Novel aminoindazole derivatives as medicinal agents and pharmeceutical compositions containing said derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to formula compounds, as well as their pharmaceutically acceptable salts, a pharmaceutical composition based on them, with inhibitory activity towards phosphorylation of protein Tau, and to methods of producing said compounds. In formula (I), R5 is aryl, aryl(C1-C6)alkyl; R6 is halogen; R3 is (C1-C6)alkyl, possibly substituted with substitutes selected from halogen, OH, NH2, azetidine; or monocyclic aryl or heteroaryl, such as thiophene or pyridine, possibly substituted with substitutes selected from NO2, CN, (C1-C6)alkoxy, (C1-C6)alkyl; or CONR1R2, SO2Ra, C(=NH)R1b, COOR1c; R1, R2 independently represent a hydrogen atom, possibly substituted with one halogen atom, (C1-C6)alkyl, moncyclic aryl or monocyclic 5- or 6-member heteroaryl containing 1 or 2 heteroatoms, such as S, O, N, possibly substituted with one or more substitutes selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxyl, trifluoromethyl, N(CH3)2; or R1 and R2 can form a 5- or 6-member ring which optionally contains a heteroatom such as N; R1a is aryl, possibly substituted with (C1-C6)alkoxy; R1b is (C1-C6)alkyl, possibly substituted aryl or 6-member heteroaryl, containing 1 or 2 N atoms, where the substitute is (C1-C6)alkoxyl; R1c is (C1-C6)alkyl, (C2-C6)alkenyl; and their pharmaceutically acceptable salts.

EFFECT: aminoindazole derivatives as kinase inhibitor.

8 cl, 44 ex

 

The present invention relates to the use of derivatives of formula (I):

or their pharmaceutically acceptable salts as a kinase inhibitor.

The object of the invention is the use of derivatives aminoindazole formula (I) and their pharmaceutically acceptable salts for pharmaceutical compositions intended for the prevention and treatment of diseases that can arise from abnormal activity of kinases, such as those involved in neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, frontoparietal dementia, corticobasal degeneration, diseases of the Peak, cerebrovascular complications, cranial and vertebral traumas and peripheral neuropathies, obesity, metabolic diseases, type II diabetes, essential hypertension, atherosclerotic cardiovascular diseases, polycystic ovarian, syndrome X, immunodeficiency and cancer; pharmaceutical compositions containing the new derivatives aminoindazole and their pharmaceutically acceptable salts and new derivatives of aminoindazole and their pharmaceutically acceptable salts.

The present invention relates to derivatives of formula (I)in which:

R3 means (C1-C6)alkyl, aryl, aryl(C1-C )alkyl, heteroaryl, heteroaryl(C1-C6)alkyl, condensed with (C1-C10)cycloalkyl aryl or heteroaryl, heterocyclic residue, heteroseksualci, cycloalkyl, substituted, politically, alkenyl, quinil, CONR1R2, CSNR1R2, COOR1, SO2R1, C(=NH)R1, C(=NH)NR1, and these radicals can be substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR1, COOH, C(O)R1, -O-C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2, SR1, S(O)R1, SO2R1, NHSO2R1, SO2NR1R2, C(S)NR1R2, NHC(S)R1, -O-SO2R1, -SO2-O-R1, aryl, heteroaryl, heterocyclic residue, formyl, trifloromethyl, cryptomelane, cryptometer, (C1-C6)alkyl;

R5, R6, independently of one another, chosen from the following radicals: halogen atom, CN, NO2, NH2, OH, COOH, C(O)OR8, -O-C(O)R8, NR8R9, NHC(O)R8, C(O)NR8R9, NHC(S)R8, C(S)NR8R9, SR8, S(O)R8, SO2R8, NHSO2R8, SO2NR8R9, -O-SO2R8, -SO2-O-R8, trifluoromethyl, tripterocarpa, (C1-C6)alkyl, (C1-C6)alkoxyl, aryl, aryl(C1-C6)alkyl, heteroaryl, heteroaryl(C1-C6)alkyl, a heterocyclic residue, cycloalkyl, alkenyl, quinil, substituted, politically, and these radicals can be substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR10, COOH, C(O)OR10, -O-C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, (S)NR10R11, SR10, S(O)R10, SO2R10, NHSO2R10, SO2NR10R11, -O-SO2R10, -SO2-O-R10, aryl, heteroaryl, formyl, trifloromethyl, cryptometer, (C1-C6)alkyl;

