SUBSTITUTED ARALKYL DERIVATIVES OF

SUBSTITUTED ARALKYL DERIVATIVES OF

Technical Field of the Invention the present invention relates to novel antidiabetic, hypolipidemic and hypocholesterolemic compounds, their

stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions, containing them. More specifically, the present invention relates to new substituted aralkilnym derivatives of the general formula (1), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions, containing them, use of these compounds in medicine and intermediate compounds, participating in their production.

The present invention also relates to method of obtaining above said new compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions, containing said compounds.

The present invention also describes new compounds of the formula (iii), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable composition, containing indicated compounds.

derivatives, their analogs, their tautomeric forms, their CI ω-

Compounds of the formula (iii) can be used as intermediate compounds for preparing compounds of the formula (1).

O

A Of - (CHj) --X-Of Al

0ΐ

ana look)

Compounds of general formulas (1) and (iii) is reduced content of glucose in blood, is reduced or modulated levels of triglyceride and/or cholesterol, and/or low density lipoprotein (LDL) and the level of high density lipoprotein (HDL) in plasma and, consequently, their may be used in treatment of various medical conditions, at which such WiFi client continuously tracks (and lifting) show beneficially. So, said compounds can be used in treatment and/or prophylaxis of obesity, hyperlipidemia, hypercholesterolemia, hypertension, phenomena, associated with atherosclerotic disease, vascular restenosis, diabetes mellitus and many other associated states.

Compounds of the general formula (1) and (iii) can be used for prevention or WiFi client continuously ny risk of development of atherosclerosis, which leads to diseases and states, such as atherosclerotic cardio - vascular disease, insult, coronary heart disease, cerebrovascular disease, peripheral vascular diseases and related disorder. These compounds of the general formula (1) and (iii) can be used for treatment and/or prevention of metabolic disorders, certain freely as syndrome X characteristic signs of X syndrome include initial tolerance to insulin with subsequent giperinsulinemiei, dyslipidemia and disturbed tolerance to glucose tolerance. Tolerance to glucose tolerance may cause insulinnezavisimomu diabetes mellitus (NIDDM, mellitus type 2), which is characterized by hyperglycemia, which no treatment may cause diabeticheskim complications or metabolic disturbances, caused by resistance to insulin. Diabetes mellitus not is considered to be coupled only with glucose metabolism, but it acts on both anatomical and physiological parameters, the intensity of which varies depending on stages/duration and severity of diabetic state. Compounds nastoyashchemuizobreteniyu may also be to use in prevention, stop or deceleration of progressing or WiFi client continuously NII risk said disorders along with occurring as a result of secondary diseases, such as cardio - vascular disease, similar arteriosklerozu, aterosklerozu, diabetic retinopathy, diabetic neuropathy and kidney diseases, including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephritic syndrome, hypertonic nefroskleroz and renal disease terminal stage of, similar microalbuminuria and albuminurii, which can jeopardised as a result of hyperglycemia or hyperinsulinemia.

Proposed compounds can be used as inhibitors of aldozo - reductase, for improvement of cognitive functions at dementia and in treatment and/or prophylaxis of disorders, such as psoriasis, ovary polycystic syndrome (PCOS), cancer, osteoporosis, resistance to leptinu, inflammation and intestine inflammatory diseases, ksantoma, pancreatitis, miotonicheskaya dystrophy, dysfunction of endothelial cells and hyperlipidemia.

Compounds the present invention can be used in treatment of said the present description diseases separately or in combination with one or more hypoglycemic, antigiperglikemicheskimi, hypolipidemic, gipolipoproteinemicheskimi means, antioxidants, antigipertenzivnymi means, such as inhibitor of GMT - koareduktazy, fibrat, statins, glitazony, sulfonylurea, insulin, inhibitors and - glikozidazy, nicotinic acid, cholestyramine, kholestipol or probucol and the like.

Hyperlipidemia has been recognized as main risk factor, of the calling cardio - vascular disease due to atherosclerosis. Atherosclerosis and other such peripheral vascular diseases affect life quality large part of population in the whole world. Treatment aims on WiFi client continuously tracks to increase the nnogo level cholesterol LDL in plasma, low density lipoprotein and triglycerides plasma for preventing or WiFi client continuously ny risk cardio - vascular diseases. Aetiology atherosclerosis and diseases of coronary arteries is discussed in specifically in article at Ross and sort Glomset [the New Engl. J. Med., 295, 369 - 377 (1976)]. Cholesterol plasma in a whole is detected esterifitsirovannym different whey lipoproteins of, and much numeric investigating showed about feedback between level cholesterol HDL in serum and risk of cardio - vascular diseases. Many investigating showed about increased risk of diseases of coronary arteries (the CAD) due to to increase the levels of nnykhLDL and cholesterol VLDL (very low density lipoprotein) [Stampfer is Et al., N Engl. J. Med., 325, 373 - 381 (1991)]. Other investigating illustrate protective effects against HDL progressing atherosclerosis. So, HDL become solver factor in treatment of diseases, at which take place to increase the ned levels of cholesterol [the Miller is Et al., brr. The MED. J. 282, 1741 - 1744 (1981); Picardo is Et al., Arteriosclerosis, 6, 434 - 441 (1986); Macikinnon is Et al., J Biol. Chem. 261, 2548 - 2552 (1986)].

Diabetes mellitus is connected with row of complications and also killed larger population. This disease usually is connected with other diseases, such as obesity, hyperlipidemia, hypertension and angina. Well is installed, that inadequate treatment can aggravate disturbed tolerance to glucose tolerance and resistance to insulin, results by means of this to true diabetes mellitus. Moreover, patients with resistance to insulin and diabetes mellitus type 2 often ned to increase the levels of triglycerides and of concentration of cholesterol HDL and therefore have larger risk of cardio - vascular diseases. The present treatment on the occasion of these diseases involves sulfonmocheviny and biguanidy along with insulin. This type of drug therapy may cause hypoglycemia from light to severe degree, which may cause coma or in some cases may cause death as a result of unsatisfactory checking these preparations of glucose content in blood. The latter addition of medicinal agents in treating diabetes mellitus is a thiazolidinediones, preparations, having sensitizing to insulin action. Thiazolidinediones, similar troglitazonu, rosiglitazonu and pioglitazonu, is separately or in combination with other antidiabetic means.

Can be also to use in treating diabetes mellitus, disorders of lipid metabolism, but there is suspicion, that they can cause development of tumors and cause disturbance of function of liver, which may hepatic insufficiency. In addition, in investigations in animals and/or people of propranolol serious undesirable by-side effects, which include gipertrofiyu heart, spider was blood coagulation and toxic effect on liver several glitazonov, which progressed at long-term tests in people. This deficiency is considered to be idiosinkraticheskim. In the present time there is necessity in safe and effective medicinal vegetative facility for treatment of insulin resistance and hyperlipidemia [Exp. Clin. Endocrinol. Diabetes: 109 (4), s548-and-9 (2001)].

Obesity is a other greater problem for health, coupled with grew frequency morbidity and mortality. This metabolic disorder, at which excess of fat is accumulated in organism. At least its aetiology unclear, common feature includes excess consumed calorie in comparison with consumable. Various types of treatment, such as diet, physical load, appetite suppression, inhibition of suction fat and T. d. were used for control with obesity. However substantial more effective methods of treatment of this pathology. Since obesity tightly is connected with several diseases, such as coronary heart disease, insult, diabetes mellitus, gout, osteoarthritis, hyperlipidemia and WiFi client continuously nnaya father. It also leads to Social and psychological issues [NatureReviews: Drug the Discovery:

1 (4), 27 β-- 8 β-(2002)].

Receptor, activated by peroxisome proliferator (ppar-), is a family receptors steroids/retinoids/hormones thyroid gland. PPARa, PPARy and ppar5 were identified as subtypes ppar-. Extensive reviews, related to ppar-, their role at different pathological states, widely published [EndocrineReviews, 20 (5), 649 - 688 (199); J MedicinalChemistry, 43 (4), 58 - 550 (2000); the Cell, 55, 932 - 943 (1999); Nature, 405, 421 - 424 (2000); Trends in vitro Pharmacological SCI to ., 469 - 473 (2000)]. Was, that activation of PPARy plays central role in the initiation and control of adipocyte differentiation [Endocrinology 135, 798 - 800, (1994)] and energy homeostasis [the Cell, 83, 803 - 812 (1995); the Cell, 99, 239 - 242 (1999)]. Agonists stimulate PPARy final differentiation precursors adipocyte and cause morphological and molecular change, characteristic for more differentiated, less than malignant state. During differentiation of adipocyte indutsiruyutsya several highly specialized proteins, which participate in accumulation and metabolism of lipids. Recognized, that activation of PPARy leads to gene expression the Cap [the Cell Biology, 95, 14751 - 14756, (1998)], however, accurate communication activation PPARy with changes metabolism of glucose and WiFi client continuously was that insulin resistance in muscles has not been clear. PPARa takes part in stimulation of p - oxidation of fatty acids [TrendsEndocrine, Metabolism, 4, 291 - 296 (1993)], brought WiFi client continuously agreed to the level of circulating free fatty acids in plasma [the Current Biol., 5, 618 - 621 (1995)]. Recently has been recognized role of activation of PPARy in final differentiation precursors adipocyte at cancer treatment [the Cell, 79, 1147 - 1156 (1994); the Cell, 377 - 389 (1996); Molecular the Cell, 465 - 470 (1998); Carcinogenesis, 1949 - 1953 (1998); the proc. Natl. Acad. SCI to ., 94, 237 - 241 (1997); Cancer Research isthe, 58, 3344 - 3352 (1998)]. Since PPARy stable expressed in certain cells, agonists PPARy led would to nontoxic chemotherapy. Is accumulated all exceeds data about the fact, that agonists of ppar-may also effect on the cardio - vascular system by means of receptors ppar and also directly modulating function of vascular wall [the MED. Resolution RES. Rev., 20 (5), 350 - 366 (2000)].

Was, that agonists of PPARa can be used in treatment of obesity (of clayey 97/36579). Instead, that double agonists and ppar-and γ can be used on the occasion of X syndrome (of clayey 97/25042). Agonists of ppar-γ and inhibitors of GMT - CoA reductase show synergism and pointed on possibility of application of the combination in treatment of atherosclerosis and ksantomy (EP 0753298).

Leptin is a protein, which at binding with receptors leptin, takes part in direction of signal fullness in treating hypothalamus. Therefore resistance to leptinu would led to excessive food consumption, WiFi client continuously nnomu flow rate energy, obesity, of disturbed tolerance to glucose and diabetes mellitus [the science, 269, 543 - 46 (1995)]. Reported, that sensibilizing agents to insulin is reduced concentration of leptin in plasma [the proc. Natl. Acad. SCI To. 93, 5793 - 5796 (1996): OF CLAYEY 98/02159)].

Derivatives of fenalkiloksifenila, having sequence SEQIDNO below general formula, which may be used in treatment of insulin resistance, have been described in of clayey 01/40170 (AstraZeneca AB).

Typical made an example of these compounds is described formula (on)

Application arilgidroksilnykh derivatives of propanol, having sequence SEQIDNO below general formula,

but

as agents for treatment of disorders, associated with resistance to insulin, was described is in w0 03008362 (fund research D - Pa Reddy).

Reported, that a row of compounds, related to class oxazole derivatives, can be used in treatment of hyperlipidemia, hypercholesterolemia and hyperglycemia; data about these compounds are contained in publication of clayey 02092084 (Hotel Hoffmann La Roche Airport), in which invention describes compounds oxazole, which has the following formula

where R is¹ represents aryl or heteroaryl; R of² , OF R³ , OF R⁴ and R⁵ independently selected from the group, consisting of from hydrogen, hydro xy, lower alkenila, halogen, lower alkyl and lower alkoxy, where, at least, one R² , OF R³ , OF R⁴ and R⁶ not represents hydrogen or R³ and R⁴ are connected to each other to form ring together with carbon atoms, to which they are connected, R³ and R⁴ together are - CH= CH--and-s--, - S-S CH-=CH -, - sn= 0 - 0 -, - 0 - sn=sn -, - sn=sn - sn=sn -, - (CH₂ )₃ - 5 -, - O - (CH₂ ) 2 - 3~or

- (CH₂ ) 2 - 3 - 0 - R OF ;⁵ represents lower alkoxy, lower alkeniloksi, or

H or lower alkyl; R of¹⁰ represents aryl; p=1, 2 or 3; connection between with_and and with_mpile is a single or double bond between carbon atoms;

in of clayey 0216331 (of eli Lilly & with.) are disclosed derivatives of oksazolila - arylpropionic acid of the general formula

Of RR

°C y.R₂

^LI , COORs

(ChynWY Of X

R₃^or- 4

to

the RJ where is a substituted or synergistic group, selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, geteroarilalkila, cycle about alkyl and alkyl, (CH₃ )₃ With -; p=2, 3, 4; of W is CH₂ , CH (IT), WITH, ABOUT; OF R₂ is H, alkyl, halogenalkyl, with₆N₅ ; Y represents substituted or nezameshchennuyu group, consisting of thiophene - 2, 5 - diila or phenylene; R of₃ is alkyl, halogenalkyl; R of₄ is substituted or unsubstituted phenyl, naphthyl, 1.2, 3.4 - tetrahydro naphthyl, quinolyl, pyridyl, benzo [1.3] dioxole - 5 - yl; R of₃ is H, alkyl, amino alkil aqueous hydrogen group.

In w0 9807699 (the Japan Tobacco, Inc.) described is propionic acid derivative of the general structure

where Ri is a

aromatic hydrocarbon,

alicyclic hydrocarbons,

heterocyclic group or

optionally optionally

optionally

optionally

condensed heterocyclic group, R of

substituted substituted substituted substituted represents lower alkyl; R of⁴=H or lower alkyl; R of^D=H or forms together with R⁹ double bond; of R^? is a carboxy, acyl, optionally substituted alkoxycarbonyl; optionally substituted lower alkyl, optionally substituted carbamoyl, optionally substituted aryloxycarbonyl, optionally substituted aralkiloksikarbonil or group of the formula --Y of R⁸ , where Y is - NHili oxygen atom, R⁸ represents optionally substituted acyl or optionally substituted alkoxycarbonyl;

R⁹=H, optionally substituted lower alkyl or optionally substituted alkoxycarbonyl; R of¹⁰ is a hydro xy, optionally substituted amino, optionally substituted lower alkoxy, optionally substituted lower alkyl, optionally substituted aryloxy or optionally substituted aralkiloksi, provided, that when R of⁷ represents alkoxycarbonyl, R⁹ is a hydrogen atom, of R is¹⁰ not represents lower alkoxy.

