 New phenalkyloxy-phenyl derivatives
专利摘要:
The present invention relates to phenalkyloxy-phenyl derivatives and analogs of formula I having utility in clinical diseases related to insulin resistance, methods of making such compounds, methods for their therapeutic use, and pharmaceutical compositions comprising such compounds. (I) 公开号:KR20020067536A 申请号:KR1020027007027 申请日:2000-11-29 公开日:2002-08-22 发明作者:조나스 파게르하그；라나 리；에바-로테 린드스테트알스테르마르크 申请人:아스트라제네카 아베； IPC主号:
专利说明:
NEW PENALKYLOXY-PHENYL DERIVATIVES < RTI ID = 0.0 > [2] Insulin resistance, defined as reduced sensitivity to insulin action in the whole body or in individual tissues such as skeletal muscle, cardiac muscle layer, fat layer and liver, is widespread among a large number of people with or without diabetes. Insulin resistance syndrome (IRS) is defined as insulin resistance syndrome (IRS), which is characterized by hyperinsulinemia, possibly Type 2 diabetes, arterial hypertension, central (internal) obesity, elevated VLDL and reduced HDL (high density lipoprotein), small, dense LDL Refers to a group of indicia that includes insulin resistance accompanied by lipidemias observed at an abnormal lipoprotein level that is representative of the presence of particles and reduced fibrinolysis. [3] Recent epidemiological studies demonstrate that people with insulin resistance have a greatly increased risk of cardiovascular morbidity and mortality, especially myocardial infarction and stroke. In non-insulin-dependent diabetes mellitus, death from such atherosclerosis-related illnesses accounts for 80% of all deaths. In clinical medicine, the current IRS is extremely limitedly recognized for the need to treat lipid anemia, which is thought to cause increased insulin sensitivity and thus accelerated progression of atherosclerosis. [4] In addition, there is currently no drug treatment available for the proper treatment of metabolic disorders associated with IRS. To date, the treatment of type 2 diabetes has focused on the treatment of disease-related abnormalities of carbohydrate metabolism. Although stimulation of endogenous insulin secretion by secretagogues such as sulfonylureas and administration of exogenous insulin, if necessary, are frequently used in the normalization of blood glucose, this may possibly further enhance insulin resistance and may cause other signs of IRS They will not be able to cure, and will not reduce cardiovascular morbidity or mortality. In addition, this treatment involves a considerable risk of hypoglycemia with associated complications. [5] Other therapeutic strategies have focused on abnormalities in glucose metabolism or absorption, including glucosidase inhibitors such as acetaminophen, such as acetaminophen, or acetaminophen. Although these drugs are somewhat effective, their limited therapeutic effect is accompanied by side effects. [6] The novel therapeutic strategies are associated with the use of insulin sensitizers such as thiazolidinediones that mediate at least in part its efficacy through an efficacious action on the nuclear receptor. Ciglitazone is the epitome of this line. In animal models of IRS, these compounds improve insulin sensitivity through action on lipid transport and work primarily in adipocytes to induce insulin resistance in skeletal muscle, liver, and adipose tissue, thereby enhancing insulin resistance in diabetes Hypertriglyceridemia and hyperinsulinemia associated with treatment and hyperglycemia. [7] In clinical development, the ciglitazone and hapthiazolidinedione were reportedly stopped or rendered inadequate due to unacceptable toxicity. Thus, there is a need for new and improved compounds with insulin sensitizing properties. [1] The present invention relates to phenalkyloxy-phenyl derivatives and analogs of formula I having utility in clinical diseases related to insulin resistance, methods of making such compounds, methods for their therapeutic use, and pharmaceutical compositions comprising such compounds. [8] The present invention relates to compounds of formula (I), stereoisomers and optical isomers and racemates thereof, and pharmaceutically acceptable salts, prodrugs, solvates and crystalline forms thereof. [9] [10] In this formula, [11] A is located in an ortho, meta or para position, [12] Lt; / RTI > [13] When X is 0, R is cyano, [14] When X is 1, R is -BR a or SCOR a wherein B represents O, S, SO or SO 2 (preferably B is O or S) and R a is hydrogen, alkyl, aryl or alkyl (Preferably R a selected from hydrogen, alkyl and alkylaryl), an alkyl, aryl or alkylaryl group, R b , wherein R b is alkyl, aryl, alkylaryl, cyano, -NR c R c , = O, halogen, -OH, -SH, -O-alkyl, -O aryl, -O-alkyl aryl, -COR c, -SR d, -SOR d, or -SO 2 R d (wherein, R c is hydrogen , alkyl, denotes an aryl or alkyl aryl, R d is alkyl, represents a represents an aryl or alkyl group) (preferably, R b is alkyl, aryl, alkylaryl, cyano, -NH 2, = O, halogen, and Optionally substituted one or more times by -OH)); -BB 1 R a wherein B and R a are as defined above and B is S, SO or SO 2 , B 1 is O and B is O, then B 1 is S, SO or SO 2 ); Or optionally, R is -NR a R a (wherein each R a may be the same or different, R a are as defined above), and; [15] R 2 is selected from the group consisting of alkyl, halogen (preferably bromo, chloro or iodo), aryl, alkylaryl, alkenyl, alkynyl, nitro or cyano where the alkyl, aryl, alkenyl, alkylaryl and alkynyl groups R b optionally substituted by (wherein, R b are as defined above)); -BR a (wherein, B and R a are as defined above); -SO 2 NR a R f wherein R f is hydrogen, alkyl, acyl, aryl or alkylaryl and R a is as defined above; -SO 2 OR a (wherein, R a is as defined above); -OCONR f R a (wherein, R f and R a are as defined above); -NR c COOR d , wherein R c and R d are as defined above; -NR c COR a wherein R c and R a are as defined above; -CONR c R a wherein R c and R a are as defined above; -NR c SO 2 R d (where, R c and R d are as defined above); - NR c CONR a R k ( where, R a and R c are as defined above, R k is hydrogen, Alkyl, aryl, or alkylaryl; Alternatively R 2 is -NR c R a wherein R c and R a are as defined above; [16] R 1, R 3 and R 4 may be the same or different, each represents hydrogen, alkyl, aryl, alkenyl, alkynyl, cyano, halogen, or alkyl aryl (where the alkyl, aryl, alkenyl or alkynyl group R b (Preferably, R 1 , R 3 and R 4 are independently selected from hydrogen or alkyl, ideally R 1 , R 3 and R 4 are hydrogen); [17] n is an integer from 1 to 6 (preferably, n is an integer from 1 to 3, ideally n is 1); [18] X is an integer 0 or 1 (preferably X is 1); [19] m is an integer 0 or 1 (preferably m is 1); [20] D is an alkyl, acyl, aryl, alkylaryl, halogen, -CN or NO 2 wherein the alkyl, aryl, or alkylaryl groups are located at the ortho, meta or para positions (preferably D is located at the para position) Optionally substituted by R b ; -NR c COOR a , wherein R c and R a are as defined above; -NR c COR a wherein R c and R a are as defined above; -NR c R a , wherein R c and R a are as defined above; -NR c SO 2 R d wherein R c and R d are as defined above; -NR c CONR k R c wherein R a , R c and R k are as defined above; -NR c CSNR a R k wherein R a , R c and R k are as defined above; -OR < a >, wherein R < a > is as defined above; -OSO 2 R d (wherein, R d are as defined above); -SO 2 R d (wherein, R d are as defined above); -OR < d >, wherein R < d > is as defined above; -SR < c >, wherein R < c > is as defined above; -SO 2 NR a R f (wherein, R f and R a are as defined above); -SO 2 OR a (wherein, R a is as defined above); -CONR c R a wherein R c and R a are as defined above; -OCONR f R a represents (wherein, R f and R a are as defined above); [21] D 'is ortho, meta or para positioned in place (preferably, D' is also located in the ortho or meta position) and represents hydrogen, alkyl, acyl, aryl, alkylaryl, halogen, -CN, -NO 2, -NR f R b , wherein R f and R b are as defined above; -OR f , wherein R f is as defined above; -OSO 2 R d , wherein R d is as defined above; [22] Alkyl, acyl, aryl, alkylaryl, halogen, -CN, -NO 2 , -NR f (preferably D " R b , wherein R f and R b are as defined above; -OR f , wherein R f is as defined above; -OSO 2 R d wherein R d is as defined above. [23] For the convenience of reference, the definitions of the above formula (I) are quoted as being defined in category A below. Unless otherwise indicated, throughout this application the definition of a number of substituents is as defined in category A. [24] The compounds of formula I have surprising effects on diseases associated with insulin resistance. [25] Category A2: Preferred compounds of the invention are as defined in category A, [26] A is located at the meta or para position (preferably A is located at the para position) [27] Lt; / RTI > [28] R is -BR < a >, wherein R < a > is as defined above; -SCOR < a >, wherein R < a > is as defined above; -OSO 2 R a wherein R a is as defined above, [29] R 1 , R 3 and R 4 may be the same or different and each represent hydrogen, alkyl, aryl, alkenyl, alkynyl or cyano, wherein the alkyl, aryl, alkenyl or alkynyl groups are optionally substituted with R b Substituted; [30] R 2 is alkyl, aryl, alkenyl, cyano, or alkynyl, wherein the alkyl, aryl, alkenyl, and alkynyl groups are optionally substituted by R b ; -BR a ; -OSO 2 R a (wherein, R a is as defined above); -OCONR f R a (wherein, R f and R a are as defined above); -NR c COOR d , wherein R c and R d are as defined above; -NR c COR a wherein R c and R a are as defined above; -CONR c , wherein R c is as defined above; [31] n is an integer of 1 to 2; [32] m is 1; [33] D is an alkyl, acyl, aryl, alkylaryl, halogen, -CN, -NO 2 wherein the alkyl group is optionally substituted by R b , Lt; / RTI > -OR < a >, wherein R < a > is as defined above; -OSO 2 R d (wherein, R d are as defined above); -OCONR a R f (wherein, R a and R f are as defined above); -NR c COOR a , wherein R c and R a are as defined above; -NR c COR a wherein R c and R a are as defined above; -SO 2 R d (wherein, R d are as defined above); -SR < c >, wherein R < c > is as defined above; -CONR a R c wherein R a and R c are as defined above; -NR c R a wherein R c and R a are as defined above; [34] D 'is ortho, meta or para positioned in place (preferably, D' is also located in the ortho or meta position) and represents hydrogen, alkyl, alkylaryl, halogen, -CN or -NO 2; -OR h wherein R h is hydrogen or alkyl; [35] D "is located in an ortho, meta or para position (preferably, D" is in ortho or meta position), hydrogen, alkyl, alkylaryl, halogen, -CN or -NO 2 ; -OR < f >, wherein R < f > is as defined above. [36] Category A3: More preferred compounds of the invention are as defined in category A2, [37] A is located at the meta or para position (preferably A is located at the para position); [38] R is -OR a , -SR a , -SCOR a or -OSO 2 R a wherein R a is hydrogen, alkyl or alkylaryl; [39] R 2 is cyano, -OR a wherein R a is as defined above; -NR c COR a where R a and R c are as defined above; -CONR c R a wherein R a and R c are as defined above; [40] R 1 , R 3 and R 4 are independently selected from hydrogen or alkyl (preferably, R 1 , R 3 and R 4 are all hydrogen); [41] D is an ortho, meta or para position (preferably, D is located at the para position), alkyl or cyano optionally substituted by R b ; -OR < a >, wherein R < a > is as defined above; -NR c COR a where R a and R c are as defined above; -CONHR c R a wherein R a and R c are as defined above; -NR c COOR a , wherein R c and R a are as defined above; -OSO 2 R a (wherein, R a is as defined above); -SO 2 R d (wherein, R d are as defined above); -OCONR c R a , wherein R c and R a are as defined above; [42] D 'is hydrogen, [43] D " is hydrogen. [44] Category A4: More preferred compounds of the invention are as defined in category A3, [45] A is located at the para-position; [46] R is -OH, -Oalkyl or -Oalkylaryl; -SCOR < a >, wherein R < a > is as defined above; -OSO 2 R d (wherein, R d are as defined above), and; [47] R < 1 > is hydrogen; [48] R 2 is -O alkyl, preferably -O lower alkyl; [49] R 3 is hydrogen; [50] R < 4 > is hydrogen; [51] n is an integer 1; [52] D is located at the para position, -NR h COOR d wherein R h represents hydrogen or alkyl, CONR a R c wherein R a and R c are as defined above; -SO 2 R d (wherein, R d are as defined above); -OSO 2 R d (wherein, R d are as defined above); -CN; -OR < a >, wherein R < a > is as defined above; -Alkyl < / RTI > [53] Category A5: More preferred compounds of the invention are as defined in category A4, [54] R is -OR a (wherein, R a is as defined above), and; [55] R 2 is -O alkyl, preferably -O lower alkyl; [56] D is -NR b COOR a wherein R b and R a are as defined above; -CN; -OSO 2 R d wherein R d is as defined above. [57] Category A5: More preferred compounds of the invention are the compounds described in Examples 1-13. [58] Category A6: A more preferred compound of the invention is a compound that is one of the possible enantiomers. [59] &Quot; Pharmaceutically acceptable salts " (where such salts are possible) include both pharmaceutically acceptable acid and base addition salts. Suitable pharmaceutically acceptable salts of the compounds of formula I include, for example, acid addition salts of compounds of formula I which are sufficiently basic, for example, inorganic or organic acids (e.g., hydrochloric acid, hydrogen bromide, sulfuric acid, trifluoro Acetic acid, citric acid or maleic acid) or a salt of a compound of formula (I) which is sufficiently acidic, for example an alkali or alkaline earth metal salt (for example sodium, calcium or magnesium salt) Or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine. [60] In vivo hydrolysable esters of the compounds of formula I are merely a class of prodrugs of the parent molecule. Other prodrugs, e. G., Amide prodrugs, of the parent molecule are contemplated and can be prepared by routine methods within the capabilities of those skilled in the art. Prodrugs of compounds of formula I are included within the scope of the present invention. A variety of prodrugs are known in the art. Examples of such prodrug derivatives are described in [a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology. 