Beta-aryl-alpha-oxiclean alkalicarbonate acids, processes for their preparation, intermediate compounds, methods for their preparation, pharmaceutical composition, methods of treating or preventing diseases based on new connections

 

(57) Abstract:

The invention relates to new compounds which can be used in medicine as hypolipidemic or antihyperglycemics funds. Describes-aryl--oxizalidinone alkalicarbonate acid of the formula (I)

where R1, R2, R3and R4may be the same or different and represent hydrogen, hydroxy, (C1-C3)-alkyl; cycle And condensed with the cycle containing X and N represents a 6-membered aromatic cyclic structure containing carbon atoms; X represents a heteroatom selected from among oxygen atoms and sulfur; Ar represents a divalent phenylene, naftilan or benzofuranyl; R5is hydrogen; R6represents hydrogen or R6forms a bond together with R5; R7represents hydrogen or optionally substituted linear or branched (C1-C16)-alkyl; R8represents hydrogen or optionally substituted linear or branched (C1-C16)-alkyl; Y is oxygen or NR10where R10represents hydrogen, phenyl, hydroxy-(C1-C16)-alkyl; n is equal to the whole number of the ATA. It also describes the intermediate compounds, methods for their preparation, methods of making compounds of formula (I), pharmaceutical composition based on compounds of the formula (I), methods of treatment and prevention of diseases based on new compounds. The technical result obtained new compounds with useful biological properties. 22 N. and 9 C.p. f-crystals, 2 tab.

The technical field to which the invention relates

The present invention relates to a new hypolipidemic and antihyperglycemics compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphic forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate and a pharmaceutically acceptable compositions containing such compounds. More specifically, the present invention relates to new aryl--oxiclean alkalicarbonate acids of General formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphic forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate and a pharmaceutically acceptable compositions containing such compounds.

The present invention takeim, their polymorphic forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate, new intermediate compounds and pharmaceutical compositions containing these compounds.

Compounds of General formula (I) useful for the treatment and/or prophylaxis of insulin resistance (type 2 diabetes), reduced glucose tolerance, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, atherosclerosis, hyperlipidemia, coronary arterial disease and other cardiovascular disorders. Compounds of the present invention is also useful for the treatment of certain kidney diseases, including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis. These compounds can also be useful as inhibitors alsoreported, for improving cognitive functions in dementia, treatment of complications in diabetes, psoriasis, polycystic ovaries (PCOS) and osteoporosis.

The level of technology

Hyperlipidemia is the root cause of cardiovascular disease (CVD) and other diseases of peripheral vessels. High risk of CVD associated with an increased content of LDL (lipoprotein low dps is hyperlipidemia, glucose tolerance and insulin resistance, have an increased risk of CVD. Previously performed numerous studies have shown that reduction in plasma triglycerides and total cholesterol, in particular LDL and VLDL, and increased levels of HDL (high density lipoprotein) helps prevent cardiovascular disease.

Diabetes is a disease that seriously affects the quality of life of large numbers of people. Insulin resistance is an impaired ability of insulin to demonstrate biological activity in a wide range of concentrations. When insulin resistance, the body secretes abnormally high amounts of insulin to compensate for this deficiency, and lack, which inevitably increases the concentration of glucose in plasma, which leads to overt diabetes. In developed countries, diabetes is a common problem and is associated with various disorders, including obesity, hypertension, hyperlipidemia (J. Clin. Invest. (1985), 75: 809-817; N. Engl. J. Med. (1987), 317: 350-357; J. Clin. Endocrinol. Metab. (1988), 66: 580-583; J. Clin. Invest. (1975), 68: 957-969) and complications in the kidney (see patent application no WO 95/21608). Increasingly, it appears that insulin resistance and relative hyperinsulinemia play the activity with obesity, hypertension and angina is described as a syndrome with insulin resistance as the Central pathogenic link of syndrome X.

Thus, therapeutic agents that improve the performance characteristics, such as insulin resistance, low levels of triglycerides in plasma total cholesterol, LDL and VLDL, and increased HDL will be of great importance in preventing the spread of cardiovascular disease and improve quality of life.

Receptors activated peroxisomal proliferators (PPAR) are members of the superfamily of nuclear receptors. Gamma()-isoforms of PPAR (PPAR) is involved in regulating the differentiation of adipocytes (Endocrinology (1994), 135: 798-800) and energy homeostasis (Cell (1995), 83: 803-812), whereas alpha()-isoforms of PPAR (PPAR) mediates the oxidation of fatty acids (Trend. Endocrin. Metab. (1993), 4: 291-296), which is manifested in the decrease in the content of free fatty acids in plasma (Current Biol. (1995), 5: 618-621). Found that PPAR agonists useful in the case of treatment of obesity (WO 97/36579). Recently discovered that there is a synergism in the case of molecules that are agonists for PPAR and PPAR, and it is assumed that they are useful for the treatment of syndrome X (WO 97/25042). Such synergism see leczenia atherosclerosis and xanthomas (EP 0753298).

It is reported that some-aryl--hydroxypropionate acid, their derivatives and their analogs useful in the treatment of hyperglycemia, hyperlipidemia and hypercholesterolemia. Some such compounds, are described in the prior art, are listed below.

i) In U.S. patent 5306726; WO 91/19702, describes derivatives of 3-aryl-2-hydroxypropionic acid of the General formula (IIA) and (IIb) as hypolipidemic and hypoglycemic agents.

Examples of such compounds are compounds of the formulas (IIc) and (IId)

ii) In the international patent applications WO 95/03038 and WO 96/04260 describes compounds of the formula (IIE)

where Rais 2-benzoxazolyl or 2-pyridyl and Rb is CF3CH2OCH3or CH3. A typical example is (S)-3-[4-[2-[N-(2-benzoxazolyl)]-N-methylamino]ethoxy]phenyl]-2-(2,2,2-triptoreline)propanoic acid (IIf).

iii) In the international patent applications No. WO 94/136050, WO 94/01420 and WO 95/17394 describes compounds of General formula (IIg)

where a1represents an aromatic heterocycle, AND2represents substituted benzene ring and a3is GRU is; X represents a substituted or unsubstituted N; Y is C=O or C=S, R2is or SIG3where R3can be an alkyl, aralkyl or aryl group. An example of such compounds shown by formula (IIh)

The invention

With the aim of developing new compounds for a more effective, powerful and less toxic treatment and/or prevention of diseases associated with a high content of lipids, in particular for the treatment of hyperglycemia and to reduce the content of free fatty acids for the treatment and/or prevention of diseases, described as syndrome X, which include hyperlipidemia, hyperinsulinemia, obesity, insulin resistance, insulin resistance leading to type 2 diabetes and the complications that diabetes, for treatment of diseases in which insulin resistance is the 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 have led to compounds of General formula (I).

The main purpose of the present invention ablauts rnie form, their stereoisomers, their polymorphic forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate and pharmaceutical compositions containing such compounds or mixtures thereof.

Another objective of the present invention are new-aryl--oxiclean alkalicarbonate acids and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphic forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate and pharmaceutical compositions containing such compounds or mixtures thereof, which may be antagonistic activity against PPAR and/or PPAR, and, in addition to antagonistic activity against PPAR and/or PPAR may be optional inhibit HMG COA reductase.

Another objective of the present invention are new-aryl--oxiclean alkalicarbonate acids and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphic forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate and pharmaceutical compositions containing such compounds or mixtures thereof, with increased activity in the absence of a toxic effect or with reduced toxic effect.

's acids and their derivatives of the above formula (I), their analogs, their tautomeric forms, their stereoisomers, their polymorphic forms, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvate.

And another purpose of the present invention are pharmaceutical compositions containing compounds of General formula (I), their analogs, their derivatives, their tautomeric forms, their stereoisomers, their polymorphic forms, their salts, solvate or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in obtaining such compositions.

Detailed description of the invention

The present invention relates to compounds of General formula (I)

where R1, R2, R3and R4may be the same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkene, aryl, aryloxy, aralkyl, Alcoxy, heterocyclyl, heteroaryl, heteroalkyl, heteroaromatic, heteroaromatic, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamines, aminoalkyl, alkoxycarbonyl, aryloxyalkyl, arylcarbamoyl, alcoxycarbenium, groups formed carboxylic acid or its derivatives, or sulfonic acid or its derivatives; the cycle And condensed with the cycle containing X and N represents a 5-6 membered cyclic structure containing carbon atoms, which may contain optionally one or more heteroatoms, selected from oxygen atoms, sulfur or nitrogen, which optionally can be substituted; the cycle And may be saturated or contain one or more double bonds, or may be aromatic; X represents a heteroatom selected from among oxygen atoms, sulfur, or NR9where R9represents hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxyalkyl, arelaxation and similar group; Ah represents an optionally substituted divalent single or fused aromatic or heterocyclic group; R5represents a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, optionally substituted aracelio group or forms a bond together with the adjacent group, R6; R6represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, optionally substituted aralkyl or R8can represent hydrogen or optionally substituted group selected among alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroalkyl groups; Y represents oxygen or NR10where R10represents hydrogen, alkyl, aryl, hydroxyalkyl or kalkilya group; R8and R10together may form a 5 - or 6-membered cyclic structure containing carbon atoms, which optionally may contain one or more heteroatoms, selected from oxygen atoms, sulfur or nitrogen; n is an integer in the range 1-4 and m is 0 or 1.

Suitable groups represented by R1-R4are hydrogen, halogen atom such as fluorine, chlorine, bromine or iodine; hydroxy, cyano, nitro, formyl; substituted or unsubstituted (C1-C12)-alkyl group, in particular a linear or branched (C1-C6) is an alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl is cyclohexyl and the like groups, and cycloalkyl group may be substituted; cyclo-(C3-C6-alkyloxy, such as cyclopropylamine, cyclobutylamine, cyclopentyloxy, cyclohexyloxy and similar groups, and cycloalkanes may be substituted; aryl group such as phenyl, naphthyl and the like group, and aryl group may be substituted; aralkyl, such as benzyl or phenethyl,6H5CH2CH2CH2naphthylmethyl and similar groups, and kalkilya group may be substituted, and the substituted aralkyl represents such a group as CH3WITH6H4CH2Hal-C6H4CH2CH3OS6H4CH2CH3OS6H4CH2CH2and similar groups; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuranyl etc., and heteroaryl group may be substituted; heterocyclyl group, such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinil and similar groups, and heterocyclyl group may be substituted; urlcategory, such as benzyloxy, penetrate, naphthalenyloxy, phenylpropoxy and such group is stalmetal, oxazolidin and similar groups, and heteroalkyl group may be substituted; aralkylamines, such as C6H5CH2NH, C6H5CH2CH2NH, C6H5CH2NCH3and similar groups which may be substituted; alcoxycarbenium group, such as benzyloxycarbonyl, ventilatsioonil, naphthylenediamine and similar groups which may be substituted; (C1-C6-alkylamino, such as N3N(CH3)2, N3(C2H5), NHC2H5, N3H7, N6H13and similar groups; alkoxyalkyl group, such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and similar groups; aryloxyalkyl group, such as6H5OCH2C6H5OCH2CH2naphthylacetyl and similar groups which may be substituted; alcoxialchil group, such as6H5CH2OCH2WITH6H5CH2OCH2CH2and similar groups which may be substituted; heteroaromatic, heteroaromatic, where heteroaryl component has the values given above, and may be substituted; alloctype, that is AK methoxycarbonyl, etoxycarbonyl etc.; aryloxyalkyl group, such as optionally substituted phenoxycarbonyl, naphthalocyanines etc.; killingray, such as HNC6H5, N3(C6H5), NHC6H4CH3, NHC6H4-Hal and the like groups; amino group; amino-(C1-C6)-alkyl; hydroxy-(C1-C6)-alkyl, (C1-C6)-alkoxy, such as methoxy, ethoxy, propyloxy, bucalossi, isopropoxy etc.; thio-(C1-C6)-alkyl, (C1-C6)-alkylthio; acyl group such as acetyl, propanol, benzoyl and the like group, and acyl group may be substituted; alluminare, such as NHCOCH3, NHCOC2H5THE N3H7, NHCOC6H5and similar groups; alcoxycarboxylates, such as the N2WITH6H5THE N2CH2WITH6H5, NCH3COOCH2C2H5THAT NC2H5COOCH2C6H5, NHCOOCH2C6H4CH3, NHCOOCH2C6H4OCH3and similar groups; aryloxypropanolamine, such as NHCOOC6H5, NCH3COOC6H5THAT NC2H5COOC6H5, NHCOOC6H4CH3THE N6UB> and so on; the remains of the carboxylic acid or its derivatives such as amides, such CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHPh, etc., carboxylic acid and its derivatives may be substituted; alloctype, such as Oocme, OOCEt, OOCPh and similar groups, which optionally can be substituted; the remains of sulfonic acid and its derivatives, such as SO2NH2, SO2NHMe, SO2NMe2, SO2NHCF3and so on, sulfonic acid and its derivatives may be substituted.