In of clayey 02100403 (of eli Lilly & with) are disclosed compounds of the general formula, suitable for treating of X syndrome

Y^{la is} represents H, (with - C3) alkylaryl, with (about) - aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy and T. d.;

CD

^ represents aryl or heteroaryl; V denotes bond or about; X represents CH₂ or o, of R⁵ represents H or C1 - with_th alkyl; each of Y² and Y⁰ independently represent H, Cl-and-svalkil or C1~with₆ alkoxy; of Y⁴ is a (Cl~of c₃ ) alkyl - iii⁵ With (about) - (with " with₅ ) alkyl-Y of⁷ , (Cl C3) alkyl - th⁵ WITH (ABOUT) - (WITH₂ - WITH₅ ) alkenyl-Y of⁷ , (Cl-cproduction₃ ) alkyl - 1750s⁵ WITH (ABOUT) - (WITH₂ - WITH₅ ) alkynyl-Y of⁷ , The CN and T. d.; of Y⁷ represents H, arylheteroaryl, s^ - s^alkil, C1 - with_b alkoxy, cycloalkyl, heterocycloalkyl, aryloxy, with (about) - heteroaryl and T. d.; U¹⁼ 2, 3, 4 or 5;

In a patent USA. № 5232945 (Pfizer's Inc.) invention describes compounds of the general formula

phenyl, mono disubstituted (Cl-cproduction₃ ) alkyl, the CF₃ , (Cl with~₃ ) alkoxy, phenyl, phenoxy, benzyl, benzyloxy, ftorilikhlor; Z of¹⁼ H or (Cl with₃ ) alkyl; of R=(not) substituted alkyl, cycloalkyl, alkenyl, alkynyl, pH of, phenylalkyl, alkanoyl; x=s, about, the NR₂ ,

SN=SN, - CH=N, - N=CH; OF R₂=H, alkyl, pH of, CH-₂ PH Of; Y=CH, Ν; X^g=0, S-, OF SO, S0₂ ; OF Y¹⁼ OH of, (not) substituted alkoxy, OPh, OCH₂ PH Of, NH-₂ and T. d.;

W=0, WITH, CH-₂ , CH-(OH of), - CH=CH; sh=0, 1, 2;

Reported several other oxazole derivatives, which may be used in treating diabetes mellitus, hyperlipidemia and T. d. (x syndrome), for example, w0 03072100,

as references.

However very few from compounds described above reached market, and so, therefore remains necessity in development of more of new medicinal agents, which better and more by consumption, have efficiency, which better or comparable with these circuits treatment, has less side effects and requires circuit lower dosage.

The aim of the invention development of new

compounds, represented by general formula (1) and (iii), used as hypocholesterinemic, hypolipidemic, gipolipoproteinemicheskikh agents, agents against obesity and antigiperglikemicheskikh means, which can and as a additional action on WiFi client continuously tracks the body weight and benefit to action in treatment and/or prophylaxis of diseases, caused by hyperlipemia, diseases, classified in form of syndrome X and atherosclerosis.

Main the aim of the invention preparing new substituted aralkyl derivatives, represented by general formula (1), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions, containing indicated compounds, or their mixtures.

Another object of the present invention is preparing new substituted aralkyl derivatives, represented by general formula (1), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions, containing indicated compounds, or their mixtures, having to increase the nnuyu activity, without toxic effects or with WiFi client continuously nnym toxic effect.

One more of the invention is provision method of producing new substituted aralkyl derivatives, represented by general formula (1), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates.

One more object of the present invention provides preparing pharmaceutical compositions, containing compounds of the general formula (1), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates or their mixtures in combination with suitable carriers, solvents, diluents and other media, usually used in such compositions.

One more the aim of the invention provision new substituted derivatives of propionic acid of the formula (iii), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions, containing indicated compounds, or their mixtures, which can be used as intermediate compounds production of compounds of general formula (1).

One more the aim of the invention provision new substituted derivatives of propionic acid, represented by general formula (iii), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions, containing indicated compounds, or their mixtures, having to increase the nnuyu activity, without toxic effects or with WiFi client continuously nnym toxic effect.

One more the aim of the invention provision method of producing new substituted derivatives of propionic acid, represented by general formula (iii), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates.

One more object of the present invention provides preparing pharmaceutical compositions, containing compounds of the general formula (iii), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates or their mixtures in combination with suitable carriers, solvents, diluents and other media, usually used in such compositions.

Respectively, the present invention relates to compounds of general formula (1)

A Of - (CH^ --X-Of Formula ^Y^_G2

Gx Nor ¢)

their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, where "and" is substituted or nezameshchennuyu group, selected from aryl, heteroaryl, heterocyclic groups, "U" is an integer from 1 to 3, provided, that when A represents substituted or nezameshchennuyu phenyl group, then "ah" is not bivalent phenyl group;"of X" represents oxygen or sulfur;

"Ah" is a substituted or nezameshchennuyu single or condensed divalent aromatic, heteroaromatic or heterocyclic group;

Gl and Ga can be the same or different, and independently are NRiR₂ , Ori of, Sri Lankan, s-(0) of R₃ , S-(0) 2R3, N-₃ , The CN, s00n, tetrazolilnye group; R of₃ and R₂ can be the same or different, and independently are hydrogen, substituted or synergistic group, selected from linear or branched (Cl-and-of CS) alkyl, (C3 - C7) cycloalkyl, acyl, aryl, heteroaryl, heterocyclyl, aminocarbonyl, aralkyl, alkilaminokarbonilnoi, arilaminokarbonilnoi, aralkilaminokarbonilnoi, geteroarilaminokarbonilnoi, geteroaralkilaminokarbonilnoi, geterotsiklilaminokarbonilnoi, alkoxycarbonyl, ariloksikarbonilnoi, aralkiloksikarbonilnoi, geteroariloksikarbonilnoi, geteroaraloksikarbonilnoi, geterotsikloksikarbonilnoi groups or s0₂R₃ , where R is₃ is a substituted or nezameshchennuyu group, selected from alkyl, aryl, poligalogenalkilnoi, heterocyclyl, heteroaryl groups; of G₃ represents hydrogen or (Cx - with₈ ) alkyl, or (with₃ - WITH₇ ) cycloalkyl group.

Suitable substituents for R₃ , OF R₂ or R₃ can be the same or different, and independently are selected from hydro ksila, oxo, halogen, thio, nitro, amino, cyano, formila, or substituted or unsubstituted groups, selected from amidino, guanidino, hydrazino, alkyl, galogenalkila, pergalogenalkila, alkoxy, galogenalkoksi, pergalogenalkoksi, alkenila, alkinila, cycloalkyl, tsikloalkenila, bitsikloalkila, bitsikloalkenila, alkoxy, alkenoksi, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, geterotsiklilalkila, heteroaralkyl, heteroaryloxy, geteroaralkoksi, geterotsikliloksi, geterotsiklilalkoksi, geterotsiklilalkoksiatsila, dehydratase, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives, such as esters and amides, karbonilamino, hydro ksialkila, aminoalkyl, alkoxyalkyl, ariloksialkila, aralkoksialkila, alkylthio, tioalkila, arylthio, alkylsulphonylamino, alkilsulfoniloksi, alkoxycarbonylamino, ariloksikarbonilamino, aralkiloksikarbonilamino, aminokarbonilamino, alkilaminokarbonilamino, alkoksiamino, hydro ksilamino, sulfenilnykh derivatives of, sulfonilnykh derivatives, sulfonic acid and its derivatives, phosphonic acid and its derivatives.

When "and" is substituted, substituents may be selected from hydro ksila, oxo, halogen, thio, nitro, amino, cyano, formila or substituted or unsubstituted groups, selected from amidino, guanidino, hydrazino, alkyl, galogenalkila, pergalogenalkila, alkoxy, galogenalkoksi, pergalogenalkoksi, alkenila, alkinila, cycloalkyl, tsikloalkenila, bitsikloalkila, bitsikloalkenila, alkoxy, alkenoksi, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, geterotsiklilalkila, heteroaralkyl, heteroaryloxy, geteroaralkoksi, geterotsikliloksi, geterotsiklilalkoksi, geterotsiklilalkoksiatsila, dehydratase, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives, such as esters and amides, karbonilamino, hydro ksialkila, aminoalkyl, alkoxyalkyl, ariloksialkila, aralkoksialkila, alkylthio tioalkila arylthio alkylsulphonylamino, alkilsulfoniloksi, alkoxycarbonylamino, ariloksikarbonilamino, aralkiloksikarbonilamino, aminokarbonilamino, alkilaminokarbonilamino, alkoksiamino, hydro ksilamino, sulfenilnykh derivatives of, sulfonilnykh derivatives, sulfonic acid and its derivatives, phosphonic acid and its derivatives.

When substituents group "and", in its turn, additionally substituted, then these additional substituents are selected from hydro ksila, oxo, halogen, thio, nitro, amino, cyano, formila or substituted or unsubstituted groups, selected from amidino, guanidino, hydrazino, alkyl, galogenalkila, pergalogenaalkila, alkoxy, galogenalkoksi, pergalogenalkoksi, alkenila, alkinila, cycloalkyl, tsikloalkenila, bitsikloalkila, bitsikloalkenila, alkoxy, alkenoksi, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, geterotsiklilalkila, heteroaralkyl, heteroaryloxy, geteroaralkoksi, geterotsikliloksi, geterotsiklilalkoksi, geterotsiklilalkoksiatsila, dehydratase, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives, such as esters and amides, karbonilamino, hydro ksialkila, aminoalkyl, alkoxyalkyl, ariloksialkila, aralkoksialkila, alkylthio, tioalkila, arylthio, alkylsulphonylamino, alkilsulfoniloksi, alkoxycarbonylamino, ariloksikarbonilamino, aralkiloksikarbonilamino, aminokarbonilamino, alkilaminokarbonilamino, alkoksiamino, hydro ksilamino, sulfenilnykh derivatives of, sulfonilnykh derivatives, sulfonic acid and its derivatives, phosphonic acid and its derivatives.

Substituents group, presented ah, are substituted or unsubstituted linear or branched alkyl, alkoxy, thioalkyl, halogen, halogenalkyl, galogenalkoksi, acyl, amino, acylamino, thio or carboxylic or sulfonic acids and their derivatives, phosphonic acid and their derivatives.

In another version presented new substituted derivatives of the formula {III and the), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates,

where "and" is 4 - oksazolilnuyu group, substituted one or two substituents, selected from substituted or unsubstituted linear or branched (Cl-and-Cl?) alkyl, substituted or unsubstituted single or condensed heteroaryl or heterocyclic groups;"ah" is unsubstituted phenyl; CI is ori of or Sri Lankan, where Ri represents hydrogen, perfluoro (C1 - C12) alkyl, substituted or synergistic group, selected from linear or branched (C1 - C12) alkyl, cyclo (C1 - C12) alkyl, aryl, the AP (Cl-and-C12) alkyl, heteroaryl, geteroar (C1 - C12) alkyl, heterocyclyl, alkoxyalkyl, ariloksialkilnoi, alkoxycarbonyl, ariloksikarbonilnoi, tsikloalkiloksikarbonilnoi, alkilaminokarbonilnoi, arilaminokarbonilnoi or acyl groups; of R₄ is it, alkoxy or aryloxy, aralkoxy or NRiR₂ group, where Ri and R₂ can be the same or different, and independently are hydrogen, substituted or synergistic group, selected from linear or branched (Cl-cproduction₈ ) alkyl, (C3 - C7) cycloalkyl, acyl, aryl, heteroaryl, heterocyclyl, aminocarbonyl, aralkyl, alkilaminokarbonilnoi, arilaminokarbonilnoi, aralkilaminokarbonilnoi, geteroarilaminokarbonilnoi, geteroaralkilaminokarbonilnoi, geterotsiklilaminokarbonilnoi, alkoxycarbonyl, ariloksikarbonilnoi, aralkiloksikarbonilnoi, geteroariloksikarbonilnoi, geteroaraloksikarbonilnoi, geterotsikloksikarbonilnoi groups or SO2R3/where R is₃ is substituted or synergistic group, selected from alkyl, aryl, poligalogenalkilnoi, heterocyclyl, heteroaryl groups;"U" O

a whole number from 1 to 3; X is 0 or S.

Suitable replacement substituents group "and" are selected from hydro ksila, oxo, halogen, thio, nitro, amino, cyano, formila or substituted or unsubstituted groups, selected from amidino, guanidino, hydrazino, alkyl, galogenalkila, pergalogenalkila, alkoxy, galogenalkoksi, pergalogenalkoksi, alkenila, alkinila, cycloalkyl, tsikloalkenila, bitsikloalkila, bitsikloalkenila, alkoxy, alkenoksi, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, geterotsiklilalkila, heteroaralkyl, heteroaryloxy, geteroaralkoksi, geterotsikliloksi, geterotsiklilalkoksi, geterotsiklilalkoksiatsila, dehydratase, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives, such as esters and amides, karbonilamino, hydro ksialkila, aminoalkyl, alkoxyalkyl, ariloksialkila, aralkoksialkila, alkylthio, tioalkila, arylthio, alkylsulphonylamino, alkyl sul fonilo xy, alkoksik AP bonilamino, ariloksikarbonilamino, aralkiloksikarbonilamino, aminokarbonilamino, alkilaminokarbonilamino, alkoksiamino, hydro ksilamino, sulfenilnykh derivatives of, sulfonilnykh derivatives, sulfonic acid and its derivatives, phosphonic acid and its derivatives;

Compounds of the formula (II1a) can be used as intermediate compounds for preparing compound of the formula (1). In addition, compounds of the formula (iii) may also be to use in prevention or decrease risk of development of atherosclerosis, which leads to diseases and states, such as arterioskleroticheskie cardio - vascular disease, insult, coronary heart disease, cerebrovascular disease, peripheral vascular diseases and related disorder. Also compounds of the formula (iii) can be used treatment or prevention, associated with syndrome of X.

The present invention also describes new methods for preparing compounds of the formula (1) and (of III).

Various groups, radicals and substituents, used anywhere in the description, are described in the following paragraphs.

Term "alkyl", used in this description or separately, or in combination with other radicals, denotes linear or branched radical, containing from 1 to 12 carbon atoms, such as methyl, ethyl, n - propyl, isopropyl, n - butyl, sec - butyl, tert - butyl, amyl, tert - amyl, n - pentyl, n - hexyl, iso - hexyl, heptyl, octyl and the like.

Term "alkenyl", used in this description or separately, or in combination with other radicals, denotes linear or branched radical, containing from 2 to 12 carbon atoms, such as vinyl, allyl, 2 - butenyl, 3 - butenyl, 2 - pentenil, 3 - pentenil, 4 - pentenil, 2 - hexenyl, 3geksenil, 4 - hexenyl, 5 - hexenyl, 2 - heptenyl, 3 - heptenyl, 4geptenil, 5 - heptenyl, B - heptenyl and the like. Term "alkenyl" includes dienes and trienes of straight and branched chains.

Term "alkynyl", used in this description or separately, or in combination with other radicals, denotes linear or branched radical, containing from 2 to 12 carbon atoms, such as ethynyl, 1 - propynyl, 2 - propynyl, 1butinil, 2 - butinyl, 3 - butinyl, 1 - pentinil, 2 - pentinil, 3 - pentinil, 4 - pentinil, 1 - hexenyl, 3 - hexenyl, 4 - hexenyl, 5geksinil and the like. Term "alkynyl" includes passive radiation source triiny.

Term "cycloalkyl", used in this description or separately, or in combination with other radicals, denotes radical, containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

Term "cycloalkenyl", used in this description or separately, or in combination with other radicals, denotes radical, containing from 3 to 7 carbon atoms, such as tsiklopropenil, 1 - cyclobutenyl, 2 - cyclobutenyl, 1 - cyclopentenyl, 2tsiklopentenil, 3 - cyclopentenyl, 1 - cyclohexenyl, 2 - cyclohexenyl, 3 - cyclohexenyl, 1 - cyclopentenyl, tsiklogeptadienil, tsiklogeptatrienil and the like.

Term "alkoxy", used in this description or separately, or in combination with other radicals, denotes alkyl radical, having defined above value, connected directly to atom oxygen, such as methoxy, ethoxy, n - propoxy, iso - propoxy, n - butoxy, tertbutoxy, iso - butoxy, pentiloksi, hexyloxy and the like.

Term "alkenoksi", used in this description or separately, or in combination with other radicals, denotes alkenilnyi radical, having defined above value, connected to atom oxygen, such as viniloxy, alliloksi, butenoksi, pentenoksi, geksenoksi and the like.