42: 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8: 1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77: 285 (1988); And e) N. Kakeya, et al., Chem Pharm Bull, 32: 692 (1984). [61] Preferred examples of prodrugs include hydrolysable esters of the compounds of formula I in vivo. Suitable pharmaceutically acceptable esters for carboxy include C 1-8 alkyl esters, C 5-8 cycloalkyl esters, cyclic amine esters, C 1-6 alkoxymethyl esters, such as methoxymethyl, C 1-6 Alkanoyloxymethyl esters such as pivaloyloxymethyl, phthalidyl esters, C 3-8 cycloalkoxycarbonyloxy C 1-6 alkyl esters such as 1-cyclohexylcarbonyloxyethyl, 1, 3-dioxolen-2-onyl methyl esters such as 5-methyl-1,3-dioxolen-2-onylmethyl and C 1-6 alkoxycarbonyloxyethyl esters such as 1-methoxycar Wherein the alkyl, cycloalkyl and cyclic amino groups are optionally substituted by, for example, phenyl, heterocyclyl, alkyl, amino, alkylamino, dialkylamino, hydroxy, alkoxy, aryloxy or benzyloxy Optionally substituted), any of the compounds of the present invention It can be formed in reubok time. [62] It is also understood that certain compounds of the present invention may exist in solvated, e. G. Hydrated, and non-resolved forms. It is understood that the invention encompasses all such solvated forms. [63] When the substituent OR a represents an alkylaryl group, the preferred alkylaryl is benzyl. [64] Throughout the specification and appended claims, a given chemical formula or name refers to a mixture of all stereoisomers and optical isomers and mixtures of different proportions of the racemate and each enantiomer (if such isomers and enantiomers are present) Acceptable salts and solvates thereof, for example hydrates. Isomers can be separated using conventional techniques, e. G., Chromatography or fractional crystallisation. Enantiomers can be separated by separation of the racemates, for example by fractional crystallisation, resolution or HPLC. The diastereoisomers can be separated by separation of the isomeric mixtures, e. G. By fractional crystallisation, HPLC or flash chromatography. Alternatively, the stereoisomers may be prepared from chiral starting materials by chiral synthesis under conditions that do not cause racemization or epimerization reactions, or by derivatisation using chiral reagents. All stereoisomers are included within the scope of the present invention. [65] The following definitions apply throughout the specification and appended claims. [66] Unless otherwise indicated or indicated, the term " alkyl " refers to a substituted or unsubstituted straight or branched chain alkyl group having 1 to 6 carbon atoms or a cyclic alkyl having 3 to 6 carbon atoms. The term " lower alkyl " refers to a substituted or unsubstituted, linear or branched alkyl group having 1 to 3 carbon atoms or a cyclic alkyl having 3 carbon atoms. Examples of such alkyl and lower alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- , Cyclopentyl, and cyclohexyl. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl and tert-butyl. [67] Unless otherwise indicated or indicated, the term " alkoxy " refers to an O-alkyl group, wherein alkyl is as defined above. [68] Unless otherwise indicated or indicated, the term " halogen " means fluorine, chlorine, bromine or iodine, preferably fluorine. [69] Unless otherwise indicated or indicated, the term " aryl " refers to a substituted or unsubstituted phenyl, furyl, thienyl or pyridyl group or a fused ring system of these groups, e.g., naphthyl. [70] Unless otherwise indicated or indicated, the term "substituted" refers to an alkyl or aryl group as defined above substituted by one or more alkyl, alkoxy, halogen, amino, thiol, nitro, hydroxy, acyl, . [71] Unless otherwise indicated or indicated, the term " alkylaryl " refers to what is represented by the following formula. [72] [73] (Wherein, n is an integer from 1 to 6, R r and R i are the same or different, each represents hydrogen or an alkyl or aryl as defined above) [74] Unless otherwise indicated or indicated, the term " acyl " refers to what is represented by the following formula. [75] [76] Wherein R < j > is hydrogen, alkyl, alkoxy, aryl or alkylaryl as defined above, [77] Unless otherwise indicated or indicated, the terms " alkenyl " and " alkynyl " refer to straight or branched, branched or cyclic, Substituted or unsubstituted unsaturated hydrocarbon group. [78] Unless otherwise indicated or indicated, the term " protecting group " refers to the protecting group described in the standard text [Protecting groups in Organic Synthesis, 2nd Edition (1991) by Greene and Wuts]. The protecting group may also be a polymeric resin, for example, a Wang resin or a 2-chlorotrityl chloride resin. [79] Manufacturing method [80] The compounds of the present invention can be prepared according to the following method as outlined below. However, the present invention is not limited to these methods, and the compounds may also be prepared as described for the structurally related compounds of the prior art. [81] A. Compounds of formula I wherein R or R < 2 > is defined as -OR d , -SCOR d , -SR d , -OSO 2 R d , -NR c COOR a , -NR c COR a , -NR a CONR a R k or -NR c SO 2 R d can be prepared by reacting a compound of formula I wherein each R or R 2 group is, for example, -OH, -SH or -NHR a, respectively, with a suitable reagent, For example, an alkyl halide or an aryl halide, in the presence of a base such as triethylamine, in the presence of a base. The reaction may be carried out according to methods known to those skilled in the art or as described in the examples herein. A suitable reference is in the case of forming alkyl or aryl ethers, " Comprehensive Organic Transformations " RC Larock (VCH Publishers Inc.) 1989, p445-448. For the formation of thioether, refer to pages 407-409 of "Advanced Organic Chemistry" J. March (4 th edition), John Wiley & Sons. When sulfonate is formed, 498-499 , And in the case of forming an amide, refer to pages 417 to 418 of the same document, and in the case of forming an amine, refer to pages 411 to 413 of the same document. [82] B. Compounds of formula I, wherein R or R 2 are as defined above, are -SR a or -SCOR a , can be prepared by reacting a compound of formula I, wherein the R or R 2 groups are each, for example, -OSO 2 R a , and the appropriate reactants, that is, each YSR a YSCOR or a (where, Y is a cation Im) are prepared by reaction with. Appropriate reaction is carried out using an inert solvent, for example in in DMF or methanol, at room temperature, a suitable reducing agent, such as sodium borohydride, LiAlH 4, DIBAH or borane-methyl sulfide. [83] C. Compounds of formula I wherein X is 1 can be prepared by a reduction reaction of a compound of formula II: [84] [85] [86] (Wherein K is -OR a or -NR a R a ) [87] The reaction is ideally carried out in an inert solvent, such as THF or methanol, and ideally at a reduced temperature. Suitable reducing agents are those known to reduce carbonyl groups, such as NaBH 4 , DIBAH, LiAlH 4 . [88] Compounds of formula IIa and IIb wherein K is -NR a R a can be prepared from compounds of formula IIA and IIBK, respectively, wherein K is -OR a . The reaction may be carried out according to methods known to those skilled in the art or as described in the examples herein. A suitable reference is " Advanced Organic Chemistry " J. March (4 th edition), John Wiley & Sons, 419-424. [89] Compounds of formula (IIa) can be prepared by alkylation of a compound of formula (VIII) with a compound of formula (IXa), and subsequently, if necessary, by a protecting group elimination reaction. [90] [91] (Wherein X is a leaving group such as a halogen, sulfonate or triplet) [92] [93] (Wherein D, D ', D ", R 1 , R 2 , R 3 , R 4 , m and n are as defined in category A) [94] In the alkylation step, the compound of formula (IXa) and the compound of formula (VIII) are reacted in the presence of at least one base such as potassium carbonate, triethylbenzylammonium chloride, sodium hydride, LDA, butyl lithium or LHMDS and in an inert solvent, Nitrile, DMF or dichloromethane at an appropriate temperature for a suitable period of time. The reaction may be carried out as described in the examples herein or in Synth. Comm. 19 (788) 1167-1175 (1989). [95] C1. A compound of formula I wherein R, D or R 2 is cyano is a compound of formula I wherein R, D or R 2 groups are each -CONH 2 , for example a compound of formula II wherein K is - Lt; / RTI > NH2). ≪ / RTI > The ideal reaction is carried out at room temperature using an inert solvent, such as DMF or methanol. The reaction reagent is an appropriate dehydrating agent, for example, trifluoroacetic anhydride. The reaction is described in the literature [e.g. Synthesis (1992) Falorni M. et al., 972-976; And J. Org. Chem. (1996), Heck MP et al., 61 (19), 6486]. [96] The compounds of formula (II) can be prepared by condensation reaction of an aldehyde compound of formula (III) with a compound of formula (IV) or (V), for example a Knoevenagel or Wittig type reaction, Can be prepared by a reduction reaction of a double bond and a protecting group elimination reaction. [97] [98] [99] [100] D, D ', D'', m, n, R 1 , R 2 and R 4 are as defined in category A, X is 1 and L 1 = L 2 = L 3 = phenyl or L 1 = L 2 = OR d (wherein R d is as defined in category A), L 3 = O) [101] Approximately the same molar quantity of the reactants is mixed in the presence of a base, such as sodium acetate, piperidine acetate, LDA or potassium tert-butoxide, to prepare compounds of formula I wherein A is an unsaturated moiety . This step can be carried out in the presence of an inert solvent or in the absence of a solvent, in which case the temperature should be high enough to at least partially melt the reaction mixture, such a preferred temperature being in the range of 100 ° C to 250 ° C have. [102] When R 4 is not hydrogen, it is necessary to add a dehydroxylating agent to remove -OH formed at the Carbon. Suitable reaction conditions and reaction reagents are described in Synthetic Communications Smonou I et al. (1988) 18, 833, and Synthesis Olag G. et al., (1991) 407 and J. Heterocyclic Chemistry Georgiadis, MP Etal., 1991) 28 (3), 599-604, and Synth. Commun. Majeticj, G. et al. (1993), 23 (16), 2331-2335, and Bioorg. Med. Chem. Lett. (1998) 8 (2), 175-178. [103] Sometimes, when R 4 is H, it is necessary to add a dehydrating agent such as p-toluenesulfonic acid to form a double bond. In a typical such reaction, approximately equimolar amounts of the starting material of formula (III) and the compound of formula (IV) are mixed with an excess of moles preferably 1 to 5 times of anhydrous sodium acetate and, if necessary, under vacuum until the mixture is melted It heats it. The compound of formula IIb is then isolated by mixing with water and acetone, and then filtering the precipitate formed. The crude product can be purified if necessary, for example, using a recrystallization method or a conventional chromatographic method. [104] This reaction