Derivatives of butyric acid

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of butyric acid of the formula (I): wherein A means carboxyl or (C6-C18)-alkoxycarbonyl; B means ethylene group -CH2-CH2-; R1 means benzyl optionally substituted in phenyl ring, optionally substituted phenyl or optionally substituted pyridyl; Z represents sulfur (S) or selenium (Se) atom; n means a whole number = 0, 1 or 2; R2 represents radical chosen from optionally substituted phenyl, optionally substituted benzopyridine, optionally substituted benzothiazole, optionally substituted quinolyl, optionally substituted naphthyl, optionally substituted triazole and radical of the formula: Also, invention describes methods for synthesis of compounds of the formula (I) and pharmaceutical composition based on thereof. Compound can be used in preparing a medicine designated for treatment or prophylaxis of dyslipidemia and diabetes mellitus.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 1 tbl, 81 ex

 

This invention relates to derivatives of 4-(arieti)or (4 heteroaromatic)butyric acid, which can be used in the treatment of dyslipidaemia, atherosclerosis and diabetes, to contain their pharmaceutical compositions, and methods of producing such compounds.

The invention also relates to the use of these compounds to obtain drugs for the treatment of dyslipidaemia, atherosclerosis and diabetes.

In most countries, cardiovascular disease remains one of the major diseases and is the leading cause of death. About a third of men the primary cardiovascular disease develops before the age of 60 years, while women show a lower risk (ratio of 1 to 10). In subsequent years (after the age of 65 years, women become more susceptible to cardiovascular disease than men) increased incidence of this disease. Cardiovascular diseases such as coronary heart disease, stroke, restenosis and peripheral vascular disease remains the leading cause of death and handicap in the world.

Despite the fact that diet and lifestyle can accelerate the development of cardiovascular disease, a genetic predisposition that leads to dyslipidemia, an important factor is oznacevanje cardiovascular disease and death.

The development of atherosclerosis is believed to be mainly associated with dyslipidemia, which means abnormal levels of lipoproteins in the serum. This violation is particularly evident in the case of coronary disease, diabetes and obesity.

The concept is intended to explain the development of atherosclerosis, mainly focuses on cholesterol metabolism and in the metabolism of triglycerides.

However, through research Randle and others (Lancet, 1963, 785-789), was proposed a new concept: the cycle of glucose-fatty acid or cycle rendle, which describes the regulation of the balance between lipid metabolism, which are in the form of triglycerides and cholesterol, and oxidation of glucose. In accordance with this concept, the inventors have developed a new program, whose main goal is to find new connections, acting simultaneously on lipid metabolism and glucose metabolism.

Fibrates are well known therapeutic agents with a mechanism of action through receptors activated proliferation peroxisome". These receptors are key regulators of lipid metabolism in the liver isoform of PPARα). In the last 10 years, the preparations of thiazolidinediones have been described as potent hypoglycemic agents for humans and animals. It has been shown that preparations of thiazolidinediones are what I powerful selective activators of other PPAR isoforms: PPARγ (Lehmann and others, J. Biol. Chem., 1995, 270, 12953-12956).

The inventors have discovered a new class of compounds that are potent activators of PPARα and PPARγ isoforms. Through this activity, these compounds have significant hypolipidemic and hypoglycemic effects.

Compounds according to the invention correspond to the formula (I)below:

where

But carboxyl; and (C6-C18)aryloxyalkyl, in which aryl group is optionally substituted; and (C1-C14)alkoxycarbonyl, in which the alkyl group is optionally substituted; - CO-NHOH; - tetrazolyl;

In represents an optionally substituted ethylene group,- CH2-CH2-;

R1represents a hydrogen atom; optionally substituted (C1-C14)alkyl; optionally substituted (C6-C18)aryl; optionally substituted heteroaryl; and (C6-C18)aryl(C1-C14)alkyl, where each of the aryl and/or alkyl radicals is optionally substituted; heteroaryl(C1-C14)alkyl, where each of the heteroaryl and/or alkyl radicals is optionally substituted;

Z represents S or Se;

n is an integer of 0, 1 or 2;

R2is the battle optionally substituted (C 6-C18)aryl; optionally substituted heteroaryl; or optionally substituted heterocycle containing aromatic group; and when R1represents an optionally substituted (C6-C18)aryl, R2can also be a (C1-C14)alkyl;

it is clear that when R1represents naphthyl or 4-methoxyphenyl, And is carboxyl or methoxycarbonyl, is ethylene, n is 0 and Z is S or Se, R2is not phenyl, their stereoisomers and salts of the accession of acid or base.

In the context of the invention, the term "alkyl" means linear or branched hydrocarbon chain containing from 1 to 14 carbon atoms, preferably from 1 to 10, preferably from 1 to 6 carbon atoms, for example from 1 to 4 carbon atoms.

Examples of alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentalogy, isopentylamine, neopentylene, 2-methylbutanoyl, 1-ethylpropyl, hexyl, isohexyl, neohexyl, 1-methylpentylamine, 3-methylpentylamine, 1,1-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutanol, 1-methyl-1-ethylpropylamine, p, 1-methylhexanoic, 1-propylboronic, 4,4-dimethylpentyl, oktilovom, 1-methylheptadecyl, 2-methylhexanoic, 5,5-dimethylhexanoic, Noni is new, dellby, 1-methylnonanoic, 3,7-dimethyloctyl and 7.7-dimethylacrylamide radicals.

The term "aryl group" means a monocyclic or polycyclic aromatic group containing from 6 to 18 carbon atoms. Aryl groups that may be mentioned include phenyl, naphthyl, antril and tenantry.

Heteroaryl groups are monocyclic or polycyclic heterocyclic aromatic groups that include heteroatoms selected from O, S and N, optionally in oxidized form (in the case of S and N).

Preferably, when at least one of monocycle comprising a heterocycle, contains from 1 to 4 endocycles heteroatoms, more preferably from 1 to 3 heteroatoms.

Preferably, when the heterocycle comprises one or more monocycles, each of which is a 5-7-membered.

Examples 5-7-membered monocyclic heteroaryl are, in particular, pyridine, furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isoxazol, isothiazol, furazan, pyridazine, pyrimidine, pyrazin, thiazine, oxazole, pyrazole, oxadiazole, triazole and thiadiazole.

Examples of bicyclic heteroaryl, in which each monocycle is a 5-7-membered ring selected from indolizine, indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, benzothiazole, benzofuran, benzothiadiazine, p is Rina, quinoline, isoquinoline, cinnoline, phthalazine, heatline, cinoxacin, naphthirydines, pyrazolidine (such as pyrazole-1,3,4-triazine, pyrazole-pyrimidine and pteridine.

Preferred heteroaryl that may be mentioned include chenail, pyridyl, benzothiazolyl and triazolyl.

Tricyclic heteroaryl, in which each monocycle is a 5-7-membered, choose, for example, acridine, phenazine and carbazole.

In accordance with the invention, the terms "heterocycle-containing aromatic group" means a heterocycle consisting of one or more monocycles, each of which preferably is a 5-7-membered ring, in which at least one monocycle is aromatic and at least one monocycle is heterocyclic and where monocycle are pairwise ortho - or peri-condensed. It is obvious that the nonaromatic monocyclic can be saturated or unsaturated and which aromatic monocycle is heterocyclic or nheterocyclic. Heterocyclic(s) monocycle(s) contains(at) one or more endocycles heteroatoms (preferably 1 to 4, better still from 1 to 3)selected from O, N and S, optionally in oxidized form (S or N).

Carbocyclic aromatic monocycle of the heterocycle-containing aromatic group site which preferably contain phenyl nucleus.

Heterocyclic aromatic monocyclic heterocycle, aryl group, preferably represents a pyridine, furan, thiophene, pyrrole, pyrazol, imidazole, thiazole, isoxazole, isothiazol, furazane, pyridazine, pyrimidine, pyrazinone, cesinovo, oxazoline, oxadiazole, triazole or thiadiazole the kernel.

Heterocyclic saturated monocyclic heterocycle, aryl group are, for example, tetrahydrofuranyl, dioxolane, imidazolidine, pyrazolidine, piperidinium, dioxane, morpholinium, diciannove, thiomorpholine, piperazinonyl, tretyakovym, doxepinum or azepino core. A heterocycle, the aryl group may contain one or more unsaturated heterocycles, originating from an aromatic or heterocyclic monocycles, as described above.

A heterocycle, the aryl group is monocyclic or polycyclic, preferably bicyclic or tricyclic.

It is clear that each saturated and/or unsaturated monocycle in the heterocycle, the aryl group may be substituted by oxo.

Examples of heterocycles, aryl group, in particular, can be a ring of the following formula:

<>

where M and T are independently selected from O, S, SO2, N and S, it is clear that each of the rings from B1 to B12 includes at least one heteroatom, optionally in oxidized form, a R is selected from O, S and N.

In accordance with preferred embodiments of the invention:

T represents O, S or SO2M represents N or S. Preferably, when B1 T represents O; B2 T - O or S; B3 T - SO2or, and M represents C or N; B4 R represents S; B5 T represents O; B6 T - O; V7 T - O; B8 T represents O; B9 R represents S; 10 T - O; B11 T - O; B12 R represents n

When M, T or R represent N, the nitrogen is preferably substituted by a hydrogen atom, alkyl or alkylcarboxylic.

Preferably, when the heterocycle, the aryl group has the formula:

The substituents of aryl groups, heteroaryl groups containing an aromatic residue, and heteroaryl groups are selected from halogen atoms; cyano; nitro; optionally halogenated (C1-C14)Alcoi (and preferably, triptoreline); optionally halogenated (C1-C14 )dialkoxy, preferably (C1-C10)dialkoxy; optionally halogenated and preferably perhalogenated (C1-C14)alkyl (in particular methyl or trifloromethyl); and (C1-C14)alkylsulphonyl, in which the alkyl group is optionally halogenated; and (C6-C18)arylcarbamoyl, in which aryl group is optionally substituted one or more times by halogen, optionally halogenated (C1-C14)alkyl and optionally halogenated (C1-C14)alkoxy; a (C1-C14)alkylcarboxylic, in which the alkyl group is optionally halogenated; and (C6-C18)arylcarboxamide, in which aryl group is optionally substituted one or more times by halogen, optionally halogenated (C1-C14)alkyl and optionally halogenated (C1-C14)alkoxy; and (C6-C18)aryl, optionally substituted one or more times by halogen, optionally halogenated (C1-C14)alkyl, such as trifluoromethyl, and optionally halogenated (C1-C4)alkoxy, such as triptoreline.

