UA73917C2 - Novel tricyclic compounds and use thereof in the medicine; a method for the preparation thereof and pharmaceutical compositions containing such compounds - Google Patents

Abstract

Novel -aryl--oxysubstituted alkylcarboxylic acids of formula (I) and compositions containing them. The compounds have hypolipidemic, antihyperglycemic uses.

Description

Description of the invention

The present invention relates to novel hypolipidemic and antihyperglycemic compounds, their derivatives, their 2 analogues, their tautomeric forms, their stereoisomers, their polymorphic forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing such compounds. More specifically, the present invention relates to novel p-aryl-o-oxysubstituted alkylcarboxylic acids of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphic forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing such compounds.

E ve fi Ho t V v o vo v vi su nen y y che , ot

The present invention also relates to a method of obtaining the above new compounds, their derivatives, their analogues, their tautomeric forms, their polymorphic forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, new intermediate compounds and pharmaceutical compositions containing said compounds.

The compounds of general formula (I) are useful for the treatment and/or prevention of insulin resistance (type 2 diabetes), impaired glucose tolerance, dyslipidemia, disorders associated with syndrome X, such as hypertension, obesity, insulin resistance, atherosclerosis, hyperlipidemia, coronary arterial disease, and other cardiovascular disorders. The compounds of this invention are also useful in the treatment of certain diseases (8) of the kidneys, including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis.

These compounds may also be useful as aldose reductase inhibitors, to improve cognitive function in dementia, treatment of complications, diabetes, psoriasis, polycystic ovary syndrome (PCOS5) and osteoporosis.

Hyperlipidemia is the primary cause of cardiovascular disease (CVD) and other peripheral vascular diseases. A high risk of SMO is associated with an increased content of low-density lipoprotein (LDL) and MO. b (very low density lipoprotein), which are observed in hyperlipidemia. Patients who, in addition to hyperlipidemia, have impaired glucose tolerance and insulin resistance have an increased risk of SMO. Previously, numerous studies carried out by the FO showed that a decrease in the content of plasma triglycerides and total cholesterol, in particular I 01. and MI C, and an increase in the content of NOI cholesterol. (high-density lipoprotein) helps prevent cardiovascular diseases.

Diabetes is a disease that seriously affects the quality of life of a large number of people.

Insulin resistance is a weakened ability of insulin to exert a biological effect in a wide range of 20 concentrations. With insulin resistance, the body secretes an abnormally high amount of insulin in order to compensate for this lack; moreover, he experiences a shortage, which inevitably increases the glucose content in the plasma, which leads to overt diabetes. In developed countries, diabetes is a common problem and is associated with various abnormalities, including obesity, hypertension, hyperlipidemia. Siip. Ipmevi (1985), 75: 809-817; M. EpoiY. U. Mea. (1987), 317: 350-357; 9. Siip. Epdoshypoiei. Meijar. (1988), 66: 580-583; 3. Siip.

Ipmevi (1975), 68: 957-969| and kidney complications (see the patent application Mo UMUO 95/21608). It is becoming increasingly clear that insulin resistance and relative hyperinsulinemia play the role of assistants in obesity, hypertension, atherosclerosis, and type 2 diabetes. The relationship of insulin resistance with obesity, hypertension, and angina is described as a syndrome with insulin resistance as the central pathogenic link - so syndrome X. 20 Thus, therapeutic agents that improve such indicators as insulin resistance, low content of triglycerides in plasma, total cholesterol content, OI and MI OI and increased NOI will be of great importance in preventing the spread of cardiovascular diseases and to improve the quality of life.

Peroxisomal proliferator-activated receptors (PRAKs) are members of the nuclear receptor superfamily. The gamma (y) isoform of PRAC (PRACU) is involved in the regulation of adipocyte differentiation dv (Epdoshypoiyudu (1994), 135: 798-800) and energy homeostasis (Seiyi (1995), 83: 803-812), while alpha ( a) isoform of PPAK (PPAK»ou) mediates the oxidation of fatty acids (Tgepa. Epadoship. Megyab. (1993), iF) 4: 291-296), which is manifested in a decrease in the content of free fatty acids in the plasma (Sitepi Vioi. (1995) ), 5: ko 618-621). PRAC agonists have been found to be useful in the treatment of obesity (MO 97/36579). Molecules that are agonists for both PRAC c and PRAC y have recently been found to be synergistic and 60 predicted to be useful in the treatment of syndrome X (UMO 97/25042). A similar synergism is observed between an insulin sensitizer (an agonist of PRAC) and an inhibitor of NMO CoA reductase, which may be useful in the treatment of atherosclerosis and xanthoma (ER 0753298).

Certain β-aryl-o-hydroxypropionic acids, their derivatives, and their analogs are reported to be useful in the treatment of hyperglycemia, hyperlipidemia, and hypercholesterolemia. Some such compounds described in the prior art are listed below.

Her) In US patent 5306726; UMO 91/19702 describes derivatives of 3-aryl-2-hydroxypropionic acid of general formulas (Ia) and (IB) as hypolipidemic and hypoglycemic agents. - A. t. 7 Sh - t tia | then oh

OO iAkoin lysOh I: i-sh--y nai 4 Me do b he Nd v. с жк -- ше (па п ) I (а ь). : 70 Examples of such compounds are compounds of formulas (Ic) and (Pa)

Vab., UN in . what am I about

NN And o uva not and ov

(Motasia) International patent applications MUO 95/03038 and UMO 96/04260 describe compounds of the formula (Pe) re V n

Sn -

Ac Y - 20.0 I-Z, base where K2 is 2-benzoxazolyl or 2-pyridyl, and РЕ? is CE", SNOSN" or СНу. A typical example is (5)-3-I4-(2-IM-(2-benzoxazolyl)|-M-methylamino|ethoxy|phenyl|-2-(2,2,2-trifluoroethoxy)propanoic acid (PV). , OSNSE "(and (about) her) In international patent applications MoMo UUO 94/136050, UMO 94/01420 and UMO 95/17394, compounds of the general formula (Id) are described in

А1-Х-(СНо)п-О-А2- АЗ - У. Vo (9), "- where A" is an aromatic heterocycle, А? is a substituted benzene ring, and АЗ is a FI group of the formula (СНо)т-СН - (OB), where B! is an alkyl group, and t is an integer; X is substituted c or unsubstituted M; Y is C - O or C - 5, B2 is OB, where BZ can be alkyl, aralkyl or aryl group. An example of such compounds is shown by the formula (PIIJ) - n sleep lice

B t. 8. Y and Y V, zy tov av "

In order to develop new compounds for more effective, potent and less toxic treatment and/or prevention of diseases associated with increased lipid content, especially for the treatment of hyperglycemia and for the reduction of free fatty acids, for the treatment and/or prevention of diseases , which are described as syndrome X, "" which include hyperlipidemia, hyperinsulinemia, obesity, insulin resistance, insulin resistance leading to type 2 diabetes and complications of such diabetes, for the treatment of diseases in which insulin resistance is a pathophysiological mechanism, for the treatment of hypertension, atherosclerosis and coronary artery disease, the authors focused their research on the development of new compounds effective in the treatment of the above diseases.Efforts in this direction led to the compounds of general formula (1).

The main object of this invention is, therefore, novel B-aryl-5-oxysubstituted alkylcarboxylic acids and their (Ce) derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphic forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing such compounds or their mixtures. "And another object of this invention is new B-aryl-y-oxysubstituted alkylcarboxylic acids and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphic forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing such compounds or mixtures thereof, which may have antagonistic activity against PRACo; and/or PRACU, and, in addition to antagonistic activity against o PRACOo; and/or PRACU, may optionally inhibit NMO CoA reductase.

Another object of this invention is new B-aryl-y-oxysubstituted alkylcarboxylic acids and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphic forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing such compounds or their mixtures, 60 which have increased activity in the absence of toxic action or with reduced toxic action.

Another object of this invention is a method of obtaining new B-aryl-5y-oxysubstituted alkylcarboxylic acids and their derivatives of the above formula (I), their analogues, their tautomeric forms, their stereoisomers, their polymorphic forms, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates because another object of this invention is pharmaceutical compositions containing compounds of the general formula (I),

their analogs, their derivatives, their tautomeric forms, their stereoisomers, their polymorphic forms, their salts, solvates or mixtures thereof in combination with suitable carriers, solvents, diluents and other media commonly used in the preparation of such compositions.

This invention belongs to the compounds of the general formula (I)

Gu: v. in vyky vy i (y 70 23 dens MO ov de B", 2, Z in can be the same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or optionally substituted groups selected from among alkyl, cycloalkyl . aryloxyalkyl, araloxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, armethoxycarbonylamino, groups formed by carboxylic acid or its derivatives or sulfonic acid or its derivatives; ring A, condensed with a ring containing X and M, forms a 5-6 membered cyclic structure, containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms, which may optionally to be replaced; ring A may be saturated or contain one or more double bonds, or may be aromatic; X is a heteroatom selected from oxygen, sulfur, or ME atoms, where BO is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, Ge! aroxycarbonyl and a similar group; Ag is an optionally substituted divalent single or condensed aromatic or heterocyclic group; KO is a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, an optionally substituted aralkyl group, or forms a bond together with the adjacent K 9 group; CC? is hydrogen, hydroxy, alkoxy, halogen, a lower alkyl group, acyl, optionally substituted aralkyl, or K b forms a bond together with BO; BE" is hydrogen or an optionally substituted group selected from among alkyl, - cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, "that arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups; KZ can be hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, F heteroaryl or heteroaralkyl groups; U is oxygen or ME", where KO is hydrogen, alkyl, aryl, (O hydroxyalkyl or aralkyl groups; KZ and 279 together can form a 5- or 6b-membered cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms, n is an integer in the range 1-4, and t is 0 or 1.

Suitable groups represented by K"-K" are hydrogen, a halogen atom such as fluorine, chlorine, bromine or iodine; « hydroxy, cyano, nitro, formyl; substituted or unsubstituted (C.4-C.42)-alkyl group, especially linear or branched (C.i.-C.v.)-alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert- butyl, - n-pentyl, isopentyl, hexyl and similar groups; cyclo-(C3-C8)-alkyl group such as cyclopropyl, cyclobutyl, and cyclopentyl, cyclohexyl and the like, and the cycloalkyl group may be substituted; cyclo"» (C5-C8)-alkyloxy group such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like, and the cycloalkyloxy group may be substituted; aryl group such as phenyl, naphthyl and the like, and the aryl group may be substituted; an aralkyl such as benzyl or phenethyl, SeNeCNoSNoSCN", naphthylmethyl and the like, and the aralkyl group may be substituted, and the substituted aralkyl is a group such as o CHZeNaSn", NaI-SenaSNH", CH2OoSeNACH", SnzoSeneNaSNoCH" and the like groups; a heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, (Ce)benzofuranyl, etc., and the heteroaryl group may be substituted; a heterocyclyl group such as aziridinyl . you are substituted; a heteroaralkyl group such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazoleethyl and the like, and the heteroaralkyl group may be substituted; an aralkylamino group such as C bNBSNoMn, SeNeSNosSNoOMN, SeNeSNoMoSNU and similar groups that may be substituted; an aryloxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethoxycarbonyl and similar groups which may be substituted; (C 4-Cv)-alkylamino group, such as МНУН з, MШ(СН3)», МОСНУ(СоНв), иФ) МНС»Нв, МНОзН;, МНСеНиз and similar groups; an alkoxyalkyl group such as methoxymethyl, ethoxymethyl, co-methoxyethyl, ethoxyethyl and the like; an aryloxyalkyl group such as C 6HBOCH", CenHBOcSNoCsnH", naphthyloxymethyl and similar groups which may be substituted; an aryloxyalkyl group, such as in СвН5СнNoОсНо, СеНеСНоОСНосСНо and similar groups which may be substituted; heteroaryloxy and heteroaralkyl, where the heteroaryl component has the values indicated earlier and may be substituted; an aryloxy group such as phenoxy, naphthyloxy and the like; the aryloxy group may be substituted; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, etc.; aryloxycarbonyl group such as optionally substituted phenoxycarbonyl, naphthyloxycarbonyl, etc.; arylamino group, such as NMS Nv, 65 MONA (SeN), MNSeNASN», MNONA-Nai! and similar groups; amino group; amino-(C4-C8)-alkyl; hydroxy-(C.4-Cv)-alkyl; (Ci-Cv)-Alkoxy, such as methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy, etc.; thio-(C 4-Cv)-alkyl;

(C4-Cv)-alkylthio; an acyl group such as acetyl, propanoyl, benzoyl and the like, and the acyl group may be substituted; acylamino groups, such as MUNSOSN»z, MNSOS»OHn, MNSOSzZN), MNSOSnN and similar groups; aralkoxycarbonylamino group, such as МНСООСН осеН5, МНСООСНоСНоСеНв, МОСНЗСООСНеСнв,

МСоНСООсСН»оСНБ, МНеСОоОСсNoSeН,; СН», МНесОоОоСсНноСНХ; ОсСНн» and similar groups; an aryloxycarbonylamino group, such as МНСООС ЕН5, МОНЗзСООСЕНв, МСоНЕСООСЕН, МНСООСН,СН»,

MNSOOOSN; OSNU and similar groups; an alkoxycarbonylamino group, such as MNHSOOS, MNHSOSN, etc.; residues of carboxylic acid or its derivatives, such as amides, similar to СОМН», СОМНМе, СОММе», SOMNEI,,

SOME, SOMNRA, etc., carboxylic acid and its derivatives can be substituted; an acyloxy group such as 70 ООСсСМе, ООСЕЙ, ООСРНИ and similar groups, which may optionally be substituted; residues of sulfonic acid and its derivatives, such as ЗО 2МНо, ЗО2МНМе, 5О2ММЕ»о, ЗО2МНСЕ», etc., sulfonic acid and its derivatives can be substituted.

When the groups represented by C1-C7 are substituted, the substituents may be selected from halogen, hydroxy, or nitro, or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, aryl, aralkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl, groups formed by carboxylic acid or its derivatives or sulfonic acid or its derivatives.

Suitable ring A is phenyl, naphthyl, cyclohexyl, cyclohexenyl, thienyl, furyl, pyrrolyl, oxazolyl, 2o-oxadiazolyl, thiazolyl, imidazolyl, isoxazolyl, pyridyl, pyranyl, dihydropyranyl, pyridazinyl, pyrimidinyl and similar rings, which may optionally be substituted, and the substitutes are chosen from the same group as in the case of CT. дя, Я have the values specified in case 7-87. The best substituents are halogen, hydroxy, amino, formyl, optionally halogenated (C1-Cv)-alkyl, (C4-Cv)-alkyl, cyclo-(Ca-Cv)-alkyl, cyclo-(C3-Cv)- alkoxy, aryl, aralkyl, aralkyl, heterocyclyl, acyl, acyloxy, carboxyl, alkoxycarbonyl, CM armethoxycarbonyl, alkylamino, acylamino, armethoxycarbonylamino, aminocarbonyl and similar groups. (5)

It is more acceptable for the cyclic structure represented by ring A to be a phenyl or pyridyl ring.

It is even more acceptable that the cyclic structure represented by ring A is a phenyl ring.

Suitable X is oxygen, sulfur or the Me group, preferably oxygen and sulfur. A suitable short circuit is hydrogen, c. (C 1 -C )-alkyl, (C 3 -C 6 )-cycloalkyl, aralkyl group such as benzyl, phenethyl; an acyl group such as acetyl, propanoyl, butanoyl, benzoyl, etc.; (С4-Св)-Alkoxycarbonyl; aryloxycarbonyl such as phenoxycarbonyl,

СНЗОоСН.ОСО, NaI-ССН,ХОСО, СНЗССНИОСО, naphthyloxycarbonyl, etc.; aralkyloxycarbonyl, such as benzyloxycarbonyl, phenethyloxycarbonyl, etc.; groups submitted to KU may be substituted or unsubstituted. "That's it

When the groups given in are substituted, the substituents can be selected from halogen, optionally halogenated m lower alkyl, hydroxy and optionally halogenated (C4-Ca)-alkyl groups.