When the groups represented by R1-R4are substituted, the substituents can be selected among halogen, hydroxy, or nitro or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkene, aryl, aralkyl, alcoxialchil, heterocyclyl, heteroaryl, heteroalkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl, groups formed carboxylic acid or its derivatives, or sulfonic acid or its derivatives.

The appropriate cycle And are phenyl, naphthyl, cyclohexyl, cyclohexenyl, thienyl, furyl, pyrrolyl, oxazolyl, oxidase cycles, which optionally can be substituted, and the substituents are selected from the same group that in the case of R1-R4and have the meanings specified in the case of R1-R4. Preferred substituents are halogen, hydroxy, amino, formyl, optionally halogenated (C1-C6)-alkyl, (C1-C6)-alkoxy, cyclo-(C3-C6)-alkyl, cyclo-(C3-C6)-alkoxy, aryl, aralkyl, Alcoxy, heterocyclyl, acyl, acyloxy, carboxyl, alkoxycarbonyl, arelaxation, alkylamino, acylamino, alcoxycarbenium, aminocarbonyl and similar groups.

Preferably, the cyclic structure represented by cycle And represented phenyl or peregrinae ring.

Even more preferably, the cyclic structure represented by cycle And were a phenyl ring.

Suitable X is oxygen, sulphur or the group NR9preferably oxygen, and sulfur. Suitable R9represents hydrogen, (C1-C6)-alkyl, (C3-C6-cycloalkyl, aracelio group, such as benzyl, phenethyl; acyl group such as acetyl, propanol, butanol, benzoyl, etc; (C1-C6-alkoxycarbonyl is B>6H4OCO, naphthalocyanines etc.; arelaxation, such as benzyloxycarbonyl, ventilatsioonil etc.; groups represented by R9may be substituted or unsubstituted. When the groups represented by R9are substituted, the substituents can choose among halogen, optionally halogenated lower alkyl, hydroxy, and optionally halogenated (C1-C3)-alkoxygroup.

The group represented AG include divalent phenylene, naftilan, pyridyl, chinoline, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, isoindolyl, isoindolines, indenyl, dihydrobenzofuran, benzopyranyl, dihydrobenzofuranyl, pyrazolyl and similar groups. Substituents in the group represented by AG, are linear or branched optionally halogenated (C1-C6)-alkyl, optionally halogenated (C1-C3)-alkoxy, halogen, acyl, amino, acylamino, thio, residues of carboxylic and sulfonic acids and their derivatives. The substituents have the meanings specified in the case of R1-R4.

More preferably, when AG is a substituted or unsubstituted divalent phenylene, naftilan, benzofuranyl, Jn/P>More preferably, when the AG represents a divalent phenylene or benzofuranyl, which optionally may be substituted by methyl, halogenmethyl, methoxy - or halogenmethyl.

Suitable R5are hydrogen, lower alkyl groups such as methyl, ethyl or propyl; hydroxy, (C1-C3)-alkoxy; halogen atom such as fluorine, chlorine, bromine or iodine; aralkyl, such as benzyl, phenethyl, which optionally may be substituted, or R5together with R6is the link.

Suitable R6can be hydrogen, lower alkyl groups such as methyl, ethyl or propyl; hydroxy, (C1-C3)-alkoxy; halogen atom such as fluorine, chlorine, bromine, iodine; acyl group such as linear or branched (C1-C9)-acyl group such as acetyl, propanol, butanol, pentanol, benzoyl, etc.; aralkyl, such as benzyl and phenethyl, which optionally may be substituted, or R6together with R5forms link.

Preferably, R5and R6represented hydrogen atoms, or R5and R6together represented the link.

Suitable groups represented by R7you can SEL the SUB>)-alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, octyl etc.; (C3-C7)-cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., and cycloalkyl group may be substituted; aryl group such as phenyl, naphthyl, etc., and the aryl group may be substituted; heteroaryl group such as pyridyl, thienyl, furyl, etc., and heteroaryl group may be substituted; heteroaryl groups, such as furanosyl, pyridylmethyl, oxazolyl, oxazolyl, etc. and heteroalkyl group may be substituted; aranceles group, where the alkyl part can contain 1-6 atoms, such as benzyl and phenethyl, etc., where the aryl component may be substituted; heterocyclyl groups, such as aziridinyl, pyrrolidinyl, piperidinyl, etc. and heterocyclyl group may be substituted; (C1-C6)-alkoxy-(C1-C6)-alkyl groups, such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxypropan, etc. and alkoxyalkyl group may be substituted; acyl group such as acetyl, propanol, butanol, benzoyl, etc; (C1-C6)-alkoxycarbonyl, where the alkyl group is and may be substituted; (C1-C6)-alkylaminocarbonyl, where the alkyl group may be substituted; arylenecarborane, such as PhNHCO, naphthaleneboronic, etc., where the aryl group can be substituted. The substituents for R7you can choose from the same group that in the case of R1-R4and they have the same value.

Suitable groups represented by R8you can choose among hydrogen, linear or branched (C1-C16)-alkyl, preferably (C1-C12)-alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, octyl etc.; (C3-C7)-cycloalkyl, such as cyclopropyl, cyclopentyl, cyclohexyl, etc., and cycloalkyl group may be substituted; aryl group such as phenyl, naphthyl, etc., and the aryl group may be substituted; heteroaryl group such as pyridyl, thienyl, furyl, etc., and heteroaryl group may be substituted; heteroaryl groups, such as furanosyl, pyridylmethyl, oxazolyl, oxazolyl, etc. and heteroalkyl group may be substituted; aranceles group, such as benzyl, phenethyl, etc.,, and kalkilya group may be substituted; heterocyclyl group, such as I R8you can choose from the same group that in the case of R1-R4.

Suitable groups represented by R10you can choose among hydrogen, linear or branched (C1-C16)-alkyl, preferably (C1-C12)-alkyl; hydroxy-(C1-C6)-alkyl; aryl groups such as phenyl, naphthyl; aranceles group, such as benzyl and phenethyl.

Suitable cyclic structures formed along R8and R10you can choose among pyrrolidinyl, piperidinyl, morpholinyl, piperazinil and similar groups.

Suitable m is an integer of 0 or 1. Preferably, when m=0, AG represents benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, dihydrobenzofuranyl or dihydrobenzofuranyl group, preferably benzofuranyl group, and when m=1, AG represents a divalent phenylene, naftilan, pyridyl, chinoline, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, isoindolyl, isoindolines, dihydrobenzofuranyl, dihydrobenzofuranyl or pyrazolidine group.

Preferably, when m=0, AG represents a divalent benzofuranyl group, preferably benzofuran-2,5-dialnow group, and predpochtitelno n represents the number 1 or 2.

Preferably, when m=1, n is 2.

Also preferably, when m=0, n is 1.

Pharmaceutically acceptable salts forming part of this invention include salts of the carboxylic acid group, such as metal salts, for example salts of Li, Na and K salts of alkaline earth metals, for example, salts of CA and mg salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline and the like bases, ammonium salts or substituted ammonium salts of aluminum. Salts can be salts of joining acids, of which are suitable sulfates, nitrates, phosphates, perchlorates, borates, hydrogenogenic, acetates, tartratami, maleate, citrates, succinate, palmitate, methansulfonate, benzoate, salicylates, hydroxynaphthoate, bansilalpet, ascorbate, glycerophosphate, Ketoglutarate, etc., Pharmaceutically acceptable solvate may be hydrates or compounds containing other crystallization solvents, such as alcohols.

Particularly useful compounds according to the present invention are

ethyl(E/Z)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxyacrylate;

ethyl-(E)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxyacrylate;

ethyl(E)-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxyacrylate;

ethyl-(Z)-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxyacrylate;

ethyl-(E/Z)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxyacrylate;

ethyl-(E)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxyacrylate;

ethyl-(Z)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxyacrylate;

()-methyl-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropanol;

(+)-methyl-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropanol;

(-)-methyl-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropanol;

()-methyl-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanol;

(+)-methyl-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanol;

(-)-methyl-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanol;

()-methyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol;

(+)-methyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol;

(-)-methyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol;

(a)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol;

(+)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol;

(-)-ethyl-3-[4-[2-(phenoxazin-10-CLASS="ptx2">

(+)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoate;

(-)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoate;

(a)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropan;

(+)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropan;

(-)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropan;

(a)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxyphenol;

(+)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxyphenol;

(-)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxyphenol;

()-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(+)-3-(4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(-)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

()-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoate acid and its salts;

(+)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoate acid and its salts;

(-)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoate acid and its salts;

()-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

()-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoate acid and its salts;

(+)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoate acid and its salts;

(-)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoate acid and its salts;

()-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its salts;

(+)-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its salts;

(-)-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its salts;

()-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(+)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

()-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoate acid and its salts;

(+)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoate acid and its salts;

(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoate acid and its salts;

()-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(+)-3-[4-[2-(phenoxazin-10-yl)etox the OIC acid and its salts;

()-3-[4-(2-(phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoate acid and its salts;

(+)-3-[4-(2-(phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoate acid and its salts;

(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoate acid and its salts;

()-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid and its salts;

(+)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid and its salts;

(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid and its salts;

()-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropan acid and its salts;

(+)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropan acid and its salts;

(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropan acid and its salts;

()-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxyphenol acid and its salts;

(+)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxyphenol acid and its salts;

(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxyphenol acid and its salts;

[(2R)-N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide;

[(2S)-N - (1S)]-3-[4-[2-(phenoxazin-10-yl)toxici-N-(2-hydroxy-1-phenylethyl)propanamide and

[(2R)-N(1S)]-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide.

In accordance with the distinguishing feature of the present invention the compound of General formula (III), where R1, R2, R3, R4, R7, R8, X, A, n, m, Ah shall have the meanings given above, and R5and R6together represent a bond, can be obtained by any of the methods shown below in scheme I. the Compound of General formula (III) is a compound of General formula (I) where all symbols have the meanings given above, and R5and R6together represent a bond and Y represents a hydrogen atom.

Method (1). The interaction of compounds of General formula (IIIa) where all symbols have the meanings given above, with a compound of formula (IIIb), where R11may be a lower alkyl group, and R7and R8have the meanings given above, with the formation of compounds of General formula (III) can be performed in the presence of a base such as an alkali metal hydride, such as NaH, KN, or organolithium compounds, such as CH3Li, BuLi, etc., or alkoxide, such as NaOMe, NaOEt, K+BuO-or mixtures thereof. The reaction can be performed in the presence of a solvent, the reaction temperature may range from -78 to 50 ° C, preferably the reaction temperature is in the range from -10 to -30 IN. The compound of General formula (IIIb) can be obtained in accordance with the method described in the literature (Annalen. Chemie(1996), 53, 699).

Method (2). The interaction of compounds of General formula (IIIa) where all symbols have the meanings given above, with a compound of formula (S), where R6represents a hydrogen atom and R7and R8have the meanings given above, can be performed under normal conditions. The base is not critical. You can use any base commonly used in the case of the aldol condensation; you can use a base, such as alkali metal hydride, such as NaH or KN, metal alkoxide, such as NaOMe, K+BuO-, NaOEt; metal amide, such as LiNH2; LiN(ipr)2. You can use aprotic solvent, such as THF, ether, dioxane. The reaction can be performed in an inert atmosphere, which can be maintained by using inert gases such as N2, Ah or Not, and the reaction is more effective in the absence of water. You can use the reaction temperature in the range from -80 to 35C. -Gidroksilirovanii the reaction product can be degidratiruth under normal conditions digitalmage agent are not critical parameters. You can use a temperature in the range from 20 ° C to boiling point of solvent, preferably the boiling temperature of the solvent in which it is possible to continuously remove the water using the water separator Dean-stark.