Term "cycloalkoxy", used in this description or separately, or in combination with other radicals, denotes cycloalkyl radical, having defined above value, connected directly to atom oxygen, such as tsiklopropiloksi, tsiklobutiloksi, cyclopentylhydroxy, cyclohexyloxy, tsiklogeptiloksi and the like.

Term "halo -" or "halogen", used in this description or separately, or in combination with other radicals, such as "halogenalkyl", "pergalogenalkil" and T. d. relates to group fluoro -, chloro -, bromi iodine -. Term "halogenalkyl" means alkyl radical, having defined above value, substituted by one or more galogenami, such as pargalogenalkil, more preferably, perfluoro (Cl-cproduction₆ ) alkyl, such as fluoromethyl, difluoromethyl, trifluoromethyl, ftoretil, diftoretil, trifluoroethyl, mono or poligalogen substituted methyl, ethyl, propyl, butyl, pentyl or hexyl group. Term "galogenalkoksi" means halogenalkyl, having defined above value, directly connected to atom oxygen, such as fluoromethoxy, khlormetoksi, fluoroethoxy, chloroethoxy group and the like. Term "pergalogenalkoksi" means pergalogenalkilnyi radical, having defined above value, directly connected to atom oxygen, such as triftormetoksi, trifluoroethoxy and the like.

Term "aryl" or "aromatic", used in this description or separately, or in combination with other radicals, denotes aromatic system, containing 1, 2 or 3 ring, and such rings can be connected together in the form of addition, or can be condensed, such as phenyl, naphthyl, tetrahydro naphthyl, indane, biphenyl and the like. Term "aralkyl" ' means alkyl group, having defined above value, connected to arilu, such as benzyl, phenethyl, naftilmetil and the like. Term "aryloxy" means aryl radical, having defined above value, connected to alkoxy group, such as phenoxy, naphthyloxy and the like, which may be substituted. Term "aralkoxy" means arilalkilnuyu part, having defined above value, such as benzyloxy, fenetiloksi, naftilmetiloksi, fenilpropiloksi and the like, which may be substituted.

Term "heterocyclyl" or "heterocyclic", used in this description separately or in combination with other radicals, denotes saturated, partially saturated and unsaturated ring radicals, where geteroatomy are selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include aziridinil, azetidinil, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2 - oksopiperidinil, 4 - oksopiperidinil, 2 - oksopiperazinil, 3 - oksopiperazinil, mofrolinil, thiomorpholinyl, 2 - oksomorfolinil, azepinyl, diazepinyl, oksapinil, tiazepinil, oxazolidinyl, tiazolidinyl and the like; examples of partially saturated heterocyclic radicals include dihydro thiophene, dihydro pyran, dihydro furan, dihydro thiazole and the like.

Term "heteroaryl" or "heteroaromatic", used in this description separately or in combination with other radicals, denotes 5 - 6 - membered heterocyclic radicals, containing one or several getroatomov, selected from O, n-or S, such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, izotiazolil, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzopyranyl, benzopiranonil, benzofuranyl, benzothienyl, indolinil, indolyl, azaindolyl, azaindolinil, benzodigidro furanyl, thienyl benzodigidro, pirazolpirimidinil, pirazolpirimidonil, azakhinazolinil, azakhinazolinoil, piridofuranil, piridotienil, tienopirimidil, tienopirimidonil, quinolinyl, pyrimidinyl, pyrazolyl, quinazolynyl, khinazolonil, pirimidonil, pyridazinyl, triazinyl, benzoxazinyl, benzoksazinonil, benzotiazinil, benzotiazinonil, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzotriazolyl, phtalazinyl, naftilidinil, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, and the like.

Term "geterotsiklilalkil", used in this description separately or in combination with other radicals, is heterocyclyl group, having defined above value, substituted alkyl group from 1 - 12 carbon atoms, such as pirrolidinalkil, piperidinalkil, morfolinalkil, tiomorfolinalkil, oksazolinalkil and the like, which may be substituted. Term "heteroaralkyl", used in this description separately or in combination with other radicals, denotes heteroaryl group, having defined above value, attached to straight or branched saturated carbon chain, containing 1 - 6 carbon atoms, such as (2 - furyl) methyl, (3 - furyl) methyl, (2 - thienyl) methyl, (3 - thienyl) methyl, (2 - pyridyl) methyl, 1 - methyl - 1 - (2 - pyrimidyl) ethyl and the like. Terms "heteroaryloxy", "geteroaralkoksi", "geterotsikloksi", "geterotsiklilalkoksi" designate respectively geteroarilnuyu, geteroarilalkilnuyu, heterocyclyl, geterotsiklilalkilnuyu group, having defined above value, connected to atom oxygen.

Term "acyl", used in this description separately or in combination with other radicals, denotes radical, containing 1 - 8 carbon atoms, such as formyl, acetyl, propanoil, butanoyl, iso - butanoyl, pentanoyl, geksanoil, heptanoyl, benzoyl and the like, which can be substituted.

Term "acyloxy", used in this description separately or in combination with other radicals, acyl radical means, having defined above value, connected to atom oxygen, such as acetyloxy, propionyloxy, butanoylhydroxy, iso - butanoylhydroxy, benzoyloxy and the like.

Term "acylamino", used in this description separately or in combination with other radicals, denotes acyl group, having defined above value, which can be a CH-₃CONH, OF C₂H₅CONH, C3H7CONH, C4H9CONH, PRSs₅Soyn and the like, which can be substituted.

Term "monosubstituted amino", used in this description separately or in combination with other radicals, denotes amino group, substituted one group, selected from (Cl-and-SB) alkyl, substituted alkyl, aryl, substituted aryl or arylalkyl groups. Examples monoalkylamino group includes methylamine, ethylamine, n - propylamine, n - butylamine, H - pentilamin and the like.

Term "disubstituted amino", used in this description separately or in combination with other radicals, denotes amino group, substituted two radicals, which may be similar or different, selected from (Cl-and-the CE) alkyl, substituted alkyl, aryl, substituted aryl or arylalkyl groups, such as dimethylamino, methylethylamino, diethylamino, phenylmethylamino and the like.

Term "arylamino", used in this description separately or in combination with other radicals, denotes arilnuyu group, having defined above value, connected through amino, having a free valence bond from the nitrogen atom, such as phenylamino, naphthalamino, of n-methylaniline and the like.

Term "aralkylamino", used in this description separately or in combination with other radicals, denotes aralkyl group, having defined above value, connected through amino, having a free valence bond from the nitrogen atom, for example, benzylamino, fenetilamino, 3 - phenylpropylamino, 1 - naftilmetilamino, 2 - (1 - naphthyl) ethylamino and the like.

Term "oxo" or "carbonyl", used in this description separately (- s=0 -) or in combination with other radicals, such as "alkilkarbonil", means carbonyl radical (- s=0 -), substituted esterification radical, such as acyl or alkanoyl, as described above.

Term "carboxylic acid", used in this description separately or in combination with other radicals, denotes group - COOH, and includes derivatives of carboxylic acid, such as esters and amides. Term "ester", used in this description separately or in combination with other radicals, denotes group - s00i includes derivatives of carboxylic acid, where part of ester are alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl and the like, which can be substituted/ariloksikarbonilnaya group, such as phenoxycarbonyl, naftiloksikarbonil and the like, which can be substituted; aralkoksikarbonilnaya group, such as benzyloxycarbonyl, fenetiloksikarbonil, naftilmetoksikarbonil and the like, which can be substituted;

geteroariloksikarbonil, geteroaralkoksikarbonil, where heteroaryl group defined above, which can be substituted; geterotsikliloksikarbonil, where heterocyclic group defined above, which may be substituted.

Term "amide", used in this description separately or in combination with other radicals, is aminokarbonilnyi radical (h of₂ Of n-of c =0 -), where aminogruppa is mono di - substituted or unsubstituted, such as methylamide, dimethylamide, ethylamide, diethylamide and the like. Term "aminocarbonyl" is used in this description separately or in combination with other radicals, with other terms, such as "aminokarbonilalkil", "H - alkilaminokarbonil", "of n-arilaminokarbonil", "n-, of n-dialkilaminokarbonil", "s - alkyl - yarilaminokarbonil", "and - alkyl - s - hydro ksiaminokarbonil" and "s - alkyl - s - hydro ksiaminokarbonilalkil", substituted or synergistic. Terms "of n-alkilaminokarbonil" and "n-, of n-dialkilaminokarbonil" designate aminocarbonyl radicals, having defined above value, which were substituted respectively one esterification radical and two alkyl radicals. Preferable is "lower alkilaminokarbonil", radicals having lower alkyls, as described above, connected to aminokarbonilnomu radical of. Terms "of n-arilaminokarbonil" and "s - alkyl - s - arilaminokarbonil" designate aminocarbonyl radicals, substituted respectively one aryl radical, or one esterification and one aryl radical. Term "aminokarbonilalkil" includes alkyl radicals, substituted aminokarbonilnymi radicals.

Term "hydro ksialkil", used in this description separately or in combination with other radicals, denotes alkyl group, having defined above value, substituted one or several hydro xy radicals, such as hydro ksimetil, hydro ksietil, hydro ksipropil, hydro ksibutil, hydro ksipentil, hydro ksigeksil and the like.

Term "aminoalkyl", used in this description separately or in combination with other radicals, denotes a part of amino (- iii₂ ), connected to alkilnomu radical of, having defined above value, which may be substituted, such as a monoi di - substituted aminoalkyl. Term "alkylamino", used in this description separately or in combination with other radicals, denotes alkyl radical, having defined above value, which is connected to aminogroup, which can be substituted, such as mono di - substituted alkylamino.

Term "alkoxyalkyl", used in this description separately or in combination with other radicals, denotes alkoxy group, having defined above value, connected to alkyl group, such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like. Term "aryloxyalkyl", used in this description separately or in combination with other radicals, includes phenoxymethyl, naftiloksimetil and the like. Term "aralkoksialkil", used in this description separately or in combination with other radicals, includes PRSs₅ CH₂ DOS₂ , PRSs₅ CH₂ DOS₂ CH₂ and the like.

Term "alkylthio", used in this description separately or in combination with other radicals, denotes straight or branched or cyclic one-valent substituent, including alkyl group of 1 - 12 carbon atoms, as defined above, connected by means of bivalent sulfur atom, having communication free valence from sulfur atom, such as methylthio, ethylthio, propyltio, benzylthio, pentiltio and the like. Examples of cyclic alkylthio are tsiklopropiltio, tsiklobutiltio, tsiklopentiltio, cyclohexylthio and the like, which may be substituted.

Term "thioalkyl", used in this description separately or in combination with other radicals, denotes alkyl group, having defined above value, connected to group of the formula - of Sr ', where R' represents hydrogen, alkyl or arilnuyu group, for example, thiomethyl, methylthiomethyl, phenylthiomethyl and the like, which may be substituted.

Term "arylthio", used in this description separately or in combination with other radicals, denotes arilnuyu group, having defined above value, connected by means of atom bivalent sulfur, having communication free valence atom from sulfur, such as phenylthio, naftiltio and the like.

Term "alkoxycarbonylamino", used in this description separately or in combination with other radicals, means alkoxycarbonyl group, having defined above value, connected with amino group, such as methoxycarbonylamino, ethoxycarbonylamino and the like. Term "ariloksikarbonilamino", used in this description separately or in combination with other radicals, denotes ariloksikarbonilnuyu group, having defined above value, connected with amino group, such as C₆H₅OCONH, OF C₆H₅OCONCH₃ , C6H5OCONC2H5, WITH₆N₄ (CH-₃ 0) C0NH, WITH₆N₄ (OCH3) OCONH and the like. Term "aralkoksikarbonilamino", used in this description separately or in combination with other radicals, denotes aralkoksikarbonilnuyu group, having defined above value, connected with amino group, such as C₆H₅ CH-₂OCONH, Sbshchsngsngseosszhn, With₆N₅ CH₂Osoynsnz, C6H5CH2OCONC2H5, With₆N₄ (CH₃ ) CH2OCONH, WITH₆N₄ (OCH₃ ) CH-₂OCONH and the like.

Term "aminokarbonilamino", "alkilaminokarbonilamino", "dialkilaminokarbonilamino", used in this description separately or in combination with other radicals, denotes karbonilamino (- CONH2) group, connected respectively with amine about (iii₂ ), alkylamino group or dialkylamino group, where alkyl group has determined described above.

Term "amidino", used in this description separately or in combination with other radicals, denotes radical - of c (=NH) - NH-₂ . Term "alkilamidino" means alkyl radical, as discussed above, connected to amidino group.

Term "hydrazino", used in this description separately or in combination with other radicals, means

- NHNH -, it is possible, other substituted radicals, such as alkilgidrazino, where alkyl group has determined described above, is connected to gidrazinovoi group.

Term "alkoksiamino", used in this description separately or in combination with other radicals, denotes alkoxy, having defined above value, connected to aminogroup. Term "hydro ksiamino", used in this description separately or in combination with other radicals, denotes a part of - NHOH, and can be substituted.

Term "sulfenil" or "sulfenil and its derivatives", used in this description separately or in combination with other radicals, means divalent group, - SOili of R_{of X} Of so, where R is_{of X} is a substituted or unsubstituted alkyl, aryl, heteroaryl, heterocyclyl and the like.

Term "sul fonil" or "sulfones and their derivatives", used in this description separately or in combination with other radicals, with other terms, such as alkylsulfonyl, means radical - So₂ - or R_{of X} S0₂ -, where R is_{of X} is a substituted or synergistic group, selected from alkyl, aryl, heteroaryl, heterocyclyl and similar. "Alkylsulfonyl" means alkyl radicals, having defined above value, connected to sulfonilnomu radical, such as methylsulfonyl, ethylsulfonyl, propilsulfonil and the like. Term "arylsulfonyl", used in this description separately or in combination with other radicals, denotes aryl radicals, having defined above value, connected to sulfonilnomu radical, such as phenylsulfonyl and similar to it.

Term "substituted", used separately in combination with other radicals, means suitable substituents on this radikale, such as substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted aryl and T. d ., said in any place description. Suitable substituents include, but not limited by, the following radicals separately or in combination with other radicals, such as hydro ksil, oxo, halogen, thio, nitro, amino, cyano, formyl, amidino, guanidino, hydrazino, alkyl, halogenalkyl, pergalogenalkil, alkoxy, galogenalkoksi, pergalogenalkoksi, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bitsikloalkil, bitsikloalkenil, alkoxy, alkenoksi, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, geterotsiklilalkil, heteroaralkyl, heteroaryloxy, geteroaralkoksi, geterotsikliloksi, geterotsiklilalkoksi, geterotsiklilalkoksiatsil, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives, such as esters and amides, karbonilamino, hydro ksialkil, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoksialkil, alkylthio, thioalkyl, arylthio, alkylsulphonylamino, alkilsulfoniloksi, alkoxycarbonylamino, ariloksikarbonilamino, aralkiloksikarbonilamino, aminokarbonilamino, alkilaminokarbonilamino, alkoksiamino, hydro ksilamino, sulfenilnye derivatives, sulfonyl derivatives, sulfonic acid and its derivatives, phosphono acid and its derivatives.

Suitable group and substituents on groups may be chosen from the, which invention describes in any place in the description.