may also conveniently be carried out in a solvent such as toluene in the presence of piperidine acetate. The reaction mixture is refluxed in a Dean-Stark apparatus to remove water. The solution is then cooled and the olefin product is separated and purified by standard methods. [105] The reaction can also be carried out by mixing the starting material with the compound of formula V in anhydrous THF, slowly adding potassium tert-butoxide at -20 ° C and quenching the reaction with acetic acid. The crude product is isolated and then dissolved in toluene and the water is removed by refluxing in p-toluenesulfonic acid and a Dean-Stark apparatus. The product is then separated and purified by standard methods. [106] The reaction may also be carried out in an inert solvent such as chloroform in the presence of titanium (IV) chloride and pyridine. [107] The condensation step can also be carried out with a Bithy type reaction (in the case of condensation with a compound of formula IV; see Comprehensive Organic Synthesis vol. 1, pp. 755-781 (Pergamon Press)). [108] Approximately equivalent molarities of reactant III and reactant IV are mixed in the presence of 1-5 molar excess of the base, for example, tetramethylguanidine or potassium carbonate. This reaction can be carried out at a suitable temperature (-10 ° C to + 60 ° C) for a sufficiently long time in the presence of an inert gas such as dichloromethane or isopropanol. [109] Compounds of formula (III) may be prepared by coupling a compound of formula (VI) with a compound of formula (VII), for example under coupling conditions or Mitsunobu reaction (Tsunoda, Tetr. Lett. 34, 1639-42 And then, if necessary, modifying the D groups as described in the Example section. [110] [111] [112] (Wherein D, D ', D ", R 1 , m and n are as defined in category A) [113] The Z group may be -OH or a leaving group such as a halogen, sulfonate or triflate. The alkylation reaction and the Mitsunobu reaction can be carried out as described below or as in the Example section. [114] Compounds of formula IV, V, VI and VII are either commercially available or can be prepared from standard starting materials known to the person skilled in the art or by analogous methods as described herein. [115] D. Reduction of the compound of formula (I) in the form of olefins to the compound of formula (I) in the saturated form can be carried out using a variety of reduction methods known to reduce the carbon-carbon double bond, for example using catalytic hydrogenation in the presence of a suitable catalyst Or by using magnesium or sodium amalgam in lower alcohols such as methanol or using a hydrogen transfer agent such as diethyl-2,5-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate . [116] The catalytic hydrogenation reaction can be carried out in the presence of a base such as alcohols, cellosolves, protic polar organic solvents, ethers, lower aliphatic acids, especially methanol, ethanol, methoxyethanol, dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, Alone or in mixtures. Examples of catalysts used include palladium black, palladium on activated carbon, platinum oxide or Wilkinson's catalyst. The reaction may proceed at different temperatures and pressures depending on the reactivity of the desired reaction. [117] In the case of the hydrogen transfer reaction using diethyl-2,5-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, the reactants are mixed in equivalent molar amounts and the mixture is heated under inert gas or under vacuum (140 DEG C to 250 DEG C). [118] E. Compounds of formula (I) of the present invention may be prepared by alkylation of compounds of formula (VIII) with compounds of formula (IXb), and then, if desired, by protecting group elimination. [119] ≪ Formula (VIII) [120] [121] (Wherein X is a leaving group such as a halogen, a sulfonate or a triplet) [122] [123] (Wherein, D, D ', R 1 , R 2, R 3, R 4, n, x , and D "are as defined in Category A) [124] In the alkylation step, the compound of formula (IX) and the compound of formula (VIII) are reacted in the presence of at least one base such as potassium carbonate, triethylbenzylammonium chloride, sodium hydride, LDA, butyl lithium or LHMDS in an inert solvent, For example, in acetonitrile, DMF or dichloromethane at an appropriate temperature for a suitable period of time. The reaction may be carried out as described in the examples or in Synth. Comm. 19 (788) 1167-1175 (1989). [125] Compounds of formula (VIII) may be prepared from alcohols of formula (X) using standard methods. [126] [127] (Wherein D, D ', D ", R 1 , R 3 and n are as defined in category A) [128] Compounds of formula X can be prepared by reducing compounds of formula III with a reducing agent known to convert a carbonyl group to a hydroxy group, such as lithium borohydride or sodium borohydride, or by reducing an organometallic compound, Can be prepared by reacting it with lithium cyanide or a Grignard reagent. [129] F. The compounds of formula (I) of the present invention may be prepared by reacting a compound of formula (VI) with a compound of formula (XI) in a reaction analogous to the above reaction, and additional protecting groups may be required. [130] [131] R 1 , R 2 , R 3 , R 4 , m, n, x and R are as defined in category A) [132] Compounds of formula XI above may be prepared from commercially available starting materials and compounds of formula IV or formula V according to method C. The reaction is carried out according to standard methods of alkylation or Mitsunobu reaction. [133] F1. In the alkylation reaction, the leaving group Z of the compound of formula (VI) may be a sulfonate, such as a mesylate, a nosylate, a tosylate, or a halogen, such as bromine or iodine. For example, potassium carbonate or cesium carbonate in an inert solvent such as isopropanol or acetonitrile using approximately equimolar amounts of the compound of formula (VI) and the compound of formula (XI) Lt; / RTI > to reflux temperature. [134] The mixture is refluxed for the required time, typically 0.5 to 24 hours, and the finishing step is usually followed by filtration, evaporation and removal of the solid salt using water and an organic solvent such as dichloromethane, ethyl acetate or diethyl ether Extraction. [135] The crude product is purified if necessary, for example using recrystallization or standard chromatographic methods. [136] F2. The Mitsunobu reaction can be carried out according to standard methods. In a typical Mitsunobu reaction, a compound of formula (VI) wherein the group F is a hydroxyl group and a compound of formula (XI) are reacted with an inert gas such as chloroform, Mix in dichloromethane or THF. (1 to 4 equivalents) such as DEAD or ADDP and phosphine (1 to 4 equivalents) such as tributylphosphine or triphenylphosphine in the presence of a slight excess of moles, The reaction mixture is stirred at a sufficiently high temperature, for example, at room temperature for a sufficiently long time (1-24 hours) to obtain a crude product. It can be finished according to the methods described in the standard literature, and if necessary purified, for example, by standard chromatographic methods. [137] G. formula I of the invention (wherein, D is -OSO 2 R d, -SR c, -OCONR f R a, -NR c COOR a, -NR c COR a, -NR c R d, -NR c CONR a R k , NR c SO 2 R d and -NR c CSNR a R k , and R a , R c , R d , R f and R k are as defined in category A, can be prepared in an inert solvent, In the presence of a base, such as triethylamine or pyridine, in dichloromethane or toluene and if appropriate in the presence of a suitable reaction reagent such as a sulfonyl halide, isocyanate, acyl halide, Mate, anhydride or alkylhalide followed by, finally, a protecting group removal reaction. [138] [139] Wherein D ', D ", n and A are as defined in category A and X 1 = -OH, -SH or -NR c H, [140] The reaction can be carried out according to methods known to those skilled in the art. [141] H. formula (I) of the present invention (wherein, D is -SO 2 R d or -SOR d (wherein, R d is a category as defined in A) Im) are compounds of the oxidizing agent to, for a compound of formula XIV, for example, m -Chloroperoxybenzoic acid or hydrogen peroxide in an inert solvent such as dichloromethane and then finally by removal of the protecting group. Compounds of formula XIV wherein R comprises -S- or -SO- group are not used unless oxidation of these groups is required. [142] [143] Wherein D ', D ", n and A are as defined in category A and X 2 is -SOR d or -SR d , wherein R d is as defined in category A, [144] The reaction may be carried out according to standard methods or as described in the Examples. [145] The compounds of the present invention can be separated from their reaction mixture using conventional techniques. [146] Those skilled in the art will appreciate that the individual process steps referred to above may be performed in a different order to obtain the compounds of the present invention in an alternative and in some cases more convenient manner, and the individual reactions may be carried out at different stages in the overall pathway That is, the chemical modification may be carried out in an intermediate different from that described above using a particular reaction). [147] If necessary, in any method of the preparation AH,, hydroxy, amino or other reactive groups protected using a protecting group as described in the literature [ "Protective groups in Organic Synthesis" , 2 nd Edition (1991) by Greene and Wuts] . The protecting group may be a resin, for example, a royal resin or a 2-chlorotrityl chloride resin. The protection and deprotection of functional groups can occur before or after any of the reaction steps described above. The protecting group may be removed according to techniques known to those skilled in the art. [148] The expression " inert solvent " refers to a solvent that does not react with starting materials, reaction reagents, intermediates or products in a manner that has a deleterious effect on the yield of the desired product. [149] Pharmaceutical preparation [150] The compounds of the present invention may be administered orally, parenterally, intravenously, orally in a pharmaceutically acceptable dosage form, usually in the form of a free acid or as a pharmaceutically acceptable organic or inorganic base addition salt, Intraperitoneally, intramuscularly, subcutaneously or by other injection, ball, rectal, vaginal, transdermal and / or intracavitary and / or inhalation. Disease and Treatment Depending on the patient and the route of administration, the composition may be administered in various doses. [151] The compounds of the present invention can also be used in combination with other therapeutic agents useful in the treatment of atherosclerosis, for example, diseases associated with the onset and progression of hypertension, hyperlipidemia, lipidemia, diabetes and obesity. A daily dose suitable for human treatment of a compound of the invention is about 0.001-10 mg / kg body weight, preferably 0.01-1 mg / kg body weight. [152] According to a further aspect of the present invention there is also provided a pharmaceutical formulation comprising a compound of the invention or a pharmaceutically acceptable derivative thereof in admixture with a pharmaceutically acceptable adjuvant, diluent and / or carrier. [153] Pharmacological properties [154] The compounds of formula (I) of the present invention are useful in the prevention and / or treatment of clinical diseases associated with reduced sensitivity to insulin (insulin resistance) and related metabolic disorders. Such clinical diseases include, but are not limited to, abdominal obesity, arterial hypertension, hyperinsulinemia, hyperglycemia, type 2 diabetes and lipidemia, which are characterized as having insulin resistance. Lipidemia, also known as atherosclerotic lipoprotein profile, phenotype B, is a combination of moderately elevated non-esterified fatty acids, triglyceride rich particles of elevated ultra low density lipoprotein (VLDL), low density lipoprotein (HDL) particle level cholesterol and small, dense Is characterized by the presence of low density lipoprotein (LDL) particles. Treatment of this compound is expected to lower cardiovascular morbidity and mortality associated with atherosclerosis. Such cardiovascular diseases include myocardial infarction, cerebrovascular disease and macroangiopathy which causes peripheral arterial insufficiency of the lower limb. Because of their insulin sensitizing effect, the compounds of formula I are also expected to block or delay the onset of type 2 diabetes, and are