Derivatives of 3-substituted 1,5-diphenylpyrazole effective as cb1 modulators

FIELD: medicine.

SUBSTANCE: invention covers compound of formula (IA) or to its pharmaceutically acceptable salts wherein R1 represents group R5S(O)2O where R5 represents C1-6alkyl group optionally substituted with one or more fluoro; Ra represents halogeno, and m is equal to 0, 1 or 2; R2a represents chloro; R2b represents chloro; R2c represents H or halogeno; R3 represents group CONHNR7R8 wherein NR7R8 represents piperidino or morpholino, or R3 represents group CONHR8 wherein R8 represents C5-7cycloalkyl group optionally substituted with C1-6alkoxycarbonyl group, or R8 represents pyridyl optionally substituted with one C1-5alkyl group where said alkyl is optionally substituted with one or more fluoro; and R4 represents H, C1-3alkyl group or halogeno. The compounds of formula (IA) are modulators of CB1 receptors and can find application in manufacturing of a medicinal agent with modulating activity in relation to CB1-receptor which can be used in treatment of obesity, psychiatric and neurologic disturbances.

EFFECT: higher clinical effectiveness.

5 cl, 21 ex

 

The scope of the invention

The present invention relates to certain compounds of formula (I), methods of producing such compounds, their use in the treatment of obesity, psychiatric and neurological disorders, to methods for their therapeutic use and to pharmaceutical compositions containing them.

Prior art

It is known that certain ST1(cannabinoid)-modulators (known as antagonists or inverse agonists are useful in the treatment of obesity, psychiatric and neurological disorders (WO 01/70700, EP 658546 and EP 656354). However, there is a need at CB1-modulators with improved physico-chemical properties, and/or DMPK-properties, and/or pharmacodynamic properties. In WO 95/15316, WO 96/38418, WO 97/11704, WO 99/64415, EP 418845 and WO 2004050632 disclosed pyrazoles having anti-inflammatory activity. In WO 2004050632 disclosed 1,1-dimethylethyl-[2-[4-[3-[(ethylmethylamino)carbonyl]-1-(4-methoxyphenyl)-1H-pyrazole-5-yl]phenoxy]ethyl]carbamate, 5-[4-(2-aminoethoxy)phenyl]-N-ethyl-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-3-carboxamide, 1-[[5-[4-(2-aminoethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazole-3-yl]carbonyl]piperidine and 1,1-dimethylethyl-[2-[4-[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-1H-pyrazole-5-yl]phenoxy]ethyl]carbamate. All connections are shown as examples in WO 2004050632, and their salts are excluded from the volume of the and claims of the present invention, related to connections.

In the US 5624941, WO 01/29007, WO 2004/052864, WO 03/020217, US 2004/0119972, Journal of Medicinal Chemistry, 46 (4), 642-645, 2003, Bioorganic & Medicinal Chemistry Letters, 14 (10), 2393-2396, 2004, Biochemical Pharmacology, 60 (9), 1315-1323, 2000, Journal of Medicinal Chemistry, 42 (4), 769-776, 1999, and the publication of the patent application US US 2003199536 disclosed derivatives of 1,5-diarylpyrazole-3-carboxamide as compounds with CB1-modulating activity.

Description of the invention

The invention relates to the compound of formula (I)

and its pharmaceutically acceptable salts, in which

R1represents (a) C1-3alkoxygroup substituted by one or more than one of the following: (1) fluorescent, (2) group NRcRdin which Rcand Rdindependently represent H, C1-6alkyl group or a C1-6alkoxycarbonyl group, provided that one of Rcand Rdis not H, or (3) 1,3-dioxolane-2-ilen group, (b) R1represents a C4-6alkoxygroup, possibly substituted by one or more than one of the following: (1) fluorescent, (2) group NRcRdin which Rcand Rdindependently represent H, C1-6alkyl group or a C1-6alkoxycarbonyl group, provided that one of Rcand Rdis not H, or (3) 1,3-dioxolane-2-ilen group, (C) a group of formula phenyl(CH2)pO, in which p is 1, 2 or 3 and the phenyl ring may substituted by 1, 2 or 3 groups represented by Z, (g) the group of R5S(O)2O or R5S(O)2NH, where R5represents a C1-6alkyl group, possibly substituted by one or more fluorescent, or R5represents a phenyl or heteroaryl group, each of which may substituted by 1, 2 or 3 groups represented by Z, (d) a group of the formula (R6)3Si in which R6represents a C1-6alkyl groups, which may be the same or different, or (e) a group of the formula RbO(CO)O, in which Rbrepresents a C1-6alkyl group, possibly substituted by one or more fluorescent;

Rarepresents halogeno, C1-3alkyl group or a C1-3alkoxygroup;

m is 0, 1, 2 or 3;

R2represents a C1-3alkyl group, a C1-3alkoxygroup, hydroxy, nitro, cyano or halogeno;

n is 0, 1, 2 or 3;

R3represents a

(a) the group X-Y-NR7R8,

in which X represents CO or SO2,

Y is absent or represents NH, possibly substituted C1-3alkyl group;

and R7and R8independently represent:

C1-6alkyl group, possibly substituted by 1, 2 or 3 groups represented by W;

With3-15cycloalkyl group, possibly substituted by 1, 2 or 3 groups represented by W;

(C3-15cycloalkyl)1-3alkylenes group, possibly substituted by 1, 2 or 3 groups represented by W;

the group -(CH2)r(phenyl)sin which r is 0, 1, 2, 3 or 4, s is 1 when r is 0 otherwise s is 1 or 2 and the phenyl group may independently substituted one, two or three groups represented by Z;

rich 5-8-membered heterocyclic group containing one nitrogen and possibly one of the following: oxygen, sulphur or an additional nitrogen, where the heterocyclic group possibly substituted by one or more C1-3alkyl groups, hydroxy or benzyl;

the group -(CH2)tHet, in which t is 0, 1, 2, 3 or 4, and Allenova chain possibly substituted by one or more C1-3alkyl groups and Het represents an aromatic heterocycle, possibly substituted by one, two or three groups selected from C1-5alkyl group, a C1-5alkoxygroup or halogeno, where alkyl and alkoxygroup may independently substituted one or more fluorescent;

or R7represents N, and R8is as defined above;

or R7and R8together with the nitrogen atom to which they are attached, represent a saturated or partially of nenasi the military 5-8-membered heterocyclic group, containing one nitrogen and possibly one of the following: oxygen, sulphur or an additional nitrogen, where the heterocyclic group possibly substituted by one or more C1-3alkyl groups, hydroxy, fluorescent or benzyl;

or b) oxazolyl, isoxazolyl, thiazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl or oxazolyl, each possibly substituted by 1, 2 or 3 groups Z;

R4represents H, halogeno, hydroxy, cyano, C1-6alkyl group, a C1-6alkoxygroup or1-6alkoxyl1-6alkylenes group containing up to 6 carbon atoms, each of which may substituted by one or more fluorescent or cyano;

Z represents a C1-3alkyl group, a C1-3alkoxygroup, hydroxy, halogeno, trifluoromethyl, triptoreline, deformedarse, triptoreline, trifloromethyl, nitro, amino, mono - or dis1-3alkylamino,1-3alkylsulfonyl, C1-3alkoxycarbonyl, carboxy, cyano, carbarnoyl, mono - or dis1-3allylcarbamate and acetyl and

W represents hydroxy, fluorescent, C1-3alkyl group, a C1-3alkoxygroup, amino, mono - or dis1-3alkylamino, C1-6alkoxycarbonyl group or a heterocyclic amine selected from morpholinyl, pyrrolidinyl, Piperi is inila or piperazinil, where the heterocyclic amine may substituted C1-3alkyl group, or hydroxyl;

with the exception of 1,1-dimethylethyl-[2-[4-[3-[(ethylmethylamino)carbonyl]-1-(4-methoxyphenyl)-1H-pyrazole-5-yl]phenoxy]ethyl]carbamate and 1,1-dimethylethyl-[2-[4-[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-1H-pyrazole-5-yl]phenoxy]ethyl]carbamate.

According to one embodiment of the invention relates to the compound of formula (I)

and its pharmaceutically acceptable salts, in which

R1represents (a) C1-3alkoxygroup substituted by one or more fluorescent or4-6alkoxygroup, possibly substituted by one or more fluorescent, (b) a group of formula phenyl(CH2)pO-in which R is 1, 2 or 3 and the phenyl ring may substituted by 1, 2 or 3 groups represented by Z, (b) the group R5S(O)2O or R5S(O)2NH,

where R5represents a C1-6alkyl group, possibly substituted by one or more fluorescent, or R5represents a phenyl or heteroaryl group, each of which may substituted by 1, 2 or 3 groups represented by Z, (g) a group of the formula (R6)3Si in which R6represents a C1-6alkyl groups, which may be the same or different, or (d) a group of the formula RbO(CO)O, in which Rbis sobeys 1-6alkyl group, possibly substituted by one or more fluorescent;

R3represents halogeno,1-3alkyl group or a C1-3alkoxygroup;

m is 0, 1, 2 or 3;

R2represents a C1-3alkyl group, a C1-3alkoxygroup, hydroxy, nitro, cyano or halogeno;

n is 0, 1, 2 or 3;

R3represents a

(a) the group X-Y-NR7R8,

in which X represents CO or SO2,

Y is absent or represents NH, possibly substituted C1-3alkyl group;

and R7and R8independently represent:

C1-6alkyl group, possibly substituted by 1, 2 or 3 groups represented by W;

With3-15cycloalkyl group, possibly substituted by 1, 2 or 3 groups represented by W;

possibly substituted (C3-15cycloalkyl)1-3alkylenes group, possibly substituted by 1, 2 or 3 groups represented by W;

the group -(CH2)r(phenyl)sin which r is 0, 1, 2, 3 or 4, s is 1 when r is 0 otherwise s is 1 or 2 and the phenyl group may independently substituted one, two or three groups represented by Z;

rich 5-8-membered heterocyclic group containing one nitrogen and possibly one of the following: oxygen, sulphur or an additional nitrogen, where the heterocyclic group possible is substituted on one or more C 1-3alkyl groups, hydroxy or benzyl;

the group -(CH2)tHet, in which t is 0, 1, 2, 3 or 4, and Allenova chain possibly substituted by one or more C1-3alkyl groups and Het represents an aromatic heterocycle, possibly substituted by one, two or three groups selected from C1-5alkyl group, a C1-5alkoxygroup or halogeno;

or R7represents H, a R8is as defined above;

or R7and R8together with the nitrogen atom to which they are attached, represent a saturated or partially unsaturated 5-8-membered heterocyclic group containing one nitrogen and possibly one of the following: oxygen, sulphur or an additional nitrogen, where the heterocyclic group possibly substituted by one or more C1-3alkyl groups, hydroxy, fluorescent or benzyl;

or b) oxazolyl, isoxazolyl, thiazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl or oxazolyl, each possibly substituted by 1, 2 or 3 groups Z;

R4represents H, halogeno, hydroxy, cyano, C1-6alkyl group, a C1-6alkoxygroup or1-6alkoxyl1-6alkylenes group containing up to 6 carbon atoms, each of which may substituted on the him or more fluorescent or cyano;

Z represents a C1-3alkyl group, a C1-3alkoxygroup, hydroxy, halogeno, trifluoromethyl, triptoreline, deformedarse, triptoreline, trifloromethyl, nitro, amino, mono - or dis1-3alkylamino, C1-3alkylsulfonyl, C1-3alkoxycarbonyl, carboxy, cyano, carbarnoyl, mono - or dis1-3allylcarbamate and acetyl and

W represents hydroxy, fluorescent, C1-3alkyl group, a C1-3alkoxygroup, amino, mono - or dis1-3alkylamino,1-6alkoxycarbonyl group or a heterocyclic amine selected from morpholinyl, pyrrolidinyl, piperidinyl or piperazinil, where the heterocyclic amine may substituted C1-3alkyl group or a hydroxyl.

According to another embodiment of the invention relates to the compound of formula (I)

and its pharmaceutically acceptable salts, in which

R1represents (a) C1-3alkoxygroup substituted by one or more fluorescent or4-6alkoxygroup, possibly substituted by one or more fluorescent, (b) a group of formula phenyl(CH2)pO-in which R is 1, 2 or 3 and the phenyl ring may substituted by 1, 2 or 3 groups represented by Z, (b) the group R5S(O)2O or R5S(O)2NH,

where R5represents a C1-6alkyl g is the SCP, possibly substituted by one or more fluorescent, or R5represents a phenyl or heteroaryl group, each of which may substituted by 1, 2 or 3 groups represented by Z, or (d) a group of the formula (R6)3Si in which R6represents a C1-6alkyl groups, which may be the same or different;

Rarepresents halogeno, C1-3alkyl group or a C1-3alkoxygroup;

m is 0, 1, 2 or 3;

R2represents a C1-3alkyl group, a C1-3alkoxygroup, hydroxy, nitro, cyano or halogeno;

n is 0, 1, 2 or 3;

R3represents a

(a) the group X-Y-NR7R8,

in which X represents CO or SO2,

Y is absent or represents NH, possibly substituted C1-3alkyl group;

and R7and R8independently represent:

C1-6alkyl group, possibly substituted by 1, 2 or 3 groups represented by W;

With3-15cycloalkyl group, possibly substituted by 1, 2 or 3 groups represented by W;

possibly substituted (C3-15cycloalkyl)1-3alkylenes group, possibly substituted by 1, 2 or 3 groups represented by W;

the group -(CH2)r(phenyl)sin which r is 0, 1, 2, 3 or 4, s is 1 when r is 0 otherwise s is 1 or 2 and phenyl is groups may independently substituted by one, two or three groups represented by Z;

rich 5-8-membered heterocyclic group containing one nitrogen and possibly one of the following: oxygen, sulphur or an additional nitrogen, where the heterocyclic group possibly substituted by one or more1-3alkyl groups, hydroxy or benzyl;

the group -(CH2)tHet, in which t is 0, 1, 2, 3 or 4, and Allenova chain possibly substituted by one or more C1-3alkyl groups and Het represents an aromatic heterocycle, possibly substituted by one, two or three groups selected from C1-5alkyl group, a C1-5alkoxygroup or halogeno;

or R7represents N, and R8is as defined above;

or R7and R8together with the nitrogen atom to which they are attached, represent a saturated or partially unsaturated 5-8-membered heterocyclic group containing one nitrogen and possibly one of the following: oxygen, sulphur or an additional nitrogen, where the heterocyclic group possibly substituted by one or more C1-3alkyl groups, hydroxy, fluorescent or benzyl;

or b) oxazolyl, isoxazolyl, thiazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl or oxazolyl, each possibly substituted by 1, 2 of the 3 groups Z;

R4represents H, C1-6alkyl group, a C1-6alkoxygroup or1-6alkoxyl1-6alkylenes group containing up to 6 carbon atoms, each of which may substituted by one or more fluorescent or cyano;

Z represents a C1-3alkyl group, a C1-3alkoxygroup, hydroxy, halogeno, trifluoromethyl, triptoreline, deformedarse, triptoreline, trifloromethyl, nitro, amino, mono - or dis1-3alkylamino, C1-3alkylsulfonyl, C1-3alkoxycarbonyl, carboxy, cyano, carbarnoyl, mono - or dis1-3allylcarbamate and acetyl and

W represents hydroxy, fluorescent, C1-3alkyl group, a C1-3alkoxygroup, amino, mono - or dis1-3alkylamino or heterocyclic amine selected from morpholinyl, pyrrolidinyl, piperidinyl or piperazinil, where the heterocyclic amine may substituted C1-3alkyl group or a hydroxyl.

In specific groups of compounds of formula (I)described in the above-mentioned three embodiments, R3represents a group described in paragraph (a). In other specific groups of compounds according to these three above-mentioned embodiments, in which R3represents a group described in paragraph (a), compounds in which R3represents N,N-dis1-6Cilk rebamol, or R3represents a group X-Y-NR7R8in which X represents CO, Y is absent, and R7and R8together with the nitrogen atom to which they are attached, represent a saturated or partially unsaturated 5-8-membered heterocyclic group containing one nitrogen and possibly one of the following: oxygen, sulphur or an additional nitrogen, where the heterocyclic group possibly substituted by one or more C1-3alkyl groups, hydroxy, fluorescent or benzyl, are excluded. Another specific group of compounds of formula (I)described in the first above-mentioned three embodiments, R3represents piperidine-1-ylcarbonyl.

It should be understood that in those cases where the Deputy Z is present in more than one group, these substituents independently selected and may be the same or different. The same is true for W. Similarly, if m is 2 or 3, the groups Raindependently selected in such a way that they may be the same or different, and similarly, if n is 2 or 3, the groups R2independently selected in such a way that they may be the same or different.

The term3-15cycloalkyl includes monocyclic, bicyclic, tricyclic system, and a Spiro-system, such as cyclopentyl, cyclohexyl and substituted.

The term heteroaryl who appoints an aromatic 5-, 6 - or 7-membered monocyclic ring or 9 - or 10-membered bicyclic ring containing ring with up to five heteroatoms selected from oxygen, nitrogen and sulfur. Suitable aromatic heteroaryl groups include, for example, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, benzofuranyl, indolyl, benzothiazyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazoles, benzofurazanyl, hinely, ethanolic, hintline, honokalani, cinnoline or naphthyridine. Preferably furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl and more preferably pyrrolyl, thienyl, imidazolyl, oxazolyl or pyridyl.

Suitable saturated or partially unsaturated 5-8-membered heterocyclic group containing one or more than one heteroatom selected from nitrogen, oxygen or sulfur, include, for example, tetrahydrofuranyl, tetrahydropyranyl, 2,3-dihydro-1,3-thiazolyl, 1,3-thiazolidine, pyrrolidyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-triazinyl, 1-externalization, 1,1-dioxalate the draw-1,4-thiazines, piperidinyl, homopiperazine, piperazinil, homopiperazine, dihydropyridines, tetrahydropyridine, dihydropyrimidine or tetrahydropyrimidines, preferably tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperidinyl or piperazinil, more preferably tetrahydrofuran-3-yl, tetrahydropyran-4-yl, pyrrolidin-3-yl, morpholino, piperidine, piperidine-4-yl or piperazine-1-yl.

Suitable group in which R1represents a group R5S(O)2O, in which R5represents a C1-6alkyl group, possibly substituted by one or more fluorescent, include methanesulfonate, econsultancy, n-propylsulfonyl, n-butylsulfonyl, 3-methylbutane-1-sulfonyloxy, 3,3-dimethylbutan-1 sulfonyloxy, pharmacysulfacet, diversityconference, tripterocalyx, mono-, di -, or three(foradil)sulfonyloxy, 3,3,3-cryptochrome-1 sulfonyloxy or 4,4,4-trifloromethyl-1 sulfonyloxy.