R1, R2, R8, R9, R10, R11, independently of one another, mean a hydrogen atom, (C1-C6)alkyl, aryl, alkenyl, quinil, heteroaryl, and they may themselves be substituted by one or more substituents selected among halogen, (C1-C6)alkyl, (C1-C6)alkoxyl, CN, NO2, NH2, OH, COOH, Coulcil, CONH2, formyl, trifloromethyl, cryptometer;

R1 and R2 or R8 and R9, or R10 and R11 may form a 5 - or 6-membered cycle, with or without heteroatom such as O, S, N;

and when R3 means a 6-membered nitrogen containing heteroaryl, or thiazolyl, or imidazolyl, or oxazolyl, then at least one of R5, R6 denotes aryl which may be substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR10, COOH, C(O)R10, -O-C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10, SO2R10, NHSO2R10, SO2NR10R11, -O-SO2R10, -SO2-O-R10, aryl, heteroaryl, formyl, trifloromethyl, cryptometer, (C1-C6)alkyl;

their racemates, the enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts.

In particular, the present invention from OSISA to the derivatives of formula (I), in which:

R3 means (C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, heteroaryl, heteroaryl(C1-C6)alkyl, condensed with (C1-C10)cycloalkyl aryl or heteroaryl, heterocyclic residue, heteroseksualci, cycloalkyl, substituted, politically, alkenyl, quinil, CONR1R2, CSNR1R2, COOR1, SO2R1, C(=NH)NR1, and these radicals can be substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR1, COOH, C(O)R1, -O-C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2, SR1, S(O)R1, SO2R1, NHSO2R1, SO2NR1R2, C(S)NR1R2, NHC(S)R1, -O-SO2R1, -SO2-O-R1, aryl, heteroaryl, formyl, carbonyl group, trifloromethyl, cryptomelane, cryptometer, (C1-C6)-alkyl;

R5 denotes aryl, possibly substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR10, COOH, C(O)OR10, -O-C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10, SO2R10, NHSO2R10, SO2NR10R11, -O-SO2R10, -SO2-O-R10, aryl, heteroaryl, formyl, trifloromethyl, cryptometer, (C1-C6)alkyl;

R6 means a halogen atom, methyl, cyclopropyl, CN, OH, methoxy group, trifluoromethyl, Etiler, acetylenyl, trifloromethyl, NO2, NH2N(CH3)2;

R1, R2 independently of one another, mean a hydrogen atom, (C1-C6)is lcil, aryl, alkenyl, quinil, heteroaryl, and they may themselves be substituted by one or more substituents selected among halogen, (C1-C6)alkyl, (C1-C6)alkoxyl, CN, NO2, NH2, OH, COOH, Coulcil, CONH2, formyl, carbonyl group, trifloromethyl, cryptometer;

R1 and R2 may form a 5 - or 6-membered cycle, with or without heteroatom such as O, S, N;

their racemates, the enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts.

Preferably, the present invention relates to derivatives of formula (I)in which:

R3 means (C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, heteroaryl, heteroaryl(C1-C6)alkyl, condensed with (C1-C10)cycloalkyl aryl or heteroaryl, heterocyclic residue, heteroseksualci, cycloalkyl, substituted, politically, alkenyl, quinil, CONR1R2, CSNR1R2, COOR1, SO2R1, C(=NH)NR1, and these radicals can be substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR1, COOH, C(O)R1, -O-C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2, SR1, S(O)R1, SO2R1, NHSO2R1, SO2NR1R2, C(S)NR1R2, NHC(S)R1, -O-SO2R1, -SO2-O-R1, aryl, heteroaryl, formyl, carbonyl group, trifloromethyl, cryptomelane, cryptometer, (C1-C6)alkyl;

R5 denotes aryl, possibly substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR10, COOH, C(O)OR10, -O-C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10, SO2R10, NHSO2R10, SO2NR10R11, -O-SO2R10, -SO2-O-R10, aryl, heteroaryl, formyl, trifloromethyl, cryptometer, (C1-C6)alkyl;

R6 means a halogen atom, methyl, cyclopropyl, CN, OH, methoxy group, trifluoromethyl, Etiler, acetylenyl, cryptometer, NO2, NH2N(CH3)2;

R1, R2 independently of one another, mean a hydrogen atom, (C1-C6)alkyl, aryl, alkenyl, quinil, heteroaryl, and they may themselves be substituted by one or more substituents selected among halogen, (C1-C6)-alkyl, (C1-C6)-alkoxyl, CN, NO2, NH2, OH, COOH, Coulcil, CONH2, formyl, carbonyl group, trifloromethyl, cryptometer;

R1 and R2 may form a 5 - or 6-membered cycle, with or without heteroatom such as O, S, N;

their racemates, the enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts.