Method (3). The interaction of the compounds of formula (I), where L1represents useplease group such as halogen atom, p-toluenesulfonate, methanesulfonate, triftoratsetata and similar group, and all the symbols have the meanings given above, with a compound of formula (IIId) where R7, R8and ar have the meanings given above, with the formation of the compounds of formula (III) can be performed in the presence of a solvent, such as THF, DMF, DMSO, DME, etc., or mixtures thereof. The reaction can be performed in an inert atmosphere, which can be maintained by using inert gases such as N2, Ar or Not. The reaction can be performed in the presence of a base, such as2CO3, PA2CO3or NaH or mixtures thereof. When in use as the basis Na2CO3or K2CO3as a solvent, you can use acetone. The reaction temperature may be in the range 0-120C, preferably in the range of 30-100C. BP is given in accordance with the known method by the reaction of the Wittig-Horner through interactions between hydroxyacetaldehyde protected hydroxyl group, such as benzyloxyacetaldehyde, and a compound of formula (IIIb) with subsequent removal of the protective group.

Method (4). The interaction of compounds of General formula (IIIg) where all the symbols have the meanings given above, with a compound of formula (IIIf) where all the symbols have the meanings given above, and L1represents useplease group such as halogen atom, p-toluenesulfonate, methanesulfonate, triftoratsetata and similar group, and preferably represents a halogen atom, with the formation of compounds of General formula (III) can be performed in the presence of a solvent, such as DMSO, DMF, DME, THF, dioxane, ether, etc. or combinations thereof.

The reaction can be performed in an inert atmosphere, which can be maintained by using inert gases such as N2, Ar or Not. The reaction can be performed in the presence of a base, such as alkali, such as sodium hydroxide, potassium hydroxide, a carbonate of an alkali metal such as sodium carbonate and potassium carbonate; alkali metal hydride such as sodium hydride or potassium hydride; ORGANOMETALLIC base such as n-utility, alkali metal amide such as sodium amide, or a mixture of bases. A positive number the amount of base is from 1 to 3 equivalents. The reaction can be performed at a temperature in the range from 0 to 150C, preferably at a temperature in the range from 15 to 100 ° C. The reaction time may range from 0.25 to 48 hours, preferably from 0.25 to 12 hours.

Method (5). The interaction of compounds of General formula (IIIh) where all the symbols have the meanings given above, with a compound of formula (IIId) can be done using a suitable agent combinations, such as dicyclohexylamine, triarylphosphine/dialkyldithiocarbamate, such as h3/DEAD, etc., the Reaction can be performed in the presence of a solvent, such as THF, DME, CH2Cl2, l3, toluene, acetonitrile, carbon tetrachloride, etc., an Inert atmosphere can be maintained by using inert gases such as N2, Ar or Not. The reaction can be performed in the presence of DMAP, HOBT, they can be used in amounts in the range of from 0.05 to 2 equivalents, preferably from 0.25 to 1 equivalent. The reaction temperature may be in the range from 0 to 100C, preferably in the range from 20 to 80C. The reaction time may be from 0.5 to 24 hours, preferably from 6 to 12 hours.

In accordance with another variant embodiment of the invention the compound of General formula (I), where R

Method (6). The recovery of the compounds of formula (III) obtained as described previously in scheme I, with the formation of compounds of General formula (I), where each of R5and R6represents hydrogen atom and all symbols have the meanings given above, can be performed in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, 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. You can apply a pressure from atmospheric up to about 550 kPa (80 f/d2). To reduce the reaction time, you can use a higher pressure. The catalyst may be preferably 5-10% Pd/C, and the amount of catalyst may range 1-100% (m/m). The reaction can also be carried out using restore with a solution of metal, such as magnesium in alcohol or sodium amalgam in alcohol.

Method (7). The interaction of the compounds of formula (Ia) where all the symbols have the meanings given above, and L3predstavleniya, mentioned previously, with the formation of the compounds of formula (I) can be performed in the presence of a solvent, such as THF, DMF, DMSO, DME, etc., or mixtures thereof. The reaction can be performed in an inert atmosphere, which can be maintained by using inert gases such as N2, Ar or Not. The reaction can be performed in the presence of a base, such as KOH, NaOH, NaOMe, NaOEt, K+BuO-or NaH or mixtures thereof. You can use interphase catalyst, such as a halide or a hydroxide of tetraalkylammonium. The reaction temperature may be in the range from 20 to 120C, preferably the reaction temperature is from 30 to 100 ° C. The reaction time may be from 1 to 12 hours, preferably from 2 to 6 hours. The compound of formula (Ia) can be obtained in accordance with the method described in concurrently pending application 08/982910 (registry attorney No. U 011410-0).

Method (8). The interaction of the compounds of formula (I), described earlier, with a compound of formula (IC) where all the symbols have the meanings given above, with the formation of the compounds of formula (I) can be performed in the presence of a solvent, such as THF, DMF, DMSO, DME, etc., or mixtures thereof. The reaction can be performed in an inert atmosphere, which can podderjivalo as2CO3, PA2CO3or NaH or mixtures thereof. When as a reason TO use2CO3or Na2CO3as a solvent, you can use acetone. The reaction temperature may be in the range from 20 to 120C, preferably the reaction temperature is in the range from 30 to 80C. The reaction time may be from 1 to 24 hours, preferably from 2 to 12 hours. The compound of formula (IC) can be obtained by the reaction of the Wittig-Horner between hydroxyacetaldehyde protected hydroxyl group and the compound of the formula (IIIb), followed by reduction of the double bond and removal of the protective group. On the other hand, the compound of formula (IC) can be obtained in accordance with the method described in WO 94/01420.

Method (9). The interaction of compounds of General formula (IIIh), described earlier, with a compound of General formula (IC) where all the symbols have the meanings given above, can be performed using a suitable agent combinations, such as dicyclohexylamine, triarylphosphine/dialkyldithiocarbamate, such as PPh3/DEAD, etc., the Reaction can be performed in the presence of a solvent, such as THF, DME, CH2Cl2, l3, toluene, acetonitrile, tetrahe. The reaction can be performed in the presence of DMAP, NOWT, and can be used in amounts in the range of 0.05 to 2 equivalents, preferably 0.25 to 1 equivalent. The reaction temperature may be in the range from 0 to 100C, preferably the reaction temperature is in the range from 20 to 80C. The reaction time may be from 0.5 to 24 hours, preferably from 6 to 12 hours.

The method (10). The interaction of the compounds of formula (Id) where all the symbols have the meanings given above, with a compound of formula (Ia) where R7has the values given above, and Hal represents CL, Br or I, with the formation of the compounds of formula (I) can be performed 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 N2, AG or Not. The reaction can be performed in the presence of a base, such as KOH, NaOH, NaOMe, K+BuO-, NaH, etc., Can be used interphase catalyst, such as a halide or a hydroxide of tetraalkylammonium. The reaction temperature may be in the range from 20 to 150C, preferably the reaction temperature is in the range from 30 to 100 ° C. The reaction time may be from 1 to 24 hours, preferably from 2 to 12 hours. Connection for">

Method (11). The interaction of compounds of General formula (IIIa), described earlier, with a compound of formula (IIIc), where6, R7and R8have the meanings given above, can be performed under normal conditions. The base is not critical. You can use any base commonly used for the aldol condensation, such as a metal hydride, such as NaH or KN; a metal alkoxide such as NaOMe, K+BuO-or NaOEt, metal amide, for example LiNH2or LiN(ipr)2. You can use aprotic solvent, such as THF, ether or dioxane. The reaction can be performed in an inert atmosphere, which can be maintained by using inert gases such as N2, Ar or Not, and the reaction is more efficient in the absence of water. You can use the reaction temperature in the range from -80 to 25S. -Hydroxyindole the reaction product can be dehydrosilybin using convenient methods usually method ionic hydrogenation, for example, by treatment with trialkylsilanes in the presence of acid, such as triperoxonane acid. You can use a solvent such as CH2CL2. The reaction well is leaking at 25C. If the reaction is slow, you can IP the all the symbols have the meanings mentioned previously, with a compound of formula (If), where L1represents useplease group such as halogen atom, p-toluensulfonate, methanesulfonate, triftoratsetata group, etc., preferably a halogen atom and all other symbols have the meanings given above, with the formation of compounds of General formula (I) can be performed in the presence of a solvent, such as DMSO, DMF, DME, THF, dioxane, ether, etc. or combinations thereof. The reaction can be performed in an inert atmosphere, which can be maintained by using inert gases such as N2, AG or Not. The reaction can be performed in the presence of a base, such as alkali, for example sodium hydroxide or potassium hydroxide; a carbonate of an alkali metal, for example sodium carbonate or potassium carbonate; an alkali metal hydride, for example sodium hydride or potassium hydride; ORGANOMETALLIC base, for example n-utility, alkali metal amide such as sodium amide, or mixtures thereof. The amount of base may range from 1 to 5 equivalents relative to the amount of the compounds of formula (IIIg), preferably the amount of base is from 1 to 3 equivalents. The reaction can be performed in the presence of a phase transfer catalyst, tcog is about 150C, preferably at a temperature in the range from 15 to 100 ° C. The reaction time may range from 0.25 to 24 hours, preferably from 0.25 to 12 hours.

The compound of General formula (I), where Y is oxygen and8matter mentioned previously, can be converted into a compound of formula (I) where Y represents NR10through interaction with the appropriate amine. Accordingly, the compound of formula (I), where Y is HE, can be turned into halogenoacetyl, preferably YR8=CL, by reaction with appropriate reagents, such as oxacillin, thionyl chloride, etc., followed by treatment with the amine. On the other hand, you can get a mixed anhydride of the compound of formula (I), where YR8is HE, and all other symbols have the meanings given above, by processing halogenoacetyl, such as acetylchloride, acetylmuramic, pivaloyloxy, dichlorobenzophenone, etc., the Reaction can be performed in the presence of a suitable base, such as pyridine, triethylamine, diisopropylethylamine, etc. Can be used solvents such as halogenated hydrocarbons, for example l3or CH2Cl2; hydrocarbons such as benzene, TS. Then thus obtained halogenoacetyl or mixed anhydride can be treated with the amine.

Methods for obtaining compounds of General formula (IIIa) described in the concurrently pending application No. 08/982910 (registry attorney No. U 011410-0).

In another embodiment, an embodiment of the present invention relates to new intermediate compounds of formula (If)

where AG represents an optionally substituted divalent single or condensed aromatic or heterocyclic group; R5represents a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, optionally substituted aracelio group or together with the adjacent group, R6forms a bond; R6represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, optionally substituted aralkyl or together with R5forms a bond; R7represents hydrogen or optionally substituted group selected among alkyl, cycloalkyl, aryl, kalkilya, alkoxyalkyl, alkoxycarbonyl, aryloxyalkyl, alkylaminocarbonyl, arylaminomethylene, acyl, heterocyclyl, heteroaryl or heteroalkyl the data cycloalkyl, aryl, kalkilya, heterocyclyl, heteroaryl or heteroalkyl groups; n is an integer in the range 1-4; m is 0 or 1 and L1represents useplease group such as halogen atom, p-toluensulfonate, methanesulfonate, triftoratsetata group, etc., preferably a halogen atom, and to a method for their production and their use in preparation of aryl substituted--hydroxyalkanoate acids.

The compound of formula (If), where m=0, and all other symbols have the meanings given above, can be obtained by reaction of compounds of formula (IC)

where R5,R6, R7, R8and ar have the meanings given above, with a compound of formula (IV)

where L1and L2may be the same or different and represent useplease group, such as CL, Br, I, methanesulfonate, triftoratsetata, p-toluensulfonate group, etc., or L2can also represent hydroxyl or protected hydroxyl group, which can then be turned into useplease group, and n is an integer in the range 1-4.

The interaction of the compounds of formula (IC) with connection f is DMF, DMSO, DME, etc., or mixtures thereof. The reaction can be performed in an inert atmosphere, which can be maintained by using inert gases such as N2, Ar or Not. The reaction can be performed in the presence of a base, such as2CO3, Na2CO3or NaH or mixtures thereof. When in use as the basis Na2CO3or2CO3as a solvent it is possible to apply the acetone. The reaction temperature may vary from 20 to 120C, preferably to carry out the reaction at a temperature in the range of 30-80C. The reaction time may be in the range from 1 to 24 hours, preferably from 2 to 12 hours.