Suitable group in which R1represents a C1-3alkoxygroup substituted by one or more fluorescent or4-6alkoxygroup, possibly substituted by one or more fluorescent, include butoxy, pentyloxy, hexyloxy, formatosi, deformedarse, triptoreline, triptoreline, 4,4,4-triptoreline, 5,5,5-cryptocentrus and 6,6,6-triptoreline.

Suitable group in which R1represents a group R5S(O)2O, in which R5represents a phenyl or heteroaryl group, each of which may substituted by 1, 2 or 3 groups represented by Z include phenylsulfonyl, thienylboronic or pyridylsulfonyl, possibly substituted by 1, 2 or 3 groups represented by z

In a particular group of compounds of the formula I R1represents (a) C1-3alkoxygroup substituted by one or more than one of the following: (1) fluorescent, (2) group NRcRdin which Rcand Rdindependently represent H, C1-6alkyl group or a C1-6alkoxycarbonyl group, provided that one of Rcand Rdis not H, or (3) 1,3-dioxolane-2-ilen group, (b) R1represents a C4-6alkoxygroup, possibly substituted by one or more than one of the following: (1) fluorescent, (2) group NRcRdin which Rcand Rdindependently represent H, C1-6alkyl group or a C1-6alkoxycarbonyl group, provided that one of Rcand Rdis not H, or (3) 1,3-dioxolane-2-ilen group, (b) the group R5S(O)2O, where R5represents a C1-6alkyl group, possibly substituted by one or more fluorescent, or R5the submitted is a phenyl or heteroaryl group, each of which may substituted by 1, 2 or 3 groups represented by Z, (g) a group of the formula RbO(CO)O, in which Rbrepresents a C1-6alkyl group, possibly substituted by one or more fluorescent;

R8represents halogeno;

m is 0, 1, 2 or 3;

R2represents halogeno;

n is 0, 1, 2 or 3;

R3is a group CONR7R8in which R7represents N, and R8represents a C3-15cycloalkyl group, possibly substituted by a group represented by W, or R8represents a group -(CH2)tHet, in which t is 0, and Het represents pyridyl, possibly substituted by one, two or three groups selected from C1-5alkyl groups may be independently substituted one or more fluorescent; or R3is a group CONHNR7R8where NR7R8represents piperidino or morpholino, and

R4represents H, halogen or C1-6alkyl group which may be substituted by one or more fluorescent; Z represents halogen and W represents

C1-6alkoxycarbonyl group.

A specific group of compounds of formula I are represented by formula IA

in which R1represents a

(a) 4-6alkoxygroup, possibly substituted by one or more fluorescent, (b) a group of formula phenyl(CH2)pO-in which R is 1, 2 or 3 and the phenyl ring may substituted by 1, 2 or 3 groups represented by Z, (b) the group R5S(O)2O or R5S(O)2NH,

where R5represents a C1-6alkyl group, possibly substituted by one or more fluorescent, or R5represents a phenyl or heteroaryl group, each of which may substituted by 1, 2 or 3 groups represented by Z, where Z is as previously defined, (g) a group of the formula (R6)3Si in which R6represents a C1-6alkyl groups, which may be the same or different, or (d) a group of the formula RbO(CO)O, in which Rbrepresents a C1-6alkyl group, possibly substituted by one or more fluorescent;

Rarepresents halogen, and m is 0, 1 or 2;

R2arepresents chloro;

R2brepresents chloro;

R2crepresents H or fluorescent;

R3is a group CONHNR7R8where NR7R8represents piperidino or morpholino, or R3is a group CONHR8in which R8represents a C5-7cycloalkyl group, possibly substituted C alkoxycarbonyl group, or R8represents a possibly substituted pyridyl and

R4represents H, C1-3alkyl group or halogeno.

A specific group of compounds of formula I are represented by formula IA, in which R1represents (a)4-6alkoxygroup, possibly substituted by one or more fluorescent, (b) a group of formula phenyl(CH2)pO-in which R is 1, 2 or 3 and the phenyl ring may substituted by 1, 2 or 3 groups represented by Z, (in)

R5S(O)2O or R5S(O)2NH, where R5represents a C1-6alkyl group, possibly substituted by one or more fluorescent, or R5represents a phenyl or heteroaryl group, each of which may substituted by 1, 2 or 3 groups represented by Z, (g) a group of the formula (R6)3Si in which R6represents a C1-6alkyl groups, which may be the same or different, or (d) a group of the formula RbO(CO)O, in which Rbrepresents a C1-6alkyl group, possibly substituted by one or more fluorescent;

Rarepresents halogen, and m is 0, 1 or 2;

R2arepresents chloro;

R2brepresents chloro;

R2crepresents N;

R3is a group CONHNR7/sup> R8where NR7R8represents piperidino or morpholino, or R3is a group CONHR8in which R8represents a C5-7cycloalkyl group, possibly substituted C1-6alkoxycarbonyl group, and

R4represents a C1-3alkyl group or halogeno.

Another specific group of compounds of formula I are represented by formula IB

in which R1represents a

(a)4-6alkoxygroup, possibly substituted by one or more fluorescent, (b) a group of formula phenyl(CH2)pO-in which R is 1, 2 or 3 and the phenyl ring may substituted by 1, 2 or 3 groups represented by Z, (b) the group R5S(O)2O or R5S(O)2NH,

where R5represents a C1-6alkyl group, possibly substituted by one or more fluorescent, or R5represents a phenyl or heteroaryl group, each of which may substituted by 1, 2 or 3 groups represented by Z, or (d) a group of the formula (R6)3Si in which R6represents a C1-6alkyl groups, which may be the same or different;

Ra1represents halogeno or N;

Ra2represents halogeno or N;

R2arepresents chloro;

R 2brepresents chloro;

R2crepresents halogeno or N;

R3is a group CONHNR7R8where NR7R8represents piperidino, and

R4represents a C1-3alkyl group.

In one particular group of compounds of formula I, formula IA or formula IB R1represents a C4-6alkoxygroup, possibly substituted by one or more fluorescent.

In another particular group of compounds of formula I, formula IA or formula IB R1represents a group R5S(O)2O or R5S(O)2NH, where R5represents a C1-6alkyl group, possibly substituted by one or more fluorescent, or R5represents a heteroaryl group, possibly substituted by 1, 2 or 3 groups represented by z In another group, R1represents a group R5S(O)2O, in which R5represents a C1-6alkyl group, possibly substituted by one or more fluorescent.

In another particular group of compounds of formula I, formula IA or formula IB R1represents a group of the formula (R6)3Si in which R6represents a C1-6alkyl groups, which may be the same or different.

A specific group of compounds of formula I are represented by formula IB

in which R1represents a

(a)4-6alkoxygroup, possibly substituted by one or more fluorescent, (b) the group R5S(O)2O, in which R5represents a C1-6alkyl group, possibly substituted by one or more fluorescent;

R2arepresents chloro;

R2brepresents chloro;

R3is a group CONHNR7R8where NR7R8represents piperidino or morpholino, and

R4represents a C1-3alkyl group or halogeno.

In a particular group of compounds of formula IB, R1represents a group R5S(O)2O, in which R5represents a C1-6alkyl group, substituted by one or more fluorescent. More specifically, R1represents a group R5S(O)2O, in which R5represents a C3-6alkyl group, substituted by one or more fluorescent.

The following other values of R1, R2, R3, R4and Rain the compounds of formula I, formula IA, formula IB or formula IB. It should be understood that such values can be used, when appropriate, with any definition, any claims or embodiments, formulated in the description above or below.

R 1is a 4,4,4-triptoreline, n-butylsulfonyl, n-propylsulfonyl, 4,4,4-trifloromethyl-1 sulfonyloxy, 3,3,3-cryptochrome-1 sulfonyloxy, propoxycarbonyl, 2-(1,3-dioxolane-2-yl)ethoxy, N-ethyl-2-aminoethoxy, N-tert-butoxycarbonyl-N-ethyl-2-aminoethoxy, 3-methylbutane-1-sulfonyloxy, 3,3-dimethylbutan-1 sulfonyloxy, 5-chloro-2-thienylboronic, 2-thienylboronic or 3-pyridylsulfonyl.

R1represents a C4-6alkoxygroup substituted by one or more fluorescent. R1is a 4,4,4-triptoreline, n-butylsulfonyl, n-propylsulfonyl, 4,4,4-trifloromethyl-1 sulfonyloxy, 3,3,3-cryptochrome-1 sulfonyloxy, propoxycarbonyl, 2-(1,3-dioxolane-2-yl)ethoxy, N-ethyl-2-aminoethoxy or N-tert-butoxycarbonyl-N-ethyl-2-aminoethoxy.

R1is a 4,4,4-triptoreline, n-butylsulfonyl, n-propylsulfonyl, 4,4,4-trifloromethyl-1 sulfonyloxy, 3,3,3-cryptochrome-1 sulfonyloxy or propoxycarbonyl.

R1is a 4,4,4-triptoreline, n-butylsulfonyl or n-propylsulfonyl.

R2represents chloro or fluorescent, and n is 2 or 3.

R3represents N-(piperidine-1-yl)carbarnoyl, 5-(trifluoromethyl)pyridin-2-yl]amino}carbonyl, morpholine-4-ylcarbonyl or N-(1-methoxycarbonyl-1-cyclopentyl)carbarnoyl.

R4represents a C1-4alkyl or halogeno. R4represents methyl or bromo.

m is 0 or, when m is 1 or 2, Rais fluorescent.

In another particular group of compounds of formula I, formula IA, formula IB or formula IB or any of their incarnations, R3represents N-(piperidine-1-yl)carbarnoyl.

"Pharmaceutically acceptable salt", if such salts is possible, includes pharmaceutically acceptable salts of accession as acids and bases. Suitable pharmaceutically acceptable salt of the compounds of Formula I represents, for example, salt accession acid compounds of Formula I which is sufficiently basic, for example salt, obtained by attaching an inorganic or organic acid, such as hydrochloric, Hydrobromic, sulfuric, triperoxonane, citric or maleic acid; or, for example, the salt of the compounds of Formula I which is sufficiently acidic, for example, salts of alkaline or alkaline-earth metal such as sodium, calcium or magnesium, or ammonium salt or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or Tris-(2-hydroxyethyl)amine.

Throughout the description of the invention and the attached claims given chemical formula or name shall encompass in the e stereo and optical isomers and racemates, as well as mixtures of the individual enantiomers in different proportions, where such isomers and enantiomers exist, as well as their pharmaceutically acceptable salt and solvate, such as, for example, hydrates. The isomers can be separated using conventional techniques such as chromatography or fractional crystallization. The enantiomers may be isolated by separation of a racemate, for example, by fractional crystallization, splitting or HPLC (high performance liquid chromatography). The diastereomers can be separated by separation of mixtures of isomers, for example by fractional crystallization, HPLC or flash chromatography. Alternative stereoisomers can be obtained by chiral synthesis from chiral starting materials under conditions which will not cause racemization or epimerization, or by obtaining derivatives using a chiral reagent. All stereoisomers are included in the scope of this invention. All tautomers, if any, included in the scope of this invention. The present invention also encompasses compounds containing one or more than one isotope, such as14C,11With or19F, and their use as isotope-labeled compounds for pharmacological and metabolic studies.

The present invention also encompasses prodrugs of the soybean is inane formula I, which are compounds that are transformed in vivo to the compound of formula I.

Throughout the description of the invention and the attached claims, will be used the following definitions.

If not specified or not specified, the term "alkyl" denotes an alkyl group with unbranched or branched chain. Examples of the specified alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl and isohexyl. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl and tertiary butyl.

If not specified or not specified, the term "alkoxy" denotes the group O-alkyl, where alkyl such as defined above.

If not specified or not specified, the term "halogen" means fluorine, chlorine, bromine or iodine.

Specific compounds according to the invention comprise one or more than one of the following:

4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ether butane-1-sulfonic acid;

piperidine-1-ylamide 1-(2,4-dichlorophenyl)-4-methyl-5-[4-(4,4,4-triptoreline)phenyl]-1H-pyrazole-3-carboxylic acid;

4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ether propane-1-sulfonic acid;

4-[2-(2,4-dichlorophenyl)-4-methyl-5-(morpholine-4-icarbon who yl)-2H-pyrazole-3-yl]phenyl ether propane-1-sulfonic acid;

4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ester 3,3,3-cryptochrome-1-sulfonic acid;

4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ester 4,4,4-triptorelin-1-sulfonic acid;

[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]-2,6-diperpanjang ether propane-1-sulfonic acid;

4-[2-(2,4-dichlorophenyl)-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ether propane-1-sulfonic acid;

4-[4-bromo-2-(2,4-dichlorophenyl)-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ether propane-1-sulfonic acid;

methyl-1-{[(1-(2,4-dichlorophenyl)-4-methyl-5-{4-[(propylsulfonyl)oxy]phenyl}-1H-pyrazole-3-yl)carbonyl]amino}of cyclopentanecarboxylate;

propyl 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ester of carbonic acid;

4-{1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidine-1-ylamino)carbonyl]-1H-pyrazole-5-yl}phenyl thiophene-2-sulfonate;

4-{1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidine-1-ylamino)carbonyl]-1H-pyrazole-5-yl}phenyl pyridine-3-sulfonate;

tert-butyl[2-(4-{1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidine-1-ylamino)carbonyl]-1H-pyrazole-5-yl}phenoxy)ethyl]ethylcarbamate;

1-(2,4-dichlorophenyl)-5-{4-[2-(ethylamino)ethoxy]phenyl}-4-methyl-N-piperidine-1-yl-1H-pyrazole-3-carboxamide;

4-{1-(2,4-dichlorophenyl)-4-methyl-3-[(Pieper is DIN-1 ylamino)carbonyl]-1H-pyrazole-5-yl}phenyl 3-methylbutane-1-sulfonate;

4-{1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidine-1-ylamino)carbonyl]-1H-pyrazole-5-yl}phenyl 3,3-dimethylbutan-1-sulfonate;

4-[1-(2,4-dichlorophenyl)-4-methyl-3-({[5-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)-1H-pyrazole-5-yl]phenyl 3,3,3-cryptochrome-1-sulfonate;

1-(2,4-dichlorophenyl)-5-{4-[2-(1,3-dioxolane-2-yl)ethoxy]phenyl}-4-methyl-N-piperidine-1-yl-1H-pyrazole-3-carboxamide;

4-[2-(2,4-dichloro-3-forfinal)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ether propane-1-sulfonic acid and

4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ester 5-chloro-thiophene-2-sulfonic acid,

and their pharmaceutically acceptable salts.

Ways to get

The compounds of formula I in which Ra, R2, R3, R4, m and n are such as defined previously, and R1represents a group R5S(O)2NH can be obtained by reacting the compounds of formula II

in which Ra, R2, R3, R4, m and n are such as defined previously, with sulfonium agent of the formula R2SO2L, in which R5such as previously defined, and L is a leaving group, e.g. chloro, in an inert solvent, for example dichloromethane, in the presence of a base, such as triethylamine, at a temperature in the range from -25°C up to 150°C.

Connect the Oia formula I, in which R1represents (a) C1-3alkoxygroup substituted by one or more fluorescent or4-6alkoxygroup, possibly substituted by one or more fluorescent, or (b) a group of formula phenyl(CH2)pO-in which R is 1, 2 or 3 and the phenyl ring may substituted by 1, 2 or 3 groups represented by Z, or (b) the group R5S(O)2O, can be obtained by reacting the compounds of formula III

in which Ra, R2, R3, R4, m and n are such as defined previously, or

a) alkylating agent of formula R9X, in which R9represents a C1-3alkyl group, substituted by one or more fluorescent or4-6alkyl group, possibly substituted by one or more fluorescent, and X represents a leaving group, for example chloro, bromo or iodine, in an inert solvent, for example acetone, in the presence of a base, for example potassium carbonate, at temperatures ranging from -25°C to 150°C; or

b) alkylating agent of formula R9X, in which R9represents a group of formula phenyl(CH2)p-in which p is 1, 2 or 3 and the phenyl ring may substituted by 1, 2 or 3 groups represented by Z, and X represents a leaving group, for example chloro, bromo or iodine, in an inert solvent, for example, Aceto is e, in the presence of a base, for example potassium carbonate, at temperatures ranging from -25°C to 150°C; or

in) sulfonium agent of the formula R5SO2L, in which R5such as previously defined, and L is a leaving group, e.g. chloro, in an inert solvent, for example dichloromethane, in the presence of a base, such as triethylamine, at a temperature in the range from -25°C to 150°C, respectively.

The compounds of formula I in which R3, R1, R2, R4, m and n are such as defined previously, and R3represents a group X-Y-NR7R8in which X represents CO, Y is absent or represents NH, possibly substituted C1-3alkyl group, and R7and R8such as previously defined, can be obtained by reacting the compounds of formula IV

in which Ra, R1, R2, R4, m and n are such as defined previously, and R10represents a C1-6alkyl group, with a compound of formula V

,

in which Y, R7and R8such as previously defined, or its salt in an inert solvent, for example toluene, in the presence of a Lewis acid such as trimethylaluminum at a temperature in the range from -25°C up to 150°C.

The compounds of formula I in which R3represents a group X-Y-NR 7R8in which X represents SO2Y is absent or represents NH, possibly substituted C1-3alkyl group, and R7and R8such as previously defined, can be obtained by reacting the compounds of formula VI

in which Ra, R1, R2, R4, m and n are such as defined previously, and a represents a leaving group, for example, halogeno, for example chloro, with a compound of formula V in which Y, R7and R8such as previously defined, or its salt in an inert solvent, for example THF or dichloromethane, in the presence of a base, for example potassium carbonate, triethylamine or pyridine, at temperatures ranging from -25°C up to 150°C.

The compounds of formula III, IV and VI can be obtained by methods similar to the next method.

I believe that some of the intermediate compounds are new and form part of the present invention. Specialists in this field of technology it is necessary to take into account that during the consecutive reactions of some functional groups will be in need of protection with a subsequent removal of the protection at an appropriate stage, see "Protective Groups in Organic Synthesis", 3rd edition (1999), Greene and Wuts.

Pharmaceutical

Connection to izobreteny is usually administered by oral, parenteral, intravenous, intramuscular, subcutaneous or other injection, transbukkalno, rectal, vaginal, transdermal and/or nazalnam by and/or by inhalation in the form of pharmaceutical preparations containing the active ingredient or pharmaceutically acceptable salt accession, in pharmaceutically acceptable dosage form. Depending on the disorder and the patient treated and the route of administration of the composition can be injected at various doses.

