substance may be included that does not substantially interfere with the inhibitory activity of the compound. The amount of carrier used in connection with the compound of the present invention is an amount sufficient to provide a substantial amount of the substance for administration per unit dose of the compound. Techniques and compositions for formulating formulations useful in the methods of the present invention are all described in the following quotations: Modern Pharmaceutics, Chapter 9 and 10 (Banker & Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms second Edition (1976).
[98] Various oral formulations can be used, including tablets, capsules, granules and bulk powders. These oral formulations comprise a safe and effective amount of a compound of the invention, typically at least about 5%, preferably about 25 to about 50%. Tablets may be compressed, tablet ground, enteric coating, sugar coating, film coating or multiple compression by containing suitable binders, lubricants, diluents, disintegrants, colorants, flavors, flow-inducing agents and solubilizers. Liquid oral formulations contain suspensions, foams, reconstituted into aqueous solutions, emulsions, suspensions, solutions and / or non-foamed granules, containing suitable solvents, preservatives, emulsifiers, suspensions, diluents, sweeteners, solubilizers, colorants and flavoring agents. Blowing agent reconstituted into granules.
[99] Pharmaceutically acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well known in the art. Typically, tablets are conventional pharmaceutically compatible excipients such as inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; Binders such as starch, gelatin and sucrose; Disintegrants such as starch, alginic acid and croscarmellose; Lubricants such as magnesium stearate, stearic acid and talc. In order to improve the flow characteristics of the powder mixture, glidants such as silicon dioxide can be used. For appearance, colorants such as FD & C dyes can be added. Sweetening and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors are useful excipients in chewable tablets. Typically, capsules contain one or more of said solid diluents. The choice of carrier components depends on minor minor aspects such as taste, cost, and storage stability, and can be readily selected by those skilled in the art.
[100] Oral compositions also include liquid solutions, emulsions, suspensions, and the like. Pharmaceutically-acceptable carriers suitable for the preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene, glycols, polyethylene glycols, liquid sucrose, sorbitol and water. For suspensions, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; Typical wetting agents include lecithin and polysorbate 80; And typical preservatives include methyl paraben and sodium benzoate. Oral liquid compositions may also include one or more ingredients such as sweeteners, flavoring agents and coloring agents.
[101] Such compositions are also coated by conventional methods, typically pH-dependent or time-dependent coating, so that the compounds of the present invention are released from the gastrointestinal tract near the desired topical application, or extend the desired action over several times. Such formulations typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coating, wax and cellac.
[102] The composition of the present invention may optionally comprise other drug active substances.
[103] Other compositions useful for achieving systemic delivery of a compound of the present invention include sublingual formulations, oral formulations and nasal formulations. Typically, such compositions are, for example, soluble precursors such as sucrose, sorbitol and mannitol; Binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents may also be included.
[104] The compositions of the present invention can also be administered to a patient transdermally topically, for example, by directly applying or applying the composition onto the epidermal or epithelial tissue of a patient or using a "patch". Such compositions may include, for example, lotions, creams, solutions, gels and solids. These topical compositions comprise a stable and effective amount of a compound of the invention, generally at least about 0.1%, preferably about 1 to about 5%. Suitable carriers for topical administration are kept in place on the skin in a continuous film state and are not removed when sweaty or soaked in water. Generally, the carrier is organic in nature and can disperse or dissolve the compound therein. Carriers may include pharmaceutically acceptable emollients, emulsifiers, thickening agents, solvents, and the like.
[105] Dosing method
[106] The compounds and compositions of the present invention can be administered locally or systemically. Systemic applications include methods of introducing the compound into body tissues, for example intraarticular, intrathecal, dural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, inhalation, rectal or oral. Included. The compound of the present invention is preferably administered orally.
[107] The duration of treatment as well as the specific dosage of compound to be administered will be individualized by the treating clinician. Typically, for adults (about 70 kg body weight), the selected compound is administered at least about 5 mg per day, preferably up to about 10 mg to about 3000 mg, more preferably up to about 1000 mg, most preferably up to 300 mg. It is understood that such ranges of dosage are by way of example only and that the daily dosage may be adjusted according to the above factors.
[108] Of course, the compounds of the present invention may be administered alone or in a mixture above, and further the composition may further comprise additional drugs or excipients to suit the indication. For example, in the treatment of cardiovascular diseases, the compounds of the present invention can be clearly used in combination with beta-blockers, calcium antagonists, ACE inhibitors, diuretics, angiotensin receptor inhibitors, or known cardiovascular agents or therapies. It was intended. Thus, in this embodiment, the novel compounds or compositions of the present invention are useful when administered with other active agents and can be mixed in a single formulation or composition.
[109] In addition, the compositions of the present invention may be administered in the form of liposome delivery systems such as small unilamellar vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from various phospholipids such as cholesterol, stearylamine or phosphatidylcholine.
[110] Justice
[111] As used herein, "alkyl" refers to straight chain alkanes, alkenes, or alkyne substituents having only carbon and hydrogen, such as methyl, ethyl, butyl, pentyl, heptyl and the like. Alkyl groups may be saturated or unsaturated (ie, including —C═C— or —C≡C— bonds) at one or several positions. When a certain degree of unsaturation is desired, the substituents refer to "alkenyl" or "alkynyl" which represent substituents each containing a -C = C- or -C≡C- bond. Carbon number may be represented as “C _i -C _j -alkyl”, where i and j refer to the minimum and maximum number of carbon atoms, respectively. Typically, the alkyl group will comprise 1 to 12 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 2 to 8 carbon atoms.
[112] As used herein, "substituted alkyl" refers to a hydrocarbon substituent that is linear, cyclic or branched, wherein one or more hydrogen atoms are carboxy, hydroxy, alkoxy, cyano, nitro, carbonyl, aryl, carboxy Substituted with alkyl, mercapto, amino, amido, ureido, carbamoyl, sulfonamido, sulfamido, or halogen. Preferred substituted alkyls have their alkyl spacers (i.e. alkyl moieties) that are 1 to about 5 carbons, may be branched or linear, and may include cyclic substituents as part or all of their structure. Preferred examples of "substituted alkyl" include 4-carboxybutyl, pyridin-2-ylmethyl, and 1,3-thiazol-2-ylmethyl, benzyl, phenethyl, and trifluoromethyl. The term "substituted alkyl" can be combined with terms accepted in the art. For example, "substituted alkoxy" means alkoxy in which the alkyl portion of the substituent is substituted, as understood in the art.
[113] As used herein, "branched alkyl" means a subset of "alkyl" and is thus a branched hydrocarbon substituent. Preferred branched alkyls have 3 to about 12 carbons and may include cycloalkyl in their structure. Examples of branched alkyl include isopropyl, isobutyl, 1,2-dimethyl-propyl, cyclopentylmethyl and the like. "Branched alkyl" can be combined with terms that are acceptable in the art. For example, "branched alkoxy" means alkoxy having an alkyl portion of the substituent, as understood in the art.
[114] As used herein, "cycloalkyl" is a hydrocarbon substituent that is cyclic and may be substituted or unsubstituted. When it is substituted, one or more hydrogen atoms are carboxy, hydroxy, alkoxy, cyano, nitro, carbonyl, aryl, carboxyalkyl, mercapto, amino, amido, ureido, carbamoyl, sulfonamido, sulfamido Or halogen. Preferred cyclic alkyls are those having from 3 to about 7 carbons. Examples of cycloalkyl include cyclopropyl, cyclopentyl, 4-fluoro-cyclohexyl, 2,3-dihydroxy-cyclopentyl and the like.
[115] As used herein, "alkylene" is an alkyl diradical, ie, alkyl having valences open to two different carbon atoms. Therefore, "(alkylene) R _i " is an alkyl diradical attached to one carbon and at least one carbon away from the point of attachment has a substituent R _i attached to the other carbon. Alkylene may be linear, branched, or cyclic. Examples of alkylene include -CH ₂ , CH ₂ CH ₂ -,-(CH ₂ ) ₄ ,-(cyclohexyl)-and the like.
[116] As used herein, "aryl" is substituted or unsubstituted with a single-ring (eg, phenyl) or multiple condensed ring (eg, naphthyl or anthryl), containing 0-4 heteroatoms. It is a cyclic aromatic group and the Huckel 4n + 2 rule applies. Therefore, the term "heteroaryl" is expressly intended to be the term "aryl". Preferred carbocyclic aryl is phenyl. Preferred monocyclic heterocycles, ie heteroaryls, are five or six membered rings. When the term "aryl" refers to an aromatic heterocycle, aryl refers to "heteroaryl" or "heteroaromatic", preferably having one or more heteroatoms. The preferred number of such heteroatoms is 1 to 3 N atoms, preferably when "heteroaryl" is a 5 membered heterocycle it has 1 or 2 heteroatoms selected from O, N, or S. Thus, preferred heterocycles have up to three, preferably up to two heteroatoms in the aromatic ring. Those skilled in the art will recognize that among heteroaryls there are both five and six membered rings. Examples of “heteroaryl” are thienyl, pyridyl, pyrimidyl, pyridazyl, furyl, oxazolyl, imidazolyl, thiazolyl, oxdiazolyl, triazylyl, triazolyl, thiadizolyl, and others skilled in the art will recognize. Including that. In this definition, it is clearly intended that the substitution in the aryl ring is within the scope of the present invention. When substitution occurs, the radical is referred to as "substituted aryl". Preferably one to three, more preferably one to two, and most preferably one substituent is attached to the aryl ring. While many substituents will be useful, preferred substituents include those commonly found in aryl compounds such as alkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkyl, mercapto and the like. Such substituents are prepared using known methods. These substituents may be attached to various positions of the aryl ring, with certain positions being preferred, which positions are denoted by "o, m, p -R _i -aryl". Thus, if the substituent R _i is attached at the para position of aryl, it is referred to as " p -R _i -substituted aryl".
[117] As used herein, "amide" includes both RNR'CO- (when R is alkyl, alkaminocarbonyl-) and RCONR'- (when R is alkyl, alkyl carbonylamino-).
[118] As used herein, "ester" includes both ROCO- (when R is alkyl, alkoxycarbonyl-) and RCOO- (when R is alkyl, alkylcarbonyloxy-).
[119] As used herein, "halogen" is a chlorine, bromine, fluorine or iodine atomic radical. Chloro, bromo and fluoro are preferred halogens. The term "halogen" is also sometimes used as the terms "halo" and "halide".
[120] As used herein, "alkylamino" is an amine radical in which at least one hydrogen atom in nitrogen is substituted with alkyl. Preferred examples include ethylamino, butylamino, isopropylamino and the like. The alkyl component can be linear, branched, cyclic, substituted, saturated, or unsaturated.
[121] As used herein, "alkylsulfanyl" is a thiol radical in which the hydrogen atom in sulfur is substituted with alkyl. Preferred examples include ethylsulfanyl, butylsulfanyl, isopropylsulfanyl and the like. The alkyl component can be linear, branched, cyclic, substituted, saturated or unsaturated.
[122] As used herein, "alkoxy" is a hydroxy radical in which a hydrogen atom is substituted with alkyl on oxygen. Preferred examples include ethoxy, butoxy, benzyloxy and the like. The alkyl component can be linear, branched, cyclic, substituted, saturated or unsaturated.
[123] As used herein, “heterocycle” means a saturated or unsaturated ring system, preferably a ring system that is 3-7 membered and non-aromatic. They may be substituted or unsubstituted and attached to any other part of the molecule using any available atoms, preferably using available carbon or nitrogen. More preferred heterocycles are 5- or 6-membered heterocycles. In a 6-membered monocyclic heterocycle, the heteroatom is 1-3 of O, N, or S, wherein the heterocycle is 5-membered, having one or two heteroatoms selected from O, N, or S desirable.
[124] As used herein, "heterocyclyl" means a radical heterocycle. It may be substituted or unsubstituted, and is attached to another using the valence which can be used, Preferably the carbon or nitrogen which can be used.
[125] As used herein, "sulfamido" refers to an alkyl-NS (O) ₂ N-, aryl-NS (O) ₂ N-, or heterocyclyl-NS (O) ₂ N- group, wherein Alkyl group, aryl group, heterocyclyl group is as defined above.
[126] As used herein, "sulfonamido" refers to an alkyl-S (O) ₂ N-, aryl-S (O) ₂ N-, or heterocyclyl-S (O) ₂ N- group, wherein Alkyl, aryl, or heterocyclyl groups are as described herein.
[127] As used herein, "ureido" refers to an alkyl-NCON-, aryl-NCON-, or heterocyclyl-NCON- group, wherein the alkyl, aryl or heterocyclyl group is as described herein.
[128] Substituents referred to herein as radicals may form a ring with other radicals described herein. When these radicals are bound, one skilled in the art will understand that there is no unsatisfied valence in this case, but one bond is made instead of a specific substituent, for example hydrogen. Therefore, certain radicals may be described as forming a ring together. Those skilled in the art will recognize that such rings are readily formed by conventional chemical reactions, and it would be within the understanding of those skilled in the art to anticipate both of these rings and methods of forming them. Preference is given to 3-7 membered rings, more preferably 5 or 6 membered rings. The compounds described herein may have cyclic structures such as R ₁ and R ₂ . In this regard, those skilled in the art will recognize that this described method is common in pharmacy, although the described method may not accurately reflect the chemical synthesis route. As used herein, the terms “ring”, “rings” when formed by the combination of two radicals refer to heterocyclic or carbocyclic radicals, which radicals may be saturated or unsaturated or aromatic. For example, preferred heterocyclic ring systems include heterocyclic rings such as morpholinyl, piperidinyl, imidazolyl, pyrrolidinyl, and pyridyl.
[129] Those skilled in the art will appreciate that radicals of the following structural formulae represent a number of different functional groups. Preferred functional groups represented by this structural formula include amides, ureas, thioureas, carbamates, esters, thioesters, amidines, ketones, oximes, nitroolefins, hydroxyguanidines, and guanidines. More preferred functional groups include urea, thiourea, amides, and carbamates.
[130]
[131] Those skilled in the art will appreciate that some of the structures shown herein may be resonant forms or tautomers of the compounds that may be clearly represented by other chemical structures. Those skilled in the art recognize that these structural forms are expressly intended to fall within the scope of the present invention, even if such resonance forms or tautomers are not described herein. For example, the following structural formulas clearly refer to the same compound, and reference to either means obviously different.
[132]
[133] In addition, the compound may be provided as a prodrug in the present invention exemplified by the following structural formula.
[134]
[135] Wherein R is a group (or bond) that is removed by a biological method. Therefore, silver, which is expressly intended in the present invention, is a compound provided as a biohydrolyzable prodrug, as is known in the art. As used herein, a "prodrug" is a compound that, when exposed to a biological process in an organism, is hydrolyzed, metabolized or derivatized to produce an active substance with the desired activity. Those skilled in the art will appreciate that a prodrug may or may not have any activity as a prodrug. The prodrugs described herein are intended to have no detrimental effect on the patient to be treated if administered in a safe and effective amount. These include, for example, biohydrolysable amides and esters. "Biohydrolysable amides" do not necessarily interfere with the activity of the compound or are readily converted in vivo by cells, tissues or human, mammalian or animal subjects, thereby obtaining the active compounds of the present invention. Compound. "Biohydrolysable ester" refers to an ester compound of the present invention that does not interfere with the activity of these compounds or is readily converted by an animal to produce the active compound (I). Such biohydrolysable prodrugs will be understood by those skilled in the art and are embodied in regulatory guidelines.
[136] The compounds and compositions of the present invention also particularly represent pharmaceutically acceptable salts, whether cationic or anionic. “Pharmaceutically acceptable salts” are anionic salts formed on acidic (eg carboxyl) groups or cationic salts formed on basic (eg amino) groups. Many such salts are known in the art, as described in International Publication No. 87/05297 to Johnston et al., Published September 11, 1987. Preferred counter-ions of salts formable at acidic groups include the cations of the salts, for example alkali metal salts (eg sodium and potassium) and alkaline earth metal salts (eg magnesium and calcium) and organic salts. Preferred salts formable at the basic position include anions such as halides (eg chloride salts). Of course, those skilled in the art know that many and various salts can be used, and examples of organic or inorganic salts useful in this process are shown in the literature.
[137] As the compounds of the present invention may contain one or more stereogenic centers, the "optical isomers", "stereoisomers", "enantiomers", "diastereomers" described herein have the meaning of standard technical recognition (see. Hawleys Condensed Chemical Dictionary , 11th Ed.), Racemates or their optical isomers, stereoisomers, enantiomers, diastereomers, are included in the claimed compounds.
[138] Likewise, compounds of the general formula (I) having several relative orientations of heteroatoms in ring C, in particular, have the meaning of standard technical recognition, as the compounds of the present invention may exist as "regio-isomers". Hawleys Condensed Chemical Dictionary , 11th Ed.), Included in the claimed compounds.
[139] As used herein, "metabolic disease" means a group of identified diseases in which metabolic abnormalities, metabolic imbalances, or suboptimal metabolism occur. Also as used herein, metabolic disease is intended to be a disease that can be treated through the regulation of metabolism, whether or not the disease itself is due to a particular metabolic disorder. Preferably, these metabolic diseases are associated with glucose and fatty acid oxidation pathways. More preferably, such metabolic disease is related to MCD or is regulated by the level of malonyl CoA, referred to herein as "MCD or MCA related disease".
[140] Starting materials used to prepare the compounds of the invention are known and can be prepared by known methods or are commercially available. It will be apparent to those skilled in the art that methods of preparing the precursors and the functional groups associated with the compounds claimed herein are generally described in the literature. It is feasible to prepare the compounds claimed by those skilled in the art by the literature and its description.
[141] Those skilled in the art of organic chemistry can readily carry out the manipulations without further guidance, that is to say, it is within the knowledge and practice of those skilled in the art to carry out these manipulations. This includes reduction of carbonyl compounds to their corresponding alcohols, reductive alkylation of amines, oxidation, acylation, aromatic substitutions, electrophilic and nucleophilic reactions, etherifications, esterifications and saponifications, and the like. These manipulations are described in standard textbooks such as March Advanced Organic Chemistry (Wiley), Carey & Sundberg, Advanced Organic Chemistry , and others.