Preferably, the present invention relates to derivatives of formula (I)in which:

R3 means (C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, heteroaryl, heteroaryl(C1-the 6)alkyl, condensed with (C1-C10)cycloalkyl aryl or heteroaryl, heterocyclic residue, heteroseksualci, cycloalkyl, substituted, politically, alkenyl, quinil, CONR1R2, COOR1, SO2R1, C(=NH)R1, C(=NH)NR1, and these radicals can be substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR1, COOH, C(O)OR1, -O-C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2, SR1, S(O)R1, SO2R1, NHSO2R1, SO2NR1R2, C(S)NR1R2, NHC(S)R1, -O-SO2R1, -SO2-O-R1, aryl, heteroaryl, formyl, trifloromethyl, cryptomelane, cryptometer, (C1-C6)alkyl;

R5 denotes phenyl;

R6 denotes chlorine;

R1, R2 independently of one another, mean a hydrogen atom, (C1-C6)alkyl, aryl, alkenyl, quinil, heteroaryl, and they may themselves be substituted by one or more substituents selected among halogen, (C1-C6)alkyl, (C1-C6)alkoxyl, CN, NO2, NH2, OH, COOH, Coulcil, CONH2, formyl, trifloromethyl, cryptometer;

their isomers, their mixtures, their racemates, the enantiomers, diastereoisomers, tautomers and their pharmaceutically acceptable salts.

In the above and in the following definitions (C1-C6)alkyl radicals contain 1 to 6 carbon atoms in linear or branched chain; alkeneamine radicals sod is rat 2-6 carbon atoms and from one to three double bonds, paired or not, linear or branched chain; alkyline radicals contain 2 to 6 carbon atoms and 1 to 3 triple bond, conjugated or not, linear or branched chain; aryl radicals chosen among phenyl, naphthyl or indenyl; heteroaryl radicals are 3-10-membered ring may contain one or more heteroatoms selected from among oxygen, sulfur and nitrogen, such as, in particular, thiazolyl, thienyl, pyrrolyl, pyridinyl, furyl, imidazolyl, oxazolyl, pyrazinyl, tetrazolyl, oxadiazolyl, thiadiazolyl, isoxazole, isothiazole, isothiazoline, isoxazole, triazole, pyrazolyl, indolyl; halogen represents chlorine, iodine, fluorine, bromine; polycyclohexylene radicals chosen among adamantyl, hinokitiol, borneil, norbornanyl, bornene, norbornene; heteroaryl radical, condensed with (C1-C10)cycloalkyl, choose among indanyl, isopropanyl, Romania, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline; heterocyclic residues containing one to two heteroatoms selected from among oxygen, sulfur, nitrogen, and represent, in particular, piperidinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidine, isothiazolinones, diazolidinyl, isoxazolidine, oxazolidine, piperazinil, azetidine, 2-piperidone, 3-piperidone, 4-piperidone, 2-Pierre is Lydon, 3-pyrrolidone.

The compounds of formula (I) contain one or more asymmetric carbon atoms and can therefore exist in the form of an isomer, racemate, enantiomers and diastereoisomers; they, as well as mixtures thereof, are also part of the invention.

Of the compounds of formula (I)which are suitable according to the invention include the following compounds:

N-(bicyclo[2,2,1]hept-5-ene-2-ylmethyl)-6-chloro-5-phenyl-1H-indazol-3-amine;

6-chloro-N-(3,3-dimethylbutyl)-5-phenyl-1H-indazol-3-amine;

6-chloro-N-(3-phenylpropyl)-5-phenyl-1H-indazol-3-amine;

6-chloro-N-(cyclopropylmethyl)-5-phenyl-1H-indazol-3-amine;

6-chloro-N-(cyclopentylmethyl)-5-phenyl-1H-indazol-3-amine;

6-chloro-N-[3-(methylthio)propyl]-5-phenyl-1H-indazol-3-amine;

6-chloro-N-(phenylethyl)-5-phenyl-1H-indazol-3-amine;

6-chloro-N-(cyclohexylmethyl)-5-phenyl-1H-indazol-3-amine;