thus expected to be effective in the treatment of type 1 diabetes mellitus, such as microangiopathy, which causes kidney disease, retinal damage and pulmonary vascular disease Limit the progression of clinical diseases associated with hyperglycemia. In addition, the present compounds may be useful for the treatment of various diseases other than cardiovascular related to insulin resistance such as polycystic ovary syndrome. [155] 1 H NMR and 13 C NMR measurements were carried out on a Varan Mercury 300 or Varian UNITY plus 400, 500 or 600 spectrometer at 1 H frequencies of 300, 400, 500 and 600 MHz, of 100, 125 and 150 MHz was carried out by operating in a 13 C frequency. The measurements were made on a delta scale (δ). [156] Unless otherwise noted, chemical shifts were expressed in ppm using solvents as internal standards. [157] Abbreviation [158] IRS Insulin Resistance Syndrome [159] LDA lithium diisopropylamide [160] LHMDS Lithium hexamethyldisilylamine [161] DMF dimethylformamide [162] DEAD diethyl azodicarboxylate [163] ADDP azodicarbonyl dipiperidine [164] EDC 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide [165] DCC dicyclohexylcarbodiimide [166] HBTU O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium [167] Hexafluorophosphate [168] TBTU O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium [169] Tetrafluoroborate [170] PyBop Benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium [171] Hexafluorophosphate [172] TEA triethylamine [173] DIPEA Diisopropylethylamine [174] TLC thin layer chromatography [175] THF tetrahydrofuran [176] HO-Su N-hydroxysuccinimide [177] Pd / C palladium on charcoal [178] HOBtxH 2 O 1-hydroxybenzotriazole-hydrate [179] DIBAH Diisobutylaluminum hydride [180] DMSO dimethylsulfoxide [181] t triplet [182] s single line [183] d double line [184] q company middle line [185] qvint [186] m multiline [187] br wide area [188] bs wide single line [189] dm double polyline [190] bt wide triplet [191] dd double double line [192] Example 1 [193] 3- [4- (2- {4-cyanophenyl} ethoxy) phenyl] -2-ethoxypropanol [194] 0.666 g (1.81 mmol) of ethyl 3- {4- [2- (4-cyanophenyl) ethoxy] phenyl} -2- ethoxypropanoate was dissolved in 13 ml of anhydrous THF and 0.5 ml of methanol, 0.0 > 20 C. < / RTI > 0.119 g (3.14 mmol) of sodium borohydride was added. After stirring for 6 hours, the temperature was allowed to warm to room temperature. After stirring for another 25 h, water was added and the product was extracted with diethyl ether, washed with water and dried (sodium sulfate). The solvent was evaporated in vacuo to give 0.573 g (yield 97%) of the desired product. [195] [196] Starting material [197] (a) Ethyl 3- {4- [2- (4-cyanophenyl) ethoxy] phenyl} -2-ethoxypropanoate [198] 6.62 g (27.78 mmole) of ethyl 2-ethoxy-3- (4-hydroxyphenyl) propanoate and 2.73 g (18.52 mmole) of p-cyanophenyl ethyl alcohol described in Example 3 (b) were dissolved in 85 ml Lt; / RTI > 7.01 g (27.78 mmole) of ADDP was added followed by 5. 83 g (22. 23 mmole) of triphenylphosphine. The reaction was stopped after 2 hours. The triphenylphosphine oxide formed in the reaction was removed by filtration and the filtrate was evaporated. The residue was purified by chromatography on silica gel using first dichloromethane followed by petroleum ether: diethyl ether as eluent to give a mixture of starting material and product dissolved in ethyl acetate, using sodium hydroxide 1N And washed. The organic phase was washed with water, dried (sodium sulfate), filtered and the solvent was evaporated, yielding 4.23 g (yield 62%) of the desired product. [199] [200] Example 2 [201] Ethoxy-3- {3- [3- (4-methylsulfonyloxyphenyl) propoxy] phenyl} propanol [202] The compound was prepared from 0.642 g (1.42 mmol) of ethyl 2-ethoxy-3- {3- [3- (4-methylsulfonyloxyphenyl) propoxy] phenyl} propanoate and 93.26 mg (2.47 mmol) of the title compound as a white amorphous solid. The reaction was stopped after 28 hours, yielding 0.574 g (yield 99%) of the desired product. [203] [204] Starting material [205] (a) 3- (3-Benzyloxyphenyl) -2-ethoxyacrylic acid ethyl ester [206] 6.5 g (56.6 mmole) of tetraethylguanidine were added to a solution of 11.7 g (55 mmole) of 3-benzyloxybenzaldehyde and (1, 2-diethoxy-2-oxoethyl) (triphenyl) phosphonium chloride 20. To a solution of 1 g (46.8 mmole) was slowly added at 0 < 0 > C. After stirring overnight at room temperature, the solvent was evaporated in vacuo. Diethyl ether was added and the insoluble material was removed by filtration. The filtrate was washed with sodium bicarbonate solution, dried (magnesium sulphate), filtered and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel using 0.5% TFT in dichloromethane as eluent. The residual aldehyde was removed by stirring with water and sodium sulfite in diethyl ether for 2 days. The phases were separated and the organic phase was evaporated in vacuo to give 10.5 g (yield 69%) of the desired product. [207] [208] (b) Ethyl 2-ethoxy-3- (3-hydroxyphenyl) propanoate [209] 10.4 g (31.8 mmol) of compound (a) was hydrogenated at atmospheric pressure in ethyl acetate using Pd / C (anhydrous, 10%) as the catalyst. The reaction mixture was filtered through celite and the solvent was evaporated in vacuo. The starting material was not consumed completely, and therefore the hydrogenation was repeated to give 7 g of the desired product (yield 92%). [210] [211] (c) 3- (4-methylsulfonyloxyphenyl) propyl methanesulfonate [212] 3- (4-methylsulfonyloxyphenyl) propyl methanesulfonate was synthesized from 3- (4-hydroxyphenyl) -1-propanol in the same manner as in Example 8. [213] [214] (d) Ethyl 2-ethoxy-3- {3- [3- (4-methylsulfonyloxyphenyl) propoxy] phenyl} propanoate [215] Compound (c) 1. 905 g (6.18 mmole) is dissolved in 13 ml of acetonitrile and 1.47 g of ethyl 2-ethoxy-3- (3-hydroxyphenyl) -propanoate in 15 ml of acetonitrile are added. 18 mmole) and 2.46 g (18.54 mmole) of potassium carbonate. The mixture was refluxed for 5 hours, then the solvent was evaporated in vacuo and water was added. The mixture was extracted twice with dichloromethane, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo. Purification by chromatography on silica gel with diethyl ether / petroleum ether (diethyl ether 33% to 100% gradient) gave 1.80 g (yield 65%) of the desired product. [216] [217] Example 3 [218] 3- {4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl} -2-ethoxypropanol [219] The compound was treated with 0. 994 g (2.17 mmol) of ethyl 3- {4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl} -2- ethoxypropanoate and sodium borohydride The title compound was synthesized by a method similar to that of Example 1 using 0. 164 g (4.34 mmol) of lead. The reaction was stopped after 21 hours and the product was extracted with ethyl acetate. The organic phase was washed with sodium sulphate and brine, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo. The crude product was purified by chromatography on silica gel using heptane: ethyl acetate (2: 1 to 1: 2 gradient) as eluent to give 0.5 g of the desired product (55% yield). [220] [221] Starting material [222] (a) 3- (4-Benzyloxyphenyl) -2-ethoxyacrylic acid ethyl ester [223] 42.3 g (0.37 mole) of tetramethylguanidine were added to a solution of 75.6 g (0.36 mole) of 4-benzyloxybenzaldehyde dissolved in 800 ml of chloroform and 130.7 g of (1,2-diethoxy-2-oxoethyl) (triphenyl) phosphonium chloride 0.304 mole) at O < 0 > C. After stirring at room temperature overnight, the solvent was evaporated in vacuo. The residue was dissolved in diethyl ether, insoluble material was removed by filtration, and the filtrate was washed with sodium bicarbonate and dried (magnesium sulfate). This process was repeated one more time after which the crude product was stirred overnight with a saturated aqueous solution of sodium bisulfate. The solid material was removed by filtration, the product was extracted with diethyl ether, dried (magnesium sulfate) and the solvent was evaporated in vacuo to give 85 g of the desired product (73% yield). [224] [225] (b) Ethyl 2-ethoxy-3- (4-hydroxyphenyl) propanoate [226] 62 g (0.19 mole) of the compound (a) was hydrogenated in 400 ml of ethyl acetate under atmospheric pressure using 10% Pd / C as a catalyst. The mixture was filtered through celite and evaporated in vacuo to give 45.6 g (yield 100%) of the desired product. [227] [228] (c) 4- (2-Hydroxyethyl) phenylcarbamic acid tert-butyl ester [229] 7.95 g (36 mmole) of di-tert-butyl dicarbonate was added to a mixture of 5 g (36 mmole) of p-aminopentyl alcohol in THF at 0 ° C. After stirring overnight at room temperature, the solvent was evaporated in vacuo to give 8 g of the desired product (94% yield). [230] [231] (d) Ethyl 3- {4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl} -2-ethoxypropanoate [232] 1.03 g (4.34 mmole) of compound (c) and 1.03 g (4.34 mmole) of compound (b) were dissolved in dichloromethane under argon at room temperature. 1.65 g (6.5 mmole) of azodicarbonyl dipiperidine was added followed by 1.37 g (5.2 mmole) of triphenylphosphine. After stirring at room temperature for 6 hours, the solvent was evaporated in vacuo. Purification by chromatography on silica gel using heptane: ethyl acetate (2: 1) as eluent gave 1.78 g (yield 89%) of the desired product. [233] [234] Example 3a [235] 3- {4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl} - (2R) -2-ethoxypropanol [236] The racemate of Example 3 was isolated using chiral purification HPLC (Chiralpak AD 250x50 mm) using heptane and isopropanol (1: 1) as mobile phase to give the desired product as the pure isomer. [237] [238] Example 3b [239] 3- {4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl} - (2S) -2-ethoxypropanol [240] The racemate of Example 3 was isolated using chiral purification HPLC (Chiralpak AD 250x50 mm) using heptane and isopropanol (1: 1) as mobile phase to give the desired product as the pure isomer. [241] [242] Example 4 [243] 3- [4- (2- {4-tert-butoxycarbonylaminophenyl} ethoxy) phenyl] -2-ethoxypropyl methanesulfonate [244] Example 3 0. 81 g (2.0 mmole) was dissolved in 10 ml of anhydrous THF and cooled to 20 캜. 0.24 g (2.4 mmole) of triethylamine was added dropwise to the mixture, and after 10 minutes, 0.27 g (2.4 mmole) of methanesulfonyl chloride was added. After 4 hours, it was checked by HPLC whether all starting materials were consumed. 5 mL of hydrochloric acid was added, THF was evaporated, and the residue was extracted three times with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated to give 1.0 g of the desired product (yield: 99%). [245] [246] Example 4a [247] 3- [4- (2- {4-tert-butoxycarbonylaminophenyl} ethoxy) phenyl] - (2S) -ethoxypropyl methanesulfonate [248] The compound was synthesized using a method analogous to that used in Example 4 using 1. 27 g (99% yield) of Example 3b. [249] [250] Example 5 [251] S- {3- [4 - ({4-tert-butoxycarbonylaminophenyl} ethoxy) phenyl] -2-ethoxypropyl ethanethioate [252] 0.7 g (1.4 mmole) of Example 4 was dissolved in 3 ml of DMF and 1.0 g (2.5 mmole) of cesium ethane thioate was added. After stirring at room temperature for 48 hours, HPLC was used to check whether the starting material was consumed. Water was added and the mixture was extracted three times with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated to give 0.57 g of the desired product (yield: 84%). [253] [254] Example 6 [255] tert-butyl N- (4-2- [4 (2-ethoxy-3-mercaptopropyl) phenoxy] ethylphenyl) carbamate [256] Example 5 0.32 g (0.66 mmole) was dissolved in 10 ml methanol, cooled to 0 占 폚 and 0.11 g (0.86 mmole) anhydrous potassium carbonate was added. After stirring at room temperature for 1 hour, it was checked using HPLC to check whether all starting materials were consumed. Water was added and the methanol was evaporated and the residue was extracted with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated. The crude product was purified using HPLC (Chromasil C8, 7 μm, 50 × 250 mm) using acetonitrile (80%) in ammonium acetate buffer (pH 7) as mobile phase to give 0.16 g (yield 52%) of the desired product. [257] [258] Example 7 [259] ethyl] phenyl] carbamate < RTI ID = 0.0 > (2-ethoxy- [260] 0.32 g (0.62 mmole) of Example 4a was dissolved in 5 ml of methanol and 0.21 g (2.49 mmole) of sodium thioethoxide was added. After stirring at room temperature for 26 hours, it was checked by HPLC whether all starting materials were consumed. Water was added, the methanol was evaporated and the residue was extracted three times with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated. The crude product was purified using a preparative HPLC (Chromasil C8, 7 μm, 50 × 250 mm) using acetonitrile (70-100%) of ammonium acetate buffer (pH 7) as mobile phase to give 0.17 g of the desired product (Yield 57 %). [261] [262] Example 8 [263] Ethoxy-3- [4- (2- {4-methylsulfonyloxyphenyl} ethoxy) phenyl-1-hydroxypropane [264] 1.1 g (2.5 mmole) of ethyl 2-ethoxy-3- [4- (2- {4- (methylsulfonyloxyphenyl} ethoxy) phenyl] propanoate were dissolved in 10 ml of dichloromethane, After 5.8 ml (5.8 mmole) of DIBAL-H 1M was added dropwise, the reaction mixture was stirred at -78 < 0 > C for 0.5 h, then warmed to room temperature and after 2 h all starting materials were consumed The reaction mixture was cooled to 40 DEG C and the reaction was quenched with sulfuric acid (2%, 5 ml). 