[142] Those skilled in the art will readily understand that certain reactions perform best when other functional groups are masked or protected in the molecule, and thus will easily understand unwanted side reactions and / or increase reaction yield. Often, those skilled in the art employ protecting groups to increase yields or avoid unwanted side reactions. These reactions are disclosed in the literature and are well known to those skilled in the art. Many examples of these manipulations are described in T. Green & P. Wuts, Protecting Groups in Organic Synthesis , 2nd Ed., John Wiley & Sons (1991).
[143] The following exemplary schemes provide guidance to the reader and represent a preferred method for preparing the compounds exemplified herein. These methods are not limiting and it will be apparent that other routes may be used to prepare these compounds. Such methods include solid-based chemistry, in particular including binding chemistry. One skilled in the art can fully prepare these compounds by the methods given in the literature and herein.
[144]
[145] As shown in Scheme 1, amino-2-mercaptobenzothiazole ( 1 ), which is commercially available or readily prepared using known methods, is condensed with aldehydes or ketones and reduced with sodium cyanoborohydride to correspond. To produce N-alkylaniline ( 2 ). Compound ( 2 ) is then subjected to the corresponding urea or thiourea ( 3 ) (R ₁₃ is an aliphatic, aromatic, heterocyclyl or heteroaryl group), amide ( 4 ) (R ₁₃ is aliphatic, under the reaction conditions shown in the above diagram. , Aromatic, heterocyclyl or heteroaryl group), sulfonamide ( 5 ) (R ₁₃ is aliphatic, aromatic, heterocyclyl or heteroaryl group) or carbamate ( 6 ) (R ₁₃ is aliphatic, aromatic, heterocyclyl Aryl or heteroaryl group).
[146] As shown in to Figure 2, the thio hydantoin analogs (7) is treated in hot pyridine, compound (1) directly to the various amino acid isothiocyanato when isocyanato ester (R ₉ is alkyl, aryl, heterocyclyl group) It was prepared by.
[147]
[148] The pyrimidine and pyridine backbone ( 10 ) was obtained as shown in figure 3 below. Repeated substitution of chlorine in compound 8 (commercially available or prepared using known methods) with sodium diethyldithiocarbamate and primary amine (R ₄ NH ₂ ), respectively, was carried out in intermediate ( 9 ), Which is reduced / thiol hydrolyzed with basic sodium sulfide and condensed with potassium chianthate salt to give compound ( 10 ).
[149]
[150] Those skilled in the art will recognize that compounds such as compound ( 10 ) are used in the same manner as compound (1), as described above for the preparation of compounds in the present invention. Those skilled in the art will appreciate the use of pyrimidine and pyridine (ie, positional isomers thereof) as described in the same manner as for compound ( 1 ) for the preparation of the compounds described herein. Other compounds described in the present invention are described in applications CH010-01.PCT, CH010-02.PCT, and CH011-01.PCT, filed on January 12, 2002, by Arrhenius, Chen et al. It is prepared in a similar manner. The contents disclosed therein are incorporated herein by reference.
[151] Biological activity
[152] In vitro MCD Inhibition Assessment
[153] Mass spectrometry to determine malonyl-CoA decarboxylase activity assessment, described in the literature, can be adapted and adapted for the evaluation of MCD inhibitory activity in high throughput format (Kolattukudy et al., Methods in Enzymology 71: 150 (1981). Add the following reagents to a 96 well titer plate: Tris-HCl buffer, 20 μl; DTE, 10 μl; I-maleate, 20 μl; NAD, 20 μl; NADH, 25 μl; Water, 80 μl; Malic dehydrogenase, 5 μl. The contents were mixed, incubated for 2 minutes, and then 5 µl of citrate synthase was added. Next, 5 mu l of malonyl-CoA decarboxylase prepared from the rat heart and 20 mu l of malonyl-CoA were added. After incubation of the contents, the absorbance was measured at 460 nM.
[154] The active compound is characterized by the concentration of the compound that results in 50% inhibition of the MCD activity (IC ₅₀ ). Preferred compounds have IC ₅₀ values of less than 10 μM. Most preferred compounds have IC ₅₀ values of less than 100 μM.
[155] Table 1 shows the IC ₅₀ of MCD inhibitors
[156] TABLE 1
[157] compound IC ₅₀ (μM) Table 3; Entry 1 0.031 Table 3; Entry 3 0.093 Table 3; Entry 16 0.023 Table 3; Entry 17 0.042 Table 4; Entry 4 0.075 Table 4; Entry 6 1.604 Table 7; Entry 1 0.062 Table 7; Entry 8 0.052 Table 8; Entry 1 0.098 Table 8; Entry 7 0.025
[158] Measurement of Glucose Oxidation and Fatty Acid Oxidation in Perfused Rat Heart:
[159] The pulsatile heart extracted from Sprague-Dawley rat males for 60 minutes with modified Krebs-Henseleit solution containing 5 mmol / L glucose, 100 μU / mL insulin, 3% BAS, and 1.2 mmol / L palmitate Perfusion was carried out in the presence of oxygen. Pulsating hearts were used in these studies to approximate the metabolic needs of the heart seen in vivo (Kantor et al., Circulation Research . 86: 580-588 (2000)). The compound under test was added for 5 minutes during the perfusion phase.
[160] The oxidation rate of glucose is determined by quantitative collection of ¹⁴ CO ₂ produced in the heart perfused with a buffer containing [U14] -glucose. The oxidation rate of fatty acids is determined by quantitatively collecting ¹⁴ CO ₂ produced in the heart perfused with a buffer containing [ ¹⁴ C] -palmitate (McNeill, JH in "Measurement of cardiovascular function" , chapter 2, CRC). press, New York (1997)).
[161] The active compound is characterized by an increase in glucose oxidation as compared to the control test (DMSO). Compounds that cause a statistically significant increase in glucose oxidation are considered to be active. Preferred compounds are 20 μΜ, resulting in a statistically significant increase in glucose oxidation. Statistical significance is calculated using Student's t test of paired or unpaired samples as needed. Results with P <0.05 are considered statistically significant.
[162] To further illustrate the invention, the following examples are included. The examples should not be construed as particularly limiting the invention. Modifications of these embodiments that are within the scope of the claims within the scope of the understanding of those skilled in the art are also considered to be within the scope of the invention described herein and set forth in the claims. The reader will appreciate that those skilled in the art with the description of the present invention and those skilled in the art can prepare and use the present invention without thorough embodiments.
[163] The trademark used in the present invention is merely an example, and reflects the exemplary materials used at the time of the present invention. Those skilled in the art will recognize that variations in items, manufacturing methods, and the like are anticipated. Therefore, the examples and trademarks used in the present invention are not limited, and are not intended to be limiting, these are merely illustrative of how one skilled in the art may choose to carry out one or more embodiments of the present invention.
[164] Unless indicated otherwise, ¹ H nuclear magnetic resonance spectra (NMR) are measured in other solvents indicated by CDCl ₃ or Varian NMR spectrometer (Unity Plus 400, 400 MHz for ¹ H), with peak positions of tetramethyl It appears in ppm downfield from silane. The shape of the peak is as follows: s, singlet; d, doublet; t, triplet; m, represented by multiple lines.
[165] The following abbreviations have the following meanings:
[166] Ac = acetyl
[167] Bn = benzyl
[168] Bz = benzoyl
[169] CDI = carbonyl diimidazole
[170] CH ₂ Cl ₂ = dichloromethane
[171] DIBAL = diisobutylaluminum hydride
[172] DMAP = 4- (dimethylamino) -pyridine
[173] DMF = N, N-dimethylformamide
[174] DMSO = dimethyl sulfoxide
[175] EDCl or ECAC = 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloric acid
[176] ESIMS = Electron Spray Mass Spectrometry
[177] Et ₃ N = triethylamine
[178] EtoAc = ethyl acetate
[179] HMTA = hexamethylenetetramine
[180] LDA = lithium diisopropylamide
[181] LHDMS = lithium bis (trimethylsilyl) amide
[182] MgSO ₄ = magnesium sulfate
[183] NaH = sodium hydroxide
[184] NBS = N-bromosuccinimide
[185] NCS = N-chlorosuccinimide
[186] NH ₄ Cl = ammonium chloride
[187] Ph = phenyl
[188] Py = pyridinyl
[189] r.t. = Room temperature
[190] TFA = trifluoroacetic acid
[191] THF = tetrahydrofuran
[192] TLC = thin layer chromatography
[193] Tf ₂ O = triple anhydride
[194] Alkyl abbreviation
[195] Me = methyl
[196] Et = ethyl
[197] n-Pr = normal profile
[198] i-Pr = isopropyl
[199] n-Bu = normal butyl
[200] i-Bu = isobutyl
[201] t-Bu = tertiary butyl
[202] s-Bu = second butyl
[203] c-Hex = cyclohexyl
[204] Table 2 shows the preparation of N-alkyl benzothiazoles.
[205] TABLE 2
[206]
[207] EntryR ₈OneIsobutyl 24-pyridyl-2-ylmethyl 32-benzyloxy-ethyl 44-thiazol-2-ylmethyl 5Isopropyl 6Carboxymethyl 7-CH ₂ (5-methyl-thiophene)
[208] Synthesis method of N-alkyl benzothiazole
[209]
[210] 6-[(2-methylpropyl) amino] -1,3-benzothiazole-2-thiol (Table 2, entry 1):
[211] In a 500 mL round bottom flask, 6-amino-1,3-benzothiazole-2-thiol (5.0 g, 0.03 mol), hexanal (3.0 g, 0.03 mol), methanol (250 mL), glacial acetic acid (2.5 ML), water (1 mL), and NaCNBH ₃ (1.9 g, 0.03 mol) were added. The mixture was stirred for 4 hours, filtered, and the filtrate was concentrated to give a pale yellow solid. This solid was washed with water and treated with diethyl ether to give 4.0 g (61%) of the title compound. ¹ H NMR (DMSO-d ₆ ) δ = 0.88 (t, 6H), 1.79 (m, 1H), 2.77 (t, 2H), 6.64 (d, 1H), 6.72 (s, 1H), 6.99 (d, 2H); ESIMS: m / z 239 (MH)
[212] Table 3 shows the preparation of benzothiazole-ureido compounds.
[213] TABLE 3
[214]
[215] EntryR ₈ R ₁₃OneIsobutyl4- (trifluoromethyl) phenyl 2Isobutyl4-bromophenyl 3Isobutyl4-cyanophenyl 4Isobutyl4-pyridin-3-yl 54-pyridin-2-yl4-bromophenyl 64-pyridin-2-yl4- (trifluoromethyl) phenyl 74-pyridin-2-yl2-chloroethyl 8-CH ₂ (5-methyl-thiophene)4-bromophenyl 9-CH ₂ (5-methyl-thiophene)4- (trifluoromethyl) phenyl 102-benzyloxy-ethyl4-bromophenyl 112-benzyloxy-ethyl4- (trifluoromethyl) phenyl 124-thiazol-2-ylmethyl2-chloroethyl 134-thiazol-2-ylmethyl4- (trifluoromethyl) phenyl 14Isopropyl4-butoxyphenyl 15Isopropyl4-cyanomethylphenyl 16Isopropyl4- (trifluoromethyl) phenyl 17Isopropyl4-carboxymethylphenyl 18Isopropyl-(CH ₂ ) ₅ CO ₂ Et
[216] Synthesis method of benzothiazole-ureido compound
[217]
[218] N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (2-methylpropyl) -N '-[4- (trifluoromethyl) phenyl] urea (Table 3, entry One):
[219] In a 50 ml round bottom flask, 6-[(2-methylpropyl) amino] -1,3-benzothiazole-2-thiol (52.36 mg, 0.22 mmol), dichloromethane (10 ml), and α, α, α-trifluoro-p-tolyl isocyanate (41.1 mg, 0.22 mmol) was added. The reaction mixture was stirred for 8 hours, filtered and the resulting solid was treated in the order of chloroform, chloroform / methanol (9: 1 mixture) to give 60 mg (64%) of the title compound. ¹ H NMR (DMSO-d ₆ ) δ = 0.84 (d, 6H), 1.66 (m, 1H), 3.49 (d, 2H), 7.30 (s, 2H), 7.50 (d, 2H), 7.60 (d, 2H), 7.71 (s, 1 H); ESIMS: m / z 424 (MH)
[220] Table 4 shows the preparation of benzothiazole-carbamyl compounds.
[221] TABLE 4
[222]
[223] EntryR ₈ R ₁₃OneIsobutyl4-chlorophenyl 2Isobutyl4-methoxyphenyl 3Isobutyl4-fluorophenyl 4Isopropyl4-chlorophenyl 5Isopropyl2-methoxy-ethyl 6Isopropyl2-benzyloxy-ethyl
[224] Synthesis method of benzothiazole-carbamyl compound
[225]
[226] 4-Chlorophenyl 2 mercapto-1,3-benzothiazol-6-yl (methylpropyl) carbamate (Table 4, entry 1):
[227] 6-[(2-methylpropyl) amino] -1,3-benzothiazole-2-thiol (100 mg, 0.42 mmol), acetone (10 mL), N, N-diiso in a 50 mL round bottom flask Propylethylamine (54.2 mg, 0.42 mmol), and 4-chlorophenyl chloroformate (78.8 mg, 0.42 mmol) were added. The reaction mixture was stirred for 10 hours, and filtered, and the obtained solid was treated with diethyl ether to give 38 mg (48%) of the title compound. ¹ H NMR (DMSO-d ₆ ) δ = 0.85 (d, 6H), 1.70 (m, 1H), 3.53 (br s, 2H), 7.12 (d, 2H), 7.31 (d, 1H), 7.41 (m , 3H), 7.79 (s, 1 H); ESIMS: m / z 393 (M + H)
[228] Synthesis method of benzothiazole-sulfonamide compound
[229]
[230] 4-Fluoro-N-isopropyl-N- (2-mercaptobenzothiazol-6-yl) benzenesulfonamide:
[231] 6-[(2-methylpropyl) amino] -1,3-benzothiazole-2-thiol (200 mg, 0.89 mmol), pyridine (10 mL), and 4-fluorophenyl in a 50 mL round bottom flask. Sulfonyl chloride (208 mg, 1.07 mmol) was added. The reaction mixture was stirred for 1 hour and then concentrated. The obtained solid was treated with diethyl ether and then purified by preparative TLC (5% MeOH in CHCl ₃ ) to give 11 mg (3%) of the title compound. ¹ H NMR (DMSO-d ₆ ) δ = 0.90 (d, 6H), 4.41 (m, 1H), 6.91 (br s, 1H), 7.24 (br s, 1H), 7.41 (m, 3H), 7.77 ( m, 2H), 13.9 (br s, 1H): ESIMS: m / z 381 (MH)
[232] Table 5 shows the preparation of benzothiazole-thiohydantoin compounds.
[233] TABLE 5
[234]
[235] EntryR ₉OneHydrogen 2ethyl 3Isopropyl 4Isobutyl 5benzyl 62-methylsulfanyl-ethyl
[236] Synthesis method of benzothiazole-thiohydantoin compound
[237]
[238] 3- (2-mercapto-1,3-benzothiazol-6-yl) -2-thioxoimidazolidin-4-one (Table 5, entry 1):
[239] 6-amino-1,3-benzothiazole-2-thiol (108 mg, 0.59 mmol), methyl-2-isothiocyanatoacetate (94.8 mg, 0.72 mmol) in 13 100 mm screw cap Pyrex® vials, and Pyridine (2 mL) was added. The vial was washed with Ar, capped and shaken for 8 hours in a 60 ° C. oven. This solution was concentrated and the residue was treated with Et ₂ O to give a greenish brown powder (59 mg, 35%). ¹ H NMR (DMSO-d ₆ ) δ = 4.27 (s, 2H), 7.26 (d, 1H), 7.35 (d, 1H), 7.61 (s, 1H), 10.40 (s, 1H), 13.86 (br s , 1H); ESIMS: m / z 280 (MH); mp> 266 ° C.
[240] Table 6 shows the preparation of 5-alkylamino-thiazole [5,4-b] pyridine (or pyrimidine) -2-thiol.
[241] TABLE 6
[242]
[243] EntryzR ₅OneCHIsopropyl 2CHethyl 3CHHydrogen 4Nethyl 5NIsopropyl
[244] Synthesis method of 5-alkylamino-thiazole [5,4-b] pyridine-2-thiol
[245]
[246] Preparation of 5-isopropylamino-thiazole [5,4-b] pyridine-2-thiol (Table 6, entry 1):
[247] Step 1: 2,6-dichloro-3-nitropyridine (15.01 g, 77.78 mmol) and anhydrous THF were added to a 1 L flask. The solution was cooled in an ice water bath for 10 minutes, drained, degassed and washed with Ar. A solution of sodium diethyldithiocarbamate (19.34 g, 85.8 mmol) in 275 mL THF was prepared and degassed and then added dropwise to the chloropyridine solution for 30 minutes. The solution was stirred at 0 ° C. for 5 hours, then warmed up to room temperature. The solvent was evaporated and the dark orange residue was taken up in EtoAc, washed three times with water and once with brine. The orange fractions were dried (with MgSO ₄ ), filtered and concentrated to give an amber oil. Purification by flash column (SiO ₂ gel; 10% EtoAc / hexanes) gave 17.3 g (73%) of an orange oil (diethyl-dithiocarbamic acid 6-chloro-3-nitro-pyridin-2-yl ether).
[248] Step 2: A 250 mL round bottom flask was charged with the product obtained in step 1 (12.38 g, 40.48 mmol), K ₂ CO ₃ (5.64 g, 40.8 mmol), and acetonitrile (100 mL). Isopropylamine (3.5 mL, 40.5 mmol) was added thereto for 5 minutes, and then the solution was stirred overnight. The reaction solution was filtered through a 2 cm pad of Celite, concentrated and the residue was taken up in EtoAc, washed three times with 1 M citric acid and then brine. The orange fraction was dried (with MgSO ₄ ), filtered and concentrated to give an orange red oil. Crystallization with Et ₂ O / hexanes gave 12.3 g (92%) of the title compound ( 9 , Z = C, R ₅ = isopropyl) as orange crystals. ¹ H NMR (CDCl ₃ ) δ = 1.98 (d, 6H), 1.24 (t, 3H), 1.28 (t, 3H), 3.81 (q, 2H), 4.08 (q, 2H), 5.08 (d, 1H) , 6.18 (d, 1 H), 8.19 (d, 1 H)
[249] Step 3: A 250 mL round bottom flask was charged with the compound obtained in step 2 ( 9 ; Z = C, R ₅ = isopropyl, 4.55 g, 13.8 mmol) and EtOH (100 mL). To this was slowly added a solution of NaOH (5.66 g, 141 mmol) and Na ₂ S (5.58 g, 71.5 mmol) in 50 mL of water, and the reaction mixture was refluxed overnight in the presence of Ar. The reaction mixture was neutralized with citric acid to pH 6 and then concentrated. The residue was taken up in EtOAc to separate the layers. The aqueous fractions were extracted twice with EtOAc and the combined organic fractions were washed with brine, then dried (with MgSO ₄ ), filtered and concentrated to 3-amino as a brown cake. -6-isopropylamino-pyridine-2-thiol was obtained.
[250] 4 steps; Into a 250 mL round bottom flask containing the crude product (~ 13.8 mmol) obtained in step 3, ethyl chitinate, potassium salt (3.42 g, 21.3 mmol), and EtOH (100 mL) were added. The reaction mixture was refluxed for 5 hours in the presence of Ar, then cooled to about 40 ° C. and bleached with charcoal. Filtration through a 2 cm pad of Celite yielded a pale brown cake, which was dissolved in a minimum amount of water and acidified with acetic acid to yield the crude product as a tan solid. Filtration followed by washing with ether and water in order to give 2.55 g (82% from compound ( 9 )) of 5-isopropylamino-thiazole [5,4-b] pyridine-2-thiol (Table 6, Entry 1) was obtained. ¹ H NMR (DMSO-d ₆ ) δ = 1.09 (d, 6H), 3.90 (m, 1H), 6.44 (d, 1H), 6.74 (d, 1H), 7.25 (d, 1H), 13.36 (br s , 1H); ESIMS: m / z 224 (MH).
[251] Table 7 shows the preparation of [5,4-b] pyridine-ureido compounds.
[252] TABLE 7
[253]
[254] EntryR ₅ R ₄Oneethyl4-butoxyphenyl 2ethyl4- (trifluoromethyl) phenyl 3ethyl4-carboxymethylphenyl 4Isopropyl4-hexyloxyphenyl 5Isopropyl4-carboxymethylphenyl 6Isopropyl4- (1-oxo-ethyl) phenyl 7Isopropyl4-tert-butoxyphenyl 8Isopropyl4- (trifluoromethyl) phenyl
[255] Synthesis of [5,4-b] pyridine-ureido compounds
[256]
[257] 3- (4-Butoxy-phenyl) -1-ethyl-1- (2-mercapto-thiazolo [5,4-b] pyridin-5-yl) -urea (Table 7, entry 1):
[258] 5-ethylamino-thiazolo [5,4-b] pyridine-2-thiol (105 mg, 0.49 mmol), anhydrous pyridine (2 mL), and 4-butoxyphenyl isocyanate (135 μL) in 13 100 mm Pyrex reaction vials. 0.74 mmol) was added. The reaction mixture is stirred for 3.5 hours and then concentrated. Purification by preparative TLC (40% EtoAc in hexane) afforded 26 mg (13%) of the title compound. ¹ H NMR (DMSO-d ₆ ) δ = 0.91 (t, 3H), 1.10 (t, 3H), 1.39 (m, 2H), 1.61 (m, 2H), 3.91 (m, 1H), 6.80 (d, 2H), 7.30 (m, 3H), 7.99 (br d, 1H), 9.43 (s, 1H); ESIMS: m / z 401 (MH); mp 134.3-135 ° C.
[259] Table 8 shows the preparation of [5,4-b] pyridine-amido compounds.
[260] TABLE 8
[261]
[262] EntryR ₅ R ₄OneethylPhenoxymethyl 2ethylbenzyl 3ethyl4-butoxyphenyl 4ethyl4-hexyloxyphenyl 5ethylPyridin-4-yl 6Isopropyl3-methyl-butyl 7Isopropyl4- (trifluoromethyl) phenyl 8Isopropyl4-chlorophenyl
[263] Synthesis method of [5,4-b] pyridine-amido compound
[264]
[265] N-ethyl-N- (2-mercapto-thiazolo [5,4-b] pyridin-5-yl) 2-phenoxy-acetamide (Table 8, entry 1):
[266] In 13 100 mm Pyrex reaction vials, anhydrous pyridine (1.5 mL), 5-ethylamino-thiazolo [5,4-b] pyridine-2-thiol (99 mg, 0.47 mmol) and 4-butoxyphenyl isocyanate (100 μL) , 0.72 mmol). The reaction mixture was stirred for 2.5 hours and then concentrated. Purification by preparative TLC (40% EtoAc in hexanes) afforded 36 mg (22%) of the title compound. ¹ H NMR (DMSO-d ₆ ) δ = 1.02 (t, 3H), 3.73 (m, 2H), 6.70 (d, 2H), 6.86 (t, 1H), 7.19 (t, 2H), 7.29 (d, 1H), 7.59 (br d, 1H); ESIMS: m / z 344 (MH); mp 107.5-109.0 ° C.
[267] Synthesis method of [5,4-b] pyridine-carbamyl compound
[268]
[269] In a 1.5 mL microwave reaction vial, 5-isopropylamino-thiazolo [5,4-b] pyridine-2-thiol (50 mg, 0.22 mmol), anhydrous pyridine (1.5 mL), and 4-chlorophenyl chloroform Mate (40 μl, 0.29 mmol) was added. The reaction mixture was heated in microwave at 120 ° C. for 15 minutes and then concentrated. Purification by preparative TLC (40% EtoAc in hexanes) afforded the title compound (10.2 mg, 12%). ¹ H NMR (DMSO-d ₆ ) δ = 1.21 (d, 6H), 4.42 (m, 1H), 7.17 (d, 2H), 7.39 (d, 2H), 7.70 (d, 1H), 8.39 (d, 1 H; ESIMS: m / z 378 (MH).
[270] Modifications of the foregoing embodiments are formally within the scope of those skilled in the art, in light of the state of the art, while providing guidance in the specification of the present invention.
[271] While particular embodiments of the invention have been described, it will be apparent to those skilled in the art that various changes and modifications of the invention may not be made without departing from the spirit and scope of the invention. All such modifications that fall within the scope of the invention are intended to be included within the scope of the appended claims. Therefore, the foregoing detailed description is considered to be sufficient to enable those skilled in the art to practice the invention. Indeed, various modifications of the foregoing preparations for carrying out the invention which are obvious to those skilled in molecular biology, chemistry, medicine, pharmaceuticals or related fields are intended to be within the scope of the following claims.