6-chloro-N-propyl-5-phenyl-1H-indazol-3-amine;

6-chloro-N-(2,2,3,3,4,4,4-heptafluorobutyl)-5-phenyl-1H-indazol-3-amerikat;

6-chloro-N-(4,4,4-trifloromethyl)-5-phenyl-1H-indazol-3-amine;

6-chloro-N-[(4-methoxyphenyl)methyl]-5-phenyl-1H-indazol-3-amine;

6-chloro-N-(phenylmethyl)-5-phenyl-1H-indazol-3-amine;

6-chloro-N-[(4-cyanophenyl)methyl]-5-phenyl-1H-indazol-3-amine;

N-[(4-chlorophenyl)methyl]-6-chloro-5-phenyl-1H-indazol-3-amine;

6-chloro-N-[(3-methoxyphenyl)methyl]-5-phenyl-1H-indazol-3-amine;

6-chloro-N-[[4-(triptoreline)phenyl]methyl]-5-phenyl-1H-indazol-3-amine;

N-[4-[[[6-chloro-5-Fe is Il-1H-indazol-3-yl]amino]methyl]phenyl]ndimethylacetamide;

6-chloro-N-[(3,5-dichlorophenyl)methyl]-5-phenyl-1H-indazol-3-amine;

6-chloro-5-phenyl-N-[[4-(trifluoromethyl)phenyl]methyl]-1H-indazol-3-amine;

6-chloro-N-[(4-forfinal)methyl]-5-phenyl-1H-indazol-3-amine;

6-chloro-N-[3-(4-methylphenoxy)phenylmethyl]-5-phenyl-1H-indazol-3-amine;

N-[2,2,3,3,4,4,4-heptafluorobutyl]-6-chloro-5-phenyl-1H-indazol-3-amine;

6-chloro-5-phenyl-N-[[3,5-bis(trifluoromethyl)phenyl]methyl]-1H-indazol-3-amine;

6-chloro-5-phenyl-N-[[3-(trifluoromethyl)phenyl]methyl]-1H-indazol-3-amine;

6-chloro-N-[(6-methoxy-2-naphthalenyl)methyl]-5-phenyl-1H-indazol-3-amine;

6-chloro-N-[(pentafluorophenyl)methyl]-5-phenyl-1H-indazol-3-amine;

6-chloro-N-[[4-(methylthio)phenyl]methyl]-5-phenyl-1H-indazol-3-amine;

N-[(4-chloro-3-forfinal)methyl]-6-chloro-5-phenyl-1H-indazol-3-amine;

6-chloro-5-phenyl-N-(3,3,3-cryptochromes)-1H-indazol-3-amine;

6-chloro-5-phenyl-N-(3-thienylmethyl)-1H-indazol-3-amine;

N-(bicyclo[2,2,1]hept-5-ene-2-ylmethyl)-6-chloro-5-phenyl-1H-indazol-3-amine;

N-([1,1'-biphenyl]-4-ylmethyl)-6-chloro-5-phenyl-1H-indazol-3-amine;

6-chloro-N-[[4-(dimethylamino)phenyl]methyl]-5-phenyl-1H-indazol-3-amine;

N-([2,2'-Bethoven]-5-ylmethyl)-6-chloro-5-phenyl-1H-indazol-3-amine;

6-chloro-5-phenyl-N-[[1-(phenylmethyl)-1H-imidazol-2-yl]methyl]-1H-indazol-3-amine;

6-chloro-N-[[1-methyl-1H-imidazol-2-yl]methyl]-5-phenyl-1H-indazol-3-amine;

6-chloro-N-[(1-methyl-1H-indol-3-yl)methyl]-5-phenyl-1H-indazol-3-amine;

6-chloro-N-[(5-methyl-2-furanyl)methyl]-5-phenyl-1H-indazol-3-amine;

6-chloro-5-phenyl-N-1H-pyrrol-2-ylmethyl)-1H-indazol-3-amine;

6-chloro-5-phenyl-N-[(1H-imidazol-2-yl)methyl]-1H-indazol-3-amine;

6-chloro-5-phenyl-N-[(1H-imidazol-4-yl)methyl]-1H-indazol-3-amine;

6-chloro-5-phenyl-N-(1H-pyrazole-3-ylmethyl)-1H-indazol-3-amine;

6-chloro-N-[[2-methyl-1H-imidazol-4-yl]methyl]-5-phenyl-1H-indazol-3-amine;