Groups represented by Ag include divalent phenylene, naphthylene, pyridyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, azaindolyl, azaindolinyl, indenyl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, pyrazolyl and similar groups. Substituents in the group represented by Аг are "di-linear or branched optionally halogenated (C 4-Cv)-alkyl, optionally halogenated - (C.-C.sub.3)-alkoxy, halogen, acyl, amino, acylamino, thio, residues of carboxylic and sulfonic acids and their derivatives. Substitutes have the meanings given in case 7-87. It is more acceptable when Ar is a substituted or unsubstituted divalent phenylene, naphthylene, benzofuranyl, indolyl, indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl group.

It is even more acceptable when Ar is divalent phenylene or benzofuranyl, which, optionally, can be substituted with methyl, halomethyl, methoxy or halomethoxy groups.

Suitable BZs are hydrogen, lower alkyl groups such as methyl, ethyl or propyl; hydroxy, (C4-C3)-alkoxy; a halogen atom such as fluorine, chlorine, bromine or iodine; aralkyl, such as benzyl, phenethyl, which may optionally (Ce) be substituted, or KZ together with EC form a bond. -l 20 Suitable 85 can be hydrogen, lower alkyl groups such as methyl, ethyl or propyl; hydroxy, (C.-C3)-alkoxy; a halogen atom such as fluorine, chlorine, bromine, iodine; an acyl group such as a linear or branched (C1-C0)-acyl group such as acetyl, propanoyl, butanoyl, pentanoyl, benzoyl, and the like; aralkyl such as benzyl and phenethyl, which optionally can be substituted, or BEZ together with E? forms a bond.

It is more acceptable for B and 29 to form hydrogen atoms, or for KZ and KU together to form a bond.

Suitable groups represented by K/" can be selected from among hydrogen, linear or branched (C.4-C-c)-alkyl,

HF) preferably (C.4-C42)-alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, octyl, etc.; (C3-C7)-cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., and the cycloalkyl group can be substituted; an aryl group such as phenyl, naphthyl, etc., and the aryl group may be substituted; a heteroaryl group such as pyridyl, thienyl, furyl, etc., and the heteroaryl group may be substituted; a heteroaralkyl group, such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazoleethyl, etc., and the heteroaralkyl group may be substituted; an aralkyl group, where the alkyl part may contain C.i-Cv atoms, such as benzyl and phenethyl, etc., where the aryl component may be substituted; a heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl, etc., and the heterocyclyl group may be substituted; (C.4-C)-Alkoxy-(C.4-C)-alkyl group, such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxypropyl, etc., and the alkoxyalkyl group may be substituted; acyl group such as acetyl, propanoyl,

butanoyl, benzoyl, etc.; (С4-Св)-Alkoxycarbonyl, where the alkyl group can be substituted; aryloxycarbonyl such as phenoxycarbonyl, naphthyloxycarbonyl, etc. where the aryl group may be substituted; (С4-Св)-alkylaminocarbonyl, where the alkyl group can be substituted; arylaminocarbonyl, such as RAMNSO, naphthylaminocarbonyl, etc., where the aryl group may be substituted. Substitutes for KV can be selected from the same group as in the case of B "-27, and they have the same values.

Suitable groups represented by KU can be selected from among hydrogen, linear or branched (С41-С-в)-alkyl, preferably (С.4-С42)-alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, pentyl, hexyl, octyl, etc.; (C3-C7)-cycloalkyl, such as cyclopropyl, cyclopentyl, cyclohexyl, etc., and the 70 cycloalkyl group can be substituted; an aryl group such as phenyl, naphthyl, etc., and the aryl group may be substituted; a heteroaryl group such as pyridyl, thienyl, furyl, etc., and the heteroaryl group may be substituted; a heteroaralkyl group, such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazoleethyl, etc., and the heteroaralkyl group may be substituted; an aralkyl group such as benzyl, phenethyl, etc., and the aralkyl group may be substituted; heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl, etc., and the 75 heterocyclyl group may be substituted. Substitutes for KU can be selected from the same group as in the case of '-vy.

Suitable groups represented by 279 can be selected from among hydrogen, linear or branched (C.-C.6)-alkyl, preferably (C.4-C.42)-alkyl; hydroxy-(C4-Cv)-alkyl; an aryl group such as phenyl, naphthyl; aralkyl group such as benzyl and phenethyl.

Suitable cyclic structures formed together by KO and KO can be selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and similar groups.

Suitable t is an integer 0 or 1. It is more acceptable that when t is 0, Ag is benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, dihydrobenzofuranyl or dihydrobenzopyranyl group, preferably a benzofuranyl group, and when t is 1, Ag is divalent phenylene, naphthylene, pyridyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, azaindolyl, azaindolinyl, (8) dihydrobenzofuranyl, dihydrobenzopyranyl or pyrazolyl group.

It is more acceptable that when t is 0, Ag is a divalent benzofuranyl group, more preferably a benzofuran-2,5-diyl group, and when t is 1, Ag is a phenylene group. Мзо Suitable n is an integer in the interval from 1 to 4, preferably n is the number 1 or 2.

It is more acceptable that when t is 1, n is equal to 2. -

It is also more acceptable that when t is 0, n is equal to 1. Gee!

Pharmaceutically acceptable salts that form part of this invention include salts from the carboxylic acid group, such as metal salts, for example, salts of iii, Ma and K, salts of alkaline earth metals, for example, salts of Ca and i)

Ma, salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline and similar bases, ammonium or substituted ammonium salts, aluminum salts. Salts can be addition salts of acids, suitable of which are sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmitates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates etc. Pharmaceutically acceptable solvates can be hydrates or compounds containing other crystallization solvents such as alcohols. Especially useful compounds according to this invention are: ethyl-(E/2)-3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl/|-2-ethoxyacrylate; ; » ethyl-(E) -3-I4-(2-(phenothiazin-10-yl)letoxy|phenyl|-2-ethoxyacrylate; ethyl-(2)-3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl|-2 -ethoxyacrylate; ethyl-(E/2)-3-(2-(phenothiazine-10-yl)umethylbenzofuran-5-yl|-2-ethoxyacrylate; -I ethyl-(E)-3-(2-(phenothiazine- 10-yl)umethylbenzofuran-5-yl|-2-ethoxyacrylate; ethyl-(2)-3-(2-(phenothiazin-10-yl)umethylbenzofuran-5-yl|-2-ethoxyacrylate; o ethyl-(E/ 2)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxyacrylate;

Ge) ethyl-(E)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl)-2-ethoxyacrylate; ethyl-(2)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl/|-2-ethoxyacrylate; - ()-methyl-3-I4-(2-(phenothiazine-10-yl)ethoxy| phenyl|-2-ethoxypropanoate; "I (t)-methyl-3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoate; (-)-methyl-3-I4-(2 -(phenothiazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoate; (-)-methyl-3-I(2-(phenothiazin-10-ylmethylbenzofuran-5-yl|-2-ethoxypropanoate); (1)-methyl -3-(2-(phenothiazin-10-yl)umethylbenzofuran-5-yl|-2-ethoxypropanoate; (-)-methyl-3-(2-(phenothiazin-10-yl)umethylbenzofuran-5-yl|-2 -ethoxypropanoate; o ()-methyl-3-I4-(2-«(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoate; ime) (t)-methyl-3-I4-(2-(phenoxazine -10-yl)ethoxy|phenyl|-2-ethoxypropanoate; (-)-methyl-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoate; 60 ()-ethyl-3 -I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoate; (t)-ethyl-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoate ; (-)-ethyl-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl)|-2-ethoxypropanoate; ()-ethyl-3-I4-(2-(phenoxazin-10-yl) ethoxy|phenyl/|-2-hydroxypropanoate; (i.e )-ethyl-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-hydroxypropanoate; 65 (-)-ethyl-3-14-(2-(phenoxazin-10-yl)ethoxy|phenyl)-2-hydroxypropanoate; (-)-ethyl-3-14-(2-«(phenoxazin-10-yl)letoxy|phenyl|-2-butoxypropanoate;

()-ethyl-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-butoxypropanoate; (-)-ethyl-3-I4-(2-«(phenoxazin-10-yl)ethoxy |phenyl|-2-butoxypropanoate; (t)-ethyl-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl)|-2-hexyloxypropanoate; (t)-ethyl-3-I4-(2 -(phenoxazin-10-yl)ethoxy|phenyl|-2-hexyloxypropanoate; (-)-ethyl-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl)|-2-hexyloxypropanoate; (-) -3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl)|-2-ethoxypropanoic acid and its salts; (-)-3-I4-(2-(phenothiazine-10-yl ethoxy|phenyl|- 2-ethoxypropanoic acid and its salts; (-)-3-(4-(2-(phenothiazin-10-yl)ethoxy|phenyl)|-2-ethoxypropanoic acid and its salts; ()-3-I4-(2 -(phenothiazin-10-yl)ethoxy|phenyl)- 2-ethoxy-2-methylpropanoic acid and its salts; (-)-3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl|-2- ethoxy-2-methylpropanoic acid and its salts; (-)-3-(4-(2-(phenothiazin-10-yl)ethoxy|phenyl)|-2-ethoxy-2-methylpropanoic acid and its salts; ()- 3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl|-2-phenoxypropanoic acid and its salts; (-)-3-I4-(2-(phenothiazin-10-ylethoxy|phenyl) |-2-phenoxypropanoic acid and its salts; (-)-3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl|-2-phenoxypropanoic acid and its salts; (-)-3-I4-(2-(phenothiazin-10-yl)ethoxy |phenyl|-2-phenoxy-2-methylpropanoic acid and its salts; (-)-3-I4-(2-(phenothiazine-10-yluethoxy|phenyl|-2-phenoxy-2-methylpropanoic acid and its salts); ( -)-3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl|-2-phenoxy-2-methylpropanoic acid and its salts; (--3-(2-(phenothiazin-10-yl)umethylbenzofuran -5-yl|-2-ethoxypropanoic acid and its salts; (13-3-(2-(phenothiazine-10-ylmethylbenzofuran-5-yl|-2-ethoxypropanoic acid and its salts); (-)-3-(2 -(phenothiazin-10-yl)umethylbenzofuran-5-yl|-2-ethoxypropanoic acid and its salts; ()-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoic acid and its salts; (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoic acid and its salts; (-)-3-I4-(2-(phenoxazin-10- yl)stoxy|phenyl|-2-ethoxypropanoic acid and its salts; c ()-3-14-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxy-2-methylpropanoic acid and its salts; Ge) (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl |-2-ethoxy-2-methylpropanoic acid and its salts; (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxy-2-methylpropanoic acid and its salts; (-)-3-I4-(2-(phenoxazin-10 -yl)ethoxy|phenyl|-2-phenoxypropanoic acid and its salts; (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-phenoxypropanoic acid and its salts; - (- )-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-phenoxypropanoic acid and its salts; "- ()-3-I4-(2-(phenoxazin-10-yl)letoxy| phenyl|-2-phenoxy-2-methylpropanoic acid and its salts; (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-phenoxy-2-methylpropanoic acid and its salts; Ф (-)-3-І4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-phenoxy-2-methylpropanoic acid and Its salts; со ()-3-І4-(2-(phenoxazin- 10-yl)ethoxy|phenyl|-2-hydroxypropanoic acid and its salts, and - (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl/|-2- hydroxypropanoic acid and its salts; (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-hydroxypropanoic acid and its salts; (--3-I4-(2-(phenoxazin- 10-yl)ethoxy|phenyl|-2-butoxypropanoic acid and its salts; (1-)-3-I4-(2-(phenoxazin-10-yl) )ethoxy|phenyl|-2-butoxypropanoic acid and its salts; « 20 (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-butoxypropanoic acid and Its salts; with (-)-3-I4-(2-(phenoxazin-10 -yl)ethoxy|phenyl|-2-hexyloxypropanoic acid and its salts; (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-hexyloxypropanoic acid and its salts; :z» (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-hexyloxypropanoic acid and its salts;

Sh2KO-M(15)1-3-I(4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxy-M-(2-hydroxy-1-phenylethyl)propanamide;

Sh25)-M(15)1-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl/|-2-ethoxy-IM-(2-hydroxy-1-phenylethyl)propanamide; -I Sh25) -M(15)1-3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl|-2-ethoxy-M-(2-hydroxy-1-phenylethyl)propanamide and

Sh2KO-M(15)1-3-I(4-(2-(phenothiazin-10-yl)ethoxy|phenyl|-2-ethoxy-M-(2-hydroxy-1-phenylethyl)propanamide. o According to the distinctive a feature of this invention is a compound of the general formula (II), where B", 2, KZ, 7, B", 8, X, A, (se) n, t, Ag have the values indicated earlier, and together they form a bond , can be obtained by any of the 20 methods presented below in scheme I. A compound of general formula (III) is a compound of general formula (I) where all symbols have the meanings indicated previously, and together form a bond, and Y is atom "and hydrogen.

F) ime) 60 b5 and

And: well at 4 | IS

Zn: vva t y br zhy u vini ov vu i

KO (Snutoman-snO ny tsa ya nina o) Spok A SNO Unit. 70 ma (Shar | (Ma) pis) method х у

II uch x KI and o

KV (SO KAN DO. rani shi Get 8 cm and method 5 . method 4 and tn What in : : m Zh. o as o t X xx TA

H) well, her DU c) i-

SHY: TV; o Another 0 me LI USNO A 2 s did prot i Z 12. khz ok o -I s scheme 1 ik Method (1). The interaction of the compound of the general formula (Ia), where all the symbols have the values indicated earlier, - 0 with the compound of the formula (IB), where K"" can represent a lower alkyl group, and K/ and BZ have the values indicated. previously, with the formation of a compound of general formula (III) can be carried out in the presence of a base such as a hydride

In an alkali metal, for example, MaH, KH, or an organolithium compound, for example, CH3, Viiii, etc., or an alkoxide, such as MaOMe, MaOebi K'ViO 7 or their mixture. The reaction can be carried out in the presence of a solvent such as THF, dioxane, DMF, DMSO, DME, etc., or a mixture thereof. NMRA can be used as a co-solvent. The reaction temperature can range from -782C to 502C, preferably the reaction temperature (F) is in the range from -102C to 302. The compound of the general formula (IV) can be obtained according to

GI of the method described in the literature (AppaIep. Spetie (1996), 53,699).

Method (2). The interaction of the compound of the general formula (Ia), where all the symbols have the values indicated previously, with the compound of the formula (Ps), where KZ is a hydrogen atom, and K/ and KZ have the values indicated previously, can be carried out under normal conditions. The basis is not a critical parameter. You can use any base that is usually used in the case of an aldol condensation reaction; a base such as an alkali metal hydride such as Man or KH may be used, a metal alkoxide such as MaOMe, K'VyO", Maoegs a metal amide such as HIMN", HIM(irg)d". An aprotic solvent such as as THF, ether, dioxane Reaction 65 can be carried out in an inert atmosphere, which can be maintained using inert gases such as Mo, Ag or

No, and the reaction is more effective in the absence of water. A reaction temperature in the range of -80°C to 359°C can be used. The B-hydroxylated reaction product can be dehydrated under conventional dehydration conditions, such as treating RTZA in a solvent such as benzene or toluene. The nature of the solvent and the dehydrating agent are not critical parameters. You can use a temperature in the range from 209C to the boiling point of the solvent, and more acceptable is the boiling point of the solvent, at which water can be continuously removed using a Dean-Stark water separator.

Method (3). The interaction of a compound of formula (Pe) where Y" is a leaving group such as a halogen atom, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like groups, all symbols having the meanings previously indicated, with a compound of formula (Pa) where B 7, 22 and Ag have the values indicated earlier, 70 with the formation of the compound of formula (II) can be carried out in the presence of a solvent such as THF, DMF, DMSO,

DME, etc. or their mixture. The reaction can be carried out in an inert atmosphere, which can be maintained by using inert gases such as Mo, Ag or Ne. The reaction can be carried out in the presence of a base such as CoCO3,

Ma»SO»z or Man or their mixture. When Ma2»СО»z or K»СО»z are used as a base, acetone can be used as a solvent. The reaction temperature can be in the range of 09С - 1202С, preferably in the range of 75 8020-1002. The reaction time can be from 1 to 24 hours, preferably from 2 to 12 hours. The compound of the formula (Xa) can be obtained according to the known method of the Wittig-Horner reaction by reaction between a hydroxyarylaldehyde with a protected hydroxyl group, such as benzyloxyarylaldehyde, and a compound of the formula (IB), followed by removal of the protective group.