The term "halogen"means chlorine atoms, bromine, iodine or fluorine.

Acyl group, heteroaryl group and hetero is ilycheskie group, containing aromatic group can be substituted one or more times by substituents listed above, preferably from one to three times, for example once or twice.

Alkyl group alkoxycarbonyl, alkyl, arylalkyl and heteroarylboronic radicals, and the ethylene group which may be substituted by one or two radicals independently selected from halogen, (C1-C14)alkoxy, (C1-C14)dialkoxy, cyano and nitro, preferably from one to three radicals of this type.

In a particularly preferred embodiment R1represents benzyl, optionally substituted in the phenyl ring; optionally substituted phenyl; or optionally substituted pyridyl; phenyl substituents and peredelnogo rings preferably selected from halogen atoms and cyano, trifloromethyl, (C1-C6)alkyl or (C1-C6)alkoxy group or (C6-C18)aryl group (such as phenyl), which is itself optionally substituted with halogen, (C1-C6)alkyl, (C1-C6)alkoxy, CF3or CN.

Preferably, when R2represents optionally substituted phenyl; optionally substituted benzoperylene; optionally substituted benzothiazole; optionally substituted naphthyl; optional is tion substituted hinely; optionally substituted triazole; or a radical:

which is optionally substituted.

Preferred substituents of these radicals representing R2are the atoms of halogen or CN, CF3, (C1-C6)alkyl, (C1-C6)CNS or (C6-C18)aryl groups such as phenyl, which may itself be optionally substituted with halogen, (C1-C6)alkyl, (C1-C6)alkoxy, CF3or CN.

Among the preferred values And we should mention - COOH.

Compounds which are particularly preferred are those for which b is ethylene.

Another group of preferred compounds are those in which Z represents S, and n is 0,1 or 2.

The following compounds are particularly preferred:

2-(dibenzofuran-yloxy)-4m-tamilselvan butyric acid

2-(dibenzofuran-yloxy)-4-(2,4-dimethylbenzenesulfonyl)butyric acid

4m-tamilselvan-2-(4-triftormetilfosfinov) butyric acid

2-(4-chlorophenoxy)-4-(2,4-dimethylbenzenesulfonyl)butyric acid

2-(3,4-dichlorophenoxy)-4-(2,5-dimethylbenzenesulfonyl)butyric acid

4-(2,4-dimethylbenzenesulfonyl)-2-(4-methoxyphenoxy)butyric acid

4-(2,4-dimethylbenzenesulfonyl)-2-(4-pertenece)m is Slana acid

4-(2,4-dimethylbenzenesulfonyl)-2-(3-triptoreline)butyric acid

4-(2,5-dimethylbenzenesulfonyl)-2-(4-methoxyphenoxy)butyric acid

2-(4-cianfrocca)-4-(2,5-dimethylbenzenesulfonyl)butyric acid

2-(4-chloro-2-methoxyphenoxy)-4-(2,5-dimethylbenzenesulfonyl)butyric acid

2-(4-chloro-3-ethylenoxy)-4-(2,5-dimethylbenzenesulfonyl)butyric acid

2-(4-chloro-2-methoxyphenoxy)-4-(naphthalene-1-ylsulphonyl)butyric acid

2-(4-chlorophenoxy)-4-(2-ethylvanillin)butyric acid

4-(2-ethylvanillin)-2-(4-methoxyphenoxy)butyric acid

2-(4-pertenece)-4-o-tamilselvan butyric acid

4-(2,4-dimethylbenzenesulfonyl)-2-(4-triptoreline)butyric acid

4-(2,5-dimethylbenzenesulfonyl)-2-(4-triptoreline)butyric acid

4m-tamilselvan-2-(4-triptoreline)butyric acid

4-(3-chlorophenylsulfonyl)-2-(4-triptoreline)butyric acid

4-o-tamilselvan-2-(4-triptoreline)butyric acid

(R)-4-o-tamilselvan-2-(4-triptoreline)butyric acid

(S)-4-o-tamilselvan-2-(4-triptoreline)butyric acid

4-phenylsulfanyl-2-(4-triptoreline)butyric acid

It is clear that the compounds of the formulas:

and

where

X represents S or Se; and

Raselected the C atom of halogen or a methyl group; and

Rbrepresents methyl,

excluded from the objects of the present invention, since they have already been described as intermediate compounds in Chem. Pharm. Bull. 32(12) 4779-4785 (1984) and/or J. Org. Chem. 1983, 48, 2630-2632.

When the compound of formula I include acid functional group and, for example, the functional group of carboxylic acid, this compound can form a salt with a mineral or organic base.

As examples of salts with organic or mineral bases should be mentioned salts formed with metals, especially alkali metals, alkaline earth metals and transition metals (such as sodium, potassium, calcium, magnesium or aluminum), or with such basics as ammonium or secondary or tertiary amines (such as diethylamine, triethylamine, piperidine, piperazine or morpholine) or with basic amino acids, or with asaminami (such as meglumine), or aminoalcohols (such as 3-aminobutanol and 2-aminoethanol)

When the compound of the formula includes a basic functional group, such as a nitrogen atom, this compound can form a salt with an organic or mineral acid.

Salts with organic or mineral acids are, for example, hydrochloride, hydrobromide, sulphates, hydrosulfate, dihydrophosphate, citrates, maleate, fumarate, 2-naphthalene is sulfonate and para-toluensulfonate.

The invention also encompasses stereoisomers of the compounds of formula I, a mixture of stereoisomers in all proportions.

The compounds of formula I can be easily obtained using any of the following processes.

A) Preparation of compounds of formula I in which a represents a - COOH, and Z represents S, with n=0.

The compounds of formula I in which A=COOH; Z=S and n=0 can, in particular, be obtained by reaction of compounds of formula II:

where and R1are as defined in paragraph 1 of the formula, with a thiol of formula III:

where R2is the same as defined above for formula I, in the presence of a base.

The Foundation, which can be used are organic or mineral bases, such as, for example, a hydroxide such as ammonium hydroxide or an alkali metal), a carbonate (such as a carbonate of an alkali metal or carbonate of alkaline-earth metal, alkali metal alkoxide, an organic hydride (such as alkali metal hydride), alkali metal amide, fluoride of an alkali metal, ammonium fluoride, ammonium, triethylamine, tributylamine, pyridine or N-methylmorpholine.

Preferred bases that may be mentioned include sodium carbonate, hydride intothree is, the cesium carbonate, potassium carbonate, tert-piperonyl sodium tert-piperonyl potassium.

The reaction is preferably carried out in a polar aprotic solvent such as a nitrile (e.g. acetonitrile or isobutyronitrile), amide (such as formamide, dimethylformamide, N-methyl-2-pyrrolidone or hexyllithium, halogenated hydrocarbons (such as metaleptic, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene) or mixtures of these solvents in any proportion. Mostly the reaction is carried out in dimethylformamide.

The reaction temperature may be installed by the average person skilled in the art as a function of the used grounds, the selected solvent and reactivity present compounds.

When used, the solvent is dimethylformamide, and the base is a carbonate of an alkali metal or hydride such as an alkali metal hydride or fluoride of an alkali metal, the temperature is preferably maintained between 80 and 150°S, more preferably from 90 to 130°C.

The reaction time is from 30 minutes to 5 hours, preferably enough from 1 hour to 2 hours.

C) Preparation of compounds of formula I in which a represents a-COOH and Z is a Se, with n=0.

The compounds of formula I in which A=COOH, Z=Se, n=0, can be the ü is obtained by the reaction of selenium compounds of the formula IV:

where R2is as defined for formula I, with a hydride, such as borohydride or alumoweld, followed by reaction of the obtained compound with a compound of formula II:

where and R1are as defined above for formula I.

At the first stage of bases which may be used are those defined above. The preferred hydrides that can be used are borhydride alkali metal such as sodium borohydride.

Solvents, which, in particular, can be used include polar aprotic solvents recommended above for the reaction of the lactone of the formula II with a thiol of formula III. Dimethylformamide is a solvent, which, in particular, is preferred at this stage.

The person skilled in the art can preimushestvenno to set the temperature for this stage to level from 80 to 150°and preferably from 90 to 130°S, as a function of the selected base and solvent.

Usually, the reaction time is from 30 minutes to 6 hours, for example from 1 hour to 3 hours.

The second stage, which involves the reaction of a lactone of the formula II with the compound obtained in the previous step, mainly carried out in polar aprotic dissolve the barely, preferably selected from halogenated hydrocarbon, amide or nitrile, such as those defined above. More specifically, the reaction is carried out in dimethylformamide.

In this case, the reaction temperature from 80 to 150°is acceptable. Similarly, the reaction time is from 30 minutes to 5 hours allows you to isolate a sufficient number of expected product of formula I.

C) Preparation of compounds of formula I in which Z represents Se or S, and n is other than 0.

The compounds of formula I in which n is not zero, can be obtained by reaction of the oxidizing agent with the appropriate compound of the formula I in which n=0,

where A, R1, R2and b are as defined above for formula I and Z represents S or Se, with acceptable oxidizing agent.

Among the oxidizing agents which can be used, you can choose meta-chlorbenzoyl acid, a mixture of acetic acid/CrO3dioxide magnesium , sodium bichromate, coupled with sulfuric acid, silicon dioxide, hypobromite sodium or silver oxide. Preferred occisum agent that can be used is m-chloroperbenzoic acid (m-SRV).

The oxidation reaction is preferably carried out in a solvent selected from halogenated hydrocarbons (such acmetelephone, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene), a lower alcohol selected from C1-C4-alkanols, in particular methanol or ethanol, or mixtures of these solvents.

When the oxidizing agent is selected from m-SRVA, the process is preferably carried out in a mixture of ethanol and dichloromethane.

It is possible to control the degree of oxidation of the final compounds by varying the number of equivalents used oxidizing agent.

In order to obtain the compounds of formula I in which n=1, the compound of formula Ia need to be brought into contact with not more than approximately one equivalenta m-SRV (preferably from 0.9 to 1.1 equivalent).

In order to obtain the compounds of formula I in which n=2, use at least about 2 equivalents of m-SRVA.

Riccio preferably carried out at moderate temperatures between 15 and 40°With, for example at room temperature, when the oxidizing agent is m-SRVA.

D) obtaining the compounds of formula I in which a represents allyloxycarbonyl or aryloxyalkyl.