6-chloro-N-[(3,5-dimethyl-1-phenyl-1H-pyrazole-4-yl)methyl]-5-phenyl-1H-indazol-3-amine;

6-chloro-5-phenyl-N-[[2-phenyl-1H-imidazol-4-yl]methyl]-1H-indazol-3-amine;

6-chloro-N-[[5-(4-chlorophenyl)-2-furanyl]methyl]-5-phenyl-1H-indazol-3-amine;

6-chloro-5-phenyl-N-[(1-methyl-1H-pyrrol-2-yl)methyl]-1H-indazol-3-amine;

4-[5-[[[6-chloro-5-phenyl-1H-indazol-3-yl]amino]methyl]-2-furanyl]benzosulfimide;

6-chloro-5-phenyl-N-(3-thienylmethyl)-1H-indazol-3-amine;

6-chloro-5-phenyl-N-[[2-phenyl-1H-imidazol-4-yl)methyl]-1H-indazol-3-amine;

ethyl-2-[[[6-chloro-5-phenyl-1H-indazol-3-yl]amino]methyl]-5-(methylthio)-1H-imidazole-4-carboxylate;

6-chloro-5-phenyl-N-[[5-[4-(trifluoromethyl)phenyl]-2-furanyl]methyl]-1H-indazol-3-amine;

6-chloro-5-phenyl-N-[2-(1-piperidinyl)ethyl]-1H-indazol-3-amine;

6-chloro-N-[2-(4-morpholinyl)ethyl]-5-phenyl-1H-indazol-3-amine;

N-(6-chloro-5-phenyl-1H-indazol-3-yl)-N'-(3,5-dichlorophenyl)urea;

N-(6-chloro-5-phenyl-1H-indazol-3-yl)-N'-(2-propenyl)urea;

N-(6-chloro-5-phenyl-1H-indazol-3-yl)-N'-(phenylmethyl)urea;

N-(6-chloro-5-phenyl-1H-indazol-3-yl)-N'-(4-phenoxyphenyl)urea;

N-(6-chloro-5-phenyl-1H-indazol-3-yl)-N'-[(4-methoxyphenyl)methyl]urea;

N-(6-chloro-5-phenyl-1H-indazol-yl)-N'-[4-(trifluoromethyl)phenyl]urea;

N-(6-chloro-5-phenyl-1H-indazol-3-yl)-N'-(4-methoxyphenyl)urea;

N-(6-chloro-5-phenyl-1H-indazol-3-yl)-N'-cyclohexylamino;

N-(6-chloro-5-phenyl-1H-indazol-3-yl)-N'-proprotein;

N-(6-chloro-5-phenyl-1H-indazol-3-yl)-N'-(4-chlorophenyl)urea;

N-(6-chloro-5-phenyl-1H-indazol-3-yl)-N'-(4-forfinal)urea;

N-[6-chloro-5-phenyl-1H-indazol-3-yl]-N'-tricyclo[3.3.1.13,7]Dec-1-rocephine;

N-(6-chloro-5-phenyl-1H-indazol-3-yl)-N'-(4-were)urea;

N-[6-chloro-5-phenyl-1H-indazol-3-yl]-4-methylbenzenesulfonamide;

N-[6-chloro-5-phenyl-1H-indazol-3-yl]methanesulfonamide;

N-[6-chloro-5-phenyl-1H-indazol-3-yl]-2-propanesulfinamide;

N-[6-chloro-5-phenyl-1H-indazol-3-yl]-2,2,2-cryptgethashparam;

N-[6-chloro-5-phenyl-1H-indazol-3-yl]-2-thiophenesulfonyl;

N-[6-chloro-5-phenyl-1H-indazol-3-yl]benzosulfimide;

N-[6-chloro-5-phenyl-1H-indazol-3-yl]-4-(trifluoromethyl)benzosulfimide;

N-[6-chloro-5-phenyl-1H-indazol-3-yl]-5-(3-isoxazolyl)-2-thiophenesulfonyl;

N-[6-chloro-5-phenyl-1H-indazol-3-yl]-4-forbindelsesfaneblad;

N-[6-chloro-5-phenyl-1H-indazol-3-yl]-4-methoxybenzenesulfonamide;

N-[6-chloro-5-phenyl-1H-indazol-3-yl]benzylethanolamine;

N-[6-chloro-5-phenyl-1H-indazol-3-yl]-1-methyl-1H-imidazole-4-sulfonamide;