Method (4). The interaction of the compound of the general formula (ISO), where all the symbols have the values indicated earlier, with the compound of the formula (II), where all the symbols have the values indicated earlier, and Y ! represents a leaving group such as a halogen atom, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and similar groups, and preferably represents a halogen atom, with the formation of a compound of the general formula (I) can be carried out in the presence of a solvent such as DMSO, DMF, DME, THF, dioxane, ether, etc., or their combination.

The reaction can be carried out in an inert atmosphere, which can be maintained by using inert gases such as CH 29 Mo, Ag or Ne. The reaction can be carried out in the presence of a base, such as an alkali, in particular sodium hydroxide, Ge) potassium hydroxide, alkali metal carbonate, such as sodium carbonate and potassium carbonate; alkali metal hydride, in particular sodium hydride or potassium hydride; an organometallic base such as n-butyllithium, an alkali metal amide, particularly sodium amide, or a mixture of bases. The amount of the base can be from 1 to 5 equivalents in relation to the amount of the compound of formula (Po), and preferably the amount of the base is from 1 to 3 equivalents. The reaction can be carried out at a temperature in the range from 09 to 1502C, preferably at a temperature in the range from 159C to 10020. The duration of the reaction can be from 0.25 to 48 hours, preferably from 0.25 to 12 hours. FU

Method (5). The reaction of a compound of general formula (II), wherein all symbols are as defined above, with a compound of formula (II) can be carried out using a suitable coupling agent such as

C5 Dicyclohexylurea, triarylphosphine/dialkylase-dicarboxylate, such as PPA z/OEAO, etc. The reaction can be carried out in the presence of a solvent such as THF, DME, CHCl, CHCl3, toluene, acetonitrile, carbon tetrachloride, etc. An inert atmosphere can be maintained by using inert gases such as M, Ag, or Ne. The reaction can be carried out at OMAR, NOVT, and they can be used in an amount in the range from 0.05 to 2 equivalents, preferably from 0.25 to 1 equivalent. The reaction temperature can be in the range from 09C to 10022, preferably in the range from 2023 to 8020. The reaction time can be from 0.5 to 24 hours, preferably from 2 to 12 hours. According to another embodiment of the invention, a compound of the general formula (I), where КК, КЗ, Кк", в, Ко, "» ТВ, А, н, т and Аг have the previously mentioned values, and У is an oxygen atom, can be obtained using one or more methods presented in scheme II. -And (95) se) - 50 what

F) name) 60 b5

"is Ko i: di M ee o still p dy de o fi TA ov: vi i A. yu 7, V s: I Y o posib 6 r

A. o eposib 12 Oh method b she ela A method 7 in two pis svv NK via V'su that S fbnyiuvA MID 0 method8b dn in skol "ni iya

Yes, sing 11,000 times, give it with minutes) 7 and. dk A Aokikh viky method 9X he

FO EpalovAsNO. osposib10 In us . the same school I ro I, uk

unit TO t. Fo Rushe (6) so 35 Scheme of

Method (6). Reduction of the compound of formula (II), obtained as previously described in scheme I, to form the compound of general formula (I), where each of B? and KU is a hydrogen atom, and all symbols have the meanings previously indicated, can be carried out in the presence of hydrogen gas and a catalyst such as Ra/C, КИ/С, "

RUS, etc. You can use a mixture of catalysts. The reaction can also be carried out in the presence of a solvent such as dioxane, acetic acid, ethyl acetate, ethanol, etc. The nature of the solvent is not critical with the 2nd parameter. It is possible to apply pressure from atmospheric to "550kPa (80f/d-). In order to reduce the time. and?" higher pressure can be used for the reaction. The catalyst can preferably be 5-1095 Pa/C, and the amount of catalyst used can be 1-10095 (m/m). The reaction can also be carried out using reduction with a solution of a metal such as magnesium in alcohol or sodium amalgam in alcohol.-I Method (7).The interaction of a compound of formula (Ia), wherein all the symbols have the meanings given previously, and I C represents a leaving group, such as a halogen atom, with an alcohol of general of formula (IB), where B" has the values indicated earlier, with the formation of a compound of formula (I) can be carried out in the presence of a solvent such as THF, (Ce) DMF, DMSO, DME, etc. or their mixtures. The reaction can be carried out in an inert atmosphere, which can be maintained by using inert gases such as Mo, Ag or Ne. The reaction can be carried out in the presence of a base such as KOH, Mn, MaOMe, MnO, Mn, or a mixture thereof. An interfacial catalyst such as tetraalkylammonium halide or hydroxide can be used. The reaction temperature can be in the range from 2097 to 1202, preferably the reaction temperature is from 302 to 1009C. The reaction time can be from 1 to 12 hours, preferably from 2 to b hours The compound of formula (Ia) can be obtained according to the method described in the simultaneously analyzed application 08/982910 (register of attorney Mo 011410-0).

GF! Method (8). The reaction of a compound of formula (Xe) described previously with a compound of formula (Ic) wherein all symbols have the meanings previously indicated to form a compound of formula (I) can be carried out in the presence of a solvent such as THF, DMF, DMSO, DME and etc., or their mixtures. The reaction can be carried out in an inert atmosphere, which can be maintained by using inert gases such as M, Ag or He. The reaction can be carried out 60 in the presence of a base such as CoCO»z, Ma»CO»z or Man, or a mixture thereof. When CoCO3 or Ma»CoO» is used as a base, acetone can be used as a solvent. The reaction temperature can be in the range from 209 to 12022, preferably the reaction temperature is in the range from 309 to 802C. The reaction time can be from 1 to 24 hours, preferably from 2 to 12 hours. The compound of formula (II) can be obtained by reaction

Wittig-Horner reaction between hydroxyarylaldehyde with a protected hydroxyl group and a compound of the formula (PV) with subsequent reduction of the double bond and cleavage of the protective group. On the other hand, the compound of formula (Ic)

can be obtained according to the method described in UMO 94/01420.

Method (9). The reaction of a compound of general formula (II) previously described with a compound of general formula (II) wherein all symbols have the meanings previously indicated can be carried out using a suitable coupling agent such as dicyclohexylurea, a triarylphosphine/dialkyl azadicarboxylate such as PPA with /OEAO, etc. The reaction can be carried out in the presence of a solvent such as THF, DME, CH 5Si», SNCI5, toluene, acetonitrile, carbon tetrachloride, etc.

An inert atmosphere can be maintained by using inert gases such as M, Ag, or Ne. The reaction can be carried out at OMAR, NOVT, and they can be used in an amount in the range of 0.05 - 2 equivalents, preferably 0.25 - 1 equivalent. The reaction temperature can be in the range from 09C to 1002C, preferably the reaction temperature is in the range from 2022 to 802C. The duration of the reaction can be from 0.5 to 24 hours, preferably from 6 to 12 hours.

Method (10). The interaction of the compound of the formula (Id), where all symbols have the values indicated earlier, with the compound of the formula (Ie), where B' has the values indicated earlier, and Na! is SI, Vg or I, with the formation of compound 75 of formula (I) can be carried out in the presence of a solvent such as THF, DMF, DMSO, DME, etc. An inert atmosphere can be maintained by using inert gases such as Mo, Ag, or Ne. The reaction can be carried out in the presence of a base, such as KOH, Mason, MaOMe, KVO 7, Man and type. An interfacial catalyst such as tetraalkylammonium halide or hydroxide can be used. The reaction temperature can be in the range from 202 to 1502, preferably the reaction temperature is in the range from 302C to 1002C. The reaction time can be from 1 to 24 hours, preferably from 2 to 12 hours. The compound of formula (II) is a compound of formula (I), where B" is H and U is an oxygen atom.

Method (11). The interaction of the compound of the general formula (Ша), described earlier, with the compound of the formula (Ps), where co. B and B8 have the values indicated earlier, can be carried out under normal conditions. The base is not a critical parameter. Any base commonly used for aldol condensation reactions can be used, such as a metal hydride such as Mann or KN; metal alkoxide, for example, MaOMe, K'VIO or i)

Maoki, a metal amide, for example, ГИМН» or ГИМ(irg). An aprotic solvent such as

THF, ether or dioxane. The reaction can be carried out in an inert atmosphere, which can be maintained by using inert gases such as Mo, Ar or He, and the reaction is more efficient in the absence of water. It is possible to use the reaction temperature in the range from -802C to 2520C. The B-hydroxyaldol reaction product can be dehydroxylated using convenient methods, usually the ionic hydrogenation method, for example, by -- treatment with trialkylsilane in the presence of an acid such as trifluoroacetic acid. You can use Ф solvent, such as СН Си». The reaction proceeds well at 252C. If the reaction is slow, you can use a higher temperature. Shk

Method (12). The interaction of a compound of the general formula (Xa), where all the symbols have the meanings indicated previously, with a compound of the formula (ID, where /' represents a leaving group, such as a halogen atom, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate group, etc. n., preferably a halogen atom, and all other symbols have the meanings indicated earlier, with the formation of a compound of the general formula (I) can be carried out in the presence of a solvent such as DMSO, DMF, DME, THF, dioxane, ether, etc. , or a combination thereof. The reaction can be carried out in an inert atmosphere, which can be maintained by using inert gases such as M 5 , Ag or - with Ne. The reaction can be carried out in the presence of a base such as a base, for example, sodium hydroxide or potassium hydroxide ; an alkali metal carbonate, for example, sodium carbonate or potassium carbonate; an alkali metal hydride, "» for example, sodium hydride or potassium hydride; an organometallic base, for example, n-butyllithium, an alkali metal amide, for example, sodium amide, or a mixture thereof. Quantity of the base can vary from 1 to 5 equivalents in relation to the amount of the compound of the formula (Po), preferably the amount of the base is from 1 to 3 equivalents. -i The reaction can be carried out in the presence of an interphase catalyst, such as tetraalkylammonium halide or hydroxide. The reaction can be carried out at a temperature in the range from 09 to 1509C, preferably at a temperature in the range from 159C to 100920. The duration of the reaction can be from 0.25 to 24 hours, preferably from 0.25 to 12 hours. -k 70 The compound of the general formula (I), where Y is oxygen, and KZ has the values indicated earlier, can be converted into a compound of the formula (I), where X is ME" by reacting with the appropriate amine. Accordingly, the compound of the formula ( I), where U is OH, can be converted into a halogen anhydride, preferably UKZ - SI, by reaction with appropriate reagents, such as oxalyl chloride, thionyl chloride, etc., followed by treatment with an amine. On the other hand, a mixed anhydride can be obtained from the compound of formula (I) wherein UZ is OH and all other symbols are as previously defined, by treatment with an anhydride such as acetyl chloride,

F) acetyl bromide, pivaloyl chloride, dichlorobenzoyl chloride, etc. The reaction can be carried out in the presence of a suitable base, such as pyridine, triethylamine, diisopropylethylamine, etc. You can use such solvents as halogen-containing hydrocarbons, for example, СНОСиз or СНоСиз; hydrocarbons, for example, benzene, toluene, xylene, etc. The reaction can be carried out at a temperature in the range from -409C to 402C, preferably from 09C to 2020. Then the halogenated anhydride or mixed anhydride obtained in this way can be treated with a suitable amine.

Methods of obtaining compounds of the general formula (Ха) are described in the concurrently analyzed application Mo08/982910 (registry of authorized representative MoO 011410-0).

In another version of its embodiment, this invention belongs to new intermediate compounds of formula (I) b5 in sonata ot and ov where Ag is an optionally substituted divalent single or condensed aromatic or heterocyclic group; KU is a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, an optionally substituted aralkyl group, or forms a bond together with the adjacent KZ group; KU is hydrogen, hydroxy, alkoxy, halogen, a lower alkyl group, acyl, optionally substituted aralkyl, or together with K 5 forms 70 bonds; BC is hydrogen or an optionally substituted group selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups; KZ can be hydrogen or an optionally substituted group selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; n is equal to a whole number in the interval 72 1-4; t is equal to 0 or 1, and Her represents a group that is split off, such as a halogen atom, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate group, etc., preferably a halogen atom, and to the method of their preparation and their use in the preparation of B- of aryl-α-substituted hydroxyalkanoic acids.

The compound of the formula (I), where t is 0, and all other symbols have the values indicated earlier, can be obtained using the interaction of the compound of the formula (I) pl, v deo

NnotANK ID.

ЗD ов (с) а см , и и и де КЕ", 85, 27, 28 and Аг have the values indicated earlier, with the compound of the formula (IM) (о)

Г1(СНао)вп-го (M), 1512 : : ; vi : - where Her 1-4, can be the same or different and constitute groups that are detached, such as SI, Vg, Y, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate group, etc., or /? can also be (87) a hydroxyl or protected hydroxyl group, which can be further converted into a leaving group; and n b is an integer in the range 1-4.

The interaction of the compound of the formula (Ic) with the compound of the formula (IM) to form the compound of the formula (I) can be carried out in the presence of a solvent such as THF, DMF, DMSO, DME, etc., or a mixture thereof. The reaction can be carried out in an inert atmosphere, which can be maintained by using inert gases such as M 5 , Ag or He.

The reaction can be carried out in the presence of a base such as CoCO3, Ma»HCO»3 or Man, or a mixture thereof. When Ma»CO3 or CoCO3 is used as a base, acetone can be used as a solvent. The reaction temperature can vary from 202 to 1202C, it is more acceptable to conduct the reaction at a temperature in the range of 309C to 8090C. The reaction time can be in the range from 1 to 24 hours, preferably from 2 to 12 hours. On the other hand, the intermediate compound of the formula (I) can be obtained by the reaction of the compound of the formula (M). и"? And 1(СНо)п-(О)т-АгСНО (У), where И is a leaving group, such as СИ, Бг, И, methanesulfonate, trifluoromethanesulfonate, -И p-toluenesulfonate group, etc. ., and all other symbols have the meanings indicated earlier, with the compound of the formula (NAME) o . i pz te ' at) i sov "4 and where all the symbols have the meanings indicated earlier, with the formation of the compound of the formula (PO), which then reduced to form a compound of the formula (I. The compound of the formula (I) is a compound of the formula (I), where

K5;do together form a bond, and all other symbols have the meanings indicated previously. (F. The interaction of a compound of formula (M) with a compound of formula (IB) can be carried out in the presence of a base, such as an alkali metal hydride, for example, MaH or KH, or an organolithium compound, such as CH zium, Vxii, etc., or alkoxide, such as MaOMe, MaOeI K'ViO 7, or a mixture thereof. The reaction can be carried out in the presence of a solvent such as THF, dioxane, DMF, DMSO, DME, etc., or a mixture thereof. As a co-solvent, NMRA can be used The reaction temperature can range from -7892C to 502C, it is more appropriate to conduct the reaction at a temperature in the range from -109C to 302C. The reduction of the compound of formula (II) can be carried out in the presence of gaseous hydrogen and a catalyst such as Ra/C, KR/C, RUS, etc. A mixture of catalysts can be used. The reaction can also be carried out in the presence of a solvent such as dioxane, 65 acetic acid, ethyl acetate, ethanol, etc. The nature of the solvent is not a critical parameter. Pressures from atmospheric to 7550 kPa can be used ( 80f/d2). higher pressure can be used during the reaction time. The catalyst may preferably be 5-1095 Pa/C, and the amount of catalyst used may be 1-10095 (m/m). The reaction can also be carried out using reduction with a metal solution such as magnesium in alcohol or sodium amalgam in alcohol.

