Heterocyclic compounds and application methods

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula I: , where L represents radical , in which R1 represents H, C1-4alkyl; n represents 0 or 1; or L represents radical , in which R1 represents H, C1-4alkyl; m equals 1; R represents H, halogen, C1-C4alkyl or C1-C4-alkoxy; Z represents a bond, -C(O)NH-, O or S; p is an integer from 1 to 5; Q represents a bond with the condition that, Z is not a bond, when p equals 1; or represents O, S or -C(O)NR6-, where R6 represents H, C1-4alkyl or C3-6cycloalkyl; or W and R6 together with a nitrogen atom, to which they are bonded, form or or Q represents -NR6-, or in the condition that, p is not equal to 1; W represents , , , , ,

, , ,

, , ,

, , , ,

, , , ,

, , , ,

, , , , ,

, , , , , and

.

EFFECT: obtaining compounds with agonistic activity towards PPAR receptors, which enables them to be used in pharmaceutical compositions and methods of treating conditions, mediated by these receptors.

12 cl, 7 ex

 

The present invention relates to heterocyclic compounds, containing their pharmaceutical compositions and to methods of treating conditions associated with retinoid X receptor (RXR) and with families peroxisome proliferation of activated receptors (PPAR), which includes three subtypes of PPARα, PPARδ and PPARγ.

In one aspect the present invention provides compounds of formula

where L denotes the radical

in which R1means hydrogen, optionally substituted alkyl, aryl, heteroaryl, aralkyl or cycloalkyl;

R2means hydrogen, hydroxyl, optionally substituted alkyl, aryl, aralkyl, alkoxygroup, alloctype, relaxerror, allylthiourea, aricioglu or arkitip;

R3means hydrogen or aryl, or R2and R3United are alkylen, which together with the carbon atoms to which they are attached, form a 5 - to 7-membered ring;

n means zero or an integer from 1 to 2;

Y represents hydrogen or Y and R2together with the carbon atoms to which they are attached, form a bond, provided that

n means 1;

R4means hydrogen or

R4and Y together with the carbon atoms to which they are linked, form a bond, provided h is o n means 1, and R2and R3together with the carbon atoms to which they are attached, form a bond; or

L means the radical

in which R1means hydrogen, optionally substituted alkyl, aryl, heteroaryl, aralkyl or cycloalkyl;

R means hydrogen, optionally substituted alkyl, alkoxygroup or halogen;

m means an integer from 1 to 2;

Y represents hydrogen;

R4and Y together with the carbon atoms to which they are linked, form a bond, provided that m is 1;

R and R' denote independently hydrogen, halogen, optionally substituted alkyl, alkoxygroup, aralkyl or heteroalkyl or

R and R'together form methylenedioxy provided that R and R' are attached to adjacent carbon atoms, or

R and R' together with the carbon atoms to which they are attached, form an optionally substituted 5 - to 6-membered aromatic or heteroaromatic ring provided that R and R' are attached to adjacent carbon atoms, or

R-C and R'-C can be independently replaced by nitrogen;

X is-Z-(CH2)p-Q-W, where Z indicates the bond, O, S, S(O), S(O)2-C(O)-or-C(O)NR5-where

R5means hydrogen, alkyl or aralkyl;

p means an integer from 1 to 8;

Q means a connection provided that Z is not a bond when p is appoints 1, or

Q means-O(CH2)r- or-S(CH2)r-, where r is zero or an integer from 1 to 8, or

Q means-O(CH2)1-8O-, -S(CH2)1-8O-, -S(CH2)1-8S-, -C(O)- or-C(O)NR6-, where R6means hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroalkyl, or

Q means-NR6-, -NR5C(O)-, -NR5C(O)NH - or-NR5C(O)O -, provided that p is not 1;

W means cycloalkyl, aryl, heterocyclyl, aralkyl or heteroalkyl or

W and R6together with the nitrogen atom to which they are attached, form a 8-12 membered bicyclic ring system, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulphur,

or their pharmaceutically acceptable salts, or optical isomers, or a mixture of optical isomers.

According to another aspect of the present invention provides methods of treating conditions mammals, oposredstvovanii activity of PPAR. Such conditions include dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin C the disease, respiratory diseases, eye diseases, IBD (a disease associated with irritation of the bowel), ulcerative colitis and Crohn's disease. Compounds according to the invention are particularly useful in mammals as hypoglycemic agents for the treatment and prevention of conditions involving impaired glucose tolerance, hyperglycemia and insulin resistance, such as diabetes type-1 and type-2 and syndrome X. the Preferred compounds according to the invention, which are dual agonists of PPARα and PPARγ.

The present invention relates to heterocyclic compounds containing pharmaceutical compositions, to methods for producing compounds and to methods of treating conditions oposredstvovanii families of receptors RXR and PPAR, including activation of PPAR receptors using such compounds. Compounds according to the invention can also be used in combination with ligands for other nuclear receptors, which are known to form heterodimeric complexes with RXR receptors.

Further, the present invention relates to pharmaceutical compositions containing the heterocyclic compounds according to the invention, for treating conditions specified above.

Listed below are definitions of various terms used to describe the compounds of this the image is to be placed. These definitions apply to the terms used in the specification or in the claims, if they are not limited to, otherwise in the specific examples or separately, or as part of a larger group, for example, where the place of attachment of a specific group specific limit within this group atom, a place of connection denoted by the arrow when a particular atom.

The term "optionally substituted alkyl" refers to unsubstituted or substituted hydrocarbon groups with straight or branched chain, containing from 1 to 20 carbon atoms, preferably from 1 to 7 carbon atoms. Examples of unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like. Substituted alkyl groups include, but are not limited to, alkyl groups substituted by one or more of the following groups: halogen, hydroxyl, cycloalkyl, alkanoyl, alkoxygroup, alkyloxyalkyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanolamines, Tolna group, allylthiourea, allylthiourea, alkylsulfonyl, arylsulfonyl, heteroarylboronic, sulfonylurea, nitrogroup, lagrappe, carboxyl group, alkoxycarbonyl, aryl, alkenyl, quinil, who alkoxygroup, guanidinium, heterocyclyl, including indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl, morpholinyl and similar groups.

The term "lower alkyl" refers to alkyl groups described above, which contain from 1 to 7, preferably from 1 to 4, carbon atoms.

The term "halogen" or "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "alkenyl" refers to any of the above alkyl groups containing at least two carbon atoms and additionally containing a double carbon-carbon bond at the connection point. Preferred groups containing from two to four carbon atoms.

The term "quinil" refers to any of the above-mentioned alkyl groups containing at least two carbon atoms and additionally containing a triple carbon-carbon bond at the connection point. Preferred groups containing from two to four carbon atoms.

The term "alkylene" refers to the bridge with a direct chain with 1-6 carbon atoms, bound simple relationships (e.g.,- (CH2)x-where x is a number from 1 to 6), which can be substituted by 1-3 lower alkilani or alkoxygroup.

The term "cycloalkyl" refers to optionally substituted monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon is different atoms, each of which may optionally be substituted by one or more substituents, such as alkyl, halogen, oxoprop, hydroxyl, alkoxygroup, alkanoyl, amino, alkylamino, dialkylamino, Tolna group, allylthiourea, nitrogroup, lagrappe, carboxyl, carboxylic, alkoxycarbonyl, alkyl - and arylsulfonyl, sulfonylurea, heterocyclyl and similar substituents.

Examples of the monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and similar groups.

Examples of bicyclic hydrocarbon groups include bornyl, Intel, hexahydrobenzyl, tetrahydronaphthyl, decahydronaphthalene, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and similar groups.

Examples of tricyclic hydrocarbon groups include substituted and the like.

The term "alkoxy" refers to alkyl-O-.

The term "acyl" refers to alkanoyl, Arola, heteroaryl, arylalkyl or heteroarylboronic.

The term "alkanoyl" refers to alkyl-C(O)-.

The term "alkanoyloxy" refers to alkyl-S(O)-O-.

The terms "alkylamino and dialkylamino" refers to alkyl-NH - (alkyl)2N -, respectively.

The term "alkanoyl the Ino" refers to alkyl-S(O)-NH-.

The term "alkylthio" refers to alkyl-S-.

The term "alkylaminocarbonyl" refers to alkyl-NHC(S).

The term "trialkylsilyl" refers to (alkyl)3Si-.

The term "trialkylsilyl" refers to (alkyl)3SiO-.

The term "alkylthio" refers to-S(O)-.

The term "alkylsulfonyl" refers to alkyl-S(O)2-.

The term "alkoxycarbonyl" refers to alkyl-O-C(O)-.

The term "alkoxycarbonyl" refers to alkyl-O-C(O)O-.

The term "carbarnoyl" refers to alkyl-NHC(O)-, (alkyl)2NC(O)-, aryl-NHC(O)-, alkyl(aryl)-NC(O)-, heteroaryl-NHC(O)-, alkyl(heteroaryl)-NC(O)-, aralkyl-NHC(O)- alkyl(aralkyl)-NC(O)-.

The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups containing from 6 to 12 carbon atoms in the ring, such as phenyl, raftiline, tetrahydronaphthalene, biphenylene and diphenylene groups, each of which may optionally be substituted by 1-4 substituents, such as alkyl, halogen, hydroxyl, alkoxygroup, alkanoyl, alkanoyloxy, optionally substituted amino group, Tolna group, allylthiourea, nitrogroup, lagrappe, carboxyl, carboxylic, alkoxycarbonyl, allylthiourea, alkyl - and arylsulfonyl, sulfonylurea, heterocyclyl and similar substituents.

The term "monocyclic aryl" refers to optionally substituted by anilu, as described for aryl.

The term "aralkyl" refers to an aryl group linked directly through an alkyl group, such as benzyl.

The term "Uralkali" refers to aralkyl-S-.

The term "arakaki" refers to an aryl group linked directly through alkoxygroup.

The term "arylsulfonyl" refers to aryl-S(O)2-.

The term "aristeo" refers to aryl-S-.

The term "aroyl" refers to aryl-C(O)-.

The term "aroylamino" refers to aryl-C(O)-NH-.

The term "aryloxyalkyl" refers to aryl-O-C(O)-.

The term "heterocyclyl" or "heterocycle" refers to optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4-7-membered monocyclic, 7-12 membered bicyclic, or 10 to 15 membered tricyclic ring system, which contains at least one heteroatom in at least one containing carbon atoms of the ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the heteroatoms nitrogen and sulfur may also be optionally oxidized. The heterocyclic group can be attached to heteroatom or carbon atom.

Examples of monocyclic heterocyclic what RUPE include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolines, imidazoles, imidazolines, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, diazolidinyl, isothiazolin, isothiazolinones, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinil, 2-oxopiperidine, 2-oxopiperidine, 2-oxopyrrolidin, 2-oxoazetidin, azepine, 4-piperidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiomorpholine, sulfoxide of thiomorpholine, sulfon of thiomorpholine, 1,3-dioxolane and tetrahydro-1,1-DIOXOLANYL, and stuff like that.

Examples of bicyclic heterocyclic groups include indolyl, dihydroindole, benzothiazolyl, benzoxazolyl, benzoxazolyl, benzothiazyl, benzothiazines, hinokitiol, chinoline, tetrahydroquinoline, decahydroquinoline, ethenolysis, tetrahydroisoquinoline, decahydroquinoline, benzimidazolyl, benzopyranyl, indolizinyl, benzofuran, chromones, coumarinyl, cinnoline, honokalani, indazoles, pyrrolopyridine, properidine (such as furo[2,3-C]pyridinyl, furo[3,2-b]pyridinyl or furo[2,3-b]pyridinyl), dihydroisoquinolyl, dihydroquinazolines (as, for example, 3,4-dihydro-4-oxothiazolidine)phthalazines and similar groups.

Examples of tricyclic heterocyclic groups include carbazolyl, dibenzoxazepines, d is teenasain, benzoindole, phenanthrolines, acridines, phenanthridines, phenoxazines, phenothiazines, xantener, carboline and similar groups.

The term "heterocyclyl" includes a substituted heterocyclic group. Substituted heterocyclic groups refer to heterocyclic groups, substituted 1, 2 or 3 of the following groups:

(a) alkyl;

(b) hydroxyl, or protected hydroxyl);

(C) halogen;

(g) oxo (i.e. =O);

(d) optionally substituted amino, alkylamino or dialkylamino;

(e) alkoxygroup;

(e) cycloalkyl;

(g) carboxyl;

(C) geterotsyklicescoe;

(and) alkoxycarbonyl, as, for example, unsubstituted (ness.)alkoxycarbonyl;

(K) mercaptopropyl;

(l) the nitro-group;

(m) langroup;

(h) sulfonylurea, sulfamidate, sulfamides or sulfidogenic;

(o) aryl;

(p) alkylcarboxylic;

(R) arylcarboxylic;

(C) aristocrata;

(t) alloctype;

(d) allylthiourea;

(f) formyl;

(x) carbarnoyl;

(C) aralkyl or

(h) aryl, substituted alkyl, cycloalkyl, alkoxygroup, hydroxyl, amino, alkylamino, dialkylamino or halogen.

The term "heterocyclic" means a heterocyclic group attached through an oxygen bridge.

The term "heteroaryl" refers to aromatic heterocycle, e.g. what to monocyclic or bicyclic the aryl, as, for example, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothiazyl, chinoline, ethenolysis, benzimidazolyl, benzofuran and similar groups, optionally substituted, for example, lower alkyl, (ness.)alkoxygroup or halogen.

The term "heteroarylboronic" refers to heteroaryl-S(O)2-.

The term "heteroaryl" refers to heteroaryl-C(O)-.