N-[6-chloro-5-phenyl-1H-indazol-3-yl]-4-(1,1-dimethylethyl)benzosulfimide;

N-[4-[[(6-chloro-5-phenyl-1H-indazol-3-yl)amino]sulfonyl]phenyl]ndimethylacetamide;

N-[6-chloro-5-phenyl-1H-indazol-3-yl]-4-METI benzylethanolamine;

6-chloro-N-(pentafluorophenyl)-5-phenyl-1H-indazol-3-amine;

6-chloro-N-(3,4-differenl)-5-phenyl-1H-indazol-3-amine;

6-chloro-5-phenyl-N-(2,3,5,6-tetrafluorophenyl)-1H-indazol-3-amine;

6-chloro-5-phenyl-N-(2,4,6-tryptophanyl)-1H-indazol-3-amine;

6-chloro-N-(4-forfinal)-5-phenyl-1H-indazol-3-amine;

6-chloro-N-[3-(trifluoromethyl)phenyl]-5-phenyl-1H-indazol-3-amine;

6-chloro-N-[4-(trifluoromethyl)phenyl]-5-phenyl-1H-indazol-3-amine;

6-chloro-N-[3-fluoro-5-(trifluoromethyl)phenyl]-5-phenyl-1H-indazol-3-amine;

6-chloro-N-(4-nitrophenyl)-5-phenyl-1H-indazol-3-amine;

6-chloro-N-(3-nitrophenyl)-5-phenyl-1H-indazol-3-amine;

6-chloro-N-(3-methoxyphenyl)-5-phenyl-1H-indazol-3-amine;

6-chloro-N-(4-methoxyphenyl)-5-phenyl-1H-indazol-3-amine;

6-chloro-N,5-diphenyl-1H-indazol-3-amine;

6-chloro-N-(1-pyridinyl)-5-phenyl-1H-indazol-3-amine;

6-chloro-N-(2-pyridinyl)-5-phenyl-1H-indazol-3-amine;

their isomers, their mixtures, their racemates, the enantiomers, diastereoisomers, tautomers and their pharmaceutically acceptable salts;

and, in particular, the following connections:

N-butyl-6-chloro-5-phenyl-1H-indazol-3-amine;

3-(6-chloro-5-phenyl-1H-indazol-3-ylamino)thiophene-2-carbonitrile;

(6-chloro-5-phenyl-1H-indazol-3-yl)pyridin-2-ylamine;

(6-chloro-5-phenyl-1H-indazol-3-yl)-(5-nitropyridine-2-yl)amine;

(6-chloro-5-phenyl-1H-indazol-3-yl)-(6-methoxypyridine-2-yl)amine;

N-(6-chloro-5-phenyl-1H-indazol-3-yl)-N'-phenylacetone;

1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(4-amoxifen the l)urea;

1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(3,4-dichlorophenyl)urea;

methyl ester of 3-[3-(6-chloro-5-phenyl-1H-indazol-3-yl)ureido]propionic acid;

1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(4-dimethylaminophenyl)urea;

1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-isopropylamino;

1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-cyclohexylamino;

1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(3-triptoreline)urea;

1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(2-thiophene-2-retil)urea;

1-benzo[1,3]dioxol-5-yl-3-(6-chloro-5-phenyl-1H-indazol-3-yl)urea;

1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(3,5-dimethylisoxazol-4-yl)urea;

1-benzyl-3-(6-chloro-5-phenyl-1H-indazol-3-yl)urea;

1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-penetrtion;

1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-[3-(4-methylpiperazin-1-yl)propyl]urea;

1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(3-imidazol-1-ylpropyl)urea;

1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(2-hydroxyethyl)urea;

1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-[3-(4-methylpiperazin-1-yl)propyl]urea;

(6-chloro-5-phenyl-1H-indazol-3-yl)amide, pyrrolidin-1-carboxylic acid;

methyl ester (6-chloro-5-phenyl-1H-indazol-3-yl)carbamino acids;

(6-chloro-5-phenyl-1H-indazol-3-yl)urea;

benzyl ether (6-chloro-5-phenyl-1H-indazol-3-yl)carbamino acids;

allyl ether (6-chloro-5-phenyl-1H-indazol-3-yl)carbamino acids;

isobutyl ether (6-chlorine is-5-phenyl-1H-indazol-3-yl)carbamino acid;

(6-chloro-5-phenyl-1H-indazol-3-yl)amide piperidine-1-carboxylic acid;