Suitable daily doses of the compounds according to the invention, used in therapeutic treatment of humans are in the range of about 0.001 to 10 mg/kg body weight, preferably 0.01 to 1 mg/kg of body weight. Preferred are oral drugs, in particular tablets or capsules, which can be prepared according to methods known to experts in this field, with the receipt of doses of active compounds in the range from 0.5 mg to 500 mg, for example 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 50 mg, 100 mg and 250 mg

According to another aspect of the invention also offered a pharmaceutical preparation containing any of the compounds according to the invention or its pharmaceutically acceptable derivatives in a mixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.

Pharmacological properties

The connection forms of the crystals (I) are useful for the treatment of obesity or excess weight (for example, for activation of losing weight and maintaining weight loss), prevention of the body mass increase (for example, drug-induced or due to cessation of Smoking), modulation of appetite and/or satiety, eating disorders (e.g. binge eating, anorexia, bulimia and compulsion), addictions (drugs, tobacco, alcohol, any geeky appetite nutrient macronutrients or non-essential food components), for the treatment of psychiatric disorders such as psychotic disorders and/or mood disorders, schizophrenia and schizoaffective disorder, bipolar disorder, anxiety, axiomatisable disorders, depression, mania, obsessive-compulsive disorder, disorders of impulse control (e.g., the syndrome of Gilles de La Tourette), disorders of attention, such as ADD/ADHD (attention deficit disorder/attention deficit disorder and hyperactivity disorder), stress, and neurological disorders such as dementia and cognitive dysfunction and/or dysfunction of memory (e.g., amnesia, Alzheimer's disease, dementia Peak, senile dementia, vascular dementia, mild cognitive disturbance, age-related cognitive bias and mild senile dementia), neurological and/or neurodegenerative disorders, (e.g. the, multiple sclerosis, Raynaud's syndrome, Parkinson's disease, Horai Huntington's and Alzheimer's disease), disorders associated with demyelination, neuropeptidergic disorders (e.g., Guillain-Barre syndrome).

The compounds are also potentially useful for the prevention or treatment of disorders and behaviors that detect the propensity for dependence and consumption (e.g., abuse of alcohol and/or drug craving for gambling, kleptomania), disorders caused by the cancellation of drugs (e.g. alcohol abstinence violation or no violation of perception; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without violation violations of perception; sedative, hypnotic or anxiolytic withdrawal delirium, and withdrawal symptoms caused by other substances), mood disorders, anxiety disorders and/or sleep disorders with seizures during withdrawal caused by alcohol and/or drug and relapse caused by alcohol and/or drug.

The compounds are also potentially useful for prevented the I or treatment of neurological dysfunctions, such as dystonia, dyskinesia, akathisia, tremor and spasticity, treatment of spinal cord injuries, neuropathies, migraine, disorders of wakefulness, sleep disorders (e.g., disturbed sleep patterns, sleep apnea, obstructive sleep apnea syndrome sleep apnea), pain disorders, cranial trauma.

The compounds are also potentially useful for the treatment of immune, cardiovascular disorders (e.g. atherosclerosis, arteriosclerosis, angina, abnormal heart rhythms and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension), for the prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischemic attack, peripheral vascular disease, systemic inflammation of the vasculature, septic shock, stroke, apoplexy of the brain, ischemic stroke, cerebral ischemia, thrombosis of cerebral vessels, cerebral embolism, cerebral hemorrhage (bleeding in the brain, metabolic disorders (e.g., state showing reduced metabolic activity or a decrease of energy expenditure at rest in percent of total mass, except for fat mass, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperor is Camii, impaired glucose tolerance, impaired fasting glucose, insulin resistance, syndrome of insulin resistance, metabolic syndrome, syndrome X, syndrome obesity-hypoventilation (syndrome piquia), diabetes type I, diabetes type II, low levels of HDL (high density lipoprotein)-cholesterol and/or high levels of LDL (low density lipoprotein)-cholesterol, low levels of adiponectin), reproductive and endocrine disorders (e.g., treatment of hypogonadism in men, treatment of infertility or as a contraceptive, treatment of menstrual disorders/emmeniopathy, polycystic ovarian disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), subjects with deficiency of GH (growth hormone), hirsutism in women, normal variant short stature) and diseases associated with respiratory (e.g. asthma and chronic obstructive pulmonary disease) and gastrointestinal systems (e.g., dysfunction of the motility of the gastrointestinal tract or intestinal propulsive, diarrhea, vomiting, nausea, gallbladder disease, gallstones, caused by obesity, gastro-esophageal reflux, ulcers).

The compounds are also potentially useful as agents in the treatment of dermatological disorders, cancers (e.g., tol is the intestine, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, bile duct), craniopharyngioma, Prader-Willi syndrome, Turner syndrome, syndrome Frolikha (Frohlich), glaucoma, infectious diseases, disorders of the urinary tract and inflammatory disorders (e.g., deforming arthritis, inflammation, inflammatory complications of viral encephalitis, osteoarthritis and orthopedic disorders. The compounds are also potentially useful as agents in the treatment of achalasia (esophagus).

In another aspect of the present invention previously proposed a specific compound of formula I for use as a medicine.

In another aspect of the present invention proposed the use of the compounds of formula I in the preparation of drugs for treatment or prevention of obesity or excess weight (for example, activation of losing weight and maintaining weight loss), prevention of the body mass increase (for example, drug-induced or due to cessation of Smoking), modulation of appetite and/or satiety, eating disorders (e.g. binge eating, anorexia, bulimia and compulsion), addictions (drugs, tobacco, alcohol, any geeky appetite nutrient macronutrients and the and minor components of food), for the treatment of psychiatric disorders such as psychotic disorders and/or mood disorders, schizophrenia and schizoaffective disorder, bipolar disorder, anxiety, axiomatisable disorders, depression, mania, obsessive-compulsive disorder, disorders of impulse control (e.g., the syndrome of Gilles de La Tourette), disorders of attention, such as ADD/ADHD, stress, and neurological disorders such as dementia and cognitive dysfunction and/or dysfunction of memory (e.g., amnesia, Alzheimer's disease, dementia Peak, senile dementia, vascular dementia, mild cognitive disturbance, age-related cognitive deviation and mild senile dementia), neurological and/or neurodegenerative disorders (e.g., multiple sclerosis, Raynaud's syndrome, Parkinson's disease, Horai Huntington's and Alzheimer's disease), disorders associated with demyelination, neuropeptidergic disorders (e.g., Guillain-Barre syndrome).

In another aspect of the present invention proposed the use of the compounds of formula I in the preparation of drugs for treatment or prevention of disorders and behaviors that detect the propensity for dependence and consumption (e.g., abuse of alcohol and/or drug craving for gambling and the RAM, kleptomania), disorders caused by the cancellation of drugs (e.g. alcohol abstinence violation or no violation of perception; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without violation violations of perception; sedative, hypnotic or anxiolytic withdrawal delirium, and withdrawal symptoms caused by other substances), mood disorders, anxiety disorders and/or sleep disorders with seizures during withdrawal caused by alcohol and/or drug and relapse caused by alcohol and/or drug.

In another aspect of the present invention proposed the use of the compounds of formula I in the preparation of drugs for treatment or prevention of neurological disorders, such as dystonia, dyskinesia, akathisia, tremor and spasticity, treatment of spinal cord injuries, neuropathies, migraine, disorders of wakefulness, sleep disorders (e.g., disturbed sleep patterns, sleep apnea, obstructive sleep apnea syndrome sleep apnea), pain disorders, cranial trauma.

In another aspect of the present invention proposed the use of the compounds of formula I, the preparation of drugs for treatment or prevention of immune, cardiovascular disorders (e.g. atherosclerosis, arteriosclerosis, angina, abnormal heart rhythms and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension), for the prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischemic attack, peripheral vascular disease, systemic inflammation of the vasculature, septic shock, stroke, apoplexy of the brain, ischemic stroke, cerebral ischemia, thrombosis of cerebral vessels, cerebral embolism, cerebral hemorrhage (bleeding in the brain, metabolic disorders (e.g., conditions showing reduced metabolic activity or a decrease of energy expenditure at rest in percent of total mass, except for fat mass, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperuricemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, syndrome of insulin resistance, metabolic syndrome, syndrome X, syndrome obesity-hypoventilation (syndrome piquia), diabetes type I, diabetes type II, low levels of HDL-cholesterol and/or high levels of LDL-cholesterol, low levels of adiponectin), reproductive and endocr is the R disorders (e.g., treatment of hypogonadism in men, treatment of infertility or as a contraceptive, treatment of menstrual disorders/emmeniopathy, polycystic ovarian disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), subjects with GH deficiency, hirsutism in women, normal variant short stature) and diseases associated with respiratory (e.g. asthma and chronic obstructive pulmonary disease) and gastrointestinal systems (e.g., dysfunction of the motility of the gastrointestinal tract or intestinal propulsive, diarrhea, vomiting, nausea, gallbladder disease, gallstones, caused by obesity gastro-esophageal reflux, ulcers).

In another aspect of the present invention proposed the use of the compounds of formula I in the preparation of drugs for treatment or prevention of dermatological disorders, cancers (e.g. colon, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, bile duct), craniopharyngioma, Prader-Willi syndrome, Turner syndrome, syndrome Frolikha, glaucoma, infectious diseases, disorders of the urinary tract and inflammatory disorders (e.g., deforming arthritis, inflammation, inflammatory complications of viral encephalitis, osteoarthritis) ortopedicheskikh disorders.

In another aspect of the present invention, a method involving the introduction of a pharmacologically effective amount of the compounds of formula I to a patient in need of this, for the prevention or treatment of obesity or excess weight (for example, activation of losing weight and maintaining weight loss), prevention of the body mass increase (for example, drug-induced or due to cessation of Smoking), modulation of appetite and/or satiety, eating disorders (e.g. binge eating, anorexia, bulimia and compulsion), addictions (drugs, tobacco, alcohol, any geeky appetite nutritional the macronutrients or non-essential food components), for the treatment of psychiatric disorders such as psychotic disorders and/or mood disorders, schizophrenia and schizoaffective disorder, bipolar disorder, anxiety, axiomatisable disorders, depression, mania, obsessive-compulsive disorder, disorders of impulse control (e.g., the syndrome of Gilles de La Tourette), disorders of attention, such as ADD/ADHD, stress, and neurological disorders such as dementia and cognitive dysfunction and/or dysfunction of memory (e.g., amnesia, Alzheimer's disease, dementia Peak, senile demen the Oia, vascular dementia, mild cognitive disturbance, age-related cognitive bias and mild senile dementia), neurological and/or neurodegenerative disorders (e.g., multiple sclerosis, Raynaud's syndrome, Parkinson's disease, Horai Huntington's and Alzheimer's disease), disorders associated with demyelination, neuropeptidergic disorders (e.g., Guillain-Barre syndrome).

In another aspect of the present invention, a method involving the introduction of a pharmacologically effective amount of the compounds of formula I to a patient in need of this, for the prevention or treatment of disorders and behaviors that detect the propensity for dependence and consumption (e.g., abuse of alcohol and/or drug craving for gambling, kleptomania), disorders caused by the cancellation of drugs (e.g. alcohol abstinence violation or no violation of perception; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with the violation or without impairing readability; sedative, hypnotic or anxiolytic withdrawal delirium, and withdrawal symptoms caused by others in the company), mood disorders, anxiety disorders and/or sleep disorders with seizures during withdrawal caused by alcohol and/or drug and relapse caused by alcohol and/or drug.

In another aspect of the present invention, a method involving the introduction of a pharmacologically effective amount of the compounds of formula I to a patient in need of this, for the prevention or treatment of neurological disorders, such as dystonia, dyskinesia, akathisia, tremor and spasticity, treatment of spinal cord injuries, neuropathies, migraine, disorders of wakefulness, sleep disorders (e.g., disturbed sleep patterns, sleep apnea, obstructive sleep apnea syndrome sleep apnea), pain disorders, cranial trauma.

In another aspect of the present invention, a method involving the introduction of a pharmacologically effective amount of the compounds of formula I to a patient in need of this, for the prevention or treatment of immune, cardiovascular disorders (e.g. atherosclerosis, arteriosclerosis, angina, abnormal heart rhythms and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension), for the prevention and treatment of left ventricular hypertrophy, myocardial infarction, preho the of the present ischemic attack, peripheral vascular disease, systemic inflammation of the vasculature, septic shock, stroke, apoplexy of the brain, ischemic stroke, cerebral ischemia, thrombosis of cerebral vessels, cerebral embolism, cerebral hemorrhage (bleeding in the brain, metabolic disorders (e.g., conditions showing reduced metabolic activity or a decrease of energy expenditure at rest in percent of total mass, except for fat mass, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperuricemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, syndrome of insulin resistance, metabolic syndrome, syndrome X, syndrome obesity-hypoventilation (syndrome piquia), diabetes type I, diabetes type II, low levels of HDL-cholesterol and/or high levels of LDL-cholesterol, low levels of adiponectin), reproductive and endocrine disorders (e.g., treatment of hypogonadism in men, treatment of infertility or as a contraceptive, treatment of menstrual disorders/emmeniopathy, polycystic ovarian disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), subjects with GH deficiency, hirsutism in women, "normal" option is microsomia) and diseases, associated with respiratory (e.g. asthma and chronic obstructive pulmonary disease) and gastrointestinal systems (e.g., dysfunction of the motility of the gastrointestinal tract or intestinal propulsive, diarrhea, vomiting, nausea, gallbladder disease, gallstones, caused by obesity, gastro-esophageal reflux, ulcers).

In another aspect of the present invention, a method involving the introduction of a pharmacologically effective amount of the compounds of formula I to a patient in need of this, for the prevention or treatment of dermatological disorders, cancers (e.g. colon, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, bile duct), craniopharyngioma, Prader-Willi syndrome, Turner syndrome, syndrome Frolikha, glaucoma, infectious diseases, disorders of the urinary tract and inflammatory disorders (e.g., deforming arthritis, inflammation, inflammatory complications of viral encephalitis, osteoarthritis) and orthopedic disorders.

Compounds of the present invention are particularly suitable for the treatment of obesity or excess weight (for example, activation of losing weight and maintaining weight loss), prevention or elimination of the body mass increase (for example the EP, "ricocheting" (rebound), drug-induced or due to cessation of Smoking), modulation of appetite and/or satiety, eating disorders (e.g. binge eating, anorexia, bulimia and compulsion), addictions (drugs, tobacco, alcohol, any geeky appetite nutrient macronutrients or non-essential food components).

The compounds of formula (I) are useful for the treatment of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorder, anxiety, axiomatisable disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorder, anorexia, bulimia, disorders of attention, such as ADHD, epilepsy, and related conditions, and neurological disorders such as dementia, neurological disorders (e.g. multiple sclerosis), Raynaud's syndrome, Parkinson's disease, Horai Huntington's and Alzheimer's disease. The compounds are also potentially useful for the treatment of immune, cardiovascular, reproductive and endocrine disorders, septic shock and related diseases of the respiratory and gastrointestinal systems (e.g. diarrhoea). Also the compounds are potentially useful as agents in the treatment of rasprostranennyh symptoms of abuse, previsani and/or relapses, for example in the treatment of drug addiction (nicotine, ethanol, cocaine, opiates, and so forth) and/or in the treatment of narcotic withdrawal symptoms (caused by the consumption of nicotine, ethanol, cocaine, opiates, and so on). The connection can also eliminate the weight gain that often accompanies stopping Smoking.

In another aspect of the present invention previously proposed a specific compound of formula I for use as a medicine.

In another aspect of the present invention proposed the use of the compounds of formula I in the preparation of drugs for treatment or prevention of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorder, anxiety, axiomatisable disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorder, anorexia, bulimia, disorders of attention, such as ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders (e.g. multiple sclerosis), Parkinson's disease, Horai Huntington's and Alzheimer's disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases associated with the respiratory and gastro-Kish who offered systems (for example, diarrhea), and common symptoms of abuse, previsani and/or relapses, for example for the treatment of drug addiction (nicotine, ethanol, cocaine, opiates, and so forth) and/or for the treatment of narcotic withdrawal symptoms (caused by the consumption of nicotine, ethanol, cocaine, opiates, and so on).

In another aspect of the present invention, a method for treatment of obesity, psychiatric disorders such as psychotic disorders such as schizophrenia and bipolar disorder, anxiety, axiomatisable disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorder, anorexia, bulimia, disorders of attention, such as ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders (e.g. multiple sclerosis), Parkinson's disease, Horai Huntington's and Alzheimer's disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases associated with respiratory and gastrointestinal systems (e.g. diarrhoea), and common symptoms of abuse, previsani and/or relapses, such as treatment for drug addiction (nicotine, ethanol, cocaine, opiates, and so forth) and/or treatment for drug abstine is the shaft of symptoms (caused by the consumption of nicotine, ethanol, cocaine, opiates, and so on), including the introduction of a pharmacologically effective amount of the compounds of formula I to a patient in need of it.

Compounds of the present invention are particularly suitable for the treatment of obesity, for example, by reducing appetite and body weight, maintain a reduced weight and "ricochet" (rebound) prevent.

Compounds of the present invention can also be used to prevent or eliminate the addition of body weight induced by medication, such as the body mass increase caused by the treatment of antipsychotic (neuroleptic) drugs. Compounds of the present invention can also be used to prevent or eliminate the body mass increase associated with Smoking cessation.

Combination therapy

Compounds according to the invention can be combined with another therapeutic agent that is useful in the treatment of obesity, for example with other drugs against obesity, which affect energy consumption, glycolysis, gluconeogenesis, glucogenolysis, lipolysis, lipogenesis, absorption of fats, fat storage, fat excretion, the mechanisms of hunger and/or satiety, and/or preferences, appetite/motivation, food intake, or the motility of the gastro-intestinal (G-I) tract.

Connection image is meniu can optionally be combined with another therapeutic agent, which is useful in the treatment of disorders associated with obesity such as hypertension, hyperlipidemia, dyslipidemia, diabetes, sleep apnea, asthma, heart disorders, atherosclerosis, diseases of the macro - and microvessels, steatosis of the liver, cancer, joint injury, and disorders of the gall bladder. For example, the compound of the present invention can be used in combination with another therapeutic agent that lowers blood pressure or reduces the ratio of LDL:HDL, or agent that causes a decrease in levels of circulating LDL-cholesterol. For patients with diabetes compounds according to the invention can also be combined with therapeutic agents used in the treatment of complications associated with microangiopathy.