Pharmaceutically acceptable salts are prepared by reacting a compound of formula (I) with 1-4 equivalents of a base, such as sodium hydroxide, sodium methoxide, sodium hydride, potassium tert-butoxide, calcium hydroxide, magnesium hydroxide, and the like, in a solvent such as ether , THF, methanol, tert-butanol, dioxane, isopropanol, ethanol, etc. Mixtures of solvents can be used. Organic bases such as lysine, arginine, diethanolamine, choline, guanidine and their derivatives, etc., can also be used. Alternatively, any acceptable 7/0 addition acid salts are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid, etc., in a solvent such as ethyl acetate, ether, alcohols, acetone, THF, dioxane, etc. .p. Mixtures of solvents can also be used.

Stereoisomers of the compounds forming part of this invention can be obtained in any possible way using reagents in their separate enantiomeric form or by reacting in the presence of reagents or catalysts in their separate enantiomeric form, or by splitting a mixture of stereoisomers by conventional methods. Some of the more acceptable methods include cleavage by microorganisms, cleavage of diastereomeric salts formed by chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid and similar acids when appropriate, or formed by chiral bases such as brucine , alkaloids of cinchona bark and their derivatives, etc. Commonly used methods are collected in dasKez et al., "Epapiotegv, Kasetaiyez apa

Rezoishiiop" (Umiieu Ipiegwsiepse, 1981). For example, the compound of formula (I), where UZ is OH, can be converted to Ha

Into a 1:1 mixture of diastereomeric amides by treatment with chiral amines, amino acids, amino alcohols obtained from amino acids; you can use the usual reaction conditions for the conversion of an acid into an amide; i) the diastereomers can be separated either by fractional crystallization or by chromatography, and the stereoisomers of the compound of formula (I) can be obtained by hydrolysis of the pure amide diastereomer.

Different polymorphic forms of the compound of the general formula (I), which are part of this invention, can be obtained by crystallization of the compound of the formula (I) under different conditions, for example, using different solvents, usually used for recrystallization, or their mixtures; crystallization at different -- temperatures; in different ways of cooling during crystallization - from very fast cooling to very Ge"! slow Polymorphs can also be obtained by heating or melting the compound followed by gradual or rapid cooling. The presence of polymorphic forms can be determined using o

NMR spectroscopy of a solid sample, IR spectroscopy, differential scanning calorimetry, X-ray diffraction on powders or other similar methods.

The present invention also relates to a pharmaceutical composition containing one or more compounds of the general formula (I) described above, their tautomeric forms, their stereoisomers, their polymorphic forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, in combination with commonly used 70 in pharmacy, carriers, diluents, etc., useful for the treatment and/or prevention of insulin resistance (type 2 diabetes), reduced glucose tolerance, dyslipidemia, disorders related to syndrome X, such as hypertension, obesity, insulin resistance, atherosclerosis, "" hyperlipidemia, ischemic heart disease, and other cardiovascular disorders. The compounds of this invention are also useful for the treatment of certain kidney diseases, including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, for the treatment of psoriasis and polycystic ovary syndrome (PCOS). These compounds may also be useful as aldose reductase inhibitors for improving improvement of cognitive (cognitive) functions in dementia and treatment of complications in diabetes and osteoporosis.

Mami The pharmaceutical composition may be in the form commonly used, such as tablets, (Se) capsules, powders, syrups, solutions, suspensions, etc., may contain corrigents, sweeteners, etc., in suitable solid or liquid forms. carriers or solvents, or in suitable sterile media for the formation of solutions or suspensions for injections. Such compositions, as a rule, contain from 1 to 20 mass. 95, preferably from 1 "I to Omas. 90, of the active compound, and the rest of the composition consists of pharmaceutically acceptable carriers, diluents or solvents.

The compound of formula (I) described above is administered to mammals, including humans, either orally or parenterally. Oral administration is more acceptable, which is more convenient and avoids possible pain and irritation from the injection. However, in conditions where the patient cannot swallow the drug or impaired absorption after oral administration due to illness or other deviation, it is necessary to administer the drug parenterally.

With any method of administration, the dosage is in the range of from about 0.01 to about 100 mg per kg of body weight of the subject per day, or preferably from about 0.01 to about 30 mg per kg of body weight per day in the form of a single dose or divided doses However, the optimal dosage for an individual treated subject will be determined by the treating physician, and, as a rule, a lower dose is first administered, and then the dose is increased and the most appropriate dose is determined.

Suitable pharmaceutically acceptable carriers are solid carriers or diluents and sterile aqueous or organic solutions. The active compound in such a pharmaceutical composition will be present in an effective amount sufficient to provide the desired dosage in the above interval. Thus, in the case of oral administration, the compound can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions, etc. Pharmaceutical compositions, if necessary, may contain additional components, such as corrigents, sweeteners, excipients, etc. In the case of parenteral administration, the compound can be combined with a sterile aqueous or organic medium to form injectable solutions or suspensions. For example, you can use solutions in sesame or peanut oil, aqueous propylene glycol, etc., as well as aqueous solutions of water-soluble pharmaceutically acceptable addition salts or salts of compounds formed with bases. Solutions for injections obtained in this way can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with 7/0 intramuscular administration being more acceptable for humans.

The invention is explained in detail by means of the following examples, which are provided by way of illustration only and should therefore not be construed as limiting the scope of the invention.

Preparation example 1

Ethyl-(E/27)-3-(4-benzyloxyphenyl)|-2-ethoxyacrylate

Srna vab o ebNsn

A solution of triethyl-2-ethoxyphosphonoacetate obtained by the method of Ogeili apa Maspieidi, Appaiep. Spetie, 1996, 699, 53, (3.53g, 13.2mmol) in dry tetrahydrofuran (1Oml) in a nitrogen atmosphere, while stirring, is gradually added to the ice-cooled suspension of sodium hydride (bO9o dispersion in oil) (0.62g, 25 .94 mmol) in dry tetrahydrofuran (bml). The mixture was stirred at 09C for 30h before adding 4-benzyloxybenzaldehyde (2.5g, 11.7U9mmol) in dry tetrahydrofuran (20ml). The mixture is heated to room temperature and stirred at this temperature for 20 hours. The solvent is evaporated, water (100 ml) is added, and the mixture is extracted with ethyl acetate (2x7 bml). The combined organic extracts are washed with water (5Oml) with pus "M (Bbml), dried (Ma»5O)), filtered and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel using a mixture of ethyl acetate and petroleum ether (2:8) as an eluent to obtain the title compound (3.84 g, quantitative yield) as an oil. "H NMR of the reaction product predicts a mixture of geometric isomers (76:24 - 7:E) (K.A. Aykep and O.I. Tropt, Zupipeziz, 1989, 958). "TN NMR (SOSIZ, 200 MHz): 5 1, 25-1.50 (complex, 6H), 3.85-4.03 (complex, 2H), 4.28 (k, 9U-7.0Hz, 2H), - 5.05, 5.09 (2s, 2H, benzyloxy-CH»o), 6.08 (s, 0.24H, E-isomer of the olefinic proton), 6.85-6.90 (complex, 2H), h 6.99 (s, 0.76H, 2-isomer), 7.33-7.45 (complex, 5H), 7.75 (d, U-8.72Hz, 2H).

Preparatory example 2 F

Methyl-3-(4-benzyloxyphenyl)-2-ethoxypropanoate

SL about Oszne

A mixture of ethyl-(E/2)-3-(4-benzyloxyphenyl)|-2-ethoxyacrylate (3.84 g, 11.7 mmol, obtained in preparative example 1) and magnesium shavings (5.09 g, 0.21 mmol) in dry methanol (40 ml) is stirred at 2523 for 1 hour. Water (8 Oml) is added and the pH of the solution is adjusted to 6.5-7.5 with 2M hydrochloric acid. Solution 3c is extracted with ethyl acetate (3x75ml). The organic layers were washed with water (50 ml), pus (50 ml), dried (MA»SO,)) with» and filtered. The solvent was evaporated under reduced pressure to obtain the title compound (3.7 g, quantitative yield) in the form of an oil.

TN NMR (SOSIi, 200MHz): 85 1.16 (t, U-6.97Hz, ZN), 2.95 (d, 9-6.55HzC, 2H), 3.30-3.38 (complex, 1H ), -1 that 3.55-3.67 (complex, 1H), 3.69 (s, ЗН), 3.99 (t, 9-6, 64Хц, 71Н), 5.04 (s, 2Н) , 6.89 (d, U-8.63HzC, 2H), 7.15 (d, U-8.62Hz, 2H), 7.31-7.41 (complex, 5H). (95) Preparative example C with Methyl-3-(4-hydroxyphenyl)-2-ethoxypropanoate; iSOOSNI t no S Tenen; "With I

A suspension of methyl-3-(4-benzyloxyphenyl|-2-ethoxypropanoate (3.7g, 11.78mmol (preparative example 2)) and 1096 Ra/C (0.37g) in ethyl acetate (5homl) is stirred at 252C and hydrogen pressure 414kPa (6b0f/d?) for 24h. The catalyst is filtered off and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel using a mixture of ethyl acetate and petroleum ether (2:68) as eluent to give the title compound (2.2g, 8490 ) in the form of oil. name) "YAN NMR (SOSIi, 200MHz) 85 1.21 (t, 9U-6.97Hz, ZN), 2.99 (d, 9-6.37Hz, 2H), 3.32- 3.49 (complex, 1H), 3.57-3.65 (complex, 1H), 3.76 (c, ЗН), 4.05 (t, U-6.64Hz, 1H), 5.19- 5.40 (ushs, 1H, capable of exchange with 020), 6.80 60 (d, 9-8.44Hz, 2H), 7.14 (d, U-8.39Hz, 2H).

Preparatory example 4

Ethyl 3-(4-hydroxyphenyl|-2-ethoxypropanoate) in KA Teneni

The title compound (1.73g, 6195) was obtained as a colorless oil from ethyl-(E/7)-3-(4-benzyloxyphenyl)|-2-ethoxyacrylate (3.85g, 11.8O0mmol), obtained in preparative example 1, by hydrogenation described in preparative example 3.

IN nMR (SOS, 200MHz): δ 1.12-1.29 (complex, 6H), 2.93 (d, 9U-6.55Hzc, 2H), 3.28-3.45 (complex, 1H), 3.51-3.68 (complex, 1H), 3.98 (t, U-6.55Hz, 1H), 4.16 (k, U-7.15Hz, 2H), 5.40 (s, 1H , capable of exchange with 020), 6.73 (d, U-8.39 Hz, 2H), 7.08 (d, U-8.53 Hz, 2H).

Preparatory example 5

Ethyl 3-(4-benzyloxyphenyl|-2-butoxypropanoate).

SU ben

A solution of ethyl 3-(4-benzyloxyphenyl|-2-hydroxypropanoate (5.0 g, 16.6 mmol)) (obtained by a method similar to the method described in reference UMO 95/18125) in dry dimethylformamide (ml) at 02C is added to a suspension of 75 of sodium hydride (0.1g, 41.bmmol) (6095% dispersion in oil) in dry dimethylformamide (3ml) and continue stirring for 1 hour. To the above reaction mixture at 0 °C, n-butyl bromide (3.4g, 24 .0 mmol) and continue stirring for 1 hour at approximately 25 °C. Water (30 mL) is added and the mixture is extracted with ethyl acetate (2 x 5 mL). The combined ethyl acetate layers are washed with water (5 mL), oleoresin (25 mL), dried (Ma33O) ), filter and evaporate the solvent.

The residue is chromatographed on silica gel using a mixture of ethyl acetate and petroleum ether (1:9) as an eluent to give the title compound (0.7 g, 20905) as an oil. "H nMR (SOS, 200MHz): δ 0.85 (t, 9U-7.38Hz, ЗН), 1.18-1.40 (complex, 5Н), 1.49-1.58 (complex, 2Н) , 2.94 (d, 9U-6.74Hz, 2H), 3.20-3.33 (complex, 1H), 3.46-3.61 (complex, 1H), 3.94 (t, 9U- 6.37 Hz, 1H), 4.16 (k, p

U-7,O0Hz, 2H), 5.04 (s, 2H), 6.89 (d, U-8.5Hz, 2H), 7.15 (d, U-8.48Hz, 2H), 7, 30-7.44 (complex, 5H).

Preparatory example 6 (8)

Ethyl 3-(4-hydroxyphenyl|-2-butoxypropanoate).

Saint no: ; Ф(сНновсну. - the compound named in the title (0.475g, 7590) is obtained in the form of an oil of Kk)-ethyl-3-(4-benzyloxyphenyl|-2-butoxypropanoate (0.85g, 2.3mmol), obtained in the preparative example 5, F by a procedure similar to that described in preparative example 3. "H nNMR (SOS, 200 MHz): 5 0.85 (t, 9U-7.24HuC, ЗН), 1.19-1.38 (complex, 5Н) , 1.44-1.58 (complex, 2H), and, 2.94 (d, 9-6.55Hz, 2H), 3.21-3.32 (complex, 1H), 3.49-3, 62 (complex, 1H), 3.94 (t, U-6.88Hz, 1H), 4.16 (k, h-

U-7.1Hz, 2H), 4.99 (s, 1H, capable of exchange with 020), 6.73 (d, U-8.53Hz, 2H), 7.09 (d, U-8.44Hz , 2H).

Preparatory example 7

Ethyl-3-(4-benzyloxyphenyl|-2-hexyloxypropanoate « a СХ AAХ Penn z с с» rt (Spas z ц The compound named in the title (1.2 g, 2290) is obtained in the form of an oil Kk) "» ethyl-3- (4-benzyloxyphenyl)-2-hydroxypropanoate (4.2 g, 14.00 mmol) and 1-bromohexane (3.4 g, 21.0 mmol) by a procedure similar to that described in preparative example 5. 5 0.86 (t, 9U-5.9HZ, ZN), 1.18-1.37 (complex, 7H), 1.45-1.66 (complex, 4H), and 2.94 (d, 9-6.55Hz, 2H), 3.22-3.33 (complex, 1H), 3.52-3.64 (complex, 71H), 3.94 (t, 9U-6.9Hz, 1H), 4.16 (k, xu -7.06Hz, 2H), 5.03 (s, 2H), 6.89 (d, 9U-8.63HzC, 2H), 7.15 (d, U-8.63HzC , 2H), 7.31-7.44 (complex, 5H).

Preparative example 8 se) Ethyl-3-I(4-hydroxyphenyl|-2-hexyloxypropanoate - 70 | sobszn "m no KA Kspshet

The title compound (0.7g, 7696) was obtained as an oil of Kk) ethyl 3-(4-benzyloxyphenyl)|-2-hexyloxypropanoate (1.2g, 3, 1mmol), obtained in preparative example 7, by the procedure, similar to that described in preparatory example 3.

F! tn NMR (SOSIZ, 200MHz): 5 0.85 (t, 9U-5.81Hz, ЗН), 1.19-1.39 (complex, 7Н), 1.48-1.68 (complex, 4Н), 2.92 (d, 9U-6.74HZ, 2H), 3.18-3.39 (complex, 1H), 3.48-3.62 (complex, 71H), 3.93 (t, 9U-7 ,0Hz, 1H), 4.16 (k, o -7.06Hz, 2H), 4.85 (s, 1H, capable of exchange with 020), 6.73 (d, 9U-8.53HzC, 2H) , 7.10 (d, U-8.31Hz, 2H).

Preparative example 9 60 Ethyl-(E/27)-3-I4-(2-bromomethoxy)phenyl)-2-ethoxyacrylate siak, SOSIN vk cho Bonn, 65 The compound named in the title (4.0g, 6695) is obtained in the form of an oil with a ratio of E:7 isomers of 45:55 (as measured by HO NMR) with 4-(2-bromomethoxy)benzaldehyde (4.0g, 174mmol) and triethyl-2-ethoxyphosphonoacetate (5.61g, 20.89mmol) by the procedure, similar to that described in preparative example 1. "NMR (SOSI, 200 MHz): 5 1.17 and 1.42 (6H, E- and 7-triplets, isomeric OSNoSNU and OSNo-SNa), 3.62-3.72 ( complex, 2H), 3.90-4.28 (complex, 2H), 4.30-4.537 (complex, 4H), 6.09 (s, 0.45H, olefinic proton

E-isomers), 6.85 and 6.92 (2H, d and d, U-8.67Hz and 8.7Hz), 6.98 (c, 0.55H, 2-isomer of the olefinic proton), 7.16 and 7.78 (d and d, combined 2H, U-8.63Hz and 8.72Hz).