1-(3-azetidin-1-ylpropyl)-3-(6-chloro-5-phenyl-1H-indazol-3-yl)urea;

1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(3-chlorpropyl)urea;

1-(6,7-debtor-5-phenyl-1H-indazol-3-yl)-3-(3-imidazol-1-yl-propyl)urea;

1-(3-aminopropyl)-3-(6-chloro-5-phenyl-1H-indazol-3-yl)urea;

1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-[4-(4-pyridine-3-eliminator-1-yl)butyl]urea;

1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(2-pyrrolidin-1-retil)urea;

(6-chloro-5-phenyl-1H-indazol-3-yl)amide 2,5-dimethylpyridin-1-carboxylic acid;

N-(6-chloro-5-phenyl-1H-indazol-3-yl)acetamide;

N-(6-chloro-5-phenyl-1H-indazol-3-yl)-6-methoxypyrazine-2-carboxamide;

N-(6-chloro-5-phenyl-1H-indazol-3-yl)benzamide;

N-(6-chloro-5-phenyl-1H-indazol-3-yl)pyridine-2-carboxamidine;

N-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-methoxybenzenesulfonamide;

their isomers, their mixtures, their racemates, the enantiomers, diastereoisomers, tautomers and their pharmaceutically acceptable salts.

The invention relates also to pharmaceutical compositions containing as an active beginning derivative of the formula (I)in which:

R3 means (C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, heteroaryl, heteroaryl(C1-C6)alkyl, condensed with (C1-C10)cycloalkyl aryl or heteroaryl, heterocyclic is the STATCOM, heteroseksualci, cycloalkyl, substituted, politically, alkenyl, quinil, CONR1R2, CSNR1R2, COOR1, SO2R1, C(=NH)R1, C(=NH)NR1, and these radicals can be substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR1, COOH, C(O)R1, -O-C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2, SR1, S(O)R1, SO2R1, NHSO2R1, SO2NR1R2, C(S)NR1R2, NHC(S)R1, -O-SO2R1, -SO2-O-R1, aryl, heteroaryl, heterocyclic residue, formyl, trifloromethyl, cryptomelane, cryptometer, (C1-C6)alkyl;

R5, R6, independently of one another, chosen from the following radicals: halogen atom, CN, NO2, NH2, OH, COOH, C(O)OR8, -O-C(O)R8, NR8R9, NHC(O)R8, C(O)NR8R9, NHC(S)R8, C(S)NR8R9, SR8, S(O)R8, SO2R8, NHSO2R8, SO2NR8R9, -O-SO2R8, -SO2-O-R8, trifluoromethyl, tripterocarpa, (C1-C6)alkyl, (C1-C6)alkoxyl, aryl, aryl(C1-C6)alkyl, heteroaryl, heteroaryl(C1-C6)alkyl, a heterocyclic residue, cycloalkyl, alkenyl, quinil, substituted, politically, and these radicals can be substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR10, COOH, C(O)OR10, -O-C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10, SO2R10, NHSO2R10, SO2NR10R11, -O-SO2R10, -SO2-O-R10, aryl, heteroaryl, formyl, trifloromethyl, cryptometer, (C1-sub> 6)alkyl;

R1, R2, R8, R9, R10, R11, independently of one another, mean a hydrogen atom, (C1-C6)alkyl, aryl, alkenyl, quinil, heteroaryl, and they may themselves be substituted by one or more substituents selected among halogen, (C1-C6)alkyl, (C1-C6)alkoxyl, CN, NO2, NH2, OH, COOH, Coulcil, CONH2, formyl, trifloromethyl, cryptometer;

R1 and R2 or R8 and R9, or R10 and R11 may form a 5 - or 6-membered cycle, with or without heteroatom such as O, S, N;

and when R3 means a 6-membered nitrogen containing heteroaryl, or thiazolyl, or imidazolyl, or oxazolyl, then at least one of R5, R6 denotes aryl, which, if necessary, substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR10, COOH, C(O)R10, -O-C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10, SO2R10, NHSO2R10, SO2NR10R11, -O-SO2R10, -SO2-O-R10, aryl, heteroaryl, formyl, trifloromethyl, cryptometer, (C1-C6)alkyl;

its racemate, its enantiomers, diastereoisomers and their mixtures, its tautomers and pharmaceutically acceptable salts.