Compounds according to the invention can be used in parallel with other therapies for the treatment of obesity and related complications, metabolic syndrome and type 2 diabetes, these include biguanide drugs, insulin (synthetic insulin analogues and oral antihyperglycemics funds (these funds are divided into prandialno regulators of glucose and alpha-glucosidase inhibitors).

In another aspect of the invention the compound of formula 1 or its pharmaceutically acceptable salt can be introduced together with PPAR (receptor-activated por what liferation peroxisome)-modulating agent. PPAR-modulating agents include PPAR-alpha and/or PPAR-gamma agonist, or pharmaceutically acceptable salt, solvate, solvate of such a salt or prodrug, but are not limited to them. Suitable PPAR-alpha and/or PPAR-gamma agonists, pharmaceutically acceptable salt, solvate, solvate of such salts or prodrugs are well known in this field.

In addition, the combination according to the invention can be used in combination with sulfonylurea. The present invention also includes the compound of the present invention in combination with an agent in order to decrease the level of cholesterol. Agents, cholesterol-lowering, of relevance to this application include inhibitors of HMG-CoA-reductase (3-hydroxy-3-methylglutaryl-And coenzyme a reductase), but are not limited to them. A suitable inhibitor of HMG-CoA reductase inhibitor is a statin.

In this application, the term "agent that lowers cholesterol level also includes chemical modification of inhibitors of HMG-CoA-reductase, such as esters, prodrugs and metabolites, whether active or inactive.

The present invention also includes the compound of the present invention in combination with an inhibitor of the transport system ileal bile acids (IBAT-inhibitor). The present invention also includes the compound of the present invention in combination with a resin, svyazivalsa the bile acids.

The present invention also includes the compound of the present invention in combination with a compound that binds bile acids, such as holestipol, or cholestyramine, or cholestagel.

According to another additional aspect of the present invention proposed a combination treatment, including the introduction of an effective amount of the compounds of formula I or its pharmaceutically acceptable salt, possibly together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate introduction of one or more of the following agents selected from:

inhibitor SETR (protein-carrier cholesterolemic esters);

antagonist cholesterol absorption;

an inhibitor of MTP (microsomal protein vector);

a derivative of nicotinic acid, including products with slow release and combination products;

fitosterinov connection;

probucol;

anticoagulant;

omega-3 fatty acids;

other compounds against obesity, such as sibutramine, phentermine, orlistat, bupropion, ephedrine, thyroxine;

antihypertensive compounds, such as angiotensin-converting enzyme (ACE), antagonist of angiotensin II receptors, adrenergic blocker, an alpha adrenergic blocker, a beta-Adra is ergicheskoe blocker, mixed alpha/beta adrenergic blocker, an adrenergic stimulant, calcium channel blocker, an at-1 blocker, saluretic, diuretic or a vasodilator;

modulator melaninconcentrating hormone (sit);

modulator receptor NPY (neuropeptide Y);

modulator receptors orexin;

the modulator phosphoinositide-dependent protein kinase (PDK) or

modulators of nuclear receptors for example LXR (X receptor liver), FXR (farnesoid X receptor), RXR (retinoid X receptor), GR (glucocorticoid receptor), ERRα, β, PPARα, β, γ and RR;

agent for modulation of monoamine transmission, for example a selective inhibitor of serotonin reuptake (SSRI), inhibitor reuptake noradrenaline (NARI), an inhibitor of reuptake of norepinephrine and serotonin (SNRI), monoamine oxidase inhibitor (MAOI), tricyclic antidepressant (TCA), noradrenergic and specific serotonergic antidepressant (NaSSA);

antipsychotic agent, such as olanzapine and clozapine;

modulator serotonin receptors;

modulator of leptin/leptin receptor;

modulator ghrelin/ghrelin receptor;

an inhibitor of DPP-IV (dipeptidylpeptidase IV);

or their pharmaceutically acceptable salts, MES, MES such salts or prodrugs, possibly in conjunction with headlamp is asepticheski acceptable diluent or carrier, warm-blooded animal, such as man, in need of such therapeutic treatment.

According to another additional aspect of the present invention proposed a combination treatment, including the introduction of an effective amount of the compounds of formula I or its pharmaceutically acceptable salt, possibly together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate introduction of very low calorie diets (VLCD) or low calorie diets (LCD).

Therefore, according to an additional characteristic of the invention, a method for treatment of obesity and its associated complications in a warm-blooded animal, such as man, in need of such treatment, which includes the introduction of specified animal an effective amount of the compounds of formula I or its pharmaceutically acceptable salt with simultaneous, sequential or separate introduction of an effective amount of a compound of one of the other classes of compounds described in this section combinations, or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs.

Therefore, according to an additional characteristic of the invention, a method of treatment hyperlipidemics conditions in a warm-blooded animal, such as man, in need whom such treatment, which includes the introduction of specified animal an effective amount of the compounds of formula I or its pharmaceutically acceptable salt with simultaneous, sequential or separate introduction of an effective amount of a compound of one of the other classes of compounds described in this section combinations, or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs.

According to another aspect of the invention proposed pharmaceutical composition comprising a compound of formula I or its pharmaceutically acceptable salt and a compound of one of the other classes of compounds described in this section combinations, or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug, together with a pharmaceutically acceptable diluent or carrier.

According to another aspect of the present invention proposed a kit including a compound of formula I or its pharmaceutically acceptable salt and a compound of one of the other classes of compounds described in this section combinations, or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug.

According to another aspect of the present invention proposed a set including:

a) compound of formula I or its pharmaceutically acceptable salt in the PE the howling standard dosage form;

b) the connection of one of the other classes of compounds described in this section combinations, or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in the second standard form of drug and

C) container means for the maintenance of the specified first and second dosage forms.

According to another aspect of the present invention proposed a set including:

a) compound of formula I or its pharmaceutically acceptable salt together with a pharmaceutically acceptable diluent or carrier in the first standard dosage form;

b) the connection of one of the other classes of compounds described in this section combinations, or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in the second standard form of drug and

C) container means for the maintenance of the specified first and second dosage forms.

According to another characteristic of the invention it is proposed to use the compounds of formula I or its pharmaceutically acceptable salt and one of the other compounds described in this section combinations, or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in the manufacture of medicaments for use in the treatment of obesity and its associated complications in those who lokalnego animal, such as people.

According to another characteristic of the invention it is proposed to use the compounds of formula I or its pharmaceutically acceptable salt and one of the other compounds described in this section combinations, or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs, in the manufacture of medicaments for use in the treatment of hyperlipidemics conditions in a warm-blooded animal such as man.

According to another aspect of the present invention proposed a combination treatment, including the introduction of an effective amount of the compounds of formula I or its pharmaceutically acceptable salt, possibly together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate introduction of an effective amount of one of the other compounds described in this section combinations, or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs, possibly together with a pharmaceutically acceptable diluent or carrier, to a warm-blooded animal, such as man, in need of such therapeutic treatment.

In addition, the connection according to the invention can also be combined with therapeutic agents that are useful in treating disorders or conditions, tie is the R with obesity (such as diabetes type II, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, non-alcoholic steatohepatitis, osteoarthritis and some cancers, and psychiatric and neurological conditions.

It should be understood that in medicine there are accepted definitions of obesity and existing excess weight. The patient may be identified, for example, by measuring the body mass index (VM), which is calculated by dividing weight in kilograms by height in metres squared, and comparing the result with the definitions.

The pharmacological activity

Compounds of the present invention are active against receptor gene product SW. The affinity of the compounds according to the invention to the Central cannabinoid receptors proved by the methods described by Devane et al, Molecular Pharmacology, 1988, 34, 605, or by methods described in WO 01/70700 or EP 656354. An alternative analysis can be performed as follows.

10 μg of membranes prepared from cells stably transfected with the gene SW, suspended in 200 μl of 100 mm NaCl, 5 mm MgCl2, 1 mm EDTA, 50 mm HEPES (pH 7.4), 1 mm DTT (dithiothreitol), 0.1% of BSA (bovine serum albumin) and 100 µm GDP. To this was added agonist (SR) in AS concentration of test compound at the desired concentration and 0.1 µci [35S]-GTPγS. Reaction p is solely to proceed for 45 minutes at 30°C. Then the samples were transferred to a GF/B filters, using a harvester cells, and washed with buffer for washing (50 mm Tris (pH 7.4), 5 mm MgCl2, 50 mm NaCl). Then the filters were covered with a scintillator and counted the number of [35S]-GTPγS, remaining on the filter.

The activity measured in the absence of ligands (minimal activity) or in the presence of SR in AS concentration (maximum activity). These activities taken for 0% and 100%activity, respectively. Different concentrations of the new ligand calculate the activity as a percentage of maximal activity and build schedule. The data is correlated with the equation y=A+((B-A)/1+((C/x)D)) and determine the value of the IC50 as the concentration required to produce half maximal inhibition GTPγS binding in used conditions.

Compounds of the present invention are active against SV receptor (IC50 less than 1 micromoles). The most preferred compounds have an IC50 less than 200 nanomoles. For example, the IC50 of Example 10 is 6.0 nm, and Example 11 of 6.4 nm.

Consider that the compounds according to the invention are selective SV antagonists or inverse agonists. Effectiveness profile of selectivity and susceptibility to side-effects may limit the clinical usefulness of known up to the present time connections, to the which attribute properties SW antagonist/inverse agonist. In this respect, pre-clinical evaluation of compounds of the present invention by simulating gastrointestinal and/or cardiovascular function shows that they provide significant benefits compared to typical control agents SV antagonists/inverse agonists.

Compounds of the present invention can provide additional advantages in terms of performance indicators, profile, selectivity, bioavailability, half-life in plasma, hematoencephalic permeability, binding plasma proteins (for example, a higher free fraction of drugs) or solubility compared to typical control agents SV-antagonists/inverse agonists.

The usefulness of the compounds of the present invention in the treatment of obesity and related conditions shown by reduction of body weight in mice with obesity induced characteristic of cafeteria food. Female mice of C57B1/6J received free access to high-calorie foods, typical for cafeterias (soft confectionery products chocolate/cocoa, chocolate, fatty cheese and nougat), and standard laboratory diet for 8-10 weeks. Then compound that was required to test systemically (intravenously, administered intraperitoneally, subcutaneously or orally) was administered once a day for the Deposit of at least 5 days and daily monitored the body weight of mice. At the beginning and at the end of the study by DEXA imaging (dual energy x-ray absorptiometry) performed simultaneous assessment of obesity. Also took blood samples for analysis of changes of plasma markers associated with obesity.

Examples

Reduction

Asónacetic acid
DHMdichloromethane
DMFdimethylformamide
Dejadiethylamin
DIAN,N-diisopropylethylamine
DMAP4-dimethylaminopyridine
tOthe ethyl acetate
Et3Nthe triethylamine
Prili ETC.Example
LiHMDShexamethyldisilazide lithium
Meonmethanol
MeCNacetonitrile
kg or CT room temperature
The teathe triethylamine
THFtetrahydrofuran
ttriplet
sthe singlet
ddoublet
qQuartet
qvintquintet
mmultiplet
LGextended
bsbroadened singlet
dmdoublet multiplet
btbroadened triplet
ddthe doublet of doublet

General experimental procedures

Mass spectra were recorded or Micromass ZQ odnokadrovaya, or on a Micromass LCZ odnokadrovaya mass spectrometer, both of which are equipped with a device for the pneumatic elektrorazpredelenie (LC-MS).1H NMR measurements were performed or on a Varian Mercury 300 or Varian Inova 500, operating at1H often the Ah 300 and 500 MHz, respectively. Chemical shifts are given in ppm with CDCl3as an internal standard. Unless otherwise specified, as the solvent for NMR was used CDCl3. Purification was performed prepreparation HPLC (high performance liquid chromatography) with header fractions, which is driven by the signal of the mass spectrometer, odnokletochnogo mass spectrometer Shimadzu QP 8000, with C8 column 19×100 mm, Unless nothing more, as the mobile phase used acetonitrile and buffer (0,1M ammonium acetate:acetonitrile 95:5).

For separation of the isomers used column Kromasil CN E (250×20 mm i.d. (inner diameter)). As mobile phase (1 ml/min) was used heptane:ethyl acetate:deja 95:5:0.1 to. Fractions were collected using a UV-detector (330 nm).

Typical HPLC-parameters for analysis of purity:

HPLC system Agilent 1100

Column: Bond Eclipse XDB-C8, 150×4.6 mm

Analysis time: 15 minutes

Flow rate: 1.5 ml/min

Mobile phase: a: water, 5% Meon

B: Meon

Temperature: 40°C

Detector: UV 240 nm

Examples according to the invention

Example 1

Stage A. 1-(4-Benzyloxyphenyl)propane-1-he

4-Hydroxypropiophenone (15.0 g, 0.10 mol) was dissolved in acetone (200 ml) with potassium carbonate (13.8 g, 0.10 mol). Added benzylbromide (17.1 g, 0.10 mol) and the reaction mixture was heated at a temperature delegal the AI during the night. After cooling to room temperature the mixture was filtered and concentrated on a rotary evaporator to obtain 24,0 g (100%) specified the title compound as a white solid.

Stage B. 1-(4-Benzyloxyphenyl)-2-bromopropane-1-he

1-(4-Benzyloxyphenyl)propane-1-he (4,80 g, 20.0 mmol) suspended in acetic acid (25 ml) and cooled to 0°C. was added dropwise bromine (3,20 g, 20.0 mmol) and the reaction mixture was stirred for two hours at room temperature, while the reaction mixture was a yellow transparent solution. After cooling, was added water (100 ml) and product was extracted with ether (2×100 ml). The combined organic extracts were washed with water, sodium bicarbonate and brine. The organic phase was dried (Na2SO4), filtered and evaporated, getting mentioned in the title compound as a pale yellow solid (6,17 g, 97%).

Stage C. Ethyl ester 2-[2-(4-benzyloxyphenyl)-2-oxoethyl]-3-oxomalonate acid

The solution ethylate sodium was obtained from metallic sodium (0,53 g, 23,0 mmol) in 30 ml of absolute ethanol. To this solution was added ethylacetoacetate (3.00 g, 23,0 mmol) at 0°C. After 30 minutes this solution was added to a solution of 1-(4-benzyloxyphenyl)-2-bromopropane-1-it (6,17 g, 19.0 mmol) in a mixture of ethanol:toluene (30:15 ml) and the reaction mixture was stirred for overnight is. In the acid treatment of 1M HCl, extraction with ethyl acetate (3x), washing with brine, drying (Na2SO4), filtration and evaporation remained the crude product, which was purified flash chromatography (hexane:tO 95:5 to 70:30) to obtain the 5,18 g specified in the title compounds as a pale yellow oil.

The stage, 5-(4-Benzyloxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid

The solution ethylate sodium was obtained from metallic sodium (0,19 g, compared to 8.26 mmol) in 20 ml of absolute ethanol. To this solution was added ethyl ester 2-[2-(4-benzyloxyphenyl)-2-oxo-ethyl]-3-oxo-butyric acid (2,13 g, 6,00 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. Keeping the temperature below 5°C, five portions was added a previously prepared solution of chloride 2,4-dichloraniline (obtained from 2,4-dichloraniline (1.19 g, 7,30 mmol) in 3 ml of 24% HCl and sodium nitrite (0.52 g, 7,50 mmol) in 3 ml of water at 0°C). After stirring for 2.5 hours at room temperature was added water and the product was extracted with tO (3). The combined organic extracts were dried (Na2SO4), filtered and evaporated. The residue was dissolved in ethanol (40 ml) was added sodium hydroxide (to 0.80 g, 20.0 mmol) in 10 ml of water. After boiling for 2 hours at the temperature of reflux distilled reaction mixture Oh what was Adali, was acidified with HCl and the product was extracted with tO (3). After washing, drying (Na2SO4), filtration and concentration the residue was purified flash chromatography (hexane:tO 70:30 to 50:50) to give 1.84 g (68%) indicated in the title compounds as a pale yellow solid.

Stage D. piperidine-1-alamid 5-(4-benzyloxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid

5-(4-Benzyloxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1.84 g, 4.07 mmol) suspended in dichloromethane and added a few drops of DMF followed by the addition of oxalicacid (1,03 g, 8,14 mmol). The reaction mixture was heated at the temperature of reflux distilled for two hours. After cooling to room temperature the solvent was removed and the crude acid chloride was again dissolved in dichloromethane and cooled to 0°C. was Added triethylamine (1,15 ml, 8.20 mmol), then 1-aminopiperidine (0.5 ml, 4,50 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature for 2 hours. Added water and the product was extracted with dichloromethane (3x). The combined extracts were dried (Na2SO4), filtered and evaporated. Using flash chromatography (hexane:tO 80:20 to 70:30) was obtained 1.13 g (52%) indicated in the title compound in the form of a solid substance.

Stage E. piperidine-1-alamid 1-(2,4-di is lorgeril)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid

Piperidine-1-alamid 5-(4-benzyloxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1,00 g of 1.87 mmol) was dissolved in 25 ml of absolute ethanol with 100 mg of palladium on charcoal (10% Pd). The reaction mixture was first made using the cylinder during the night. In the filtration, concentration and flash chromatography (hexane:tO 50:50 - tO) received 0,83 g (100%) specified in the connection header in the form of solids.

Stage g 4-[2-(2,4-Dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]-phenyl ester of propane-1-sulfonic acid

Piperidine-1-alamid 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (222 mg, 0.50 mmol) was dissolved in dichloromethane (10 ml) was added triethylamine (of 0.07 ml, 0.50 mmol). Added propanesulfonate (71 mg, 0.50 mmol) at 0°C, the cooling bath was removed and the reaction mixture was stirred at room temperature for 2 hours. Added water and the product was extracted with dichloromethane, dried (Na2SO4), filtered and concentrated. Using flash chromatography (hexane:tO 70:30 to 50:50) received the product, which was recrystallized from a mixture of hexane:tO to obtain 135 mg (49%) indicated in the title compounds as white solids, TPL 190°C.

1H NMR (CDCl3): δ 7.66 (1H, broadened s), 7.44-7.17 (7H, m), 3.25 (2H, t), 2.90 4H, m), 2.39 (3H, s), 2.09-1.97 (2H, m), 1.78 (4H, m), 1.45 (2H, m), 1.17 (3H, t).

MS m/z 573 (M+Na).