The term "heteroalkyl" refers to a heteroaryl group, which is connected via an alkyl group.

The invention covered by proletarienne derivatives, for example, any pharmaceutically acceptable proletarienne ester derivatives of carboxylic acids according to the invention, which can turn when the solvolysis or under physiological conditions to the free carboxylic acid.

Examples of such esters of carboxylic acids are preferably complex (ness.)alkalemia esters, complex cycloalkyl esters, complex (ness.)alkenilovyh esters, complex benzyl esters, complex mono - or disubstituted by (ness.)alkalemia esters, such as complex ω-(amino, mono - or di-(ness.)alkylamino-, carboxy-, (ness.)alkoxycarbonyl)-(ness.)alkalemia esters, complex α-((ness.)alkanoyloxy-, (ness.)alkoxy bonil or di(ness.)alkylaminocarbonyl)-(ness.)alkalemia esters, as, for example, a complex pivaloyloxymethyl ether, and the like, usually used in this field.

Compounds according to the invention depending on the nature of the substituents may have one or more asymmetric centers. The resulting diastereoisomers, optical isomers, i.e. enantiomers and geometric isomers are covered directly by the present invention.

Preferred compounds of formula I, where

X is-Z-(CH2)p-Q-W, where Z indicates the bond, O, S, -C(O)- or-C(O)NR5-where

R5means hydrogen, alkyl or aralkyl;

p means an integer from 1 to 8;

Q means a connection provided that Z is not a bond when p is 1, or

Q means-O(CH2)r- or-S(CH2)r-, where r is zero or an integer from 1 to 8, or

Q means-O(CH2)1-8O-, -S(CH2)1-8O-, -S(CH2)1-8S-, -C(O)- or-C(O)NR6-, where R6means hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroalkyl, or

Q means-NR6-, -NR5C(O)-, -NR5C(O)NH - or-NR5C(O)O -, provided that p is not 1;

W means cycloalkyl, aryl, heterocyclyl, aralkyl or heteroalkyl or

W and R6together with the nitrogen atom to which they are attached, form an 8-12-membered millionsquare system, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulphur,

or their pharmaceutically acceptable salts, or optical isomer or mixture of optical isomers.

Further preferred compounds of formula

where L denotes the radical

in which R1means hydrogen or optionally substituted alkyl;

R2and R3mean hydrogen or

R2and R3United are alkylen, which together with the carbon atoms to which they are attached, form a 6-membered ring;

n means zero or an integer from 1 to 2;

Y represents hydrogen;

R4means hydrogen or

L means the radical

in which R1means hydrogen or optionally substituted alkyl;

R means hydrogen, optionally substituted alkyl, alkoxygroup or halogen;

m means an integer from 1 to 2;

Y represents hydrogen;

R4means hydrogen;

R and R' denote independently hydrogen, halogen, optionally substituted (C1-C6)alkyl or (C1-C6)alkoxygroup or

R and R'together form methylenedioxy provided that R and R' are attached to adjacent atoms angle of the ode;

Z means a bond, O, S, or-C(O)NR5-, where R5means hydrogen, alkyl or aralkyl;

p means an integer from 1 to 5;

Q means a connection provided that Z is not a bond when p is 1,

or

Q means-O(CH2)r- or-S(CH2)r-, where r is zero, or

Q means-C(O)- or-C(O)NR6-, where R6means hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroalkyl, or

Q means-NR6-, -NR5C(O)-, -NR5C(O)NH - or-NR5C(O)O -, provided that p is not 1;

W means cycloalkyl, aryl or heterocyclyl or

W and R6together with the nitrogen atom to which they are attached, form a 9-10-membered bicyclic ring system, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulphur,

or their pharmaceutically acceptable salts, or optical isomers, or a mixture of optical isomers.

More preferred compounds of formula IA, where

L means the radical

in which R1means hydrogen or optionally substituted alkyl;

R2and R3mean hydrogen;

n indicates 0 or an integer from 1 to 2 or

L means the radical

in which R1about the means hydrogen or optionally substituted alkyl;

R ' signifies hydrogen;

m means an integer from 1 to 2;

R means hydrogen, halogen, optionally substituted (C1-C6)alkyl or (C1-C6)-alkoxygroup;

R' signifies hydrogen;

Z means a bond, O or S;

p means an integer from 1 to 5;

Q means a connection provided that Z is not a bond when p is 1,

or Q denotes O, S or-C(O)NR6-, where R6means hydrogen, optionally substituted alkyl or cycloalkyl, or

Q means-NR6-, -NR5C(O)NH - or-NR5C(O)O-, where R5means hydrogen, alkyl or aralkyl provided that p is not 1;

W means cycloalkyl, aryl or heterocyclyl or

W and R6together with the nitrogen atom to which they are attached, form a 9-10-membered bicyclic ring system, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulphur,

or their pharmaceutically acceptable salts, or optical isomers, or a mixture of optical isomers.

The most preferred compounds of formula

where L denotes the radical

in which R1means hydrogen or optionally substituted alkyl;

n denotes zero or 1, or

L means the radical

in which R1means hydrogen or optionally substituted alkyl;

m is 1;

R means hydrogen, halogen, optionally substituted (C1-C6)alkyl or (C1-C6)-alkoxygroup;

Z means a bond, O or S;

p means an integer from 1 to 5;

Q means a connection provided that Z is not a bond when p is 1, or

Q denotes O, S, or-C(O)NR6-, where R6means hydrogen, optionally substituted alkyl or cycloalkyl, or

Q means-NR6-, -NR5C(O)NH - or-NR5C(O)O-, where R5means hydrogen, alkyl or aralkyl provided that p is not 1;

W means cycloalkyl, aryl or heterocyclyl or

W and R6together with the nitrogen atom to which they are attached, form a 9-10-membered bicyclic ring system, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur;

or their pharmaceutically acceptable salts, or optical isomers, or a mixture of optical isomers.

Further preferred compounds of formula IB, where

L means the radical

in which R1means hydrogen and n is 0 or 1;

R means hydrogen, halogen, optionally substituted (C1-C6)alkyl or (C1-C6)-alkoxygroup;

Z about the mean relationship, O or S;

p means an integer from 1 to 4;

Q means a connection provided that Z is not a bond when p is 1,

or

Q denotes O or S;

W stands for aryl or heterocyclyl,

or their pharmaceutically acceptable salts, or optical isomers, or a mixture of optical isomers.

Then, preferred are also the compounds of formula IB, where

L means the radical

in which R1means hydrogen;

R means hydrogen, halogen, optionally substituted (C1-C6)alkyl or (C1-C6-alkoxyl;

Z means a bond, O or S;

p means an integer from 1 to 4;

Q means a connection provided that Z is not a bond when p is 1,

or Q denotes O or S;

W stands for aryl or heterocyclyl,

or their pharmaceutically acceptable salts, or optical isomers, or a mixture of optical isomers.

Further preferred are also the compounds of formula IB, where the asymmetric center in the radical L is (R)-configuration, or their pharmaceutically acceptable salts.

In addition, preferred are also the compounds of formula IB, denoted as group a, where

R1means hydrogen or optionally substituted alkyl;

R means hydrogen, halogen, optionally substituted (C1-C6)alkyl or (C1-C6)-alkoxygroup the u;

Z denotes O or S;

p represents 2;

Q means-NR6-, where R6means lower alkyl;

Q denotes O or S;

W stands for aryl or heterocyclyl,

or their pharmaceutically acceptable salts, or optical isomers, or a mixture of optical isomers.

Preferred compounds of group a, where

R denotes hydrogen, chlorine, n-propyl or methoxy group, or their pharmaceutically acceptable salts, or optical isomers, or a mixture of optical isomers.

Further preferred are also the compounds of formula IB, denoted as group, where

R1means hydrogen or optionally substituted alkyl;

R means hydrogen, halogen, optionally substituted (C1-C6)alkyl or (C1-C6)-alkoxygroup;

Z represents a relationship;

p represents 2;

Q means-C(O)NR6-, where R6means optionally substituted alkyl;

W stands for aryl or heterocyclyl or

W and R6together with the nitrogen atom to which they are attached, form a 9-10-membered bicyclic ring system, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulphur,

or their pharmaceutically acceptable salt or optical isomer or mixture of optical isomers.

Preferred compounds of group b, where

R oznacza the t hydrogen, chlorine, n-propyl or methoxy group, or their pharmaceutically acceptable salts, or optical isomers, or a mixture of optical isomers.

Further preferred are also the compounds of formula IB, denoted as group, where

R1means hydrogen or optionally substituted alkyl;

R means hydrogen, halogen, optionally substituted (C1-C6)alkyl or (C1-C6)-alkoxygroup;

Z means a bond, O or S;

p means an integer from 2 to 3;

Q denotes O or S;

W stands for aryl or heterocyclyl,

or their pharmaceutically acceptable salts, or optical isomers, or a mixture of optical isomers.

Preferred compounds of group C, where

R denotes hydrogen, chlorine, n-propyl or methoxy group,

or their pharmaceutically acceptable salts, or optical isomers, or a mixture of optical isomers.

Another preferred group of compounds in the group are compounds where W is selected from the group consisting of

,,,,,

,,,

,, ,

,and,

or their pharmaceutically acceptable salts, or optical isomers, or a mixture of optical isomers.

Further preferred are also the compounds of formula IB, denoted as group D, where

R1means hydrogen or optionally substituted alkyl;

R means hydrogen, halogen, optionally substituted (C1-C6)alkyl or (C1-C6)-alkoxygroup;

Z denotes O or S;

p means an integer from 1 to 2;

Q means the connection;

W stands for aryl or heterocyclyl,

or their pharmaceutically acceptable salts, or optical isomers, or a mixture of optical isomers.

The preferred compound in group D, where R is hydrogen, chlorine, n-propyl or methoxy group, or their pharmaceutically acceptable salts, or optical isomers, or a mixture of optical isomers.

Another preferred group of compounds in group D are compounds where W is selected from the group consisting of

,,,,

,,, ,

,,,,

,,,,

,,,,,

,,,,,

,,and;

or their pharmaceutically acceptable salts, or optical isomers, or a mixture of optical isomers.

Another preferred group of compounds in group D are also connections, where

R1means hydrogen or optionally substituted alkyl;

R means hydrogen, halogen, optionally substituted (C1-C6)alkyl or (C1-C6)-alkoxygroup;

Z denotes O or S;

p represents 2;

Q means the connection;

W is chosen from the group consisting of

,,, ,,,

,,,,,,

,,,,,

,,,,and,

or their pharmaceutically acceptable salts, or optical isomers, or a mixture of optical isomers.

Specific examples of the invention are the following:

(R)-1-{4-[4-(4-phenoxy-2-propylenoxide)butoxy]benzazolyl}azetidin-2-carboxylic acid;

(R)-1-{4-[3-(4-phenoxy-2-propylenoxide)propoxy]benzazolyl}azetidin-2-carboxylic acid;

(R)-1-[4-(5-methyl-2-phenyloxazol-4-ylethoxy)benzazolyl]azetidin-2-carboxylic acid;

(R)-1-{4-[2-(4-forfinal)-5-methoxazole-4-ylethoxy]benzazolyl}azetidin-2-carboxylic acid;

(R)-1-{4-[5-methyl-2-(4-(triptoreline)oxazol-4-ylethoxy] benzazolyl}azetidin-2-carboxylic acid;

(R)-1-{4-[2-(3,5-bis(triptorelin the l)-5-methoxazole-4-ylethoxy]benzazolyl}azetidin-2-carboxylic acid;

(R)-1-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzazolyl}azetidin-2-carboxylic acid;

(R)-1-{4-[4-(4-phenoxy-2-propylenoxide)butoxy]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-{4-[3-(4-phenoxy-2-propylenoxide)propoxy]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-(4-{3-[2-propyl-4-(4-(trifluoromethyl)phenoxy)phenoxy]propoxy}benzazolyl)pyrrolidin-2-carboxylic acid;

(R)-1-{4-[2-(4-phenoxy-2-propylenoxide)ethoxy]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-(4-{2-[2-propyl-4-(4-(trifluoromethyl)phenoxy)phenoxy]ethoxy}benzazolyl)pyrrolidin-2-carboxylic acid;

(R)-1-{3-methoxy-4-[3-(4-phenoxy-2-propylenoxide)propoxy]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-{3-chloro-4-[3-(4-phenoxy-2-propylenoxide)propoxy]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-{4-[3-(4-phenoxy-2-propylenoxide)propoxy]-3-propylbenzenesulfonyl}pyrrolidin-2-carboxylic acid;

(R)-1-{4-[3-(4-phenoxy-2-propylenoxide)propylsulfonyl]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-{4-[2-(4-phenoxy-2-propylenoxide)ethylsulfanyl]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-{4-[3-(4-phenoxy-2-propylenoxide)propyl]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-[4-(5-methyl-2-phenyloxazol-4-ylethoxy)benzazolyl]pyrrolidin-2-carboxylic acid;

(R)-1-{4-[2-(4-shall terphenyl)-5-methoxazole-4-ylethoxy]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-{4-[5-methyl-2-(4-(triptoreline)oxazol-4-ylethoxy]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-{4-[2-(3,5-bis(triptoreline)-5-methoxazole-4-ylethoxy]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-[4-(2-biphenyl-4-yl-5-methoxazole-4-ylethoxy)benzazolyl]pyrrolidin-2-carboxylic acid;

(R)-1-[3-methoxy-4-(5-methyl-2-phenyloxazol-4-ylethoxy)benzazolyl]pyrrolidin-2-carboxylic acid;