Preparatory example 10

Ethyl-3-I(4-(2-bromomethoxy)phenyl|-2-ethoxypropanoate; /SOOCIN" "Сн

The title compound (4.0g, 8090) was obtained as a colorless oil from ethyl-(E/2)-3-I4-(2-bromomethoxy)phenyl|-2-ethoxyacrylate (5.0g, 14.5mmol), obtained in preparative example 75 9, using H 2/1095 Ra/C (4g) in dioxane as a solvent by a procedure similar to that described in preparative example 3.

IN nMR (SOS, 200 MHz): δ 1.12-1.30 (complex, 6H), 2.95 (d, 9U-6.64 Hz, 2H), 3.25-3.45 (complex, 1H) . 9U-6.3Hz, 2H), 6.81 (d,

U-8.67Hz, 2H), 7.16 (d, U-8.63Hz, 2H).

Example 1 / Ethyl-(E/2)-3-(4-I(2-(phenothiazin-10-yl)ethoxy|phenyl)-2-ethoxyacrylate

The title compound is obtained as a mixture of E:2 1:1 isomers (1.46g, quantitative yield) in the form of a syrupy liquid from 4-(2-(phenothiazin-10-yl)ethoxy|benzaldehyde (1.08g, 3.11 mmol) ) and triethyl-2-ethoxyphosphonoacetate (MU. Ogeii 5 N. Maspiedi, Appaiep spetii, 1966, 699, 53) (1.0 g, 33,/mmol) by a procedure similar to that described in preparative example 1. "-

IN NMR (SOSIZ, 200MHz): 5 1.15-1.43 (complex, 6H), 3.89-4.03 (complex, 2H), 4.11-4.17 (complex, 2H), b 4 ,30,4,33 (combined, 4Н, -СНоСНо-singlets), 6.07 (c, 0О,5Н, olefinic proton of the E-isomer), 6.80-7.10 (complex, 6,5Н), 7 ,14-7.20 (complex, 4H), 7.7Z(d, U-8.39Hz, 2H). She

Example 2 cha

Ethyl-(E/2)-3-(2-(phenothiazine-10-ylmethylbenzofuran-5-yl|-2-ethoxyacrylate) ve « : - y The title compound is obtained as a mixture of isomers E:7 (38:62) ( when measured by the "H NMR" method) (1.5 g, 10095) in the form of a colorless liquid from 5-formyl-2-(phenothiazin-10-yl)umethylbenzofuran (1.14 g, 3.2 mmol) -1 395 by a procedure similar to the one described in preparatory example 1.

IN NMR (SOSIZ, 200MHz): 5 1.23-1.45 (complex, 6H), 3.55-3.78 (complex, 1H), 3.88-4.19 (complex, 1H), about 4 ,22-4.35 (complex, 2H), 5.14 (c, 2H), 6.18 (c, 0.38H, olefinic proton of the E-isomer), 6.47 and 6.54 co (combined, 1H ), 6.78-7.12 (complex, 8.62H), 7.37-7.48 (complex, 1H), 7.71 (d, U-7.57Hz, 1H), 7.95 (s , 1H). 20 Example C - Ethyl-(E/2)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl)|-2-ethoxyacrylate

HF) The title compound is obtained as a mixture of isomers E:7 (36:64) (when measured by H NMR) g) (144g, 7695) as a white solid with 4-(2-(phenoxazin-10-yl) )uethoxy|benzaldehyde (14.OHg, 42.3 mmol) by a procedure similar to that described in preparative example 1. M.p. 110-11296, in IN NMR (SOCI3, 200 MHz): δ 1.16 and 1.38 (combined , 6H, triplet signals of isomeric -OSNoCH»), 3.89-4.05 (complex, 4H), 4.14-4.31 (complex, 4H), 6.06 (c, 0.36H, olefinic proton E -isomer), 6.66-6.95 (complex, 10.64H), 7.75 (d, U-8.76Hz, 2H).

Example 4

Methyl-3-I4-(2-(phenothiazin-10-yl)letoxy|phenyl|-2-ethoxypropanoate b5

The title compound (1.3 g, 9495) is obtained as a resinous liquid from ethyl-(E/2)-3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl)|-2-ethoxyacrylate (1 ,43g, C, 1Omole), obtained in example 1, by a procedure similar to that described in preparative example 2. 70 TN nNMR (SOS, 200MHz): 85 1.15 (t, 9U-7.0Hz, ZN), 2, 93 (d, 9-6.64Hz, 2H), 3.33-3.42 (complex, 1H), 3.52-3.63 (complex, 1H), 3.69 (s, ЗН), 3, 97 (t, 9U-6.2Hz, 1H), 4.29 (s, 4H), 6.81 (d, 9U-8.62Hz, 2H), 6.92-6.96 (complex, 4H), 7.12-7.22 (complex, 6H).

Example 5

Methyl 3-(2-(phenothiazin-10-yl)umethylbenzofuran-5-yl|-2-ethoxypropanoate

AND

CODE is the same

Ot tosSnesnu

The title compound (1.Og, 6896) is obtained in the form of resin Kk) ethyl-(E/2)-3-(2-(phenothiazin-10-yl)umethylbenzofuran-5-yl|-2-ethoxyacrylate (1, 5g, Z, Ommol), obtained in example 2, by a procedure similar to that described in preparative example 2.

TN nMR (SOSIZ, 200 MHz): δ 1.16 (t, 9U-7.0Hz, ZN), 3.07 (d, 9-6.55Hz, 2H), 3.30-3.49 (complex, 1H ), c 29 3.56-3.68 (complex, 1H), 3.70 (c, ЗН), 4.05 (t, U -6.3HzC, 1H), 5.13 (c, 2H), 6.48 (c, 2H), 6.79-7.48 (complex, 11H). Gee)

Example 6

Methyl 3-I4-(2-«(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoate

SO Guchuekov and "DSA nen g

Method A o

The title compound (0.68g, 5290) was obtained as a white solid from ethyl-(E/2)-3-I4-(2-(phenoxazin-10-ylethoxy|phenyl|-2-ethoxyacrylate) (1, 3g, 2.b0mmol), obtained in the example

With, by a procedure similar to that described in preparative example 2. T.pl. 88-90. -

Method B

A mixture of 2-(phenoxazin-10-yl)ethyl methanesulfonate (1.75 g, 5.0 mmol), methyl 3-(4-hydroxyphenyl)-2-ethoxypropanoate (1.5 g, 0.8 mmol) and potassium carbonate (3.16 g ) in dry dimethylformamide (200 ml) is stirred at 802 for 12 hours. The reaction mixture is cooled to room temperature (approx. 2592). Water (30 ml) was added, and the mixture was extracted with ethyl acetate (2 x 5 ml). The combined organic extracts were washed with water (50 ml), dried (Ma»5O)) and evaporated. The residue was chromatographed using a mixture of ethyl acetate and petroleum ether (1:9) to give the title compound (1.15 g, 4795) as a white solid. T.pl. 89-902C. H NMR data correspond to the required product (see

Above). -I TN NMR (SOSIi, 200MHz): 85 1.16 (t, U-6.92Hz, ZN), 2.96 (d, 9-6.64Hz, 2H), 3.22-3.40 (complex . 6.55-6.89 (complex, 1 mni OH), 7.12 (d, U-8.63Hz, 2H). (se) Example 7 shu 20 Ethyl-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoate welds with C blowing (neo Osn

Method A (F. To the solution of ethyl-(E/2)-3-I(4-(2-(phenoxazin-10-yl)ethoxy|phenyl/|-2-ethoxyacrylate) obtained in example C) (1.Og, 2.24 mmol) in dioxane (HOml) add 1095 Pa/cС (0.25 g) and the mixture is stirred at 25923 at a hydrogen pressure of -414 kPa for 24 hours. At the end of this time, the reaction mixture is filtered and the solvent is evaporated under reduced pressure. The residue is treated with petroleum with ether to give the title compound (0.96 g, 9690) as a white solid, mp 51-5396.

IN nMR (SOS, 200MHz): δ 1.12-1.27 (complex, 6H), 2.94 (d, 9U-6.31Hzc, 2H), 3.26-3.41 (complex, 1H), 3.52-3.75 (complex, 1H), 3.96 (t, 9U-6.64HZ, 2H), 4.10-4.28 (complex, 5H), 6.55-6.92 (complex , 1 OH), 7.16 (d, U-8.39Hz, 2H). 65 Method B

The title compound (0.55g, 7590) is obtained as a white solid with

2-(phenoxazin-10-yl)ethylmethanesulfonate (0.5g, 1.6mmol) and ethyl 3-(4-hydroxyphenyl)-2-ethoxypropanoate (0.46g, 1.9mmol), obtained in preparative example 4, by a procedure similar to that described in example 6 (method B). T.pl. 52-532C. H NMR data correspond to the required product (see above).

Method C

To a suspension of sodium hydride (6095% dispersion in oil) (0.098g, 4.0mmol) in dry dimethylformamide (3ml) in a nitrogen atmosphere at 0, add a solution of phenoxazine (0.3g, 1.bmmol) in dry dimethylformamide (5ml) and stirring is continued for about 30 minutes. at 25 C. A solution of ethyl 3-I(4-(2-bromomethoxy)phenyl|-2-ethoxypropanoate 70. (0.85 g, 24 mmol) obtained in Preparative Example 10 in dry dimethylformamide (5 ml ) and stirring is continued for another 1 h at approximately 2590. Water (40 mL) is added and the mixture is extracted with ethyl acetate (2 x 3 3 O mL). The combined organic extracts are washed with water (25 mL), brine (25 mL), dried (MgO)), filtered and evaporated. The residue was chromatographed on silica gel using a mixture of ethyl acetate and petroleum ether (1:9) as eluent to give the title compound (0.3 g, 4095) as a colorless solid. T.pl. 52-532C. H NMR data correspond to the required product (see above).

Example 8

Ethyl-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl/|-2-hydroxypropanoate a

The title compound (1.0bg, 4395) was obtained as a pale yellow liquid from 2-(phenoxazin-10-yl)ethylmethanesulfonate (1.8g, 5.ummol) and ethyl 2-hydroxy-3-(4- hydroxyphenyl) propanoate Ge (1.36 g, 6.49 mmol) by a procedure similar to that described in example 6 (method B). o "YAN NMR (SOSIZ, 200 MHz): 5 1.29 (t, 9U-6.96 Hz, ZN), 2.85-3.12 (complex, 2H), 3.92 (ushs, 2H), 4, 10-4.27 (complex, 4H), 4.39 (t, U-6.1Hz, 1H), 6.68-6.89 (complex, 1 OH), 7.13 (d, uU- 8, 39 GHz, 2H), the OH proton is too extended for observation.

Example 9 in

Ethyl-3-14-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-butoxypropanoate)

The title compound (0.25g, 5395) was obtained as a colorless liquid from 2-(phenoxazin-10-yl)ethylmethanesulfonate (0.3g, 0.98mmol) and ethyl 2-butoxy-3-(4-hydroxyphenyl) propanoate (0.26 g, 0.97 mmol), obtained in preparative example b, by a procedure similar to that described in example 6 (method B).

TN nMR (SOS, 200MHz): δ 0.92 (t, U-6.4Hz, ZN), 1.21-1.39 (complex, 5H), 1.45-1.58 (complex, 2H), - s 2.94 (d, 9U-6.32 ХС, 2Н), 3.24-3.31 (complex, 1Н), 3.50-3.57 (complex, 1Н), 3.94 (t, 9 -6.13HuCs, 1H), 4.13-4.23 h" (complex, 6H), 6.61-6.84 (complex, 1OH), 7.16 (d, 9U-8.3Hz, 2H ). " Example 10

Ethyl-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-hexyloxypropanoate lk v. -7 EU that so o sur (Sp. blue OISNaSNa se) shu 20 The compound named in the title (0, 52g, 5395) is obtained as a pale yellow oil from 2-(phenoxazin-10-yl)ethylmethanesulfonate (0.6bg, 1.97mmol) and ethyl 3-(4-hydroxyphenyl)-2-hexylpropanoate "I (0, 70 g, 2.4 mmol), obtained in preparative example 8, by a procedure similar to that described in example 6 (method B). , 1.20-1.27 (complex, 7H), 1.48-1.57 (complex, 4H), 2.94 (d, 9U-60HZ, 2H), 3.21-3.30 (complex, 1H), 3.52-3.56 (complex, IN), 3.90-3.99 (complex, ZN), about 4.13-4.22 (complex, 4H), 6.60-6.83 (complex, 1OH), 7.15 (d, U-8.62Hz, 2H).

Example 11 ko 3-I4-(2-(Phenothiazine-10-yluethoxy|phenyl|-2-ethoxypropanoic acid)

Snow and the rest

To a solution of methyl-3-14-(2-(phenothiazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoate) obtained in example 4 (7.5 g, 16.7 mol) in methanol (5 mol) add aqueous 1095 sodium hydroxide solution (20ml). The reaction mixture is stirred at approx. 252C for 10 minutes. The solvent is removed under reduced pressure and the residue is acidified with 2M hydrochloric acid and extracted with ethyl acetate (2x100ml). The combined ethyl acetate extract is washed with water (50Oml), oleoresin (50ml) , dry (Ma»zO)), filter and evaporate the solvent under reduced pressure.

The residue is chromatographed on silica gel using a mixture of dichloromethane and methanol (9:1) as an eluent to obtain the title compound (6b, 0g, 83905) as a white solid. T.pl. 79-8226.

IN NMR (SOSIZ, 200MHz): 5 1.18 (t, U-6.8Hz, ZN), 2.88-3.11 (complex, 2H), 3.39-3.64 (complex, 2H), 4.06 (dd, 9U-9.2 and 4.3HZ, 1H), 4.30 (s, 4H), 5.30-5.98 (ushs, 1H, capable of exchange with 020), 6.80 -7.02 (complex, 6H), 7.12-7.21 (complex, 6H).

Example 12

Sodium salt 3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl)| 2-ethoxypropanoic acid

WITH

: and Oma se SKIT. osNnasni hall

A mixture of 3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoic acid (0.3g, 0.689ummol) and sodium methoxide (0.041g, 0.758mmol) in methanol (5ml) is stirred for approx. at 2523 for 2 hours. The solvent is removed under reduced pressure and the residue is treated with dry diethyl ether (3x10ml). The precipitated solid is filtered off, washed with dry diethyl ether (2xbml) and dried under reduced pressure over

RoOrB, and obtain the title compound (0.25 g, 8990) as a white solid. T.pl. 188-19126.