权利要求:
Claims (34)
[1" claim-type="Currently amended] A compound selected from the group consisting of the compounds of the following formulas (I) and (II), the corresponding enantiomers, diastereomers or tautomers, or pharmaceutically acceptable salts, or pharmaceutically acceptable Their prodrugs in the carrier:
Wherein Y is selected from S or O; C is a substituted monocyclic 5-7 membered ring containing 1 to 3 heteroatoms, wherein these heteroatoms are selected from O, N, or S, wherein these substituents are from R ₁ and R ₂ is independently selected), R ₁ and R ₂ are different from each other, and each is hydrogen, halogen, hydroxy, nitro, cyano, C ₁ -C ₁₂ alkyl, substituted C _1- C ₁₂ alkyl, alkylamino, alkylsulfanyl, Aryl, C ₁ -C ₁₂ alkoxy, substituted C ₁ -C ₁₂ alkoxy, -C (X) R ₃ , -CR ₁₁ (V) R ₁₂ , -CH ₂ CR ₁₁ (V) R ₁₂ , -S (O) _n R _3- , -NR ₄ P (O) (R ₅ ) _2- , -P (O) (R ₅ ) ₂ , or a substituted or unsubstituted monocyclic 3-7 member containing 0 to 3 heteroatoms Independently selected from a ring wherein the heteroatoms are selected from O, N, or S, wherein the substituents are independently selected from R ₉ , or R ₁ or R ₂ may be a group of the following structural formulas: And