(R)-1-[3-chloro-4-(5-methyl-2-phenyloxazol-4-ylethoxy)benzazolyl]pyrrolidin-2-carboxylic acid;

(R)-1-[4-(5-methyl-2-phenyloxazol-4-ylethoxy)-3-propylbenzenesulfonyl]pyrrolidin-2-carboxylic acid;

(R)-1-[4-(5-methyl-2-phenyloxazol-4-elmersolver)benzazolyl]pyrrolidin-2-carboxylic acid;

(R)-1-{4-[2-(4-forfinal)-5-methoxazole-4-elmersolver]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-{4-[5-methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4-elmersolver]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-(4-[2-(3,5-bis(triptoreline)-5-methoxazole-4-elmersolver]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-{3-methoxy-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-{3-chloro-4-[2-(5-methyl-2-phenyloxazol-4-yl)ETH is XI]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-(4-{2-[5-methyl-2-(4-(triptoreline)oxazol-4-yl]ethoxy}benzazolyl)pyrrolidin-2-carboxylic acid;

(R)-1-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethylsulfanyl]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-{4-[4-(4-phenoxy-2-propylenoxide)butoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[3-(4-phenoxy-2-propylenoxide)propoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[2-(4-phenoxy-2-propylenoxide)ethoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{3-methoxy-4-[3-(4-phenoxy-2-propylenoxide)propoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{3-chloro-4-[3-(4-phenoxy-2-propylenoxide)propoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-[4-(5-methyl-2-phenyloxazol-4-ylethoxy)benzazolyl]-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[2-(4-forfinal)-5-methoxazole-4-ylethoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[5-methyl-2-(4-(triptoreline)oxazol-4-ylethoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[2-(3,5-bis(triptoreline)-5-methoxazole-4-ylethoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-[3-methoxy-4-(5-methyl-2-phenyloxazol-4-ylethoxy)benzazolyl]-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-[3-chloro-4-(methyl-2-phenyloxazol-4-ylethoxy)benzazolyl]-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-[4-(5-methyl-2-phenyloxazol-4-ylethoxy)-3-propylbenzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-[4-(5-methyl-2-phenyloxazol-4-elmersolver)benzazolyl]-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[2-(4-forfinal)-5-methoxazole-4-elmersolver]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[5-methyl-2-(4-(triptoreline)oxazol-4-elmersolver]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[2-(3,5-bis(triptoreline)-5-methoxazole-4-elmersolver]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{3-chloro-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[5-methyl-2-(4-(triptoreline)oxazol-4-elmersolver]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-{4-[5-methyl-2-(4-(triptoreline)oxazol-4-elmersolver]-benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid,

or their pharmaceutically acceptable salts, or their enantiomers, or a mixture of enantiomers.

Pharmaceutically acceptable salts of any acid compounds according to the invention are salts formed with bases, namely salts of the cations, such as alkaline salts, Melo rosemaling metals, as, for example, sodium, lithium, potassium, calcium, magnesium, and ammonium salts, such as salts of ammonium, trimethylammonium, diethylamine and Tris(hydroxymethyl)methylamine.

Similarly, the acid additive salts, such as salts of mineral acids, organic carboxylic acids and organic sulfonic acids, for example hydrochloric acid, methanesulfonate, maleic acid, subject to the condition that the main group, such as pyridyl, is part of the structure.

The compounds of formula I can be obtained on the basis of analogues of sulfonic acids of the formula

where R and R' have the values listed here, X' is X, as defined here, or X' is a group, turn in X. the compounds of formula II can be first processed gloriouse means, as, for example, thionyl chloride or oxalicacid to obtain sulphonylchloride formula

where R, R' and X' have the meanings given above, using these reaction conditions, or conditions that are well known in this field.

Sulphonylchloride formula III, where R, R' and X' have the above values, can then be subjected to reaction with amines of the formula

or

where R1, R2, R3, R 4, n, Y, R" and m have the values listed here,

in the presence of a base, such as triethylamine, diisopropylethylamine or N-methylmorpholine, in an inert solvent, such as dichloromethane, N,N-dimethylformamide or tetrahydrofuran, to obtain compounds of the formula

where R, R' and X' have the above meanings and L represents the radical

where R1, R2, R3, R4, n, Y, R" and m have the above values.

Amines of formulas IV and V can be obtained using these methods or their modifications, or using methods known in this field.

The compounds of formula I'where X' is X, as defined here, can be obtained from compounds of formula I'where X' is a group, turn in X using these methods or their modifications, or using methods well known in the field. For example, the compounds of formula I'where X' is benzyloxypropionic, can be first converted into the compounds of formula

where R, R' and L have the above values, for example, by reduction with hydrogen in the presence of a catalyst, such as palladium on charcoal, in a polar organic solvent, such as ethyl acetate, or ethane is L. The resulting phenols of formula VI can then be treated with an alkylating agent of the formula

,

where p, Q and W have the above meanings and Lg is a leaving group, such as bromide, chloride or triftorbyenzola, in the presence of a base, such as potassium carbonate or sodium hydride, in an inert solvent, such as N,N-dimethylformamide or tetrahydrofuran, to obtain the compounds of formula I'where X' is-O-(CH2)p-Q-W and p, Q and W have the values listed here.

Alternative compounds of formula I'where X' is-O-(CH2)p-Q-W and p, Q and W have the values listed here may be obtained from the analogues of sulfonic acids of the formula II', where X' is hydroxyl and R and R' have the values listed here, by transformation of compounds of formula II in his salt, including the two atoms of an alkali metal, for example the disodium salt using aqueous base, for example aqueous sodium hydroxide, in a polar solvent, such as 1,4-dioxane, followed by treatment with alkylating agent of formula VII, where p, Q and W have the values listed here and Lg is a leaving group, such as bromide, chloride or triftorbyenzola, to obtain compounds of the formula

where R, R', R, Q and W have given the data value.

The compounds of formula VIII, where R, R', R, Q and W have the values listed here, can be processed gloriouse agent, such as thionyl chloride or oxalicacid to obtain sulphonylchloride formula

where R, R', R, Q and W have the values listed here.

Sulphonylchloride formula IX can be subjected to reaction with amines of the formula IV or V or with their acid additive salts, where R1means hydrogen and R2, R3, n, Y, R" and m have the values listed here, in the presence of a base, such as aqueous sodium hydroxide, in a polar solvent, such as 1,4-dioxane to obtain compounds of formula I'where X' is-O-(CH2)p-Q-W and p, Q and W have the values listed here.

Similarly the compounds of formula I', where R, R' and L have the above meanings and X' is a thiol, can be converted into compounds of the formula I'in which X' represents an-S-(CH2)p-Q-W. for Example, thiols of the formula

where R and R' have the values listed here, can be subjected to a dimerization using methods known in this field, with the formation of disulfides of the formula

where R and R' have the values listed here.

The compounds of formula XI, where R and R' are given here of the meaning of the Oia, can be converted into analogues of sulphonylchloride formula

where R and R' have the values listed here, by processing chlorosulphonate in an inert solvent, such as dichloromethane, followed by alkaline hydrolysis, for example using aqueous sodium hydroxide. The resulting bis-sodium salt can then be processed gloriouse agent, such as thionyl chloride or oxalicacid to obtain sulphonylchloride formula XII.

Sulphonylchloride formula XII where R and R' have the values listed here may interact with amines of the formula

in which R1, R2, R3, R4, n, Y, R" and m have the values listed here, in the presence of a base, such as triethylamine, diisopropylethylamine or N-methylmorpholine, in an inert solvent, such as dichloromethane, N,N-dimethylformamide or tetrahydrofuran, to obtain the disulfides of the formula

,

where R and R' have the above meanings and L represents the radical

where R1, R2, R3, R4, n, Y, R" and m have the above values.

The disulfides of formula XIII, where R, R' and L have the values listed here, can be restored to the thiols of the formula

where R, R' and L have the above meanings, in the processing of regenerating agent, as, for example, borohydride sodium or triphenylphosphine in a polar solvent, such as ethanol or tetrahydrofuran, respectively.

The thiols of formula XIV can then be treated with an alkylating agent of the formula

,

where p, Q and W have the values listed here and Lg is a leaving group, such as bromide, chloride or triftorbyenzola, in the presence of a base, such as potassium carbonate or sodium hydride, in an inert solvent, such as N,N-dimethylformamide or tetrahydrofuran, to obtain the compounds of formula I′in which X' represents an-S-(CH2)p-Q-W and p, Q and W have the values listed here.

Preferably the alkylating agent of formula VII are selected from the group, where p is an integer from 2 to 5, Q means oxygen, Lg means the chloride or bromide, and W means

,,,,,

,,,

,,

,

or an alkylating agent of formula VII are selected from the group, where R means 1-2, Q means the link, Lg means the chloride or bromide, and W means

,,,,

,,,,

,,,,

,,,,

,,,,,

,,,,,

,,or,

or an alkylating agent of formula VII are selected from the group, where p is 2, Q means the link, Lg means the chloride or bromide, and W means

p> ,,,,,,

,,,,,,

,,,,,

,,,,or;

Alkylating agents of the formula VII can be obtained by using these methods or their modifications, or using methods known in this field, for example, 4-chloromethyl-5-methyl-2-phenyloxazol and 4-chloromethyl-5-methyl-2-[4-(trifluoromethyl)phenyl]oxazol can be obtained using methods described in international patent application PCT WO 00/64888, or according to J. Med. Chem., Vol.43, pp. 995-1010 (2000). 1-(3-Bromopropane)-4-phenoxy-2-propylbenzoyl can be obtained as described in international patent application PCT WO 00/78312.

Preferably the alkylating agents of the formula VII, and Elsie the formula

where Raand Rbmeans independently hydrogen, halogen, alkyl, alkoxy, trifluoromethyl or aryl, can be obtained by treatment of the compounds of formula

where Raand Rbhave the meanings given for formula VIIa, glorieuses agent, such as phosphorus oxychloride (POCl3), in acetonitrile. It is essential that the reaction is carried out in acetonitrile in order to receive alkylating agents of the formula VIIa with high chemical yield and high purity, i.e. alkylating agents of the formula VIIa receive according to the present method with high regiospecificity, preferably with a selectivity greater than 99%. The chlorination is preferably carried out at ambient temperature, for example at room temperature.

The compounds of formula VIIb can be obtained by condensation of an aldehyde of the formula

where Raand Rbhave the meanings given for formula VIIb, monooxime 2,3-butadiona formula

in the presence of an acid catalyst, such as HCl gas, and an organic solvent, such as ethyl acetate, or acetic acid, preferably glacial acetic acid, leading to compounds of formula VIIb, where Raand Rband EUT values, above.

In a preferred variant of the invention, the alkylating agent of the formula VIIa is 4-chloromethyl-5-methyl-2-[4-(trifluoromethyl)phenyl]oxazol.

Alternative phenols of formula VI and the thiols of formula XIV can also react with alcohols of the formula

,

where p, Q and W have the values listed here, under the reaction conditions, Mitsunobu, for example, in the presence of triphenylphosphine and diethyl ester of azodicarboxylic acid in an organic solvent, such as tetrahydrofuran, to obtain the compounds of formula I'where X' is-O-(CH2)p-Q-W or-S-(CH2)p-Q-W, respectively, and p, Q and W have the values listed here. The alcohols of formula VII can be obtained by using these methods or their modifications, or using methods well known in the field.

The compounds of formula I'where X' is -(CH2)p-Q-W and R and W have the values listed here, Q denotes O or S, can be obtained by reaction of compounds of the formula

where R, R' and R have the above values and Pg represents a protective group such as acyl, for example acetyl, or (ness.)alkoxycarbonyl, chlorosulphonate in an inert solvent, such as dichloromethane, followed by treatment gloriouse agent is m, as, for example, thionyl chloride or oxalicacid that leads to sulphonylchloride formula

where R, R', R and Pg have the above values.

Sulphonylchloride formula XVI can connect with amines of the formula VI or V, as described above, to form compounds of the formula

where R, R', R, Pg and L have the values listed here. Subsequent removal of the protective group using a base, for example aqueous sodium hydroxide, in a polar solvent, such as methanol, tetrahydrofuran or 1,4-dioxane, in particular, when Pg means acetyl, leads to the alcohols of the formula

where R, R', R and L have the values listed here.

The alcohols of formula XVIII can connect with phenols of the formula W-OH or thiols of the formula W-SH, for example, under the reaction conditions, Mitsunobu with the formation of compounds of formula I', where R, R' and L have the values listed here and X' represents -(CH2)p-Q-W, where R and W have the values listed here, Q denotes oxygen or sulfur, respectively.

Alternative alcohols of formula XVIII can be converted into compounds of the formula

where R, R', R and L have the values listed here and Lg represents a leaving group, such as chloride, bromide or triptorelin is, using these methods or their modifications or well-known in the field of methods. Subsequent reaction with phenols of the formula W-OH or thiols of the formula W-SH in the presence of a base, such as potassium carbonate, or sodium hydride, in an inert solvent, such as N,N-dimethylformamide or tetrahydrofuran, leads to compounds of formula I', where R, R' and L have the values listed here and X' represents -(CH2)p-Q-W, where R and W have the values listed here and Q denotes oxygen or sulfur, respectively.