On the other hand, the intermediate compound of formula (If) can be obtained by reaction of compounds of formula (V)

L1-(CH2)n-(O)m-Ar-CHO (V)

where L1is useplease group, such as CL, Br, I, methanesulfonate, triftoratsetata, p-toluensulfonate group, etc., and all other symbols have the meanings given above, with a compound of formula (IIIb)

where all the symbols have the meanings given above, with the formation of the compounds of formula (IIIf), which is then restored with the formation of the establet communication, and all other characters have the meanings previously indicated.

The interaction of the compounds of formula (V) with the compound of the formula (IIIb) can be performed in the presence of a base such as an alkali metal hydride, such as NaH or KN or organolithium compound, such as CH3Li, BuLi, etc., or alkoxide, such as NaOMe, NaOEt, K+BuO-or mixtures thereof. The reaction can be performed in the presence of a solvent, such as THF, dioxane, DMF, DMSO, DME, etc., or mixtures thereof. As a co-solvent can be applied, NMRA. The reaction temperature may range from -78 to 50 ° C, it is preferable to conduct the reaction at a temperature in the range from -10 to -30 IN. The recovery of the compounds of formula (IIIf) can be performed in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, 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. You can apply a pressure from atmospheric up to about 550 kPa (80 f/d2). To reduce the reaction time, you can use a higher pressure. The catalyst may be preferably 5-10% Pd/C, and the share of the recovery with a solution of metal, such as magnesium in alcohol or sodium amalgam in alcohol.

Pharmaceutically acceptable salts receive by reaction of compounds of formula (I) with 1-4 equivalents of base, such as sodium hydroxide, sodium methoxide, sodium hydride, tert-piperonyl potassium, calcium hydroxide, magnesium hydroxide and the like of the base, in a solvent such as ether, THF, methanol, tert-butanol, dioxane, isopropanol, ethanol, etc., you Can use a mixture of solvents. It is also possible to use organic bases such as lysine, arginine, diethanolamine, choline, guanidine, derivatives thereof, etc., on the other hand, any acceptable salt accession acids get by treatment with acids such as chloromethane acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluensulfonate acid, methanesulfonate acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzolsulfonat acid, tartaric acid, etc., in a solvent such as ethyl acetate, ether, alcohols, acetone, THF, dioxane, etc. you Can also use the but to get any way possible with the use of chemicals in their single enantiomeric form or through interaction in the presence of reagents or catalysts in their single enantiomeric form, or by splitting the mixture of stereoisomers by conventional methods. Some of the preferred methods include decomposition by microorganisms, the splitting of the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and similar acids, when they are acceptable, or formed chiral bases such as brucine, alkaloids Hinn's crust and their derivatives, etc., Commonly used methods are collected in the publication Jackes and others, "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981). For example, the compound of formula (I), where YR8is IT possible to turn in a mixture of 1:1 diastereomeric amides by treatment of chiral amines, aminoacids, aminoalcohols derived from aminoacids; you can use the normal reaction conditions, the conversion of the acid amide; the diastereomers can be divided or by fractional crystallization or by chromatography and the stereoisomers of the compounds of formula (I) can be obtained by hydrolysis of the pure diastereoisomer amide.

Different polymorphic forms of the compounds of General formula (I), forming part of this invention, it is possible to get periodicaly, usually used for recrystallization, or mixtures thereof; crystallization at different temperatures; various methods of cooling during crystallization from very rapid cooling to very slow. Polymorphs can also be obtained by heating or melting compounds with subsequent gradual or fast cooling. The presence of polymorphic forms can be determined using NMR spectroscopy solid sample, IR spectroscopy, differential scanning calorimetry, x-ray diffraction on powders or other such methods.

The present invention also relates to pharmaceutical compositions containing one or more compounds of General formula (I) described above, their tautomeric forms, their stereoisomers, their polymorphic forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate, in combination with commonly used pharmaceutical carriers, diluents, etc., useful for the treatment and/or prevention of insulinrezistentnosti (type 2 diabetes), reduced glucose tolerance, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, atherosclerosis, hyperlipidemia, salesny to treat some diseases of the kidneys, including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, for the treatment of psoriasis and polycystic ovaries (PCOS). These compounds can also be useful as inhibitors alsoreported, for improving cognitive functions in dementia and treatment of complications in diabetes and osteoporosis.

The pharmaceutical composition may be in a commonly used form, such as tablets, capsules, powders, syrups, solutions, suspensions, etc. may contain corrigentov, podslushivala, etc. in suitable solid or liquid carriers or solvents, or in suitable sterile media to form solutions or suspensions for injection. Such compositions typically contain from 1 to 20 wt.%, preferably from 1 to 10 wt.%, active connections, and the rest of the compositions comprise pharmaceutically acceptable carriers, diluents or solvents.

The compound of formula (I) described above, to impose a mammal, including man, or oral, or parenteral way. Preferably the introduction of the oral method, which is more convenient and to avoid the possible pain and irritation from inyecte oral administration due to illness or other abnormalities you must enter the drug parenterally. Any method of administration the dosage is in the range from about 0.01 to about 100 mg per 1 kg of body weight of the subject per day or preferably from about 0.01 to about 30 mg per 1 kg of body weight per day in a single dose or divided doses. However, the optimal dosage for an individual subject, which is treated will be determined by the attending physician, and, as a rule, first imposed lower dose and then increase the dose, and determine the most appropriate dose.

Suitable pharmaceutically acceptable carriers are solid carriers or diluents and a sterile aqueous or organic solutions. The active compound in such pharmaceutical compositions will be present in an effective amount, sufficient to provide the desired dosage in the above interval. So, in the case of oral administration the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions, etc., the Pharmaceutical compositions may optionally contain additional components, such as corrigentov, podslushivala, acceskey environment with the formation of solutions or suspensions for injection. For example, you can use the solutions in sesame or peanut oil, aqueous propylene glycol, etc., and aqueous solutions of water-soluble pharmaceutically acceptable salts of joining compounds or salts formed with bases. Injectable solutions obtained in this way can then be administered intravenously, administered intraperitoneally, subcutaneously or intramuscularly, and for people preferably intramuscular injection.

Information confirming the possibility of carrying out the invention.

The invention is explained in detail using the following examples which are given only as an illustration and therefore should not be construed as limiting the scope of the invention.

Preparative example 1

Ethyl-(E/Z)-3-[4-benzyloxyphenyl]-2-ethoxyacrylate

A solution of triethyl-2-ethoxypropionate obtained by the method Grell and Machleidt, Annalen. Chemie, 1996, 699, 53, (3,53 g, 13,2 mmol), in dry tetrahydrofuran (10 ml) under nitrogen atmosphere with stirring, gradually add cooled to ice suspension of sodium hydride (60% dispersion in oil) (0,62 g, 25,94 mmol) in dry tetrahydrofuran (5 ml). The mixture was stirred at 0C for 30 min before adding 4-borax and stirred at this temperature for 20 hours. The solvent is evaporated, water is added (100 ml) and the mixture extracted with ethyl acetate (275 ml). The combined organic extracts washed with water (50 ml), brine (50 ml), dried (Na2SO4), filtered and evaporated the solvent under reduced pressure. The remainder chromatographic on silica gel using as eluent a mixture of ethyl acetate and petroleum ether (2:8) and get named in the title compound (3,84 g, yield quantitative) in the form of butter.1H NMR of the reaction product involves a mixture of geometric isomers (76:24=Z:E) (R. A. Aitken and G. L. Thom, Synthesis, 1989, 958).

1H NMR (Dl3, 200 MHz): 1,25-1,50 (complex, 6N), 3,85-a 4.03 (complex, 2H), 4,28 (K, J=7,0 Hz, 2H), of 5.05, 5,09 (2s, 2H, benzyloxy-CH2), between 6.08 (s, 0,24 N, E-isomer olefinic proton), 6,85-of 6.90 (complex, 2H), 6,99 (0,76 N, Z-isomer), 7,33 was 7.45 (complex, 5H), of 7.75 (d, J=8,72 Hz, 2H).

Preparative example 2

Methyl-3-[4-benzyloxyphenyl]-2-ethoxypropanol

A mixture of ethyl-(E/Z)-3-[4-benzyloxyphenyl]-2-ethoxyacrylate (3,84 g to 11.79 mmol, obtained in preparative example 1) and magnesium turnings (5,09 g, 0.21 mmol) in dry methanol (40 ml) was stirred at 25C for 1 hour. Add water (80 ml) and adjusted pH to 6.5 and 7.5 using 2 N. hydrochloric acid. Rast is O4) and filtered. The solvent is evaporated under reduced pressure and get named in the title compound (3.7 g, yield quantitative) in the form of butter.

1H NMR (Dl3, 200 MHz): to 1.16 (t, J=6,97 Hz, 3H), 2.95 points (d, J=6,55 Hz, 2H), 3,30-3,38 (complex, 1H), 3,55-3,67 (complex, 1H), 3,69 (s, 3H), 3,99 (t, J=6,64 Hz, 1H), 5,04 (s, 2H), 6.89 in (d, J=8,63 Hz, 2H), 7,15 (d, J=8,62 Hz, 2H), 7,31-7,41 (complex, 5H).

Preparative example 3

Methyl-3-[4-hydroxyphenyl]-2-ethoxypropanol

A suspension of methyl-3-[4-benzyloxyphenyl]-2-ethoxypropionate (3.7 g, 11,78 mmol, preparative example 2) and 10% Pd/C (0,37 g) in ethyl acetate (50 ml) was stirred at 25 ° C and hydrogen pressure, ~414 kPa (60 f/d2) within 24 hours. The catalyst is filtered off and the solvent evaporated under reduced pressure. The remainder chromatographic on silica gel using as eluent a mixture of ethyl acetate and petroleum ether (2:8) and get named in the title compound (2.2 g, 84%) as oil.

1H NMR (CDCl3, 200 MHz): to 1.21 (t, J=6,97 Hz, 3H), 2,99 (d, J=6,37 Hz, 2H), 3,32-3,49 (complex, 1H), 3,57-the 3.65 (complex, 1H), 3,76 (s, 3H), of 4.05 (t, J=6,64 Hz, 1H), 5,19-5,40 (Ushs, 1H, able to exchange with D2O) to 6.80 (d, J=8,44 Hz, 2H), 7,14 (d, J= 8,39 Hz, 2H).

Preparative example 4

Ethyl-3-[4-hidroxizina oil from ethyl(E/Z)-3-[4-benzyloxyphenyl]-2-ethoxyacrylate (3,85 g, 11,80 mmol) obtained in preparative example 1, by hydrogenation, as described in preparative example 3.

1H NMR (CDCl3, 200 MHz): 1,12-1,29 (complex, 6N), with 2.93 (d, J=6,55 Hz, 2H), 3,28 is-3.45 (complex, 1H), 3,51-3,68 (complex, 1H), 3,98 (t, J=6,55 Hz, 1H), 4.16 the (K, J=7,15 Hz, 2H), of 5.40 (s, 1H, able to exchange with D2O) of 6.73 (d, J=8,39 Hz, 2H), was 7.08 (d, J=8.53 Hz, 2H).

Preparative example 5

Ethyl-3-[4-benzyloxyphenyl]-2-butoxypropan

A solution of ethyl-3-[4-benzyloxyphenyl]-2-hydroxypropanoate (5.0 g, of 16.6 mmol) (obtained in a manner similar to the method described in reference WO 95/18125), in dry dimethylformamide (5 ml) at 0C is added to a suspension of sodium hydride (0.1 g, to 41.6 mmol) (60% dispersion in oil) in dry dimethylformamide (3 ml) and continue stirring for 1 hour. To the above reaction mixture at 0C add n-butylbromide (3.4 g, 24,0 mmol) and continue stirring for 10 hours at about 25C. Add water (30 ml) and the mixture extracted with ethyl acetate (250 ml). United an ethyl acetate layers washed with water (50 ml), brine (25 ml), dried (Na2SO4), filtered and evaporated the solvent.