Wherein the D ring is a substituted or unsubstituted monocyclic 3-7 membered ring containing 0-3 heteroatoms (wherein said heteroatom is selected from O, N, or S, these substituents are R ₉ And R ₃ and R ₄ together may form a substituted or unsubstituted monocyclic 3-7 membered ring containing 0 to 3 heteroatoms (wherein the heteroatoms are O, N, Or S are independently selected from R ₉ ), or R ₁ and R ₂ may together form a substituted or unsubstituted monocyclic 5-7 membered ring containing 0 to 3 heteroatoms. Wherein the heteroatom is selected from O, N, or S and these substituents are selected from R ₉ ;
R ₃ is hydrogen, hydroxy, amino, C ₁ -C ₁₂ alkyl, substituted C ₁ -C ₁₂ alkyl, alkylamino, aryl, C ₁ -C ₁₂ alkoxy, substituted C ₁ -C ₁₂ alkoxy, or 0-3 Monocyclic 3-7 membered ring comprising a heteroatom, wherein said heteroatom is selected from O, N, or S and these substituents are independently selected from R ₉ ;
R ₄ is hydrogen, C ₁ -C ₁₂ alkyl, substituted C ₁ -C ₁₂ alkyl, aryl, or a monocyclic 3-7 membered ring containing 0 to 3 heteroatoms, wherein the heteroatoms are O, N Or is selected from S, and these substituents are independently selected from R ₉ ;
R ₅ is hydrogen, C ₁ -C ₁₂ alkyl, substituted C ₁ -C ₁₂ alkyl, alkylamino, alkoxy, aryl, or a monocyclic 3-7 membered ring containing 0 to 3 heteroatoms, wherein the hetero The atom is selected from O, N, or S, these substituents are independently selected from R ₉ ),
As defined in formula (II), R ₆ located at the 5-position or the 6-position is selected from -NR ₈ P (O) (R ₅ ) ₂ , or a group of the formula