Especially useful compounds according to the present invention include

ethyl ester (2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - thiophene - 2 - iloksazol - 4 - ylmethoxy) phenyl] propionic acid;

ethyl ester (2s) - ethoxy - 3 - (4 - [2 - (5 - methyl - 2 - thiophene - 2 - iloksazol - 4 - yl) ethoxy] phenyl} propionic acid;

ethyl ester (2s) - ethoxy - 3 - {4 - [5 - methyl - 2 - (5 - methylthiophene - 2 - yl) oxazol - 4 - ylmethoxy] phenyl} propionic acid;

ethyl ester (2s) - ethoxy - 3 - (4 - {2 - [5 - methyl - 2 - (5 - methylthiophene - 2 - yl) oxazol - 4 - yl] ethoxy} phenyl) propionic acid;

ethyl ester (2s) - ethoxy - 3 - {4 - [5 - methyl - 2 - (3 - methylthiophene - 2 - yl) oxazol - 4 - ylmethoxy] phenyl} propionic acid;

ethyl ester (2s) - ethoxy - 3 - (4 - {2 - [5 - methyl - 2 - (3 - methylthiophene - 2 - yl) oxazol - 4 - yl] ethoxy} phenyl) propionic acid;

ethyl ester (2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - thiophene - 3 - iloksazol - 4 - ylmethoxy) phenyl] propionic acid;

ethyl ester (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - thiophene - 3 - iloksazol - 4 - yl) ethoxy] phenyl} propionic acid;

ethyl ester of 3 - [4 - (2 - benzo thiophene - 2 - yl - 5 - methyloxazol - 4 - ylmethoxy) phenyl] - (2s) - etoksipropionovoi acid;

ethyl ester of 3 - {4 - [2 - (2 - benzo thiophene - 2 - yl - 5 - methyloxazol - 4 - yl) ethoxy] phenyl} - (2s) - etoksipropionovoi acid;

ethyl ester (2s) - ethoxy - 3 - [4 - (2 - furan - 2 - yl - 5 - methyloxazol - 4 - ylmethoxy) phenyl] propionic acid;

ethyl ester (2s) - ethoxy - 3 - {4 - [2 - (2 - furan - 2 - yl - 5 - methyloxazol - 4 - yl) ethoxy] phenyl} propionic acid;

ethyl ester (2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - quinoline - 2 - iloksazol - 4 - ylmethoxy) phenyl] propionic acid and its pharmaceutically acceptable salts;

ethyl ester (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - quinoline - 2 - iloksazol - 4 - yl) ethoxy] phenyl} propionic acid and its pharmaceutically acceptable salts;

ethyl ester (2s) - ethoxy - 3 - {4 - [3 - (5 - methyl - 2 - thiophene - 2 - iloksazol - 4 - yl) propoxy] phenyl] propionic acid;

ethyl ester (2s) - ethoxy - 3 - {4 - [5 - methyl - 2 - (5 - phenylthiophen - 2 - yl) oxazol - 4 - ylmethoxy] phenyl} propionic acid;

ethyl ester (2s) - ethoxy - 3 - {4 - [5 - methyl - 2 - (5 - chlorothiophene - 2 - yl) oxazol - 4 - ylmethoxy] phenyl} propionic acid;

ethyl ester (2s) - ethoxy - 3 - {4 - [5 - methyl - 2 - (5 - bromothiophen - 2 - yl) oxazol - 4 - ylmethoxy] phenyl} propionic acid;

ethyl ester (2s) - ethoxy - 3 - {4 - [5 - methyl - 2 - (5 - methylfuran - 2 - yl) oxazol - 4 - ylmethoxy] phenyl} propionic acid;

ethyl ester (2s) - ethoxy - 3 - (4 - {2 - [5 - methyl - 2 - (5 - phenylthiophen - 2 - yl) oxazol - 4 - yl] ethoxy} phenyl) propionic acid;

ethyl ester (2s) - ethoxy - 3 - (4 - {2 - [5 - methyl - 2 - (5 - chlorothiophene - 2 - yl) oxazol - 4 - yl] ethoxy} phenyl) propionic acid;

ethyl ester (2s) - ethoxy - 3 - (4 - {2 - [5 - methyl - 2 - (5 - bromothiophen - 2 - yl) oxazol - 4 - yl] ethoxy} phenyl) propionic acid;

ethyl ester (2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - pyridine - 2 - iloksazol - 4 - ylmethoxy) phenyl] propionic acid and its pharmaceutically acceptable salts;

ethyl ester (2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - pyridine - 4 - iloksazol - 4 - ylmethoxy) phenyl] propionic acid and its pharmaceutically acceptable salts;

ethyl ester (2s) - ethoxy - 3 - [4 - {2 - (5 - methyl - 2 - pyridine - 3 - iloksazol - 4 - yl) ethoxy} phenyl] propionic acid and its pharmaceutically acceptable salts;

ethyl ester (2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - pyridine - 3 - iloksazol - 4 - ylmethoxy) phenyl] propionic acid and its pharmaceutically acceptable salts;

(2s) - Ethoxy - 3 - [4 - (5 - Methyl - 2 - Thiophene - 2 - Iloksazol - 4 -

ylmethoxy) phenyl] propionic acid and its pharmaceutically acceptable salts;

(2s) - Ethoxy - 3 - {4 - [2 - (5 - Methyl - 2 - Thiophene - 2 - Iloksazol - 4 -

dwg) ethoxy] phenyl} propionic acid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - {4 - [5 - methyl - 2 - (5 - methylthiophene - 2 - yl) oxazol - 4 - ylmethoxy] phenyl} propionic acid and its pharmaceutically acceptable salts;

(2s) - Ethoxy - 3 - (4 - {2 - [5 - Methyl - 2 - (5 - Methylthiophene - 2 -

dwg) oxazol - 4 - yl] ethoxy} phenyl) propionic acid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - {4 - [5 - methyl - 2 - (3 - methylthiophene - 2 - yl) oxazol - 4 - ylmethoxy] phenyl} propionic acid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - (4 - {2 - [5 - methyl - 2 - (3 - methylthiophene - 2 -

dwg) oxazol - 4 - yl] ethoxy} phenyl) propionic acid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - thiophene - 3 - iloksazol - 4 - ylmethoxy) phenyl] propionic acid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - thiophene - 3 - iloksazol - 4 -

dwg) ethoxy] phenyl} propionic acid and its pharmaceutically acceptable salts;

of 3 - [4 - (2 - benzo thiophene - 2 - yl - 5 - methyloxazol - 4 -

ylmethoxy) phenyl] - (2s) - etoksipropionovuyu acid and its pharmaceutically acceptable salts;

of 3 - {4 - [2 - (2 - benzo thiophene - 2 - yl - 5 - methyloxazol - 4 -

dwg) ethoxy] phenyl} - (2s) - etoksipropionovuyu acid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - [4 - (2 - furan - 2 - yl - 5 - methyloxazol - 4 - ylmethoxy) phenyl] propionic acid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - {4 - [2 - (2 - furan - 2 - yl - 5 - methyloxazol - 4 -

dwg) ethoxy] phenyl} propionic acid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - quinoline - 2 - iloksazol - 4 - ylmethoxy) phenyl] propionic acid and its pharmaceutically acceptable salts;

(2s) - Ethoxy - 3 - {4 - [2 - (5 - Methyl - 2 - Quinoline - 2 - Iloksazol - 4 -

dwg) ethoxy] phenyl} propionic acid and its pharmaceutically acceptable salts;

(2s) - Ethoxy - 3 - {4 - [3 - (5 - Methyl - 2 - Thiophene - 2 - Iloksazol - 4 -

dwg) propoxy] phenyl} propionic acid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - {4 - [5 - methyl - 2 - benzofuran - 2 - yl) oxazol - 4 - ylmethoxy] phenyl} propionic acid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - {4 - [5 - methyl - 2 - (5 - chlorothiophene - 2 - yl) oxazol - 4 - ylmethoxy] phenyl} propionic acid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - {4 - [5 - methyl - 2 - (5 - bromothiophen - 2 - yl) oxazol - 4 - ylmethoxy] phenyl} propionic acid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - {4 - [5 - methyl - 2 - (5 - methylfuran - 2 - yl) oxazol - 4 - ylmethoxy] phenyl} propionic acid and its pharmaceutically acceptable salts;

(2s) - Ethoxy - 3 - (4 - {2 - [5 - Methyl - 2 - (5 - Phenylthiophen - 2 -

dwg) oxazol - 4 - yl] ethoxy} phenyl) propionic acid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - (4 - {2 - [5 - methyl - 2 - (5 - chlorothiophene - 2 - yl) oxazol - 4 - yl] ethoxy} phenyl) propionic acid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - (4 - {2 - [5 - methyl - 2 - (5 - bromothiophen - 2 - yl) oxazol - 4 - yl] ethoxy} phenyl) propionic acid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - (4 - {2 - [5 - methyl - 2 - (5 - methylfuran - 2 - yl) oxazol - 4 - yl] ethoxy} phenyl) propionic acid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - pyridine - 2 - iloksazol - 4 - ylmethoxy) phenyl] propionic acid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - pyridine - 4 - iloksazol - 4 - ylmethoxy) phenyl] propionic acid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - pyridine - 3 - iloksazol - 4 - ylmethoxy) phenyl] propionic acid and its pharmaceutically at emlemye with Oli;

of 3 - (b - benziloksinaftalin - 2 - yl) - 2 - etoksipropan - 1 - ol;

(2s) - Ethoxy - 3 - {4 - [2 - (5 - Methyl - 2 - Phenyloxazol - 4 -

dwg) ethoxy] phenyl} propane - 1 - ol;

(2s) - Ethoxy - 3 - {4 - [4 - Hydro Xy - 3 - Methyl - 3, 4 - Dihydro Quinazoline - 2 - Ylmethoxy) Phenyl} Propane - 1 - Ol;

2gidro xy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 -

dwg) ethoxy] phenyl} propane - 1 - ol;

3 - {4 - [2 - (2.3 - dihydro benzo [1.4] thiazine - 4 - yl) ethoxy] phenyl} (2s) - etoksipropan - 1 - ol;

(2s) - Ethoxy - 3 - [4 - (2 - (Phenoxazin - 10 - Yl) Ethoxy) Phenyl] Propane - 1 - Ol;

3 - [4 - 2 - (carbazole - 9 - yl) ethoxy) phenyl] - (2s) - etoksipropan - 1 - ol;

of 3 - {4 - [2 - (3.4 - dihydro - 2h - quinoline - 1 - yl) ethoxy) phenyl] - (2s) etoksipropan - 1 - ol;

(2s) - Ethoxy - 3 - [4 - (2 - (Indole - 1 - Yl) Ethoxy) Phenyl] Propane - 1 - Ol;

(2s) - Ethoxy - 3 - [4 - (2 - (Phenothiazine - 10 - Yl) Ethoxy) Phenyl] Propane - 1 - Ol;

of 3 - {4 - [2 - (2.3 - dihydro benzo [1.4] oxazin - 4 - yl) ethoxy] phenyl} (2s) - etoksipropan - 1 - ol;

of 3 - [4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} - 2 - fenilsulfanilpropan - 1 - ol;

(2s) - Ethoxy - 3 - {4 - (2 - (2 - Methylpyridine -

ylamino) ethoxy] phenyl} propane - 1 - ol and its pharmaceutically acceptable salts;

(2s) - Ethoxy - 3 - {4 - (2 - (5 - Ethylpyridin - 2 -

dwg) ethoxy] phenyl} propane - 1 - ol and its pharmaceutically acceptable salts;

(2s) - Ethoxy - 3 - [4 - (5 - Methyl - 2 - Thiophene - 2 - Iloksazol - 4 - Ylmethoxy) Phenyl] Propane - 1 - Ol;

(2s) - Ethoxy - 3 - {4 - [2 - (5 - Methyl - 2 - Thiophene - 2 - Iloksazol - 4 -

dwg) ethoxy] phenyl] propane - 1 - ol;

(2s) - Ethoxy - 3 - (4 - {2 - [2 - Methyl - 5 - (4 -

methylsulfanylphenyl) pyrrol - 1 - yl] ethoxy} phenyl) propane - 1 - ol;

(3s) - Ethoxy - 4 - {4 - [2 - (5 - Methyl - 2 - Phenyloxazol - 4 -

dwg) ethoxy] phenyl} butane - 1 - ol;

(2s) - ethoxy - 3 - (4 - {2 - [5 - methyl - 2 - (4 -

methylsulfanylphenyl) oxazol - 4 - yl] ethoxy '} phenyl) propane - 1 - ol;

(2s) - Amino - 3 - {4 - [2 - (5 - Methyl - 2 - Phenyloxazol - 4 -

dwg) ethoxy] phenyl} propane - 1 - ol and its pharmaceutically acceptable salts;

(2s) - Tert - Butoksikarbonilamino - 3 - [4 - (5 - Methyl - 2 - Phenyloxazol - 4 - Ylmethoxy) Phenyl] Propane - 1 - Ol;

(2s) - Tert - Butoksikarbonilamino - 3 - {4 - [2 - (5 - Methyl - 2 - Phenyloxazol - 4 - Yl) Ethoxy] Phenyl} Propane - 1 - Ol;

(2s) - ethoxy - 3 - (4 - {2 - (2 - methyl - 5 - (benzofuran - 2 - yl) pyrrol - 1 - yl] ethoxy] phenyl) propane - 1 - ol;

(2s) - ethoxy - 3 - (4 - {2 - [2 - methyl - 5 - (benzo [1/3] dioxole - 5 -

dwg) pyrrol - 1 - yl] ethoxy} phenyl) propane - 1 - ol;

(2s) - ethoxy - 3 - [4 - (1 - methyl - 1H - benzimidazole - 2 -

ylmethoxy) phenyl] propane - 1 - ol;

(2s) - Ethoxy - 3 - [4 - (5 - Methyl - 3 - Phenylisoxazole - 4 -

ylmethoxy) phenyl] propane - 1 - ol;

(2s) - ethoxy - 3 - {4 - [2 - (5 - ethylpyridin - 2 - yl) - 2 - hydro ksietoksi] phenyl} propane - 1 - ol;

(2s) - Ethoxy - 3 - [4 - (2 - Benzimidazole - 1 - Iletoksi) Phenyl] Propane - 1 - Ol;

(2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - phenyloxazol - 4 -

ylmethoxy) phenyl] propane - 1 - ol;

(2s) - ethoxy - 3 - (4 - {2 - [2 - methyl - 5 - (5 - methylthiophene - 2 - yl) pyrrol - 1 - yl] ethoxy} phenyl) propane - 1 - ol;

(2s) - Ethoxy - 3 - [4 - (5 - Methyl - 2 - Phenyloxazol - 4 -

ylmethoxy) phenyl] propane - 1/2 - diol;

1etoksi - (2s) - ethoxy - 3 - [4 - {2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy} phenyl] propane;

2 - ((2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 -

dwg) ethoxy] phenyl} propoxy) ethanol;

2 - ((2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 -

dwg) ethoxy] phenyl} propoxy) benzoic acid and its pharmaceutically acceptable salts;

bromoacetate (2s) - ethoxy - 3 - [4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} slit;

of 1 - ethoxy - (2s) - ethoxy - 3 - [4 - {2 - (3.4 - dihydro - 2h -

benzo [1/4] thiazine - 1 - yl) ethoxy} phenyl] propane;

of 1 - propoxy - (2s) - ethoxy - 3 - [4 - {2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy} phenyl] propane;

2 - ((2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - phenyloxazol - 4 -

ylmethoxy) phenyl] propoxy) benzoic acid and its pharmaceutically acceptable salts;

1etoksi - (2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - phenyloxazol - 4 - ylmethoxy) phenyl] propane;

(2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - phenyloxazol - 4 -

ylmethoxy) phenyl] - 1 - fenoksipropan;

(2s) - Ethoxy - 1 - Ethylsulphinyl - 3 - {4 - (5 - Methyl - 2 - Phenyloxazol - 4 - Ylmethoxy) Phenyl} Propane;