IN nMR (dDdMOO-ab, 200MHz): δ 1.04 (t, 9U-6.9Hz, ZN), 2.71-2.89 (complex, 1H), 2.90-3.06 (complex, 1H ), 3.16-3.30 (complex, 1H), 3.36-3.54 (complex, 1H), 3.88-3.91 (complex, 1H), 4.21 (c, 4H), 6.72 (d, U-8.3 GHz, CM 2H), 6.89-6.99 (complex, 4H), 7.05-7.21 (complex, 6H). at

Example 13 3-(2-(Phenothiazin-10-yl)umethylbenzofuran-5-yl|-2-ethoxypropanoic acid

So " aka - at 7

The title compound (0.8g, 8395) was obtained as a white solid from methyl 3-(2-(phenothiazin-10-yl)umethylbenzofuran-5-yl|-2-ethoxypropanoate (1.0g, 2, 0 mmol), obtained in Example 5, by a procedure similar to that described in Example 11. M.p. 120-121. The COOH proton is too extended to be observed. "

IN nMR (SOCIz, 200MHz): 85 1.15 (t, U-6.95Hz, ZN), 3.00-3.26 (complex, 2H), 3.40-3.68 (complex, 2H), 4.08 (t, 9-4, A7 HC, 1H), 5.11 (s, 2H), 6.46 (s, 1H), 6.77-7.40 (complex, 11H). Example 14 sodium salt of 3-(2-(phenothiazin-10-yl)umethylbenzofuran-5-yl|-2-ethoxypropanoic acid) The title compound (0.12g, 6790) was obtained as a white solid from 20 3-(2-(phenothiazine-10-ylmethylbenzofuran-5-yl1-2-ethoxypropanoic acid) (0.16g, 0.38mmol) , obtained in Example 13, by a procedure similar to that described in Example 12. Melting point 258-26196. "H NMR (SOCI3, 200 MHz): δ 2.89-3.02 (complex, 1H), 3.06 -3.18 (complex, 1H), 3.22-3.31 (complex, 1H),

C.50-3.61 (complex, 1H), 5.25 (c, 2H), 6.64 (c, 1H), 6.90-7.39 (complex, 11H). 5 Example 15 3-I4-(2-"Phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoic acid

F bl t SS bo su Osnisn

The title compound (54g, 7795) was obtained as a white solid from methyl 3-14-(2-(phenoxazin-10-yl)-ethoxy|phenyl|-2-ethoxypropanoate (7.5g, 16.8mmol ), obtained in example 6, by a procedure similar to that described in example 11. Tpl. 90-9296, 65 "TN nNMR (SOSIZ, 200MHz): δ 1.19 (t, 9U-7.0Hz, ZN), 2.90-3.18 (complex, 2H), 3.41-3.62 (complex, 2H), 3.90-4.10 (complex, ZN), 4.18 (t, 9-6.2Hz , 2H), 6.58-6.89 (complex, 1 OH), 7.16 (d, 9-8.4Hz, 2H), proton

The UN is too vast to observe.

Example 16

Sodium salt of 3-I4-(2-(phenoxazin-10-yl)letoxy|phenyl|-2-ethoxypropanoic acid 0. mainly osNnane 76) The title compound (0.27g, 85950) was obtained as a white solid from 3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoic acid (0.3 g, 0.72 mmol), obtained in example 15 by a procedure similar to that described in example 12. M.p. . 194-20296. "H nMR (SOS, 200MHz): δ 0.92 (t, 9U-6.97Hz, ЗН), 2.65-2.82 (complex, 1Н), 2.96-3.14 (complex, 2H), 3.31-3.41 (complex, 1H), 3.70-3.90 (complex, ZH), 3.94-4.04 (complex, 2H), 6.47-6 .74 (complex, 1OH), 75. 7.05 (d, U-8.93Hz, 2H).

Example 17 3-I4-(2-"Phenoxazin-10-yl)ethoxy|phenyl|-2-hydroxypropanoic acid

ОО и ИСдоН (sn ped, on

The title compound (040g, 7295) was obtained as a brown liquid from ethyl 3-14-(2-(phenoxazin-10-yl)ethoxy|phenyl)|-2-hydroxypropanoate (0.6bg, 1.4mmol), obtained in example 8, c by a procedure similar to that described in example 11.

IN NMR (SOCIz, 200 MHz): 5 2.75 (ushs, 1H, capable of exchange with 020), 2.86-3.23 (complex, 2H), 3.85 (t, o

U-6,O0Hz, 2H), 4.18 (t, 9-5.9Hz, 2H), 4.47 (complex, 1H), 6.58-6.89 (complex, 1OH), 7.17 (d, U-8.63Hz, 2H), the COOH proton is too extended to be observed.

Example 18 - 3-I4-(2-«(Phenoxazin-10-yl)ethoxy|phenyl|-2-butoxypropanoic acid - soy o

Nadke snaven 9 pasta eat-

The title compound (0.13g, 6990) was obtained as a cream-colored solid from ethyl 3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-butoxypropanoate (0.2g, 0, 42 mmol), obtained in example 9, by a procedure similar to that described in example 11. Melting point 84-8820.

IN NMR (SOSIZ, 200MHz): 5 0.88 (t, 9U-7.5HzC, ZN), 1.26-1.47 (complex, 2H), 1.47-1.66 (complex, 2H), 2.87-3.16 (complex, 2H), 3.35-3.58 (complex, 2H), 3.88-4.08 (complex, ZN), 4.15 (t, 9U-64Hz, 2H ), c) c 6.65-6.86 (complex, 1 OH), 7.15 (d, U-8.63Hz, 2H), the COOH proton is too extended for observation. "» Example 19 "Sodium salt of 3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-butoxypropanoic acid)

V. | The title compound (0.07g, 8395) is obtained as a cream-colored hygroscopic solid from 3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl) |-2-butoxypropanoic acid (0.08g, 0.178mmol) obtained in Example 18 by a procedure similar to that described in Example 12.

IN IN YAM (DMSO-av, 200MHz): 5 0.78 (t, 9U-7.28Hz, ZN), 1.19-1.52 (complex, 4H), 2.72-3.02 (complex, 2H), 3.45-3.67 (complex, 2H), 4.01 (ushs, ZN), 4.18 (ushs, 2H), 6.61-6.89 (complex, 8H), 7.10 -7.24 (complex, 4H).

Example 20 59 3-I4-(2-"Phenoxazin-10-yl)ethoxy|phenyl|-2-hexyloxypropanoic acid

F) du. »m СО s 0-Х sna bo i end " (snah eН»

The title compound (0.10g, 2395) was obtained as a syrupy liquid from ethyl 3-I4-(2-(phenoxazin-10-yl)-ethoxy|phenyl|-2-hexyloxypropanoate (0.46bg, 0.9bmmol ), obtained in example 10, by a procedure similar to that described in example 11. c5 IN NMR (SOSIZ, 200 MHz): 5 0.86 (t, U-6.0 HzC, ZN), 1.18-1.30 (complex , 4H), 1.42-1.80 (complex, 4H), 2.88-3.18 (complex, 2H), 3.32-3.60 (complex, 2H), 3.89-4.09 (complex, ZN), 4.16 (t, 9U-6.0HZ, 2H),

6.58-6.89 (complex, 1OH), 7.14 (d, U-8.63Hz, 2H), COOH is too extended to observe.

Example 21

Sh2KO-M(15)1-3-I(4-(2-(Phenoxazin-10-yl)ethoxy|phenyl/|-2-ethoxy-M-(2-hydroxy-1-phenylethyl)propanamide (218) which » and also D neon in DOG 70 21a

Ш25)-M(15)1-3-I4-(2-(Phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxy-M-(2-hydroxy-1-phenyl ethyl)propanamide (2165) se con he (snh ha mai y 21

When cooled with ice to the solution obtained in example 15

3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl)-2-ethoxypropanoic acid (1.2g, 2.9mmol) and triethylamine (0.48g, 5.8mmol) in dry dichloromethane (25ml) are added pivaloyl chloride (0.38 g, 3.1 µmole) and stirring is continued at 09C for another 30 minutes. A mixture of (5)-2-phenylglycinol (0.39g, 2.9mmol) and triethylamine (0.58g, 5.8mmol) in dichloromethane (20ml) was added to the resulting reaction mixture at 0 9C and stirring was continued for 2 hours. at 25 C. Water (5 Oml) is added and the mixture is extracted with dichloromethane (2x5 Oml). with

The organic extracts are washed with water (2x25ml) and pus (25ml), dried (Ma»5O)) and evaporated. The residue is chromatographed on silica gel using as an eluent a mixture of ethyl acetate and petroleum ether with a gradient of ethyl acetate from 40 to 6095 and the diastereomer previously designated as (2K,

M(15)1-3-I4-(2-(phenoxazin-10-yl)ethoxy|-phenyl/|-2-ethoxy-IM-(2-hydroxy-1-phenylethyl)propanamide (0.55 g, 3590) (21a), and then che (25-M(15)1-3-I4-(2-(phenoxazin-10-yl)ethoxy|-phenyl|-2-ethoxy-M-(2-hydroxy-1-phenylethyl ) propanamide (0.5g, 3290) (216). - 21a: mp 126-12890; b

IoTro? - 24.6 (c- 1.096, SNO"); co

IN nMR (SOSIz, 200MHz): δ 1.16 (t, 9U-7.20Hz, ZN), 2.50 (ushs, 1H, capable of exchange with 020), 2.92-3.20 (complex, 2H ), 3.52 (k, 9U-7.05Hz, 2H), 3.72 (ushs, 2H), 3.99 (complex, ZN), 4.21 (t, 9U-6.64Hz, 2H), - 4.98-5.01 (complex, 1H), 6.64-6.70 (complex, 5BN), 6.73-6.89 (complex, 4H), 7.03 (d, 9U-7, 15HzC, 1H), 7.18-7.29 (complex, 4H), 7.32-7.39 (complex, ZN), SOMN is too extended for observation. 216B: t.pl. 139-1412C; « 20 or? - -13.3 (c-1,096, SNSIs); -vs IN nNMR (SOSIz, 200 MHz): 5 1.18 (t, U-6.96 Hz, ZN), 2.05 (ushs, 1H, capable of exchange with 020), 2.80-3.14 . (complex, 2H), 3.54 (k, U-7.0Hz, 2H), 3.85 (ushs, 2H), 3.97 (complex, ZN), 4.14 (t, 9-6.23Hz , 2H), 4.92-5.01 and (complex, 1H), 6.62-6.85 (complex, 9H), 7.02-7.20 (complex, 5H), 7.26-7, 30 (complex, ZN), SOMN is too extended for observation.

Example 22 - and (K)-3-I4-(2-(Phenoxazin-10-yl)letoxy|phenyl|-2-ethoxypropanoic acid a so sy; Ff ia - Co 9 H Osan that Solution of the diastereomer obtained in example 21a

Sh2KO-M(15)1-3-I(4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxy-M-(2-hydroxy-1-phenylethyl)propanamide) (0.45 g,

0.4 mmol) in a mixture of 1 M sulfuric acid (17 ml) and a mixture of dioxane and water (1:1.39 ml) is heated in an oil bath at 1009 for 60 hours. Adjust the pH of the mixture to 3.0 by adding an aqueous solution of sodium bicarbonate. The mixture is extracted with ethyl acetate (2x25ml) and the organic extract is washed with water (50ml), pus (25ml), dried (NaCl3O)) and evaporated. The residue was chromatographed on silica gel using a gradient of ethyl acetate in petroleum ether from 50 to 7595 to give the title compound (0.2g, 5790) as a white solid. T.pl. 777-789, 680 1A1r25 and 4121 (se1,096, SNO").

TN NMR (SOSI", 200 MHz): 5 1.16 (t, U-7.0 Hz, ZN), 1.43-1.85 (ushs, 1H, capable of exchange with O020), 2.86-3, 14 (complex, 2H), 3.40-3.67 (complex, 2H), 3.90-4.08 (complex, ZN), 4.15 (t, 9U-665ГЦц, 2Н), 6.59- 6.83 (complex, 1OH), 7.13 (d, U-8.4Hz, 2H). в5 Example 23 (5)-3-I4-(2-(Phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoic acid len on Y Mono

The title compound (0.19g, 5490) was obtained as a white solid from the diastereomer

Sh25-M(15)1-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxy-M-(2-hydroxy-1-phenylethyl)propanamide (0.45g, 0O, in 4 mmol), obtained in example 216, by a procedure similar to that described in example 22. Melting point 89-9096,

IoSho? - -12.6 (c-1.096, SNO).

IN NMR (SOSIz, 200MHz): 8 1.16 (t, 9U-7.02HzC, ZN), 1.42-1.91 (ushs, 1H, capable of exchange with Х2О), 2.94-3.15 (complex, 2H), 3.40-3.65 (complex, 2H), 3.86-4.06 (complex, ЗН), 4.15 (t, 9У-665ГЦц, 2Н), 6.63-6 .83 (complex, 1 OH), 7.13 (d, U-8.54Hz, 2H).

The compounds of this invention reduce the randomized content of blood sugar, triglycerides, total cholesterol,

GOS, MO. and increase NOI. This is demonstrated by ip miggo as well as ip mimo experiments on animals.

A) ip migo a) Determination of PRRACo-activity

The binding site of the NRRAK ligand is fused with the DNA binding site of the yeast transcription factor

SAIG4 in a eukaryotic expression vector. Using superfect (Oiadep, Germany) as a transfection reagent, NEK-393 cells are transfected with the specified plasmid and a reporter plasmid containing the luciferase gene controlled by the specific SZA14 promoter. The compound is added in different concentrations 42 hours after transfection and incubated overnight. Luciferase activity as a function of PRRACo binding/activating capacity is measured using the RasKaga I assay kit (RasKaga, USA) in

Tor Soshpi (I map badomuzki, Vgepdap VeiYi, Rebeg Vgozd apa Meimup Noiv, Sepe, 1992, 118: 137-141; Burepesi

Tgapetesiop Keadepi Naparsok, Rergiagu, 1997, Oiadep, Septapu). (o) b) Definition of PRRAK»U-activity

The PRRAK ligand-binding site is fused to the DNA-binding site of the yeast transcription factor

SAGA4 in a eukaryotic expression vector. Using Lipofectamine (Sirso VKI, USA) as a transfection reagent, NEK-393 cells are transfected with the indicated plasmid and a reporter plasmid containing the luciferase gene controlled by a specific CA 4 promoter. The compound is added at a concentration of 1 µM after 48 hours (87 after transfection and Incubate overnight.Luciferase activity as a function of binding/activating capacity of PRRAKU is measured using a Raskaga II kit (Raskaga, USA) at Raskaga Tor

Sotspi (map Zadomuzki, Vgepdap VeiYi, Rebeg Vgoad apa Meimup Noiv, Sepe, 1992, 118: 137-141; Scide yu She EikKaguoiis TgtapeTesiope myy Saiopis I Irid Keadepiv, I Pe Tesppoiodiev, OIIVSO VEK, OA). cha ch what Y | s c c) Determination of inhibitory activity in relation to NMO CoA reductase.

Liver microsome-bound reductase is obtained from rats fed with the addition of 290 µg of cholestyramine under a 12-hour light-dark cycle. Spectrophotometric analyzes are carried out in a mixture containing 100 mM KNoRO, 4 mM OTT, 02 mM MarPH, 03 mM NMO CoA and 125 μg of microsomal liver enzyme. The total volume of the reaction mixture is iml. The reaction is initiated by -I by adding NMO CoA. The reaction mixture is incubated at 37 °C for 30 minutes and the decrease in absorbance at 34 Ohm is recorded. A reaction mixture without a substrate is used as a "pacifier" (Soyazivip, 9... apa Vgom/p, and M.5., Rgodgevzv ip ipaegviapaipud (She I ОЙ. geseriog apa NMO SoA gedysiaze, yo tetrbgape rgoieipz ypai gedshaye so She riazta spoieviego 1, 9. Iiriy Kevz., 1984, 25: 1450-1461). The tested compounds inhibit the NMO enzyme

CoA reductase. - C) Ip mimo

And a) Efficiency on genetic models

Animal models with non-insulin-dependent diabetes and hyperlipidemia associated with obesity and possible 5B insulin resistance have been developed using colony mutation of experimental animals and different sensitivities to feeding regimes. Genetic models, such as ar/ar and or/ob mice (Oiareiv (1982), 31(1): 1-6) and 7Keg Ta/a rats, have been developed by various laboratories to understand the pathophysiology of the disease and to study the effectiveness (F) of new antidiabetic drugs compounds (YuOiareiv (1983), 32: 830-838; Appy. Ker. ZapKuo Kez. I ar. (1994), 46: 1-57). ka Homozygous animal mice C57 VI /Kv.)-dr/4dr, bred by Daskwop I aroghaiog, USA, suffer from obesity, are hyperglycemic, hyperinsulinemic and insulin resistant (U. (zip. Ipmevi. (1990), 85: 962-967), while heterozygous animals are non-obese and normoglycemic.In the 4B/d5 model, mice progressively develop insulinopenia with age, a feature commonly seen in late stages of type 2 diabetes

P in a person, when the blood sugar content is insufficiently regulated. The state of the pancreas and its development vary according to the models. Because this model is similar to a type I diabetes model, the compounds of this invention are being investigated for blood sugar and triglyceride lowering activity. 65 In this experiment, male C57VI /Kv.-ar/ar mice aged 8-14 weeks with a body weight in the range of 35-60 g are used, which are bred in the animal room of Dr. Reddy's research organization (OKE). Mice were fed standard chow (Maiyopa! Ipviyshe oi Mygyop (MIM), Hyderabad, India) and acidified water ai Irisht.