The compounds of formula I in which a represents a - COOH, can be easily converted into the compounds of formula I in which a represents alkoxycarbonyl or aryloxyalkyl, by reaction with the corresponding alkilany Speer is om or allowin alcohol, accordingly, alkoxycarbonyl or arylcarbamoyl, by reaction with the corresponding alkilany alcohol or allowin alcohol, respectively.

One of the preferred embodiments of the invention is an active derivative of the carboxylic acid of the formula I in which A=COOH, with the specified derivative reacts with alkilany or allowin alcohol, respectively.

An activated derivative of carboxylic acid is the corresponding compound of formula I in which A= -- WITH-K, where K is an activating group for the carboxylic acid group.

Preferred activating groups which may be mentioned are the chloride, bromide, azide, imidazole, p-nitrophenoxy, 1-benzotriazole, N-O-succinimide, acyloxy, and more preferably, pivaloyloxy, (C1-C4alkoxy)carbonyloxy, such as2H5O-CO-O-, dialkyl - or bicycloalkyl-O-acylceramide.

When=HE, reaction of compounds of formula I in which A=-COOH, with alkilany alcohol, respectively, preferably in the presence of a binding agent, such as carbodiimide, optionally in the presence of an activating agent, such as hydroxybenzotriazole or hydroxysuccinimide with intermediate formation of dialkyl - or bicycloalkyl-O-acylceramide. Representatives of binding agents are on the cyclohexyl and diisopropylcarbodiimide, carbodiimide, which are soluble in aqueous medium, or bis(2-oxo-3-oxalidales)phosphonyl chloride.

When It is a halogen atom, it is desirable to conduct the process in the presence of a mineral or organic base, such as, for example, a hydroxide such as ammonium hydroxide or alkali metal hydroxide), a carbonate (such as a carbonate of an alkali metal or carbonate alkaline-earth metal, alkali metal alkoxide, amide alkali metal, ammonium, triethylamine, tributylamine, pyridine or N-methylmorpholine.

Another reasonable basis, which can be used is the base attached to the resin. Resins of this type are commercially available.

Examples that may be mentioned include N,N-(aminobutiramida)aminomethylpyridine and morpholinobutyrophenone resin.

The reaction is preferably carried out in a solvent.

In some cases it is desirable to choose a polar aprotic solvent, for example, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloride, chlorobenzene or dichlorobenzene, and the dichloromethane is particularly preferred.

E) obtaining the compounds of formula I, where a represents a-CONH-OH.

The compounds of formula I, where a represents a-CONH-OH can be obtained from the corresponding compounds of the formula I, where a represents-COOH, under the action of hydroxylamine, the reaction is carried out by a method which is known in itself, when using the known methods in organic chemistry.

In accordance with a particularly preferred embodiment of this invention the reaction is carried out in two stages.

At the first stage trigger group a=COOH. To accomplish this, you can get any activated derivative of carboxylic acid (formula I, where A=-JUICE) in the manner described above in section D.

Preferably, when activated derivative is the acid chloride, carbodiimide or mixed anhydride.

In the second stage, indicated by an activated derivative is reacted with hydroxylamine in the presence of a base, for example, one of the grounds described in section D above. Preferably, when the substrate is a triethylamine or N-methylmorpholine.

Step preferably is carried out in a polar aprotic solvent such as a halogenated hydrocarbon (particularly dichloromethane), simple ether (particularly tetrahydrofuran) or amide (particularly dimethylformamide).

F) obtaining the compounds of formula I, where a is tetrazolyl.

The compounds of formula I, where a is tetrazolyl, can easily be prepared from corresponding compounds of formula I, where a PR is dstanley a-COOH, when performing two-stage process.

At the first stage receives the corresponding amide of formula IX:

from carboxylic acids of formula Ib, which is described below:

where R1, V, Z, n and R2are as defined for formula I.

The transformation of compounds Ib amide can be carried out by any means, for example, if the action is:

a - ammonium in methanol in the presence of resin Dowex 50W × 8;

b - ethylchloride and ammonium;

with - SO2(NH2)2in pyridine; or

d - thionyl chloride and ammonium hydroxide in 1,4-dioxane.

In the second stage amide of formula IX is subjected to reaction with an alkali metal azide such as sodium azide) in the presence of tetrachlorosilane.

This step is carried out, for example, using as solvent a nitrile such as acetonitrile or isobutyronitrile, preferably acetonitrile.

To establish conditions of experience the person skilled in the art can refer to the studies of El-Ahl, A.A.S: Elmorsy S.S. and others, published in Tetrahedron Letters, 1997, 38/7, 1257.

The lactones of the formula II:

in which b and R1are as defined above for formula I, can be obtained by reaction of the corresponding α-galactono formula V:

Hal represents a halogen atom, preferably selected from chlorine, bromine and iodine (bromine is preferred), with the appropriate alcohol of formula VI:

in the presence of an organic or mineral base.

As a variant, it is possible to synthesize the intermediate compounds of formula II when exposed to the appropriate α-hydroxylation formula VII:

on acceptable halide of the formula VIII:

where the values of R1and b are as defined for formula I and Hal represents a halogen atom, preferably selected from chlorine, bromine, iodine (bromine atom is particularly preferred), this reaction is carried out in the presence of an organic or mineral base.

Bases that can be used in the preparation of compounds of formula II are as defined above.

In the case of the first variant (the reaction of V with VI) it is preferable to use a carbonate of an alkali metal (such as cesium carbonate or alkoxide of an alkali metal (such as ethoxide sodium) as the base.

If the second option is acceptable is based on such basis as the alkali metal hydride, sodium hydride is particularly acceptable.

Reaction conditions, particularly the reaction temperature and dissolve the spruce, depend on the type of Foundation.

In the first variant (the reaction of V with VI) the process is preferably carried out by:

- or ketone (such as acetone) in the presence of a carbonate of an alkali metal such as cesium carbonate, at temperatures from 40 to 100°S, and preferably from 50 to 70°C;

or in a lower alcohol (such as1-C4alkanol, such as ethanol) in the presence of an appropriate alkali metal alkoxide at a temperature of from 40 to 120°With, for example, from 50 to 100°S, and especially preferably from 60 to 80°C.

In the second embodiment, the preferred conditions are the use of alkali metal hydride such as sodium hydride, the choice of the amide as a solvent and preferably of dimethylformamide, when interval of temperature from 5 to 45°C. In accordance with one of preferred embodiments of the invention, the base reacts with α-hydroxyacetone at low temperature (from - 5 to +10° (C), after which the reaction medium is added to the halide of formula VIII, then leave the reaction mixture to undergo reaction at temperature from 15 to 45°With, for example at room temperature, the time required to complete the reaction.

The enantiomers of compounds of formula I which contain an asymmetric carbon atom α group a:

* who appoints the position of the asymmetric center, can be obtained from the corresponding enantiomeric lactones of the formula II:

where the carbon marked with an asterisk, has the same configuration as the corresponding carbon in formula Ib above, when performing the same type of reaction as described above in (A).

One way to obtain optically active compounds of the formula II is as follows.

The alcohol of formula VI, R1OH subjected to reaction with optically active α-hydroxyacetone formula VIIa:

where In is the same as defined above for formula I, in the presence of diethylazodicarboxylate and triphenylphosphine.

Ideally, when the reaction is carried out in a polar aprotic solvent, such as a simple ether, particularly diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylethylenediamine ether. As options you can use halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene.

Since this reaction proceeds with inversion of the chiral center in endocycles asymmetric carbon atom which carries the group-HE, then choose α-hydroxylation formula VIIa, which has the opposite configuration relative to the configuration of the soo the relevant carbon atom of formula II.

Schematically:

The invention also relates to pharmaceutical compositions containing a pharmaceutically effective amount of the compounds of formula (I)as defined above, in combination with one or more pharmaceutically acceptable carriers.

Such compositions can be administered orally in the form of tablets, gel capsules or granules immediate-release or delayed release, intravenously in the form of injectable solutions, in the form of transdermal adhesive transdermal devices or topically in the form of a solution, cream or gel.

Pharmaceutical compositions in accordance with the present invention can also be entered using a nasal spray or by inhalation when using the nebulizer, dry powder inhaler and inhalation omaranui dose. Such compositions are prepared in accordance with techniques well known in the field of pharmaceutical compositions, such compositions can be obtained as solutions on the basis of physiological solution when using benzyl alcohol or other acceptable preservatives, absorption promoters to enhance bioavailability, HFC, and/or other traditional solubilizing or dispersing agents.

The solid component is iciu for oral administration is prepared by adding a filler to the active start and if it's acceptable binder, dezintegriruetsja agent, lubricant, dye or agent to improve the taste, and by giving a mixture of the forms of tablets, coated tablets, granules, powder or capsules.

Examples of fillers include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide, examples of the binder include poly(vinyl alcohol), poly(vinyl simple ether), ethylcellulose, methylcellulose, gum Arabic, tragacanth gum, gelatin, shellac, hydroxypropylcellulose, hypromellose, calcium citrate, dextrin and pectin. Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil. The dye may be any of those that are possible for use in medicines. Examples of the agents for improving taste include cocoa powder, mint in the form of herbs, aromatic powder, peppermint in the form of an oil, a powder, borneol and cinnamon. Obviously, the tablet or granule may be reasonably covered sugar, gelatin, etc.

Injectable form containing the compound in accordance with the present invention as active principle is prepared, if appropriate, by mixing the compounds with a pH regulator, a buffer agent, suspension agent, Sol is bilization, stabilizer, isotonic agent and/or a preserving agent, and by turning the mixture into a form for intravenous, subcutaneous or intramuscular injection in accordance with the standard method.

Examples of suspension agents include methylcellulose, Polysorbate 80, hydroxyethyl cellulose, gum Arabic, crushed tragacanth gum, carboxymethylcellulose and polyethoxysiloxane monolaurate sorbitol.

Examples of solubilization include castor oil, utverjdenie with polyoxyethylene, Polysorbate 80, nicotinic, polyethoxysiloxane monolaurate sorbitol and ethyl ester of fatty acids of castor oil.

In addition, the stabilizer comprises sodium sulfite, metasulfite sodium and simple ether, at that time, as a preserving agent comprises methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenyl [sic], cresol and cholesterol.

The invention is also directed to the use of the active agent, selected from compounds of formula (I)as defined above, to obtain a medicinal product intended for the prevention or treatment of dyslipidaemia, atherosclerosis and diabetes.