The remainder chromatographic on silica gel using as eluent a mixture of Etiler>1H NMR (Dl3, 200 MHz): 0,85 (t, J=7,38 Hz, 3H), 1.18 to 1,40 (complex, 5H), 1,49-1,58 (complex, 2H), 2,94 (d, J=6,74 Hz, 2H), 3,20-3,33 (complex, 1H), 3.46 in-3,61 (complex, 1H), 3,94 (t, J=6,37 Hz, 1H), 4.16 the (K, J=7,0 Hz, 2H), 5,04 (s, 2H), 6.89 in (d, J=8.5 Hz, 2H), 7,15 (d, J=8,48 Hz, 2H), 7,30-7,44 (complex, 5H).

Preparative example 6

Ethyl-3-[4-hydroxyphenyl]-2-butoxypropan

Named the title compound (value (0.475) g, 75%) was obtained as oil from ethyl-3-[4-benzyloxyphenyl]-2-butoxypropan of 0.85 g of 2.38 mmol) obtained in preparative example 5, through a procedure similar to that described in preparative example 3.

1H NMR (Dl3, 200 MHz): 0,85 (t, J=7,24 Hz, 3H), 1,19-1,38 (complex, 5H), 1,44-1,58 (complex, 2H), 2,94 (d, J=6,55 Hz, 2H), 3,21-3,32 (complex, 1H), 3,49-3,62 (complex, 1H), 3,94 (t, J=6,88 Hz, 1H), 4.16 the (K, J=7,1 Hz, 2H), 4,99 (s, 1H, able to exchange with D2O) of 6.73 (d, J=8.53 Hz, 2H), to 7.09 (d, J=8,44 Hz, 2H).

Preparative example 7

Ethyl-3-[4-benzyloxyphenyl]-2-hexyloxyphenol

Named the title compound (1.2 g, 22%) was obtained as oil from ethyl-3-(4-benzyloxyphenyl)-2-hydroxypropanoate (4,2 g, 14.0 mmol) and 1-Bromhexine (3.4 g, 21,0 mmol) by a procedure similar to that described in preparative example 5.

1H NMR 2-3,64 (complex, 1H), 3,94 (t, J=6,9 Hz, 1H), 4.16 the (K, J=7,06 Hz, 2H), to 5.03 (s, 2H), 6.89 in (d, J=8, 63 Hz, 2H), 7,15 (d, J=8,63 Hz, 2H), 7,31-7,44 (complex, 5H).

Preparative example 8

Ethyl-3-[4-hydroxyphenyl]-2-hexyloxyphenol

Named the title compound (0.7 g, 76%) was obtained as oil from ethyl-3-[4-benzyloxyphenyl]-2-hexyloxyphenol (1.2 g, 3.1 mmol) obtained in preparative example 7, through a procedure similar to that described in preparative example 3.

1H NMR (CDCl3, 200 MHz): 0,85 (t, J=5,81 Hz, 3H), 1,19-1,39 (complex, 7H), 1,48-1,68 (complex, 4H), of 2.92 (d, J=6,74 Hz, 2H), 3,18-3,39 (complex, 1H), 3,48-3,62 (complex, 1H), 3,93 (t, J=7,0 Hz, 1H), 4.16 the (K, J=7,06 Hz, 2H), around 4.85 (s, 1H, able to exchange with D2O) of 6.73 (d, J=8.53 Hz, 2H), 7,10 (d, J=8,31 Hz, 2H).

Preparative example 9

Ethyl-(E/Z)-3-[4-(2-bromoethoxy)phenyl]-2-ethoxyacrylate

Named the title compound (4.0 g, 66%) receive in the form of oil at the ratio of isomers (E:Z equal to 45:55 (when measuring method1H NMR) of 4-(2-bromoethoxy)benzaldehyde (4.0 g, to 17.4 mmol) and triethyl-2-ethoxypropionate (5,61 g, 20,89 mmol) by a procedure similar to that described in preparative example 1.

1H NMR (Dl3, 200 MHz): 1.17 and 1,42 (6N, E - and Z-triplet isomery is 0,45 N, olefinic proton E-isomers), 6,85 and 6,92 (2H, d, d, J=8,67 Hz and 8.7 Hz), 6,98 (C 0,55 N, Z-isomer olefinic proton), 7,16 and 7.78 (d and d, combined 2H, J=8,63 Hz and 8,72 Hz).

Preparative example 10

Ethyl-3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropanol

Named the title compound (4.0 g, 80%) was obtained as colorless oil from ethyl(E/Z)-3-[4-(2-bromoethoxy)phenyl]-2-ethoxyacrylate (5.0 g, 14.5 mmol) obtained in preparative example 9, using N2/10% Pd/C (4 g) in dioxane as solvent through a procedure similar to that described in preparative example 3.

1H NMR (CDCl3, 200 MHz): 1,12-1,30 (complex, 6N), 2,95 (d, J=6,64 Hz, 2H), of 3.25 to 3.45 (complex, 1H), 3,56-3,68 (complex, 3H), of 3.96 (t, J=6,65 Hz, 1H), 4.16 the (K, J=7,1 Hz, 2H), 4,27 (t, J=6.3 Hz, 2H), for 6.81 (d, J=8,67 Hz, 2H), 7,16 (d, J=8,63 Hz, 2H).

Example 1

Ethyl-(E/Z)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxyacrylate

Named in the header connection receive as a mixture of isomers (E:Z, 1:1) (of 1.46 g, yield quantitative) as a syrupy liquid from 4-[2-(phenothiazines-10-yl)ethoxy]benzaldehyde (1.08 g, 3.11 mmol) and triethyl-2-ethoxypropionate (W. Grell & N. Machleidt, Annalen chemie, 1966, 699, 53) (1.0 g, 3.73 mmol) by a procedure similar to that described what), 4,11-4,17 (complex, 2H), 4,30, 4,33 (combined, 4H, -CH2CH2-singlets), 6,07 (s, 0.5 H, olefinic proton of E-isomer), 6,80-7,10 (complex 6,5 N), 7,14-7,20 (complex, 4H), 7,73 (d, J=8,39 Hz, 2H).

Example 2

Ethyl-(E/Z)-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxyacrylate

Named in the header connection receive as a mixture of isomers (E:Z (38:62) (when measuring method1H NMR) (1.5 g, 100%) as a colourless liquid from 5-formyl-2-(phenothiazines-10-yl)methylbenzofuran (1,14 g, 3.2 mmol) by a procedure similar to that described in preparative example 1.

1H NMR (CDCl3, 200 MHz): 1,23-1,45 (complex, 6N), 3,55-3,78 (complex, 1H), 3,88-4,19 (complex, 1H), 4,22-4,35 (complex, 2H), 5,14 (s, 2H), 6,18 (C 0,38 H, olefinic proton of E-isomer), 6,47 and 6,54 (combined, 1H), 6,78-7,12 (complex, 8,62 N), 7,37-of 7.48 (complex, 1H), 7,71 (d, J=EUR 7.57 Hz, 1H), 7,95 (s, 1H).

Example 3

Ethyl-(E/Z)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxyacrylate

Named in the header connection receive as a mixture of isomers (E:Z, 36:64) (when measuring method1H NMR) (14.4 g, 76%) as a white solid from 4-[2-(phenoxazin-10-yl)ethoxy]benzaldehyde (14.0 g, of 42.3 mmol) by a procedure similar to that described in preparative the crystals isomeric-och2CH3), 3,89-4,05 (complex, 4H), 4,14-or 4.31 (complex, 4H), 6,06 (with, of 0.36 H, olefinic proton of E-isomer), 6,66-6,95 (complex, at 10.64 H) of 7.75 (d, J=8,76 Hz, 2H).

Example 4

Methyl-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropanol

Named the title compound (1.3 g, 94%) was obtained as a resinous liquid from ethyl(E/Z)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxyacrylate (1,43 g, 3.10 mmol) obtained in example 1, through a procedure similar to that described in preparative example 2.

1H NMR (CDCl3, 200 MHz): to 1.15 (t, J=7.0 Hz, 3H), of 2.93 (d, J=6,64 Hz, 2H), 3.33 and-3,42 (complex, 1H), 3,52-3,63 (complex, 1H), 3,69 (s, 3H), of 3.97 (t, J=6.2 Hz, 1H), 4,29 (s, 4H), for 6.81 (d, J=8,62 Hz, 2H), 6,92-of 6.96 (complex, 4H), 7,12-7,22 (complex, 6N).

Example 5

Methyl-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanol

Named the title compound (1.0 g, 68%) receive resin from ethyl(E/Z)-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxyacrylate (1.5 g, 3.0 mmol) obtained in example 2, through a procedure similar to that described in preparative example 2.

1H NMR (Dl3, 200 MHz): to 1.16 (t, J=7.0 Hz, 3H), of 3.07 (d, J=6,55 Hz, 2H), 3,30-3,49 (complex, 1H), 3,56-3,68 (complex, 1H), 3,70 (s, 3H), of 4.05 (t, J=6.3 Hz, 1H), 5,13 oxopropanoic

Method AND

Named the title compound (0.68 g, 52%) was obtained as white solid from ethyl(E/Z)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxyacrylate (1.3 g, 2.9 mmol) obtained in example 3 by the procedure similar to that described in preparative example 2. So pl. 88-90S.

Method IN

A mixture of 2-(phenoxazin-10-yl)ethylmethanesulfonate (1.75 g, 5.0 mmol), methyl-3-(4-hydroxyphenyl)-2-ethoxypropionate (1.5 g, of 0.68 mmol) and potassium carbonate (3,16 g) in dry dimethylformamide (20 ml) is stirred at 80 ° C for 12 hours. The reaction mixture is cooled to room temperature (approx. 25S). Add water (30 ml) and the mixture extracted with ethyl acetate (250 ml). The combined organic extracts washed with water (50 ml), dried (Na2SO4) and evaporated. The remainder chromatographic using a mixture of ethyl acetate and petroleum ether (1:9) and get named in the title compound (1,15 g, 47%) as a white solid. So pl. 89-90S. Data1H NMR correspond to the desired product (see above).

1H NMR (Dl3, 200 MHz): to 1.16 (t, J=6,92 Hz, 3H), 2,96 (d, J=6,64 Hz, 2H), 3,22-3,40 (complex, 1H), 3,51-3,66 (complex, 1H), 3,68 (s, 3H), 4.00 points (t, J=7,0 Hz, 1H), 4,18 (complex, 4H), 6,55-6,89 (complex, 10H), 7,12 (d, J=8,63 Hz, 2H).

Method AND

To the solution obtained in example 3, ethyl-(E/Z)-3-[4-2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxyacrylate (1.0 g, 2,24 mmol) in dioxane (50 ml) is added 10% Pd/C (0.25 g) and the mixture was stirred at 25 ° C under a pressure of hydrogen ~414 kPa for 24 hours. At the end of this time the reaction mixture was filtered and evaporated the solvent under reduced pressure. The residue is treated with petroleum ether and get named in the title compound (0.96 g, 96%) as a white solid. So pl. 51-S.

1H NMR (CDCl3, 200 MHz): 1,12-1.27mm (complex, 6N), to 2.94 (d, J=of 6.31 Hz, 2H), 3,26-to 3.41 (complex, 1H), 3,52-3,75 (complex, 1H), 3.96 points (t, J=6,64 Hz, 2H), 4,10-4,28 (complex, 5H), 6,55-6,92 (complex, 10H), 7,16 (d, J=8,39 Hz, 2H).

Method IN

Named the title compound (0.55 g, 75%) was obtained as white solid from 2-(phenoxazin-10-yl)ethylmethanesulfonate (0.5 g, and 1.63 mmol) and ethyl-3-(4-hydroxyphenyl)-2-ethoxypropionate ones (0.46 g, 1.9 mmol) obtained in preparative example 4, through a procedure similar to that described in example 6 (method B). So pl. 52-S. Data1H NMR correspond to the desired product (see above).

The way TO

To a suspension of sodium hydride (60% dispersion in oil) (0,098 g, 4.0 mmol) in dry dimethylformamide (3 ml) in the W continue for another 30 min at approximately 25C. To the obtained reaction mixture at 0C add the solution obtained in preparative example 10 ethyl-3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropionate of 0.85 g, 2.4 mmol) in dry dimethylformamide (5 ml) and stirring is continued for 10 hours at about 25C. Add water (40 ml) and the mixture extracted with ethyl acetate (230 ml). The combined organic extracts washed with water (25 ml), brine (25 ml), dried (Na2SO4), filtered and evaporated. The remainder chromatographic on silica gel using as eluent a mixture of ethyl acetate and petroleum ether (1:9) and get named in the title compound (0.3 g, 40%) as a colourless solid. So pl. 52-S. Data1H NMR correspond to the desired product (see above).