Animals with a blood sugar content of more than 35 Ω/dL are used for experiments. The number of animals in each group is 4.

The tested compounds are suspended in a 0.2595 solution of carboxymethylcellulose and administered to the experimental group at a dose of 0.1mg to ZOmg/kg orally through a stomach tube for 6 days. The control group receives the carrier (dose 1Oml/kg). On the b day, blood samples are taken for the assessment of biological activity one hour after the administration of the tested compounds or carrier.

The random content of sugar and triglycerides in the blood is measured by taking blood (10 Ωcl) from the 7/0 orbital cavity using a heparinized capillary into tubes containing EDTC, then they are subjected to centrifugation and plasma is obtained. The content of glucose and triglycerides in the plasma is measured spectrometrically by the glucose oxidase method and the method with glycerol-3-PO,-oxidase/peroxidase, respectively (Og. Keadu I ab.

Oiadpowiis Oimiziop Kiez, Hyderabad, India).

The reducing activity of the tested compounds in relation to blood sugar and triglycerides is calculated according to the formula.

In the experiment described above, no harmful effects of the specified compounds of the invention were observed. (mg/kg) IV blood (95) triglycerides (95) that Example) at 6615

Or/or6 mice were obtained at 5 weeks of age from Votoidag, Denmark, and used at 8 weeks of age. Fatty 2isKeg TtaLa rats are obtained from Chasstedeau, France at 10 weeks of age and used at 13 weeks of age.

Animals are kept under a 12-hour light-dark cycle at 25,412C. The animals were given standard SM feed (MIM, Hyderabad, India) and ai Iriisht water (Riimaga, T., MozpiokKa, 5., MozpiokKa, T., Ozpiuata, I!., apa Go)

Nogikozpi, N., SNagasiegigayop oi pem/ oga! apiidiareis adepi C5-045. Bitsaev ip KK apa or/or tise apa 7iskKeg Tatsu gayiv, Oiareyez, 1988, 37: 1549-1558).

The tested compounds are administered at a dose of 0.1-ZOmg/kg/day for 9 days. Control animals receive a carrier (0.2596% solution of carboxymethylcellulose, dose 10 ml/kg) orally through a gastric tube. -

Blood samples are taken in a full state 1 hour after administration of the medicinal product on day 0 and day 9 "-- of treatment. Blood is taken from the retroorbital cavity through a heparinized capillary into tubes containing

EDTK. After centrifugation, the plasma sample is divided to assess the content of triglycerides, glucose, free fatty acids, total cholesterol and insulin. Measurements of the content of triglycerides, glucose and total cholesterol in the plasma are carried out using commercial kits (Og. Kedauz Iarogaiogu, Oiadpoviis Oimiviop,

India). The content of free fatty acids in plasma is measured using a commercial kit from Voepgipdeg -

Mappweit, Germany. The content of insulin in the plasma is measured using a KIA kit (VAKS, India). The reduction of various tested parameters is calculated according to the formula.

Or/or mice were tested for oral glucose tolerance 9 days after treatment. "

Mice are not fed for 5 hours. and inject them orally with Zmg/kg of glucose. Blood samples for assessment of glucose content in plasma are taken after 0, 15, 30, 60 and 120 minutes. c c Experimental results obtained in ar/db, oB/or mice and 7isKeg Ta/La rats suggest that the new compounds of this invention also have therapeutic utility as a prophylactic or regularly used therapeutic agent in the case of diabetes, obesity, cardiovascular disorders, such as hypertension, hyperlipidemia and other diseases; because it is known from the literature that such diseases are interdependent.

At doses above TOmg/kg, the content of glucose and triglycerides in the blood also decreases. As a rule, the degree of reduction depends on the dose and at a certain dose reaches a constant level.

Ge) 5) Cholesterol-lowering activity in a rat model of hypercholesterolemia

Male Z5rgadce Yuam/ieu rats (line MIM) are bred in the animal facility of the OKR. The animals are kept on a 12-hour light-dark cycle at 25-41C. Rats with a body weight of 180-200 kg are used for the experiment. Animals are made hypercholesterolemic by feeding 295 cholesterol and 195 . of sodium cholate mixed with standard laboratory feed (Maiyyopai! Ipeiishe oi Miiyiop (MIM), Hyderabad, and India) for 6 days. During the entire period of the experiment, the animals are kept on this same diet (Rey, 0.,

Voppeiyiz, M.T., Keu, S, apa Iptapiye, K., EPesiv oi sirgoiirgabe op Imeg Iiriaz apa Iirorgoieip zupipeviv ip pogto- apa puregiridetis gayiv. Aipegozsiegov, 1988, 74:215-225). 25 The tested compounds are administered orally at a dose of 0.1-ZOmg/kg/day for 3 days. Control group

HF) are treated with one carrier (0.2596 carboxymethyl cellulose solution; dose 10 ml/kg). Blood samples are taken in a full state after 1 hour. after administration of the medicinal product on day 0 and 3 of treatment with the compound. Blood is taken from the retroorbital cavity through a heparinized capillary into tubes containing

EDTK. After centrifugation, the plasma sample is separated to assess the content of total cholesterol, NOI and 60 triglycerides. Measurements of plasma triglycerides, total cholesterol and NOI. carried out using commercial kits (Og. Kedau's I arogaiogu, Oiadpowiis Oimiviop, India). GO - and MI OI -cholesterol are calculated from the data obtained for total cholesterol, NOI and triglycerides. The reduction of various tested parameters is calculated according to the formula. c) Lowering activity on plasma triglycerides and total cholesterol in 62 Aripo mice and guinea pigs

Male Zm/izz airbipo (ZAM) mice and guinea pigs were obtained from MIM and maintained in the OKR animal facility. All these animals are kept under a 12-hour light-dark cycle at 25-126.

Animals were given standard feed (MIM, Hyderabad, India) and water ai Irisht. ZAM with a body weight of 20-25g and guinea pigs with a body weight of 500-700g are used (Oiimeg, R., RiapsKe, M.O., Maghip, O., Siameu, M., Zatsygiev

U., apa Rgysnai, U9.S., EPesiv oi Tepoiirgaye, deptiirgogi apa pisoiipis asii op riazta Irorgoivip IemeiYiv ip pogtai! apa Ppuregiiridetis tise, A(Pegozsiegovov, 1988, 70: 107-114.

Tested compounds are administered orally to Zm/izz airippo mice at a dose of 0.3-ZOmg/kg/day for 6 days.

Control mice are treated with a carrier (0.2595 carboxymethylcellulose solution; dose 1 Oml/kg). The tested compounds were administered orally to 7/0 guinea pigs at a dose of 0.3-ZOmg/kg/day for 6 days. Control animals are treated with a carrier (0.2596 solution of carboxymethyl cellulose; dose 5 ml/kg).

Blood samples are taken in a full state after an hour. after administration of the medicinal product on day 0 and 6 of treatment.

Blood is taken from the retroorbital cavity through a heparinized capillary into tubes containing EDTC. After centrifugation, the plasma sample is divided to assess the content of triglycerides and total cholesterol (UMiviapa, 75 O., Meijod5e oi Epgutaiis apaiuziz, Wegdegteueg, N.O., Ed., 1963, 211-214; Tgipteg, R., App. Siip. Viospet ., 1969, 6: 24-27). Measurements of plasma triglycerides, total cholesterol and NOI are carried out using commercial kits (Og. Kedau's I arogaigu, Oiadpowiis Oimiziop, India).

Formulas for calculations 1. The percentage of reduction in the content of sugar, triglycerides and total cholesterol in the blood is calculated according to the formula in tya TATO "Percentage reduction of si - 1 tes o

OS is the value in the control group on day 0

OT - the value in the treated group on day 0

TS - the value in the control group on the day of the tests p

TT - the value in the treated group on the day of the tests 5) 2. The content of I O/-- and MI OI -cholesterol is calculated according to the formulas

TSO cholesterinmt/ dp - Total cholesterin - NO. Cholesterol "triglycerides.

NECK

MI 0 -cholesterol, mg/dL "Total cholesterol-NOI -cholesterol-i! 0-cholesterol "-

Claims (25)