The compounds of formula I', where R, R' and L have the values listed here and X' represents-C(O)NR5-(CH2)p-Q-W, and R5, p, Q and W have the values listed here, can be obtained by reaction of an activated carboxylic acid derivative of the formula

where R, R' and L have the values listed here and R1means optionally substituted alkyl, aryl, heteroaryl, aralkyl or cycloalkyl, with amines or acid additive salts of the formula

,

where R5, p, Q and W have the values listed here. Carboxylic acid of formula XX and amines of formula XXI can be obtained using these methods or their modifications, or known in the field the way the century

Similarly, compounds of formula I', where R, R and L have the values listed here and X' represents-Z-(CH2)p-C(O)NR6-W, and Z, p, R6and W have the values listed here, can be obtained by reaction of an activated carboxylic acid derivative of the formula

where R, R', L, Z and R have the values listed here and R1is optionally substituted by alkyl, aryl, heteroaryl, aralkyl or cycloalkyl, with amines or acid additive salts of the formula

,

where R6and W have the values listed here. Carboxylic acid of formula XXII and amines of formula XXIII can be obtained using these methods or their modifications, or known in the field of methods.

In the above-cited methods activated derivatives of carboxylic acids, for example, formulas XX and XXII, include acid chlorides, bromohydrin and foramerica, mixed anhydrides, complex (ness.)alkalemia esters and activated esters and adducts formed with combining agents, as, for example, hydrochloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, tetrafluoroborate O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethylurea and similar compounds. Mixed anhydrides are preferably so is e from trimethylhexanoic acid or complex (ness.)alilovic of profirov carboxylic acid, as, for example, ethyl or isobutyl counterparts. Activated esters include, for example, a complex Succinimidyl, phthalimidomethyl or 4-nitrophenolate esters. Reaction of the activated carboxylic acid derivative, for example, compounds of formula XXI or XXIII, respectively, can be carried out in the presence of a base, such as triethylamine, diisopropylethylamine or N-methylmorpholine, in an inert solvent, such as dichloromethane, N,N-dimethylformamide or tetrahydrofuran. Carboxylic acid of formula XX and XXII can be converted to their activated derivatives, using methods described herein or known in this field.

The compounds of formula I', where R, R' and L have the values listed here and X' represents-Z-(CH2)p-NR5C(O)-W, -Z-(CH2)p-NR5C(O)NH-W, or-Z-(CH2)p-NR5C(O)-O-W, and Z, R, R5and W have the values listed here, can be obtained by reaction of amines of the formula

where R, R', Z, R, R5and L have the values listed here and R1is optionally substituted by alkyl, aryl, heteroaryl, aralkyl or cycloalkyl, with a reagent to obtain the derivative at the amino group, such as, for example, derived from an activated carboxylic acid, isocyanate or ether of Harborview acid, sootvetstvenno is, in the presence of a base, such as triethylamine, diisopropylethylamine or N-methylmorpholine, in an inert solvent, such as dichloromethane, N,N-dimethylformamide or tetrahydrofuran. Amines of formula XXIV can be obtained using these methods or their modifications, or known in the field of methods.

The compounds of formula I'in which R, R', L and X' have the values listed here and R1means optionally substituted alkyl, aryl, heteroaryl, aralkyl or cycloalkyl, can be converted into compounds of the formula I'in which R1means hydrogen, using these reaction conditions or modifications, or using known in this field ways, for example, the compounds of formula I'in which R1means lower alkyl, for example methyl or ethyl, can be treated with aqueous base, such as sodium hydroxide or potassium hydroxide, in a polar solvent, such as methanol, ethanol, 1,4-dioxane or tetrahydrofuran, as a result, the compounds of formula I'in which R, R', L and X' have the values listed here and R1means hydrogen.

In the original substances and intermediate compounds, which are converted into compounds according to the invention described here by way of present functional groups, such as amino group, tilina, carb is xylina and hydroxyl groups, optional protected by conventional protective groups that are common in preparative organic chemistry. Protected amino group, Tilney, carboxyl and hydroxyl groups are such groups that can be converted under mild conditions into free amino group, Tilney, carboxyl and hydroxyl groups without destroying the structure of a molecule or the occurrence of other undesirable side reactions.

The purpose of introducing protective groups is to protect the functional groups against undesirable reactions with the components of the reaction under the conditions used to carry out the desired chemical transformations. The need for protective groups and the choice of protective groups for a particular reaction is known to specialists in this field and depend on the nature of functional groups that should be protected (hydroxyl group, amino group, etc.), structure and stability of the molecule, Deputy which is part of it, and the reaction conditions.

Well-known protective groups that meet these conditions and their introduction and removal are described, for example, in the book McOmie, "Protective Groups in Organic Chemistry", ed. Plenum Press, London, new York (1973), and in the book by Greene and Wuts, "Protective Groups in Organic Synthesis", ed. John Wiley and Sons, Inc., New York (1999).

The above-mentioned reactions are carried out according to standard methods, in the presence or absence of solvents, those that are inert to the reagents and are solvents or catalysts, condensing mentioned other agents respectively and/or in an inert atmosphere at low temperatures, room temperature or elevated temperatures (preferably at the boiling point or close to the boiling point of the used solvent)and at atmospheric pressure or a pressure above atmospheric. Preferred solvents, catalysts and reaction conditions are presented in the following illustrative examples.

The invention further includes any variant of the presented methods by which the intermediate product obtained at any stage is used as starting substances in carrying out other stages, or on which the original substances are formed in situ under the reaction conditions, or in which the components of the reaction are used in the form of their salts or optically pure antipodes.

Compounds according to the invention and intermediate compounds can also be converted into each other according to the methods usually essentially known.

The invention also applies to any new source substances and methods for their preparation.

Depending on the choice of initial substances and methods compounds may be in the form of one of the possible isomers or mixtures thereof, for example, in considerably the degree of pure geometric (CIS or TRANS) isomers, optical isomers (antipodes), racemates or mixtures thereof. The above-mentioned possible isomers or mixtures thereof are within the scope of this invention.

Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the components on a clean, geometric or optical isomers, diastereoisomers, racemates, for example by chromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can be separated into the optical antipodes by known methods, for example by separating them diastereoisomeric salts obtained by using an optically active acid or base, and the allocation of optically active acidic or basic compound. Intermediate compounds in the form of carboxylic acids can thus be separated into their optical antipodes, for example by fractional crystallization of D - or L-salts with α-methylbenzylamino, cinchonidine, cinchonine, quinine, quinidine, ephedrine, dehydroabietylamine, brucine or strychnine. Racemic products can also be separated using chiral chromatography, for example using liquid chromatography high pressure using a chiral adsorbent.

Finally, the compounds according to the image the structure are given either in free form, either in the form of their salts, if present soleobrazutaya group.

Acid compounds according to the invention can be converted into salts with pharmaceutically acceptable bases, such as aqueous alkali metal hydroxide, preferably in the presence of a solvent in the form of ether or alcohol solvent, such as, for example, (ness.)alkanol. From solutions in recent salt can be deposited using ethers, such as diethyl ether. The resulting salt can be converted into the free compounds when handling acids. These or other salts can also be used for purification of the compounds obtained.

Compounds according to the invention, having a basic group can be converted into acid additive salts, especially pharmaceutically acceptable salts. These salts are formed, for example, with inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric or galoidvodorodnykh acid, or with organic carboxylic acids, such as, for example, (C1-C4)alcancarao acids, for example, not substituted or substituted by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, succinic, maleic or fumaric acid, such as hydroxycarbonate acid is, for example glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or with organic sulfonic acids, such as, for example, (C1-C4-alkylsulfonate, such as methanesulfonate, or arylsulfonate, which is not substituted or substituted, for example halogen. Preferred salts formed with hydrochloric acid, methanesulfonate or maleic acid.

Given the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound referred to in this context also refers to the corresponding salt, provided that such salt is possible or appropriate under the circumstances.

The compounds, including their salts, can also be obtained in the form of their hydrates or include other solvents used for crystallization.

The pharmaceutical compositions according to the invention are suitable for insertion through the small intestine, such as oral or rectal, transdermal and parenteral administration to mammals, including humans, for treatment of conditions oposredstvovanii receptors PPAR, in particular PPARα and PPARγ. Such conditions include the following condition, given the treatment for which can be used is soedineniya directly present invention. Mentioned pharmaceutical compositions include an effective amount of the pharmacologically active compounds according to this invention one or in combination with one or more pharmaceutically acceptable carriers.

The pharmacologically active compounds according to the invention can be used in the preparation of pharmaceutical compositions comprising effective amounts in combination or in a mixture with excipients or carriers suitable for use through the small intestine and for parenteral use. These compositions can be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, stimulants dissolution, salts for regulating osmotic pressure and/or buffers. In addition, they can also contain other therapeutically valuable substances. These compositions are prepared according to conventional methods of mixing, granulating or coating, respectively, and they contain about 0.1 to 75%, preferably about 1-50% of the active ingredient.

Suitable finished dosage forms for percutaneous applications include therapeutically effective amount of the compounds according to the invention together with a carrier. Preferred carriers include absorbed farmacologicas is acceptable solvents to facilitate penetration through the skin of the host body. Typically, devices for percutaneous penetration exist in the form of a bandage comprising a back, a reservoir containing the compound optionally with carriers, optionally with the regulatory speed partition for delivery connection with the skin of the host body with controlled and predetermined rate over a prolonged period of time, and means for attaching the device to the skin.

Pharmaceutical form containing a therapeutically effective amount of the compounds according to the invention, as defined above, alone, or in combination with another therapeutic agent, e.g., each at an effective therapeutic dose, as determined in the field. Such therapeutic agents include insulin, insulin derivatives and mimetics; a means of enhancing insulin secretion, such as sulfonylureas, such as glipizide and amaryl; ligands of the receptor insulinotropic sulfonylureas, such as, for example, meglitinide, such as nateglinide and Repaglinide; insulin-sensitizing agents, such as inhibitors (protein-tyrosine-phosphatase-1B (PTP-1B)inhibitors, GSK3 (glikogensintetazy kinase-3) or RXR ligands; biguanides, such as Metformin; inhibitors α-glucosidase, as for example, acarbose; GLP-1 (glucagon-like peptide-1), analogues of GLP-1, for example the EP, on the basis of 4, and GLP-1 mimetics; DPPIV inhibitors (dipeptidylpeptidase IV), for example isoleucine-thiazolidin; DPP728 and LAF237, lipid-lowering means, as, for example, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A(HMG-CoA)reductase inhibitor such as lovastatin, pitavastatin, simvastatin, pravastatin, tseriwastatina, mevastatin, vasostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin, plugindomain and mevastatin inhibitors stvalentines or FXR ligands (liver X receptor) and LXR (farnesoid X-receptor), cholestyramine, fibrates, nicotinic acid and aspirin. The compound of the present invention can be introduced simultaneously or before or after the other active ingredient, or separately using the same or different route of administration or together in the same pharmaceutical composition.

The standard dose for a mammal weighing 50 to 70 kg may contain between about 1 and 1000 mg, preferably about 5-500 mg of the active ingredient. A therapeutically effective dose of the active compound depends on the species of warm-blooded animal (mammal), body weight, age and individual condition, the form of the introduction and involved connection.

Compounds of the present invention bind to receptors PPAR and therefore can be used to treat conditions, oposredstvovanii recipe is Rami PPAR, in particular PPARα and PPARγ. Such compounds can therefore be used for the treatment of dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, eye diseases, IBD (disease irritable bowel), ulcerative colitis and Crohn's disease. In particular, the compounds according to the invention can be used in mammals as hypoglycemic agents for the treatment and prevention of conditions involving impaired glucose tolerance, hyperglycemia and insulin resistance, such as diabetes type-1 and type-2, and syndrome X.

The above properties demonstrated in vitro and in vivo studies mainly on mammals, e.g. mice, rats, dogs, monkeys, or when using isolated organs, tissues and their products. The said compounds can be applied in vitro in the form of solutions, for example, preferably aqueous solutions, and in vivo and through the small intestine, and parenteral, mainly intravenously, for example, in suspension or in aqueous solution. The dosage in vitro may range within the Ah between about 10 -5and 10-10molar concentrations. A therapeutically effective amount in vivo may, depending on the method of administration to be in the range of between about 1 and 500 mg/kg, preferably between about 5 and 100 mg/kg

Compounds according to the invention bind to receptors PPARα and PPARγ and, thus, can be used as a dual agonist of PPARα and PPARγ in mammals.

The active compounds according to the invention can be assessed using the following methods, or methods, described in detail in this field.

In vitro functional binding to PPARα, PPARδ and PPARγ determined as follows.

Analyses of functional binding to PPARα, PPARδ and PPARγ are a variation of the analysis of ligand-dependent coactivator receptor (CARLA) (see Krey and others, "Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands peroxisome proliferation of activated receptors by analyzing ligand-dependent coactivator receptor". Molecular Endocrinology, vol. 11, str-791 (1997)). Data analyses CARLA using the previously discussed method of determining the TR-FRET (allowed time spectra of fluorescence resonance energy transfer) (see Hemmila, "LANCE: Homogeneous Assay Platform for HTS", J. Biomol. Screening, vol. 4, str-307 (1999); Mathis, "HTRF Technoloy", J. Biomol. Screening, vol. 4, str-313 (1999)). All analyses included 3 nm integral proteins glutathione-3-transferase (GST) or a ligand-binding hPPARα domain (LBD) (amino acids 167-468) (GST-hPPARα LBD), GST-hPPARδ LBD (amino acids 139-442), or GST-hPPARγ LBD (amino acids 175-476); 3 nm labeled with europium antibody against GST (Wallac); 30 nm biotinylated peptide coactivator-1 steroid receptor (SRC-1) (N-terminal biotinylated peptide, CPSSHSSLTERHKILHRLLQEGSPS derived from amino acids 676-700 SRC-1); and 10 nm labeled streptavidin allophycocyanin (ARS; Prozyme). Attaching a ligand for PPAR LBD changes the conformation of the LBD and allows biotinylating the SRC peptide-1 contact. It really brings labeled with europium antibody against GST and labeled with streptavidin APC while making the energy transfer fluorescence. Biotinylated peptide SRC-1 are obtained by standard methods of solid-phase peptide synthesis. GST-PPAR LBD Express in the pGEX vectors (firm Amersham Pharmacia) in the E.coli strain BL21 (DE3)using standard conditions expression at 18°C. In some cases, GST-PPAR LBD at the same time Express with groESL. Integral proteins GST purified on columns for affinity chromatography with glutathione-separate (Amersham Pharmacia), using the method described by the manufacturer. Buffer for analysis contains 50 mm Tris, pH 7.4, 50 mm KCl, 0.1% of bovine serum albumin (BSA) and 1 mm dithiothreitol (DD). The analysis is performed in 96-cell tablets, half of which surface is black, the final volume is 25 ál. After mixing all of the components of the reaction mixture is kept for 3 hours at room temperature before counting signal TR-FRET (allowed time spectra of fluorescence resonance energy transfer) to read from a tablet device Wallac Victor 2 (measurement of the ratio of the signal at 665 and 620 nm). Values EU50(effective concentration leading to 50%increase effect) was determined using the Excel add-on module XLFit (ID Business Solutions, Guildford, Surrey, UK), using a 4-parameter logistic equation.