Example 8

Ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoate

Named the title compound (1.06 g, 43%) was obtained as a pale yellow liquid of 2-(phenoxazin-10-yl)ethylmethanesulfonate (1.8 g, 5.9 mmol) and ethyl-2-hydroxy-3-(4-hydroxyphenyl)propanoate (1,36 g of 6.49 mmol) by a procedure similar to that described in example 6 (method B).

1H NMR (CDCl3, 200 MHz): of 1.29 (t, J=6, 96 Hz, 3H), 2,85-3,12 (complex, 2H), 3,92 (Ushs, 2H), 4,10-4,27 S="ptx2">

Example 9

Ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropan

Named the title compound (0.25 g, 53%) was obtained as a colorless liquid of 2-(phenoxazin-10-yl)ethylmethanesulfonate (0.3 g, 0.98 mmol) and ethyl-2-butoxy-3-(4-hydroxyphenyl)propanoate (0.26 g, 0.97 mmol) obtained in preparative example 6, through a procedure similar to that described in example 6 (method B).

1H NMR (CDCl3, 200 MHz): to 0.92 (t, J=6.4 Hz, 3H), 1,21-1,39 (complex, 5H), 1,45-1,58 (complex, 2H), 2,94 (d, J=6,32 Hz, 2H), 3,24-3,31 (complex, 1H), 3,50 is 3.57 (complex, 1H), 3,94 (t, J=6,13 Hz, 1H), 4,13-to 4.23 (complex, 6N), 6,61-6,84 (complex, 10H), 7,16 (d, J=8,3 Hz, 2H).

Example 10

Ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxyphenol

Named the title compound (0.52 g, 53%) was obtained as a pale-yellow oil from 2-(phenoxazin-10-yl)ethylmethanesulfonate (0.6 g, 1.97 mmol) and ethyl-3-(4-hydroxyphenyl)-2-lexipafant (0,70 g, 2.4 mmol) obtained in preparative example 8, through a procedure similar to that described in example 6 (method B).

1H NMR (CDCl3, 200 MHz): 0,85 (t, J=6.0 Hz, 3H), 1,20-1.27mm (complex, 7H), to 1.48-1.57 in (complex, 4H), to 2.94 (d, J=6.0 Hz, 2H), 3,21-3,30 (complex, 1H), 3,52-3,56 (complex, 1H), 3,90-3,99 (to the zine-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid

To the solution obtained in example 4 methyl-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropionate (7.5 g, 16,70 mmol) in methanol (50 ml) is added aqueous 10% sodium hydroxide solution (20 ml). The reaction mixture was stirred at approximately 25 ° C for 3 hours. The solvent is removed under reduced pressure, the residue acidified with 2 N. hydrochloric acid and extracted with ethyl acetate (2100 ml). United an ethyl acetate extract is washed with water (50 ml), brine (50 ml), dried (Na2SO4), filtered and evaporated the solvent under reduced pressure. The remainder chromatographic on silica gel using as eluent a mixture of dichloromethane and methanol (9:1) and get named in the title compound (6.0 g, 83%) as a white solid. So pl. 79-S.

1H NMR (CDCl3, 200 MHz): of 1.18 (t, J=6.8 Hz, 3H), 2,88-3,11 (complex, 2H), 3,39-3,64 (complex, 2H), 4,06 (DD, J=9,2 and 4.3 Hz, 1H), 4,30 (s, 4H), 5,30 is 5.98 (Ushs, 1H, able to exchange with D2O), 6,80-7,02 (complex, 6N), 7,12-7,21 (complex, 6N).

Example 12

Sodium salt of 3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid

A mixture of 3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid (0.3 g, 0,689 mmol) and sodium methoxide (0,041 g, 0,758 the m pressure and the residue treated with dry diethyl ether (310 ml). Precipitated precipitated solid is filtered off, washed with dry diethyl ether (25 ml) and dried under reduced pressure over P2ABOUT5get named in the title compound (0.25 g, 89%) as a white solid. So pl. 188-S.

1H NMR (DMSO-d6, 200 MHz): 1,04 (t, J=6, 9 Hz, 3H), 2.71 to 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), is 4.21 (s, 4H), 6,72 (d, J=8,3 Hz, 2H), 6.89 in-6,99 (complex, 4H), 7,05-7,21 (complex, 6N).

Example 13

3-[2-(Phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid

Named the title compound (0.8 g, 83%) was obtained as white solid from methyl 3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropionate (1.0 g, 2.0 mmol) obtained in example 5, through a procedure similar to that described in example 11. So pl. 120-S. Proton COOH too extended for observation.

1H NMR (CDCl3, 200 MHz): to 1.15 (t, J=6, 95 Hz, 3H), 3.00 and-3,26 (complex, 2H), 3,40-3,68 (complex, 2H), 4,08 (t, J=4,47 Hz, 1H), 5,11 (s, 2H), 6,46 (s, 1H), 6,77-7,40 (complex, 11N).

Example 14

Sodium salt of 3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid

Named in the title of the propanoic acid (0.16 g, 0.38 mmol) obtained in example 13, through a procedure similar to that described in example 12. So pl. 258-S.

1H NMR (Dl3, 200 MHz): 2,89-3,02 (complex, 1H), 3,06-3,18 (complex, 1H), 3,22-3,31 (complex, 1H), 3,50-3,61 (complex, 1H), 5.25 in (s, 2H), only 6.64 (s, 1H), 6.90 to-7,39 (complex, 11N).

Example 15

3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid

Named the title compound (5.4 g, 77%) was obtained as white solid from methyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropionate (7.5 g, a 16.8 mmol) obtained in example 6 by the procedure similar to that described in example 11. So pl. 90-S.

1H NMR (Dl3, 200 MHz): 1,19 (t, J=7.0 Hz, 3H), 2,90-3,18 (complex, 2H), 3,41-3,62 (complex, 2H), 3,90-4,10 (complex, 3H), 4,18 (t, J=6.2 Hz, 2H), 6,58-6,89 (complex, 10H), 7,16 (d, J=8,4 Hz, 2H), COOH proton is too extended for observation.

Example 16

Sodium salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid

Named the title compound (0.27 g, 85%) was obtained as white solid from 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid (0.3 g, to 0.72 mmol) obtained in example 15, through a procedure similar to that described the complex, 2H), 3,31-to 3.41 (complex, 1H), 3,70-3,90 (complex, 3H), 3,94-4,04 (complex, 2H), 6,47-6,74 (complex, 10H), 7,05 (d, J=8,3 Hz, 2H).

Example 17

3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid

Named the title compound (0.40 g, 72%) was obtained as a brown liquid from ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoate (0.6 g, was 1.43 mmol) obtained in example 8, through a procedure similar to that described in example 11.

1H NMR (CDCl3, 200 MHz): 2,75 (Ushs, 1H, able to exchange with D2O), 2,86-3,23 (complex, 2H), 3,85 (t, J=6.0 Hz, 2H), 4,18 (t, J=5,9 Hz, 2H), 4,47 (complex, 1H), 6,58-6,89 (complex, 10H), 7,17 (d, J=8,63 Hz, 2H), COOH proton is too extended for observation.

Example 18

3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropan acid

Named the title compound (0,13 g, 69%) are obtained in the form of a cream solid color from ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropan (0.2 g, 0.42 mmol) obtained in example 9, through a procedure similar to that described in example 11. So pl. 84-88P.

1H NMR (Dl3, 200 MHz): 0,88 (t, J=7.5 Hz, 3H), 1.26 in-1,47 (complex, 2H), 1,47-1,66 (complex, 2H), 2,87-3,16 (complex, 2H), 3,35-to 3.58 (complex, 2H), 3,88-4,P CLASS="ptx2">

Example 19

Sodium salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropan acid

Named the title compound (0.07 g, 83%) are obtained in the form of a hygroscopic solid cream color 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropan acid (0.08 g, 0,178 mmol) obtained in example 18, through a procedure similar to that described in example 12.

1H NMR (DMSO-d6, 200 MHz): 0,78 (t, J=7,28 Hz, 3H), 1,19-1,52 (complex, 4H), 2,72-3,02 (complex, 2H), 3,45-3,67 (complex, 2H), 4,01 (Ushs, 3H), 4,18 (Ushs, 2H), 6,61-6,89 (complex, 8H), 7,10-7,24 (complex, 4H).

Example 20

3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxyphenol acid

Named the title compound (0.10 g, 23%) are obtained in the form of a syrupy liquid of ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxyphenol (0,46 g, 0.96 mmol) obtained in example 10, through a procedure similar to that described in example 11.

1H NMR (Dl3, 200 MHz): 0,86 (t, J=6.0 Hz, 3H), 1.18 to 1.30 on (complex, 4H), 1,42-1,80 (complex, 4H), 2,88-3,18 (complex, 2H), 3,32-3,60 (complex, 2H), with 3.89-4.09 to (complex, 3H), of 4.16 (t, J=6.0 Hz, 2H), 6,58-6,89 (complex, 10H), 7,14 (d, J=8,63 Hz, 2H), COOH too extended for observation.

P is SS="ptx2">

[(2S)-N - (1S)]-3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide (21b)

Under ice cooling to a solution obtained in example 15 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid (1.2 g, 2.9 mmol) and triethylamine (0,48 g, 5.8 mmol) in dry dichloromethane (25 ml) add pivaloate (0,38 g, 3,19 mmol) and continue stirring at 0C for 30 minutes To the resulting reaction mixture at 0C add a mixture of (S)-2-phenylglycinol (0.39 g, 2.9 mmol) triethylamine (0,58 g, 5.8 mmol) in dichloromethane (20 ml) and continue stirring for 2 hours at 25C. Add water (50 ml) and the mixture extracted with dichloromethane (250 ml). The organic extracts washed with water (225 ml) and brine (25 ml), dried (Na2SO4) and evaporated. The remainder chromatographic on silica gel using as eluent a mixture of ethyl acetate and petroleum ether with a gradient of ethyl acetate from 40 to 60% and get the first diastereoisomer, tentatively identified as [2R, N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide (0.55 g, 35%) (21A), and then [2S-N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide (0.5 g, 32%) (21b).

21A: so pl. 126-S is), 2,50 (Ushs, 1H, able to exchange with D2O), 2,92-3,20 (complex, 2H), 3,52 (K, J=7,05 Hz, 2H), 3.72 points Ushs, 2H), 3,99 (complex, 3H), is 4.21 (t, J=6,64 Hz, 2H), 4,98-5,01 (complex, 1H), 6,64-6,70 (complex, 5H), 6.73 x-6,89 (complex, 4H), 7,03 (d, J=7,15 Hz, 1H), 7.18 in-7,29 (complex, 4H), 7,32-7,39 (complex, 3H), CONH too extended for observation.

21b: so pl. 139-S;

[]25D=margin of 13.3 (C=1.00%, in l3).

1H NMR (CDCl3, 200 MHz): of 1.18 (t, J=of 6.96 Hz, 3H), 2.05 is (Ushs, 1H, able to exchange with D2O), 2,80-3,14 (complex, 2H), 3,54 (K, J=7,0 Hz, 2H), 3,85 (Ushs, 2H), 3,97 (complex, 3H), 4,14 (t, J=6,23 Hz, 2H), 4.92 in-5,01 (complex, 1H), 6,62-6,85 (complex N), 7,02-7,20 (complex, 5H), 7,26-7,30 (complex, 3H), CONH too extended for observation.

Example 22

(R)-3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid

The solution obtained in example 21A diastereoisomer of [(2R)-N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide (0.45 g, 0.84 mmol) in a mixture of 1 M sulfuric acid (17 ml) and a mixture of dioxane and water (1:1, 39 ml) warm oil bath at 100C for 60-68 hour. Bring the pH of the mixture to 3.0 by adding an aqueous solution of sodium bicarbonate. The mixture is extracted with ethyl acetate (225 ml), the organic extract washed with water (50 ml), brine (25 ml), dried (Na< is in petroleum ether from 50 to 75% and get named in the title compound (0.2 g, 57%) as a white solid. So pl. 77-S.

[]25D=+12,1 (C=1,0%, l3).