The formula of the invention F co 1. Compound of formula (I) - J.; t z da -I Y and OB (se) where B", 2, BZ and E7 are hydrogen, hydroxy, (C 4-C3)-alkyl; ring A is a phenylene ring; X sho 90 is a heteroatom selected among oxygen or sulfur atoms; Ag represents phenylene or benzofuranyl; o represents hydrogen, alkyl or forms a bond together with K 6. Shb represents hydrogen, alkyl or forms a bond "m together with 25; B" is hydrogen, alkyl or aryl; K 8 is hydrogen, alkyl or aryl; Y is oxygen or MH; n is an integer in the range 1-4 and t is 0 or 1, its stereoisomers, pharmaceutically acceptable salts or its pharmaceutically acceptable solvates. 2. The compound according to claim 1, where, when t is 0, Ag is a benzofuranyl group. F! 3. The compound according to claim 1, where, when t is 1, Ag is phenylene. 4. The compound according to claim 1, selected from the group which includes: o ethyl-(E/2)-3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl|-2-ethoxypropenoate; ethyl-( E)-3-I4-(2-(phenothiazin-10-yl)letoxy|phenyl|-2-ethoxypropenoate; 60 ethyl-(2)-3-I4-(2-(phenothiazin-10-yl ethoxy|phenyl|- 2-ethoxypropenoate; ethyl-(E/2)-3-(2-(phenothiazine-10-yl)umethylbenzofuran-5-yl|-2-ethoxypropenoate; ethyl-(E)-3-(2-(phenothiazine-10 -yl)umethylbenzofuran-5-yl|-2-ethoxypropenoate; ethyl-(2)-3-(2-(phenothiazin-10-yl)umethylbenzofuran-5-yl|-2-ethoxypropenoate; ethyl-(E/2) -3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropenoate; bo ethyl-(E)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|- 2-ethoxypropenoate; ethyl-(2)-3-14-(2-«(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropenoate; ()-methyl-3-I4-(2-(phenothiazine-10-yl ethoxy|phenyl|-2-ethoxypropanoate; (t)-methyl-3-I4-(2-(phenothiazine-10-yl)ethoxy|phenyl| -2-ethoxypropanoate; (-)-methyl-3-I4-(2-(phenothiazine-10-yl)ethoxy|phenyl|-2-ethoxypropanoate; (-)-methyl-3-I(2-(phenothiazine-10 -ylmethylbenzofuran-5-yl|-2-ethoxypropanoate; (1)-methyl-3-(2-(phenothiazin-10-yl)methylbenzofuran-5-yl|-2-ethoxypropanoate; (-)-methyl-3-( 2-(phenothiazin-10-yl)umethylbenzofuran-5-yl|-2-ethoxypropanoate; ()-methyl-3-14-(2-«(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoate; ( t)-methyl-3-14-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoate; 710 (-)-methyl-3-14-(2-(phenoxazin-10-yl)ethoxy |phenyl|-2-ethoxypropanoate; (-)-ethyl-3-I4-(2-«"phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoate; (t)-ethyl-3-I4-(2 -(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoate; (-)-ethyl-3-14-(2-(phenoxazin-10-yl)ethoxy|phenyl)|-2-ethoxypropanoate; (t) -ethyl-3-14-(2-(phenoxazin-10-yl)ethoxy|phenyl/|-2-hydroxypropanoate; (t)-ethyl-3-14-(2-(phenoxazin-10-yl)ethoxy|phenyl) |-2-hydroxypropanoate; (-)-eth yl-3-14-(2-(phenoxazin-10-yl)ethoxy|phenyl)-2-hydroxypropanoate; (-)-ethyl-3-I4-(2-«(phenoxazin-10-yl)letoxy|phenyl|-2-butoxypropanoate; ()-ethyl-3-I4-(2-(phenoxazin-10-yl)ethoxy |phenyl|-2-butoxypropanoate; (-)-ethyl-3-I4-(2-«(phenoxazin-10-yl)ethoxy|phenyl|-2-butoxypropanoate; (t)-ethyl-3-I4-(2 -(phenoxazin-10-yl)ethoxy|phenyl)|-2-hexyloxypropanoate; (t)-ethyl-3-14-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-hexyloxypropanoate; (-) -ethyl-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl)|-2-hexyloxypropanoate; (-)-3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl)| -2-ethoxypropanoic acid and its salts; (-)-3-I4-(2-(phenothiazine-10-yl ethoxy|phenyl|-2-ethoxypropanoic acid and its salts; c (-)-3-(4-(2 -(phenothiazin-10-yl)ethoxy|phenyl)|-2-ethoxypropanoic acid and its salts; Ge) ()-3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl|-2-ethoxy- 2-methylpropanoic acid and its salts; (-)-3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl|-2-ethoxy-2-methylpropanoic acid and its salts; (-)-3-I4 -(2-(phenothiazin-10-yl)ethoxy|phenyl)-2-ethoxy-2-methylpropanoic acid and its salts; ()-3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl|- 2-phen oxypropanoic acid and its salts; - 3o (-)-3-I4-(2-(phenothiazine-10-ylethoxy|phenyl|-2-phenoxypropanoic acid and its salts); -- (-)-3-I4-(2-(phenothiazine-10-yl) )ethoxy|phenyl|-2-phenoxypropanoic acid and its salts; (-)-3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl|-2-phenoxy-2-methylpropanoic acid and its salts; F (-)-3-I4-(2-(phenothiazine-10-yluethoxy|phenyl|-2-phenoxy-2-methylpropanoic acid and Its salts; (ze)-3-I4-(2-(phenothiazine- 10-yl)ethoxy|phenyl|-2-phenoxy-2-methylpropanoic acid and its salts; -ethoxypropanoic acid and its salts; (13-3-(2-(phenothiazine-10-ylmethylbenzofuran-5-yl|-2-ethoxypropanoic acid and its salts; (-)-3-(2-(phenothiazine-10-yl )umethylbenzofuran-5-yl|-2-ethoxypropanoic acid and its salts; ()-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoic acid and its salts; "(-) -3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoic acid and its salts; -o c (-)-3- I4-(2-(phenoxazin-10-yl)ethoxy |phenyl|-2-ethoxypropanoic acid and its salts; ()-3-I4-(2-(phenox azin-10-yl)ethoxy|phenyl|-2-ethoxy-2-methylpropanoic acid and its salts; ;" ()-3- I4-(2-(phenoxazin-10-yl)ethoxy|phenyl)|- 2-ethoxy-2-methylpropanoic acid and its salts; (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|- 2-ethoxy-2-methylpropanoic acid and its salts; (-)-3-I4-(2-(phenoxazin-10) -yl)ethoxy|phenyl|-2-phenoxypropanoic acid and its salts; -I (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-phenoxypropanoic acid and its salts; ( -)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-phenoxypropanoic acid and its salts; o ()-3-I4-(2-(phenoxazin-10-yl)letoxy| phenyl|-2-phenoxy-2-methylpropanoic acid and its salts; (Ce) (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-phenoxy-2-methylpropanoic acid and Its salts; 20 (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-phenoxy-2-methylpropanoic acid and Its salts; ()-3-I4-(2- (phenoxazin-10-yl)ethoxy|phenyl|-2-hydroxypropanoic acid and its salts; that (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl/|-2-hydroxypropanoic acid and its salts; (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-hydroxypropanoic acid and its salts; (--3-I4-(2-(phenoxazin-10-yl) )ethoxy|phenyl|-2-butoxypropanoic acid and its salts; (1-)-3-I4- (2- (phenoxazin-10-yl)e toxy|phenyl|-2-butoxypropanoic acid and its salts; o (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-butoxypropanoic acid and its salts; (-)-3-I4-(2-(phenoxazin-10-yl) ethoxy|phenyl|-2-hexyloxypropanoic acid and its salts; o (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-hexyloxypropanoic acid and its salts; (-)-3 -I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-hexyloxypropanoic acid and its salts; because Ш2КО-М(15)1-3-И4-(2-(phenoxazin-10-yl)ethoxy |phenyl|-2-ethoxy-M-(2-hydroxy-1-phenylethyl)propanamide; SHK25)-M(15)1-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl/|- 2-Ethoxy-M-(2-hydroxy-1-phenylethyl)propanamide; Х25)-M(15)1-3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl|-2-ethoxy-M -(2-hydroxy-1-phenylethyl) propanamide and Sh2KO-M(15)1-3-I(4-(2-(phenothiazin-10-yl)ethoxy|phenyl/)|-2-ethoxy-M-( 2-hydroxy-1-phenylethyl) propanamide. 5. The compound according to claim 4, selected from the group that includes: 65 (-)-3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoic acid and its derivatives, Ma, K , Ca, Ma salts, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; acid and its II, Ma, K, Ca, Ma salts, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; (-)-3-I4-(2-(phenothiazine-10-yl) ethoxy|phenyl|-2-ethoxypropanoic acid and its Ma, K, Ca, Ma salts, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; ()-3-I4-(2- (phenothiazin-10-yl)ethoxy|phenyl|-2-ethoxy-2-methylpropanoic acid and its, Ma, K, Ca, Ma salts, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum ; (-)-3-I4-(2-(phenothiazine-10-iluethoxy|phenyl|-2-ethoxy-2-methylpropanoic acid and its derivatives, Ma, K, Ca, Ma 70 salts, salts of lysine, arginine, guanidine) y, diethanolamine, choline, ammonium, substituted ammonium or aluminum; (-)-3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl|-2-ethoxy-2-methylpropanoic acid and its salts, Ma, K, Ca, Ma salts, salts of lysine, arginine, guanidine , diethanolamine, choline, ammonium, substituted ammonium or aluminum; , salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; , Ma, K, Ca, Ma salts, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; (-)-3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl| -2-phenoxypropanoic acid and its salts, Ma, K, Ca, Ma, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; ()-3-I4-(2-(phenothiazine-10 -yl)ethoxy|phenyl|-2-phenoxy-2-methylpropanoic acid and its His, Ma, K, Ca, Ma salts, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum by her; (-)-3-I4-(2-(phenothiazine-10-yluethoxy|phenyl|-2-phenoxy-2-methylpropanoic acid and its, Ma, K, Ca, Ma salts, salts of lysine, arginine, guanidine, diethanolamine) , choline, ammonium, substituted ammonium or aluminum; (-)-3-I4-(2-(phenothiazin-10-yl)ethoxy|phenyl|-2-phenoxy-2-methylpropanoic acid and its derivatives, Ma, K, Ca . her Her, Ma, K, Ca, Mo salts, o salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; (- 3-3-(2-(phenothiazine-10-yl. )umethylbenzofuran- 5-yl|-2-ethoxypropanoic acid and its Ma, K, Ca, Ma salts, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; (-)-3-(2-( phenothiazine-10-yl)umethylbenzofuran-5-yl|-2-ethoxypropanoic acid and its salts, Ma, K, Ca, Mod salts, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; - ()-3-I4-(2-(phenoxazin-10-yl)letoxy|phenyl|-2-ethoxypropanoic acid and its salts, Ma, K, Ca, Ma salts, salts of lysine, arginine, guanidine, diethanolamine, choline , ammonium, substituted ammonium or aluminum; Ge) (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxypropanoic acid and its salts, Ma, K, Ca, Ma, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; Ma, K, Ca, Mo salts, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; ()-3-I4-(2-(phenoxazin-10-yl)letoxy|phenyl| -2-ethoxy-2-methylpropanoic acid and its Ma, K, Ca, Ma salts, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; "(-)-3-I4-( 2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxy-2-methylpropanoic acid and its its, Ma, K, Ca, Ma salts, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium steel or aluminum; o, c (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-ethoxy-2-methylpropanoic acid and its ii, Ma, K, Ca, Ma "» salts, salts lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; ()-3-I4-(2-(phenoxazin-10-yl)letoxy|phenyl|-2-phenoxypropanoic acid and its derivatives, Ma, K, Ca, Ma salts, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2- phenoxypropanoic acid of Tapia, Ma, K, Ca, Ma salts, salts of Sh- lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; Ha (-)-3-I4-(2-(phenoxazine-10- illethoxy|phenyl|-2-phenoxypropanoic acid and its His, Ma, K, Ca, Ma salts, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; and, (-)-3-I4- (2-(phenoxazin-10-yl)letoxy|phenyl|-2-phenoxy-2-methylpropanoic acid and its salts, Ma, K, Ca, Ma - 70 salts, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium , substitute ammonium or aluminum; (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-phenoxy-2-methylpropanoic acid and its salts, Ma, K, Ca, Ma "m salts, salts of lysine, arginine , guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-phenoxy-2-methylpropanoic acid and its its, Ma , K, Ca, Ma salts, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; 29 (-)-3-I4-(2-(phenoxazin-10-yl)letoxy|phenyl|- 2-hydroxypropanoic acid and its salts, Ma, K, Ca, Ma salts, GF) salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; t (-)-3-I4-(2-( phenoxazin-10-yl)ethoxy|phenyl|-2-hydroxypropanoic acid and its salts, Ma, K, Ca, Ma, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; (-)- 3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-hydroxypropanoic acid and its |i, Ma, K, Ca, Ma salts, 60 salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium , replaced of ammonium or aluminum; (--3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-butoxypropanoic acid and its salts, Ma, K, Ca, Mo salts, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; (1)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-butoxypropanoic acid and its II, Ma, K, Ca, Ma salts, lysine salts, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; for (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-butoxypropanoic acid and its Her, Ma, K , Ca, Ma salts, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; (-)-3-I4-(2-(phenoxazin-10-yl)letoxy|phenyl|2-hexyloxypropanoic acid and its salts, Ma, K, Ca, Ma salts, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; (-)-3-I4-(2-(phenoxazin-10-yl)ethoxy |phenyl|-2-hexyloxypropanoic acid and its II, Ma, K, Ca, Ma salts, salts of lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum; (- )-3-I4-(2-(phenoxazin-10-yl)ethoxy|phenyl|-2-hexyloxypropanoic acid and its salts, Ma, K, Ca, Ma, lysine, arginine, guanidine, diethanolamine, choline, ammonium salts , substituted ammonium or aluminum. 6. The compound according to any of claims 1-3, where the pharmaceutically acceptable salt is a salt of II, Ma, K, Ca, Ma, lysine, 7o arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum. 7. The method of obtaining the compound of the formula (ІІІ) Ей , (I) СЗШ шив » VO DOM DAK p she MY noya Ok se de B", 22, VZ, 7, X, Ag, A, n, t and B" have values , specified in claim 1; 2? is hydrogen, alkyl or aryl; or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate, which includes interaction with compounds of the formula (Ча) BZ ; (Sha) cha yai I dai a ru o , Her m KO Den - No: where all the symbols have the meanings indicated above, with the compound of the formula (NAME) « yo se , (Nv) y Y YAN - - shi . MY By KO. where KE" represents a lower alkyl group, and B" and EZ have the values indicated above; and (95) optionally converting the compound of formula (IP) into a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate. 8. The method of obtaining the compound of formula (I) - vai () that ro: sya OO Den V Av o, vo PE, sa, pi 8 Orvkh de B", 2, 23, B, X, A, Ag, p, t , B, 25 and 27 have the values specified in claim 1; C is hydrogen, alkyl or aryl; XU is oxygen; or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, for which includes: a) recovery of the compound of formula (II) obtained according to claim 7 and (1) with more "I - it and i - te t tives; Кк , и и и, if necessary, B) conversion of the compound of formula (I), obtained in stage a), into a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate. 9. The method of obtaining the compound of the formula (I) o Ks Ko) DSHM of beaten xx de "De sho nu Di shirdzhi Pi vtyatyavnykh - to melon g "- Oh F de B", K2, 23, 27, X, A, Ag, p , t, KO, 5 27 have the values specified in claim 1; BZ is hydrogen, alkyl or aryl; XU represents oxygen; or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, including: them a) the interaction of the compound of the formula (She) is ; (Ше) where are you? represents a leaving group, and all other symbols have the meanings indicated above with a compound of formula (Is) Te as Zk. (c) - 2 | Zhe -h SCHE Ar tot she B where all the symbols have the values specified above; (F) and, if necessary, ka B) conversion of the compound of formula (I) obtained in stage a) into a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate. in 10. The method of obtaining the compound of formula (I) b5 Hey 0) IN the question "Where are the first 70 and the first 75 where are the В", 82, 23, Б, Х, А, Аг, п, т, VU, 587 have the values specified in claim 1; C is hydrogen, alkyl, or aryl; XU is oxygen; or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, which includes: the interaction of a compound of formula (Pa) cen (to) and Another 7 The two R Ych where all symbols have the meaning, indicated above, with the compound of formula (II) m (yu z o v ! sh !! ke en pen nn sny Ka "КН Ф 35 ОВ иде- И" represents a group that is separated, and all other symbols have the meanings indicated above , and, if necessary, B) conversion of the compounds of formula (I) obtained at stage a) into a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate. From 70 11. The method of obtaining the compound of formula (I) with ЖЯ. that in! oschl y p t Ve: : that 45 Y n Y chu. shu vo DON z t As races NI "I and Okh de B", 2, 3, B, X, A, Ag, p, t, B, 25, c" and 28 have the values specified in claim 1; M represents is MV 79; where BO represents hydrogen; or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, which HF) includes: ky a) the interaction of a compound of formula (I), where all symbols have the meanings indicated above, and Y represents oxygen, with the appropriate amine, and, if necessary, B) converting the compound of formula (I) obtained above into a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate. 12. Pharmaceutical composition containing the compound of formula (I) b5 Hey 0) WHAT IS HER WITH Z svia sten: MAK - and CODEK Av No 75 according to any of claims 1-3 or 6 and a pharmaceutically acceptable carrier, diluent, excipient or solvent. 13. Pharmaceutical composition according to claim 12 in the form of a tablet, capsule, powder, syrup, solution or suspension. 14. Pharmaceutical composition according to claim 12 for the treatment and/or prevention of type II diabetes, impaired glucose tolerance, dyslipidemia, disorders associated with syndrome X, such as hypertension, obesity, insulin resistance, atherosclerosis, hyperlipidemia, coronary artery disease and others cardiovascular disorders, certain kidney diseases, including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, psoriasis and polycystic ovaries (ROS), to inhibit aldose reductase, to improve cognitive functions in dementia and to treat complications in diabetes and osteoporosis. 15. The intermediate compound of the formula (II) p EI (Yusch IY BE IY o Beze - , etc. ! where Ag represents phenylene or benzofuranyl; K ? represents hydrogen, alkyl or forms a bond together with - 25; 5 represents is hydrogen, alkyl or forms a bond with B 5; BK" is hydrogen, alkyl or aryl; K Z is He! is hydrogen, alkyl or aryl; n is a whole number in the interval 1-4, t is 1, and represents a halogen, p-toluenesulfonate, methanesulfonate or trifluorosulfonate group. 16. The method of obtaining the compound of the formula (ІІ according to claim 15, which includes the interaction of the compound of the formula (І) - вых Зо Бе: approx. '(Іс) с BO ;» "where КЕ", 85, 27, 28 and Аг have values, specified in claim 9, with the compound of the formula (IM) 11 -(СНо)в- 15, (М) - 45 where 7 and 1? can be the same or different and represent halogen, p-toluenesulfonate, methanesulfonate or trifluorosulfonate groups, or I? can also be a hydroxy group or a protected (95) hydroxy group, which can then be converted into a leaving group, and n is an integer in the interval c 1-4. 17. The method of prevention or treatment of hyperlipemia, hypercholesterolemia, hyperglycemia, osteoporosis, - obesity, glucose intolerance, insulin resistance or diseases in which insulin resistance is the basis of the pathophysiological mechanism, which includes the administration of the compound of formula (I) to a patient in need of it according to any with claims 1-6. 18. The method according to claim 17, where the disease is type II diabetes, impaired glucose tolerance, dyslipidemia, disorders associated with syndrome X, such as hypertension, obesity, insulin resistance, atherosclerosis, hyperlipidemia, coronary artery disease and other cardiovascular disorders, certain kidney diseases, HF) including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, psoriasis 7 and polycystic ovary syndrome (POCS), used to inhibit aldose reductase, to improve cognitive function in dementia and to treat complications of diabetes and osteoporosis. 19. The method according to claim 17 for the treatment and/or prevention of disorders associated with syndrome X, which includes administering to a patient in need of it an agonist RRABx (or RRANA, which is a compound of formula (I) according to any of claims 1-6 . 20. A method of reducing the content of glucose, triglycerides, cholesterol, OG, MI OG or free fatty acids in the blood plasma, which includes administering to a patient in need of it a compound of formula (I) according to any of claims 1-6. 65 21. Compound of formula (Is) ra OO (c) that 00001 ee its stereoisomers or its salts, 70 where Ag represents phenylene or benzofuranyl; В В represents hydrogen, alkyl or forms a bond together with ВЗ; C is hydrogen, alkyl or forms a bond with K 5. B" is hydrogen, alkyl or aryl; K 8 is hydrogen, alkyl or aryl. 22. The compound according to claim 21, selected from: methyl 3-I(4-hydroxyphenyl|-2-ethoxypropanoate ethyl 3-|4-hydroxyphenyl|-2-ethoxypropanoate ethyl 3-I4-hydroxyphenyl)|-2-butoxypropanoate ethyl 3- I4- hydroxyphenyl|-2-hexyloxypropanoate. 23. The compound according to claim 21, selected from: (U isopropyl 3-(4-hydroxyphenyl|-2-ethoxypropanoate) -ethoxypropanoate (U propyl C-(4-hydroxyphenyl|-2-ethoxypropanoate (propyl C3-I4-hydroxyphenyl|-2-ethoxypropanoate (U propyl 3-(4-hydroxyphenyl|-2-ethoxypropanoate) with (U methyl 3-(4 -hydroxyphenyl|-2-ethoxypropanoate Ge) (I methyl 3-I(4-hydroxyphenyl|-2-ethoxypropanoate (in methyl 3-(4-hydroxyphenyl|-2-ethoxypropanoate (U ethyl 3-(4-hydroxyphenyl|-2 -ethoxypropanoate (ethyl 3-14-hydroxyphenyl|-2-ethoxypropanoate - (u ethyl 3-14-hydroxyphenyl|-2-ethoxypropanoate "- (U ethyl 3-(4-hydroxyphenyl)|-2-butoxyprolanoate F (8 ethyl 3 -I4-hydroxyphenyl|-2-butoxypropanoate (-) ethyl 3-I4-hydroxyphenyl|-2-butoxypropanoate co (U ethyl 3-I(4-hydroxyphenyl|-2-hexyloxypropanoate 35 . ! in. (ethyl 3-I(4-hydroxyphenyl|-2-hexyloxypropanoate) (in ethyl 3-I4-hydroxyphenyl|-2-hexyloxypropanoate. 24. A composition containing a compound according to claim 21 and a carrier, solvent, excipient or solvate. 25. The compound of the formula (She) « 20 t ; (She) with s ve: shchi . bo ptn: Ку, и 2 гл Another t art y - і- І І VO peM-y se) where В", В2, ВЗ and КЕ? represent hydrogen; cycle A is a phenylene ring; X is a heteroatom, - is selected from oxygen or sulfur atoms; n is an integer in the range of 1-4, and 17 is halogen or a leaving group I, stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof. Official Bulletin of Industrial Property. Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2005, M 10, 15.10.2005. State Department of Intellectual Property of the Ministry of Education and (F. of Sciences of Ukraine. name) 60 b5