Example 2

Piperidine-1-alamid 1-(2,4-dichlorophenyl)-4-methyl-5-[4-(4,4,4-triptoreline)-phenyl]-1H-pyrazole-3-carboxylic acid

Piperidine-1-alamid 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid from Example 1, step E (250 mg, 0,56 mmol), was dissolved in acetone (10 ml) was added potassium carbonate (77 mg, 0,56 mmol)and then 1-iodine-4,4,4-triptorelin (140 mg, 0,56 mmol). The reaction mixture was heated at the temperature of reflux distilled over night, concentrated and purified flash chromatography (hexane:tO 70:30 and 60:40) to give 130 mg (42%) of white solid, which was triturated with a mixture of hexane:tO (95:5) and was filtered.

1H NMR (CDCl3): δ 7.63 (1H, broadened s), 7.43 (1H, m), 7.30 (2H, m), 7.10-7.00 (2H, m), 6.85-6.78 (2H, m), 4.05 (2H, t), 2.90 (4H, m), 2.40-2.19 (5H, s and m), 2.15-1.97 (2H, m). 1.78 (4H, m), 1.45 (2H, m).

MS m/z 577 (M+Na). HPLC: 98.4%.

Example 3

4-[2-(2,4-Dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]-phenyl ether of butane-1-sulfonic acid

Piperidine-1-alamid 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1 H-pyrazole-3-carboxylic acid, obtained as in Example 1, step E (350 mg, 0.78 mmol), was dissolved in dichloromethane (10 ml) was added triethylamine (of 0.11 ml, 0.78 mmol). Added butanesulfonate (0.12 g, 0.78 mmol) at 0°C, the cooling bath was removed and the reaction mixture peremeshivaniya room temperature over night. Added water, the product was extracted with dichloromethane, dried (Na2SO4), filtered and concentrated. Using flash chromatography (hexane:tO 70:30 to 50:50) received the product, which was recrystallized from a mixture of hexane:tO to obtain 200 mg (45%) indicated in the title compound in the form of a solid substance.

1H NMR (CDCl3): δ 7.48-7.19 (8H, m), 3.29 (2H, m), 2.96 (4H, t), 2.41 (3H, s), 2.09-1.97 (2H, m), 1.81 (4H, m), 1.64-1.50 (4H, m), 1.02 (3H, t).

Example 4

4-[2-(2,4-Dichlorophenyl)-4-methyl-5-(morpholine-4-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ester of propane-1-sulfonic acid

Stage A. Morpholine-4-alamid 5-(4-benzyloxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid

To a solution of 5-(4-benzyloxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid, obtained as in Example 1, step G (1.18 g, 2.6 mmol)in 25 ml of CH2CL2added 2 drops of DMF, and then oxalicacid (of 0.44 ml, 5.2 mmol). The mixture was heated at the temperature of reflux distilled for 2 hours, cooled to room temperature and was evaporated until dry. The residue was dissolved in 25 ml of CH2Cl2and cooled to 0°C. was Added triethylamine (to 0.73 ml, 5.2 mmol)and then 1-aminopiperidine (of 0.28 ml, 2.9 mmol) and the mixture was stirred at room temperature for 3 hours. Was added water (100 ml) and the mixture was extracted with CH2Cl2(3×50 ml), dried (Na2SO ), filtered and concentrated. Using flash chromatography (silica, hexane:tO 1:2, tO) received 215 mg (15%) indicated in the title compound as a white solid.

Stage B. Morpholine-4-alamid 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid

Morpholine-4-alamid 5-(4-benzyloxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (215 mg, 0.40 mmol) was dissolved in 20 ml of CH2CL2and cooled to 0°C. was added dropwise tribromide boron (78 μl, 0.80 mmol) and the reaction mixture was stirred at room temperature for 2.5 hours. Was added water (50 ml) and the solution was extracted with tO (3×50 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated. Using flash chromatography (silica, hexane:tO 1:2, tO) received 180 mg (99%) indicated in the title compound as a white solid.

Stage C. 4-[2-(2,4-Dichlorophenyl)-4-methyl-5-(morpholine-4-ylcarbonyl)-2H-pyrazole-3-yl]-phenyl ester of propane-1-sulfonic acid

A solution of morpholine-4-ylamide 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (180 mg, 0.40 mmol) in 10 ml of CH2Cl2was cooled to 0°C. was Added triethylamine (56 μl, 0.40 mmol)and then 1-propanesulfonate (45 μl, 0.40 mmol) and the reaction mixture was stirred at room is the temperature for 5 hours. Added water and the mixture was extracted with CH2CL2(3×20 ml), dried (Na2SO4), filtered and concentrated. Using flash chromatography (silica, hexane:tO 1:2) was obtained 82 mg (46%) indicated in the title compound as a white solid.

1H NMR (CDCl3): δ 7.7 (1H, s), 7.5-7.4 (1H, m), 7.4-7.1 (6N, m), 3.9-3.8 (4H, m), 3.3-3.2 (2H, m), 3.0-2.9 (4H, m), 2.4 (3H, s), 2.1-1.9 (2H, m), 1.2 (3H, t).

MC m/z 576 (M+Na). HPLC: 98,0%.

Example 5

4-[2-(2,4-Dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ester of 3,3,3-cryptochrome-1-sulfonic acid

Stage A. piperidine-1-alamid 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid

Piperidine-1-alamid 5-(4-benzyloxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid, obtained as in Example 1, step D (330 mg, of 0.62 mmol), was dissolved in 20 ml of CH2Cl2and cooled to 0°C. was added dropwise tribromide boron (120 μl, of 1.24 mmol) and the reaction mixture was stirred at room temperature for 1 hour. Was added water (50 ml) and the solution was extracted with tO (3×20 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated. Using flash chromatography (silica, hexane:tO 1:3, tO) was obtained 130 mg (47%) indicated in the title compound as a white solid.

Stage B. 4-[2-(2,4-Dichlor the Nile)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ester of 3,3,3-cryptochrome-1-sulfonic acid

A solution of piperidine-1-ylamide 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (130 mg, 0.30 mmol) in 10 ml of CH2Cl2was cooled to 0°C. was Added triethylamine (42 μl, 0.30 mmol), and then 3,3,3-cryptochrome-1-sulphonylchloride (59 mg, 0.30 mmol)was purchased from Manchester Organics (but can also be obtained in a manner analogous to the method described in WO 200010968 for 4,4,4-triptorelin-1-sulphonylchloride), and the reaction mixture was stirred at room temperature for 2 hours. Added water and the mixture was extracted with CH2Cl2(3×20 ml), dried (Na2SO4), filtered and concentrated. Using flash chromatography (silica, hexane:tO 7:3, 6:4) was obtained 150 mg (82%) indicated in the title compounds as white solids, TPL°C.

1H NMR (CDCl3): δ 7.7 (1H, broadened s), 7.5-7.2 (7H, m), 3.6-3.5 (2H, m), 3.0-2.7 (6H, m), 2.4 (3H, s), 1.9-1.7 (4H, m), 1.6-1.4 (2H, m).

MC m/z 628 (M+Na). HPLC: 92.5%.

Example 6

4-[2-(2,4-Dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ester 4,4,4-triptorelin-1-sulfonic acid

Piperidine-1-alamid 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid, obtained as in Example 5, step A (0,49 g, 1.20 mmol), was dissolved in dichloromethane (20 ml), cooled to 0°C was added triethylamine (of 0.67 ml, 4.8 mmol), and then 4,4,4-triptorelin-1-sulphonylchloride, is received, as described in WO 200010968 (0,38 g of 1.80 mmol). The reaction mixture was stirred at room temperature overnight. Added water and the product was extracted with dichloromethane, dried (Na2SO4), filtered and concentrated. Using flash chromatography (hexane:tO 1:1 - tO) and subsequent recrystallization (hexane:tO) was obtained 0.32 g (43%) indicated in the title compound as a colourless solid.

1H NMR (CDCl3): δ 7.80 (1H, broadened s), 7.50-7.19 (7H, m), 3.40 (2H, m), 3.05-2.90 (4H, m), 2.50-2.20 (7H, s and m), 1.92-1.70 (4H, m), 1.57-1.40 (2H, m).

MC m/z 641 (M+Na).

HPLC: 96.5%.

Example 7

[2-(2,4-Dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]-2,6-differenly ether propane-1-sulfonic acid

Stage A. 1-(4-Benzyloxy-3,5-differenl)-propane-1-he

1-(3,5-Debtor-4-hydroxyphenyl)propane-1-he (5,00 g, 26.9 mmol) was dissolved in acetone (100 ml) with potassium carbonate (3,90 g of 28.2 mmol). Added benzylbromide (4,82 g of 28.2 mmol) and the reaction mixture was heated at the temperature of reflux distilled during the night. After cooling to room temperature the mixture was filtered and concentrated on a rotary evaporator to obtain the 7.43 g (100%) specified the title compound as a white solid.

Stage B. 1-(4-Benzyloxy-3,5-differenl)-2-bromopropane-1-he

1-(4-Benzyloxy-3,5-differenl)propane-1-he (7,43 g, 26.9 mmol) suspended in kusnoy acid (35 ml). Was added dropwise bromine (4,28 g, 26.8 mmol) and the reaction mixture was stirred for two hours at room temperature, at this stage, the reaction mixture was a yellow transparent solution. After cooling, was added ice water (100 ml) and product was extracted with ether (2×100 ml). The combined organic extracts were washed with water, sodium hydrogen carbonate solution and brine. The organic phase was dried (Na2SO4), filtered and evaporated, receiving of 9.30 g (98%) indicated in the title compounds as a pale yellow oil.

Stage C. Ethyl ester of 2-acetyl-4-(4-benzyloxy-3.5-differenl)-3-methyl-4-oxomalonate acid

The solution ethylate sodium was obtained from metallic sodium (0.74 g, 32,0 mmol) in 40 ml of absolute ethanol. To this solution was added ethylacetoacetate (4,16 g of 32.0 mmol) at 0°C. After 30 minutes this solution was added to a solution of 1-(4-benzyloxy-3,5-differenl)-2-bromopropane-1-it (of 9.30 g, to 26.2 mmol) in a mixture of ethanol:toluene (40:20 ml) and the reaction mixture was stirred over night. In the acid treatment of 1M HCL, extraction with ethyl acetate (3x), washing with brine, drying (Na2SO4), filtration and evaporation remained the crude product, which was purified flash chromatography (hexane:tO 95:5 to 70:30) with the receipt of 6.95 g (66%) indicated in the title compound in the form of oil.

The stage, 5-(4-BAA is siloxy-3,5-differenl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid

The solution ethylate sodium was obtained from metallic sodium (0,53 g of 22.0 mmol) in 60 ml of absolute ethanol. To this solution was added ethyl ester of 2-acetyl-4-(4-benzyloxy-3,5-differenl)-3-methyl-4-oxomalonate acid (6,95 g, and 17.2 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. Keeping the temperature below 5°C, five portions was added a previously prepared solution of chloride 2,4-dichloraniline (obtained from 2,4-dichloraniline (3,39 g, 21,0 mmol) in 9 ml of 24% HCl and sodium nitrite 1. (48 g, 21,0 mmol) in 3 ml of water at 0°C). After stirring at 0°C for 2 hours the reaction mixture was left to warm to room temperature and mixed during the night. Added water, the product was extracted with EtOAc (3x). The combined organic extracts were dried (Na2SO4), filtered and evaporated, getting to 9.20 g of the crude complex ethyl ester in the form of oil.

The residue (9,20 g) was dissolved in ethanol (120 ml) was added sodium hydroxide (2.30 g, 57.5 mmol) in 15 ml of water. After two hours of boiling at the temperature of reflux distilled, the reaction mixture was cooled, acidified with HCl and the product was extracted with EtOAc (3x). After washing, drying (Na2SO4), filtration and concentration the residue was purified flash chromatography (hexane:tO:Asón 80:20:2 - hexane:EtOAc:AcOH 50:50:2) to obtain the 5,46 g (65%in two stages) of the criminal code is related to the title compound in the form of a solid substance.

Stage D. piperidine-1-alamid 5-(4-benzyloxy-3,5-differenl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid

5-(4-Benzyloxy-3,5-differenl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (5,46 g, and 11.2 mmol) suspended in dichloromethane (60 ml) was added a few drops of DMF followed by the addition of oxalicacid (4,70 ml and 55.8 mmol). The reaction mixture was heated at the temperature of reflux distilled for 1.5 hours. After cooling to room temperature the solvent was removed and the crude acid chloride was again dissolved in dichloromethane, cooled to 0°C was added Et3N (3,10 ml of 22.2 mmol)and then 1-aminopiperidine (1.2 ml, and 11.2 mmol). Removed the cooling bath and the reaction mixture was stirred at room temperature overnight. Added water and the product was extracted with dichloromethane (3x), the combined extracts were dried (Na2SO4), filtered and evaporated. Using flash chromatography (hexane:tO 80:20 to 70:30) received 1.86 g (30%) indicated in the title compound as a yellow solid.

Stage E. piperidine-1-alamid 5-(4-hydroxy-3,5-differenl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid

Piperidine-1-alamid 5-(4-benzyloxy-3,5-differenl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1.86 g, 3.25 mmol) was dissolved in 50 ml dichloromethane and cooled to -78°C. Madl the NGO added VVG 3(of 0.60 ml of 6.50 mmol) and the reaction mixture was stirred at 0°C for 30 minutes. Added water and the product was extracted with CH2Cl2(X3). The combined organic extracts were dried (Na2SO4), filtered and concentrated. Using flash chromatography (hexane:tO 50:50) was obtained 0.64 g (41%) indicated in the title compounds as a pale yellow solid.

Stage J. [2-(2,4-Dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]-2,6-differenly ether propane-1-sulfonic acid

Piperidine-1-alamid 5-(4-hydroxy-3,5-differenl)-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3-carboxylic acid (0.64 g, 1,32 mmol) was dissolved in dichloromethane (20 ml), cooled to 0°C was added triethylamine (of 0.18 ml of 1.32 mmol), and then propanesulfonate (0,19 g of 1.31 mmol). The reaction mixture was stirred at room temperature overnight. Added water, the product was extracted with dichloromethane, dried (Na2SO4), filtered and concentrated. Using flash chromatography (hexane:tO 70:30 to 50:50) received 410 mg (53%) indicated in the title compounds as a pale yellow solid.

1H NMR (CDCl3): δ 7.66 (1H, broadened s), 7.60-7.24 (4H, m), 6.97-6.78 (1H, m), 3.50-3.37 (2H, m), 3.02-2.80 (4H, m), 2.40 (3H, s), 2.20-2.00 (2H, m), 1.92-2.72 (4H, m), 1.60-1.40 (2H, m), 1.08 (3H, t).

MC m/z 609 (M+Na). HPLC: 97.5%.

Example 8

4-[2-(2,4-Dichlorophenyl)-5-(piperidine-1-and the carbarnoyl)-2H-pyrazole-3-yl]phenyl ester of propane-1-sulfonic acid

Stage A. Ethyl ester of 4-(4-benzyloxyphenyl)-2,4-dioxolane acid

To a solution of LiHMDS (88 ml, 1M in THF) in ether (50 ml) in a nitrogen atmosphere at -78°C for 1 hour was added to a suspension of 1-(4-benzyloxyphenyl)ethanone (20 g, to 88.4 mmol)dissolved in ether (150 ml), and THF (50 ml). The resulting mixture was stirred at -78°C for 1 hour and then was added diethyl ester of oxalic acid (14.2 g, 97,2 mmol). The resulting mixture was slowly heated to room temperature and then left overnight. The reaction mixture was diluted with pentane (90 ml) and the crude product was besieged in the form of a lithium salt. Built solid to 27.2 g) was dried under vacuum and directly used in the next stage.

Stage B. Ethyl ester 5-(4-benzyloxyphenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid

Ethyl ester of 4-(4-benzyloxyphenyl)-2,4-dioxolane acid (27,2 g, in the form of Li-salt from the previous phase) suspended in ethanol (350 ml) was added 2,4-dichloropyridazin (17.8 g, and 83.3 mmol). The reaction mixture was stirred over night at room temperature. Then under reduced pressure, the solvent was removed, the residue was dissolved in acetic acid and the resulting mixture was heated at the temperature of reflux distilled within 24 hours. The reaction mixture was diluted with ethyl acetate (1 l) and then washed with saturated Panso3(6×250 ml) and Rasso is Ohm (100 ml). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to obtain oil. The oil was purified flash chromatography (SiO2, 20% tO in heptane). The fraction containing the product was concentrated under reduced pressure, and the remaining substance is then further purified by recrystallization (ethyl acetate/heptane) to give white solids (19,6; 57% over two stages).

1H NMR (CDCl3): δ 1.42 (t, 3H), 4.45 (q, 2H), 5.03 (s, 2H), 6.88 (d, 2H), 7.01 (s, 1H), 7.11 (d, 2H), 7.3-7.45 (m, 8H).

MS:467(M+1).

Stage C. Ethyl ester 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-1H-pyrazole-3-carboxylic acid

To a solution of ethyl ester 5-(4-benzyloxyphenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid (735 mg, 1.57 mmol) and (CH3)2S (of 0.58 ml, 7,86 mmol) in dichloromethane (30 ml) under nitrogen atmosphere was added dropwise F3-diethylether (1.0 ml, 7,86 mmol). The resulting mixture was stirred over night at room temperature. Then add an additional amount (CH3)2S (of 0.58 ml, 7,86 mmol) and F3detragiache (1.0 ml, 7,86 mmol) and the resulting mixture was stirred for another 3 days. The reaction mixture was diluted with dichloromethane and 80 ml and washed with water (3×30 ml) and brine (40 ml). The organic layer was dried (gSO4), filtered and concentrated under reduced pressure to obtain white firmly what about the substance (573 mg, 96%). The crude substance was used directly.

1H NMR (CDCl3): δ 1.41 (t, 3H), 4.44 (q, 2H), 6.74 (d, 2H), 7.00 (s, 1H), 7.06 (d, 2H), 7.3-7.45 (m, 3H). MS: 375 (M-1).

Stage, Ethyl ester 1-(2,4-dichlorophenyl)-5-[4-(propane-1-sulfonyloxy)-phenyl]-1H-pyrazole-3-carboxylic acid

Ethyl ester of 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-1 H-pyrazole-3-carboxylic acid (510 mg, 1.35 mmol) suspended in dichloromethane (20 ml) under nitrogen atmosphere was added triethylamine (0.75 ml, 5.4 mmol). The resulting mixture was cooled to 0°C. and was added dropwise 1-propanesulfonate (0,30 ml, 2.7 mmol). The mixture was stirred at 0°C for 1 hour. Then the reaction mixture was diluted to 40 ml of dichloromethane, and then washed with saturated Panso3(3×20 ml) and brine (20 ml). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to obtain oil (0.64 g, 98%). The crude substance was used as such without further purification.