Reducing glucose and insulin activity in vivo can be estimated as follows.

Adult male C57BL (Jackson Lab, Bar Harbor, Middle East), obtained by crossing individuals of the mouse obese (ob/ob mouse), at the age of 11 weeks placed six individuals in a cage in a room with a reverse light cycle (light from 6:00 in the afternoon until 6:00 a.m. to noon) and mice give a Casuarina homenidou for Purina rodent and water. Day 1 take blood samples from the tail at 8:00 am until noon and determine the levels of glucose in plasma. Animals blind selection referred to as the control group and the group for the study compounds. Been agreed average value of the levels of Glu is eskers in groups. The animals are then administered orally media (0.5% of carboxymethyl cellulose with 0.2% tween-80) or compound (at a dose of 30 mg/kg) in the media. Mice is administered daily in total over 3 days. Day 4 take basal blood samples. In the plasma samples to determine the concentration of glucose using two channel analyzer for Biochemical studies YSI2700 (Yellow Springs Instrument Co., Yellow Springs, OH), and concentrations of insulin, using enzyme immunosorbent assay (ELISA).

Illustrating the invention, the compound of example 1 shows EU50approximately 27 nm in the analysis of the binding of the receptor PPARαEC50about 23 nm in the analysis of the binding of the receptor PPARγ and EC50about 173 nm in the analysis of the binding of the receptor PPARδ; connection example 5-10 shows EU50approximately 3 nm in the analysis of the binding of the receptor PPARαEU50approximately 3 nm in the analysis of the binding of the receptor PPARγ and EC50about 1250 nm in the analysis of the binding of the receptor PPARδ and connection example 6-39 shows EC50approximately 7 nm in the analysis of the binding of the receptor PPARαEU50approximately 2 nm in the analysis of the binding of the receptor PPARγ and EC50about 1165 nm in the analysis of the binding of the receptor PPARδ. Moreover, these compounds significantly reduce the levels of glucose and insulin in serum after three days at a daily dose primerno mg/kg orally in ob/ob mice.

Have in mind that the following examples illustrate the invention and are not considered as limiting it. Temperatures are given in degrees Celsius. If not otherwise indicated, all operations of the evaporation is conducted under reduced pressure, preferably between about 15 and 100 mm Hg (20-133 mbar). The structure of final products, intermediates and starting compounds is confirmed by standard analytical methods, such as using microanalysis and spectral characteristics, for example using mass spectrometry (MS), infrared spectrometry (IR) and nuclear magnetic resonance (NMR). Abbreviations are common in this area.

Example 1

(R)-1-{4-[3-(4-Phenoxy-2-propylenoxide)propoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid

A. (R)-1-(4-Benzyloxybenzoate)-2,3-dihydro-1H-indole-2-carboxylic acid

To a solution of (R)-2,3-dihydro-1H-indole-2-carboxylic acid (2,89 g, 14.5 mmole) and 1 N. sodium hydroxide (37,7 ml of 37.7 mmole) in water (79 ml), stir at room temperature, added dropwise chloride 4-benzyloxybenzaldehyde (4.1 g, 14.5 mmole) in dioxane (104 ml). Upon completion of addition, regulate the pH of the reaction mixture, and support between 7 and 8 by slow addition of 1 N. water guide is ookii sodium within the next 2 hours. The reaction mixture was stirred over night at room temperature. The solution was poured into crushed ice and the resulting mixture is acidified to pH 2-3 with 1 N. aqueous hydrochloric acid (15 ml). The product is extracted with dichloromethane (2×150 ml). The extract was washed with water (150 ml), with brine (150 ml), dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated, to obtain 5.5 g of (R)-l-(4-benzyloxybenzoate)-2,3-dihydro-1H-indole-2-carboxylic acid in the form of an oil; [M+1]+=410,32, [M-1]-=408,24.

B. Methyl ester (R)-1-(4-benzyloxybenzoate)-2,3-dihydro-1H-indole-2-carboxylic acid

The solution obtained in stage A (R)-1-(4-benzyloxybenzoate)-2,3-dihydro-1H-indole-2-carboxylic acid (5,55 g, 13, 6 mmole) and monohydrate p-toluenesulfonic acid (0.52 g, 2.7 mmole) in methanol (260 ml) is refluxed under nitrogen atmosphere for 4 hours. The solution was incubated overnight at room temperature, which leads to the formation of solid crystalline substances. The crystals are collected by filtration under vacuum and dried in high vacuum. The second portion of the crystals obtained from the mother liquor, is isolated and dried in high vacuum. Just get of 3.84 g of methyl ester of (R)-1-(4-benzyloxybenzoate)-2,3-dihydro-1H-indole-2-carboxylic acid in the form of pure crystallizes the second product; [M+1]+=424,27.

Century Methyl ester (R)-1-(4-hydroxybenzenesulfonic)-2,3-dihydro-1H-indole-2-carboxylic acid

To the suspension obtained in stage B methyl ester (R)-1-(4-benzyloxy-benzazolyl)-2,3-dihydro-1H-indole-2-carboxylic acid (3.00 g, 7.1 mmole) in ethanol (200 ml) under nitrogen atmosphere was added 10% palladium on coal (0.3 g). The resulting mixture hydronaut when the pressure 3,234 kg/cm2in a period of 18.5 hours at room temperature. The mixture is filtered through a zeolite under vacuum. The filtrate was concentrated in vacuo, to obtain 1.31 g of the methyl ester of (R)-1-(4-hydroxybenzenesulfonic)-2,3-dihydro-1H-indole-2-carboxylic acid, which is used without further purification; [M+1]+=334,22, [M-1]-=332,16.

, Methyl ester (R)-1-(4-[3-(4-phenoxy-2-propylenoxide)propoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid

To the solution obtained at the stage In methyl ester of (R)-1-(4-hydroxybenzenesulfonic)-2,3-dihydro-1H-indole-2-carboxylic acid (1.31 g, 3.9 mmole) in N,N-dimethylformamide (50 ml) at room temperature was added in one anhydrous potassium carbonate (2.16 g, 15.6 mmole). After 15 minutes added at room temperature a solution of 3-(4-phenoxy-2-propylenoxide)propane-1-bromide (1,37 g, 3.9 mmole) in N,N-dimethylformamide (10 ml). The reaction mixture was stirred for 64 hours at room temperature. The reaction mixture is shown that the comfort, the filtrate is diluted with water (150 ml) and the resulting mixture extracted with diethyl ether (2×150 ml). The organic extract was washed with water (3×100 ml) and with brine (100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, get 2,32 g technical methyl ester (R)-1-{4-[3-(4-phenoxy-2-propylenoxide)propoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid. Cleaning technical product by chromatography (SiO2: 100 g; eluent 30%→50% ethyl acetate in hexane) leads to 1.47 g of purified methyl ester (R)-1-{4-[3-(4-phenoxy-2-propylenoxide)propoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid as colorless resinous substance; [M+1]+=602,49.

D. (R)-1-{4-[3-(4-Phenoxy-2-propylenoxide)propoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid

To the mixture obtained in stage g of methyl ester of (R)-1-{4-[3-(4-phenoxy-2-propylenoxide)propoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid (1.47 g, 2,44 mmole) in methanol (50 ml) under nitrogen atmosphere at room temperature was added dropwise 1 N. aqueous sodium hydroxide (4.9 ml, 4.9 mmole). Upon completion of addition, the mixture is stirred at room temperature for 45 minutes, during this time, add 5 ml of tetrahydrofuran to facilitate dissolution of the original substance. The mixture is stirred during their night. The reaction mixture was concentrated in vacuo, the residue partitioned between water (50 ml) and diethyl ether (50 ml). The aqueous layer was separated and acidified with 1 N. aqueous hydrochloric acid. The product is extracted with dichloromethane. The extract is washed with brine, dried over anhydrous sodium sulfate (Na2SO4), filtered and concentrated receive 1,02 g (R)-1-{4-[3-(4-phenoxy-2-propylenoxide)propoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid in the form of a solid foamy substance of white color. The solid is treated with ethanol (1 ml), which leads to the dissolution of solid substances, and after exposure begin to form crystals. The crystals are separated and dried in a high vacuum at 40°receive 0,85 g of purified (R)-1-{4-[3-(4-phenoxy-2-propylenoxide)propoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid; [M+1]+=588,46; [M-1]-=586,41.

Example 2

(R)-1-[4-(5-Methyl-2-phenyloxazol-4-ylethoxy)benzazolyl]-2,3-dihydro-1H-indole-2-carboxylic acid

A. the Disodium salt of 4-hydroxybenzenesulfonate

The solution dihydrate sodium salt of 4-hydroxybenzenesulfonate (20 g, 86 mmol) in 1 N. aqueous sodium hydroxide (86 ml, 86 mmol) is stirred and heated at 50-60°C for 1 hour. The solution was concentrated in vacuo at 50°and receive solid vases is in. The solid is suspended in anhydrous toluene and concentrated in vacuo. This processing is repeated twice. The solid is dried at 50°C in high vacuum for 18 hours, get 21,34 g disodium salt of 4-hydroxybenzenesulfonate.

B. Sodium salt of 4-(5-methyl-2-phenyloxazol-4-ylethoxy)benzosulfimide

The mixture obtained at the stage And the disodium salt of 4-hydroxybenzenesulfonate (3.50 g, 16,1 mmole) and 4-chloromethyl-5-methyl-2-phenyloxazole (4,00 g, and 19.3 mmole) in 20 ml of N,N-dimethylformamide is stirred and heated in nitrogen atmosphere at 110°C for 18 hours. The cooled reaction mixture is filtered and the obtained solid is washed thoroughly with dichloromethane. The solid is dried during the night, get 1.42 g of sodium salt of 4-(5-methyl-2-phenyloxazol-4-ylethoxy)benzosulfimide; [M+1]+=346,05, [M-1]-=344,02.

Century Chloride 4-(5-methyl-2-phenyloxazol-4-ylethoxy)benzazolyl

To a solution of thionyl chloride (8.0 ml) and 2 drops of N,N-dimethylformamide with stirring under nitrogen at 0°With add at once obtained in stage B sodium salt of 4-(5-methyl-2-phenyloxazol-4-ylethoxy)benzosulfimide (1.42 g, 3.8 mmole). The resulting suspension is stirred at 0°C for 10 minutes. Bath ice is removed and the suspension is stirred at room temperature for 1.5 hours. Probabl is jut another three drops of N,N-dimethylformamide, then get the result after stirring additionally for one hour a clear solution. The solution was concentrated in vacuo to obtain a solid residue. The residue is partitioned between water (20 ml) and ethyl acetate (20 ml). The organic layer is separated and washed successively with water (3×20 ml), 0.1 G. of aqueous sodium hydroxide (3×20 ml) and with brine (20 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo get oily substance which slowly solidifies with the formation of 0.48 g of chloride of 4-(5-methyl-2-phenyloxazol-4-ylethoxy)benzosulfimide; [M+1]+=363,99.

G (R)-1-[4-(5-Methyl-2-phenyloxazol-4-ylethoxy)benzazolyl]-2,3-dihydro-1H-indole-2-carboxylic acid

To a solution of hydrochloride of (R)-2,3-dihydro-1H-indole-2-carboxylic acid (0,92 g, 4.6 mmole), 1 N. aqueous sodium hydroxide (12.0 ml, 12 mmol) and water (25 ml) at room temperature was added dropwise a solution obtained at the stage In chloride 4-(5-methyl-2-phenyloxazol-4-ylethoxy)benzosulfimide (1.65 g, 4.6 mmole) in dioxane (33 ml). After completion of addition, the pH of the reaction mixture, monitor and support between 7 and 8 by slow addition of 1 N. aqueous sodium hydroxide in the next 2 hours. The reaction mixture was stirred over night at room temperature. The solution howled who try to crushed ice and the resulting mixture is acidified to pH 2-3 with 1 N. aqueous hydrochloric acid (11 ml). The precipitation is collected, washed with water and dried in high vacuum over night, get 1.5 g of (R)-1-[4-(5-methyl-2-phenyloxazol-4-ylethoxy)benzazolyl]-2,3-dihydro-1H-indole-2-carboxylic acid; [M+1]+=491,2, [M-1]-=489,1.