1H NMR (CDCl3, 200 MHz): to 1.16 (t, J=7.0 Hz, 3H), 1,43-1,85 (Ushs, 1H, able to exchange with D2O), 2,86-3,14 (complex, 2H), 3,40-3,67 (complex, 2H), 3,90-4,08 (complex, 3H), 4,15 (t, J=6,65 Hz, 2H), 6,59-6,83 (complex, 10H), 7,13 (d, J=8,4 Hz, 2H).

Example 23

(S)-3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid

Named the title compound (0,19 g, 54%) was obtained as white solids from the diastereoisomer [(2S-N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide (0.45 g, 0.84 mmol) obtained in example 21b, through a procedure similar to that described in example 22. So pl. 89-90S.

[]25D= -12,6 (C=1,0%, l3).

1H NMR (Dl3, 200 MHz): to 1.16 (t, J=7,02 Hz, 3H), 1,42 is 1.91 (Ushs, 1H, able to exchange with D2O) to 2.94-3.15 in (complex, 2H), 3.40 in-the 3.65 (complex, 2H), 3,86-4,06 (complex, 3H), 4,15 (t, J=6,65 Hz, 2H), 6,63-6,83 (complex, 10H), 7,13 (d, J=8.54 in Hz, 2H).

Compounds of the present invention reduce the randomized content in blood sugar, triglycerides, total cholesterol, LDL, VLDL and increase HDL. This is demonstrated by experiments in vitro and in vivo in animal is t

Region binding ligand hPPAR merge with region DNA binding transcription factor of yeast GAL4 in eukaryotic expressing vector. Using superfect (Qiagen, Germany) as transfection reagent cells SOME 393 transfection the indicated plasmid and reporter plasmid containing the luciferase gene driven by the specific GAL4 promoter. Connection type at various concentrations, after 42 hours after transfection and spend incubation over night. Luciferase activity as a function of binding/activating ability hPPAR measured using a set of Packard Luclite (Packard, USA) in a Top Count (Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Hollis, Gene, 1992, 118: 137-141; Superfect Transfection Reagent Handbook, February, 1997, Qiagen, Germany).

b) determining the hPPAR-activity

Region binding ligand hPPAR merge with region DNA binding transcription factor of yeast GAL4 in eukaryotic expressing vector. Using lipofectamine (Gibco BRL, USA) as transfection reagent cells SOME 393 transfection the indicated plasmid and reporter plasmid containing the luciferase gene driven by the specific GAL4 promoter. The connection is added to a concentration of 1 μm at 48 hours after transfection and spend Inc. is t using a set of Packard Luclite (Packard, USA) in a Packard Top Count (Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Hollis, Gene, 1992, 118: 137-141; Guide to Eukaryotic Transfections with Cationic Lipid Reagents, Life Technologies, GIBCO BRL, USA), see table.1.

C) Determination of inhibitory activity against the HMG COA reductase. Reductase associated with liver microsomes receive from rats fed with the addition of 2% cholestyramine, when the 12-hour cycle of alternation of light and darkness. Spectrophotometric analysis is carried out in a mixture containing 100 mm KN2RHO4, 4 mm DTT, 0.2 mm NaDPH, 0.3 mm HMG CoA and 125 μg of microsomal liver enzyme. The total volume of the reaction mixture is 1 ml Reaction start by adding HMG CoA. The reaction mixture was incubated at C for 30 min and record the decrease in absorption at 340 nm. As a "dummy" is used, the reaction mixture without substrate (Goldstein J. L. and Brown, M. S., Progress in understanding the LDL receptor and HMG CoA reductase, two membrane proteins that regulate the plasma cholesterol, J. Lipid Res., 1984, 25: 1450-1461). The test compounds inhibit the enzyme HMG COA reductase.

C) In vivo

(a) the Effectiveness of the genetic models

Using mutation colonies experimental animals and different sensitivity to feeding regimes developed animal models with non-insulin-dependent deakie as mice db/db and ob/ob (Diabets (1982), 31(1): 1-6) and zuker rats fa/fa, developed by different laboratories for understanding the pathophysiology of disease and efficacy trials of new antidiabetic compounds (Diabets (1983), 32: 830-838; Annu. Rep. Sankyo Res. Lab. (1994), 46: 1-57). Homozygous animals mouse S BL/KsJ-db/db derived Jackson Laboratory, USA, obese, are giperglikemicakie, hyperinsulinemic and insulinorezistentne (J. Clin. Invest. (1990), 85: 962-967), while heterozygous animals are not obese and are normoglycemic. Model db/db mice with progressive age evolves insulinopenia - sign, usually observed in the late stages of type II diabetes in humans, when the sugar content in the blood is regulated sufficiently. The condition of the pancreas and its development vary according to models. Since this model is analogous to the model of diabetes mellitus type II, the compounds of the present invention have the activity of lowering blood sugar and triglycerides.

In this experiment, we used male mice C57BL/KsJ-db/db aged 8-14 weeks with body weight in the range of 35-60 g, bred in the area for animals research organization Dr. Reddy (DRF). Mice given standard food (National Institute in the blood of more than 350 mg/DL. The number of animals in each group is equal to 4.

Test compounds suspended in a 0.25% solution of carboxymethyl cellulose and administered the test group at a dose of from 0.1 to 30 mg/kg orally via a stomach tube for 6 days. The control group receives the media (dose 10 ml/kg). On the 6th day, for the evaluation of biological activity take samples of blood one hour after administration of the test compounds or the media.

Random blood sugar and triglyceride levels measured by blood (100 µl) of the orbital cavity using heparinised capillary tube containing add, then subjecting them to centrifugation and get a plasma. The plasma glucose and triglyceride levels measured spectrometrically glucose oxydase method and the method with glycerol-3-RO4-oxidase/peroxidase, respectively (Dr. Reddy's Lab. Diagnostic Division Kits, Hyderabad, India).

Reducing the activity of the test compounds against content in the blood sugar and triglyceride levels calculated in accordance with formula.

When the above test is not observed any harmful action of these compounds of the invention (see tab.2).

The test compound is administered at a dose of 0.1-30 mg/kg per day for 9 days. Control animals receive vehicle (0.25% solution of carboxymethyl cellulose, a dose of 10 ml/kg) orally via a stomach tube.

Blood samples taken in the fed state after 1 hour after administration of the drug in 0 and day 9 of treatment. Blood is withdrawn from zaglaniczny cavity through a heparinized capillary tube containing etc. After centrifugation, the plasma samples separated for estimation of triglycerides, glucose, free fatty acids, total cholesterol and insulin. Measurements of the concentration of plasma triglycerides, glucose, and total cholesterol carried out using commercial kits (Dr. Reddy's Laboratory, Diagnostic Division, India). The content of free fatty acids in plasma was measured using a commercial kit from Boehringer Mannheim, Germany. Contents insuli the ut formula.

Test oral glucose tolerance of mice ob/ob spend 9 days after treatment. Mice not fed for 5 hours and enter them oral 3 mg/kg glucose. Blood samples for estimation of glucose in plasma taken after 0, 15, 30, 60 and 120 minutes

The experimental results obtained in mice db/db, ob/ob rats and Zucker fa/fa lead us to the conclusion that the new compounds of the present invention also have therapeutic utility as a prophylactic or regularly used remedies in the case of diabetes, obesity, cardiovascular disorders such as hypertension, hyperlipidemia and other diseases, as it is known from literature that such diseases are interrelated.

At doses above 10 mg/kg also reduced blood glucose and triglycerides. As a rule, the degree of reduction depends on the dose and at a certain dose tends to a constant level.

b) holesterin lowering activity in a rat model of hypercholesterolemia

Male rats Sprague Dawley (line NIN) bred in the area for animals DRF. Animals are kept at a 12-hour cycle of alternation of light and darkness when S. For the experiment using rats weighing 180-200 g W is with standard laboratory food [National Institute of Nutrition (NIN), Hyderabad, India], for 6 days. During the entire period of the experiment the animals kept on the same diet (Petit D., Bonnefis M. T., Rey, S. and R. Infante, Effects of ciprofibrate on liver lipids and lipoprotein synthesis in normo - and hyperlipidemic rats. Atherosclerosis, 1988, 74: 215-225).

The test compound is administered orally at a dose of 0.1-30 mg/kg per day for 3 days. The control group treated with a single medium (0.25% solution of carboxymethyl cellulose; a dose of 10 ml/kg).

Blood samples taken in the fed state after 1 hour after administration of the drug in 0 and 3 day processing connection. Blood is withdrawn from zaglaniczny cavity through a heparinized capillary tube containing etc. After centrifugation, the plasma samples separated for estimation of total cholesterol, HDL and triglycerides. Measurements of the concentration of plasma triglycerides, total cholesterol and HDL performed using commercial kits (Dr. Reddy's Laboratory, Diagnostic Division, India). LDL - and VLDL-cholesterol is calculated from the data obtained for total cholesterol, HDL and triglycerides. The reduction of various control parameters are calculated by the formula.

(C) Reducing the activity in the content of plasma triglycerides and total cholesterol in mice Swiss albino and sea pig is all of these animals are kept at a 12-hour cycle of alternation of light and darkness when S. Animals given standard feed (NIN, Hyderabad, India) and water ad libitum. Use SAM weighing 20-25 g and Guinea pigs weighing 500-700 g (Oliver P., Plancke M. O., Marzin D., Clavey V., Sauzieres J. and Fruchart J. C., Effects of fenofibrate, gemfibrozil and nicotinic acid on plasma lipoprotein levels in normal and hyperlipidemic mice, Atherosclerosis, 1988, 70: 107-114.

Test compounds administered orally mytam Swiss albino at a dose of 0.3-30 mg/kg per day for 6 days. Control mice treated with vehicle (0.25% solution of carboxymethyl cellulose; a dose of 10 ml/kg). Guinea pigs test compounds administered orally at a dose of 0.3-30 mg/kg per day for 6 days. Control animals treated with vehicle (0.25% solution of carboxymethyl cellulose; a dose of 5 ml/kg).

Blood samples taken in the fed state after 1 hour after administration of the drug in 0 and day 6 of treatment. Blood is withdrawn from zaglaniczny cavity through a heparinized capillary tube containing etc. After centrifugation, the plasma samples separated for estimation of triglycerides and total cholesterol (Wieland O., Methods of Enzymatic analysis, Bergermeyer, H. O., Ed., 1963, 211-214; Trinder P., Ann. Clin. Biochem., 1969, 6: 24-27). Measurements of the concentration of plasma triglycerides, total cholesterol and HDL performed using commercial kits (Dr. Reddy's Lab, triglycerides and total cholesterol is calculated by the formula

OS = the value in the control group at day 0,

FROM = the value in the treated group at day 0,

TC = the value in the control group on the day of testing,

TT = the value in the treated group on the day of the test.

2. The content of the LDL - and VLDL-cholesterol is calculated by the formula

LDL-cholesterol, mg/DL = Total cholesterol - HDL-cholesterol -

VLDL-cholesterol, mg/DL = Total cholesterol - HDL cholesterol - LDL-cholesterol.

1. Aryl--oxizalidinone alkalicarbonate acid of the formula (I)

where R1, R2, R3and R4may be the same or different and represent hydrogen, hydroxy, C1-C3alkyl;

cycle And condensed with the cycle containing X and N represents a 6-membered aromatic cyclic structure containing carbon atoms;

X represents a heteroatom selected from among oxygen atoms and sulfur;

AG represents a divalent phenylene, naftilan or benzofuranyl;

R5represents hydrogen;

R6represents hydrogen or R6forms a bond together with R5;

16)alkyl;

R8represents hydrogen or optionally substituted linear or branched (C1-C16)alkyl;

Y is oxygen or NR10where R10represents hydrogen, phenyl, hydroxy-(C1-C16)-alkyl;

n is an integer in the range 1-4$

m = 0 or 1,

or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate.

2. Connection on p. 1, where the substituents in R1-R4choose among, hydroxy or C1-C3alkyl groups.

3. Connection on p. 1, where, when m = 0, AG represents a divalent benzofuranyl group.

4. The compound according to any one of paragraphs.1-3, where the cycle And represents a phenyl ring.

5. Connection PP.1-4, where the pharmaceutically acceptable salt is a salt of Li, Na, K, Ca, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum.