1H NMR (CDCl3): δ 1.12 (t, 3H), 1.43 (t, 3H), 2.01 (m, 2H), 3.23 (m, 2H), 4.46 (q, 2H), 7.07 (s, 1H), 7.19-7.46 (m, 7H).

MS: 483 (M+1).

Stage D. 4-[2-(2,4-Dichlorophenyl)-5-{piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ester of propane-1-sulfonic acid

Hydrochloride of 1-aminopiperidine (36 mg, 0.26 mmol) was dissolved in toluene (1.0 ml) in nitrogen atmosphere. At room temperature was added dropwise trimethylaluminum (2M in toluene, 0.17 ml). For the eat the resulting mixture was stirred at room temperature for 40 minutes. Then this mixture was added to a stirred suspension of ethyl ether 1-(2,4-dichlorophenyl)-5-[4-(propane-1-sulfonyloxy)-phenyl]-1H-pyrazole-3-carboxylic acid (42 mg, 0,087 mmol) in DHM (1.0 ml) and the resulting mixture was heated at 60°C over night. The reaction was suppressed by the addition of water and then the mixture was distributed between water (20 ml) and DHM (20 ml). The organic layer was washed with water (3×10 ml) and then concentrated under reduced pressure. The residue was purified by reversed-phase HPLC, C8 column, 5-100% acetonitrile in water (buffer: 0.1m ammonium acetate). The fraction containing the product was diluted with ethyl acetate and washed several times with water. The organic layer was concentrated under reduced pressure and the residue was subjected to freeze-drying to obtain a white solid (26 mg, 55%).

1H NMR (CDCl3): 1.11 (t, 3H), 1.43 (m, 2H), 1.76 (m, 4H), 2.00 (m, 2H), 2.85 (m, 4H), 3.22 (m, 2H), 7.11 (m, 1H), 7.20 (m, 4H), 7.37 (m, 2H), 7.49 (m, 1H).

MS:537(M+1).

Example 9 4-[4-Bromo-2-(2,4-dichlorophenyl)-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ester of propane-1-sulfonic acid

Stage A. Ethyl ester 4-bromo-1-(2,4-dichlorophenyl)-5-[4-(propane-1-sulfonyloxy)phenyl]-1H-pyrazole-3-carboxylic acid

Ethyl ester of 1-(2,4-dichlorophenyl)-5-[4-(propane-1-sulfonyloxy)phenyl]-1H-pyrazole-3-carboxylic acid, obtained as in Example 8, step G (597 mg, of 1.23 mmol), was dissolved in dichloromethane (15 ml), was added bromine (0.06 ml, 23 mmol) in dichloromethane (1 ml) and the resulting mixture was stirred at room temperature overnight. Added additional amount of bromine (0.06 ml, of 1.23 mmol) and the mixture was stirred for another 20 hours. The reaction mixture was diluted to 80 ml of dichloromethane and then washed with saturated Panso3(40 ml), 20%Na2S2O5(40 ml), saturated Panso3(2×40 ml) and brine (40 ml). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to obtain an orange oil (0,598, 73%). The crude substance was used without further purification.

1H NMR (CDCl3): δ 1.12 (t, 3H), 1.44 (t, 3H), 2.01 (m, 2H), 3.24 (m, 2H), 4.48 (q, 2H), 7.2-7.46 (m, 7H). MC: 561.

Stage B. 4-[4-Bromo-2-(2,4-dichlorophenyl)-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ester of propane-1-sulfonic acid

This compound was obtained in the same way as described in Example 8, step D, by reacting ethyl ester 4-bromo-1-(2,4-dichlorophenyl)-5-[4-(propane-1-sulfonyloxy)phenyl]-1H-pyrazole-3-carboxylic acid hydrochloride 1-aminopiperidine to obtain 26 mg specified in the title compounds as white solids. Yield: 25%.

1H NMR (CDCl3): 1.12 (t, 3H), 1.43 (m, 2H), 1.74 (m, 4H), 2.01 (m, 2H), 2.90 (m, 4H), 3.24 (m, 2H), 7.21-7.45 (m, 7H).

MC: 615.

Example 10

Methyl-1-{[(1-(2,4-dichlorophenyl)-4-methyl-5-{4-[(propylsulfonyl)oxy]-phenyl}-1H-pyrazole-3-yl)carbonyl]amino}cyclopentanecarboxylate

Stage A. Hydrochloride methyl-1-aminocyclopentane is oxalate

Thionyl chloride (1.5 ml) was dissolved in methanol (15 ml) and was poured into 1-aminocyclopentane acid (100 mg, 0,774 mmol). The mixture was heated at the temperature of reflux distilled for 1 hour. The solvent is evaporated to obtain the product (107 mg, 77%).

1H NMR (399.964 MHz) δ 9.00-8.60 (br, 3H), 3.79 (s, 3H), 2.23 (s, 4H), 2.14-2.00 (m, 2H), 1.90-1.76 (m, 2H).

Stage B. Methyl-1-({[5-[4-(benzyloxy)phenyl]-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]carbonyl}amino)cyclopentanecarboxylate

A solution of 5-[4-(benzyloxy)phenyl]-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid, obtained as in Example 1, step G (59 mg, 0,130 mmol)in DHM (2 ml) was mixed with a solution of oxalicacid (2 ml) in DHM (20 ml). Added one drop of DMF and the reaction continued at room temperature in the dark for 1 hour. Evaporated the solvent, was added DHM (2 ml) and the mixture of acid chloride was added to a mixture of the hydrochloride of methyl-1-aminocyclohexanecarboxylic (23 mg, 0,130 mmol) in DHM (2 ml) and K2CO3(water, 10 wt.%, 2 ml). The reaction was continued at room temperature for 3 hours. Separated phase and the organic phase is washed with water and dried over gSO4with the receipt of product (71 mg, 94%).

1H NMR (399.964 MHz) δ 7.43-7.23 (m, 9H), 7.06-7.00 (m, 2H), 6.93-6.87 (m, 2H), 5.02 (s, 2H), 3.75 (s, 3H), 2.40-2.30 (m, 2H), 2.34 (s, 3H), 2.14-2.04 (m, 2H), 1.87-1.77 (m, 4H).

MC m/z 578, 580, 582 (M+H)+.

Stage Century. Methyl-1-({[1-(2,4-dichlorophenyl)-5-(4-hydroxyben the l)-4-methyl-1H-pyrazole-3-yl]carbonyl}amino)cyclopentanecarboxylate

Athirat of boron TRIFLUORIDE (156 μl, of 1.23 mmol) was added to a mixture of methyl 1-({[5-[4-(benzyloxy)phenyl]-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]carbonyl}amino)cyclopentanecarboxylate (51 mg, 0,088 mmol) and dimethyl sulfide (90 μl, of 1.23 mmol) in DHM (2 ml). The reaction was continued at room temperature in the dark for 46 hours. Added water and DHM, are of the same phase and the organic phase is washed with water and dried over MgSO4(39 mg, 90%).

1H NMR (399.964 MHz) δ 7.60-6.60 (m, 8H), 3.72 (s, 3H), 2.43-2.23 (m, 2H), 2.26 (s, 3H), 2.15-2.00 (m, 2H), 1.85-1.75 (m, 4H).

MC m/z 488, 490, 492 (M+H)+.

Stage, Methyl-1-{[(1-(2,4-dichlorophenyl)-4-methyl-5-{4-[(propylsulfonyl)oxy]phenyl}-1H-pyrazole-3-yl)carbonyl]amino}cyclopentanecarboxylate

The tea (100 μl), and then 1-propanesulfonate (30 μl, 0,268 mmol) was added to a mixture of methyl 1-({[1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-yl]carbonyl}amino)cyclopentanecarboxylate (39 mg, 0,088 mmol) in dry DHM (1.5 ml) at -78°C. the Reaction was continued at -78°C in the atmosphere

N2(gas) for 1.5 hours. Added water and DHM and the temperature was raised to room temperature. Separated phase and the organic phase is washed with water and dried over gSO4. The product was purified preparative HPLC (column Kromasil C8, ammonium acetate (aqueous, 0,1M) : acetonitrile, the product was at approximately 88% acetonitrile) to give the product as a nearly white powder (17 mg, 35%)

1H NMR (399.964 MHz) δ 7.45-7.39 (br, 1H), 7.32-7.28 (m, 2H), 7.27-7.19 (m, 3H), 7.18-7.12 (m, 2H), 3.76 (s, 3H), 3.26-3.20 (m, 2H), 2.40-2.30 (m, 2H), 2.35 (s, 3H), 2.15-2.05 (m, 2H), 2.05-1.95 (m, 2H), 1.88-1.78 (m, 4H), 1.12 (t, 3H).

MCBP. Calculated for [C27H29Cl2NaO6S+H]+: 594.123. Found: 594.121.

Example 11

Propyl 4-[2-{2,4-dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]-phenyl ester carbonic acid

Propyl 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]-phenyl ester carbonic acid

Piperidine-1-alamid 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid, obtained as in Example 1, step E (0,44 g, 1.00 mmol), was dissolved in dichloromethane (10 ml) was added triethylamine (0.28 in ml, of 2.24 mmol). Was added at 0°C propylchloride (0,14 ml of 1.24 mmol), the reaction mixture was stirred for 40 minutes, concentrated and the product was purified flash chromatography (hexane:tO 70:30 to 50:50) to give 345 mg (65%) specified in the connection header. As a result of additional purification preparative HPLC received 239 mg specified in the connection header.

1H NMR (CDCl3): δ 7.71-7.18 (8H, m), 4.24 (2H, t), 2.93 (4H, m), 2.40 (3H, s), 1.78 (6H, m), 1.46 (2H, m), 1.03 (3H, t).

MC m/z 553 (M+Na).

HPLC: 94.15%.

Example 12

4-{1-(2,4-Dichlorophenyl)-4-methyl-3-[(piperidine-1-ylamino)carbonyl]-1H-pyrazole-5-yl}phenylthiophene-2-sulfonate

Thiophene-2-sulphonylchloride (433 mg, 2,37 mm is l) in DHM (2.5 ml) was added to a mixture of 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-piperidine-1-yl-1H-pyrazole-3-carboxamide, obtained as in Example 1, step E (200 mg, 0.45 mmol)and tea (0.5 ml, 3,59 mmol) in DHM (2.5 ml) at -78°C in an atmosphere of N2(gas). The reaction was continued at -78°C for 2 hours and then at room temperature for 19 hours. Added water and separated phases. The organic phase is washed with water and dried over gSO4. The product was additionally purified preparative HPLC (column Kromasil C8, ammonium acetate (aqueous, 0,1M) : acetonitrile, the product was at 100% acetonitrile) to obtain the almost white powder (158 mg, 60%).

1H NMR (399.964 MHz) δ 7.71-7.67 (m, 1H), 7.67-7.57 (br, 1H), 7.50-7.46 (m, 1H), 7.35 (s, 1H), 7.25 (s, 2H), 7.07-7.00 (m, 3H), 6.98-6.92 (m, 2H), 2.86-2.76 (m, 4H), 2.29 (s, 3H), 1.73-1.65 (m, 4H), 1.42-1.33 (m, 2H).

Msvr. Calculated for [C26H24Cl2N4O4S2+H]+: 591.069. Found: 591.067.

Example 13

Hydrochloride 4-{1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidine-1-ylamino)carbonyl]-1H-pyrazole-5-yl}vinylpyridin-3-sulfonate

Stage A. 4-{1-(2,4-Dichlorophenyl)-4-methyl-3-[(piperidine-1-ylamino)carbonyl]-1H-pyrazole-5-yl}vinylpyridin-3-sulfonate

A suspension of pyridine-3-sulphonylchloride (144 mg, 0.67 mmol) in DHM (10 ml) was added to a mixture of 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-piperidine-1-yl-1H-pyrazole-3-carboxamide, obtained as in Example 1, step E (200 mg, 0.45 mmol)and tea (0.5 ml, 3,59 mmol) in DHM (2.5 ml) at -78°C in an atmosphere of N2(gas). The reaction was continued at -78°C for 1.5 hours and then at room temperature for 30 minutes. Added water and separated phases. The organic phase is washed with water and dried over MgSO4. The product was additionally purified flash chromatography (SiO2, toluene : ethyl acetate, the product was at 42% ethyl acetate) to obtain the almost white powder (216 mg, 82%).

1H NMR (399.964 MHz) δ 8.95-8.85 (m, 2H), 8.10-8.04 (m, 1H), 7.64 (s, 1H), 7.50-7.45 (m, 1H), 7.44-7.40 (m, 1H), 7.34-7.24 (m, 2H), 7.09-7.04 (m, 2H), 7.00-6.95 (m, 2H), 2.88-2.78 (m, 4H), 2.33 (s, 3H), 1.78-1.68 (m, 4H), 1.46-1.36 (m, 2H).

Msvr. Calculated for [C27H25Cl2N5O4S+H]+: 586.108. Found: 586.111.

Stage b of the Hydrochloride of 4-{1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidine-1-ylamino)carbonyl]-1H-pyrazole-5-yl}vinylpyridin-3-sulfonate

4-{1-(2,4-Dichlorophenyl)-4-methyl-3-[(piperidine-1-ylamino)carbonyl]-1H-pyrazole-5-yl}vinylpyridin-3-sulfonate (150 mg, 0.26 mmol) was dissolved in 0,1M HCl in acetic acid (10 ml) and subjected to freeze-drying to obtain salt as a white powder (159 mg, 99.8 per cent).

Example 14

tert-Butyl[2-(4-{1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidine-1-ylamino)carbonyl]-1H-pyrazole-5-yl}phenoxy)ethyl]ethylcarbamate

Stage A. tert-Butyl ethyl(2-hydroxyethyl)carbamate

Di-tert-BUTYLCARBAMATE (3,19 g, 14.6 mmol) in THF (10 ml) was added to 2-(ethylamino)ethanol (1,00 g, and 11.2 mmol) and the reaction was carried out at room temperature for 3 hours. The solvent is evaporated under reduced pressure to get crude product (2.28 g).

1H NMR (499.961 MHz) δ 3.71-3.65 (br, 2H), 3.55-3.35 (br, 1H), 3.35-3.30 (br, 2H), 3.30 - 3.20 (br, 2H), 1.43 (s, 9H), 1.07 (t, 3H).

Stage B. tert-Butyl-[2-(4-{1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidine-1-ylamino)carbonyl]-1H-pyrazole-5-yl}phenoxy)ethyl]ethylcarbamate

1-(2,4-Dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-piperidine-1-yl-1H-pyrazole-3-carboxamide obtained as in Example 1, step E (USD 151.6 mg, 0.34 mmol), and tert-butyl ethyl(2-hydroxyethyl)carbamate (408,6 mg of 1.73 mmol) were mixed in toluene (1 ml) and subjected interaction in single mode (single node) microwave oven at 180°C. the total time of reaction was 2 hours. Before each heating was added cyanomethylene-N-butylphosphate (the total number of 925 mg, a 3.83 mmol). The solvent is then evaporated and the product was purified preparative HPLC (column Kromasil C8, ammonium acetate (aqueous, 0,1M) : acetonitrile, the product was at 100% acetonitrile) and flash chromatography (SiO2, toluene : ethyl acetate, the product was at 30% ethyl acetate) to obtain the almost white powder (125 mg, 60%).

1H NMR (399.964 MHz) δ 7.62 (s, 1H),7.37 (s, 1H), 7.23 (s, 2H), 7.01-6.95 (m, 2H), 6.81-6.75 (m, 2H), 4.05-3.95 (br, 2H), 3.55-3.45 (br, 2H), 3.35-3.25 (br, 2H), 2.86-2.78 (br, 4H), 2.32 (s, 3H), 1.75-1.65 (m, 4H), 1.41 (s, 9H), 1.45-1.35 (m, 2H), 1.08 (t, 3H).

MC m/z 616, 618, 620 (M+H)+.

Example 15

The dihydrochloride of 1-(2,4-dichlorophenyl)-5-{4-[2-(ethylamino)ethoxy]phenyl}-4-methyl-N-piperidine-1-yl-1H-pyrazole-3-carboxamide

Thionyl chloride (1 ml, 13,71 mmol) in methanol 10 ml) was added to a suspension of tert-butyl[2-(4-{1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidine-1-ylamino)carbonyl]-1H-pyrazole-5-yl}phenoxy)ethyl]ethylcarbamate from Example 14, Stage B (137 mg, 0.22 mmol)in methanol (2 ml). After 2.5 hours, the solvent evaporated, and the product was subjected to freeze-drying. The compound was purified preparative HPLC (column Kromasil C8, ammonium acetate (aqueous, 0,1M) : acetonitrile, the product was at 72% of acetonitrile), was subjected to freeze-drying and after this was dissolved in 0.1m HCl in acetic acid (15 ml) and again subjected to freeze-drying to obtain almost white powder (53 mg, 40%).

1H NMR (399.964 MHz) δ 7.54-7.47 (m, 2H), 7.44-7.39 (m, 1H), 7.19-7.14 (m, 2H), 7.01-6.96 (m, 2H), 4.24 (t, 2H), 3.41 (t, 2H), 3.18-3.06 (m, 6H), 2.27 (s, 3H), 1.87-1.78 (m, 4H), 1.57-1.48 (m, 2H), 1.32 (t, 3H).

Msvr. Calculated for [C26H31Cl2N5O2+H]+: 516.193. Found: 516.195.

Example 16

4-{1-(2,4-Dichlorophenyl)-4-methyl-3-[(piperidine-1-ylamino)carbonyl]-1H-pyrazole-5-yl}phenyl 3-methylbutane-1-sulfonate

3-Methylbutane-1-sulphonylchloride (84 mg, 0.49 mmol) in DHM (2 ml) was added to a mixture of 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-piperidine-1-yl-1H-pyrazole-3-carboxamide, obtained as in Example 1, step E (100 mg, 0.23 mmol)and tea (0.5 ml, 3,59 mmol) in DHM (2 ml) at -78°C in an atmosphere of N2(gas). The reaction was continued at -78°C for 1 hour. Added water and separated phases. The organic phase is washed with water and dried over gS4. The product was additionally purified preparative HPLC (column Kromasil C8, ammonium acetate (aqueous, 0,1M) : acetonitrile, the product is yhotel at 100% acetonitrile) to obtain the almost white powder (94 mg, 72%).