(2s) - Ethoxy - 1 - Ethylsulphanyl - 3 - {4 - (5 - Methyl - 2 - Phenyloxazol - 4 - Ylmethoxy) Phenyl} Propane;

(2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - phenyloxazol - 4 -

ylmethoxy) phenyl] - 1 - izopropoksipropan;

(3s) - ethoxy - 4 - [4 - (5 - methyl - 2 - phenyloxazol - 4 -

ylmethoxy) phenyl] butironitryl;

(2s) - Ethoxy - 1h-- Tetrazole - 3 - [4 - (5 - Methyl - 2 - Phenyloxazol - 4 - Ylmethoxy) Phenyl] Propane;

2etoksi - 1 - [4 - (5 - methyl - 2 - phenyloxazol - 4 -

ylmethoxy) phenyl] pentane - 3 - ol;

2. 3dietoksi - 1 - [4 - (5 - methyl - 2 - phenyloxazol - 4 -

ylmethoxy) phenyl] pentane;

of 2 - ethoxy - 1 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 -

dwg) ethoxy] phenyl} pentane - 3 - ol;

2. 3dietoksi - 1 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 -

dwg) ethoxy] phenyl} pentane;

((2s) - Ethoxy - 3 - {4 - [2 - (5 - Methyl - 2 - Phenyloxazol - 4 -

dwg) ethoxy] phenyl} propoxy) acetic acid and its pharmaceutically acceptable salts;

methane sulfonate 3 - (4 - benzyloxyphenyl) - (2s) - etoksipropila;

methane sulfonate (2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - phenyloxazol - 4 - ylmethoxy) phenyl] slit;

methane sulfonate (2s) - ethoxy - 3 - {4 - [2 - (2 - methyl - 5 - (5 - methylthiophene - 2 - yl) pyrrol - 1 - yl) ethoxy] phenyl} slit;

methane sulfonate (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} slit;

methane sulfonate (2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - thiophene - 2 - iloksazol - 4 - ylmethoxy) phenyl} slit;

methane sulfonate (2s) - ethoxy - 3 - {4 - [2 - (5 - ethylpyridin - 2 - yl) ethoxy] phenyl} slit;

(2s) - Ethoxy - 1 - Methoxy - 3 - {4 - [2 - (5 - Methyl - 2 - Thiophene - 2 - Iloksazol - 4 - Yl) Ethoxy] Phenyl} Propane;

of 1 - ethoxy - (2s) - ethoxy - 3 - (4 - {2 - [5 - methyl - 2 - (4 - methylsulfanylphenyl) oxazol - 4 - yl] ethoxy} phenyl) propane;

of 1 - ethoxy - (2s) - ethoxy - 3 - {4 - {2 - [5 - methyl - 2 - thiophene - 2 - iloksazol - 4 - yl) ethoxy] phenyl} propane;

(2s) - Ethoxy - 3 - [4 - (5 - Methyl - 2 - Thiophene - 2 - Iloksazol - 4 - Ylmethoxy) Phenyl] - 1 - Etoksipropan;

methane sulfonate (2s) - ethoxy - 3 - {4 - [2 - (2 - methyl - 5 - benzofuran - 2 - ilpirrol - 1 - yl) ethoxy] phenyl} slit;

methane sulfonate (2s) - ethoxy - 3 - {4 - [2 - (2 - methyl - 5 - benzo [1.3] dioxole - 5 - ilpirrol - 1 - yl) ethoxy] phenyl} slit;

(2s) - Ethoxy - 3 - {4 - [2 - (2 - Methyl - 5 - Benzofuran - 2 - Ilpirrol - 1 - Yl) Ethoxy] Phenyl} Propyl - (4 - Methylphenyl) Sulfonate;

(2s) - Ethoxy - 3 - {4 - [2 - (2 - Methyl - 5 - Benzo [1.3] Dioxole - 5 - Ilpirrol - 1 - Yl) Ethoxy] Phenyl} Propyl - (4 - Methylphenyl) Sulfonate;

of 1 - ethoxy - (2s) - ethoxy - 3 - [4 - (1 - methyl - 1H - benzimidazole - 2 - ylmethoxy) phenyl] propane;

(2s) - Ethoxy - 3 - {4 - (5 - Methyl - 2 - Phenyloxazol - 4 -

ylmethoxy) phenyl} - 1 - propoksipropan;

of 1 - ethoxy - (2s) - ethoxy - 3 - [4 - (5 - methyl - 3 - phenylisoxazole - 4 - ylmethoxy) phenyl] propane;

methane sulfonate (2s) - tert - butoksikarbonilamino - 3 - [4 - (5 - methyl - 2 - phenyloxazol - 4 - ylmethoxy) phenyl] slit;

(2s) - Ethoxy - 3 - {4 - [2 - (5 - Methyl - 2 - Phenyloxazol - 4 -

dwg) ethoxy] phenyl} propylamine and its pharmaceutically acceptable salts;

(2s) - Ethoxy - 3 - [4 - {3 - Methyl - Troublesome Zone - Quinazoline - 4 - It - 2 -

ylmethoxy} phenyl] propylamine and its pharmaceutically acceptable salts;

((2s) - Ethoxy - 3 - {4 - [2 - (5 - Methyl - 2 - Phenyloxazol - 4 -

dwg) ethoxy] phenyl} propyl) isopropylamine and its pharmaceutically acceptable salts;

3 - {4 - [2 - (2.3 - dihydro benzo [1.4] thiazine - 4 - yl) ethoxy] phenyl} (2s) - etoksipropilamin and its pharmaceutically acceptable salts;

of 3 - (4 - benzyloxyphenyl) - (2s) - etoksipropilamin and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - thiophene - 2 - iloksazol - 4 - ylmethoxy) phenyl} propylamine and its pharmaceutically acceptable salts;

(2s) - Ethoxy - 3 - [4 - (5 - Methyl - 2 - Phenyloxazol - 4 -

ylmethoxy) phenyl] propylamine and its pharmaceutically acceptable salts;

Of N-Tert-Butoxycarbonyl - (2s) - Ethoxy - 3 - [4 - (5 - Methyl - 2 - Phenyloxazol - 4 - Ylmethoxy) Phenyl] Propylamine;

(2s) - ethoxy - 3 - {4 - [2 - (2 - methyl - 5 - (5 - methylthiophene - 2 - yl) pyrrol - 1 - yl) ethoxy] phenyl} propylamine and its pharmaceutically acceptable salts;

Ν - ((2s) - Ethoxy - 3 - {4 - (5 - Methyl - 2 - Phenyloxazol - 4 -

ylmethoxy) phenyl} propyl) methanesulfonamide;

(2s) - Ethoxy - 3 - [4 - (5 - Methyl - 2 - Phenyloxazol - 4 -

ylmethoxy) phenyl} propylamine and its pharmaceutically acceptable salts;

[(2s) - Ethoxy - 3 - [4 - (5 - Methyl - 2 - Phenyloxazol - 4 -

ylmethoxy) phenyl] propyl] ethylamine and its pharmaceutically acceptable salts;

[(2s) - Ethoxy - 3 - [4 - (5 - Methyl - 2 - Phenyloxazol - 4 -

ylmethoxy) phenyl] propyl] isopropylamine and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - {4 - [2 - (2 - methyl - 5 - benzo [1.3] dioxole - 5 - ilpirrol - 1 - yl) ethoxy] phenyl} propylamine and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - {4 - [2 - (2 - methyl - 5 - benzofuran - 2 - ilpirrol - 1 - yl) ethoxy] phenyl} propylamine and its pharmaceutically acceptable salts;

Of N - [(2s) - Ethoxy - 3 - [4 - (5 - Methyl - 2 - Phenyloxazol - 4 -

ylmethoxy) phenyl] propyl] - 2.2, 2 - trifluoroacetamide;

Of N-Ethoxycarbonyl - ((2s) - Ethoxy - 3 - {4 - (5 - Methyl - 2 - Phenyloxazol - 4 - Ylmethoxy) Phenyl} Propyl) Amine;

Of n-benzyloxycarbonyl - ((2s) - ethoxy - 3 - {4 - (5 - methyl - 2 - phenyloxazol - 4 - ylmethoxy) phenyl} propyl) amine;

Of n - [(2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - phenyloxazol - 4 -

ylmethoxy) phenyl] propyl] acetamide;

(2s) - hydro xy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 -

dwg) ethoxy] phenyl} propilazid;

of 3 - (4 - benzyloxyphenyl) - (2s) - etoksipropilazid;

(2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 -

dwg) ethoxy] phenyl} propilazid;

(2s) - ethoxy - 3 - {4 - [2 - (5 - ethylpyridin - 2 -

dwg) ethoxy] phenyl} propilazid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - phenyloxazol - 4 -

ylmethoxy) phenyl] propilazid;

(2s) - ethoxy - 3 - {4 - [2 - (2 - methyl - 5 - (5 - methylthiophene - 2 - yl) pyrrol - 1 - yl) ethoxy] phenyl} propilazid;

(2s) - ethoxy - 3 - {4 - [2 - (5 - ethylpyridin - 2 - yl) - 2 - (tretbutildimetilsilaniloksi) ethoxy] phenyl} propilazid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - {4 - [2 - (5 - ethylpyridin - 2 - yl) - 2 - hydro ksietoksi] phenyl} propilazid and its pharmaceutically acceptable salts;

(2s) - ethoxy - 3 - {4 - [2 - (2 - methylpyridine -

ylamino) ethoxy] phenyl} propilazid and its pharmaceutically acceptable salts;

(2s) - Ethoxy - 3 - [4 - (5 - Methyl - 2 - Thiophene - 2 - Iloksazol - 4 - Ylmethoxy) Phenyl] Propilazid;

(2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - thiophene - 2 - iloksazol - 4 -

dwg) ethoxy] phenyl} propilazid;

(2s) - hydro xy - 3 - [4 - (5 - methyl - 2 - phenyloxazol - 4 -

dwg) methoxy) phenyl] propilazid;

(2s) - amino - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 -

dwg) ethoxy] phenyl} propilazid and its pharmaceutically acceptable salts;

(2s) - amino - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 -

dwg) methoxy] phenyl} propilazid and its pharmaceutically acceptable salts;

(2s) - Tert - Butoksikarbonilamino - 3 - [4 - (5 - Methyl - 2 - Phenyloxazol - 4 - Ylmethoxy) Phenyl] Propilazid;

(2s) - tert - butoksikarbonilamino - 3 - [4 - (5 - methyl - 2 - phenyloxazol - 4 - iletoksi) phenyl] propilazid;

(2s) - ethoxy - 3 - {4 - [2 - (2 - methyl - 5 - benzo [1.3] dioxole - 5 - ilpirrol - 1 - yl) ethoxy] phenyl} propilazid;

(2s) - ethoxy - 3 - {4 - [2 - (2 - methyl - 5 - benzofuran - 2 - ilpirrol - 1 - yl) ethoxy] phenyl} propilazid;

Of n-benzyloxycarbonyl - (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} propylamine;

Of N-Tert-Butoxycarbonyl - (2s) - Ethoxy - 3 - {4 - [2 - (5 - Methyl - 2 - Phenyloxazol - 4 - Yl) Ethoxy] Phenyl} Propylamine;

Of N-Tert-Butoxycarbonyl-And-3 - {4 - [2 - (2.3 -

dihydro benzo [1.4] thiazine - 4 - yl) ethoxy] phenyl} - (2s) etoksipropilamin;

Of N - ((2 S-) - Ethoxy - 3 - {4 - [2 - (5 - Methyl - 2 - Phenyloxazol - 4 -

dwg) ethoxy] phenyl} propyl) acetamide;

of 3 - (4 - benzyloxyphenyl) - of n-tert-butoxycarbonyl - (2 s-) etoksipropilamin;

Of N-Tert-Butoxycarbonyl - (2s) - Ethoxy - 3 - (4 - Hydro Ksifenil) Propylamine;

Of N-Tert-Butoxycarbonyl - (2s) - Ethoxy - 3 - {4 - [2 - (5 - Ethylpyridin - 2 - Yl) Ethoxy] Phenyl} Propylamine;

(2s) - Ethoxy - 1 - Ethylsulphanyl - 3 - {4 - [2 - (5 - Methyl - 2 - Phenyloxazol - 4 - Yl) Ethoxy] Phenyl} Propane;

(2s) - ethoxy - 1 - ethylsulfonyl - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} propane.

Compounds of the general formula (1), namely (La is), (1), (1c), (of ID) and (1e), can be one or several methods, described on scheme 1.

i) compounds of the general formula (1a), where all symbols are defined above value, can be by reduction of compounds of general formula (of III), where all symbols are defined above value, R₄ is it, alkoxy, aryloxy or aralkoxy and the like.

ii) compounds of the general formula (1a), where all symbols are defined above value, can be turn in compounds of general formula (1), where all symbols are defined above value, alkylation, acylation or sulfonirovaniem.

iii) compounds of the general formula (1), where all symbols are defined above value, a of ori of is exhaust group, such as mesylate, tosylate and the like, converted into compounds of the general formula (the IC), (of ID) or (1e), where all symbols are defined above value, by interaction with metal salts of alcohols, phenols, thiols, respectively sodium azide or cyanide sodium or potassium.

Method And: Compounds of the general formula (of III) are reduced in compounds of the general formula (1a) use of suitable reducing agents, such as LiAlH₄ , NaBH₄ , diborane, NaBH₄/ OF BF₃OEt₂ , LiBH₄ , DIBAH and similar. Can be used suitable solvents, for reasonable husbandry used reducing agents, for example, for LiAlH₄ , NaBH₄ , diborane, NaBH₄/ OF BF₃OEt₂ ; preferable aprotonnye solvents, such as THF, ether, and the like compounds. With NaBH₄ , LiBH₄ and T. d. use may be also alcoholic solvents. Reaction can be carried out at temperature in the range from 0 theoretically up to temperature of reverse return reflux solvent used (solvents). Inert atmosphere may be maintained using n-gases₂ , Not or argon. Range of reaction time can be from 1 to 48 hour.

Method In: Compounds of the general formula (1a) can be alkylate by, atsilirovat or sulfonirovat in corresponding compounds of the general formula (lb-). Galidy alkyl, mesylates or tosylates and the like can be used for alkylation. Galidy dehydratase or anhydrides and suitable galidy sulfonyl can be used respectively for acylation and sulfonation. Can be used suitable base, similar gidridam metals, for example, NaH-and the like, carbonates of alkali metals, for example, potassium carbonate, sodium carbonate and the like, hydro sodium oxide, hydro potassium oxide, organic bases, for example, trialkylamines and the like. Reaction can be carried out in suitable solvents, similar the DMF, DMSO, THF, acetone, dikhlormetanu, toluolu and T. d ., or mixtures thereof. Inert atmosphere may be maintained using n-gases₂ , Not or argon. Range of reaction time can be from 1 to 48 hour.

Method With: Compounds of the general formula (1), where ori of is leaving group, such as mesyl, tosyl and the like, can be turn in compounds of the general formula (1c) by reaction with thiols in the presence of bases, similar NaH-, kN, metal of Na, karbonatu potassium, hydro of sodium oxide, potassium oxide hydro and like. Reaction can be carried out in solvents, similar the DMF, DMSO, toluolu, acetone, THF and similar or in their mixtures. Reaction can be carried out at temperature in the range from 0 theoretically up to temperature of reverse return reflux solvent used (solvents). Inert atmosphere may be maintained using n-gases₂ , HE or argon. Range of reaction time can be from 1 to 48 hour.