Example 3

(R)-1-[4-(5-Methyl-2-phenyloxazol-4-elmersolver)benzazolyl]-2,3-dihydro-1H-indole-2-carboxylic acid

A. 4,4'-Dithiobisbenzothiazole

To a solution of phenoldisulfonic (4,36 g, 20 mmol) in dichloromethane (40 ml) at 0°With added dropwise a solution of chlorosulfonic acid (with 4.64 g, 2,95 ml, 40 mmol) in dichloromethane (60 ml). The mixture was stirred at 0°C for 1 hour, and then 1.5 hours at room temperature. The reaction mixture is concentrated to dryness in vacuo and the residue partitioned between diethyl ether and water. The aqueous phase is separated, alkalinized with 2 N. aqueous sodium hydroxide and concentrated in vacuo to half volume. The resulting solution is kept in the refrigerator over night. Formed during the night the precipitate discarded, the filtrate is then concentrated in vacuo to starting solids. The mixture is placed in the refrigerator for 2 hours. The mixture is treated with ethanol, the resulting solid is filtered off, washed twice with ethanol and dried in high in the sky? " the cosmology vacuum overnight at room temperature, obtain 6.0 g of 4,4'-dithiobisbenzothiazole in the form of a solid white; [M-1]-=398,8.

B. 4,4'-Dithiobisbenzothiazole

To thionyl chloride (70 ml) at 0°With added portions received on the stage And 4,4'-dithiobisbenzothiazole (5.9 g, 14 mmol)and then N,N-dimethylformamide (1.4 ml). The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture is concentrated to dryness in vacuo and treated with ethyl acetate, then ice and water. The organic phase is separated, washed with water, saturated sodium bicarbonate solution and with brine, dried over sodium sulfate and concentrated in vacuo, to obtain 4.0 g of 4,4'-dithiobisbenzothiazole in the form of a solid, yellowish-brown.

C. 4,4'-Dithio-bis-[(R)-1-benzazolyl-2,3-dihydro-1H-indole-2-carboxylic acid]

To a solution of hydrochloride of (R)-2,3-dihydro-1H-indole-2-carboxylic acid (4.35 g, and 21.7 mmole), 1 N. aqueous sodium hydroxide (43,5 ml, 43.5 mmole) and water (20 ml) at 0°With added dropwise to the solution obtained in stage B 4,4'-dithiobisbenzothiazole (3.0 g, 7,24 mmole) in dioxane (60 ml). Upon completion of addition, pH control of the reaction mixture and keep it between 7 and 8 by slow addition of 1 N. aqueous sodium hydroxide in the next two hours. The reaction mixture is stirred during the course the e night at room temperature. The reaction mixture is filtered, the filtrate poured into crushed ice and the resulting mixture is acidified to pH 2-3 with 1 N. aqueous hydrochloric acid. The mixture is extracted with ethyl acetate, the organic phase is washed with 1 N. aqueous hydrochloric acid, with water, with brine and dried over sodium sulfate, concentrated in vacuo, to obtain 4.0 g of 4,4'-dithio-bis-(1-benzazolyl-2,3-dihydro-1H-indole-2-carboxylic acid) in the form of a solid foamy substance; [M-1]-=667,25.

G (R)-1-(4-Mercaptoethanesulfonate)-2,3-dihydro-1H-indole-2-carboxylic acid

To a solution of sodium borohydride (0,185 g, a 4.86 mmole) in ethanol (60 ml) at 0°With added portions obtained at the stage In 4,4'-dithio-bis-(1-benzazolyl-2,3-dihydro-1H-indole-2-carboxylic acid (0.65 g, 0,973 mmole). The reaction mixture was stirred at room temperature overnight. The mixture is treated with ice/water, acidified with 2 N. aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic extracts washed with water and with brine, dried over sodium sulfate and concentrated in vacuo, get 0,63 g (R)-1-(4-mercaptoethanesulfonate)-2,3-dihydro-1H-indole-2-carboxylic acid in the form of a resinous substance; [M-1]-=333,9.

D. (R)-1-[4-(5-Methyl-2-phenyloxazol-4-elmersolver)benzazolyl]-2,3-dihydro-1H-indole-2-carboxylic acid

To the solution is obtained in stage g of (R)-1-(4-mercaptoethanesulfonate)-2,3-dihydro-1H-indole-2-carboxylic acid (0.56 g, to 1.67 mmole) in dioxane (8 ml) was added at room temperature 1 N. aqueous sodium hydroxide (3.4 ml) and water (2 ml). The resulting solution is treated dropwise with a solution of 4-chloromethyl-5-methyl-2-phenyloxazole (0,423 g, 2,04 mmole) in dioxane (4 ml). After stirring for 1.5 hours the reaction mixture is concentrated almost to dryness in a vacuum. The residue is treated with water, the aqueous phase washed with diethyl ether, acidified with 2 N. aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic phases are washed with water, with brine and dried over sodium sulfate. The organic phase was concentrated in vacuo and dried overnight in high vacuum, the gain of 0.68 g (R)-1-[4-(5-methyl-2-phenyloxazol-4-elmersolver)benzazolyl]-2,3-dihydro-1H-indole-2-carboxylic acid in the form of a resinous substance; [M-1]-=504,9.

Example 4

The following connections get analogously to example 1 with the treatment received at the stage In example 1 compound with a suitable alkylating agent, or following the Protocol described in examples 2 or 3:

Example 7

4-Chloromethyl-5-methyl-2-[4-(trifluoromethyl)phenyl]oxazol

A. Hydrochloric salt of 3-oxide 4,5-dimethyl-2-[4-(trifluoromethyl)phenyl]oxazole

To a solution of 4-(trifluoromethyl)benzaldehyde (400,0 g, 2.3 mmole) and monooxime 2,3-butandione (212 g, 2,055 mol) in 800 ml of glacial acetic acid at 2-5°pass by slow ozonation for 1.5 hours with HCl gas (250 g). The mixture was stirred at the same temperature for another 1 hour. Add 3,75 l simple (tert-butyl)methyl ether, maintaining the temperature between 5-25°With (when adding the first 400 ml of heat). The resulting suspension is stirred for 30 minutes, then cooled to 10°and the solid precipitate filtered off. The filter cake is washed with 500 ml of a simple (tert-butyl)methyl ether and dried at 55-60° (20 mbar) for 18 hours, get 550 g (91%) hydrochloric salt of 3-oxide 4,5-dimethyl-2-[4-(trifluoromethyl)phenyl]oxazole; tPL182-184°C (decomp.).

B. 4-Chloromethyl-5-methyl-2-[4-(trifluoromethyl)phenyl]oxazol

The suspension obtained in stage a of the hydrochloride of 3-oxide 4,5-dimethyl-2-[4-(trifluoromethyl)phenyl]oxazole (500 g, of 1.70 mol) in 4,06 ml of acetonitrile is stirred for 15 minutes at room temperature, then cooled to 10°C. Add 491 g (3,17 mole) of phosphorus oxychloride at 15°C for 30 minutes. The suspension is stirred at room temperature for 16 hours, the mixture is cooled to 10°and slowly add in reactio the ing a mixture of 6 liters of water (the addition of the first 400 ml of water is accompanied by a very strong heat). The suspension is then stirred at room temperature for another 6 hours and the solid is collected by filtration, washed with 2 l of water and dried to constant weight at 50° (20 mbar), receive a 4-chloromethyl-5-methyl-2-[4-(trifluoromethyl)phenyl]oxazol in a solid white color (400 g, yield 85%); tPL97-98°C.

1. The compound of the formula

,

where L denotes the radicalin which R1means hydrogen or C1-4alkyl;

n denotes zero or 1; or

L means the radicalin which R1means hydrogen or C1-4alkyl;

m is 1;

R means hydrogen, halogen, C1-C4alkyl or C1-C4alkoxygroup;

Z means a bond, -C(O)NH-, O or S;

p means an integer from 1 to 5;

Q means a connection provided that Z is not a bond when p is 1; or

Q denotes O, S, or-C(O)NR6-, where R6means hydrogen, C1-4alkyl or C3-6cycloalkyl; or W and R6together with the nitrogen atom to which they are attached, form

or

or Q means-NR6-, provided that p is not 1;

W means

,,,,,

,,,

,,,

,,,,

,,,,

,,,,

,,,,,

,,,,and

or its pharmaceutically acceptable salt or optical isomer or mixture of optical isomers.

2. The compound according to claim 1, where

L means the radicalin the cat the rum R 1means hydrogen and n is 0 or 1;

R means hydrogen, halogen, C1-C4alkyl or C1-C4-alkoxygroup;

Z means a bond, O or S;

p means an integer from 1 to 4;

Q means a connection provided that Z is not a bond when p is 1; or

Q denotes O or S;

or its pharmaceutically acceptable salt or optical isomer or mixture of optical isomers.

3. The compound according to claim 1, where

L means the radicalin which R1means hydrogen;

R means hydrogen, halogen, C1-C4alkyl or C1-C4alkoxygroup;

Z means a bond, O or S; R denotes an integer from 1 to 4;

Q means a connection provided that Z is not a bond when p is 1; or

Q denotes O or S;

or its pharmaceutically acceptable salt or optical isomer or mixture of optical isomers.

4. The compound according to claim 1, where the asymmetric center in the radical L is (R)-configuration;

or its pharmaceutically acceptable salt.

5. The compound according to claim 1, where

R denotes hydrogen, chlorine, n-propyl or methoxy group;

or its pharmaceutically acceptable salt or optical isomer or mixture of optical isomers.

6. The connection is about to claim 1, which is selected from the group consisting of:

(R)-1-{4-[4-(4-Phenoxy-2-propylenoxide)butoxy]benzazolyl}azetidin-2-carboxylic acid;

(R)-1-{4-[3-(4-Phenoxy-2-propylenoxide)propoxy]benzazolyl}azetidin-2-carboxylic acid;

(R)-1-[4-(5-Methyl-2-phenyloxazol-4-ylethoxy)benzazolyl]azetidin-2-carboxylic acid;

(R)-1-{4-[2-(4-Forfinal)-5-methoxazole-4-ylethoxy]benzazolyl}-azetidin-2-carboxylic acid;

(R)-1-{4-[5-Methyl-2-(4-(trifluoromethyl-phenyl)oxazol-4-ylethoxy]benzazolyl}azetidin-2-carboxylic acid;

(R)-1-{4-[2-(3,5-Bistritei-phenyl)-5-methoxazole-4-ylethoxy]benzazolyl}azetidin-2-carboxylic acid;

(R)-1-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]benzazolyl} azetidin-2-carboxylic acid;

(R)-1-{4-[4-(4-Phenoxy-2-propylenoxide)butoxy]benzazolyl} -pyrrolidin-2-carboxylic acid;

(R)-1-{4-[3-(4-Phenoxy-2-propylenoxide)propoxy]benzazolyl}-pyrrolidin-2-carboxylic acid;

(R)-1-(4-{3-[2-Propyl-4-(4-(trifluoromethyl)phenoxy)phenoxy]propoxy}-benzazolyl)pyrrolidin-2-carboxylic acid;

(R)-1-{4-[2-(4-Methoxy-2-propylenoxide)ethoxy]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-(4-{2-[2-Propyl-4-(4-(trifluoromethyl)phenoxy)phenoxy]ethoxy}benzazolyl)pyrrolidin-2-carboxylic acid;

R)-1-{3-Methoxy-4-[3-(4-phenoxy-2-propylenoxide)propoxy]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-{3-Chloro-4-[3-(4-phenoxy-2-propyl, phenoxy)propoxy]benzazolyl}-pyrrolidin-2-carboxylic acid;

(R)-1-{4-[3-(4-Phenoxy-2-propylenoxide)propoxy]-3-propylbenzoyl-sulfonyl}pyrrolidin-2-carboxylic acid;

(R)-1-{4-[3-(4-Phenoxy-2-propylenoxide)propylsulfonyl]benzazolyl}-pyrrolidin-2-carboxylic acid;

(R)-1-{4-[2-(4-Phenoxy-2-propylenoxide)ethylsulfanyl]benzazolyl}-pyrrolidin-2-carboxylic acid;

(R)-1-{4-[3-(4-Phenoxy-2-propylenoxide)propyl]benzazolyl}-pyrrolidin-2-carboxylic acid;

(R)-1-[4-(5-Methyl-2-phenyloxazol-4-ylethoxy)benzazolyl]pyrrolidin-2-carboxylic acid;

(R)-1-{4-[2-(4-Forfinal)-5-methoxazole-4-ylethoxy]benzazolyl}-pyrrolidin-2-carboxylic acid;

(R)-1-{4-[5-Methyl-2-(4-(trifluoromethyl-phenyl)oxazol-4-ylethoxy]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-{4-[2-(3,5-Bistritei-phenyl)-5-methoxazole-4-ylethoxy]-benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-[4-(2-Biphenyl-4-yl-5-methoxazole-4-ylethoxy)benzazolyl]-pyrrolidin-2-carboxylic acid;

(R)-1-[3-Methoxy-4-(5-methyl-2-phenyloxazol-4-ylethoxy)benzazolyl]-pyrrolidin-2-carboxylic acid;

(R)-1-[3-Chloro-4-(5-methyl-2-phenyloxazol-4-ylethoxy)benzazolyl]-pyrrolidin-2-carboxylic acid;

(R)-1-[4-(5-METI the-2-phenyloxazol-4-ylethoxy)-3-propylbenzenesulfonyl]-pyrrolidin-2-carboxylic acid;

(R)-1-[4-(5-Methyl-2-phenyloxazol-4-elmersolver)benzazolyl]-pyrrolidin-2-carboxylic acid;

(R)-1-{4-[2-(4-Forfinal)-5-methoxazole-4-elmersolver]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-{4-[5-Methyl-2-(4-(trifluoromethyl-phenyl)oxazol-4-elmersolver]-benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-{4-[2-(3,5-Bistritei-phenyl)-5-methoxazole-4-ylmethyl-sulfanyl]benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]benzazolyl}-pyrrolidin-2-carboxylic acid;