Wherein the D ring is a substituted monocyclic 5-7 membered ring containing 1 to 3 heteroatoms, wherein the heteroatom is selected from O, N, or S, which substituents are independent from R ₉ And the E ring is a substituted 5 membered heteroaromatic ring containing 1 to 3 heteroatoms, or a monocyclic 3, 4, 6, or 7 membered heterocyclyl, wherein the heteroatoms are O, N , Or S, these substituents are independently selected from R ₉ ), and Q is selected from -NR _8- , -C (O)-, or -O-;
R ₇ is selected from hydrogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy, halogen, cyano, SO ₂ R ₄ , SO ₂ NR ₄ R ₄ , or R ₇ and R ₆ together are 1 to May form a fused substituted 5-7 membered ring comprising three heteroatoms, wherein the heteroatom is selected from O, N, or S, and these substituents are independently selected from R ₉ ,
R ₈ is C ₂ -C ₁₂ substituted alkyl, C ₃ -C ₁₂ branched alkyl, C ₂ -C ₆ (alkylene) R ₁₄ , -CH (CF ₃ ) ₂ , -CH ((CF ₂ ) _n CF ₃ ) _n , -CH (CF ₃ ) R ₁₁ , -CHR ₁₂ (aryl), -CHR ₁₁ (heteroaryl), -CHR ₁₁ (heterocyclyl), cycloalkyl, or a group containing 0 to 3 heteroatoms A cyclic 3-7 membered ring, wherein the heteroatom is selected from O, N, or S, these substituents are independently selected from R ₉ , and
R ₉ is hydrogen, halogen, -CN, -C (O) CF ₃ , -S (O) _n CF ₃ , -C (O) CH ₂ F, -CH (OH) CF ₃ , -N (CN) ₂ , -C (CN) ₃ , -CHR ₁₀ R ₁₁ , C ₁ -C ₁₂ alkyl, substituted C ₁ -C ₁₂ alkyl, -CF ₃ ,-(CF ₂ ) _m CF ₃ , -CH (CF ₃ ) ₂ , -CF (CF ₃ ) _2- , -SO ₃ H, alkylamino, alkylsulfanyl, aryl, C ₁ -C ₁₂ alkoxy, substituted C ₁ -C ₁₂ alkoxy, C (X) R ₁₀ , -CR ₁₁ (V ) R ₁₂ , -CH ₂ CR ₁₁ (V) R ₁₂ , -S (O) _n R ₁₂ , -S (O) ₂ NHMe (OH), -S (O) ₂ NH (2-thiazolyl),- (4-oxo-2-thioxo-thiazolidine-5-ylidene), tetrazolyl, CH ₂ (1,1-dioxo-1 lambda * 6 * -thiomorpholin-4-yl), -S (O) ₂ CH ₂ NO ₂ , -S (O) ₂ CH ₂ S (O) ₂ R ₁₂ , -P (O) (OR ₁₁ ) R ₁₂ , -NR ₁₁ P (O) OR ₁₂ , -P ( O) (NR ₁₁ R ₁₂ ), a substituted or unsubstituted monocyclic 3-7 membered ring containing 1 to 3 heteroatoms, wherein the heteroatom is selected from O, N, or S;
R ₁₀ is selected from hydroxy, amino, NHCN, C ₁ -C ₁₂ alkyl, substituted C ₁ -C ₁₂ alkyl, cycloalkyl, alkylamino, C ₁ -C ₁₂ alkoxy, -CF ₃ , heterocyclyl, aryl Become;
R ₁₁ is selected from hydrogen, C ₁ -C ₁₂ alkyl, substituted C ₁ -C ₁₂ alkyl, heterocyclyl, or aryl;
R ₁₂ is selected from C ₁ -C ₁₂ alkyl, substituted C ₁ -C ₁₂ alkyl, heterocyclyl, or aryl;
R ₁₃ is substituted C ₂ -C ₁₂ alkyl, substituted C ₂ -C ₁₂ alkenyl, substituted C ₂ -C ₁₂ alkynyl, heterocyclyl, alkylether, alkylamino, and unsubstituted or substituted heteroaryl or p − R ₉ -substituted phenyl;
R ₁₄ is selected from -COR ₃ , R ₆ ;
A is a bond, -NR _5- , or -CR ₄ R _5- ;
B is a bond, -NR _4- , -CR ₄ H-, -CR ₄ (OH)-or -CR ₄ R _5- ;
G is -CH (CH ₂ ) _m -,> C = CH-, -N (CH ₂ ) _m ;
L is a bond, -O-, -C (O)-, -NR _5- , -CR ₄ H-, -CR ₄ (OH)-, or -CR ₄ R _5- , -NHNR _5- ;
Q is a bond, -NR _5- , -C (O)-, -O-, or -CR ₄ R _5- ;
X is O, S, NR ₄ , NOR ₄ , NCN, NNO ₂ , CR ₁₁ NO ₂ , CR ₁₁ CN, C (CN) ₂ , CR ₁₁ R ₁₂ , or N-NR ₁₁ R ₁₂ ;
V is -OH, -SH, -CN;
m is 0, 1, 2, or 3;
n is 1 or 2.
[2" claim-type="Currently amended] The compound of claim 1, wherein Y is sulfur.
[3" claim-type="Currently amended] 3. A compound according to claim 1 or 2, wherein said ring C is pyridine or pyrimidine.
[4" claim-type="Currently amended] 4. A compound according to claim 3, wherein R ₁ and R ₂ are attached at the 5 or 6-position according to the arrangement defined by ring numbering as defined in formula (II) herein.
[5" claim-type="Currently amended] The compound of claim 4, wherein R ₁ or R ₂ is attached at the 6-position according to the arrangement defined in ring numbering as defined in formula (II) herein.
[6" claim-type="Currently amended] A compound according to claim 5 having the general formula