Method D Of: Compounds of the general formula (lb-), where ori of is exhaust group, such as mesyl, tosyl and the like, can be turn in compounds of the general formula (of ID) or (1e) by interaction with azidami metals, for example, sodium azide or it similar, respectively or cyanide sodium or cyanide of potassium and similar to them. Reaction can be carried out in solvents, similar the DMF, DMSO, toluolu, THF and similar or in their mixtures. Reaction can be carried out at temperature in the range from 0 theoretically up to temperature of reverse return reflux solvent used (solvents). Inert atmosphere may be maintained using n-gases₂ , Not or argon. Range of reaction time can be from 1 to 72 hour.

Compounds of the general formula (of if) and (of Ig) can be one or several methods, described on circuit of II.

i) compounds of the general formula (of III), where all symbols are defined above value, of a r. 4 represents NH₂ , NRiR₂ , where Ri and R₂ have defined above value, are reduced in compounds of the general formula (of if), where in all compounds symbols are defined above value.

ii) compounds of the general formula (of if), where all symbols are defined above value, converted into compounds of the general formula (of Ig), where all symbols are defined above value, alkylation or acylation.

iii) compounds of the general formula (of ID), where all symbols are defined above value, are reduced compounds about

of the general formula (of if), where all symbols are defined above value.

Method And: Compounds of the general formula (of III), where R is₄ is ν ¾ or NRiR₂ , where Ri and R? have defined above value, can be restoration in compounds of the general formula (of if) procedure, similar procedure, produced in the method and circuit. 1.

Method In: Compounds of the general formula (of if) can be turn in compounds of the general formula (of Ig) procedure, similar procedure, produced in the method in circuit 1.

Method E: Compounds of the general formula (of ID) can be restoration in compounds of the general formula (of if) with the use of reducing agents, for example, Pd on activated carbon, Raney nickel and their similar. Can be used suitable solvents, similar alcohols, ethyl acetate and the like or their mixture. Interaction can be carried out under pressure of gaseous hydrogen. Reaction temperature may be in range from 0 theoretically up to temperature of reverse return reflux solvent used (solvents). Interaction may also be performed with the use of presence of cooling systems₃ in wet solvents, such as wet THF.

Compounds of the general formula (1) may also be allows common method, described in the circuit of III

Method Of F_{t of} 2

then, compounds of the general formula (1 f0 and (of Ig) can be one or several methods, described in the circuit of III (and)

Circuit Ilia:

A of-CCHj) - L-+ Hx processors-and-of formula

γ- THE NR, R OF₂

(Iv) (Of Va)

) 4

Method Of F

^A (^CH- 2>of X n-^{Of Formula} '^Y^' THE NR₁R₂

(ig)

OF G,

Method Of G

OF A~(CH-₂ )_n- --X-Of Formula

η - - γ- NH-₂

(If)® 1

i) compounds of the general formula (of Ig), where all symbols are defined above value, can be by interaction of compounds of general formula (of IV) with compounds of the general formula (Ve), where all symbols are defined above value, of A L is group, such as halogen, mesylate, tosylate, triflat and the like.

ii) compounds of the general formula (of Ig), where one of Ri is and R? represents hydrogen, and the other is acyl, for example, tert butoxycarbonyl or benzyloxycarbonyl, and the like, can be optionally turn in compounds of the general formula (of if).

Compounds of the general formula (1a) and (1) can be one or several methods, described in the circuit of III (mpile)

Circuit Of III (Mpile):

A OF - (CH-₂ ) ^ - L-+ HX - AH

(IV)

(Vb)^G L-

" OR-, - ^^oco6f ". A OF - (CH-₂ ) OF X - -

(lb)

Or-, Of G, Method Of Η

A OF - (CH-₂ ) --x-an Ar-γ-^οη (La is)^G 1

i) compounds of the general formula (lb-), where all symbols are defined above value, can be by interaction of compounds of general formula (of IV) with compounds of the general formula (VB25), where all symbols are defined above value, of A L is group, such as halogen, mesylate, tosylate, triflat and the like.

ii) compounds of the general formula (lb-), which when Ri is is acyl, benzyl, alkoxycarbonyl, aralkoxycarbonyl and the like, can be optionally turn in compounds of the general formula (1a).

Method Of F: Compound of the general formula (IgA) or (lb-) can be by interaction of compounds of general formula (of IV), is L-group, such as halogen, mesylate, tosylate, triflat and the like, respectively with compounds of the general formula (Ve) or (of VB25). Can be used suitable base, similar gidridam metals, for example, NaH-and the like, carbonates of alkali metals, for example, potassium carbonate, sodium carbonate and the like, hydro sodium oxide, hydro potassium oxide, organic bases, for example, trialkylamines and the like. Interaction can be carried out in suitable solvents, similar the DMF, DMSO, THF, acetone, dikhlormetanu, toluolu and like, or mixtures thereof. Temperature interaction may be in range from 0 theoretically up to temperature of reverse return reflux solvent used (solvents). Inert atmosphere may be maintained using gaseous N2 of, not or argon. Time of interaction of may be in range from 1 to 72 hour.

Method Of G: Compounds of the general formula (of Ig), where one of Ri is and R₂ represents hydrogen, and the other is acyl, for example, tert - butoxycarbonyl or benzyloxycarbonyl and the like, can be optionally turn in compounds of the general formula (of if) use of suitable methods deacylation, for example, trifluoroacetic acid, for removing protection tretbutoksikarbonila or hydro bicycle using Pd/c and similar under hydrogen pressure for removing protection benziloksikarbonilnykh groups. Can be used suitable solvents, appropriate for reagent, for example, can be used chlorinated hydrocarbons, similar dikhlormetanu and the like, along with triforuksusnoi acid. For hydro bicycle preferable alcohols. Temperature interaction may be in range from 0 theoretically up to temperature of reverse return reflux solvent used (solvents). Time of interaction of may be in range from 1 to 72 hour.

Method H: Compounds of the general formula (1), where Ri represents acyl, benzyl, alkoxycarbonyl, aralkoxycarbonyl and the like, can be optionally turn in compounds of the general formula (1a) use of methods deacylation or debenzilirovaniya, for example, acid or alkali hydro bicycle for removing protection of acyl group or hydro bicycle using Pd/c and similar under hydrogen pressure for removing protection of benzyl group. Can be used suitable solvents, for reasonable husbandry of used reagent, for example, for reactions hydro bicycle can be used, for example, aqueous alcohols. For hydrogenation of preferable alcohols, ester solvents or dioxane. Temperature interaction may be in range from 0 theoretically up to temperature of reverse return reflux solvent used (solvents). Time of interaction of may be in range from 1 to 72 hour.

Compounds of the formula (iii) can be in accordance with the general circuit

i. interaction of compounds of the formula (IVb), where "and" is 4 - oksazolilnuyu group, substituted one or two substituents, selected from substituted or unsubstituted linear or branched (Cl-and-ci2) alkyl, substituted or unsubstituted single or condensed heteroaryl or heterocyclic groups;"ah" is substituted or unsubstituted phenyl dvukhvalentnyi; CI is ori of or Sri Lankan, where Ri represents hydrogen, perfluoro (C1 - C12) alkyl, substituted or synergistic group, selected from linear or branched (Cl-cproduction_i2 ) alkyl, cyclo (Cl-cproduction_i2 ) alkyl, aryl, AP (C1 - C12) alkyl, heteroaryl, geteroar (C1 - C12) alkyl, heterocyclyl, alkoxyalkyl, ariloksialkilnoi, alkoxycarbonyl, ariloksikarbonilnoi, cyclo alkiloksikarbonil hydroxide, alkyl amino Qar bonil hydroxide, arilaminokarbonilnoi or acyl groups; of R₄ is it, alkoxy or aryloxy, aralkoxy or NRiR₂ group, where Ri and R₂ have defined above value of;"U" is an integer from 1 to 3; X is O or S, by, to similar method, the above described in method of f.

of II. optional hydro lys compounds of the formula (iii), where R is₄ group is alkoxy, aralkoxy, aryloxy or NR₄R₂ , where Ri and R₂1sheyut defined above value, in one more compound of the formula (iii), where R is₄ is it.

Compounds (1) and (iii) according to the present invention may have asymmetric centers and can meet or in the form of racemates or racemic mixtures, and also in the form of separate stereoisomers, including optical isomers, inserted in the present invention. Mixture of stereoisomers may be separated by common methods, such as microbial separation, separation formed by diastereometric salts with khiralnymi acids or khiralnymi bases. Chiral acid can be a tartaric acid, mindalnuyu acid, lactic acid, camphorsulfonic acid, amino acids and the like. Chiral base can be a alkaloids khinnogo tree, (+) or (-) brucine, and - methylbenzylamine, (+) or (-) phenylglycinol, ephedrine, aminosugars, such as glyukozaminy or main amino acids, such as lysine, arginine and the like.

Compounds (1) and (iii) according to the present invention may have asymmetric centers and can meet or in the form of racemates or racemic mixtures, and also in the form of separate diastereomers of any of possible isomers, including optical isomers, inserted in the present invention. Can be to isolate using normal techniques, known professionals in this area (Jaques is Et al. "Enantiomers, Racemates and sort Resolution", WileyInterscience, 1981; R.A. Sheldon, in vitro "Chirotechnology", the Marcel Dekker, Inc.NY, the Basel, 1993, 173 - 204 and references in them; and. N Batman, g N Sheldrack and sort of j Crosby, in vitro "Chirality of in vitro the Industry of II", the John Wiley and sort Sons, Inc., 1997, 81 - 98 and references in them; E. l Eliel and sort S η. Wilen, in vitro "Stereochemistry care organiccompound", the John Wiley and sort Sons, Inc., 1999, 297 - 464 and references in them).

Should be understand, that in any from the above mentioned reactions any reactive group in molecule substrate can be protected by in accordance with usual chemical practice. Suitable protective groups in any from the above mentioned reactions are those, which usually are used in the given area. Methods of formation and removal of such protective groups are those common methods, which considered desirable for protected molecules. T. w Greene and sort p. G. m. Wuts "Protective the Groups of in vitro OrganicSynthesis", the John Wiley and sort Sons, Inc., 1999, 3^rd.Ed., 201 - 245 along with them given in the links.

Should be understand, that specified above preparing compounds of the formula (1) or (of II 1a) or their pharmaceutically acceptable salts and/or their pharmaceutically acceptable solvate is a stereoselektivnuyu procedure, and that compounds of the formula (1) or (IIIa) are single stereoisomer. Favorable, to compound of the formula (1) or (iii) attended in mixture with less than 50% mass, its racemic isomer, it is possible, at purity of 80 - 100%, and preferably, at purity of 90 - 100%, for example, 90 - 95%, most preferably, 95 - 100%, for example, 95%, 96%, 97%, 98%, 99%, and optical purity of 99.99%.

Preferably, compounds of the formula (1) or (iii) or their pharmaceutically acceptable salt and/or their pharmaceutically acceptable solvate is presented in optically pure form.

Absolute stereochemistry compounds can be determined using normal methods, such as x-ray crystallography.

Should be understand, that when substituents have different sections, where they may be are connected, and such otherwise connected substituents also are included in the present invention.

"Pharmaceutically acceptable salt", when such salts are possible, includes and pharmaceutically acceptable acid - additive, and basically a - additive salts. Pharmaceutically acceptable basically a - additive salts, part of components of the present invention, can be suitable by treatment of compounds of the invention 1 - 6 equivalents of base, such as sodium hydride, metoksid sodium, sodium ethoxide, hydro sodium oxide, tert - butoxide potassium, hydro calcium oxide, calcium acetate, calcium chloride, hydro magnesium oxide, magnesium chloride, magnesium acetate, alkoxide magnesium and by whomsoever similar. Can be used solvents, such as water, acetone, ether, THF, methanol, ethanol, tert - butanol, 2 - butanone, dioxane, propanol, butanol, isopropanol, simple diisopropyl ether, simple tert - butyl ether or their mixture. Can be used organic bases, such as lysine, arginine, methylbenzylamine, ethanolamine, diethanolamine, tromethamine, choline, guanidine and their derivatives. Acid - additive salts, in cases, when they are used, can be by treatment of acids, such as tartaric acid, almond acid, fumaric acid, malic acid, lactic acid, maleicor acid, salicylic acid, citric acid, ascorbic acid, benzenesulfonic acid, steam - toluenesulfonic acid, hydro ksinaftoevaya acid, methanesulfonic acid, acetic acid, benzoic acid, succinic acid, nitric acid and the like in solvents, such as water, alcohols, ethers, ethyl acetate, dioxane, THF, acetonitrile, the DMF or lower alkilketon, such as acetone, or their mixture.

Another aspect of the present invention includes a pharmaceutical composition, containing, at least, one of compounds of general formula (1) or (iii), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates as an active component together ' with pharmaceutically carriers used, by solvents similar to them.

Pharmaceutical compositions, containing compound of the present invention, can be common methodologies, for example, as described in Guide Remington: the science of The and sort the Practice care Pharmacy, 19^{of Th}Ed., 1995. Compositions can be in ordinary forms, such as capsule, tablets, powders, solutions, suspension, syrups, aerosol or means for local application. They may contain suitable solid or liquid carriers or in suitable sterile media for formation of solutions or suspensions for injection. Compositions can contain from 0.5 to 20%, preferably, from 0.5 to 10% mass, active compound, the rest is pharmaceutically acceptable carriers, excipients, diluents, solvents and the like.

Typical composition, containing compound of the formula (1) or (iii) or its pharmaceutically acceptable acid - additive salt, coupled with pharmaceutically acceptable excipients, which may be a carrier or solvent, or are spaced apart carrier, or are enclosed in carrier, which can be in the form of capsule, sachet, paper or other carrier. When carrier serves as diluent, it can be a solid, -solid or liquid material, which acts as a carrier, excipient or medium for active compound. Active compound can absorb on granulyarnom solid container, for example, in sachet. Some of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydro ksietoksilirovannoe castor oil, peanut oil, olive oil, gelatin, lactose, white ground, sucrose, tsiklodekstran, amilozu, magnesium stearate, talc, gelatin, agar, pectin, akatsiyu, stearic acid or lower simple alkyl esters of cellulose, silicic acid, fatty acids, amines fatty acids, monoglycerides and diglycerides of fatty acids, complicated fatty acid esters pentaeritriola, polyoxyethylene, hydro ksimetiltsellyulozu and polyvinylpyrrolidone. Similar manner, carrier or rastoritel may include any material long-term release, known in this area, such as monostearate glitserila emulsifying glitserila, separately or in mixture with wax. Compositions can also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. Composition of the invention can be be so, to provide rapid, prolonged or delayed release of active ingredient after administration to the patient, use of procedures, well known in this area.

If desired, pharmaceutical compositions can be sterilize and mixed with auxiliary agents, emulsifiers, buffers and/or staining substances and it similar, which is not performed harmful interaction with active compounds.

Path of administration may be any route, which effectively transports active preparation to corresponding or desirable section of action, such as oral, nasal, transdermal, pulmonary or parenteral, for example, rectal, stored, subcutaneous, intravenous, intrauretralnyi, intramuscular, intranasal, in the form of solution or ointment, preferably, by means of oral track.

If solid carrier is used for oral administration, the preparation can be pelletized, is placed in solid gelatin capsule in form of powder or cake, or it can be in the form of troshe or of strip. If is used liquid carrier, preparation can be in the form of syrup, emulsion, soft gelatin capsule or sterile liquid STI for injection, such as aqueous or nonaqueous, liquid suspension or solution.

For nasal injection of preparation can contain compound of the formula (1) or (iii), dissolved or suspended in liquid carrier, in particular, aqueous carrier, for aerosol application. Carrier can contain additive, such as solubilizing agents are also, for example, polyethylene glycol, surface - active substances, amplifiers suction, such as lecithin (phosphatidylcholine) or cyclodextrin, or preserving agents, such as parabens.