(R)-1-{3-Methoxy-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzazolyl}-pyrrolidin-2-carboxylic acid;

(R)-1-{3-Chloro-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzazolyl}-pyrrolidin-2-carboxylic acid;

(R)-1-(4-{2-[5-Methyl-2-(4-(trifluoromethyl-phenyl)oxazol-4-yl]ethoxy}benzazolyl)pyrrolidin-2-carboxylic acid;

(R)-1-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethylsulfanyl]benzazolyl}-pyrrolidin-2-carboxylic acid;

(R)-1-{4-[4-(4-Phenoxy-2-propylenoxide)butoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[3-(4-Phenoxy-2-propylenoxide)propoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[2-(4-Phenoxy-2-propylenoxide)ethoxy]benzazolyl}-2,3-dihydro-1H-indole-2-arbonboy acid;

(R)-1-{3-Methoxy-4-[3-(4-phenoxy-2-propylenoxide)propoxy]benzene-sulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{3-Chloro-4-[3-(4-phenoxy-2-propylenoxide)propoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-[4-(5-Methyl-2-phenyloxazol-4-ylethoxy)benzazolyl]-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[2-(4-Forfinal)-5-methoxazole-4-ylethoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[5-Methyl-2-(4-(trifluoromethyl-phenyl)oxazol-4-ylethoxy]benzazolyl}-2,3-Dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[2-(3,5-Bis(trifluoromethyl-phenyl)-5-methoxazole-4-ylethoxy]benzazolyl}-2,3-Dihydro-1H-indole-2-carboxylic acid;

(R)-1-[3-Methoxy-4-(5-methyl-2-phenyloxazol-4-ylethoxy)benzazolyl]-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-[3-Chloro-4-(5-methyl-2-phenyloxazol-4-ylethoxy)benzazolyl]-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-[4-(5-Methyl-2-phenyloxazol-4-ylethoxy)-3-propylbenzenesulfonyl]-2,3-Dihydro-1H-indole-2-carboxylic acid;

(R)-1-[4-(5-Methyl-2-phenyloxazol-4-elmersolver)benzazolyl]-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[2-(4-Forfinal)-5-methoxazole-4-elmersolver]benzoylphenyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[5-Methyl-2-(4-(trifter ethyl-phenyl)oxazol-4-elmersolver]-benzazolyl}-2,3-Dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[2-(3,5-Bistritei-phenyl)-5-methoxazole-4-ylmethyl-sulfanyl]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{3-Chloro-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)oxazol-4-elmersolver]-benzazolyl}pyrrolidin-2-carboxylic acid;

(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)oxazol-4-elmersolver]-benzazolyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

or its pharmaceutically acceptable salt, or enantiomer, or a mixture of its enantiomers.

7. The activation method peroxisome proliferation of activated receptors (PPAR), including introduction to the mammal in case of need, a therapeutically effective amount of a compound according to claim 1.

8. The use of compounds according to claim 1 for the preparation of medicines for treating conditions oposredstvovanii receptor PPAR.

9. The use of claim 8, which includes the introduction of the above compounds in combination with a therapeutically effective amount of DPPIV inhibitor or an inhibitor of HMG-CoA-reductase.

10. Method of treating conditions oposredstvovanii receptors PPAR selected from dyslipid the MIA, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, syndrome X, inflammation, arthritis, inflammatory bowel disease, ulcerative colitis and Crohn's disease, diabetes type-1 and type-2, which includes an introduction to the mammal in need a therapeutically effective amount of a compound according to claim 1.

11. Pharmaceutical composition having agonistic activity against PPAR, comprising a therapeutically effective amount of a compound according to claim 1 in combination with one or more pharmaceutically acceptable carriers.

12. The pharmaceutical composition according to claim 11 for the treatment of dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, syndrome X, inflammation, arthritis, inflammatory bowel disease, ulcerative colitis and Crohn's disease, reduced glucose tolerance, hyperglycemia, insulin resistance, diabetes type-1 and type-2.



 

Same patents:

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula 1 and their pharmaceutically acceptable salts as inhibitors of post-proline aminopepdidases, as well as to pharmaceutical composition based on them and application for manufacturing such composition, and to method of inhibition with their application. Compounds can be applied for treatment of diseases mediated by activity of post-proline aminopeptidases, such as type II diabetes and disturbed tolerance to glucose. In general formula 1 ,

either G1 represents -CH2-X2-(CH2)a-G3, and G2 represents H, or G2 represents -CH2-(CH2)a-G3, and G1 represents H; G3 is selected from group according to general formula 2 ,

group according to general formula 3

and group according to general formula 4 ;

a is 0, 1 or 2; b is 1 or 2; X1 is selected from CH2, S, CF2, CHF and O; X2 is selected from CH2; X3, X4 and X5 are selected from N; X6 is selected from NH; X7 is selected from NH; R1 is selected from H and CN; R2 represents H; R3 is selected from H, Cl, OH, NH2, NH-C1-C10alkyl and N(C1-C10alkyl)2; R4, R5, R6, R7 and R8 are independently selected from H, Br, Cl, F, OH, NO2; R9 represents H; R10, R11, R12, R13 and R14 are independently selected from H, Cl and CF3; R15 and R16 are independently selected from H, C1-C10alkyl, C1-C10alkenyl, C3-C10cycloalkyl, C3-C10cycloalkenyl, quinoline, naphtyl and -CH2-L-R17; R17 is selected from C1-C10alkyl, phenyl, naphtyl, quinolinyl and indolyl; L is selected from covalent bond, CH=CH and -C6H4-; on condition that when R15 and R16 both represent H, and b is 1, then X1 does not represent S or CH2.

EFFECT: obtaining compounds that can be applied for treatment of diseases mediated by activity of post-proline aminopeptidases, such as type II diabetes and disturbed tolerance to glucose.

58 cl, 10 tbl, 1705 ex

FIELD: chemistry.

SUBSTANCE: this invention refers to compounds of formula where one of R6, R7 or R8 means , and X, Y, substitutes of R1-R13 and n are as it is defined in item 1 of formula of invention, and to all their enantiomers, to pharmaceutically acceptable salts and/or esters.

EFFECT: production of compounds for treatment and/or prevention of diseases modulated by PPARδ and/or PPARα agonists.

26 cl, 1 tbl, 35 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to methods of obtaining rosiglytasone, rosiglytasone, obtained by said methods, and its pharmacological compositions and methods of treatment using it.

EFFECT: obtaining of new crystalline modifications of rosiglytasone, which have useful biological properties.

58 cl, 4 dwg, 2 tbl, 9 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, possessing qualities of chemokine receptor modulators. Compounds can be applied for asthma, allergic rhinitis, COLD, inflammatory intestinal disease, irritated intestine syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer. In compound of formula (I) , R1 represents group selected from C1-8alkyl, said group is possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4 , -NR5R6 , phenyl, phenyl is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4,-NR5R6,-SR10,C1-6alkyl and trifluoromethyl; R2 represents group selected from C1-8alkyl, said group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-(C1-6alkyl)-N-(phenyl)amino; R3 represents hydrogen, R4 represents hydrogen or group selected from C1-6alkyl and phenyl, R5 and R6, independently, represent hydrogen or group selected from C1-6alkyl and phenyl, said group being probably substituted with 1, 2 or 3 substituents, independently selected from -OR14, -NR15R16, -COOR14,-CONR15R16, or R5 and R6 together with nitrogen atom, to which they are bound, form 4-7-member saturated heterocyclic ring system, possibly containing additional heteroatom, selected from oxygen and nitrogen atoms, ring possibly being substituted with 1, 2 or 3 substituents, independently selected from -OR14, -COOR14,-NR15R16,CONR15R16 and C1-6alkyl; R10 represents hydrogen or group selected from C1-6alkyl or phenyl; and each from R7, R8, R9, R14, R15, R16 independently represents hydrogen, C1-6alkyl or phenyl; X represents hydrogen, halogeno; Rx represents trifluoromethyl, -NR5 R6 , phenyl, naphtyl, heteroaryl, heteroring can be partly or fully saturated, and one or more ring carbon atoms can form carbonyl group, each phenyl or heteroaryl group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR4, -NR5R6, -CONR5R6, -COR7, -COOR7, -NR8COR9, -SR10, -SO2R10, -SO2NR5R6, -NR8SO2R9, C1-6alkyl or trifluoromethyl; or Rx represents group selected from C1-6alkyl, said group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6, phenyl or heteroaryl, where heteroaryl represents monocyclic or bicyclic aryl ring, containing from 5 to 10 ring atoms, from which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen. Invention also relates to methods of obtaining compounds, versions, pharmaceutical composition and application for manufacturing medications using compounds of invention.

EFFECT: obtaining novel compounds of formula (I), its pharmaceutically acceptable salts, possessing properties of chemokine receptor moduators.

25 cl, 138 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula (I) HetAr represents pyrimidinyl or thiadiasolyl; R1 and R2 represent H; A represents C1-C2-alkyl; B represents aryl(CH2)0-3-O-C(O)-or arylcyclopropyl-C(O)-, in which aryl can be substituted with 1-5 substituents, each substituent represents C1-C4-alkyl. Invention also relates to pharmaceutical composition and to application of compounds of item 1. Obtaining novel compounds, as well as pharmaceutical composition possessing NMDA/NR2B antagonist activity.

EFFECT: increase of composition efficiency.

13 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula: , where R is -(CH2)n-A, where A: where each of B and C independently represent phenyl or phenyl substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl) and -NO2; or n equals an integer from 0 to 3; n1 equals an integer from 1 to 3; n2 equals an integer from 0 to 4; n3 equals an integer from 0 to 3; n4 equals an integer from 0 to 2; X1 is chosen from a chemical bond -S-, -S(O)2-, -NH-, -NHC(O)- and -C=C-, R1 is chosen from C1-C6alkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, tetrahydropyranyl, CN, -N(C1-C6alkyl)2, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, naphtyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperizinyl, thiazolydinyl, thiomopholinyl, tetrazolyl, benzoxazolyl, imidazolidine-2-thionyl, 7,7-dimethylbicyclo[2.2.1]heptane-2-onyl, benzo[1.2.5]oxadiazolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl and pyrrolyl, each of which can be optionally substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NO2, -SO2(C1-C3alkyl), -SO2NH2, -SO2N(C1-C3alkyl)2, -COOH, -CH2-COOH, pyridyl, 2-methylazolyl, morpholino, 1-chloro-2-methylpropyl, phenyl, (optionally substituted with one or more halogens), benzyloxy, and , X2 selected from -O-, -CH2-, -S-, -SO-, -SO2-, -NH- and , R2 represents a ring group, chosen from a phenyl or thienyl group. Each ring group is substituted with a group with formula -(CH2)n4-CO2H; and besides that, the ring group can optionally be substituted with 1 or 2 extra substitutes, independently chosen from halogen, - C1-C6alkyl and -C1-C6alkoxy; R3 is chosen from H, halogen and -NO2; R4 is chosen from H, halogen and morpholino; or its salt form, used in pharmaceuticals. The invention also relates to pharmaceutical compositions, to methods of treatment, and to compounds with formula (A).

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on them, which have inhibiting effect on cytosolic phospholipase A2.

45 cl, 300 ex

FIELD: medicine; pharmacology.

SUBSTANCE: subjects of invention are also pharmaceutical drugs or agents for prophylaxis and treatment of neuropathy, increase of production and treatment of the neurotrophic factor, for pain relief, for nerve protection, for prophylaxis and treatment of the neuropathic pain containing compound of the formula or of the formula . In the compounds of the formulas (I) and (II) symbols and radicals have the meanings mentioned in the invention formula. The specified agents have an excellent effect and low toxicity. There are also proposed ways of treatment and prophylaxis of the abovementioned conditions by means of the compounds of the formula (I) or (II) and application of these compounds for production of the abovementioned agents. Besides, one has proposed methods for production of the specified compounds and intermediate pyrazol compounds.

EFFECT: compound has an effect increasing production and secretion of the neurotrophic factor.

46 cl, 1 tbl, 233 ex

Carbonyl compounds // 2337099

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to novel compounds of general formula(I) , where D represents phenyl, pyridyl or tienyl, each of which is single-substituted or double-substituted with Hal; R1 represents H, =O, COOR3, OH, OA, NH2, alkyl, which has 1, 2, 3, 4, 5 or 6 carbon atoms, N3, ethinyl, vinyl, allyloxy, -OCOR3, NHCOA or NHSO2A; R2 represents H, =O, OH, OA or alkyl, which has 1, 2, 3, 4, 5 or 6 carbon atoms; R1 and R2 together alternatively represent spirocyclically linked 3-6-member carbocyclic ring, R3 represents H or A, R4 represents H or A; represents pyrrolidine-1,2-diyl, piperidine-1,2-diyl, oxazolidine-3,4 or 3,5-diyl, thiazolidine-3,4-diyl, 2,5-dihydro-1H-pyrrol-1,5-diyl, 1,3-dioxolane-4,5-diyl; G represents (CH2)n or (CH2)nNH-; X represents CONH; Y represents 1,3- or 1,4-phenylene, which is not substituted or is single-substituted with methyl, trifluoromethyl, ethyl, propyl, Cl or F; T represents morpholine-4-yl, which is single-substituted or double-substituted with carbonyl oxygen; A represents non-branched or branched alkyl, which has 1-10 carbon atoms and in which 1-7 hydrogen atoms can be substituted with F; Hal represents F, CI, Br or I, n represents 0, 1 or 2; and their pharmaceutically acceptable derivatives, solvates, salts or sterioisomers, including their mixtures in all ratios. Invention also relates to method of obtaining formula I compounds, to medication based on formula I compound and application of formula I compounds for preparation of medication, which has inhibiting activity with respect to coagulation factors Xa and VIla.