Wherein R ₁ is selected from the group of the following structural formula:

[7" claim-type="Currently amended] The compound of claim 6, wherein R ₁ is selected from the group of the following structural formula.

[8" claim-type="Currently amended] 8. The [5,4-b] pyridine compound according to claim 7, consisting of a compound selected from the group of amido compounds:
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (1-methylethyl) -4- (trifluoromethyl) benzamide,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (1-methylethyl) pyridine-4-carboxamide,
4-{(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) (1-methylethyl) amino] carbonyl} benzoic acid,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (1-methylethyl) -4- (2H-tetrazol-5-yl) benz amides,
4-cyano-N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (1-methylethyl) benzamide,
4- (3-hydroxyisoxazol-5-yl) -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (1-methylethyl Benzamide,
4- (cyanomethyl) -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (1-methylethyl) benzamide,
7-[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) (1-methylethyl) amino] -7-oxoheptanoic acid,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (1-methylethyl) -6- (1H-tetrazol-5-yl) hexane amides,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (1-methylethyl) -4-[(1,1,3,3,3 , -Pentafluoropropyl) oxy] benzamide,
4- (aminosulfonyl) -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (1-methylethyl) benzamide,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (2-methylpropyl) -4- (trifluoromethyl) benzamide,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (2-methylpropyl) pyridine-4-carboxamide,
4-{(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) (2-methylpropyl) amino] carbonyl} benzoic acid,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (2-methylpropyl) -4- (2H-tetrazol-5-yl) benz amides,
4-cyano-N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (2-methylpropyl) benzamide,
4- (3-hydroxyisoxazol-5-yl) -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (2-methylpropyl Benzamide,
4- (cyanomethyl) -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (2-methylpropyl) benzamide,
7-[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) (2-methylpropyl) amino] -7-oxoheptanoic acid,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (2-methylpropyl) -6- (1H-tetrazol-5-yl) hexane amides,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (2-methylpropyl) -4-[(1,1,3,3,3 , -Pentafluoropropyl) oxy] benzamide,
4- (aminosulfonyl) -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (2-methylpropyl) benzamide,
5-((2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) {[4-trifluoromethyl) phenyl] carbonyl} amino) pentanoic acid,
5-[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) (pyridin-4-ylcarbonyl) amino] pentanoic acid,
4-{[(4-carboxybutyl) (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] carbonyl} benzoic acid,
5-((2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) {[4- (2H-tetrazol-5-yl) phenyl] carbonyl} amino) penta Old Mountain,
5-[[(4-cyanophenyl) carbonyl] (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] pentanoic acid,
5-[{[4- (3-hydroxyisoxazol-5-yl) phenyl] carbonyl} (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino ] Pentanoic acid,
5-[{[4- (cyanomethyl) phenyl] carbonyl} (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] pentanoic acid,
7-[(4-carboxybutyl) (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] -7-oxoheptanoic acid,
5-{(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) [6- (1H-tetrazol-5-yl) hexanoyl] amino} pentanoic acid,
5-[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) ({4-[(1,1,3,3,3, -pentafluoropropyl) Oxy] phenyl} carbonyl) amino] pentanoic acid,
5-[{[4- (aminosulfonyl) phenyl] carbonyl} (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] pentanoic acid,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- [4- (2H-tetrazol-5-yl) butyl] -4- (tri Fluoromethyl) benzamide,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- [4- (2H-tetrazol-5-yl) butyl] pyridine-4-car Replica,
4-({(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) [4- (2H-tetrazol-5-yl) butyl] amino} carbonyl) benzoic acid ,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -4- (2H-tetrazol-5-yl) -N- [4- (2H-tetra Azol-5-yl) butyl] benzamide,
4-cyano-N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- [4- (2H-tetrazol-5-yl) butyl] Benzamide,
4- (3-hydroxyisoxazol-5-yl) -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- [4- (2H -Tetraazol-5-yl) butyl] benzamide,
4- (cyanomethyl) -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- [4- (2H-tetrazol-5-yl ) Butyl] benzamide,
7-{(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) [4- (2H-tetrazol-5-yl) butyl] amino} -7-oxohepta Old Mountain,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -6- (1H-tetrazol-5-yl) -N- [4- (2H-tetra Azol-5-yl) butyl] hexanamide,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -4-[(1,1,3,3,3, -pentafluoropropyl) oxy] -N- [4- (2H-tetrazol-5-yl) butyl] benzamide,
4- (aminosulfonyl) -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- [4- (2H-tetrazol-5-yl ) Butyl] benzamide,
N-ethyl-N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -4- (trifluoromethyl) benzamide,
N-ethyl-N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) pyridine-4-carboxamide,
4-{[ethyl (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] carbonyl} benzoic acid,
N-ethyl-N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -4- (2H-tetrazol-5-yl) benzamide,
4-cyano-N-ethyl-N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) benzamide,
N-ethyl-4- (3-hydroxyisoxazol-5-yl) -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) benzamide,
4- (cyanomethyl) -N-ethyl-N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) benzamide,
7- [ethyl (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] -7-oxoheptanoic acid,
N-ethyl-N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -6- (1H-tetrazol-5-yl) hexanamide,
N-ethyl-N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -4-[(1,1,3,3,3, -pentafluoro Propyl) oxy] benzamide,
4- (aminosulfonyl) -N-ethyl-N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) benzamide,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N-methyl-4- (trifluoromethyl) benzamide,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N-methylpyridine-4-carboxamide,
4-{[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) (methyl) amino] carbonyl} benzoic acid,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N-methyl-4- (2H-tetrazol-5-yl) benzamide,
4-cyano-N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N-methylbenzamide,
4- (3-hydroxyisoxazol-5-yl) -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N-methylbenzamide,
4- (cyanomethyl) -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N-methylbenzamide,
7-[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) (methyl) amino] -7-oxoheptanoic acid,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N-methyl-6- (1H-tetrazol-5-yl) hexanamide,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N-methyl-4- (1,1,3,3,3, -pentafluoropropyl ) Oxy] benzamide, and
4- (aminosulfonyl) -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N-methylbenzamide.
[9" claim-type="Currently amended] 8. The [5,4-b] pyridine compound according to claim 7, consisting of a compound selected from the group of ureido compounds:
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (1-methylethyl) -N '-[4- (trifluoromethyl) phenyl ] Urea,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (1-methylethyl) -N'-pyridin-4-ylurea,
4-({[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) (1-methylethyl) amino] carbonyl} amino) benzoic acid,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (1-methylethyl) -N '-[4- (2H-tetrazol-5 -Yl) phenyl] urea,
N '-(4-cyanophenyl) -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (1-methylethyl) urea,
N '-[4- (3-hydroxyisoxazol-5-yl) phenyl] -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N -(1-methylethyl) urea,
N '-[4- (cyanomethyl) phenyl] -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (1-methylethyl) Urea,
6-({[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) (1-methylethyl) amino] carbonyl} amino) hexanoic acid,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (1-methylethyl) -N '-[5- (1H-tetrazol-5 Pentyl] urea,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (1-methylethyl) -N '-{4-[(1,1,3 , 3,3, -pentafluoropropyl) oxy] phenyl} urea,
4-({[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) (1-methylethyl) amino] carbonyl} amino) benzenesulfonamide,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (2-methylpropyl) -N '-[4- (trifluoromethyl) phenyl ] Urea,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (2-methylpropyl) -N'-pyridin-4-ylurea,
4-({[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) (2-methylpropyl) amino] carbonyl} amino) benzoic acid,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- [4- (2-methylpropyl) -N '-(2H-tetrazol-5 -Yl) phenyl] urea,
N '-(4-cyanophenyl) -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (2-methylpropyl) urea,
N '-[4- (3-hydroxyisoxazol-5-yl) phenyl] -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N -(2-methylpropyl) urea,
N '-[4- (cyanomethyl) phenyl] -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (2-methylpropyl) Urea,
6-({[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) (2-methylpropyl) amino] carbonyl} amino) hexanoic acid,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (2-methylpropyl) -N '-[5- (1H-tetrazol-5 Pentyl] urea,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- (2-methylpropyl) -N '-{4-[(1,1,3 , 3,3, -pentafluoropropyl) oxy] phenyl} urea,
4-({[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) (2-methylpropyl) amino] carbonyl} amino) benzenesulfonamide,
5-[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) ({[4- (trifluoromethyl) phenyl] amino} carbonyl) amino] pentanoic acid ,
5-{(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) [(pyridin-4-ylamino) carbonyl] amino} pentanoic acid,
4-({[(4-carboxybutyl) (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] carbonyl} amino) benzoic acid,
5-[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) ({[4- (2H-tetrazol-5-yl) phenyl] amino} carbonyl) Amino] pentanoic acid,
5-[{[(4-cyanophenyl) amino] carbonyl} (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] pentanoic acid,
5-[({[4- (3-hydroxyisoxazol-5-yl) phenyl] amino} carbonyl) (2-mercapto [1,3] thiazolo [5,4-b] pyridine-5- Yl) amino] pentanoic acid,
5-[({[4-cyanomethyl) phenyl] amino} carbonyl) (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] pentanoic acid,
6-({[(4-carboxybutyl) (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] carbonyl) amino] hexanoic acid,
5-[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) ({[5- (1H-tetrazol-5-yl) pentyl] amino} carbonyl) Amino] pentanoic acid,
5-{(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) [({4- (1,1,3,3,3, -pentafluoropropyl) Oxy] phenyl} amino) carbonyl] amino} pentanoic acid,
5-[({[4- (aminosulfonyl) phenyl] amino} carbonyl) (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] pentanoic acid,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- [4- (2H-tetrazol-5-yl) butyl] -N '-[ 4- (trifluoromethyl) phenyl] urea,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N'-pyridin-4-yl-N- [4- (2H-tetrazol-5- 1) butyl] urea,
4-[({(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) [4- (2H-tetrazol-5-yl) butyl] amino} carbonyl) Amino] benzoic acid,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- [4- (2H-tetrazol-5-yl) butyl] -N '-[ 4- (2H-tetrazol-5-yl) phenyl] urea,
N '-(4-cyanophenyl) -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- [4- (2H-tetrazol- 5-yl) butyl] urea,
N '-[4- (3-hydroxyisoxazol-5-yl) phenyl] -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N -[4- (2H-tetrazol-5-yl) butyl] urea,
N '-[4- (cyanomethyl) phenyl] -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- [4- (2H- Tetraazol-5-yl) butyl] urea,
6-[({(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) [4- (2H-tetrazol-5-yl) butyl] amino} carbonyl) Amino] hexanoic acid,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N- [4- (2H-tetrazol-5-yl) butyl] -N '-[ 5- (1H-tetrazol-5-yl) pentyl] urea,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N '-{4-[(1,1,3,3,3, -pentafluoro Propyl) oxy] phenyl} -N- [4- (2H-tetrazol-5-yl) butyl] urea,
4-[({(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) [4- (2H-tetrazol-5-yl) butyl] amino} carbonyl) Amino] benzenesulfonamide,
N-ethyl-N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N '-[4- (trifluoromethyl) phenyl] urea,
N-ethyl-N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N'-pyridin-4-ylurea,
4-({[ethyl (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] carbonyl} amino) benzoic acid,
N-ethyl-N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N '-[4- (2H-tetrazol-5-yl) phenyl] Urea,
N '-(4-cyanophenyl) -N-ethyl-N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) urea,
N-ethyl-N '-[4- (3-hydroxyisoxazol-5-yl) phenyl] -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridine-5- Urea,
N '-[4- (cyanomethyl) phenyl] -N-ethyl-N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) urea,
6-({[ethyl (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] carbonyl} amino) hexanoic acid,
N-ethyl-N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N '-[5- (1H-tetrazol-5-yl) pentyl] Urea.
N-ethyl-N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N '-{4-[(1,1,3,3,3, -Pentafluoropropyl) oxy] phenyl} urea,
4-({[ethyl (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] carbonyl} amino) benzenesulfonamide,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N-methyl-N '-[4- (trifluoromethyl) phenyl] urea,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N-methyl-N'-pyridin-4-ylurea,
4-({[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) (methyl) amino] carbonyl} amino) benzoic acid,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N-methyl-N '-[4- (2H-tetrazol-5-yl) phenyl] Urea,
N '-(4-cyanophenyl) -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N-methylurea,
N '-[4- (3-hydroxyisoxazol-5-yl) phenyl] -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N Methylurea,
N '-[4- (cyanomethyl) phenyl] -N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N-methylurea,
6-({[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) (methyl) amino] carbonyl} amino) hexanoic acid,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N-methyl-N '-[5- (1H-tetrazol-5-yl) pentyl] Urea,
N- (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) -N-methyl-N '-{4-[(1,1,3,3,3, -Pentafluoropropyl) oxy] phenyl} urea, and
4-({[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) (methyl) amino] carbonyl} amino) benzenesulfonamide.
[10" claim-type="Currently amended] 8. The [5,4-b] pyridine compound according to claim 7, consisting of a compound selected from the group of carbamyl compounds:
4- (trifluoromethyl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (1-methylethyl) carbamate,
Pyridin-4-yl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (1-methylethyl) carbamate,
4- (2H-tetrazol-5-yl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (1-methylethyl) carbamate,
4-chlorophenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (1-methylethyl) carbamate,
4-cyanophenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (1-methylethyl) carbamate,
4- (3-hydroxyisoxazol-5-yl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (1-methylethyl) carbamate,
4- (cyanomethyl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (1-methylethyl) carbamate,
6-({[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) (1-methylethyl) amino] carbonyl} oxy) hexanoic acid,
5- (1H-tetrazol-5-yl) pentyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (1-methylethyl) carbamate,
4-[(1,1,3,3,3, -pentafluoropropyl) oxy] phenyl2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (1-methyl Ethyl) carbamate,
4- (aminosulfonyl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (1-methylethyl) carbamate,
4- (trifluoromethyl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (2-methylpropyl) carbamate,
Pyridin-4-yl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (2-methylpropyl) carbamate,
4- (2H-tetrazol-5-yl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (2-methylpropyl) carbamate,
4-chlorophenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (2-methylpropyl) carbamate,
4-cyanophenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (2-methylpropyl) carbamate,
4- (3-hydroxyisoxazol-5-yl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (2-methylpropyl) carbamate,
4- (cyanomethyl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (2-methylpropyl) carbamate,
6-({[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) (2-methylpropyl) amino] carbonyl} oxy) hexanoic acid,
5- (1H-tetrazol-5-yl) pentyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (2-methylpropyl) carbamate,
4-[(1,1,3,3,3, -pentafluoropropyl) oxy] phenyl2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (2-methyl Carbamate,
4- (aminosulfonyl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (2-methylpropyl) carbamate,
5-[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) ({[4- (trifluoromethyl) phenyl] oxy} carbonyl) amino] pentanoic acid ,
5-{(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) [(pyridin-4-yloxy) carbonyl] amino} pentanoic acid,
5-[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) ({[4- (2H-tetrazol-5-yl) phenyl] oxy} carbonyl) Amino] pentanoic acid,
5-[{[(4-chlorophenyl) oxy] carbonyl} (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] pentanoic acid,
5-[{[(4-cyanophenyl) oxy] carbonyl} (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] pentanoic acid,
5-[({[4- (3-hydroxyisoxazol-5-yl) phenyl] oxy} carbonyl) (2-mercapto [1,3] thiazolo [5,4-b] pyridine-5- Yl) amino] pentanoic acid,
5-[({[4- (cyanomethyl) phenyl] oxy} carbonyl) (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] pentanoic acid,
6-({[(4-carboxybutyl) (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] carbonyl} oxy) hexanoic acid,
5-[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) ({[5- (1H-tetrazol-5-yl) pentyl] oxy} carbonyl) Amino] pentanoic acid,
5-{(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) [({4-[(1,1,3,3,3, -pentafluoropropyl ) Oxy] phenyl} oxy] carbonyl] amino} pentanoic acid,
5-[({[4- (aminosulfonyl) phenyl] oxy} carbonyl) (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] pentanoic acid,
4- (trifluoromethyl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl [4- (2H-tetrazol-5-yl) butyl] carbamate ,
Pyridin-4-yl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl [4- (2H-tetrazol-5-yl) butyl] carbamate,
4- (2H-tetrazol-5-yl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl [4- (2H-tetrazol-5-yl) butyl ] Carbamate,
4-chlorophenyl2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl [4- (2H-tetrazol-5-yl) butyl] carbamate,
4-cyanophenyl2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl [4- (2H-tetrazol-5-yl) butyl] carbamate,
4- (3-hydroxyisoxazol-5-yl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl [4- (2H-tetrazol-5-yl ) Butyl] carbamate,
4- (cyanomethyl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl [4- (2H-tetrazol-5-yl) butyl] carbamate,
6-[({(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) [4- (2H-tetrazol-5-yl) butyl] amino} carbonyl) Oxy] hexanoic acid,
5- (1H-tetrazol-5-yl) pentyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl [4- (2H-tetrazol-5-yl) butyl ] Carbamate,
4-[(1,1,3,3,3, -pentafluoropropyl) oxy] phenyl2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl [4- ( 2H-tetrazol-5-yl) butyl] carbamate,
4- (aminosulfonyl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl [4- (2H-tetrazol-5-yl) butyl] carbamate,
4- (trifluoromethyl) phenyl ethyl (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) carbamate,
Pyridin-4-yl ethyl (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) carbamate,
4- (2H-tetrazol-5-yl) phenyl ethyl (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) carbamate,
4-chlorophenyl ethyl (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) carbamate,
4-cyanophenyl ethyl (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) carbamate,
4- (3-hydroxyisoxazol-5-yl) phenyl ethyl (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) carbamate,
4- (cyanomethyl) phenyl ethyl (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) carbamate,
6-({[ethyl (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) amino] carbonyl} oxy) hexanoic acid,
5- (1H-tetrazol-5-yl) pentyl ethyl (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) carbamate,
4-[(1,1,3,3,3, -pentafluoropropyl) oxy] phenyl ethyl (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) carbox Barmate,
4- (aminosulfonyl) phenyl ethyl (2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl) carbamate,
4- (trifluoromethyl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (methyl) carbamate,
Pyridin-4-yl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (methyl) carbamate,
4- (2H-tetrazol-5-yl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (methyl) carbamate,
4-chlorophenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (methyl) carbamate,
4-cyanophenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (methyl) carbamate,
4- (3-hydroxyisoxazol-5-yl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (methyl) carbamate,
4- (cyanomethyl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (methyl) carbamate,
6-({[(2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (methyl) amino] carbonyl} oxy) hexanoic acid,
5- (1H-tetrazol-5-yl) pentyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (methyl) carbamate,
4-[(1,1,3,3,3, -pentafluoropropyl) oxy] phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (methyl) carbox Barmate, and
4- (aminosulfonyl) phenyl 2-mercapto [1,3] thiazolo [5,4-b] pyridin-5-yl (methyl) carbamate.
[11" claim-type="Currently amended] 9. A compound according to claim 8, selected from amido compounds having a [4,5-b] pyridine ring.
[12" claim-type="Currently amended] 10. A compound according to claim 9 selected from ureido compounds having a [4,5-b] pyridine ring.
[13" claim-type="Currently amended] A compound according to claim 10, selected from carbamyl compounds having a [4,5-b] pyridine ring.
[14" claim-type="Currently amended] 9. A compound according to claim 8 selected from amido compounds having a [4,5-c] pyridine ring.
[15" claim-type="Currently amended] 10. A compound according to claim 9 selected from ureido compounds having a [4,5-c] pyridine ring.
[16" claim-type="Currently amended] The compound of claim 10 selected from carbamyl compounds having a [4,5-c] pyridine ring.
[17" claim-type="Currently amended] 3. A compound according to claim 2, which is R ₇ dihydrogen and attached at the 6-position as defined in formula (II) below R ₆ .