In the above description, pharmaceutical compositions containing the preferred connection is equivalent to the expression "introduction", "introduction of something", "to enter the, "enter something" used in relation to these pharmaceutical compounds. Thus, these expressions are intended to refer to the provision of patient who needs treatment, a pharmaceutical composition according to this invention by any of the described in this application by way of introduction, the active ingredient is the preferred connection or proletarienne means, derivative or metabolite that are useful in the treatment of disease, disorder or symptom mediated by or associated with modulation of the activation of PPARα and PPARγ isoforms in the specified patient. Accordingly, the scope of the present invention includes any compound that when administered to a patient is capable, directly or indirectly, to provide the preferred connection. Such compounds are called proletarienne means, and for obtaining such proletarienne forms preferred compounds are well known for a number of known methods.

Dosage the normal dosage of compounds effective for the treatment or prevention of a disease, disorder, or symptom mediated by or associated with modulation of the activation of PPARα and PPARγ isoforms, will depend on a variety of factors such as the nature of the activator, the weight of the patient, the goal of treatment, the t nature of pathology, which is subjected to the treatment used specific pharmaceutical composition, observations and conclusions of the treating physician.

For example, when the dosage form is oral, for example a tablet or capsule, the acceptable dose levels of the compounds of formula I will be in the range from 0.1 μg/kg to 50.0 mg/kg of body weight per day, preferably from about 5,0 μg/kg to 50 mg/kg of body weight per day, more preferably from approximately 10.0 μg/kg to about 1.0 mg/kg of body weight per day and most preferably from about 20,0 mg/kg to about 0.5 mg/kg of body weight per day of the active ingredient.

When the dosage form to be administered topically in the bronchi and lungs, for example by means of a powder inhaler or nebulizer, with acceptable levels of dose of the compounds will be in the range of from about 0.001 microg/kg to about 10.0 mg/kg of body weight per day, preferably in the range from about 0.5 μg/kg to about 0.5 mg/kg of body weight per day, more preferably in the range from approximately 1.0 μg/kg to about 0.1 mg/kg of body weight per day and most preferably from about 2.0 µg/kg to about 0.05 mg/kg body weight in day of the active ingredient.

Using typical body weight of 10 to 100 kg in order to illustrate the interval daily oral d is C, which can be used as described above, acceptable levels of doses of the compounds of formula I will be in the range of about from 1.0 to 10.0 μg and up to 500,0-5000,0 mg per day, preferably from about 50,0-500,0 μg and up to 10.0-100.0 mg per day and most preferably from about 200,0-2000,0 μg to about 5.0 to 50.0 mg per day of the active ingredient, contains the preferred connection. These boundaries dosages represent the total dosage of the active ingredient per day for a given patient. The number of injections per day will depend on such pharmacological and pharmacokinetic factors as the half-life of the active ingredient, which reflects its rate of catabolism and clearance, as well as the minimum and optimum levels in plasma and other biological fluids specified active ingredient obtained from a patient that required for therapeutic efficacy.

Activity of compounds in accordance with the invention, which leads to the hypolipidemic and hypoglycemic effects have been demonstrated in the following vypolnennyh tests in vitro and in vivo.

Measurement of PPAR activation was carried out in accordance with the methodology described by Lehmann and others (1995, J. Biol. Chem. 270: 12953-12956).

Cells CV (cells monkey kidney) together trapezious and using the expression vector for chimeric proteins PPARα -Gal4 or PPARγ-Gal4 and "reporter" plasmid that allows expression of the luciferase gene, which is under the control of a promoter containing Gal4 response elements.

The cells were made in microtiter plates at 96 wells and was co-transferrable when using commercial reagent with reporter plasmid (pG5-tk-pGL3) and expression vector for the chimeric protein (PPARα-Gal4 or PPARγ-Gal4). After incubation for 4 hours solid culture medium (containing 10% fetal calf serum) was added to the tubes. After 24 hours the medium was removed and replaced by a solid medium containing the test products (final concentration 50 μm). The products were left in contact with the cells for 18 hours. After that, the cells were literally and luciferase activity was measured using a luminometer. PPAR activating factor can then be calculated by activation of the expression of the reporter gene induced by the product (compared to control cells that have not received the product).

As an example, the compound of Example 5 at a concentration of 50 µg activates protein PPARα-Gal4 factor 9, and the chimeric protein PPARγ-Gal4 - factor 6. In the absence of a binding site for PPARα or γ ligand (vector, which expresses only the Gal4) luciferase activity measured in the presence of e is th product was equal to zero.

Antidiabetic and hypolipidemic activity of the compounds was determined by oral administration in db/db mice.

Mice db/db at the age of 16 weeks oral was administered for 15 days connection in accordance with Example 5 (20 mg/kg/day). Each study group contained seven animals. 15 days after the treatment took retroorbital samples under mild anesthesia and after a period of fasting, is 4 hours.

We measured the following parameters.

Analysis on glycemia (pianosounds) and analysis of lipid parameters in a series D15 (COBAS): triglycerides, total cholesterol (CHOL), HDL (high density lipoprotein) cholesterol (HDL-C) and free fatty acids (FFA) (BioMerieux and Waco Chemicals, test kits).

The results obtained are summarized in the following table. Presents measurement data represent the average value of ± standard error.

ControlExample 5%change compared to control
Glycemia mm27,1±7,011,1±3,3-59*
Triglycerides mm1,3±0,30,7±0,1-47*
HDL-C mm3,2±0,24,3±0,6 36*
CHOL mm3,65±0,25,4±0,947*
FFA mm0,7±0,10,4±0,0-38*
% var.: percentage change vs. control

Test Mann-Whitney:

*, p<0,05 vs. control

These results show antidiabetic and hypolipidemic activity of compounds in accordance with the invention on the triglycerides and free fatty acids. Can be shown a noticeable increase in HDL cholesterol level by using compounds such as these.

The examples that follow illustrate, but not limit the invention.

In the data relative to the proton nuclear magnetic resonance (300 MHz NMR) were used the following abbreviations: C - for singlet, d for doublet, t for triplet, Quartet, for octet and m - for a complex multiplet. Chemical shift δ expressed in parts per million; other represents the melting point.

Getting 1: 3-(4-pertenece)dihydrofuran-2-he

α-bromobutyrate (12.4 g, 0,075 mol) was added to a mixture of 4-terfenol (5.6 g, 0.05 m) and cesium carbonate (17.9 g, by 0.055 mole) in acetone (100 ml). Reaction medium was boiled for two hours. After cooling to room temperature reacts the mixture was filtered through a layer of celite and the filtrate evaporated. The oily residue was purified using flash chromatography (1/2 EtOAc/heptane) to obtain the expected product in the form of oil (9.8 g, 87%).

1H NMR (CDCl3, 300 MHz): 2,4 (1H, m), 2,65 (1H, m), 4,3 (1H, m), 4,8 (1H, m), 4,8 (1H, t, J=7.5 Hz), to 6.95 (4H, m).

Preparation 2: 3(4 bromophenoxy)dihydrofuran-2-he

Sodium (23 g, 1 mol) was introduced into the pieces into the reactor containing ethanol (1 l). The temperature of the reaction medium was set at 70° (exothermic) before addition of a solution of 4-bromophenol (173 g, 1 mol) in ethanol (150 ml). After cooling to room temperature was slowly added α-bromo-γ-butyrolactone (83 ml, 1 mol). The reaction medium was stirred for 10 hours, and then subjected to treatment with 1N hydrochloric acid (600 ml). The aqueous phase was extracted with ethyl acetate (2×1 l) and the combined organic phases were washed with water (1 l), dried over sodium sulfate, filtered and concentrated. The precipitate was recrystallized from isopropanol (2.2 l) to obtain the expected compound in the form of a white powder (80,1 g, 31%).

Melting point: 90°IR: 1690, 1770, 1790.

1H NMR (CDCl3, 300 MHz): 2,5 (1H, m), 2,7 (1H, m), 4,4 (1H, m), 4,5 (1H, m), 4,9 (1H, t, J=7.5 Hz)and 6.9 (2H, m), and 7.4 (2H, m).

Preparation 3: 3-(4-triptoreline)dihydrofuran-2-he

The compound was prepared according to the experimental method described is diversified in Preparation 1, starting with α-bromo-γ-butyrolactone (6.7 g, 0.040 mol) and 4-triptoreline (5.0 g, 0,031 mol) to obtain 3.51 g of the expected compound in the form of white powder.

Melting point: 84-86°C.

1H NMR (DMSO-d6, 300 MHz): 2,20-of 2.45 (1H, m), 2,70-2,90 (1H, m), 4,20-a 4.53 (2H, m), the 5.51 (1H, t, J=9.0 Hz), 7,74 (2H, d, J=8,9 Hz), 7,69 (2H, d, J=8,9 Hz).

Preparation 4: 3-(biphenyl-2-ylethoxy)dihydrofuran-2-he

Sodium hydride (0,43 g, 10.8 mmole) was added in portions to a solution α-hydroxy-γ-butyrolactone (1 g, 9.8 mmole) in DMF (15 ml) at a temperature of 0°C in nitrogen atmosphere. Then quickly added 2-bromomethylbiphenyl (2,42 g, 9.8 mmole). The reaction mixture was stirred for 2 hours at room temperature, and then subjected to processing by adding 1N hydrochloric acid (10 ml). The aqueous phase was extracted with ethyl acetate (2×20 ml) and the combined organic phases were washed with water (4×15 ml), dried over sodium sulfate, filtered and concentrated. After purification using flash chromatography (2/1 heptane/EtOAc), the expected compound were obtained in the form of a colorless oil (1,32 g, 50%).

1H NMR (CDCl3, 300 MHz): 2,00 to 2.35 (2H, m), 3,85-4,00 (1H, m), 4,00-to 4.15 (1H, m), 4,15-4,30 (1H, m), 4,40-4,80 (2H, m), 7,10-7,40 (8H, m), 8,40 at 8.60 (1H, m).

Preparation 5: (S)-3-(4-triptoreline)dihydrofuran-2-he

Diethylazodicarboxylate (2,31 ml, 14, 7 mmole) was slowly added to dissolve the (R)-(+)-α -hydroxy-γ-butyrolactone (1 g, 9.8 mmole), 4-triptoreline (1,58 g, 9.8 mmole) and triphenylphosphine (3,86 g, 14.7 mmole) in anhydrous THF (80 ml), cooled to 0°C. After stirring for 5 minutes at a temperature of 0°and over night at room temperature the solvent is evaporated and the triphenylphosphine oxide was besieged from simple ether and was filtered. The filtrate is then washed with water, dried over magnesium sulfate and evaporated. After purification using flash chromatography (3/1 heptane/EtOAc) of the expected compound were obtained in the form of a white powder (1,14 g, 47%).