10 ml of 2M hydrochloric acid was added and the mixture was extracted three times with ethyl acetate. [265] The organic phase was washed with sodium hydrogencarbonate, dried over magnesium sulfate and evaporated to give 0.97 g of the desired product (yield: 98%). [266] [267] Starting material [268] (a) 2- (4-methylsulfonyloxyphenyl) ethyl methanesulfonate [269] 15 g (0.108 mole) of 4-hydroxyphenethyl alcohol was dissolved in dichloromethane. 27.3 g (0.27 mole) of triethylamine were added, followed by a solution of 27.2 g (0.239 mole) of methanesulfonyl chloride in dichloromethane at 0 占 폚. The reaction mixture was allowed to warm to room temperature, followed by stirring at room temperature followed by TLC. The reaction mixture was filtered. The filtrate was washed with water, the phases were separated, the organic phase was dried over sodium sulfate and evaporated to give 28 g of the expected product (yield 88%). [270] [271] (b) 4- [2- (4-formylphenoxy) ethyl] phenyl methanesulfonate [272] (0.102 mole) of compound (a) was dissolved in acetonitrile and slowly added to a mixture of 31.1 g (0.255 mole) of 4-hydroxybenzaldehyde and 41.46 g (0.3 mole) of potassium carbonate in acetonitrile, ) Was refluxed until consumed. The salt was removed by filtration, the solvent was evaporated in vacuo and dichloromethane was added. The organic phase was washed with water and evaporated. Purification by chromatography on silica gel using dichloromethane as eluent gave 21.6 g (yield 66%) of the desired product. [273] [274] (c) 2-Ethoxy-3- {4- [2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl} acrylic acid ethyl ester [275] (15.0 mmole) of tetramethylguanidine was added to a solution of 4.49 g (14.0 mmole) of the compound (b) and 5.62 g of (1,2-diethoxy-2-oxoethyl) (triphenyl) phosphonium chloride in 50 ml of chloroform at 0 ° C. (13.1 mmole). After stirring at room temperature overnight, the solvent was evaporated in vacuo. Diethyl ether was added to the residue, and triphenylphosphine oxide crystallized as white crystals which were removed by filtration. The filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel with ethyl acetate in heptane (gradient 1.25-100%) as eluent. The crude product crystallized during standing. To obtain 2.18 g (yield: 35%) of the desired product as white crystals. [276] [277] (d) Ethyl 2-ethoxy-3- [4- (2- {4-methylsulfonyloxyphenyl} ethoxy) phenyl] propanoate [278] 1.47 g (3.38 mmole) of compound (c) was hydrogenated in 50 ml of ethyl acetate under atmospheric pressure with 0.74 g (5%) Pd / C as catalyst for 3 hours. The reaction mixture was filtered through celite, dried (magnesium sulfate) and the solvent was evaporated in vacuo to give the desired product (1.44 g, 98% yield). [279] [280] Example 9 [281] Ethoxy-3- [4- (2- {4-methylsulfonyloxyphenyl} ethoxy) phenyl-1-methoxypropane [282] 0.45 g (1.2 mmole) of Example 8 was dissolved in 10 ml of acetone and 1.78 g (12.5 mmole) of methyl iodide and 2.64 g (11 mmole) of silver oxide were added. The reaction mixture was stirred at room temperature. [283] After 48 hours, HPLC was used to check if all starting materials were consumed. The reaction mixture was filtered through celite, the acetone was evaporated and the crude product was purified by preparative HPLC (Kramosil C8, 7 um, 50 x 250 mm) using acetonitrile in ammonium acetate buffer (pH 7) (Yield: 84%). [284] [285] Example 10 [286] 2-Cyano-3- {4- [2- (4-methylsulfonyloxyphenyl) ethoxy] phenyl} propanol [287] 1.37 g (36 mmol) of sodium borohydride are added to 3.0 g (7.2 mmol) of ethyl 2-cyano-3- {4- [2- (4- methylsulfonyloxyphenyl) ethyl] phenyl} propanoate in 40 ml of methanol ) In < / RTI > After the addition, the mixture was stirred for 2 hours. Hydrochloric acid (10%) was then added dropwise to the mixture to pH = 4-5. The reaction mixture was evaporated in vacuo to remove methanol. The residue was extracted with ethyl acetate. The solvent was removed in vacuo. Column chromatography of the residue on silica gel using ethyl acetate / heptane (20:80 to 60:40) as eluent gave 1.9 g (yield 70%) of the desired product. [288] [289] Starting material [290] (a) 2-Cyano-3- {4- [2- (4-methylsulfonyloxyphenyl) ethoxy] phenyl} acrylic acid ethyl ester [291] 2 g (6. 24 mmole) of 4- [2- (4-formylphenoxy) ethyl] phenyl methanesulfonate, 1.41 g (12.48 mmole) of ethyl cyanoacetate and 1.34 g 6 mmole) was heated to 120 < 0 > C. The melted mixture was then cooled by heating. Dichloromethane was added and the solution was washed with water and brine. The organic phase was dried using sodium sulfate, filtered and the solvent was evaporated in vacuo. Chromatography of the crude product on silica gel with heptane: ethyl acetate (gradient 9: 1 to 1: 1) as eluent followed by crystallization gave 1.98 g (77% yield) of the desired product. [292] [293] (b) Ethyl 2-cyano-3- {4- [2- (4-methylsulfonyloxyphenyl) ethoxy] phenyl} propanoate [294] A mixture of 1.69 g (4.07 mmol) of the compound (a) and 2.06 g (8.14 mmol) of diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate was slowly After heating, it was cooled to room temperature. The crude product was purified by chromatography on silica gel using heptane: ethyl acetate as eluent to give 1.55 g (yield 91%) of the desired product. [295] [296] Example 11 [297] Ethoxy-3- {4- [2- (4-ethoxyphenyl) ethoxy] phenyl} propanol [298] (2.393 mmol) of ethyl 2-ethoxy-3- {4- [2- (4-ethyloxyphenyl) ethoxy] phenyl} propanoate and 0.157 g (4.14 mmol) of sodium borohydride Prepared by a method similar to Example 1 and the reaction was stopped after 24 hours to give 0.723 g (yield 89%) of the desired product. [299] [300] Starting material [301] (a) Ethyl 2-ethoxy-3- {4- [2- (4-ethyloxyphenyl) ethoxy] phenyl} propanoate [302] The compound was prepared using the procedure described in Example 3 (b) using 3.431 g (20.64 mmol) 2- [4-ethoxyphenyl] ethanol and 4.919 g (20.64 mmol) ethyl 2- d). < / RTI > Purification by chromatography on silica gel using heptane: ethyl acetate (gradient 1: 1 to 3: 5) as eluent gave 6.3 g (yield 79%) of the desired product. [303] [304] Example 12 [305] 1-Cyano-2- [4- (2- {4-tert-butyloxycarbonylaminophenyl} ethoxy) phenyl] -1-ethoxyethane [306] 0.63 g (1.47 mmol) of 1-carbamoyl-2- [4- (2- {4- tert-butyloxycarbonylaminophenyl} ethoxy) phenyl] -1- ethoxyethane was dissolved in 20 ml of dioxane 0.35 g (4.41 mmol) of pyridine was added. The mixture was poured into an ultrasonic cleaner for 5 minutes and then 0.37 g (1.76 mmol) of trifluoroacetic acid anhydride was added. After stirring at room temperature for 16 hours, HPLC was used to check if all starting materials were consumed. Sodium carbonate solution was added and extracted three times with dichloromethane. The organic phase was dried with magnesium sulfate and evaporated. The crude product was purified using a preparative HPLC (Chromasil C8, 7 μm, 50 × 250 mm) using acetonitrile (70-80%) in ammonium acetate buffer (pH 7) as mobile phase to give 0.47 g of the desired product %). [307] [308] Starting material [309] (a) 1-Carbamoyl-2- [4- (2- {4-tert-butyloxycarbonylaminophenyl} ethoxy) phenyl] -1- [310] 1.18 g (2.75 mmol) of 3- {4- [2- (4-tert-butoxycarbonylaminophenyl} ethoxy] phenyl] -2-ethoxypropanoic acid, and benzotriazol- (2.75 mmol) of pyrrolidinophosphonium hexafluorophosphate were dissolved in 20 ml of anhydrous DMF. The mixture was bubbled through ammonia gas for 5 minutes. Water was added, extracted three times with ethyl acetate, Dried over magnesium sulfate and evaporated.The residue was redissolved in dichloromethane and chromatographed on silica gel using a gradient system of dichloromethane: methanol (0-5%) to give 1.04 g of the desired product (Yield 85 %). [311] [312] (b) 3- {4- [2- (4-tert-Butoxycarbonylaminophenyl) ethoxy] phenyl} -2-ethoxypropanoic acid [313] 77 mg (1.85 mmole) of lithium hydroxyhydrate in 5.5 ml of water was added to a solution of ethyl 3- {4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl} -2- Lt; / RTI > propanoate in 5 ml of tetrahydrofuran. After stirring at room temperature for 4 hours, the reaction mixture was kept in the freezer for 4 days. The THF was removed by evaporation in vacuo. Additional water was added and the mixture was acidified to pH 1 with hydrochloric acid. The product was extracted with ethyl acetate, washed twice with water, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo to give 0.712 g (yield 98.7%) of the desired product. [314] [315] Example 13 [316] tert-butyl 4- (2- {4 - [(2S) -3-amino-2-ethoxypropyl] phenoxy} ethyl) phenylcarbamate [317] (2S) -3- {4- (2- {4 - [(tert-butoxycarbonyl) amino] phenyl} ethoxy) phenyl] -2-ethoxypropyl methanesulfonate (described in Example 4a) g (0.87 mmol) were dissolved in 5 ml of anhydrous DMF. 0.23 g (3.50 mmol) sodium azide was added and the reaction mixture was heated to 80 < 0 > C and stirred overnight. The reaction was quenched with water and extracted with diethyl ether. The organic phase was washed with water, dried over magnesium sulphate and evaporated. The crude product was dissolved in anhydrous diethyl ether and added to a solution of 0.10 g (2.62 mmol) of LAH in 50 ml of diethyl ether. After 1 hour the reaction was quenched with 0.5 ml water, 1 ml 5 M NaOH and again 0.5 ml water. The mixture was refluxed for 30 minutes, the white precipitate was removed by filtration, and the filtrate was dried over magnesium sulfate and evaporated to give 0.63 g (yield 72%) of the product. [318] [319] Example 14 [320] N- (4- {2- [4- (2-cyano-3-hydroxypropyl) phenoxy] ethyl} phenyl) -2-methylpropanamide [321] 0.5 g (1.22 mmol) of ethyl 2-cyano-3- (4- {2- [4- (isobutyrylamino) phenyl] ethoxy} phenyl) propanoate was dissolved in 10 ml of methanol. 0.24 g (6.34 mmol) of sodium borohydride was carefully added. The mixture was stirred at room temperature for 4 hours and then evaporated to dryness in vacuo. Ethyl acetate and water were added to the residue. After separation, the organic phase was washed with 0.3 M hydrochloric acid, water and brine. The solvent was evaporated in vacuo. The crude product was subjected to column chromatography on silica gel using ethyl acetate / heptane as eluent to obtain 0.33 g (yield: 74%) of the desired product. [322] [323] Starting material [324] (a) N- [4- (2-hydroxyethyl) phenyl] -2-methylpropanamide [325] 21 g (0.153 mol) of 4-aminophenyl ethyl alcohol was dissolved in 200 ml of acetone. The solution was heated to reflux, and 24.15 g (0.153 mol) of 2-methylpropionic anhydride was added dropwise. The mixture was heated to reflux for 1 hour and HPLC indicated that the reaction was not complete. Additional 1.0 g of 2-methylpropionic anhydride was added and heated for an additional 1.5 h. The reaction mixture was then evaporated to dryness in vacuo. The residue was dissolved in 150 ml of warm dichloromethane and then cooled to room temperature. 200 ml of heptane was added dropwise to the solution, and crystals were precipitated. The crystals were filtered off and washed with heptane. 30.7 g of the title compound was obtained (yield: 97%). [326] [327] ( b) Ethyl 2-cyano-3- (4- {2- [4- (isobutyrylamino) phenyl] ethoxy} phenyl) propanoate [328] (6.85 mmol) of ethyl 2-cyano-3- (4-hydroxyphenyl) propanoate and 1.42 g (4.55 mmol) of N- [4- (2- hydroxyethyl) Were mixed in 40 ml of dichloromethane. Then 2.3 g (9.12 mmol) of 1,1 '- (azodicarbonyl) dipiperidine and 2.4 g (9.15 mmol) of triphenylphosphine were added, respectively. The mixture was stirred overnight and filtered. The filtrate was evaporated in vacuo to dryness. The residue was subjected to column chromatography on silica gel using ethyl acetate / heptane as an eluent to give 0.5 g (yield 27%) of the desired product. [329] [330] Example 15 [331] 2- {4- [2- (4-ethylphenyl) ethoxy] benzyl} -3-hydroxypropanenitrile [332] 0.31 g (0.9 mmol) of methyl 2-cyano-3- {4- [2- (4-ethylphenyl) ethoxy] phenyl} propanoate was dissolved in methanol. 