[18" claim-type="Currently amended] 18. The compound of claim 17, wherein R ₆ is selected from the following structural formulas:

Wherein R ₈ is C ₃ -C ₁₂ branched alkyl, C ₂ -C ₈ (alkylene) R ₁₄ , -CH (CF ₃ ) ₂ , -CH (CF ₂ ) _n CF ₃ ) _n , -CH (CF ₃ ) R ₁₁ , -CHR ₁₂ (aryl), -CHR ₁₁ (heteroaryl), -CHR ₁₁ (heterocyclyl), cycloalkyl, heterocyclyl, R ₁₃ is substituted C ₆ -C ₁₂ alkyl, C ₂ -C ₈ (alkylene) R ₁₄ , unsubstituted or substituted heteroaryl or p- R ₉ -substituted phenyl.
[19" claim-type="Currently amended] 18. The compound of claim 17, wherein R ₈ is C ₃ -C ₇ branched alkyl, C ₃ -C ₇ cycloalkyl, 5-6 membered heterocyclyl, -CH ₂ (heterocyclyl), or C ₂ -C ₈ ( Alkylene) R ₁₄ , R ₁₃ is C ₂ -C ₈ (alkylene) R ₁₄ , unsubstituted or R ₉ -substituted heteroaryl or p -R ₉ -substituted phenyl, wherein R ₉ is -CN,- C (O) CF ₃ , S (O) _n CF ₃ , -C (O) CH ₂ F, -CH (OH) CF ₃ , -N (CN) ₂ , -C (CN) ₃ , -CHR ₁₀ R ₁₁ , C ₁ -C ₁₂ alkyl, substituted C ₁ -C ₁₂ alkyl, -CF ₃ ,-(CF ₂ ) _m CF ₃ , -CH (CF ₃ ) ₂ , -CF (CF ₃ ) ₂ , -SO ₃ H , C ₂ -C ₁₂ alkoxy, substituted C ₂ -C ₁₂ alkoxy, -C (X) R ₁₀ , -CR ₁₁ (V) R ₁₂ , -CH ₂ CR ₁₁ (V) R ₁₂ , -S (O) _n R ₁₂ , -S (O) ₂ NHMe (OH), -S (O) ₂ NH (2-thiazolyl),-(4-oxo-2-thioxo-thiazolidine-5-ylidene), tetra Zolyl, -CH ₂ (1,1-dioxo-1 lambda * 6 * -thiomorpholin-4-yl), -S (O) ₂ CH ₂ NO ₂ , -S (O) ₂ CH ₂ S (O ) ₂ R ₁₂ , -P (O) (OR ₁₁ ) R ₁₂ , -NR ₁₁ P (O) OR ₁₂ , -P (O) (NR ₁₁ R ₁₂ ), or a compound selected from the following structural formulas.