EFFECT: obtained novel compounds have inhibiting activity with respect to said coagulation factors.

11 cl, 1 tbl, 14 ex

Amid derivative // 2336273

FIELD: chemistry.

SUBSTANCE: invention relates to amid derivatives of formula (I), method of disease treatment and pharmaceutical composition based on them. Compounds can be applied in treatment of different herpes virus infections. In general formula (I) , Z: 1,2,4-oxydiazol-3-yl, 4-oxazolyl, 1,2,3-triazol-2-yl or 2-pyridyl, A: phenyl, which can have a substitute (substitutes) selected from group, including lower alkyl, halogen, halogen-substituted lower alkyl, O-lower alkyl, O-lower alkylene -OH, CN, OH, O-lower alkylene-phenyl, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N-(lower alkyl)2 ,NH-lower alkylene-OH, NH-lower alkylene-O-lower alkyl, O-lower alkylene- NH2, O-lower alkylene-NH-lower alkyl and O-lower alkylene-N(lower alkyl)2; heteroaryl, representing monocyclic 6-member ring, which contains nitrogen atom as heteroatom or bicyclic 9-member ring, containing 1-2 heteroatoms selected from nitrogen and/or sulfur, which can have a substitute (substitutes), selected from lower alkyl; or phenyl group, condensed with saturated 5-member hydrocarbon cycle; or phenyl group, condensed with saturated 5-member heterocyclic cycle, which contains 1-2 heteroatoms, selected from nitrogen and/or oxygen, which can have a substitute (substitutes), selected from group, including lower alkyl, halogen, -C(O)-lower alkyl, lower alkylene-O-lower alkyl, on condition, that aryl group, condensed with saturated hydrocarbon cycle or aryl group, condensed with saturated heterocyclic cycle is bound with nitrogen atom through carbon atom in aromatic cycle, X: CO, R3: C3-C6cycloalkyl, which can have a substitute (substitutes), selected from group, which includes oxo, OH, halogen, CN, O-lower alkyl, -C(O)-NH2, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2, lower alkylene-OH, lower alkylene-O-lower alkyl; aryl, selected from phenyl, naphtyl, which can have a substitute (substitutes), selected from halogen; pyridyl; 9-member bicyclic heteroaryl, containing 1-3 heteroatoms, selected from S, N, O; or saturated heterocyclic group, representing monocyclic 6-member group, which contains 1-2 heteroatoms selected from S, SO, SO2, N, O, which can have a substitute (substitutes), selected from halogen.

EFFECT: obtaining amid derivatives that can be applied for treating various herpes virus infections.

17 cl, 26 tbl, 125 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , where R1 represents phenyl group, containing 1-3 substitutes, selected from halogen and cyano group; R2 represents pyridyl group, which has 1-3 substitutes, selected from monocyclic or polycyclic heterocyclic group, which can have 1-3 substitutes, selected from halogen atoms, cyanogroup, as well as other values of R2 radical, given in formula of invention, R3 represents phenyl group or pyridyl group, which has 1-2 substitutes, selected from halogen and trihalogenmethyl group; R4 represents hydrogen atom; and X represents -SO2-; its salt or its solvate. As well as to medication and pharmaceutical composition, inhibiting production or secretion of β-amyloid protein, and containing compound of formula (I), and to application of compound of pt.1 in order to obtain medication.

EFFECT: obtaining novel compounds, inhibiting production or secretion of β-amyloid protein.

14 cl, 1 tbl, 296 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: claimed invention relates to application of indazole derivatives of general formula (I) , in which: R stands for O; R3 stands for radical (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, said radicals being unsubstituted or substituted with one or several substitutes, given in item 1 of the formula; R4, R5, R6 and R7, independently on each other are selected from following radicals; hydrogen atom, halogen, CN, NO2, NH2, NHSO2R9, trifluoromethyl, trifluoromethoxygroup, (C1-C6)-alkyl, phenyl, phenyl-(C1-C6)-alkyl, pyridyl, possibly substituted with amino or hydroxygroup, thienyl, furanyl, morpholino, phenyl being unsubstituted or substituted with one or several substitutes, given in item 1 of the formula; R8, R9, R10, R11, independently on each other, stand for hydrogen atom, (C1-C6)-alkyl, phenyl possibly substituted with halogen; their racemates, enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts for obtaining medication, inhibiting phosphorylation of Tau-protein. Invention also relates to novel compounds of formula (I), particular indazole derivatives, their racemates, enantiomers, tautomers and pharmaceutically acceptable salts, pharmaceutical composition and based on them medication which inhibits Tau-protein phosphorylation, as well as to method of obtaining compounds of formula (I).

EFFECT: obtaining medication based on indazole derivatives, inhibiting Tau-protein phosphorylation.

9 cl, 118 ex, 3 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1 represents similar or different 2 groups, each of which is selected from group consisting of C1-3alkyl, or when R1 are two adjacent groups, two groups R1, taken together, can form saturated or unsaturated 5- or 6-member cyclic group, which can have 1 or 2 oxygens as heteroatom; X represents oxygen or sulphur; values of other radicals are given in invention formula.

EFFECT: increase of composition efficiency.

16 cl, 11 tbl, 31 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, possessing qualities of chemokine receptor modulators. Compounds can be applied for asthma, allergic rhinitis, COLD, inflammatory intestinal disease, irritated intestine syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer. In compound of formula (I) , R1 represents group selected from C1-8alkyl, said group is possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4 , -NR5R6 , phenyl, phenyl is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4,-NR5R6,-SR10,C1-6alkyl and trifluoromethyl; R2 represents group selected from C1-8alkyl, said group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-(C1-6alkyl)-N-(phenyl)amino; R3 represents hydrogen, R4 represents hydrogen or group selected from C1-6alkyl and phenyl, R5 and R6, independently, represent hydrogen or group selected from C1-6alkyl and phenyl, said group being probably substituted with 1, 2 or 3 substituents, independently selected from -OR14, -NR15R16, -COOR14,-CONR15R16, or R5 and R6 together with nitrogen atom, to which they are bound, form 4-7-member saturated heterocyclic ring system, possibly containing additional heteroatom, selected from oxygen and nitrogen atoms, ring possibly being substituted with 1, 2 or 3 substituents, independently selected from -OR14, -COOR14,-NR15R16,CONR15R16 and C1-6alkyl; R10 represents hydrogen or group selected from C1-6alkyl or phenyl; and each from R7, R8, R9, R14, R15, R16 independently represents hydrogen, C1-6alkyl or phenyl; X represents hydrogen, halogeno; Rx represents trifluoromethyl, -NR5 R6 , phenyl, naphtyl, heteroaryl, heteroring can be partly or fully saturated, and one or more ring carbon atoms can form carbonyl group, each phenyl or heteroaryl group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR4, -NR5R6, -CONR5R6, -COR7, -COOR7, -NR8COR9, -SR10, -SO2R10, -SO2NR5R6, -NR8SO2R9, C1-6alkyl or trifluoromethyl; or Rx represents group selected from C1-6alkyl, said group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6, phenyl or heteroaryl, where heteroaryl represents monocyclic or bicyclic aryl ring, containing from 5 to 10 ring atoms, from which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen. Invention also relates to methods of obtaining compounds, versions, pharmaceutical composition and application for manufacturing medications using compounds of invention.

EFFECT: obtaining novel compounds of formula (I), its pharmaceutically acceptable salts, possessing properties of chemokine receptor moduators.

25 cl, 138 ex

FIELD: chemistry.

SUBSTANCE: described are novel compounds of series 2-propen-1-on of general formula or their tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, where Q stands for heteroaryl cycle, containing up to 2 nitrogen atoms. Compounds I induce HSP-70 and are useful in treatment of diseases accompanying pathologic process in organisms of mammals, including humans.

EFFECT: novel compounds possess useful biological properties.

26 cl, 7 tbl, 179 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: described are 2,6-substituted pyridine-3-carbonyl derivatives of formula (I) , in which A stands for alkandiyl, is necessary disrupted by oxygen; X stands for halogen, alkylsulfonyl with 1-6 carbon atoms; Y stands for heterocycle and, if necessary, heterocycle can contain SO2-group or oxo-group (C=O), possibly substituted by alkyl, alkoxy, alkylthio with 1-6 carbon atoms in alkyl groups; Z stands for group of formula: or . Also described are intermediate derivatives of formulas (II) and (IV) .

EFFECT: extension of range of substituted pyridylketones with herbicidal activity.

3 cl, 3 tbl, 49 ex

FIELD: chemistry.

SUBSTANCE: compounds of formula (I) can be efficient with respect to diseases, in which phosphorylation of Tau protein takes place. , R3 stands for CONR1R2, where R1 and R2 can be substituted with heterocycle; R5, R6, R7 independently on each other are selected from halogen and phenyl; R1, R2 independently on each other stand for hydrogen, (C1-C6)alkyl or together with nitrogen of group CONR1R can form heterocycle.

EFFECT: obtaining novel biologically active compounds.

4 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula (I) X stands for C, N; R1 stands for H or (lower) alkyl, R2 stands for 9(lower) alkyl, -(CH2)n-R2a; R2a stands for C3-C8cycloalkyl, optionally and independently mono-, di-, tri- or tetrasubstituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent saturated heterocyclic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent heteroaromatic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, C3-C6cycloalkyl; R3 stands for C3-C6cycloalkyl, being optionally and independently mono-, di- or tri- or tetra-substituted with groups: OH, (lower) alkyl, (lower)alkoxy, phenyl, which optionally and independently is mono-, di- or tri- or tetra-substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; R4 stands for 5- or 6-member single-valent heteroaromatic ring, containing from one to two nitrogen heteroatoms, said heteroaromatic ring being optionally and independently mono-, di- or tri- substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, halogen; naphtyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; or phenyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, nitro, halogenated (lower)alkyl, halogenated (lower)alkoxy, cyano, (lower)alkylsulfonyl, -NR7R8; or two neighbouring substituents in said phenyl residue together represent -O-(CH2)p-O-, -(CH2)2-C(O)NH-; R5 and R6 each independently represent H, (lower)alkyl; R7 and R8 each independently represent hydrogen, (lower)alkyl, or R7 and R8 together with nitrogen atom, to which they are bound, form 5- or 6- member saturated or aromatic heterocyclic ring, which optionally contain nitrogen as additional heteroatom; said saturated or aromatic heterocyclic ring, being optionally substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy; m equals 1 or 2, n equals 0 or 1, p equals 1, 2 or 3; or their pharmaceutically acceptable salts.

EFFECT: increased antagonistic activity of compounds.

19 cl

FIELD: chemistry.

SUBSTANCE: invention pertains to acidylated heteroarylcondensed cycloalkenylamines with formula I in any of their stereoisomeric form or in form of their mixtures in any ratio, or their pharmaceutical salts, where in formula I: ring A represents an aromatic 6-member ring, containing 1 nitrogen atom, or a 5-member aromatic ring, containing 1 sulphur atom; one or two of R1, R2, R3 and R4 is independently chosen from a group consisting of hydrogen, halogen or C1-C4-alkyl, and the other R1, R2, R3 and R4 represent hydrogen; R5 represents an Ar group or Hetar group. Description is also given of a pharmaceutical composition based on compound with formula I and use of the latter.

EFFECT: regulation of the expression of the enzyme endothelial NO-synthesis.

10 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula (I) , where: R and Ri stand for phenyl, which can be substituted with 1, 2, 3 or 4 substitutes, which can be identical or different and chosen from a group consisting of chlorine, iodine, bromine, fluorine, trifluoromethyl and cyano. R2 and R3 can be identical or different and represent C1-5 branched or straight alkyl group. The alkyl group can be substituted with 1-3 fluorine atoms, or R2 and R3 - together with a nitrogen atom, with which they are bonded to, form pyrrolidine or piperidine ring. R7 represents hydrogen, C3-8 cycloalkyl, pyrrolidinyl or piperidinyl. The invention also pertains to salts of these derivatives used in pharmacology, as well as to compounds with general formula (IV), their pharmaceutical compositions, and their use.

EFFECT: obtaining new biologically active compounds which can function as modulators of cannabinoid receptors.

9 cl, 3 ex, 2 tbl

FIELD: chemistry, pharmaceutics.

SUBSTANCE: claimed invention relates to improved method of obtaining sulphinyl compound of formula (I) or its pharmaceutically acceptable salt, hydrate or solvate, which includes oxidation of sulphide compound of formula (II) , where in both formulae (I) and (II) R1 and R3 are selected from group including hydrogen, methyl or C1-4alkoxy, R2 is selected from group including substituted or unsubstituted C1-4alkoxy, and R4 is selected from group including hydrogen or substituted or unsubstituted C1-4alkoxy; which differs in the following: oxidiser, including water solution of hypohalogenite of alkali or alkali earth metal in concentration from 2 to 5% is added into suspension or solution of sulphide compound of formula (II), obtaining reaction mixture, in which, at least, during said oxidation solution of hydroxide of alkali or alkali earth metal is present, value of reaction mixture pH, at least, during said oxidation is within the range from 9 to 12; and, optionally, sulphinyl compound of formula (I) is converted into its pharmaceutically acceptable salt, hydrate or solvate.

EFFECT: obtaining sulphinyl compounds with greater output and lower amount of admixtures.

14 cl, 4 ex

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