0.17 g (4.5 mmol) of sodium borohydride was added and the reaction mixture was stirred until TLC indicated that all starting material had been consumed. HCl 1M was added until pH ~ 4-5. The methanol was evaporated and the residue was extracted with ethyl acetate. Further purification and purification yielded 0.15 g of 2- {4- [2- (4-ethylphenyl) ethoxy] benzyl} -3-hydroxypropanenitrile (yield: 54%). [333] [334] Starting material [335] (a) Methyl 2-cyano-3- {4- [2- (4-ethylphenyl) ethoxy] phenyl} propanoate [336] 0.8 g (5.3 mmol) of 2- (4-ethylphenyl) ethanol and 0.9 g (4.4 mmol) of methyl 2-cyano-3- (4-hydroxyphenyl) propanoate were dissolved in 20 ml of anhydrous dichloromethane. 2.3 g (8.8 mmol) of triphenylphosphine was added, followed by 2.22 g (8.8 mmol) of ADDP to give a dark orange solution. The reaction mixture was stirred overnight, then filtered and evaporated. The residue was treated with a mixture of dichloromethane and diethyl, filtered once more. Addition of SiO 2 to the filtrate and then was evaporated. The residue was chromatographed using diethyl ether / pentane (1: 1) to give 0.31 g of methyl 2-cyano-3- {4- [2- (4- ethylphenyl) ethoxy] phenyl} propanoate (Yield: 20.8%). [337] [338] Example 16 [339] 3- (4- {2- [4- (methylsulfonyl) phenyl] ethoxy} phenyl) -2- (phenylthio) propan- [340] 0.58 g (1.20 mmol) of ethyl 3- (4- {2- [4- (methylsulfonyl) phenyl] ethoxy} phenyl) -2- (phenylthio) propanoate was dissolved in 15 ml of anhydrous dichloromethane. The solution was cooled to -78 < 0 > C and DIBAL-H (1 M hexane solution, 3.0 ml, 3.0 mmol) was added. The coolant was removed after 20 minutes. After 2 hours, the reaction mixture was cooled in an ice bath and HCl 1M (15 ml) was added. The mixture was extracted with dichloromethane, the organic phase was washed twice with 15 ml of water and dried over Na 2 SO 4 . Evaporation gave 0.554 g (~ 100%) of the desired product as a colorless oil. [341] [342] The starting materials are described in WO9962871. [343] Example 17 [344] 2- (4- {2- [4- (methylsulfonyl) phenyl] ethoxy} benzyl) butan- [345] 0.40 g (1.02 mmol) of methyl 2- (4- {2- [4- (methylsulfonyl) phenyl] ethoxy} benzyl) butanoate was dissolved in 10 ml of anhydrous methylene chloride and cooled to -78 ° C. 3.00 ml (3.00 mmol) of 1M DIBAH was slowly added and the reaction was stirred overnight and warmed to room temperature. The reaction was cooled to -10 < 0 > C, quenched with 5 ml 2M hydrochloric acid and extracted with methylene chloride. The organic phase was dried using magnesium sulfate. The crude product was purified by preparative HPLC (Chromasil C8, 7 탆, 50 x 250 mm) using acetonitrile (50%) in ammonium acetate buffer pH 7 as mobile phase to give 0.24 g (63% yield) of the desired product. [346] [347] Starting material [348] (a) Methyl 2- (4- {2- [4- (methylsulfonyl) phenyl] ethoxy} benzyl) butanoate [349] (2.5 mmol) of methyl 2- (4-hydroxybenzyl) butanoate and 0.52 g (2.5 mmol) of 2- [4- (methylsulfonyl) phenyl] ethanol were mixed in 10 ml of dichloromethane. 0.76 g (3.0 mmol) of ADDP was added followed by 0.79 g (3.0 mmol) of triphenylphosphine. The reaction was stopped after 16 hours. The triphenylphosphine oxide formed during the reaction was removed by filtration, and the filtrate was evaporated. Chromatography of the crude product with 0 to 32% elution gradient of methanol and dichloromethane gave 0.64 g (66% yield) of the product. [350] [351] Example 18 [352] 2- (4- {2- [4- (methoxymethyl) phenyl] ethoxy} benzyl) butan- [353] The compound was synthesized in the same manner as in Example 17 (1) using 0.427 g (1.20 mmol) of methyl 2- (4- {2- [4- (methoxymethyl) phenyl] ethoxy} benzyl) butanoate and 4.76 ml To give 0.383 g of the desired product (yield: 97%). [354] [355] Starting material [356] (a) [4- (methoxymethyl) phenyl] acetic acid [357] 4.85 g (21.17 mmol) of 4- (bromomethyl) phenylacetic acid, sodium methoxide (30%, ~ 12 ml, ~65 mmol in methanol) and 30 ml of methanol were mixed and refluxed overnight. The reaction mixture was cooled and then acidified with HCl 1M. The methanol was evaporated. Water was added and the reaction mixture was extracted with three portions of dichloromethane. The combined organic phases were washed with brine and dried over Na 2 SO 4 . Evaporation gave 3.6 g of the desired product (94.4%). [358] [359] (b) 2- [4- (methoxymethyl) phenyl] ethanol [360] 3.6 g (20 mmol) of [4- (methoxymethyl) phenyl] acetic acid were dissolved in 100 ml of THF and cooled in an ice bath. 40 ml (40 mmol) of 1 M BH 3 x THF were added. The reaction mixture was stirred for 6 h and then quenched with 1 M HCl (80 ml) and water-100 ml. THF was evaporated and the residue was extracted with dichloromethane and ethyl acetate. The phases were separated and the organic phase was washed with 100 ml of 0.3 M HCl and dried over Na 2 SO 4 . Evaporation gave 3.31 g of the desired product (99.6%). [361] [362] (c) Methyl 2- (4- {2- [4- (methoxymethyl) phenyl] ethoxy} benzyl) butanoate [363] 1.23 g (4.89 mmol) of ADDP and 1.03 g (3.92 mmol) of triphenylphosphine were added under argon to a solution of 0.54 g (3.26 mmol) of 2- [4- (methoxymethyl) phenyl] (4-hydroxybenzyl) butanoate in 20 ml of tetrahydrofuran was added to a solution of 0.68 g (3.26 mmol) of 4-hydroxybenzyl) butanoate. After 5 min, additional 10 ml of dichloromethane was added. The reaction mixture was stirred at room temperature for 5.5 hours and then filtered. Purification by chromatography on silica gel using heptane: ethyl acetate 1: 1 as eluent gave a mixture of product and starting material which was dissolved in ethyl acetate and washed 3 times with 1 N sodium hydroxide. The organic phase was washed with brine, dried (sodium sulfate), filtered and the solvent was evaporated to give 0.27 g (yield 60%) of the desired product. [364] [365] Example 19 [366] N- [2-hydroxy-1- (4- {2- [4- (methoxymethyl) phenyl] ethoxy} benzyl) ethyl] -2-methylpropanamide [367] 0.4 g (1 mmol) of N-isobutyryl-O- {2- [4- (methoxymethyl) phenyl] ethyl} tyrosine was dissolved in 3 ml of dichloromethane (anhydrous). 85 ml (1.05 mmol, anhydrous) of pyridine were added. The mixture was cooled to -20 < 0 > C. 200 ml (2.2 mmol) of cyanuric fluoride was added under a nitrogen atmosphere. The mixture was stirred at -20 < 0 > C to -7 [deg.] C for 1 hour, then 10 ml of ice cold water and 10 ml of dichloromethane were added. The phases were separated. The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with 10 ml of ice cold water, dried with sodium sulfate and concentrated to about 3 ml. 76 mg (2 mmol) of sodium borohydride was added, followed by dropwise addition of 2 ml of methanol over 15 minutes. After 15 minutes of further stirring, the mixture was neutralized with 2 ml of 2M potassium hydrogensulfate and 15 ml of water. The dichloromethane was evaporated in vacuo. The residue was extracted with 30 ml x 2 of ethyl acetate. The combined organic phases were washed with 1M potassium hydrogensulfate (20ml), water and brine, and dried over sodium sulfate. The solvent was evaporated in vacuo. [368] The residue was subjected to column chromatography on silica gel using ethyl acetate / heptane / isopropyl alcohol (45:45:10) as an eluent to give 0.22 g (yield: 57%) of the desired product. [369] [370] Starting material [371] (a) Methyl N-isobutyryltylosinate [372] 5.78 g (0.054 mol) of sodium carbonate in 50 ml of water was added to 25 g (0.108 mol) of tyrosine methyl ester hydrochloride in 500 ml of dichloromethane. The mixture was vigorously stirred and cooled to 0 < 0 > C. 12.3 ml (0.119 mol) of isobutyryl chloride and 8.58 g (0.081 mol in 50 ml water) of sodium carbonate were added dropwise with two additional tubes. The resulting mixture was stirred for 2 h at 0 < 0 > C and then at room temperature overnight. HPLC indicated that the reaction was not complete. 6.15 ml (0.059 mol) of additional isobutyryl chloride and 5.78 g (0.054 mol in 50 ml water) of sodium carbonate were added dropwise. The mixture was stirred for an additional 6 hours and then filtered. The crystals were washed with water and diethyl ether. 27 g of a white crystalline product was obtained (yield: 94%). [373] [374] (b) Methyl N-isobutyryl-O- {2- [4- (methoxymethyl) phenyl] ethyl} thyrosinate [375] 0.6 g (3.61 mmol) of 2- [4- (methoxymethyl) phenyl] ethanol and 1.15 g (4.34 mmol) of methyl N-isobutyryltylosinate were mixed in 20 ml of dichloromethane (anhydrous). Then 1.1 g (4.36 mmol) of 1,1 '- (azodicarbonyl) dipiperidine and 1.14 g (4.35 mmol) of triphenylphosphine were added, respectively. The mixture was stirred at room temperature overnight and filtered. The filtrate was evaporated in vacuo to dryness. Column chromatography on silica gel using ethyl acetate / heptane (gradient 5:95 to 50:50) as eluent afforded 0.71 g (yield 48%) of the desired product. [376] [377] (c) N-isobutyryl-O- {2- [4- (methoxymethyl) phenyl] ethyl} tyrosine [378] 0.7 g (1.69 mmol) of methyl N-isobutyryl-O- {2- [4- (methoxymethyl) phenyl] ethyl} tyrosinate was dissolved in 6 ml of dioxane. 0.25 g (5.95 mmol) of lithium hydroxide monohydrate in 6 ml of water was added. The mixture was stirred overnight, then diluted with water and evaporated in vacuo to remove dioxane. The residue was acidified with 1 M hydrochloric acid, pH ~ 3, and then extracted twice with dichloromethane. The organic phase was washed with brine and dried over sodium sulfate. The solvent was then evaporated to give 0.67 g of the desired product (yield: 99%). [379] [380] Example 20 [381] N- (1- {4- [2- (4-ethoxyphenyl) ethoxy] benzyl} -2-hydroxyethyl) -2-methylpropanamide [382] 186 mg (0.47 mmol) of O- [2- (4-ethoxyphenyl) ethyl] -N-isobutyryl tyrosine was dissolved in 1.5 ml (anhydrous) of dichloromethane. 40 ml (0.5 mmol, anhydrous) of pyridine were added. The mixture was cooled to -20 < 0 > C. 90 ml (1 mmol) of cyanuric fluoride were added under an inert gas. The mixture was stirred at -20 < 0 > C for 1 hour, then 10 ml of ice cold water and 15 ml of dichloromethane were added. The organic phases were combined, washed with 10 ml of ice cold water and concentrated to about 2 ml with sodium sulfate. 38 mg (1 mmol) of sodium borohydride were added, followed by dropwise addition of 1 ml of methanol over 10 minutes. After 10 minutes of further stirring, the mixture was neutralized with 2M potassium hydrogen sulfate and water. The dichloromethane was evaporated in vacuo. The residue was extracted with 20 ml x 2 of ethyl acetate. The combined organic phases were washed with 1M potassium hydrogensulfate (15 ml), water and brine, and dried over sodium sulfate. The solvent was evaporated in vacuo. The residue was subjected to column chromatography on silica gel using ethyl acetate / heptane / isopropyl alcohol (45:45:10) as an eluent to give 0.12 g (yield 67%) of the desired product. [383] [384] Starting material [385] (a) Methyl O- [2- (4-ethoxyphenyl) ethyl] -N-isobutyryltylosinate [386] 0.6 g (3.61 mmol) of 4-ethoxy-phenethyl alcohol and 1.15 g (4.34 mmol) of methyl N-isobutyryltylosinate were mixed in 20 ml (anhydrous) of dichloromethane. 1.1 g (4.36 mmol) of 1,1 '- (azodicarbonyl) dipiperidine and 1.14 g (4.35 mmol) of triphenylphosphine were subsequently added, respectively. The mixture was stirred at room temperature overnight and filtered. The filtrate was evaporated in vacuo to dryness. The residue was column-chromatographed on silica gel using ethyl acetate / heptane (gradient from 10:90 to 50:50) as eluent to give 0.75 g (yield 50%) of the desired product. [387] [388] (b) O- [2- (4-ethoxyphenyl) ethyl] -N-isobutyryl tyrosine [389] 0.25 g (0.61 mmol) of methyl O- [2- (4-ethoxyphenyl) ethyl] -N-isobutyryltylosinate was dissolved in 4 ml of dioxane. 0.1 g (2.38 mmol) of lithium hydroxide monohydrate in 4 ml of water was added. The mixture was stirred overnight and then acidified with 1 M hydrochloric acid pH ~ 3-4. The dioxane was removed by evaporation in vacuo. The residue was diluted with water and then extracted with dichloromethane. The organic phase was washed with brine and dried over sodium sulfate. The solvent was then evaporated to give 0.25 g of the desired product (100% yield). [390] [391] Example 21 [392] Ethoxy-3- {4- [2- (4-ethylphenyl) ethoxy] phenyl} propan- [393] 0.48 g (1.4 mmol) of 2-ethoxy-3- {4- [2- (4-ethylphenyl) ethoxy] phenyl} propanoic acid was dissolved in 15 ml (anhydrous) of tetrahydrofuran and then cooled in an ice bath . Borane-tetrahydrofuran complex (1M in tetrahydrofuran, 3 ml, 3 mmol) was added. After the addition, the ice bath was removed. The reaction mixture was stirred for 4 hours at room temperature and then quenched with 1 M hydrochloric acid and water. Tetrahydrofuran was evaporated in vacuo. [394] The residue was diluted with water and then diluted with dichloromethane. The organic phase was washed with brine and dried over sodium sulfate. The solvent was then evaporated. 