For parenteral administration especially suitable are solutions or suspension for injection, preferably, aqueous solutions with active compound, dissolved in polyhydro ksilirovannomkastorovom butter.

Tablet, dragee or capsule, having talc and/or hydrocarbon carrier or binding substance or the like, are useful especially for oral use. Preferably, carriers for tablets, dragee or capsules include lactose, corn starch and/or potato starch. Syrup or elixir can be used in cases, when can be used tea carrier.

A typical tablet, which can be common methodologies tableting, may contain:

Coating can be composed of the following ingredients in changing compositions:

Crude shellac

Gelatin

Gumiarabik

Sucrose

Titanium dioxide

Bee wax

Carnauba wax

Etilvanilin

Composition of the general formula (1) or (iii) or their compositions can be used for treatment and/or prophylaxis of diseases, caused by metabolic disorders, such as hyperlipidemia, resistance to insulin, resistance to

leptinu, hyperglycemia, obesity or inflammation.

These compounds can be used for treatment of hypercholesterolemia, family hypercholesterolemia, hypertriglyceridemia, type 2 diabetes, dyslipidemia, disorders, associated with syndrome of X, such as hypertension, obesity, resistance to insulin, coronary heart disease, atherosclerosis, ksantoma, insult, peripheral vascular disease and related disorder, such as glomerulonephritis, glomeruloskleroz, nephritic syndrome, hypertonic nefroskleroz, retinopathy, nephropathy, psoriasis, ovary polycystic syndrome, osteoporosis, inflammatory intestinal disease, miotonicheskaya dystrophy, arteriosclerosis, ksantoma, pancreatitis, and for treatment of cancer.

Compound of the invention may be introduced mammal, in particular, a human, requiring such treatment, prevention, elimination, alleviating or facilitating of said diseases.

Proposed compounds are effective in wide range of butadiene, however, accurate dose of, path administration and form of composition depends on treatment to be an individual, and is determined doctor or vet, responsible treatment an individual. As a whole, can be used dosage from approximately 0.025 to approximately 200 mg, preferably, from approximately 0.1 to approximately 100 mg/d. As a whole, standard medicinal formulation approximately from 0.01 to 100 mg of compound of the formula (1) or (iii) as an active ingredient with a pharmaceutically acceptable carrier. Usually suitable medicinal forms for nasal, transdermal or pulmonary administration include from approximately 0.001 mg to about 100 mg, preferably, from 0, 01 mg to approximately 50 mg of active ingredient, mixed with pharmaceutically acceptable carrier or vehicle.

In another aspect of the present invention is provided method of treatment and/or prevention of diseases, said•

In one more aspect of the present invention is provided use of one or several compounds of the formula (1) or (iii) or pharmaceutically acceptable salts for them of medication for treatment and/or prevention of diseases, said in the present invention.

In one more aspect of the present invention is provided use of compounds of the present invention separately or in combination with statinami, glitazonami, biguanidami, inhibitors of angiotensin ii, aspirin, stimulator of insulin secretion, inhibitor of sitosterol, sulphonylureas, insulin, derivatives fibrovoi acid, nicotinic acid, kholestiraminom, kholestipolom or probukolom, inhibitors of and - glikozidazy or antioxidants, which may be introduced together or within such period, that they acted synergistically together.

The invention is explained specifically given below examples, which presented only as illustration and therefore should not be considered as limiting volume of invention.

Spectral data¹ H nuclear magnetic resonance, given in the tables (cm. below) registered with use of spectrometer 300 MHz (BrukerAVANCE-and-300) and are presented on scale of Δ. No other directives of used solvent for nuclear magnetic resonance is a cdc1₃ using tetramethylsilane as internal standard.

Production of 1

Ethyl ester (2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - thiophene - 2 - iloksazol - 4 -ylmethoxy) phenyl] propionic acid (compound № 1)

Mixture ethyl ester (2s) - ethoxy - 3 - (4 - hydro ksifenil) propionic acid (4.09 g) and anhydrous potassium carbonate (3.33 g) in the DMF (40 ml) is heated at 80 theoretically for 1 hour. Mixture is cooled to 50 theoretically and added 4 - chloromethyl - 5 - methyl - 2 - thiophene - 2 - iloksazol (4.4 g). Reaction mixture is further heated at 80 theoretically for 6 hour. Later than its cooled to 20 theoretically - 25°с and water is added (80 ml), and crude product is extracted with ethyl acetate (2χ40 ml), washed with water (2x50 ml), saline buffer (50 ml) and dried over anhydrous sodium sulfate. Solvent is evaporated under spider nnym pressure for production of oily product. Crude oily product chromatographed through silica gel using ethyl acetate: petroleum ether (60 - 8 0) (1:9) as eluent to produce said in the heading of the product in the form of colorless solid substance.

Production of 2

Ethyl ester (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - thiophene - 2 -

iloksazol - 4 - yl) ethoxy] phenyl} propionic acid

Mixture ethyl ester (2s) - ethoxy - 3 - (4 - hydro ksifenil) propionic acid (1.9 g) and potassium carbonate (1.51 g) in toluene (15 ml) is heated at 80 theoretically for 1 hour. Mixture is cooled to 50 theoretically and added methyl - 2 - [5 - methyl - 2 - thiophene - 2 - iloksazol - 4 - yl] etilsulfonat (2.56 g). Reaction mixture is further heated at 80 theoretically for 16 hour. Later than its cooled to 20 theoretically - 25°с, water is added (20 ml), and crude product is extracted with ethyl acetate (2x25 ml). Organic extract is washed with water (2χ20 ml), saline buffer (25 ml) and dried over anhydrous sodium sulfate. Solvent is evaporated under spider nnym pressure for production of oily product. Crude oily product chromatographed through silica gel using ethyl acetate: petroleum ether (60 - 80) (1:9) as eluent to produce said in the heading of the product in the form of yellow oil.

Similar manner is obtained the following compounds in the table 1 in accordance with the method, a method similar, above described in polucheniyakh 1 and 2.

Table 1:

O

Production of 3

(2s) - ethoxy - 3 - [4 - (5 - methyl) - 2 - thiophene - 2 - iloksazol - 4 -

ylmethoxy) phenyl] propionic acid (compound № 27)

Mixture ethyl ester (2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - thiophene - 2 - iloksazol - 4 - ylmethoxy) phenyl] propionic acid (0.5 g), hydro of sodium oxide (0, 062 g in 5 ml of water) in methanol (10 ml) is stirred at 20 theoretically - 25°с for 16 hour. Solvents is evaporated under spider nnym pressure. Residue is dissolved water (10 ml) and acidified diluted hydrochloric acid. Product is extracted with ethyl acetate (2x25 ml), washed with water (2χ25 ml), saline buffer (30 ml) and dried over sodium sulfate. Solvent is evaporated under spider nnym pressure for production of 0.4 g of said in the heading of the compounds. Similar manner is obtained the following compounds in the table 2 in accordance with procedure, similar procedure, produced in production of 3.

Table 2:

O

Production of 4 (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 -

dwg) ethoxy] phenyl} propane - 1 - ol (compound " № 64)

Lithium hydride - aluminum (465 mg) is added by portions to ice solution ethyl ester (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} propionic acid (2.7 g) in tetrahydro furane during period of 15 min, and reaction mixture is mixed more for 15 min at the same temperature. Reaction is suppressed the precautionary addition by drops of saturated solution of sodium sulfate in water. Solid substances is filtered hot and washed with ethyl acetate. Combined filtrate is dried above sodium sulfate and evaporated. A crude product chromatographed through silica gel using 5 - 25% ethyl acetate in petroleum ether for production of 2.6 g of said in the heading of the compounds. Similar manner is obtained the following compounds in the table 3 and 4 in accordance with procedure, produced in production of 4.

Table 3:

Table 4:

R¹ 0-And-Of Formula^//4f^^G 2

Specific Gl

Production of 5 of L-ethoxy - (2s) - ethoxy - 3 - [4 - {2 - (5 - methyl - 2 - phenyloxazol - 4 -

To mixed suspension powder-like hydro of sodium oxide (250 mg) in dimethylsulfoxide (10 ml) is added (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} propane - 1 - ol (compound № 64) (1.15 g) and stirred at ambient temperature for 20 min. Reaction mixture is cooled in ice bath and is added ethyl iodide (0.5 g) and mixed for more 30 min at the same temperature mixing for 17 h at environmental temperature in nitrogen atmosphere. Reaction mixture is poured in ice water and extracted simple diethyl ether (3x50 ml). Combined organic extract is washed with water (100 ml), saline buffer (100 ml), dried over sodium sulfate and evaporated under spider nnym pressure. A crude product chromatographed through silica gel using 5% ethyl acetate in simple petroleum ether for production of 0.6 g of said in the heading of the compounds.

Production of 6

Of 2 - ((2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 -

Stage 1: Production of methyl - 2 - ((2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} propoxy) benzoate.

To the solution of the sulfonate (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} slit (compound № 91) (0.9 g) in toluene (10 ml) is added potassium carbonate (0.5 g) followed by addition of methyl salicylate (0.25 ml), and reaction mixture is boiled in vessel with reflux condenser for 3 hour. Reaction mixture is cooled to ambient temperature and is poured in ice water. Its is extracted with ethyl acetate (3x50 ml). Combined organic extract is washed with water (100 ml), saline buffer (100 ml), dried over sodium sulfate and evaporated under spider nnym pressure for production of 818 mg product.

Stage 2; Of 2 - ((2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} propoxy) benzoic acid.

To the solution of methyl - 2 - ((2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} propoxy) benzoate (518 mg) in methanol (10 ml) is added other solution hydro of sodium oxide (241 mg) in water (5 ml) and reaction mixture is stirred at ambient temperature for 72 hour. Solvents is evaporated under spider nnym pressure. Residue is dissolved in water (50 ml), acidified 1h-ns1 and extracted simple diethyl ether (3x50 ml). Combined organic extract is washed with water (50 ml), saline buffer (50 ml), dried over sodium sulfate and evaporated under spider nnym pressure. A crude product repeatedly is crystallized from mixture of diisopropyl ether and simple petroleum ether for production of 345 mg product.

Production of 7

((2s) - Ethoxy - 3 - (4 - [2 - (5 - Methyl - 2 - Phenyloxazol - 4 -

dwg) ethoxy] phenyl} propoxy) acetic acid (compound № 87)

Stage 1: Production of ethyl - 2 - ((2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} propoxy) acetate.

To mixed 50% suspension of sodium hydride (189 mg) in tetrahydro furane (10 ml) solution is added (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} propane - 1 - ol (1.0 g) in 5 ml tetrahydro furane at temperature below 10 theoretically and stirred at ambient temperature for 2 hour. Reaction mixture again is cooled below 10 theoretically and to it is added ethyl bromoacetate (1.75 ml) and stirred at ambient temperature for 15 hours. Reaction mixture is poured in ice water (50 ml) and extracted simple diethyl ether (3x50 ml). Combined organic extract is washed with water (100 ml), saline buffer (100 ml), dried over sodium sulfate and evaporated under spider nnym pressure. A crude product chromatographed through silica gel using 7% ethyl acetate in simple petroleum ether for production of 350 mg of said in the heading of the product and 300 mg bromatsetata (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 -

dwg) ethoxy] phenyl} slit (compound № 90)

Stage 2: Production of ((2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} propoxy) acetic acid.

Specified in the heading of the compound is prepared from ethyl - 2 - ((2s) ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 -

dwg) ethoxy] phenyl} propoxy) acetate in accordance with procedure, similar procedure, produced at stage 2 of producing 6.

Production of 8

Methane sulfonate (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} slit (compound № 91)

To the solution of the (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} propane - 1 - ol (compound 64) (5.4 g) in dichloromethane (80 ml) is added triethylamine (3.0 guide vanes) and cooled to 10 theoretically. To it by drops chloride is added metansulfonila (1.1 ml), and reaction mixture is stirred at ambient temperature for 3 hour. Reaction mixture is diluted with dichloromethane (100 ml) and washed with water (100 ml). Organic layer dried over sodium sulfate and evaporated under spider nnym pressure for production of 6.0 g of said in the heading of the compounds.

Similar manner is obtained the following compounds in the table 5 in accordance with procedure, produced in polucheniyakh 5 - 8, use of corresponding reagents and conditions of interaction.

Table 5:

Production of 9

of 2 - ethoxy -! - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} - 3 -

K2CO3 (0.645 g) added to solution of 4 - (pentane - 2 - ethoxy - zgidro xy) phenol (700 mg) in toluene (5 ml) at 20 - 30 theoretically. Reaction mixture is stirred at reverse return reflux for 1 hour. To reaction mixture sulfonate is added 2 - (2 - phenyl - 5 - methyloxazol - 4 - yl) etilmetana (878 mg). Reaction mixture is stirred for 36 h at the temperature of reverse return reflux. Reaction mixture is poured into water (25 ml) and extracted with ethyl acetate (2x25 ml). Combined organic layer is washed with water (2χ50 ml) and saline buffer (50 ml), dried over sodium sulfate and evaporated under spider nnym pressure. A crude product chromatographed through silica gel using a simple petroleum ether: ethyl acetate (9:1) as eluent for production of 157 mg pure product.

Production of 10

of 2 - ethoxy -! - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} - 3 - etoksipentan (compound № 115)

K₂ CS (0, 368 g) added to solution of 4 - (pentane - 2, 3 - diethoxy) phenol (403 mg) in toluene (5 ml) at 20 - 30 theoretically. Reaction mixture is mixed at temperature of reverse return reflux for 1 hour. To reaction mixture sulfonate is added 2 - (2 - phenyl - 5 - methyloxazol - 4 - yl) etilmetana (500 mg). Reaction mixture is stirred for 36 h at the temperature of reverse return reflux. Reaction mixture is poured into water (25 ml) and extracted with ethyl acetate (2x25 ml) . Combined organic layer is washed with water (2 * 50 ml), saline buffer (50 ml), dried over sodium sulfate and evaporated under spider nnym pressure for outlet of said crude in the heading of the compounds (206 mg). A crude product chromatographed through silica gel using a simple petroleum ether: ethyl acetate (9:1) as eluent - for production of 90 mg pure product.

Similar manner is obtained the following compounds in the table 6 in accordance with the method, described in polucheniyakh 9 - 10.

Table 6:

G3

Production of 11

Azide (2s) - Ethoxy - 3 - {4 - [2 - (5 - Methyl - 2 - Phenyloxazol - 4 -

N₃

To the solution of the sulfonate (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} slit (compound 91) (6.5 g) in dimethylformamide (30 ml) is added sodium azide (5.3 g), and reaction mixture is heated to 90 theoretically for 4 hour. Reaction mixture is cooled to 25 theoretically and poured in water and extracted with ethyl acetate (3x100 ml). Combined organic layer is washed with water (100 ml), saline buffer (100 ml), dried over sodium sulfate and evaporated under spider nnym pressure. A crude product grated powder with methanol (30 ml) for outlet of 4.5 g of said in the heading of the compounds.

Similar manner is obtained the following compounds in the table 7 procedure, similar the, which described is for production of 11.

R¹ Of Q-Of Formula

Table 7:

Production of 12

(2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 -

dwg) ethoxy] phenyl} propylamine (compound № 134)

To emulsion 10% palladium on activated carbon (450 mg)

ethyl acetate solution is added (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} propilazida. (compounds 116) (4.5 g) in ethyl acetate (15 ml) and mixture is stirred in hydrogen atmosphere for 17 hour. Catalyst is filtered and filtrate is evaporated under spider nnym pressure for outlet of 3.2 g of said in the heading of the compounds.