1H NMR (DMSO-d6, 300 MHz): 2,20-of 2.45 (1H, m). 2,70-2,90 (1H, m), 4,20-a 4.53 (2H, m), the 5.51 (1H, t, J=9.0 Hz), 7,74 (2H, d, J=8,9 Hz), 7,69 (2H, d, J=8,9 Hz).

Preparation 6: (R)-3-(4-triptoreline)dihydrofuran-2-he

The compound was obtained in accordance with the described experimental procedure starting from (S)-(-)-α-hydroxy-γ-butyrolactone (2 g, 19.6 mmole) and 4-triptoreline (3,18 g, 19.6 mmole) to obtain 1.7 g (35%) of the expected compound in the form of white powder.

1H NMR (DMSO-d6, 300 MHz): 2,20-of 2.45 (1H, m), 2,70-2,90 (1H, m), 4,20-a 4.53 (2H, m), the 5.51 (1H, t, J=9.0 Hz), 7,74 (2H, d, J=8,9 Hz), 7,69 (2H, d, J=8,9 Hz).

Example 1: 2-(4-pertenece)-4-phenylsulfanyl butyric acid

1N solution trebuetsya sodium in DMF (0,2 ml of 0.2 mmole) was added to a solution of thiophenol (25 mg, of 0.23 mmole) in DMF (1 ml). After paramashiva the Oia within 15 minutes at room temperature was added a solution obtained from Preparation 1 (30 mg, 0.15 mmole) in DMF (1 ml) and the mixture was heated at 120° within 1 hour. After cooling to room temperature the reaction mixture was subjected to processing 1N hydrochloric acid (1 ml) and the product was extracted using ethyl acetate (3 ml). The organic phase is washed with water (3×2 ml) and then concentrated to a final volume of 1 ml of This solution was purified using flash chromatography (2/1 heptane/EtOAc) to obtain the expected compound in the form of a white powder (27 mg, 57%).

1H NMR (CDCl3, 300 MHz): 2,35 (2H, m), and 3.0 (2H, m), 4,7 (1H, DD, J=9.5 Hz), 6.75 in (1H, m), 6,95-6,8 (3H, m), 7,0 (2H, m); MS AR-(M-1)=305.

Example 2: 2-(4-bromophenoxy)-4-o-tamilselvan butyric acid

The compound was prepared according to the experimental procedure described in Example 1, starting from the compound obtained in Preparation 2 (2 g, and 7.8 mmole) and ortho-thiocresol (1,38 ml of 11.6 mmole), to obtain the compound of Example 2 in the form of an oil which crystallizes upon standing (2.3 g, 77%).

Melting point: 96-98°C.

1H NMR (CDCl3, 300 MHz): 2,2 (2H, m), 2,3 (3H, s), 3,1 (2H, m), 4,8 (1H, DD, J=3.5 and 9.5)is, of 6.7 (2H, m)and 7.1 (2H, m), 7,2 (2H, m), and 7.3 (2H, d, J=9 Hz).

Example 3: 4-of-tamilselvan-2-(4-triptoreline) butyric acid

The compound was prepared according to the experimental procedure described in Example 1, since the link is, obtained from Preparation 3 (6.7 g, 0,040 mol) and ortho-thiocresol (1,38 ml of 11.6 mmole) to obtain 3.51 g of the expected compound in the form of white powder.

1H NMR (CDCl3, 300 MHz): 2,20-of 2.50 (3H, s + 2H, m); 3,00-3,25 (2H, m), 4,94 (1H, m), 6,85-7,00 (2H, m); 7,00-7,20 (3H, m), 7,20-7,40 (1H, m), 7,50-the 7.65 (2H, m), (N.B.: acidic Oh groups is not observed).

Example 4: 2-(biphenyl-2-ylethoxy)-4-phenylsulfanyl butyric acid

Sodium hydride (60% dispersion) (12 mg, 0.9 mmole) was added to a solution of thiophenol (100 mg, 0.9 mmole) in DMF (1 ml) at room temperature. After stirring for 30 minutes was added a solution of the compound obtained according to Preparation 4 (52 mg, 0.2 mmole) in DMF (1 ml), and the temperature of the reaction medium was maintained at a level of 120°C for 3 hours. After cooling to room temperature the reaction mixture was subjected to processing 1N hydrochloric acid (2 ml), and the reaction product was extracted using ethyl acetate (3 ml). The organic phase is washed with water (3×3 ml)and then dried over magnesium sulfate, filtered and evaporated. After purification using flash chromatography (heptane) of the expected compound were obtained in the form of a colorless oil (50 mg, 69%).

1H NMR (DMSO-d6, 300 MHz): 1,80-2,00 (2H, m), 2,85-3,10 (2H, m), of 3.95 (1H, m), 4,20-4,60 (2H, m), 7,10-7,30 (6N, m), 7,30 is 7.50 (7H, m), 7,50-of 7.60 (1H, m), 12,83 (1H, exchanged, broad s).

Example 5: 4-panels lpanel-2-(4-triptoreline) butyric acid

The compound was prepared according to the experimental method described for Example 1, starting from the compound obtained from Preparation 3 (6.7 g, 0,040 mol) and thiophenol (1,38 ml of 11.6 mmole) to obtain 3.51 g of the expected compound in the form of white powder.

Melting point: 108-110°C.

1H NMR (DMSO-d6, 300 MHz): 2,10-of 2.30 (2H, m)3,00-3,20 (2H, m)5,00 (1H, m), 7,00-7,10 (2H, m), 7,10-of 7.60 (5H, m), 7,60-7,80 (2H, m), 13,35 (1H, exchanged, broad s); MS AP-(M-1)=355.

Example 6: 4-phenylsulfanyl-2-(4-triptoreline) butyric acid

Borohydride sodium (30 mg, 0.8 mmole) was added to a solution of diphenyldisulfide (111 mg, 0.35 mmole) in DMF (1.5 ml) at room temperature. The mixture was heated at 100°C for 20 minutes, then was added a solution of the compound obtained from Preparation 3 (160 mg, 0.65 mmole) in DMF (1 ml). The reaction mixture is then stirred at a temperature of 120°C for 2.5 hours. After cooling to room temperature, the reaction medium was treated with 10%hydrochloric acid (1 ml), then the product was extracted with ethyl acetate (4 ml). The organic phase is washed with water (3×2 ml)and then dried over magnesium sulfate, filtered and evaporated. After purification using flash chromatography (2/1 heptane/EtOAc), the expected product is obtained in the form of a white powder (176 mg, 67%).

1H NMR (CDCl3, 300 MHz):2,20-to 2.55 (2H, m); 2,90-3,30 (2H, m); to 4.92 (1H, m); 6,80-7,00 (2H, m); 7,10-7,30 (3H, m); 7,40-of 7.60 (4H, m); (N.B.: the acid group has not observed).

Example 7: methyl-4-(toluene-2-sulfonyl)-2-(4-triptoreline)-butyrate

A catalytic amount of N2SO4(2 drops) was added to the compound of Example 3 (5,14 g, 13.9 mmole) in methanol (40 ml). The reaction mixture was subjected to boiling for 12 hours. The solvent is later evaporated under vacuum, the residue is transferred into ethyl acetate (50 ml)and the organic phase washed with water (2×50 ml), dried over sodium sulfate, filtered and concentrated. After purification using flash chromatography (1/5 EtOAc/heptane) compound of Example 7 was obtained in the form of a yellow oil (5 g, 93%).

1H NMR (CDCl3): 2,11 is 2.44 (5H, m); 2,96-is 3.21 (2H, m), 3,74 (3H, s); 4.80 to equal to 4.97 (1H, m); 6,84-6,97 (2H, m); 7.03 is-7,33 (4H, m), 7,47-7,58 (2H, m).

Example 8: 4-o-tamilselvan-2-(S)-(4-triptoreline) butyric acid

The cesium carbonate was added to a solution of ortho-thiocresol (66 mg, of 0.53 mmole) in anhydrous DMF (1 ml) under nitrogen atmosphere. After stirring for 15 minutes at room temperature was added a solution of the compound obtained according to Preparation 5 (100 ml, 0.4 mmole) in anhydrous DMF (1 ml)and the reaction medium was heated at 120°C for 1 hour. After cooling to room temperature the reaction product was subjected to processing 1N hydrochloric acid (1 ml), and prod the CT was extracted with ethyl acetate (3 ml). The organic phase is washed with water (3×2 ml)and then concentrated to a final volume of 1 ml of the Solution was purified using flash chromatography (2/1 heptane/EtOAc) to obtain the compound of Example 8 in the form of a white powder (93 mg, 62%).

[a]D=-32.5 (C=0.5, Meon)

1H NMR (CDCl3, 300 MHz): 2,20-of 2.50 (3H, s+2H, m); 3,00-3,25 (2H, m); 4,94 (1H, m); 6,85-7,00 (2H, m); 7,00-7,20 (3H, m); 7,20-7,40 (1H, m) 7,50-the 7.65 (2H, m) (N.B.: the acid group has not observed).

Example 9: 4-o-tamilselvan-2-(S)-(4-triptoreline) butyric acid

The compound was obtained in accordance with the experimental procedure described for Example 8, starting from the compound of Preparation 6 (100 mg, 0.4 mmole) and ortho-thiocresol (66 mg, of 0.53 mmole) to obtain 90 mg of the expected compound in the form of white powder.

[a]D=+33.0 (C=0.5, Meon)

1H NMR (CDCl3, 300 MHz): 2,20-of 2.50 (3H, s+2H, m); 3,00-3,25 (2H, m); 4,94 (1H, m); 6,85-7,00 (2H, m); 7,00-7,20 (3H, m); 7,20-7,40 (1H, m); 7,50-the 7.65 (2H, m) (N.B.: the acid group has not observed).

Example 10: methyl 4-(toluene-2-sulfonyl)-2-(4-triptoreline)-butyrate

70% MSRV (1,49 g, 3.9 mmole) was added to a solution of compound of Example 7 (500 mg, 1.3 mmole) in CH2Cl2(10 ml) at a temperature of 0°C. the Reaction mixture was stirred at room temperature for one hour. The reaction mixture was then diluted with CH2Cl2(10 ml) and poured into a saturated solution of sodium bisulfite (0 ml). The organic phase was washed with saturated solution of NaHCO3(2×20 ml), N2O (20 ml), dried over sodium sulfate, filtered and concentrated. The compound of Example 10 was obtained in the form of a colorless oil (540 mg, 99%).