1H NMR (399.964 MHz) δ 7.85-7.45 (br, 1H), 7.38 (s, 1H), 7.29-7.25 (m, 2H), 7.23-7.18 (m, 2H), 7.16-7.11 (m, 2H), 3.25-3.18 (m, 2H), 2.88-2.80 (m, 4H), 2.33 (s, 3H), 1.86-1.77 (m, 2H), 1.76-1.65 (m, 5H), 1.45-1.34 (m, 2H,), 0.92 (d, 6H).

Msvr. Calculated for [C27H32CL2N4O4S+N]+: 579.160. Found: 579.159.

Example 17

4-{1-(2,4-Dichlorophenyl)-4-methyl-3-[(piperidine-1-ylamino)carbonyl]-1H-pyrazole-5-yl}phenyl-3,3-dimethylbutan-1-sulfonate

3,3-Dimethylbutan-1-sulphonylchloride (59 mg, 0.32 mmol) in DHM (2 ml) was added to a mixture of 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-piperidine-1-yl-1H-pyrazole-3-carboxamide, obtained as in Example 1, step E (103 mg, 0.23 mmol)and tea (0.5 ml, 3,59 mmol) in DHM (2 ml) at -78°C in an atmosphere of N2(gas). The reaction was continued at -78°C for 1 hour. Added water and separated phases. The organic phase is washed with water and dried over MgSO4. The product was additionally purified preparative HPLC (column Kromasil C8, ammonium acetate (aqueous, 0,1M) : acetonitrile, the product was at 100% acetonitrile) to obtain the almost white powder (94 mg, 68%).

1H NMR (399.964 MHz) δ 8.20-7.40 (br, 1H), 7.36 (s, 1H), 7.28-7.22 (m, 2H), 7.21-7.16 (m, 2H), 7.15-7.09 (m, 2H), 3.20-3.13 (m, 2H), 2.87-2.80 (m, 4H), 2.31 (s, 3H), 1.83-1.76 (m, 2H), 1.73-1.65 (m, 4H), 1.43-1.32 (m, 2H,), 0.89 (s, 9H).

MCBP. Calculated for [C28H34Cl2N4O4S+H]+: 593.176. Found: 593.176.

Example 18

4-[1-(2,4-Dichlorophenyl)-4-methyl-3-({[5-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)-1H-pee the azole-5-yl]phenyl 3,3,3-cryptochrome-1-sulfonate

Stage A. 5-[4-(Benzyloxy)phenyl]-1-(2,4-dichlorophenyl)-4-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-3-carboxamide

Oxalicacid (1 ml) in DHM (4 ml) was added to a suspension of 5-[4-(benzyloxy)phenyl]-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid, obtained as in Example 1, step G (202 mg, 0.45 mmol), DHM (4 ml). Added 1 drop of DMF and the reaction continued at room temperature for 1 hour. DHM and excess oxalicacid was removed under reduced pressure, the acid chloride suspended in DHM (4 ml) and added to 5-(trifluoromethyl)pyridin-2-amine (87,6 mg, 0.54 mmol) in DHM/K2CO3(10%, water)/(1/1,8 ml). The reaction was continued at room temperature for 24 hours. Then added 50 mg DMAP and the reaction continued at room temperature for 1 hour. The phases were separated and the organic phase is washed with water and dried over MgSO4. The product was additionally purified flash chromatography (SO2, toluene) (108 mg, 41%).

1H NMR (399.964 MHz) δ 9.66 (s, 1H), 8.58-8.48 (m, 2H), 7.95-7.90 (m, 1H), 7.44-7.14 (m, 8H), 7.10-7.04 (m, 2H), 6.94-6.90 (m, 2H), 5.02 (s, 2H), 2.42 (s, 3H).

MS m/z 597, 599, 601 (M+H)+.

Stage b 1-(2,4-Dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-3-carboxamide

5-[4-(Benzyloxy)phenyl]-1-(2,4-dichlorophenyl)-4-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-3-carboxamide (108 mg, 0.18 mmol) suspended in 4,1M Nug in acetic acid, 10 ml) and the reaction was carried out at room temperature for 6 hours. Added ethanol (95%, 75 ml), and under reduced pressure the solvent evaporated. Was added methanol and the product was neutralized Panso3(1M, water). The solvent is evaporated and the mixture was dissolved in DHM and water. The phases were separated and the organic phase is washed with water and dried over MgSO4(87 mg, 95%).

1H NMR (399.964 MHz) δ 9.64 (s, 1H), 8.58-8.48 (m, 2H), 7.97-7.91 (m, 1H), 7.45-7.41 (m, 1H), 7.32-7.23 (m, 2H), 7.03-6.98 (m, 2H), 6.80-6.75 (m, 2H), 5.50-5.30 (br, 1H), 2.40 (s,3H).

MS m/z 507, 509, 511 (M+H)+.

Stage C. 4-[1-(2,4-Dichlorophenyl)-4-methyl-3-({[5-(trifluoromethyl)pyridin-2-yl}amino}carbonyl)-1H-pyrazole-5-yl]phenyl 3,3,3-cryptochrome-1-sulfonate

3,3,3-Cryptochrome-1-sulphonylchloride (105 mg, of 0.53 mmol) was added to a mixture of 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-3-carboxamide (87 mg, 0,17 mmol) and tea (0.5 ml, 3,59 mmol) in DHM (3 ml) at -78°C in an atmosphere of N2(gas). The reaction was continued at -78°C for 2 hours and then at room temperature overnight. Added water and separated phases. The organic phase is washed with water and dried over MgSO4. The product was additionally purified preparative HPLC (column Kromasil C8, ammonium acetate (aqueous, 0,1M) : acetonitrile, the product was at 100% acetonitrile) to obtain the almost white powder (86 mg, 75%).

1H NMR (399.964 MHz) δ 9.70 (s, 1H), 8.57-8.48 (m, 2H), 7.99-7.92 (m, 1H), 7.43 (s, 1H). 7.32 (s, 2H), 7.28-7.19 (m, 4H), 3.53-3.44 (m, 2H), 2.85-2.71 (m, 2H), 2.42 (s, 3H).

MCBP. Asciano for [C 26H18CL2F6N4O4S+N]+: 667.041. Found: 667.031.

Example 19

1-(2,4-Dichlorophenyl)-5-{4-[2-(1,3-dioxolane-2-yl)ethoxy]phenyl}-4-methyl-N-piperidine-1-yl-1H-pyrazole-3-carboxamide

2-(2-Bromacil)-1,3-dioxolane (60 mg, 0.33 mmol), 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-piperidine-1-yl-1H-pyrazole-3-carboxamide obtained as in Example 1, step E (100 mg, 0.22 mmol), and potassium carbonate (150 mg, of 1.09 mmol) was heated at the temperature of reflux distilled in acetonitrile (25 ml) for 15 hours. Evaporated the solvent, adding water and DHM, are of the same phase and the organic phase is washed with water and dried (MgSO4). The product was additionally purified preparative HPLC (column Kromasil C8, ammonium acetate (aqueous, 0,1M) : acetonitrile, the product was at 100% acetonitrile) to obtain the almost white powder (60 mg, 49%).

1H NMR (399.964 MHz) δ 7.80-7.50 (br, 1H), 7.36 (s, 1H), 7.21 (s, 2H), 7.00-6.94 (m, 2H), 6.80-6.74 (m, 2H), 5.02 (t, 1H), 4.04 (t, 2H), 3.96-3.78 (m, 4H), 2.86-2.78 (m, 4H), 2.30 (s, 3H), 2.09 (q, 2H), 1.74-1.65 (m, 4H), 1.42-1.32 (m, 2H).

MCBP. Calculated for [C27H30CL2O4+N]+: 545.172. Found: 545.172.

Example 20

4-[2-(2,4-Dichloro-3-forfinal)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ester of propane-1-sulfonic acid

Stage A. 1-(2,4-Dichloro-3-forfinal)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid

The solution ethylate sodium was obtained from the metal on the rija (0.18 g, 7,89 mmol) in 20 ml of absolute ethanol. To this solution was added ethyl ester of 2-acetyl-4-(4-methoxy-phenyl)-3-methyl-4-oxomalonate acid (1.73 g, of 5.92 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. Keeping the temperature below 5°C, five portions was added prior chloride solution of 2,4-dichloro-3-fortiusone (obtained from 2,4-dichloro-3-foronline (1,30 g, 7.22 mmol) in 3 ml of 24% HCl and sodium nitrite (0.51 g, 7,39 mmol) in 3.5 ml of water at 0°C). After stirring at room temperature for 2.5 hours was added water, the product was extracted with tO (3). The combined organic extracts were dried (Na2SO4), filtered and evaporated. The residue was dissolved in ethanol (40 ml) was added sodium hydroxide (1,00 g 25,0 mmol) in 5 ml of water. After boiling for 2 hours at the temperature of reflux distilled, the reaction mixture was cooled, acidified with HCl and the product was extracted with tO (3). After washing, drying (Na2SO4), filtration and concentration the residue was purified flash chromatography (hexane:tO 70:30 to 50:50) with the receipt of 1.37 g (31%) indicated in the title compound as a light brown solid.

Stage B. piperidine-1-alamid 1-(2,4-dichloro-3-fluoro-phenyl)-5-(4-methoxy-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid

1-(2,4-Dichloro-3-forfinal)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-to benovoy acid (1,37 g, of 3.43 mmol) suspended in dichloromethane (20 ml) was added a few drops of DMF followed by the addition of oxalicacid (0.87 g, 6,86 mmol). The reaction mixture was heated at the temperature of reflux distilled for two hours. After cooling to room temperature the solvent was removed, the crude acid chloride was again dissolved in dichloromethane (20 ml), cooled to 0°C was added Et3N (of 0.96 ml, 6,94 mmol)and then 1-aminopiperidine (0,37 ml, 3.62 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature overnight. Added water and the product was extracted with dichloromethane (3x), the combined extracts were dried (Na2SO4), filtered and evaporated. Using flash chromatography (hexane:tO 50:50) received 0,79 g (48%) indicated in the title compound as a light brown solid.

Stage C. piperidine-1-alamid 1-(2,4-dichloro-3-fluoro-phenyl)-5-(4-hydroxy-phenyl)-4-methyl-1 H-pyrazole-3-carboxylic acid

Piperidine-1-alamid 1-(2,4-dichloro-3-fluoro-phenyl)-5-(4-methoxy-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (0,79 g of 1.66 mmol) was dissolved in 40 ml dichloromethane at 0°C. was Added tribromide boron (0,32 ml of 3.31 mmol), removed the cooling bath was continued stirring for 2 hours at room temperature, then was poured into ice water and was extracted with DHM (X3). The combined extract is dried (Na 2SO4), filtered and concentrated. Using flash chromatography (tO) was obtained 0.36 g (47%) indicated in the title compound as a colourless solid.

Phase, 4-[2-(2,4-Dichloro-3-fluoro-phenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ester of propane-1-sulfonic acid

To a solution of piperidine-1-ylamide 1-(2,4-dichloro-3-fluoro-phenyl)-5-(4-hydroxy-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (0.36 g, 0.78 mmol) in dichloromethane (10 ml) was added triethylamine (to 0.22 ml, 1.56 mmol) and the reaction mixture was cooled to 0°C. was Added 1-propanesulfonate (0,22 g, 1.56 mmol), removed the cooling bath and the reaction mixture was stirred at room temperature for 2 hours. Added water, the product was extracted with DHM (x2), the combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated. Using flash chromatography (gradient hexane:tO) received 100 mg (23%) indicated in the title compound as a colourless solid. HPLC: purity of 80%. Preparative HPLC received 40 mg specified in the connection header.

1H NMR (CDCl3): δ 7.50-7.20 (7H, m), 3.57-3.23 (6H, m), 2.37 (3H, s), 2.10-1.80 (6H, m), 1.70-1.50 (2H, m), 1.10 (3H, t).

MC: 591 (M+Na).

HPLC: 97.1%.

Example 21

4-[2-(2,4-Dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ester of 5-chlorothiophene-2-sulfones is th acid

Piperidine-1-alamid 1-(2,4-dichloro-phenyl)-5-(4-hydroxy-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid, obtained as in Example 1, step E (100 mg, 0.22 mmol), was dissolved in dry dichloromethane (3 ml) under nitrogen atmosphere was added triethylamine (0,09 ml). Then added 5-chlorothiophene-2-sulphonylchloride (0.54 mg, 0.24 mmol)dissolved in dry dichloromethane (2 ml). The reaction mixture was stirred at room temperature over a weekend. The reaction mixture was diluted with dichloromethane 20 ml and then washed with water (2×5 ml) and brine (5 ml). The organic layer was concentrated under reduced pressure to obtain oil. The crude substance was purified by reversed-phase HPLC, Kromasil C8, 5-100% MeCN in water with 0,1M ammonium acetate. The fraction containing the product was concentrated under reduced pressure, the residue was dissolved in dichloromethane and washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to obtain specified in the title compound as a yellow solid.

1H NMR (CDCl3): δ 1.42-1.50 (m, 2H), 1.73-1.81 (m, 4H), 2.39 (s, 3H), 2.84-2.92 (m, 4H). 6.95 (d, 1H), 7.04-7.14 (m, 4H), 7.30-7.36 (m, 3H), 7.44 (d, 1H), 7.63 (s,1H).

MS: 625 (M+1). HPLC: purity > 99%.

Example 22

Pharmacological data for the compounds according to the invention (activity against SW-receptor)

Number exampleIC50 nmol, SV
11,8
31,1
49,0
50,67
60,67
85,5
91,8
160,58
170,94
180,82
207,3

1. The compound of formula 1A

or its pharmaceutically acceptable salt,
in which R1represents a group R5S(O)2O, where R5represents a C1-6alkyl group, possibly substituted by one or more fluorescent;
Rarepresents halogen, and m is 0, 1 or 2;
R2arepresents chloro;
R2brepresents chloro;
R2crepresents H or halogeno;
R3is a group CONHNR7R8 where NR7R8represents piperidino or morpholino, or R3is a group CONHR8in which R8represents a C5-7cycloalkyl group, possibly substituted C1-6alkoxycarbonyl group, or R8represents pyridyl, possibly substituted With one1-5alkyl group, where the alkyl possibly substituted by one or more fluorescent; and
R4represents H, C1-3alkyl group or halogeno.

2. The compound according to claim 1 represented by formula IB
,
in which R1represents a group R5S(O)2O, where R5represents a C1-6alkyl group, possibly substituted by one or more fluorescent;
Ra1represents halogeno or N;
Ra2represents halogeno or N;
R2arepresents chloro;
R2brepresents chloro;
R2crepresents halogeno or N;
R3is a group CONHNR7R8where NR7R8represents piperidino; and
R4represents a C1-3alkyl group.

3. The compound according to claim 1 represented by formula IB
,
in which R1represents a group R5S(O)2O, where R5is Soboh the C 1-6alkyl group, possibly substituted by one or more fluorescent;
R2arepresents chloro;
R2brepresents chloro;
R3is a group CONHNR7R8where NR7R8represents piperidino or morpholino;
and R4represents a C1-3alkyl group or halogeno.

4. The compound according to claim 1, selected from one or more than one of the following:
4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ether butane-1-sulfonic acid;
4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]-phenyl ester propane-1-sulfonic acid;
4-[2-(2,4-dichlorophenyl)-4-methyl-5-(morpholine-4-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ether propane-1-sulfonic acid;
4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl] phenyl ester 3,3,3-cryptochrome-1-sulfonic acid;
4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ester 4,4,4-triptorelin-1-sulfonic acid;
[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]-2,6-diperpanjang ether propane-1-sulfonic acid;
4-[2-(2,4-dichlorophenyl)-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl] phenyl ether propane-1-sulfonic acid;
4-[4-bromo-2-(2,4-dichlorophenyl)-5-(piperidine-1-ylcarbonyl-2H-pyrazole-3-yl]phenyl ether propane-1-sulfonic acid;
methyl-1-{[(1-(2,4-dichlorophenyl)-4-methyl-5-{4[(propylsulfonyl)oxy]phenyl}-1H-pyrazole-3-yl)carbonyl]amino}-cyclopentanecarboxylate;
4-{1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidine-1-ylamino)carbonyl]-1H-pyrazole-5-yl}phenyl 3-methylbutane-1-sulfonate;
4-{1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidine-1-ylamino)carbonyl]-1H-pyrazole-5-yl}phenyl 3,3-dimethylbutan-1-sulfonate;
4-[1-(2,4-dichlorophenyl)-4-methyl-3-({[5-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)-1H-pyrazole-5-yl]phenyl 3,3,3-cryptochrome-1-sulfonate;
4-[2-(2,4-dichloro-3-forfinal)-4-methyl-5-(piperidine-1-ylcarbonyl)-2H-pyrazole-3-yl]phenyl ether propane-1-sulfonic acid;
or their pharmaceutically acceptable salt.

5. The compound according to any one of claims 1 to 4 for use in the manufacture of drugs having modulating activity against SW-receptor.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: object of present invention is the following compounds: thiazol-2-ylamide 2-(3,4-dichlorophenoxy) hexanoic acid, 2-(4-fluorophenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-K-pyridin-2-ylhexaneamide, 2-(3,4-dichlorophenoxy)-4-methyl-N,3-thiazol-2-ylpentaneamide, 2-(1,1'-biphenyl-4-yloxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-isopropylphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(3-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, and others, named in the formula of invention. Present invention also relates to a pharmaceutical composition, which contains the invented compound as an active ingredient and use of compounds in preparing a medicinal agent which increases activity of glucose. The invention also pertains to a compound of formula (I) where G is -C(O)-; L1 is a direct bond, A is >N-, X is a direct bond, R1 is cyclohexyl, R3 is cyclohexyl, substituted with R34, R4 is hydrogen; R5 is thiazol-5-yl, substituted with R48.

EFFECT: obtaining compounds which can be used for preparing a medicinal agent which can be used for treating diseases caused by glucokinase deficiency, for preparing a medicinal agent for treating diseases where increased activity of glucokinase is favourable.