Production of 13 (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 -

dwg) ethoxy] phenyl} propylamine (compound № 134)

To the solution of the of n-tert-butoxycarbonyl - (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} propylamine (compound 152) (500 mg) in dichloromethane (10 ml) is added trifluoroacetic acid (0.3 ml) and reaction mixture is stirred at ambient temperature for 16 hour. Reaction mixture is diluted dichloromethane (25 ml) and washed aqueous solution of sodium bicarbonate (50 ml). Organic extract is dried above calcium carbonate and evaporated under spider nnym pressure for outlet of 300 mg of said in the heading of the compounds.

Lithium hydride - aluminum (236 mg) is added by portions to ice solution (2s) - ethoxy - 3 - {4 - [2 - (2 - methyl - 5 - (5 - methylthiophene - 2 - yl) pyrrol - 1 - yl] ethoxy] phenyl} - 1 - azidopropana (2.4 g) in tetrahydro furane (25 ml) for 15 min and reaction mixture is stirred for 3 more hours at the same temperature. Saturated solution of sodium sulfate in water is added by drops is carefully the, until otdelyalos crystalline white solid substance. Solid substances is filtered hot and washed with ethyl acetate. Combined extract is dried above sodium sulfate and evaporated. A crude product chromatographed through silica gel using 5 - 25% ethyl acetate in simple petroleum ether for outlet of 1.9 g of said in the heading of the compounds.

Production of 15

N- {(2s) - Ethoxy - 3 - [4 - (5 - Methyl - 2 - Phenyloxazol - 4 -

ylmethoxy) phenyl] propyl} methanesulfonamide (compound № 140)

To solution (2s) - ethoxy - 3 - [4 - (5 - methyl - 2 - phenyloxazol - 4 - ylmethoxy) phenyl] propylamine (200 mg) in dichloromethane (5 ml) is added triethylamine (55 mg) and cooled to 10 theoretically. To it by drops chloride is added methanesulfonyl (0.042 ml) and reaction mixture is stirred at ambient temperature for 3 hour. Reaction mixture is diluted dichloromethane (10 ml) and washed with water (10 ml). Organic layer dried over sodium sulfate and evaporated under spider nnym pressure for outlet of 227 mg crude product. A crude product chromatographed through silica gel using 5 - 25% ethyl acetate in simple petroleum ether for outlet of 141 mg of said in the heading of the compounds.

Similar manner is obtained compound in table 8 in accordance with procedure, produced in polucheniyakh 12 - 15.

Table 8:

R¹ 0-And-Of Formula

2

Specific Gl

Production of 16

Ν - ((2 S-) - Ethoxy - 3 - {4 - [2 - (5 - Methyl - 2 - Phenyloxazol - 4 -

dwg) ethoxy] phenyl} propyl) acetamide (compound № 151)

To the solution of the (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} propylamine (compound 134) (100 mg) in dichloromethane (5 ml) is added triethylamine (53 mg) followed by addition of acetic anhydride (40 mg) at 10 theoretically and stirred at the same temperature for 2 hour. Reaction. mixture is poured in ice water and extracted simple diethyl ether (3χ50 ml). Combined organic extract is washed with water (50 ml), saline buffer (50 ml), dried over sodium sulfate and evaporated under spider nnym pressure for outlet of 70 mg of said in the heading of the compounds.

Production of 17

Of N-Tert-Butoxycarbonyl - (2s) - Ethoxy - 3 - (4 -

hydro ksifenil) propylamine (compound № 150)

To solution of 3 - (4 - benzyloxyphenyl) - of n-tert-butoxycarbonyl (2s) - etoksipropilamina (compound 149) (10.7 g) in methanol (100 ml) emulsion is added 10% palladium on activated carbon (1.0 g) in methanol and formiate ammonium (7.0 g) and mixture is boiled in vessel with reflux condenser in nitrogen atmosphere for 2 hour. Catalyst filtered and filtrate is concentrated in vacuum. To the residue water is added and extracted with ethyl acetate (3x100 ml). Combined extract is washed with water (100 ml), saline buffer (100 ml), dried over sodium sulfate and evaporated under spider nnym pressure for outlet of 8.0 g of said in the heading of the compounds.

Production of 18

Of N-Tert-Butoxycarbonyl - (2s) - Ethoxy - 3 - {4 - [2 - (5 - Methyl - 2 -

phenyloxazol - 4 - yl) ethoxy] phenyl} propylamine (compound № 152)

Mixture sulfonate 2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethyl (1.0 g), of n-tert-butoxycarbonyl - (2s) - ethoxy - 3 - (4 - hydro ksifenil) propylamine (compounds № 150) (1.0 g) and potassium carbonate (1.0 g) in dimethylformamide (15 ml) is stirred at 75 theoretically for 16 hour. Reaction mixture is cooled to 25 theoretically, is poured in ice water and extracted with ethyl acetate (3χ50 ml). Organic layer is washed with water (100 ml), saline buffer (100 ml), dried over sodium sulfate and evaporated under spider nnym pressure. A crude product chromatographed through silica gel using 7% ethyl acetate in petroleum ether for outlet of 1.3 g of said in the heading of the compounds.

Similar manner is obtained compound in table 9 in accordance with procedure, produced in polucheniyakh 16 - 18, with use of suitable acylating agents.

Table 9:

R¹ 0-And-Of Formula

G₂

(2 s-) - ethoxy - 1 - ethylsulphanyl - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} propane (compound № 161)

To mixed mixture of metal sodium (150 mg) and ethanethiol (0.49 ml) in tetrahydro furane (10 ml) is added by drops solution (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} propilmetansulfonata (compounds № 91) (0.6 g) in 5 ml tetrahydro furan during period of 10 min and the reaction mixture is stirred at ambient temperature for 15 hours. Reaction mixture is poured in ice water and extracted with ethyl acetate (3x50 ml). Organic layer is washed with water (100 ml), saline buffer (100 ml), dried over sodium sulfate and evaporated under spider nnym pressure. A crude product

chromatographed through silica gel using 10 - 15% ethyl acetate in petroleum ether as eluent for outlet of 420 mg of said in the heading of the compounds.

To ice solution (2s) - ethoxy - 1 - ethylsulphanyl - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} propane (compounds № 161) (250 mg) in acetone (10 ml), is added okson (900 mg) and reaction mixture is stirred at ambient temperature for 2 hour. Solvent is evaporated under spider nnym pressure, precipitate is added to water and extracted with ethyl acetate (3x50 ml). Organic layer is washed with water (50 ml), saline buffer (50 ml), dried over sodium sulfate and evaporated under spider nnym pressure. A crude product chromatographed through silica gel using 15% ethyl acetate in petroleum ether for outlet of 85 mg of said in the heading of the compounds.

Production of 21

(3s) - Ethoxy - 4 - [4 - (5 - Methyl - 2 - Phenyloxazol - 4 -

ylmethoxy) phenyl] butironitryl (compound № 165)

ylmethoxy) phenyl} propilmetana (1.5 g) in the DMF (7.5 ml) at 20 - 30 theoretically. Reaction mixture is stirred at 85 - 90 theoretically for 18 hour. Reaction mixture is poured into water (20 ml) and product is extracted with ethyl acetate (2x20 ml). Combined extract is washed with water (2χ40 ml), saline buffer (40 ml), dried over sodium sulfate and evaporated under spider nnym pressure for outlet of 1.2 g of said in the heading of the compounds.

Production of 22 (2s) - ethoxy - 1h-- tetrazole - 3 - [4 - (5 - methyl - 2 - phenyloxazol - 4 - ylmethoxy) phenyl] propane (compound № 166)

(Bu)₃SnN₃ (1.27 g) is added to solution (3s) - ethoxy - 4 - [4 - (5 - methyl - 2 - phenyloxazol - 4 - ylmethoxy) phenyl] butironitrila

(compound № 165) (1.2 g) in xylene (15 ml) at 20 - 30 theoretically. The reaction mixture is stirred at boiling in vessel with reflux condenser for 18 hour. Reaction mixture is cooled to 20 - 30 theoretically. Reaction mixture is diluted with ethyl acetate (25 ml), washed 10% ns1 (20ml), water (3 * 25 ml), saline buffer (25 ml), organic layer dried over sodium sulfate and evaporated under spider nnym pressure for outlet of said crude in the heading of the compound (1.1 g). A crude product chromatographed through silica gel using a simple petroleum ether: ethyl acetate (9:1) as eluent for production of 700 mg pure product at outlet yield of 52%.

Similar manner is obtained compound in table 10 in accordance with procedure, produced in polucheniyakh 19 - 22 with the use of suitable acylating agents.

Table 10:

R¹ Of 0 - Ah

Production of 23

Bisulfate (25) - ethoxy - 3 - {4 - [2 - (5 - methyl~2 - phenyloxazol - 4 -dwg) ethoxy] phenyl} propylamine (compound 167)

To (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) ethoxy] phenyl} propilaminu (compound № 134) (300 mg) is added cooled solution of acetone (3 ml), containing sulfuric acid (77 mg), and stirred at 0 theoretically for 30 min. Solvent is evaporated in flow of nitrogen and residue is mixed with simple diisopropyl ether for production of product (138 mg).

Production of 24

Oxalate (2s) - ethoxy - 3 - {4 - [2 - (5 - methyl - 2 - phenyloxazol - 4 - yl) methoxy] phenyl} propylamine (compound 173)

₀AJ s^cOOH

To the solution of the (2s) - ethoxy - 3 - {4 - (5 - methyl - 2 - phenyloxazol - 4 - yl) methoxy] phenyl} propylamine (compound № 141) (200 mg) in isopropyl alcohol (5 ml) is added oxalic acid dihydrate (64 mg) and stirred at 28 theoretically for 30 min. And separated solid filtered and dried for obtaining said in the heading of the compound (140 mg).

Similar manner is obtained compound in table 11 in accordance with procedure, produced in polucheniyakh 23 - 24.

Compounds of the present invention inhibited levels of triglycerides, total cholesterol, LDL, VLDL and glucose and volts level HDL in serum. This dapsone displayed a experiments on animals in vivo of.

And) demonstration efficiency of compounds in vivo of:

i) activity, decreasing triglyceride and total cholesterol in serum Swiss white mice:

Male Swiss white mice (the SAM) spent in vivarium Zydus. All these animals contained at cycle light - darkness by 12 h at 25 ± 1 theoretically. Animal obtained standard laboratory feed (NIH, Hyderabad, India MRT) and water without restrictions. The SAM used with body weight in the range of 20 - 30 g.

Tested compounds 1.20 perorally Swiss white mice in a dose of from 0.001 to 50 mg/kg/day for B days. Compound 1.20 after suspending it in 0.25% detergent (carboxymethylcellulose) or in water, when compound soluble in water. Control mice treated carrier (0.25% detergent karboksimetiltsellyulozoi; dose 10 ml/kg).

Of blood samples took on 0 - day in sytom state through 1 hour after preparation introduction on B - treatment day. Blood took in not geparinizirovannyi capillary tube and serum analyzed for determining level of triglyceride and total cholesterol (Wieland, about. Methods from care Enzymaticanalysis. Bergermeyer, η ., 0 ., Ed., 1963, 211 - 214; Trinder, p. Ann. Clin. Biochem. 1969. 6:24 - 27). Measurement of level of triglyceride and total cholesterol was carried out with the use of available in sale of sets of (Zydus-and-Cadila,

Pathline, Ahmedabad, India MRT).

Formula for calculating:

Percentage WiFi client continuously tracks the level of triglycerides/total cholesterol in % expected in compliance with formula WiFi client continuously tracks the percentage (%)=

HP/FROM

1 - X 100

VEHICLE/OC

OC=value in control group in 0 - day

From=value in treated group in 0 - day

Vehicle=day dough in control group

HP=day dough in treated group

ii) decreasing cholesterol level activity on models hypercholesterolemia in rats

Male rats of livestock SpragueDawley contained in vivarium Zydus at cycle light - darkness by 12 h at 25 ± 1 theoretically. For experiment used rats with body weight in the range of 100 - 150 g. Hypercholesterolemia in animals summoned feeding 1% cholesterol and 0.5% sodium kholatom, mixed with standard laboratory feed (NIH, Hyderabad, India MRT). Said feed and water animals obtained without restrictions for 5 days. Animals kept at the same diet for experiment [the Petit prosthetic, Bonnefis m. τ ., the Rey with and sort Infante R, to Effects care ciprofibrate of an liverlipids and sort lipoproteinsynthesis in vitro the Normal and sort hyperlipidemicrats, Atherosclerosis, 74, 215 - 225 tested compounds 1.20 in oral from 0.03 to 50 mg/kg/day for 4 days after suspending it in 0.25% detergent or in water, when compound soluble in water. Control group treated carrier (0.25% detergent karboksimetiltsellyulozoi; dose 10 ml/kg).

Of blood samples took on 0 - day in sytom state through 0 hour and 1 hour after preparation introduction on B - treatment day. Blood took from retroorbitalnoi cavity through not geparinizirovannyi capillary tube and serum samples analyzed for determining level of triglyceride and total cholesterol using available in sale of sets of (Zydus-and-Cadila, Pathline, Ahmedabad, India MRT). Levels of LDL and HDL determined available in sets of sale (the Point of Scientific, the USA). Level of cholesterol LDL and VLDL expected by data, obtained by level of total cholesterol, HDL and triglyceride.

WiFi client continuously tracks the cholesterol level VLDL is calculated in accordance with formula:

Cholesterol VLDL in mg/PCL=common cholesterol - cholesterol HDL - cholesterol LDL

Table 2

iii) decreasing glucose level in serum activity on models in mice dB is/dB is

Animal homozygous mouse C57BL/KSJ-and-dB is/dB is suffer obesity, hyperglycemia, giperinsulinemiei and are resistant to insulin (j-. Clin. And not to ., 85, 962 - 967, 1990), while heterozygous mouse evil and have normal blood glucose level. Homozygous animals very close simulate diabetes mellitus of type II in human, when levels of blood sugar not sufficiently are controlled. Since this type of model recalls diabetes mellitus of type II in human, compound of the invention

to determine their anti-diabetic activity on this model.

Proposed compounds expressed activity, roof glucose level and triglycerides in serum.

In experiment used male mice C57BL/KSJ-and-dB is/dB age 8 - 14 weeks with body weight in the range of 40 - 60 g, shipped from Jackson Laboratory and, the USA.

Tested compounds suspended in 0.25% carboxymethylcellulose or dissolved in volatile water, when compound soluble in water, and 1.20 tested group, including 6 animals at a dose of from 0.001 mg to 50 mg/kg by means of oral administration daily for 6 d. Control group receives carrier (in a dose of 10 ml/kg). On 6 - day through 1 hour after preparation introduction took blood from retroorbitalnoi cavity and analyzed content and glucose and triglycerides in serum using available in sale of sets of (Zydus-and-Cadila, Pathline, Ahmedabad, India MRT). Roof glucose level and triglycerides in serum activity of tested compounds expected in compliance with formula

Decreasing glucose level activity (%)=

hP/from

1 - X 100

VEHICLE/OC

OC=value in control group in 0 - day

From=value in treated group in 0 - day

Vehicle=day dough in control group

HP=day dough in treated group

Neither for one of the indicated compounds invention not observed side effects. Compounds of the present invention expressed sufficient roof glucose level, lipids and serum cholesterol activity used in experimental animals. These compounds can be used for treatment or prophylaxis of diseases, caused by hyperlipemia, hypercholesteremia, giperinsulinemiei, hyperglycemia, such as insulin - independent diabetes mellitus, cardio - vascular disease, insult, hypertension, obesity, since such disease are interconnected.