1H NMR (CDCl3): 2,21 at 2.59 (2H, m); to 2.67 (3H, s); 3,21-3,51 (2H, m), 3,74 (3H, s); 4,73-of 4.95 (1H, m); 6,72-to 6.95 (2H, m); 7,26 to 7.62 (5H, m); 7,79-of 8.09 (1H, m), MS ES+(M+1)=417.

Example 11: methyl-4-(toluene-2-sulfinil)-2-(4-triptoreline)-butyrate

13%solution of sodium hypochlorite (0,246 ml of 0.250 mmole) was added to a solution of compound of Example 7 (200 mg, 0,520 mmole) in methanol (4 ml) at a temperature of -78°C. the Reaction mixture was stirred at -78°C for 1 hour. The methanol is evaporated and the residue was transferred into ethyl acetate (5 ml), the organic phase is washed with 1N hydrochloric acid (3 ml), filtered through a filter (pore size 5 μm) and concentrated. After purification using flash chromatography (1/2EtOAc/heptane, and then 1/2/mean/EtOAc/heptane), the compound of Example 11 was obtained in the form of a colorless amorphous product (60 mg, 29%).

1H NMR (CDCl3): 1,93-2,70 (5H, m); 2,70-up 3.22 (2H, m); to 3.73 and 3.75 (3H, 2s); 4,65-4,99 (1H, m); 6,72? 7.04 baby mortality (2H, m); 7,07-7,63 (5H, m); 7,75-8,00 (1H, m), MS ES+(M+1)=401.

Example 12: 4-(toluene-2-sulfonyl)-2-(triptoreline) butyric acid

1N solution of sodium hydroxide (0.7 ml, 0.7 mmole) was added dropwise to a solution of compound of Example 10 (220 mg, of 0.53 mmole) in THF (5 ml) at 0�B0; C. the Reaction mixture was stirred at room temperature for 1 hour. THF is evaporated, the residue was transferred into ethyl acetate (5 ml)and the organic phase was washed with 1N hydrochloric acid (3 ml), water (4 ml), dried over sodium sulfate, filtered and evaporated to obtain the compound of Example 12 (210 mg, 99%) in the form of a colorless amorphous product.

1H NMR (CDCl3): 2,29-2,70 (5H, m); 3,22-of 3.54 (2H, m); 4,76-free 5.01 (1H, m); is 6.54 (1H, broad s); 6,78-6,97 (2H, m); 7,19-the 7.43 (2H, m); 7,43-7,63 (3H, m); 7,87-8,08 (1H, M), MS ES-(M-1)=401.

Example 13: 4-(toluene-sulfonyl)-2-(4-triptoreline) butyric acid

1N solution of sodium hydroxide (0.2 ml, 0.2 mmole) was added dropwise to a solution of compound of Example 11 (60 mg, 0.12 mmole) in THF (2 ml) at 0°C. the Reaction mixture was stirred at room temperature for 1 hour and then at 50°C for one hour. Evaporated THF; the remainder was transferred into ethyl acetate (5 ml) and the organic phase is washed with 1N hydrochloric acid (3 ml), water (4 ml), dried over magnesium sulfate, filtered and evaporated to obtain the compound of Example 12 (210 mg, 99%) in the form of a colorless amorphous product.

1H NMR (CDCl3): 2.06 to 2,69 (5H, m); 2,87-of 3.32 (2H, m); 4,67-of 5.15 (1H, m); 5,80 (1H, broad s); for 6.81? 7.04 baby mortality (2H, m); 7,14-7,33 (1H, m); 7,33-of 7.60 (4H, m); 7,79-to 7.99 (1H, M), MS ES-(M-1)=385.

The synthesis of compounds of Examples 10-13 schematically represented in the following scheme the E.

The table below illustrates Examples of from 10 to 60, which are compounds of formula I, with And represents-COOH, and represents-CH2-CH2.

Table 1
R1R2ZnDescription
1p-forfinalphenylS0CDCl3: 2.35 (2H, m), 3.0 (2H, m), 4.7 (1H, DD, J=9.5 Hz), 6.75 (1H, m), 6.95-6.8 (3H, m), 7.0 (2H, m)
2p-bromophenyl2-wereS0CDCl3: 2.15-2.20 (3H, s+2H, m), 3.00-3.25 (2H, m); 4.82 (1H, m); 6.70-6.90 (2H, m); 7.00-7.50 (6N, m) (N.B.: the acid group has not observed)
34-trifluoromethyl-phenyl2-wereS0DMSO-d6: CDCl3: 2.20-2.50 (5H, m), 3.00-3.25 (2H, m), 4.94 (1H, m); 6.90-7.00 (2H, m), 7.00-7.20 (3H, m); 7.20-7.35 (1H, m); 7.45-7:65 (2H, m) (N.B.: the acid group has not observed)
4o-phenylbenzylphenylS0DMSO-d6: 1.80-2.00(2H, m); 2.85-3.10 (2H, m); 3.95 (M, m); 4.20-4.60 (2H, m); 7.10-7.30 (6N, m); 7.30-7.50 (7H, m); 7.50-7.60 (1H, m); 12.83 (1H, exchanged, broad s)
54-trifluoromethyl-phenylphenylS0DMSO-d6: 2.10-2.30 (2H, m); 3.00-3.20 (2H, m); 5.00 (1H, m), 7.00-7.10 (2H, m); 7.10-7.60 (5H, m); 7.60-7.80 (2H, m); 13.35 (1H, exchanged, broad s) MS AP-(M-1)=355
64-trifluoromethyl-phenylphenylSe0CDCl3: 2.20-2.55 (2H, m); 2.90-3.30 (2H, m), 4.92 (1H, m); 6.80-7.00 (2H, m); 7.10-7.30 (3H, m); 7.40-7.60 (4H, m); (N.B.: the acid group has not observed)
74-trifluoromethyl-phenyl2-wereS2CDCl3: 2.25-2.80 (3H, s+2H, m); 3.20-3.60 (2H, m), 4.88 (1H, m); 6.85-7.20 (3H, m); 7.20-7.45 (1H, m); 7.45-7.70 (3H, m); 7.80-8.15 (1H, m); (N.B.: the acid group has not observed) MS ES-(M-1)=401
84-trifluoromethyl-phenyl2-wereS0CDCl3: 2.20-2.50 (3H, s +2H, m), 3.00-3.25 (2H, m), 4.94 (1H, m); 6.85-7.00 (2H, m), 7.00-7.20 (3H, m); 7.20-7.40 (1H, m), 7.50-7.65 (2H, m) (N.B.: the acid group has not observed)
94-trifluoromethyl-phenyl2-wereS0CDCl3: 2.20-2.50 (3H, s+2H, m), 3.00-3.25 (2H, m), 4.94 (1H, m); 6.85-7.00 (2H, is); 7.00-7.20 (3H, m); 7.20-7.40 (1H, m), 7.50-7.65 (2H, m) (N.B.: the acid group has not observed)
104-tert-butylbenzylphenylS0MS AP+(M+1)=359
114-tert-butylbenzyl3-methoxyphenylS0MS AR+(M+1)=389
124-tert-butylbenzyl4-forfinalS0MS AP+(M+1)=377
134-tert-butylbenzylS0MS AP+(M+1)=503
144-chlorophenylphenylS0MS AP-(M-1)=321
154-chlorophenyl3-methoxyphenylS0DMSO-d6: 2.00-2.20 (2H, m); 3.00-3.20 (2H, m); 3.74 (3H, s); 4.85 (1H, m); 6.60-6.85 (1H, m); 6.85-7.10 (4H, m); 7.10-7.40 (3H, m); 2.06-14.00 (1H, exchanged, broad s) MSAP product family-(M-1)=351
164-chlorophenyl4-forfinalS0MS AP-(M-1)=340
174-chloranilS 0MS AR-(M-1)=466
184 trifter-were3-methoxyphenylS0MS AP-(M-1)=385
194 trifter-were4-forfinalS0MS AR-(M-1)=373
204 trifter-wereS0DMSO-d6: 2.20-2.40 (2H, m); 2.70-2.90 (2H, m); 4.90-5.10 (1H, m); 7.00-7.40 (3H, m); 7.40-7.80 (6N, m); 7.80-8.25 (4H, m); 13.16(1H, exchanged, broad s) MS AP-(M-1)=499
21o-cyanophenyl2-wereS0MS AP-(M-1)=326
224-forfinal3,4-dichlorophenylS0MS AP-(M-1)=373
234-forfinal4-forfinalS0MS AP-(M-1)=323
244-forfinalS0MS AR-(M-1)=362
25o-cyanophenylphenylS0MS AP-(M-1)=312
26o-cyanophenyl3,4-dichlorophenylS0MS AP-(M2)=380
27o-cyanophenyl4-forfinalS0MS AP-(M-1)=330
28o-cyanophenylS0MS AP-(M-1)=369
294-bromophenylphenylS0DMSO-d6: 2.00-2.20 (2H, m), 3.00-3.25 (2H, m), 4.58 (1H, m); 6.80-6.90 (2H, m); 7.15-7.30 (1H, m); 7.30-7.65 (6N, m); 13.28 (1H, exchanged, broad s)
304-bromophenyl3,4-dichlorophenylS0DMSO-d6: 2.05-2.25 (2H, m), 3.10-3.25 (2H, m), 4.83 (1H, m); 6.80-6.90 (2H, m); 7.15-7.30 (1H, m); 7.30-7.50 (2H, m); 7.50-7.70 (2H, m); (N.B.: the acid group has not observed)
31o-phenylbenzyl3,4-dichlorophenylS0DMSO-d6: 1.80-2.00 (2H, m);2.90-3.15(2H, m); 3.90-4.00 (1H, m); 4.25-4.70 (2H, m); 7.20-7.30 (2H, m); 7.30-7.50 (7H, m); 7.50-7.60 (3H, m); 12.84 (1H, exchanged, broad s)
324-{3,4-dichloro-phenyl}phenyl2-wereS0CDCl3: 2.15-2.50 (3H, s +2H, m); 3.00-3.0 (2H, m); 4.94 (1H, m); 6.90-7.05 (2H, m); 7.05-7.20 (3H, m); 7.20-7.40 (2H, m); 7.40-7.70 (4H, m) (N.B.:the acid group has not observed) MS AR-(M-2)=445
334-trifluoromethyl-phenyl3-wereS0MS ES-(M-1)=369
344-trifluoromethyl-phenyl4-wereS0MS ES-(M-1)=369
354-trifluoromethyl-phenyl2,6-dimetilfenilS0MS ES-(M-1)=383
364-trifluoromethyl-phenyl2-naphthylS0MS ES-(M-1)=405
374-trifluoromethyl-phenyl1-naphthylS0MS ES-(M-1)=405
384-trifluoromethyl-phenyl2-tert-butylphenylS0MS ES-(M-1)=397
394-trifluoromethyl-phenyl2-methoxyphenylS0MS ES-(M-1)=385
404-trifluoromethyl-phenyl4-methoxyphenylS0MS ES-(M-1)=385
41 4-trifluoromethyl-phenyl2,4-dimethyl-phenylS0CDCl3: 2.10-2.45 (3H, s + 3H,+2H, m); 2.90-3.20 (2H, m), 4.93 (1H, m); 6.80-7.05 (4H, m); 7.15-7.30(1H, m); 7.45-7.60 (2H, m); (N.B.: the acid group has not observed)
424-trifluoromethyl-phenyl2,5-dimethyl-phenylS0CDCl3: 2.15-2.50 (3H, s+3H,+2H, m); 2.95-3.20 (2H, m); 4.95 (1H, m), 6.85-7.15 (5H, m); 7.45-7.60 (2H, m); (N.B.: the acid group has not observed)
434-trifluoromethyl-phenyl3,4-dichlorophenylS0MS ES-(M-2)=423
444-trifluoromethyl-phenyl4-chlorophenylS0MS ES-(M-1)=389
454-trifluoromethyl-phenyl3-chlorophenylS0MSES-(M-1)=389
464-trifluoromethyl-phenyl2-chlorophenylS0MS ES-(M-1)=389
474-trifluoromethyl-phenylS0MS ES-(M-1)=360
484-trifluoromethyl-phenyl S0MS ES+(M+1)=408
494-methoxyphenyl3-wereS0MS ES-(M-1)=331
504-methoxyphenylS0MS ES-(M-l)=322
512-wereS0CDCl3: 2.20-2.45 (1H, m+3H, s); 2.45-2.85 (2H, m); 2.85-3.05 (1H, m); 5.25 (1H, m); 6.71 (1H, m); 7.00-7.30 (4H, m); 7.50-7.85 (2H, m); (N.B.: the acid group has not observed) MS ES-(M-1)=370
524-methoxyphenylS0MS ES-(M-1)=386
534-chlorophenylS0MS ES-(M-1)=390
54phenylS0MS ES-(M-1)=356
552-ethylphenylS0MS ES-(M-1)=384
56 2,4-dimethyl-phenylS0CDCl3: 2.20-2.45 (3H, s+3H,+1H, m);2.45-2.75 (2H, m); 2.90-3.00 (1H, m); 5.22 (1H, m); 6.65-7.20 (4H, m); 7.50-7.80 (2H, m); (N.B.: the acid group has not observed) MS ES-(M-1)=384
574-trifluoromethyl-phenylCH3S0CDCl3: 2.12 (3H, s); 2.25-2.45 (2H, m); 2.60-2.90 (2H, m); 5.00 (1H, m); 6.84 (2H, d, J=8.79 Hz); 7.57 (2H, d, J=8.79 Hz); (N.B.: the acid group has not observed)
584-trifluoromethyl-phenylphenylS2CDCl3: 2.20-2.80 (2H, m), 3.10-3.55 (2H, m), 4.91 (1H, m); 6.75-7.05 (2H, m); 7.40-7.80 (5H, m); 7.80-8.10 (2H, m); (N.B.: the acid group has not observed). MS ES-(M-1)=387
594-trifluoromethyl-phenyl2-ethylphenylS0CDCl3: 1.10-1.30 (3H, t, J=7.49 Hz); 2.20-2.40 (2H, m); 2.70-2.80 (2H, K, J=7.49 Hz); 3.00-3.30 (2H, m), 4.94 (1H, m); 6.85-7.00 (2H, m); 7.05-7.45 (4H, m); 7.45-7.65 (2H, m); (N.B: the acid group has not observed)
604-trifluoromethyl-phenylS0CDCl3: 2.20-2.40 (2H, m); 3.20-3.40 (2H, m), 4.88 (1H, m); 6.70-6.90 (2H, m); 7.35-7.50 (2H, m); 7.80-8.50 (4H, m), 8.85-9.00 (1H, m); 9.25-9.40 (1H, m) (N.B.: the acid group has not observed)