0.42 g of the desired product was obtained (yield: 91%). [395] [396] Starting material [397] (a) Ethyl 2-ethoxy-3- {4- [2- (4-ethylphenyl) ethoxy] phenyl} propanoate [398] 0.45 g (3 mmol) of 4-ethyl-phenyl alcohol and 0.86 g (3.6 mmol) of ethyl 2-ethoxy-3- (4-hydroxyphenyl) propanoate were mixed in 15 ml of dichloromethane. 0.91 g (3.6 mmol) of 1,1 '- (azodicarbonyl) dipiperidine and 0.95 g (3.6 mmol) of triphenylphosphine were subsequently added, respectively. The mixture was stirred at room temperature overnight and filtered. The filtrate was evaporated and dried in vacuo. The residue was subjected to column chromatography on silica gel using ethyl acetate / heptane (gradient 10:90 to 50:50) as an eluent to give 0.49 g (yield 44%) of the desired product. [399] [400] (b) 2-ethoxy-3- {4- [2- (4-ethylphenyl) ethoxy] phenyl} propanoic acid [401] 0.48 g (1.3 mmol) of ethyl 2-ethoxy-3- {4- [2- (4-ethylphenyl) ethoxy] phenyl} propanoate was dissolved in 5 ml of dioxane. 0.2 g (4.76 mmol) of lithium hydroxide monohydrate in 5 ml of water was added. The mixture was stirred overnight and then acidified using 1 M hydrochloric acid pH ~ 3-4. The dioxane was removed by evaporation in vacuo. The residue was diluted with water and then extracted with dichloromethane. The organic phase was washed with brine and dried over sodium sulfate. Subsequently, the solvent was evaporated to obtain 0.48 g of the desired product (yield: 100%). [402] [403] Example 22 [404] 2- (phenylthio) -3- (4- {2- [4- (phenylthio) phenyl] ethoxy} phenyl) propan- [405] 0.65 g (1.26 mmol) of ethyl 2- (phenylthio) -3- (4- {2- [4- (phenylthio) phenyl] ethoxy} phenyl) propanoate was dissolved in 15 ml of anhydrous dichloromethane under argon. The solution was cooled to -78 [deg.] C and then DIBAL-H (1M hexane solution, 2.6 ml, 2.90 mmol) was added. The coolant was removed after 0.5 h and after 3 h 30 ml of 2M NH 4 Cl and 30 ml of dichloromethane were added. The resulting mixture was filtered using suction. The filter cake was washed with dichloromethane and ethyl acetate. The phases of the filtrate were separated and the organic phase was washed with water and then dried. [406] After flash chromatography with heptane: diethyl ether (3: 1), 0.373 g of the desired product was obtained (yield: 62%). [407] [408] The starting material is described in the priority application of WO9962871. [409] Example 23 [410] 4- [2- (4- {3-benzyl (ethyl) amino] -2-ethoxypropyl} phenoxy) ethyl] -N-methylaniline [411] (9.5 mmol) of tert-butyl 4- [2- (4- {3- [benzyl (ethyl) amino] -2-ethoxy-3- oxopropyl} phenoxy) ethyl] phenylcarbamate was dissolved in anhydrous THF 0.0 > 0 C. < / RTI > 11.9 ml (23.8 mmol) of borane methyl sulfide 2M was added dropwise. The reaction mixture was stirred at 0 < 0 > C for 0.5 h, then warmed to room temperature and then refluxed for 5 h. The reaction was quenched with water, extracted three times with ethyl acetate, dried over magnesium sulfate and evaporated. The residue was redissolved in ethyl acetate and chromatographed on silica gel using a gradient system of ethyl acetate: heptane (0-100%) to give 2.55 g (yield 49%) of the desired product. [412] [413] Starting material [414] (a) 3- (4-Benzyloxyphenyl) -2-ethoxyacrylic acid ethyl ester [415] 42.3 g (0.37 mol) of tetramethylguanidine was slowly added to 75.6 g (0.36 mol) of 4-benzyloxybenzaldehyde, and 130.7 g (0.304 mol) of (1,2-diethoxy-2-oxoethyl) (triphenyl) phosphonium chloride mol) were dissolved in 800 ml of chloroform at 0 < 0 > C. After stirring overnight at room temperature, the solvent was evaporated in vacuo. The residue was dissolved in diethyl ether, insoluble material was removed by filtration, the filtrate was washed with sodium bicarbonate and dried (magnesium sulfate). This process was repeated one more time, after which the crude product was stirred overnight with a saturated aqueous sodium sulfite solution. The solid material was removed by filtration, the product was extracted with diethyl ether, dried (magnesium sulfate) and the solvent was evaporated in vacuo to give 85 g of the desired product (73% yield). [416] (b) Ethyl 2-ethoxy-3- (4-hydroxyphenyl) propanoate [417] 62g (0.19mol) of compound (a) was hydrogenated with Pd / C (10%) as a catalyst in 400ml of ethyl acetate at atmospheric pressure. The mixture was filtered through celite and evaporated in vacuo to give 45.6 g of the desired product (100% yield). [418] [419] (c) 4- (2-Hydroxyethyl) phenylcarbamic acid tert-butyl ester [420] 7.95 g (36 mmol) of di-tert-butyl dicarbonate were added to a mixture of 5 g (36 mmol) of p-aminopentyl alcohol in THF at 0 ° C. After stirring overnight at room temperature, the solvent was evaporated in vacuo to give 8 g of the desired product (94% yield). [421] [422] (d) Ethyl 3- {4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl} -2-ethoxypropanoate [423] 1.03 g (4.34 mmol) of the compound (c) and 1.03 g (4.34 mmol) of the compound (b) were dissolved in dichloromethane under argon at room temperature. 1.65 g (6.5 mmol) of azodicarbonyl dipiperidine was added followed by 1.37 g (5.2 mmol) of triphenylphosphine. After stirring at room temperature for 6 hours, the solvent was evaporated in vacuo. Purification by chromatography on silica gel using heptane: ethyl acetate (2: 1) as eluent gave 1.78 g (yield 89%) of the desired product. [424] [425] (e) Synthesis of 3- {4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl} -2-ethoxypropanoic acid [426] 77 mg (1.85 mmol) of lithium hydroxide hydrate in 5.5 ml of water was added to a solution of ethyl 3- {4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl} -2- Lt; / RTI > was slowly added to 0.77 g (1.68 mmol) of < RTI ID = 0.0 > After stirring at room temperature for 4 hours, the reaction mixture was stored in the freezer for 4 hours. The THF was removed by evaporation in vacuo. Additional water was added and the mixture was acidified to pH 1 using hydrochloric acid. The product was extracted with ethyl acetate, washed twice with water, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo to give 0.712 g (yield 98.7%) of the desired product. [427] [428] (f) Synthesis of tert-butyl 4- [2- (4- {3- [benzyl (ethyl) amino] -2-ethoxy-3- oxopropyl} phenoxy) -ethyl] phenylcarbamate [429] (14.2 mmol) of 3- {4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl} -2-ethoxypropanoic acid was dissolved in 150 ml of acetonitrile, Lt; / RTI > (17 mmol) of DCC, 1.96 g (17 mmol) of HO-Su and 2.2 g (17 mmol) of DIPEA were added and stirred for 15 min before 2.72 g (17 mmol) of N- ethylbenzylamine were added. The reaction mixture was stirred overnight, then filtered and evaporated. 2 M hydrochloric acid (200 ml) was added to the residual oil, and the resulting mixture was then extracted with ethyl acetate three times. The organic phase was washed with sodium hydrogencarbonate solution, dried over magnesium sulfate and evaporated. The residue was chromatographed using heptane: ethyl acetate (1.25-100%) using the elution gradient technique to give 5.32 g (yield 68.5%) of the desired product. [430] [431] Example 24 [432] phenoxy) ethyl] phenyl (methyl) carbamate < / RTI > [433] 2.55 g (5.71 mmol) of Example 1 are dissolved in 50 ml of THF and 0.23 g (5.7 mmol) of sodium hydroxide are dissolved in 20 ml of water and 1.25 g (5.7 mmol) of di-tert-butyl dicarbonate are added . After stirring at room temperature for 48 h, HPLC was used to check if all starting materials were consumed. Water was added, THF was evaporated, and the residue was extracted three times with ethyl acetate. The organic phase was dried using magnesium sulfate and evaporated. The crude product was purified using purified HPLC (Chromasil C8, 10 탆, 50 x 500 mm) using acetonitrile (60-80%) in ammonium acetate buffer pH 7 as mobile phase to give 2.28 g (yield 69%) of the desired product . [434] [435] Example 25 [436] butyl 4- [2- {4- [2-ethoxy-3- (ethylamino) propyl] phenoxy} ethyl] phenyl (methyl) carbamate [437] 1.0 g (1.8 mmol) of Example 2 was dissolved in 100 ml of ethanol. Palladium on 0.12 g (1.8 mmol) of acetic acid and 5% (0.5 g) of activated carbon was added. The mixture was stirred at room temperature under hydrogen gas. After 16 hours, HPLC was used to check whether all starting materials were consumed. [438] The reaction mixture was filtered through celite, the solvent was evaporated and the residue was extracted three times with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated to give 0.74 g of the desired product (yield: 84%). [439] [440] Example 26 [441] 4- [2- (4- {3- [benzyl (ethyl) amino] -2-ethoxypropyl} phenoxy) ethyl] -N-methylaniline [442] (9.5 mmol) of tert-butyl 4- [2- (4- {3- [benzyl (ethyl) amino] -2-ethoxy-3- oxopropyl} phenoxy) ethyl] phenylcarbamate was dissolved in anhydrous THF 0.0 > 0 C. < / RTI > 11.9 ml (23.8 mmol) of borane methyl sulfide 2M was added dropwise. The reaction mixture was stirred at 0 < 0 > C for 0.5 h, then allowed to warm to room temperature and then refluxed for 5 h. The reaction was quenched with water, extracted three times with ethyl acetate, dried over magnesium sulfate and evaporated. The residue was redissolved in ethyl acetate and chromatographed on silica gel using a gradient of ethyl acetate: heptane (0-100%) to give 2.55 g (yield 49%) of the desired product. [443] Starting material [444] (a) 3- (4-Benzyloxyphenyl) -2-ethoxyacrylic acid ethyl ester [445] 42.3 g (0.37 mol) of tetramethylguanidine was slowly added to a solution of 75.6 g (0.36 mol) of benzyloxybenzaldehyde and 130.7 g (0.304 mol) of (1,2-diethoxy-2-oxoethyl) (triphenyl) Lt; / RTI > After stirring at room temperature, the solvent was evaporated in vacuo. The residue was dissolved in diethyl ether, insoluble material was removed by filtration, and the filtrate was washed with sodium bicarbonate and dried (magnesium sulfate). After this process was repeated one more time, the crude product was stirred overnight with a saturated aqueous sodium sulfite solution. The solid material was removed by filtration, the product was extracted with diethyl ether, dried (magnesium sulfate) and the solvent was evaporated in vacuo to give 85 g of the desired product (73% yield). [446] (b) Ethyl 2-ethoxy-3- (4-hydroxyphenyl) propanoate [447] 62 g (0.19 mmol) of the compound (a) was hydrogenated in 400 ml of ethyl acetate using 10% Pd / C as a catalyst at atmospheric pressure. The mixture was filtered through celite and evaporated in vacuo to give 45.6 g (yield 100%) of the desired product. [448] [449] (c) 4- (2-Hydroxyethyl) phenylcarbamic acid tert-butyl ester [450] 7.95 g (36 mmol) of di-tert-butyl dicarbonate was added to a mixture of 5 g (36 mmol) of p-aminopentyl alcohol in THF at 0 ° C. After stirring overnight at room temperature, the solvent was evaporated in vacuo to give 8 g of the desired product (94% yield). [451] [452] (d) Ethyl 3- {4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl} -2-ethoxypropanoate [453] 1.03 g (4.34 mmol) of the compound (c) and 1.03 g (4.34 mmol) of the compound (b) were dissolved in dichloromethane under argon at room temperature. 1.65 g (6.5 mmol) of azodicarbonyl dipiperidine was added followed by 1.37 g (5.2 mmol) of triphenyl propyne. After stirring at room temperature for 6 hours, the solvent was evaporated in vacuo. Purification by chromatography on silica gel using heptane: ethyl acetate (2: 1) as eluent gave 1.78 g (yield 89%) of the desired product. [454] [455] (e) Synthesis of 3- {4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl} -2-ethoxypropanoic acid [456] 77 mg (1.85 mmol) of lithium hydroxide hydrate in 5.5 ml of water was slowly added to a solution of ethyl 3- {4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl} -2- (1.68 mmol) < RTI ID = 0.0 > of ethoxy < / RTI > After stirring at room temperature for 4 hours, the reaction mixture was stored in the chiller for 4 days. The THF was removed by evaporation in vacuo. Additional water was added and the mixture was acidified to pH 1 using hydrochloric acid. The product was extracted with ethyl acetate, washed twice with water, evaporated (sodium sulfate), filtered and the solvent was evaporated in vacuo to give 0.712 g (yield 98.7%) of the desired product. [457] [458] (f) Synthesis of tert-butyl 4- [2- (4- {3- [benzyl (ethyl) amino] -2-ethoxy-3- oxopropyl} phenoxy) -ethyl] phenylcarbamate [459] (14.2 mmol) of 3- {4- [2- (4-tert-butoxycarbonylaminophenyl) ethoxy] phenyl} -2-ethoxypropanoate was dissolved in 150 ml of acetonitrile, Lt; / RTI > (17 mmol) of DCC, 1.96 g (17 mmol) of HO-Su and 2.2 g (17 mmol) of DIPEA were added and stirred for 15 min before 2.72 g (17 mmol) of N- ethylbenzylamine were added. The reaction mixture was stirred overnight and then filtered and evaporated. 