6 cl, 143 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new benzimidazole derivatives with general formula (I), where A represents -CH2-, -C(O), -C(O)-C(Ra)(Rb)-, X represents a -CH- radical; Ra and Rb independently represent a hydrogen atom or (C1-C6)alkyl radical; R1 represents a hydrogen atom or (C1-C8)alkyl radical; R2 represents a (C1-C8)alkyl radical; R3 represents -(CH2)P-Z3, -C(O)-Z'3 or -C(O)-NH-Z"3; Z3 represents (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl-N(RN)carbonyl, (C3-C7)cycloalkyl, aryl, arylthio or heteroaryl radical, Z3 is bonded to the -(CH2)P- through a carbon atom, heteroaryl radical, which is a 5-10- member heteroaryl, which contains 1-2 identical or different heteroatoms, chosen from sulphur, nitrogen or oxygen, and optionally substituted with one or more identical or different substitutes, chosen from halogen, nitro group or -(CH2)P'-V30-Y3; aryl radical, chosen from phenyl or naphthyl, optionally substituted with one or more identical or different substitutes, chosen from halogen, nitro group, cyano group, (C2-C6)alkenyl, pyrrolidinyl, phenyl, phenyloxy, phenylalkyloxy, 5-7- member heteroaryl, containing 1-3 nitrogen atoms and -(CH2)p'-V31-Y3; V30 represents -O-, -C(O)-, -C(O)-O- or a covalent bond; V31 represents -O-, -S-, -SO2-, -C(O)-, -C(O)-O-, -N(RN)-, -NH-C(O)- or a covalent bond; Y3 represents a hydrogen atom or (C1-C6)alkyl radical, optionally substituted with one or more identical or different halogen radicals; RN represents a hydrogen atom or (C1-C6)alkyl radical; Z3 represents a radical with a given formula (see below); Z'3 represents a phenyl radical, optionally substituted with one ore more identical or different substitutes, chosen from -(CH2)P"-V'3-Y'3; V'3 represents -O-; Y'3 represents a hydrogen atom or (C1-C6)alkyl radical; Z"3 represents a hydrogen atom or -(CH2)q-A"3 radical; A"3 represents (C1-C6)alkyl, phenyl or thienyl radical; alkyl or phenyl radical can be optionally substituted with one or more identical or different substitutes, chosen from halogen and -V"3-Y"3; V"3 represents -O-, -C(O)-, -C(O)-O- or a covalent bond; Y"3 represents a hydrogen atom or (C1-C6)alkyl radical; p is an integer from 0 to 6; p' and p" independently represent an integer from 0 to 1; q is an integer from 0 to 2; R4 represents a radical with formula -(CH2)S-R'4; R'4 represents a 5-7- member heterocycloalkyl, containing at least one nitrogen atom and optionally substituted with (C1-C6)alkyl; or a radical with formula -NW4W'4; W4 represents a hydrogen atom; W'4 represents a hydrogen atom; s is an integer from 0 to 6; in racemic or enantiomeric form or any combination of the said forms, or its pharmaceutically acceptable salt. The invention also relates to a method of obtaining a compound in paragraph 1, a pharmaceutical composition based on the said compound and its use in making a medicinal agent.

EFFECT: new benzimidazole derivatives have good affinity to certain subtypes of melanocortin receptors.

26 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new a compound of formula I or formula II, or to its pharmaceutically acceptable salts, I II, where X is S; R1 is H or C1-C6alkyl; R2 is NR5R6; R3 is aryl, substituted with a halogen; R4 is H; R5 is H; R6 is H; R7 is CH2NR8R9 where R8 is H, C1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), heterocycle(C1-C6alkyl), heterocycle(C2-C6alkenyl), hydroxyl(C1-C6alkyl), hydroxyl(C2-C6alkyl), C1-C6alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbamoyl(C1-C6alkyl); where the above mentioned aryl is an aromatic ring and is not substituted or substituted with one to three substituting groups, each of which, independently from the others, is chosen from: methylenedioxy, hydroxy, C1-C6-alkoxy, halogen, C1-C6alkyl, trifluoromethyl, trifluoromethoxy, NO2, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-acyl, N(C1-C6alkyl)-acyl, hydroxy(C1-C6alkyl), dihydroxy(C1-C6alkyl), CN, C(=O)O(C1-C6alkyl), phenyl, phenyl(C1-C6alkyl), phenyl(C1-C6alkenyl), phenoxy and phenyl(C1-C6alkoxy), R9 is H, C1-C10alkyl, heterocycle(C1-C6alkyl) or heterocycle(C2-C6alkenyl); where the above mentioned heterocycle represents a 5-member saturated monocyclic ring system, consisting of carbon atoms, as well as heteroatoms, chosen from a group comprising N, O, and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes NO2, aryl(C1-C6alkyl), arylsulphonyl; or R8 and R9 together with nitrogen, to which they are bonded, form a heterocycle, which represents a 5 - 7-member saturated monocyclic ring system, consisting of carbon atoms, as well as one to three heteroatoms, chosen from a group comprising N, O and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes C1-C6alkoxy, hydroxy, C1-C6alkyl, C2-C6-alkenyl, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6-alkyl)2, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), aryl(C1-C6alkoxy) and pyrimidin-2-yl; and m equals 0. The invention also relates to a pharmaceutical composition, as well as to use of formula I or formula II compounds.

EFFECT: obtaining new biologically active compounds, with inhibitory properties towards casein kinase 1ε.

32 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: present invention refers to compounds of general formula (I) in the state of base salt or acid-addition salt, to method of their preparation and to the pharmaceutical composition thereof In the said formula R1 is (C1-C6)alkyl; (C3-C7)cycloalkyl unsubstituted or substituted once or more than once; (C3-C7)cycloalkylmethyl unsubstituted or substituted once or more than once; phenyl unsubstituted or substituted ; benzyl unsubstituted or substituted once or twice ; thienyl unsubstituted or substituted ; R2 is atom hydrogen or (C1-C3)alkyl; R3 is (C1-C5)alkyl; R4, R5, R6, R7, each R8 and R9 independently represents the atom of hydrogen, atom of halogen, (C1-C7)alkyl, (C1-C5)alkoxy or trifluoromethyl radical; n is 0, 1 or 2; Alk is (C1-C4)alkyl.

EFFECT: new compounds possess useful biological activity.

5 cl, 5 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of formula (I): and to its salts with acid, where: R1 and R2 represent hydrogen; Q represents (CH2)m-X-(CH2)n-A; A represents direct bond, O, SO2, NR5; X represents direct bond, O, SO2, C(O) or NR5; Z represents group selected from : m and n represent, each independently, 0, 1, 2, 3 or 4; p represents 1, 2, 3 or 4; q represents 0, 1 or 2; dotted line means that R8 and/or R9 can be situated in any position of benzothiophene ring; R3 and R8 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11 or NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10; when Q-Z represents n 0, 1 or 2 and p represents 1, one of R3 and R8 represents hydroxy, nitro, NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CONR10R11, and the other represents hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11 OSO2NR10R11, NR12SO2NR10R11, CO2R10; R4 and R9 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CHO; when p represents 2, 3 or 4, R9 can be similar or different; R6 and R7 represent hydrogen; each R5, R10, R11 and R12 represents hydrogen; when Z represents and p represents 1, then R8 and R9 can also together with phenyl ring form benzoxathiazine dioxide. Invention also relates to pharmaceutical composition and to application of derivatives by any of ii.1-25.

EFFECT: obtaining novel biologically active compounds which possess inhibiting activity with respect to aromatase and/or steroid-sulfatase and/or carboanhydrase.

36 cl, 67 ex, 5 tbl

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: invention refers to Sertaconasole mononitrate process by reaction of 1-(2,4-dichlorphenyl)-2-(1H-imidazole-1-yl)ethanol and 3-bromomethyl-7-chlorbenzo[b]thiophene with tetrabutylammonium hydrosulphate and sodium hydroxide in toluene at 30-45°C. Produced free base of Sertaconasole is transferred into Sertaconasole mononitrate monohydrate with the latter being transferred into Sertaconasole mononitrate. There is disclosed and characterised intermediate Sertaconasole mononitrate monohydrate.

EFFECT: method allows simplifying process technology considerably.

6 cl, 5 dwg, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) where R1 stands for hydrogen or linear, branched, saturated or unsaturated hydrocarbon radical; D stands for nitrogen atom or C-R2; E stands for nitrogen atom or C-R3; F stands for nitrogen atom or C-R4; G stands for nitrogen atom or C-R5; R2, R3, R4 and R5 are identical or different and individually represent hydrogen, halogen, alkoxy, linear or branched, saturated or unsaturated hydrocarbon radical; W stands for oxygen atom; X stands for radical of formula radical -(CH2)k-C(O)-(CH2)m-, -(CH2)n- or -(CH2)r-O-(CH2)s-, where k, m, r and s are equal to integers 0 to 6, and n is equal to an integer 1 to 6. Said radicals are optionally substituted with one or more substitutes independently chosen from the group consisting of R7; Y stands for radical of formula radical -(CH2)i-NH-C(O)-(CH2)j-, -(CH2)n-, -(CH2)r-O-(CH2)s-, -(CH2)t-NH-(CH2)u-, where i, j, n, r, s, t and u are equal to integers 0 to 6. Said radicals are optionally substituted C1-3alkyl, or C1-3alkyl-C1-3alkylsulphonylamino; radicals R7, B, R8, A, R9 are as it is presented in the patent claim. The invention also describes the pharmaceutical composition possessing inhibitory activity of receptor tyrosine kinase to KDR receptor including described compounds.

EFFECT: compounds possess inhibitory activity of receptor tyrosine kinase to KDR receptor and can be effective in therapy of the diseases associated uncontrolled angiogenesis.

29 cl, 746 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: object of present invention is the following compounds: thiazol-2-ylamide 2-(3,4-dichlorophenoxy) hexanoic acid, 2-(4-fluorophenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-K-pyridin-2-ylhexaneamide, 2-(3,4-dichlorophenoxy)-4-methyl-N,3-thiazol-2-ylpentaneamide, 2-(1,1'-biphenyl-4-yloxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-isopropylphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(3-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, and others, named in the formula of invention. Present invention also relates to a pharmaceutical composition, which contains the invented compound as an active ingredient and use of compounds in preparing a medicinal agent which increases activity of glucose. The invention also pertains to a compound of formula (I) where G is -C(O)-; L1 is a direct bond, A is >N-, X is a direct bond, R1 is cyclohexyl, R3 is cyclohexyl, substituted with R34, R4 is hydrogen; R5 is thiazol-5-yl, substituted with R48.

EFFECT: obtaining compounds which can be used for preparing a medicinal agent which can be used for treating diseases caused by glucokinase deficiency, for preparing a medicinal agent for treating diseases where increased activity of glucokinase is favourable.

6 cl, 143 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula (I) , Q is: (IIa) or (IIb) , R1 is chosen from a group which consists of carboxylic aryl and carboxylic aryl which is substituted with substitute(s) independently chosen from a group which consists of halogen, cyano, nitro, C1-10alkyl, C1-10alkyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-9alkoxy, C1-9alkoxy which is substituted with substitute(s) independently chosen from a group which consists of halogen, mono-C1-5alkylamino, and heterocyclyl or heterocyclyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-5alkyl; R2 is C1-5alkyl, C1-5alkyl which is substituted with halogen, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, -N(R2a)(R2b); where R2a and R2b are each independently hydrogen, C1-5alkyl or C1-5alkyl, substituted with substitute(s) independently chosen from a group which consists of hydroxyl, carboxylic aryl; L represents formula (IIIa); , where R3 and R4 are each hydrogen; A is a single bond, and B is a single bond or -CH2-; Z1, Z3, and Z4 are each independently hydrogen, halogen, C1-5alkyl, C1-5alkyl, substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Z2 is hydrogen, C1-5alkyl, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Y is -C(O)NH-, -C(O)-, -C(S)NH-, -C(O)O- or -CH2-; where carboxylic aryl is phenyl; heterocyclyl is 1H-indolyl, 9H- xanthenyl, benzo[1,3]dioxolyl, furyl, imidazolyl, isoxazolyl, morpholinyl, piperazinyl, pyridyl, pyrrolidyl; halogen is fluorine, chlorine, bromine or iodine. The invention also relates to a pharmaceutical composition.

EFFECT: compounds can be used for treating central nervous system diseases, and for improving memory functioning, sleep, awakening, diabetes.

16 cl, 8 dwg, 4 tbl, 525 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds with formula I: , in which: R1 is R6C(O)-, HC(O)-, R6SO2-, R6OC(O)-, (R6)2NC(O)-, R6-, (R6)2NC(O)C(O)-; R2 is a hydrogen atom, -CF3 or R8; R3 is a hydrogen atom or (C1-C4)aliphatic group-; R4 is -COOH; R5 is -CH2F or -CH2O-2,3,5,6- tetrafluorophenyl; R6 is (C1-C12)aliphatic or (C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-; and where R6 is substituted with up to 6 substitutes, independently chosen from R; R is a halogen atom, OR7 and -R7; R7 is (C1-C6)aliphatic group-, (C3-C10)cycloaliphatic group; R8 is (C1-C12)aliphatic- or (C3-C10)cycloaliphatic group; to a pharmaceutical composition with caspase-inhibiting activity, based on compound with formula I, to methods of treatment as well as to methods of inhibiting caspase-mediated functions and to a method of reducing production of IGIF or IFN-β. The invention also relates to a method of preserving cells, as well as to a method of producing compound with formula I.

EFFECT: new compounds are obtained and described, which can be used for treating diseases in the development of which caspase activity takes part.

34 cl, 4 tbl, 43 ex

FIELD: medicine.

SUBSTANCE: invention refers to salt N,2-dimetyl-6-[7-(2-morpholinoethoxy)chinoline-4-iloxy]benzofuran-3-carboxamide, particularly bismaleate N,2-dimetyl-6-[7-(2-morpholinoethoxy)chinoline-4-iloxy]benzofuran-3-carboxamide with antitumor activity.

EFFECT: cancer treatment availability.

11 cl, 35 dwg, 9 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new a compound of formula I or formula II, or to its pharmaceutically acceptable salts, I II, where X is S; R1 is H or C1-C6alkyl; R2 is NR5R6; R3 is aryl, substituted with a halogen; R4 is H; R5 is H; R6 is H; R7 is CH2NR8R9 where R8 is H, C1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), heterocycle(C1-C6alkyl), heterocycle(C2-C6alkenyl), hydroxyl(C1-C6alkyl), hydroxyl(C2-C6alkyl), C1-C6alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbamoyl(C1-C6alkyl); where the above mentioned aryl is an aromatic ring and is not substituted or substituted with one to three substituting groups, each of which, independently from the others, is chosen from: methylenedioxy, hydroxy, C1-C6-alkoxy, halogen, C1-C6alkyl, trifluoromethyl, trifluoromethoxy, NO2, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-acyl, N(C1-C6alkyl)-acyl, hydroxy(C1-C6alkyl), dihydroxy(C1-C6alkyl), CN, C(=O)O(C1-C6alkyl), phenyl, phenyl(C1-C6alkyl), phenyl(C1-C6alkenyl), phenoxy and phenyl(C1-C6alkoxy), R9 is H, C1-C10alkyl, heterocycle(C1-C6alkyl) or heterocycle(C2-C6alkenyl); where the above mentioned heterocycle represents a 5-member saturated monocyclic ring system, consisting of carbon atoms, as well as heteroatoms, chosen from a group comprising N, O, and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes NO2, aryl(C1-C6alkyl), arylsulphonyl; or R8 and R9 together with nitrogen, to which they are bonded, form a heterocycle, which represents a 5 - 7-member saturated monocyclic ring system, consisting of carbon atoms, as well as one to three heteroatoms, chosen from a group comprising N, O and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes C1-C6alkoxy, hydroxy, C1-C6alkyl, C2-C6-alkenyl, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6-alkyl)2, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), aryl(C1-C6alkoxy) and pyrimidin-2-yl; and m equals 0. The invention also relates to a pharmaceutical composition, as well as to use of formula I or formula II compounds.

EFFECT: obtaining new biologically active compounds, with inhibitory properties towards casein kinase 1ε.

32 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to N-substituted aniline and diphenylamine analogues, chosen from 3,4-bisdifluoromethoxy-(3-carboxyphenyl)-N-(5-(2-chloropyridinylmethyl))-aniline, 3,4-bisdifluoromethoxy - N-(3-carboxyphenyl) - N-(3-(2-chloropyridylmethyl))-aniline, 3,4 - bisdifluoromethoxy - N-(3-carboxyphenyl) - N-(4-(3,5-dimethylisoxazolylmethyl)) aniline, 3 - cyclopentyloxy - 4-methoxy - N-(3-aminocarbonylphenyl) - N-(3-pyridylmethyl) aniline and other compounds given in paragraph 1 of the formula of invention and to their pharmaceutically acceptable salts as inhibitors of PDE4 enzyme.

EFFECT: compounds can be used for treating and preventing diseases caused by activity of the PDE4 enzyme.

15 cl, 8 dwg, 58 ex

FIELD: chemistry.

SUBSTANCE: in formula (1) compound, cysteinprotease is cathepsin K, cathepsin S, cathepsin L or cathepsin B. In formula (I) R is , AA1 is a bond, AA2 is a bond, R7 and R8 each independently represents hydrogen, C1-8 alkyl, CycA or C1-8 alkyl, substituted CycA, R9 is hydrogen, values of the rest of the radicals are given in the formula of invention. The invention also relates to a pharmaceutical composition, containing a formula (I) compound as an active ingredient, to a cysteinprotease inhibitor, method of inhibiting cysteinprotease, use of formula (I) compound in obtaining cysteinprotease inhibitor.

EFFECT: compound has inhibitory activity towards cysteinprotease.

10 cl, 16 tbl, 8 dwg, 224 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the new compounds of general formula (II) , whereat values R1, R2, X, R11, R12, R18, R19, m, n are displayed in claim 1 of the formula.

EFFECT: compounds display agonistic and antagonistic activity which allows to propose their usage in pharmaceutical compositions for treatment of diseases and distresses connected with histamine H3 receptor.

38 cl, 80 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I

, where R1 is hydrogen or alkyl; R2 is hydrogen, alkyl or halogen; R3 is hydrogen, alkyl or halogen; R4 is phenyl or piperidinyl, optionally substituted with one or more substitutes, independently selected from alkyl, halogen, alkoxy, alkoxyalkyl, hydroxyalkoxy, trifluoromethyl, trifluoromethoxy, aryl, alkylcarbonylamino, alkoxycarbonylalkoxy and alkyl-SO2-; R5 is hydrogen or alkyl; R6, R7, R8, R9 and R10 are independently selected from hydrogen, alkyl, halogen, trifluoromethyl, alkoxy and alkyl-SO2; A is nitrogen or C-R10; E is nitrogen or C-R9; G is nitrogen or C-R8; where not more than one of A, E and G is nitrogen; and to their pharmaceutically acceptable salts and esters, as well as to a pharmaceutical composition with inhibitory activity towards enzyme 11beta-hydroxysteroid dehyrogenase 1 (11-beta-HSD1).

EFFECT: new compounds are obtained and described, which can be used in treating and preventing type II diabetes.

22 cl, 177 ex, 1 tbl

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