Can be similarly synthesized following connections:

Example 61

Example 62

Example 63

Example 64

Example 65

Example 66

Example 67

Example 68

Example 69

Example 70

Example 71

(DMSO-d6): 1,94-2,11 (2H, m); 2,80-3,03 (2H, m); 4,71 to 4.92 (1H, m); 6,55-6,83 (2H, m); 6.90 to-of 7.70 (2H, m); 7,12-7,33 (2H, m); 7,45-7,73 (2H, m). (NB: exchangeable protons were not observed).

Example 72

(CDCl3): 1,79-2,11 (2H, m); 2,17 (3H, s); 2,59-of 2.93 (2H, m); 4,60-of 4.77 (1H, m); to 4.92 (2H, s); to 6.43-to 6.57 (2H, m); 6,62-6,76 (2H, m); 6,99-7,13 (3H, m); 7,19-to 7.35 (4H, m); 7,70-7,89 (2H, m). (NB: acid N-groups were not observed).

Example 73

(CDCl3): 1,12-of 1.29 (3H, m); 2,17 is 2.44 (8H, m); 2,60-of 2.81 (2H, m); 2,98-of 3.27 (2H, m) 4,88-of 5.06 (1H, m); 6,60-7,28 (6N, m); 11.24 (1H, s).

Example 74

(CDCl3): 02-2,57 (5H, m); 2,94-of 3.32 (2H, m); 4,86 is 5.07 (1H, m); 6,76-7,06 (3H, m); 7,06-7,30 (3H, m); 7,44-to 7.67 (2H, m); 9,68 (1H, broad s).

Example 75

(CDCl3): 2,112,44 (5H, m); 2,96-is 3.21 (2H, m), 3,74 (3H, s); 4.80 to equal to 4.97 (1H, m); 6,84-6,97 (2H, m); 7.03 is-7,33 (4H, m), 7,47-7,58 (2H, m)

Example 76

(DMSO-d6): 1,95-to 2.18 (2H, m); of 2.25 (3H, s); 2,98-3,18 (2H, m); 4,27-4,50 (1H, m); 6,83-7,22 (5H, m); 7,22-7,37 (1H. m); 7,41-to 7.64 (2H, m).

Example 77

(DMSO-d6): 1,98-2,32 (10H, m); 2,96-3,17 (4H, m); 4,43-to 4.62 (2H, m); 6,88-7,21 (10H, m); 7,21-7,33 (2H, m); 7,44-7,58 (4H, m).

Example 78

(CDCl3): 2,21 at 2.59 (2H, m); to 2.67 (3H, s); 3,21-3,51 (2H, m), 3,74 (3H, s); 4,73-of 4.95 (1H, m); 6,72-to 6.95 (2H, m); 7,26 to 7.62 (5H, m); 7,79-of 8.09 (1H, m).

Example 79

(CDCl3): 2,29-2,70 (5H, m); 3,22-of 3.54 (2H, m); 4,76-free 5.01 (1H, m); is 6.54 (1H, broad s); 6,78-6,97 (2H, m); 7,19-the 7.43 (2H, m); 7,43-7,63 (3H, m); 7,87-8,08 (1H, m).

Example 80

(CDCl3): 1,93-2,70 (5H, m); 2,70-up 3.22 (2H, m); to 3.73 and 3.75 (3H, 2s); 4,65-4,99 (1H, m); 6,72? 7.04 baby mortality (2H, m); 7,07-7,63 (5H, m); 7,75-8,00 (1H, m).

Example 81

(CDCl3): 2.06 to 2,69 (5H, m); 2,87-of 3.32 (2H, m); 4,67-of 5.15 (1H, m); 5,80 (1H, broad s); for 6.81? 7.04 baby mortality (2H, m); 7,14-7,33 (1H, m); 7,33-of 7.60 (4H, m); 7,79-to 7.99 (1H, m).

1. The compound of the formula I

where a represents carboxyl or (C6-C18)alkoxycarbonyl;

In represents an ethylene group,- CH2-CH2-;

R1represents benzyl, optionally substituted in the phenyl ring; optional samewe the hydrated phenyl; or optionally substituted pyridyl; phenyl substituents and peredelnogo rings preferably selected from halogen atoms and cyano groups, triptoreline groups, (C1-C6)alkyl or (C1-C6)alkoxygroup or (C6-C18)aryl group, which itself optionally substituted with halogen, (C1-C6)alkyl, (C1-C6)alkoxy, CF3or CN;

Z represents S or Se;

n is an integer of 0, 1 or 2;

R represents a radical selected from optionally substituted phenyl; optionally substituted benzopyrene; optionally substituted benzothiazole; optionally substituted chinoline; optionally substituted naphthyl; optionally substituted triazole; and radical:

which is optionally substituted, and the substituents on the radicals mainly selected from halogen atoms, -CN, -CF3, (C1-C6)alkyl, (C1-C6)CNS groups or (C6-C18)aryl group, optionally substituted with halogen, (C1-C6)alkyl, (C1-C6)alkoxy, CF3or CN, and, when R1represents an optionally substituted benzyl or phenyl, R2can also be a C1 -C6alkyl, their stereoisomers and salts of the accession of acid or base, it is obvious that the compounds of formula (I) are excluded the compounds in which:

(i) R1represents naphthyl or 4-methoxyphenyl, And represents a carboxy, A is an ethylene, n is O, Z represents S or Se, R2represents phenyl;

(ii) R1represents 4-methoxyphenyl, And is methoxycarbonyl, Z[O]nrepresents the SO2, R2represents phenyl, A represents ethylene;

(iii) R1represents methyl, R2represents phenyl, Z[O]nrepresents Se, But metocarbamol and is a 1-cyanoethylene or 1.2 dicyanomethylene;

(iv) R1represents 4-chlorophenyl; And is methoxycarbonyl;

Z[O]nrepresents S, R2represents methyl and represents ethylene;

(v) R1is a 4-methoxybenzyl; And is methoxycarbonyl, Z[O]nis a Se, R2represents phenyl and represents ethylene.