200 ml of 2M hydrochloric acid was added to the residual oil, and the resulting mixture was then extracted with ethyl acetate. The organic phase was washed with sodium hydrogencarbonate solution, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel using heptane: ethyl acetate (1.25-100%) using gradient elution techniques to give 5.32 g (yield 68.5%) of the desired product. [460] [461] Example 27 [462] ethyl] phenyl (methyl) carbamate < / RTI > < RTI ID = 0.0 & [463] 2.55 g (5.71 mmol) of Example 26 are dissolved in 50 ml of THF and 0.23 g (5.7 mmol) of sodium hydroxide are dissolved in 20 ml of water and 1.25 g (5.7 mmol) of di-tert-butyl dicarbonate are added. After stirring at room temperature for 48 h, HPLC was used to check if all starting materials were consumed. Water was added, THF was evaporated, and the residue was extracted three times with ethyl acetate. The organic phase was dried using magnesium sulfate and evaporated. The crude product was purified using purified HPLC (Chromasil C8, 10 탆, 50 x 500 mm) using acetonitrile (60-80%) in ammonium acetate buffer pH 7 as mobile phase to give 2.28 g (yield 69%) of the desired product . [464] [465] Example 28 [466] butyl 4- [2- {4- [2-ethoxy-3- (ethylamino) propyl] phenoxy} ethyl] phenyl (methyl) carbamate [467] Example 27 1.0 g (1.8 mmol) was dissolved in 100 ml of ethanol. 0.12 g (1.8 mmol) of acetic acid and 0.5 g of 5% palladium on activated carbon were added. The mixture was stirred at room temperature under hydrogen gas. After 16 hours, HPLC was used to check whether all starting materials were consumed. The reaction mixture was filtered through celite, the solvent was evaporated and the residue was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated to give 0.74 g of the desired product (yield: 84%). [468] [469] Example 29 [470] 1-Aminomethyl-2- [4- (2- {4-methylsulfonyloxyphenyl} ethoxy) phenyl-1-ethoxyethan hydrochloride [471] (Anhydrous) in THF and the solution was cooled in an ice bath. To a solution of borane-methyl sulphate The mixture was stirred for 30 min and then gently refluxed for 6 h with heating. After cooling to room temperature, the reaction mixture was cooled to room temperature, (10%, 0.8 ml) was added dropwise. The resulting mixture was stirred for 2 hours, then it was evaporated in vacuo to dryness. The residue was treated with tetrahydrofuran / diethyl ether . A white precipitate formed and was filtered to give 0.73 g of the desired product (yield: 87%). [472] [473] Starting material [474] (a) 2-Ethoxy-3- [4- (2- {4-methylsulfonyloxyphenyl} ethoxy) phenyl] propanoic acid [475] 0.12 g (2.82 mmol) of lithium hydroxide hydrate dissolved in 10 ml of water was slowly added to a solution of ethyl 2-ethoxy-3- [4- (2- (4-methylsulfonyloxyphenyl) ethoxy) ] Propanoate (technique of Example 8) in 10 ml of tetrahydrofuran. After stirring at room temperature for 3 hours, 50 ml of water was added and THF was removed by evaporation in vacuo. The residue was acidified with 2M hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were dried using magnesium sulfate. The solvent was evaporated to obtain 1 g of the desired product (yield: 96%). [476] [477] (b) 1-Carbamoyl 1-ethoxy-2- [4- (2- {4-methylsulfonyloxyphenyl} ethoxy) phenyl] [478] A mixture of 2.9 g (7.1 mmol) of the compound (a) and 3.7 g (7.1 mmol) of benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexaphosphate in 30 ml of DMF in the form of bubbles of ammonia was stirred at room temperature 3 hours. Water and ethyl acetate were added. The phases were separated, the organic phase was washed with water, dried over magnesium sulfate and the solvent was evaporated in vacuo. The crude product was crystallized from diethyl ether to give 2.5 g of the desired product as a white powder (yield: 86%). [479]
权利要求:
Claims (8) [1" claim-type="Currently amended] Compounds of formula (I) and stereoisomers and optical isomers and racemates thereof, and pharmaceutically acceptable salts, prodrugs, solvates and crystalline forms thereof. (I) (Wherein, A is located in an ortho, meta or para position, Lt; / RTI > When X is 0, R is cyano, Where X is 1, R is a -BR or SCOR a (wherein, B is O, S, SO or an SO 2, R a represents hydrogen, alkyl, aryl or alkylaryl, alkyl, aryl or alkylaryl groups R b , wherein R b is alkyl, aryl, alkylaryl, cyano, -NR c R c , ═O, halogen, -OH, -SH, -O alkyl, -O aryl, -O alkylaryl, -COR c , -SR d , -SOR d , or -SO 2 R d , wherein R c represents hydrogen, alkyl, aryl or alkylaryl, and R d represents alkyl, aryl or alkylaryl. Optionally substituted more than once; -BB 1 R a wherein B and R a are as defined above and B is S, SO or SO 2 , B 1 is O and B is O, then B 1 is S, SO or SO 2 ); Or optionally, R is -NR a R a (wherein each R a may be the same or different, R a are as defined above), and; R 2 is alkyl, halogen, aryl, alkyl aryl, alkenyl, alkynyl, nitro or cyano (where the alkyl, aryl, alkenyl, alkylaryl and alkynyl group R b (wherein R b is as defined above Lt; / RTI > -BR a (wherein, B and R a are as defined above); -SO 2 NR a R f wherein R f is hydrogen, alkyl, acyl, aryl or alkylaryl and R a is as defined above; -SO 2 OR a (wherein, R a is as defined above); -OCONR f R a (wherein, R f and R a are as defined above); -NR c COOR d , wherein R c and R d are as defined above; -NR c COR a wherein R c and R a are as defined above; -CONR c R a wherein R c and R a are as defined above; -NR c SO 2 R d (where, R c and R d are as defined above); - NR c CONR a R k ( where, R a and R c are as defined above, R k is hydrogen, Alkyl, aryl, or alkylaryl; Alternatively R 2 is -NR c R a wherein R c and R a are as defined above; R 1, R 3 and R 4 may be the same or different, each represents hydrogen, alkyl, aryl, alkenyl, alkynyl, cyano, halogen, or alkyl aryl (where the alkyl, aryl, alkenyl or alkynyl group R b Lt; / RTI > n is an integer from 1 to 6; X is an integer 0 or 1; m is an integer 0 or 1; D is an alkyl, acyl, aryl, alkylaryl, halogen, -CN or NO 2 , wherein the alkyl, aryl, or alkylaryl groups are optionally substituted by R b ; -NR c COOR a , wherein R c and R a are as defined above; -NR c COR a wherein R c and R a are as defined above; -NR c R a , wherein R c and R a are as defined above; -NR c SO 2 R d wherein R c and R d are as defined above; -NR c CONR k R c wherein R a , R c and R k are as defined above; -NR c CSNR a R k wherein R a , R c and R k are as defined above; -OR < a >, wherein R < a > is as defined above; -OSO 2 R d (wherein, R d are as defined above); -SO 2 R d (wherein, R d are as defined above); -OR < d >, wherein R < d > is as defined above; -SR < c >, wherein R < c > is as defined above; -SO 2 NR a R f (wherein, R f and R a are as defined above); -SO 2 OR a (wherein, R a is as defined above); -CONR c R a wherein R c and R a are as defined above; -OCONR f R a represents (wherein, R f and R a are as defined above); D 'is located at the ortho, meta or para position and is selected from the group consisting of hydrogen, alkyl, acyl, aryl, alkylaryl, halogen, -CN, -NO 2 , -NR f R b where R f and R b are as defined above equivalence); -OR f , wherein R f is as defined above; -OSO 2 R d , wherein R d is as defined above; Alkyl, aryl, alkylaryl, halogen, -CN, -NO 2 , -NR f R b where R f and R b are as defined above, -OR f where R f is as defined above, -OSO 2 R d , wherein R d is as defined above, [2" claim-type="Currently amended] The method according to claim 1, A is located in the meta or para position, Lt; / RTI > R is -BR a ; -SCOR a ; -OSO < 2 > R < a & R 1 , R 3 and R 4 may be the same or different and each represent hydrogen, alkyl, aryl, alkenyl, alkynyl or cyano, wherein the alkyl, aryl, alkenyl or alkynyl groups are optionally substituted with R b Substituted; R 2 is alkyl, aryl, alkenyl, cyano, or alkynyl, wherein the alkyl, aryl, alkenyl, and alkynyl groups are optionally substituted by R b ; -BR a ; -OSO 2 R a ; -OCONR < f > -NR c COOR d ; -NR c COR a ; -CONR c ; n is an integer of 1 to 2; D is an alkyl, acyl, aryl, alkylaryl, halogen, -CN, -NO 2 , wherein the alkyl group is optionally substituted by R b ; -OR a ; -OSO 2 R d ; -OCONR a R f ; -NR c COOR a ; -NR c COR a ; -SO 2 R d ; -SR c ; -CONR a R c ; -NR c R d ; D 'is ortho, meta or para-positioned to the place of hydrogen, alkyl, alkylaryl, halogen, -CN or -NO 2; -OR h wherein R h is hydrogen or alkyl; D "is ortho, meta or para-positioned to the place of hydrogen, alkyl, alkylaryl, halogen, -CN or -NO 2; -OR represents a f; A compound of formula I, wherein R a , R b , R c , R d , R f and R g are as defined in claim 1. [3" claim-type="Currently amended] 3. The method of claim 2, A is located at the meta or para position; R is -OR a , -SR a , -SCOR a or -OSO 2 R a wherein R a is hydrogen, alkyl or alkylaryl; R 2 is cyano, -OR a wherein R a is as defined above; -NR c COR a (wherein, R a is as defined above); -CONR c R a wherein R a is as defined above; R 1 , R 3 and R 4 are independently selected from hydrogen or alkyl (preferably, R 1 , R 3 and R 4 are all hydrogen); D is an ortho, meta or para position (preferably, D is located at the para position), alkyl or cyano optionally substituted by R b ; -OR < a >, wherein R < a > is as defined above; -NR c COR a (wherein, R a is as defined above); -CONHR c R a (wherein, R a is as defined above); -NR c COOR a (where, R a are as defined above); -OSO 2 R a (wherein, R a is as defined above); -SO 2 R d ; -NR c COOR a wherein R a is as defined above; D 'is hydrogen; D " is hydrogen; R < c > and R < d > are as defined in claim 1. [4" claim-type="Currently amended] The method of claim 3, A is located at the para-position; R is -OH, -Oalkyl or -Oalkylaryl; -SCOR a ; -OSO 2 R d, and; R < 1 > is hydrogen; R 2 is -O alkyl, preferably -O lower alkyl; R 3 is hydrogen; R < 4 > is hydrogen; n is an integer 1; D is located at the para position, -NR h COOR d wherein R h represents hydrogen or alkyl, -OCONR a R c ; -SO 2 R d ; -OSO 2 R d ; -CN; -OR a ; -Alkyl; R a is as defined in claim 2; R < c > and R < d > are as defined in claim 1. [5" claim-type="Currently amended] 5. The method of claim 4, R is -OR < a >; R 2 is -O alkyl; D is -NR a COOR b; -CN; -OSO 2 R d, and; R a is as defined in claim 2; Wherein R < d > is as defined in claim 1. [6" claim-type="Currently amended] 6. Compounds of formula I according to any one of claims 1 to 5, which have utility as medicaments. [7" claim-type="Currently amended] A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 5, and a pharmaceutically acceptable adjuvant, diluent or carrier. [8" claim-type="Currently amended] Use of a compound of formula I as defined in any one of claims 1 to 5 in the manufacture of a medicament for the treatment or prevention of a disease associated with a patient having reduced sensitivity to insulin.
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同族专利:
公开号 | 公开日 EP1237857A1|2002-09-11| TR200402529T4|2004-12-21| DK1237857T3|2004-09-20| AT270270T|2004-07-15| AU766547B2|2003-10-16| CN1433401A|2003-07-30| DE60011932D1|2004-08-05| NZ518922A|2003-11-28| DE60011932T2|2005-08-25| IL149584D0|2002-11-10| PT1237857E|2004-10-29| CA2392035A1|2001-06-07| BR0016133A|2002-08-20| NO20022603D0|2002-05-31| AR034112A1|2004-02-04| TW574193B|2004-02-01| MXPA02005328A|2002-11-29| MY135920A|2008-07-31| JP2003515581A|2003-05-07| AU2240101A|2001-06-12| WO2001040170A1|2001-06-07| ES2222261T3|2005-02-01| CN1211359C|2005-07-20| EP1237857B1|2004-06-30| CO5271654A1|2003-04-30| NO20022603L|2002-07-10| US20030018207A1|2003-01-23| US6630509B2|2003-10-07|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题
法律状态:
1999-12-03|Priority to SE9904418A 1999-12-03|Priority to SE9904422A 1999-12-03|Priority to SE9904418-2 1999-12-03|Priority to SE9904422-4 2000-11-29|Application filed by 아스트라제네카 아베 2000-11-29|Priority to PCT/SE2000/002383 2002-08-22|Publication of KR20020067536A
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申请号 | 申请日 | 专利标题 SE9904418A|SE9904418D0|1999-12-03|1999-12-03|New compounds| SE9904422A|SE9904422D0|1999-12-03|1999-12-03|New compounds| SE9904418-2|1999-12-03| SE9904422-4|1999-12-03| PCT/SE2000/002383|WO2001040170A1|1999-12-03|2000-11-29|New phenalkyloxy-phenyl derivatives| 相关专利
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