[20" claim-type="Currently amended] 18. The compound of claim 17, wherein R ₈ is C ₃ -C ₇ branched alkyl, C ₃ -C ₇ cycloalkyl, 5-6 membered heterocyclyl,-(CH ₂ ) _4-8 R ₁₄ , and R ₁₃ is R ₉ -substituted heteroaryl, or p -R ₉ -substituted phenyl, wherein R ₉ is F, Cl, Br, I, OH, -CN, -N (CN) ₂ , -C (CN) ₃ , -CF ₃ ,-(CF ₂ ) _m CF ₃ , -CH (CF ₃ ) ₂ , -CF (CF ₃ ) ₂ , -SO ₃ H, C ₂ -C ₁₂ alkylsulfanyl, C ₂ -C ₁₂ alkoxy, substituted C ₂ -C ₁₂ alkoxy, -C (X) R ₁₀ , tetrazolyl, 3-hydroxy-isoxazol-4-yl, 3-hydroxy-isoxazol-5-yl, R ₁₀ is -OH, amino, Alkylamino, CF ₃ , NHCN, a 5-6 membered heterocyclyl, R ₁₄ is —C (X) R ₁₀ , and X is O, NH ₂ , NCN, NNO ₂ .
[21" claim-type="Currently amended] 19. A compound according to claim 18, consisting of a compound selected from the group of ureido compounds:
N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (1-methylethyl) -N '-[4- (trifluoromethyl) phenyl] urea,
N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (1-methylethyl) -N'-pyridin-4-ylurea,
4-({[(2-mercapto-1,3-benzothiazol-6-yl) (1-methylethyl) amino] carbonyl} amino) benzoic acid,
N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (1-methylethyl) -N '-[4- (2H-tetrazol-5-yl) phenyl] urea,
N '-(4-cyanophenyl) -N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (1-methylethyl) urea,
N '-[4- (3-hydroxyisoxazol-5-yl) phenyl] -N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (1-methylethyl) Urea,
N '-[4- (cyanomethyl) phenyl] -N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (1-methylethyl) urea,
6-({[(2-mercapto-1,3-benzothiazol-6-yl) (1-methylethyl) amino] carbonyl} amino) hexanoic acid,
N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (1-methylethyl) -N '-[5- (1H-tetrazol-5-yl) pentyl] urea,
N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (1-methylethyl) -N '-{4-[(1,1,3,3,3-pentafluoro Ropropyl) oxy] phenyl} urea,
4-({[(2-mercapto-1,3-benzothiazol-6-yl) (1-methylethyl) amino] carbonyl} amino) benzenesulfonamide,
N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (2-methylpropyl) -N '-[4- (trifluoromethyl) phenyl] urea,
N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (2-methylpropyl) -N'-pyridin-4-ylurea,
4-({[(2-mercapto-1,3-benzothiazol-6-yl) (2-methylpropyl) amino] carbonyl} amino) benzoic acid,
N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (2-methylpropyl) -N '-[4- (2H-tetrazol-5-yl) phenyl] urea,
N '-(4-cyanophenyl) -N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (2-methylpropyl) urea,
N '-[4- (3-hydroxyisoxazol-5-yl) phenyl] -N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (2-methylpropyl) Urea,
N '-[4- (cyanomethyl) phenyl] -N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (2-methylpropyl) urea,
6-({[(2-mercapto-1,3-benzothiazol-6-yl) (2-methylpropyl) amino] carbonyl} amino) hexanoic acid,
N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (2-methylpropyl) -N '-[5- (1H-tetrazol-5-yl) pentyl] urea,
N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (2-methylpropyl) -N '-{4-[(1,1,3,3,3-pentafluoro Ropropyl) oxy] phenyl} urea,
4-({[(2-mercapto-1,3-benzothiazol-6-yl) (2-methylpropyl) amino] carbonyl} amino) benzenesulfonamide,
N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (pyridin-4-ylmethyl) -N '-[4-trifluoromethyl) phenyl] urea,
N- (2-mercapto-1,3-benzothiazol-6-yl) -N'-pyridin-4-yl-N- (pyridin-4-ylmethyl) urea,
4-({[(2-mercapto-1,3-benzothiazol-6-yl) (pyridin-4-ylmethyl) amino] carbonyl} amino) benzoic acid,
N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (pyridin-4-ylmethyl) -N '-[4- (2H-tetrazol-5-yl) phenyl] Urea,
N '-(4-cyanophenyl) -N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (pyridin-4-ylmethyl) urea,
N '-[4- (3-hydroxyisoxazol-5-yl) phenyl] -N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (pyridin-4-yl Methyl) urea,
N '-[4- (cyanomethyl) phenyl] -N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (pyridin-4-ylmethyl) urea,
6-({[(2-mercapto-1,3-benzothiazol-6-yl) (pyridin-4-ylmethyl) amino] carbonyl} amino) hexanoic acid,
N- (2-mercapto-1,3-benzothiazol-6-yl) -N- (pyridin-4-ylmethyl) -N '-[5- (1H-tetrazol-5-yl) pentyl] Urea,
N- (2-mercapto-1,3-benzothiazol-6-yl) -N '-{4-[(1,1,3,3,3-pentafluoropropyl) oxy] phenyl} -N -(Pyridin-4-ylmethyl) urea,
4-({[(2-mercapto-1,3-benzothiazol-6-yl) (pyridin-4-ylmethyl) amino] carbonyl} amino) benzenesulfonamide,
5-[(2-mercapto-1,3-benzothiazol-6-yl) ({[4- (trifluoromethyl) phenyl] amino} carbonyl) amino] pentanoic acid,
5-{(2-mercapto-1,3-benzothiazol-6-yl) [(pyridin-4-ylamino) carbonyl] amino} pentanoic acid,
4-({[(4-carboxybutyl) (2-mercapto-1,3-benzothiazol-6-yl) amino] carbonyl} amino) benzoic acid,
5-[(2-mercapto-1,3-benzothiazol-6-yl) ({[4- (2H-tetrazol-5-yl) phenyl] amino} carbonyl) amino] pentanoic acid,
5-[{[(4-cyanophenyl) amino] carbonyl} (2-mercapto-1,3-benzothiazol-6-yl) amino] pentanoic acid,
5-[({[4- (3-hydroxyisoxazol-5-yl) phenyl] amino} carbonyl) (2-mercapto-1,3-benzothiazol-6-yl) amino] pentanoic acid,
5-[({[4- (cyanomethyl) phenyl] amino} carbonyl) (2-mercapto-1,3-benzothiazol-6-yl) amino] pentanoic acid,
6-({[(4-carboxybutyl) (2-mercapto-1,3-benzothiazol-6-yl) amino] carbonyl} amino) hexanoic acid,
5-[(2-mercapto-1,3-benzothiazol-6-yl) ({[5- (1H-tetrazol-5-yl) pentyl] amino} carbonyl) amino] pentanoic acid,
5-{(2-mercapto-1,3-benzothiazol-6-yl) [({4-[(1,1,3,3,3-pentafluoropropyl) oxy] phenyl} amino) carr Carbonyl] amino} pentanoic acid,
5-[({[4- (aminosulfonyl) phenyl] amino} carbonyl) (2-mercapto-1,3-benzothiazol-6-yl) amino] pentanoic acid,
N- (2-mercapto-1,3-benzothiazol-6-yl) -N- [4- (2H-tetrazol-5-yl) butyl] -N '-[4- (trifluoromethyl ) Phenyl] urea,
N- (2-mercapto-1,3-benzothiazol-6-yl) -N'-pyridin-4-yl-N- [4- (2H-tetrazol-5-yl) butyl] urea,
4-[({(2-mercapto-1,3-benzothiazol-6-yl) [4- (2H-tetrazol-5-yl) butyl] amino} carbonyl) amino] benzoic acid,
N- (2-mercapto-1,3-benzothiazol-6-yl) -N- [4- (2H-tetrazol-5-yl) butyl] -N '-[4- (2H-tetraazole -5-yl) phenyl] urea,
N '-(4-cyanophenyl) -N- (2-mercapto-1,3-benzothiazol-6-yl) -N- [4- (2H-tetrazol-5-yl) butyl] urea ,
N '-[4- (3-hydroxyisoxazol-5-yl) phenyl] -N- (2-mercapto-1,3-benzothiazol-6-yl) -N- [4- (2H- Tetraazol-5-yl) butyl] urea,
N '-[4- (cyanomethyl) phenyl] -N- (2-mercapto-1,3-benzothiazol-6-yl) -N- [4- (2H-tetrazol-5-yl) Butyl] urea,
6-[({(2-mercapto-1,3-benzothiazol-6-yl) [4- (2H-tetrazol-5-yl) butyl] amino} carbonyl) amino] hexanoic acid,
N-[(2-mercapto-1,3-benzothiazol-6-yl) -N- [4- (2H-tetrazol-5-yl) butyl] -N '-[5- (1H-tetra Azole-5-yl) pentyl] urea,
N- (2-mercapto-1,3-benzothiazol-6-yl) -N '-{4-[(1,1,3,3,3-pentafluoropropyl) oxy] phenyl} -N -[4- (2H-tetrazol-5-yl) butyl] urea, and
4-[({(2-mercapto-1,3-benzothiazol-6-yl) [4- (2H-tetrazol-5-yl) butyl] amino} carbonyl) amino] benzenesulfonamide.
[22" claim-type="Currently amended] 19. A compound according to claim 18, consisting of a compound selected from the group of carbamyl compounds:
4- (trifluoromethyl) phenyl 2-mercapto-1,3-benzothiazol-6-yl (1-methylethyl) carbamate,
Pyridin-4-yl 2-mercapto-1,3-benzothiazol-6-yl (1-methylethyl) carbamate,
4- (2H-tetrazol-5-yl) phenyl 2-mercapto-1,3-benzothiazol-6-yl (1-methylethyl) carbamate,
4-chlorophenyl 2-mercapto-1,3-benzothiazol-6-yl (1-methylethyl) carbamate,
4-cyanophenyl 2-mercapto-1,3-benzothiazol-6-yl (1-methylethyl) carbamate,
4- (3-hydroxyisoxazol-5-yl) phenyl 2-mercapto-1,3-benzothiazol-6-yl (1-methylethyl) carbamate,
4- (cyanomethyl) phenyl 2-mercapto-1,3-benzothiazol-6-yl (1-methylethyl) carbamate,
6-({[(2-mercapto-1,3-benzothiazol-6-yl) (1-methylethyl) amino] carbonyl} oxy) hexanoic acid,
5- (1H-tetrazol-5-yl) pentyl 2-mercapto-1,3-benzothiazol-6-yl (1-methylethyl) carbamate,
4-[(1,1,3,3,3-pentafluoropropyl) oxy] phenyl 2-mercapto-1,3-benzothiazol-6-yl (1-methylethyl) carbamate,
4- (aminosulfonyl) phenyl 2-mercapto-1,3-benzothiazol-6-yl (1-methylethyl) carbamate,
4- (trifluoromethyl) phenyl 2-mercapto-1,3-benzothiazol-6-yl (2-methylpropyl) carbamate,
Pyridin-4-yl 2-mercapto-1,3-benzothiazol-6-yl (2-methylpropyl) carbamate,
4- (2H-tetrazol-5-yl) phenyl 2-mercapto-1,3-benzothiazol-6-yl (2-methylpropyl) carbamate,
4-chlorophenyl 2-mercapto-1,3-benzothiazol-6-yl (2-methylpropyl) carbamate,
4-cyanophenyl 2-mercapto-1,3-benzothiazol-6-yl (2-methylpropyl) carbamate,
4- (3-hydroxyisoxazol-5-yl) phenyl 2-mercapto-1,3-benzothiazol-6-yl (2-methylpropyl) carbamate,
4- (cyanomethyl) phenyl 2-mercapto-1,3-benzothiazol-6-yl (2-methylpropyl) carbamate,
6 ({[(2-mercapto-1,3-benzothiazol-6-yl) (2-methylpropyl) amino] carbonyl} oxy) hexanoic acid,
5- (1H-tetrazol-5-yl) pentyl 2-mercapto-1,3-benzothiazol-6-yl (2-methylpropyl) carbamate,
4-[(1,1,3,3,3-pentafluoropropyl) oxy] phenyl 2-mercapto-1,3-benzothiazol-6-yl (2-methylpropyl) carbamate,
4- (aminosulfonyl) phenyl 2-mercapto-1,3-benzothiazol-6-yl (2-methylpropyl) carbamate,
4- (trifluoromethyl) phenyl 2-mercapto-1,3-benzothiazol-6-yl (pyridin-4-ylmethyl) carbamate,
Pyridin-4-yl 2-mercapto-1,3-benzothiazol-6-yl (pyridin-4-ylmethyl) carbamate,
4- (2H-tetrazol-5-yl) phenyl 2-mercapto-1,3-benzothiazol-6-yl (pyridin-4-ylmethyl) carbamate,
4-chlorophenyl 2-mercapto-1,3-benzothiazol-6-yl (pyridin-4-ylmethyl) carbamate,
4-cyanophenyl 2-mercapto-1,3-benzothiazol-6-yl (pyridin-4-ylmethyl) carbamate,
4- (3-hydroxyisoxazol-5-yl) phenyl 2-mercapto-1,3-benzothiazol-6-yl (pyridin-4-ylmethyl) carbamate,
4- (cyanomethyl) phenyl 2-mercapto-1,3-benzothiazol-6-yl (pyridin-4-ylmethyl) carbamate,
6-({[(2-mercapto-1,3-benzothiazol-6-yl) (pyridin-4-ylmethyl) amino] carbonyl} oxy) hexanoic acid,
5- (1H-tetrazol-5-yl) pentyl 2-mercapto-1,3-benzothiazol-6-yl (pyridin-4-ylmethyl) carbamate,
4-[(1,1,3,3,3-pentafluoropropyl) oxy] phenyl 2-mercapto-1,3-benzothiazol-6-yl (pyridin-4-ylmethyl) carbamate,
4- (aminosulfonyl) phenyl 2-mercapto-1,3-benzothiazol-6-yl (pyridin-4-ylmethyl) carbamate,
5-[(2-mercapto-1,3-benzothiazol-6-yl) ({[4- (trifluoromethyl) phenyl] oxy} carbonyl) amino] pentanoic acid,
5-{(2-mercapto-1,3-benzothiazol-6-yl) [(pyridin-4-yloxy) carbonyl] amino} pentanoic acid,
5-[(2-mercapto-1,3-benzothiazol-6-yl) ({[4- (2H-tetrazol-5-yl) phenyl] oxy} carbonyl) amino] pentanoic acid,
5-[{[(4-chlorophenyl) oxy] carbonyl} (2-mercapto-1,3-benzothiazol-6-yl) amino] pentanoic acid,
5-[{[(4-cyanophenyl) oxy] carbonyl} (2-mercapto-1,3-benzothiazol-6-yl) amino] pentanoic acid,
5-[({[(4- (3-hydroxyisoxazol-5-yl) phenyl] oxy} carbonyl) (2-mercapto-1,3-benzothiazol-6-yl) amino] pentanoic acid ,
5-[({[4- (cyanomethyl) phenyl] oxy} carbonyl) (2-mercapto-1,3-benzothiazol-6-yl) amino] pentanoic acid,
6-({[(4-carboxybutyl) (2-mercapto-1,3-benzothiazol-6-yl) amino] carbonyl} oxy) hexanoic acid,
5-[(2-mercapto-1,3-benzothiazol-6-yl) ({[5- (1H-tetrazol-5-yl) pentyl] oxy} carbonyl) amino] pentanoic acid,
5-{(2-mercapto-1,3-benzothiazol-6-yl) [({4-[(1,1,3,3,3-pentafluoropropyl) oxy] phenyl} oxy) car Carbonyl] amino} pentanoic acid,
5-[({[4- (aminosulfonyl) phenyl] oxy} carbonyl) (2-mercapto-1,3-benzothiazol-6-yl) amino] pentanoic acid,
4- (trifluoromethyl) phenyl 2-mercapto-1,3-benzothiazol-6-yl [4- (2H-tetrazol-5-yl) butyl] carbamate,
4- (2H-tetrazol-5-yl) phenyl 2-mercapto-1,3-benzothiazol-6-yl [4- (2H-tetrazol-5-yl) butyl] carbamate,
4-chlorophenyl 2-mercapto-1,3-benzothiazol-6-yl [4- (2H-tetrazol-5-yl) butyl] carbamate,
4-cyanophenyl 2-mercapto-1,3-benzothiazol-6-yl [4- (2H-tetrazol-5-yl) butyl] carbamate,
4- (3-hydroxyisoxazol-5-yl) phenyl 2-mercapto-1,3-benzothiazol-6-yl [4- (2H-tetrazol-5-yl) butyl] carbamate,
4- (cyanomethyl) phenyl 2-mercapto-1,3-benzothiazol-6-yl [4- (2H-tetrazol-5-yl) butyl] carbamate,
6-[({(2-mercapto-1,3-benzothiazol-6-yl) [4- (2H-tetrazol-5-yl) butyl] amino} carbonyl) oxy] hexanoic acid,
5- (1H-tetrazol-5-yl) pentyl 2-mercapto-1,3-benzothiazol-6-yl [4- (2H-tetrazol-5-yl) butyl] carbamate,
4-[(1,1,3,3,3-pentafluoropropyl) oxy] phenyl 2-mercapto-1,3-benzothiazol-6-yl [4- (2H-tetrazol-5-yl ) Butyl] carbamate, and
4- (aminosulfonyl) phenyl 2-mercapto-1,3-benzothiazol-6-yl [4- (2H-tetrazol-5-yl) butyl] carbamate.
[23" claim-type="Currently amended] A method of inhibiting malonyl-CoA decarboxylase in a patient, comprising administering a therapeutically effective amount of a compound as defined in claim 1.
[24" claim-type="Currently amended] A method of converting fatty acid metabolism to carbohydrate metabolism in a patient, comprising administering a therapeutically effective amount of a compound as defined in claim 1.
[25" claim-type="Currently amended] A method of treating a fatty acid and glucose metabolism related disease or indication by increasing a malonyl-CoA concentration in a patient, comprising administering a therapeutically effective amount of a compound as defined in claim 1.
[26" claim-type="Currently amended] The method of claim 25, wherein the disease is a cardiovascular disease.
[27" claim-type="Currently amended] 27. The method of claim 26, wherein the cardiovascular disease is congestive heart failure.
[28" claim-type="Currently amended] The method of claim 26, wherein the disease is an ischemic cardiovascular disease.
[29" claim-type="Currently amended] The method of claim 25, wherein the method is for the treatment of angina resulting from an ischemic cardiovascular disease.
[30" claim-type="Currently amended] The method of claim 25, wherein the disease is diabetes.
[31" claim-type="Currently amended] The method of claim 25, wherein the disease is acidosis.
[32" claim-type="Currently amended] The method of claim 25, wherein the disease is obesity.
[33" claim-type="Currently amended] The method of claim 25, wherein the disease is cancer.
[34" claim-type="Currently amended] A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in claim 1 in a pharmaceutically acceptable carrier, wherein said composition is useful for the treatment of diseases related to fatty acid and glucose metabolism by increasing malonyl CoA concentration.

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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:
2001-02-20|Priority to US27003401P

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2001-02-20|Priority to US60/270,034

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2002-02-19|Application filed by 추가이 세이야쿠 가부시키가이샤

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2002-02-19|Priority to PCT/US2002/004777

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2003-09-29|Publication of KR20030077015A

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2006-12-18|Application granted

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2006-12-18|Publication of KR100659427B1

优先权:

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申请号 | 申请日 | 专利标题

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US27003401P| true| 2001-02-20|2001-02-20|

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US60/270,034|2001-02-20|

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PCT/US2002/004777|WO2002066035A2|2001-02-20|2002-02-19|Azoles as malonyl-coa decarboxylase inhibitors useful as metabolic modulators|