2. The compound of formula I according to claim 1, characterized in that Z represents S.

3. The compound according to claim 1

p> 4. The method of obtaining the compounds of formula I according to claim 1, where a represents-COOH, Z represents S, n=0, characterized in that the compound of formula II

where and R1are as defined in claim 1, is subjected to reaction with a thiol of formula III

where R2is such as defined in claim 1, in the presence of a base.

5. The method according to claim 4 for the preparation of enantiomers of formula Ib

where a, b, Z, R1n and R2are as defined in claim 1, and * denotes an asymmetric carbon, characterized in that the compound of formula II is an enantiomer of the formula

where and R1are as defined for formula Ib, and * indicates an asymmetric carbon, which has the same configuration as the corresponding carbon in formula Ib.

6. The method of obtaining the compounds of formula I according to claim 1, where a represents-COOH, Z is a Se and n=0, wherein the selenium compound of the formula IV

where R2is such as defined in claim 1,

subjected to reaction with an organic or mineral base, and the compound obtained p will gorhaut reaction with the compound of the formula II

where and R1are as defined in claim 1 for formula I.

7. The method of obtaining the compounds of formula I according to claim 1, where a represents-COOH and n is not equal to 0, wherein the compound of formula I, where n=0;

where R1,, Z, and R2are as defined in claim 1, and a represents a-COOH,

subjected to reaction with an oxidizing agent such as m-chloroperbenzoic acid.

8. The pharmaceutical composition intended for the prevention or treatment of dyslipidemia and diabetes and containing an effective amount of at least one compound selected from the compounds of formula I according to any one of claims 1 to 3, and compounds of the formula I for which R1represents naphthyl or 4-methoxyphenyl; And is carboxyl or methoxycarbonyl; represents ethylene; n is zero; Z represents S or Se, and R2represents phenyl, together with at least one pharmaceutically acceptable carrier.

9. The use of the compounds of formula I according to any one of claims 1 to 3 to obtain a medicinal product intended for the prevention or treatment of dyslipidemia and diabetes.



 

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The invention relates to new compounds of the formula (I)

< / BR>
where AG represents a radical selected from formulas (a) and (b) below:

< / BR>
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The invention relates to selenoorganicheskikh compounds, namely 1-methoxy-1-(2-chlorpheniramine)alkanal formula I

CH3-O-H-SEwhere R is methyl or isopropyl, exhibiting anti-inflammatory and antimicrobial activity

The invention relates to new biologically active compounds, specifically to hydrochloridum of aminosilanes aromatic series formula I

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FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzoic acid of the formula (I): , wherein represents 0, 1 or 2; R1 represents halogen atom, (C1-C4)-alkyl group that is possibly substituted with one or more fluorine atoms, (C1-C4)-alkoxyl group that is possibly substituted with one or more fluorine atoms and when n represents 2 then substitutes at R1 can be similar or different; R2 represents direct (C2-C7)-alkyl group; R3 represents hydrogen atom (H) or -OCH3; W represents oxygen (O) or sulfur (S) atom, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition used in treatment of hyperlipidemia, dyslipidemia, diabetes mellitus and obesity and comprising derivative of benzoic acid of the formula (I) in mixture with pharmaceutically acceptable adjuvants, excipients and/or carriers. Also, invention relates to using derivative of benzoic acid of the formula (I) for preparing a medicinal agent used in treatment of resistance to insulin. Also, invention relates to a method for synthesis of derivative of benzoic acid of the formula (I) and used for synthesis of intermediate compound of the formula (II) given in the invention description. Invention provides preparing derivatives of benzoic acid representing selective modulators of PPARα.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 14 ex

The invention relates to a method of deriving dibenzothiazepine interest as intermediate compounds for pharmaceutical preparations

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< / BR>
where AG represents a radical selected from formulas (a) and (b) below:

< / BR>
R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)

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The invention relates to sulfur-containing derivative of an aryl having antibacterial and antiviral activity, in particular Aristotelianism the following formula (I), their pharmaceutically acceptable salts and solvate, a pharmaceutical composition having antibacterial and antiviral activity, and method of treating bacterial or viral infections

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SUBSTANCE: invention relates to novel compounds of the formula (I) and their physiologically acceptable salts also possessing properties for decrease the blood sugar content. In compound of the formula (I) A means phenyl wherein phenyl residue can be substituted up to three times with fluorine (F), chlorine (Cl) and bromine (Br) atoms; R1 and R2 mean hydrogen atom (H); R3, R4, R5 and R6 mean independently of one another H, F, Cl, Br, -NO2, -O-(C1-C6)-alkyl, (C1-C6)-alkyl, -COOH; R7 means H, (C1-C6)-alkyl wherein alkyl can be substituted up to three times with -OH, -CF3, -CN, COOH, -COO-(C1-C6)-alkyl, -CO-NH2, -NH2, -NH-(C1-C6)-alkyl, -N-[(C1-C6)-alkyl]2, -NHCO-(C1-C6)-alkyl, -NHCOO-(C1-C6)-alkyl or -NHCOO-(C1-C4)-alkylenephenyl; in (CH2)m m can mean 0-6 and aryl means phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, pyridyl, indolyl, piperidinyl, tetrahydronapthyl, 2,3-dihydrobenzo[1,4]dioxynyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, morpholinyl wherein aryl residue can be substituted mono- or multiple with R9 wherein R9 means F, Cl, Br, -OH, -NO2, -CF3, -OCF3, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, -O-(C1-C6)-alkyl, -COOH, -COO-(C1-C6)-alkyl. Also, invention relates to a pharmaceutical composition and a method for preparing a medicinal agent.

EFFECT: valuable medicinal properties of derivatives and pharmaceutical composition.

7 cl, 2 sch, 1 tbl, 293 ex

FIELD: medicine, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to preparing agent used in prophylaxis or relief of syndrome of the multiply risk factors. The agent used for prophylaxis or relief of syndrome of the multiple risk factors comprises at least one component taken in the definite amount and chosen from the group consisting of licorice hydrophobic extract, yellow radix extract (turmeric), clove extract and cinnamon extract. The above describes agent promotes to effective prophylaxis and relief of syndrome of multiple risk factors.

EFFECT: valuable medicinal properties of composition.

9 cl, 18 tbl, 35 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel class of 5-membered heterocyclic compounds of the general formula (I): or cosmetically acceptable salts. Invention describes a compound represented by the formula (I) and its pharmaceutically or cosmetically acceptable salt wherein R1 is chosen from linear or branched (C1-C12)-alkyl, (C3-C7)-cycloalkyl, phenyl, naphthyl, C3-, C4-, C5- or C8-heteroaryl wherein one or some heteroatoms when they present are chosen independently from oxygen (O), nitrogen (N) or sulfur (S) atom and substituted optionally wherein substitutes are chosen from the first group comprising halogen atom, hydroxy0, nitro-, cyano-, amino- oxo-group and oxime, or from the second group comprising linear or branched (C1-C8)-alkyl wherein a substitute from indicated second group is optionally substituted with R10, or wherein heteroaryl is substituted with -CH2-C(O)-2-thienyl; Y is absent or chosen from the group consisting of (C1-C12)-alkyl-Z or (C2-C8)-alkyl wherein Z is chosen from sulfur, oxygen or nitrogen atom; A and B are chosen independently from nitrogen atom (N), -NH, -NR6, sulfur, oxygen atom to form heteroaromatic ring system; R2, R3 and R4 are chosen independently from the first group comprising hydrogen, halogen atom, or R3 and R4 form phenyl ring in adjacent positions; R5 is absent or chosen from the group comprising -CH2-phenyl, -CH2(CO)R7, -CH2(CO)NHR8 and -CH2(CO)NR8R9 that are substituted optionally with R10; R6, R7, R8 and R are chosen independently from the group comprising linear or branched (C1-C8)-alkyl, (C3-C7)-cycloalkyl, C5-heterocycloalkyl, benzylpiperidinyl, phenyl, naphthyl, heteroaryl, alkylheteroaryl, adamantyl, or R8 and R9 form piperidine ring, and R means 3,4-ethylenedioxyphenyl wherein substitutes in indicated group are substituted optionally with R10, and heteroaryl means C3-, C4-, C5- or C8-heteroaryl wherein one or some heteroatom when they present are chosen independently from O, N or S; R10 is chosen from halogen atom, hydroxy-, nitro-, cyano-, amino-, oxo-group, perhalogenalkyl-(C1-C6) or oxime; X means halide ion under condition that when groups/substitutes present at the same or at adjacent carbon or nitrogen atoms then can form optionally 5-, 6- or 7-membered ring optionally containing one o some double bonds and containing optionally one or some heteroatoms chosen from O, N or S. Also, invention describes a method for synthesis of these compounds, their therapeutic and cosmetic using, in particular, in regulation of age and diabetic vascular complications. Proposed compounds show effect based on the triple effect as agent destroying AGE (terminal products of enhanced glycosylation), inhibitors of AGE and scavengers of free radicals that do their suitable in different therapeutic and cosmetic using. Also, invention relates to pharmaceutical and cosmetic compositions comprising these compounds and to methods for treatment of diseases caused by accumulation of AGE and/or free radicals in body cells. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds.

73 cl, 4 tbl, 63 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel pyrimidotriazines of the general formula (I):

wherein each R1 and R2 is chosen from the group comprising hydrogen atom, or R1 and R2 form in common chemical bond, -CH2-Ar and Ar is chosen from the group comprising unsubstituted phenyl, unsubstituted naphthyl, phenyl, mono- or disubstituted with (lower)-alkoxy-group and naphthyl mono- or disubstituted with (lower)-alkyl, or their pharmaceutically acceptable salts. Also, invention relates to a method for synthesis of these compounds, pharmaceutical composition based on thereof and to using novel pyrimidotriazines for prophylaxis and/or treatment of diabetes mellitus as these compounds possess the strong expressed inhibitory effect on activity of protein tyrosine phosphatase PTP1B.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 27 ex

FIELD: medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising epidermal growth factor (EGF) used in treatment of wounds on skin and soft tissues of lower limb in diabetic patient. Method of treatment involves topical infiltration of EGF-containing solution into different points and by contours of tissue damaged zone to provide administration of the solution into wound in the total volume 4-20 ml and irrigation of all deep surface of wound base and edges with the indicated composition. Invention provides prevention of diabetic limb amputation, stimulation of cellular proliferation in patients with foot ulcer being especially in geriatrics.

EFFECT: valuable medicinal properties of pharmaceutical composition.

19 cl, 1 tbl, 9 ex

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