6. The method of obtaining the compounds of formula (III)

where R1, R2, R3, R4, X, Ar, A, n, m and R7have the values listed in paragraph 1;

R8represents hydrogen or optionally substituted linear or Razvitie is="ptx2">

where all the symbols have the meanings specified above

with the compound of the formula (IIIb)

where R11may be a lower alkyl group;

R7and R8have the meanings specified above

and optional conversion of the compounds of formula (III) into a pharmaceutically acceptable salt or pharmaceutically acceptable MES.

7. The method of obtaining the compounds of formula (III)

including the interaction of the compounds of formula (IIIa)

where all the symbols have the meanings specified in paragraph 1,

with the compound of the formula (S)

where R6represents hydrogen;

R7and R8have the values listed in paragraph 1,

with subsequent dehydration, and optional conversion of the compounds of formula (III) into a pharmaceutically acceptable salt or pharmaceutically acceptable MES.

8. The method of obtaining the compounds of formula (III)

including the interaction of the compounds of formula (IIIe)

where L1is useplease group;

all other symbols have the meanings specified in paragraph 1,

with the compound of the formula (IIId)

9. The method of obtaining the compounds of formula (III)

including the interaction of the compounds of formula (IIIg)

where all the symbols have the meanings specified above

with the compound of the formula (IIIf)

where all the symbols have the meanings specified in paragraph 1;

L1represents useplease group; and optional conversion of the compounds of formula (III) into a pharmaceutically acceptable salt or pharmaceutically acceptable MES.

10. The method of obtaining the compounds of formula (III)

including the interaction of the compounds of formula (IIIh)

where all the symbols have the meanings specified in paragraph 1,

with the compound of the formula (IIId)

where all the symbols have the meanings specified in paragraph 1,

and optional conversion of the compounds of formula (III) into a pharmaceutically acceptable salt or pharmaceutically acceptable MES.

11. The method of obtaining the compounds of formula (I)

where R1, R2, R3, R4, X, A, Ar, n, m, R5, R6and R7have the values listed in paragraph 1;

R8represents hydrogen or optionally substituted linear resolution of the compounds of formula (III), received via any of the methods on PP.6-10,

and optional conversion of the compounds of formula (I) into a pharmaceutically acceptable salt or pharmaceutically acceptable MES.

12. The method of obtaining the compounds of formula (I)

where R1, R2, R3, R4, X, A, Ar, n, m, R5, R6and R7have the values listed in paragraph 1;

R8represents hydrogen or optionally substituted linear or branched (C1-C16)alkyl;

Y represents oxygen, including the interaction of the compounds of formula (Ia)

where all the symbols have the meanings indicated above;

L3represents useplease group such as halogen atom,

with the alcohol of formula (Ib)

R7HE (Ib)

where R7matter above

and optional conversion of the compounds of formula (I) into a pharmaceutically acceptable salt or pharmaceutically acceptable MES.

13. The method of obtaining the compounds of formula (I)

where R1, R2, R3, R4, X, A, Ar, n, m, R5, R6and R7have the values listed in paragraph 1;

R the keel;

Y represents oxygen, including the interaction of the compounds of formula (I)

where L1represents useplease group;

all other symbols have the meanings specified above

with the compound of the formula (IC)

where all the symbols have the meanings specified above

and optional conversion of the compounds of formula (I) into a pharmaceutically acceptable salt or pharmaceutically acceptable MES.

14. The method of obtaining the compounds of formula (I)

where R1, R2, R3, R4, X, A, Ar, n, m, R5, R6and R7have the values listed in paragraph 1;

R8represents hydrogen or optionally substituted linear or branched (C1-C16)alkyl;

Y represents oxygen, including the interaction of the compounds of formula (IIIh)

where all the symbols have the meanings specified above

with the compound of the formula (IC)

where all the symbols have the meanings specified above

and optional conversion of the compounds of formula (I) into a pharmaceutically acceptable salt or pharmaceutically acceptable MES.

15. The way 5, R6and R7have the values listed in paragraph (1; R8represents hydrogen or optionally substituted linear or branched (C1-C16)alkyl; Y is oxygen; including the interaction of the compounds of formula (Id)

where all the symbols have the meanings indicated above, with a compound of formula (S)

R7- Hal (Ie)

where R7has the values given above and Hal represents CL, Br or I; and optional conversion of the compounds of formula (I) into a pharmaceutically acceptable salt or pharmaceutically acceptable MES.

16. The method of obtaining the compounds of formula (I)

where R1, R2, R3, R4, X, A, Ar, n, m, R5, R6and R7have the values listed in paragraph 1;

R8represents hydrogen or optionally substituted linear or branched (C1-C16)alkyl;

Y represents oxygen, including the interaction of the compounds of formula (IIIa)

where all the symbols have the meanings specified above

with the compound of the formula (IIIc)

where R6, R7and R8have the meanings specified above

subsequent dehydrations acceptable MES.

17. The method of obtaining the compounds of formula (I)

where R1, R2, R3, R4, X, A, Ar, n, m, R5, R6and R7have the values listed in paragraph 1;

R8represents hydrogen or optionally substituted linear or branched (C1-C16)alkyl;

Y represents oxygen, including the interaction of the compounds of formula (IIIg)

where all the symbols have the meanings specified above

with the compound of the formula (If)

where L1represents useplease group; and

all other symbols have the meanings specified above

and optional conversion of the compounds of formula (I) into a pharmaceutically acceptable salt or pharmaceutically acceptable MES.

18. The method of obtaining the compounds of formula (I)

where R1, R2, R3, R4, X, A, Ar, n, m, R5, R6, R7and R8have the values listed in paragraph 1;

Y represents NR10where R10represents hydrogen, phenyl, hydroxy-(C1-C6)alkyl,

including (a) the interaction of the compounds of formula (I) where all symbols have the meanings indicated above and Y Pfennig above, in pharmaceutically acceptable salt, or pharmaceutically acceptable salt of wool.

19. Connection on p. 1, selected from the group which includes

ethyl-(E/Z)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropionate;

ethyl-(E)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropionate;

ethyl-(Z)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropionate;

ethyl-(E/Z)-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropionate;

ethyl(E)-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropionate;

ethyl-(Z)-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropionate;

ethyl-(E/Z)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropionate;

ethyl-(E)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropionate;

ethyl-(Z)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropionate;

(±)-methyl-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropanol;

(+)-methyl-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropanol;

(-)-methyl-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropanol;

(±)-methyl-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanol;

(+)-methyl-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanol;

(the hydroxy]phenyl]-2-ethoxypropanol;

(+)-methyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol;

(-)-methyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol;

(±)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol;

(+)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol;

(-)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol;

(±)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoate;

(+)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoate;

(-)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoate;

(±)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropan;

(+)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropan;

(-)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropan;

(±)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxyphenol;

(+)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxyphenol;

(-)-ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxyphenol;

(±)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(+)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(+)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoate acid and its salts;

(-)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoate acid and its salts;

(±)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(+)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(-)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(±)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoate acid and its salts;

(+)-3-(4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoate acid and its salts;

(-)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoate acid and its salts;

(±)-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its salts;

(+)-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its salts;

(-)-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its salts;

(±)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(+)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(-)-3-[4-[2-(phenoxazin-10-yl)etox Romanova acid and its salts;

(+)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoate acid and its salts;

(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoate acid and its salts;

(±)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(+)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(±)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoate acid and its salts;

(+)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoate acid and its salts;

(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoate acid and its salts;

(±)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid and its salts;

(+)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid and its salts;

(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid and its salts;

(±)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropan acid and its salts;

(+)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropan acid and its salts;

(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-acid and its salts;

(+)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxyphenol acid and its salts;

(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxyphenol acid and its salts;

[(2R)-N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide;

[(2S)-N - (1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide;

[(2S)-N - (1S)]-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide and

[(2R)-N(1S)]-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide.

20. Connection on p. 19, selected from the group comprising(±)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(+)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(-)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum alloy is lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(+)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoate acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(-)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoate acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(±)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(+)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(-)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(±)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoate acid and its Li, Na, K, CA, Mg, salts, whether the-(phenothiazines-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoate acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(-)-3-[4-[2-(phenothiazines-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoate acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(±)-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(+)-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(-)-3-[2-(phenothiazines-10-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(±)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(+)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid and the aluminum;

(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanol acid or its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(±)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoate acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(+)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoate acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-2-methylpropanoate acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(±)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(+)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(±)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoate acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(+)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoate acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxy-2-methylpropanoate acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(±)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(+)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoic acid and its Li, Na, K, CA, Mg, salt, lysine salt, oxazin-10-yl)ethoxy]phenyl]-2-butoxypropan acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(+)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropan acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-butoxypropan acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(±)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxyphenol acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(+)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxyphenol acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum;

(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hexyloxyphenol acid and its Li, Na, K, CA, Mg, salt, lysine salt, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum.

21. Pharmaceutical composition having activity against PPAR and/elematics acceptable carrier, thinner, excipient or thinner.

22. The composition according to p. 21 in the form of tablets, capsules, powder, syrup, solution or suspension.

23. The intermediate compound of formula (If)

where AG represents a divalent phenylene, naftilan or benzofuranyl;

R5represents hydrogen;

R6represents hydrogen or R6forms a bond together with R5;

R7represents hydrogen or optionally substituted linear or branched (C1-C16) alkyl;

R8represents hydrogen or optionally substituted linear or branched (C1-C16)alkyl;

n is an integer in the range 1-4;

m = 0 or 1;

L1is halogen, p-toluensulfonate, methanesulfonate or trevorcurrent group.

24. The method of obtaining the compounds of formula (If), as described in paragraph 23, which includes the interaction of the compounds of formula (1C)

where R5, R6, R7, R8and Ah shall have the meanings specified in paragraph 13,

with the compound of the formula (IV)

L1-(CH2)n-L2(IV)

where L1and L2consultatie group or L2may also represent a hydroxy-group or a protected hydroxy-group, which can then be turned into useplease group;

n is an integer in the range 1-4.

25. The method of obtaining the compounds of formula (If), as described in paragraph 23, which includes the interaction of the compounds of formula (V)

L1-(CH2)n-(O)m-Ar-CHO (V)

where L1is halogen, p-toluensulfonate, methanesulfonate or trevorcurrent group;

all other characters have the meanings previously indicated,

with the compound of the formula (IIIb)

where R11represents a lower alkyl group;

R7and R8have the meanings specified in paragraph 23,

with the formation of the compounds of formula (IIIf), which is subjected to a recovery in the presence of gaseous hydrogen and a catalyst.

26. 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 pathophysiological mechanism that includes an introduction to the needy in this patient connection Faure is Aya glucose tolerance, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, atherosclerosis, hyperlipidemia, coronary arterial disease and other cardiovascular disorders, some kidney diseases, including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, psoriasis, polycystic ovaries (PCOS), used for inhibition alsoreported, for improving cognitive functions in dementia and treatment of complications in diabetes and osteoporosis.

28. The method of treatment and/or prevention of disorders related to syndrome X, including the introduction of the needy in this patient agonist of PPAR and/or PPAR, representing a compound of formula (I) as defined in any of paragraphs.1-5, 19 or 20.

29 a Method of reducing the content in plasma glucose, triglycerides, cholesterol, LDL, VLDL or free fatty acids, including introduction to the needy in this patient, the compounds of formula (I) as defined in any of paragraphs.1-5, 19 or 20.

30. The composition according to p. 21 for the treatment and/or prevention of type II diabetes, impaired glucose tolerance, dyslipidemia, disorders related to syndrome X such as hypertension, th cardio-vascular disorders, some kidney diseases, including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, psoriasis and polycystic ovaries (PCOS), used for inhibition alsoreported, for improving cognitive functions in dementia and treatment of complications in diabetes and osteoporosis.

31. The compound of formula (IIIe)

where R1, R2, R3and R4may be the same or different and represent hydrogen, hydroxy, (C1-C3) alkyl;

cycle And condensed with the cycle containing X and N represents a 6-membered aromatic cyclic structure containing carbon atoms;

X represents a heteroatom selected from among oxygen atoms and sulfur;

n is an integer in the range 1-4;

L1represents halogen or useplease group

its pharmaceutically acceptable salts and pharmaceutically acceptable solvate.

 

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in which R denotes an element of the formula

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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
where X represents the group< / BR>
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< / BR>
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