In particular, the present invention relates to pharmaceutical compositions containing as an active beginning derivative of the formula (I)in which:

R3 means (C1 -C6)alkyl, aryl, aryl(C1-C6)alkyl, heteroaryl, heteroaryl(C1-C6)alkyl, condensed with (C1-C10)cycloalkyl aryl or heteroaryl, heterocyclic residue, heteroseksualci, cycloalkyl, substituted, politically, alkenyl, quinil, CONR1R2, CSNR1R2, COOR1, SO2R1, C(=NH)NR1, and these radicals can be substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR1, COOH, C(O)R1, -O-C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2, SR1, S(O)R1, SO2R1, NHSO2R1, SO2NR1R2, C(S)NR1R2, NHC(S)R1, -O-SO2R1, -SO2-O-R1, aryl, heteroaryl, formyl, carbonyl group, trifloromethyl, cryptomelane, cryptometer, (C1-C6)alkyl;

R5 denotes aryl, possibly substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR10, COOH, C(O)OR10, -O-C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10, SO2R10, NHSO2R10, SO2NR10R11, -O-SO2R10, -SO2-O-R10, aryl, heteroaryl, formyl, trifloromethyl, cryptometer, (C1-C6)alkyl;

R6 means a halogen atom, methyl, cyclopropyl, CN, OH, methoxy group, trifluoromethyl, Etiler, acetylenyl, trifloromethyl, NO2, NH2N(CH3)2;

R1, R2 independently of one another, mean a hydrogen atom, (C1-C6)alkyl, aryl, alkenyl, quinil, hetero is the Rila, moreover, they can be substituted by one or more substituents selected among halogen, (C1-C6)alkyl, (C1-C6)alkoxyl, CN, NO2, NH2, OH, COOH, Coulcil, CONH2, formyl, carbonyl group, trifloromethyl, cryptometer;

R1 and R2 may form a 5 - or 6-membered cycle, with or without heteroatom such as O, S, N;

its racemate, its enantiomers, diastereoisomers and their mixtures, its tautomers and pharmaceutically acceptable salts.

Preferably, the present invention relates to pharmaceutical compositions containing as an active beginning derivative of the formula (I)in which:

R3 means (C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, heteroaryl, heteroaryl(C1-C6)alkyl, condensed with (C1-C10)cycloalkyl aryl or heteroaryl, heterocyclic residue, heteroseksualci, cycloalkyl, substituted, politically, alkenyl, quinil, CONR1R2, COOR1, SO2R1, C(=NH)R1, C(=NH)NR1, and these radicals can be substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR1, COOH, C(O)OR1, -O-C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2, SR1, S(O)R1, SO2R1, NHSO2R1, SO2NR1R2, C(S)NR1R2, NHC(S)R1, -O-SO2R1, -SO2-O-R1, aryl, heteroaryl, formyl, trifloromethyl, cryptomelane, cryptometer, (the 1-C6)alkyl;

R5 denotes phenyl;

R6 denotes chlorine;

R1, R2 independently of one another, mean a hydrogen atom, (C1-C6)alkyl, aryl, alkenyl, quinil, heteroaryl, and they may themselves be substituted by one or more substituents selected among halogen, (C1-C6)alkyl, (C1-C6)alkoxyl, CN, NO2, NH2, OH, COOH, Coulcil, CONH2, formyl, trifloromethyl, cryptometer;

its isomers, their mixtures, its racemate, its enantiomers, diastereoisomers, tautomers, as well as its pharmaceutically acceptable salt.

The present invention relates also to the use as a medicinal product derived aminoindazole formula (I)in which:

R3 means (C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, heteroaryl, heteroaryl(C1-C6)alkyl, condensed with (C1-C10)cycloalkyl aryl or heteroaryl, heterocyclic residue, heteroseksualci, cycloalkyl, substituted, politically, alkenyl, quinil, CONR1R2, CSNR1R2, COOR1, SO2R1, C(=NH)R1, C(=NH)NR1, and these radicals can be substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR1, COOH, C(O)R1, -O-C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2, SR1, S(O)R1, SO2R1, NHSO2R1, SO2NR1R2, C(S)NR1R2, NHC(S)R1, -O-SO2R1, -SO2-O-R1, aryl, heteroaryl heterocyclic residue, of formyl, trifloromethyl, cryptomelane, cryptometer, (C1-C6)alkyl;

R5, R6, independently of one another, chosen from the following radicals: halogen atom, CN, NO2, NH2, OH, COOH, C(O)OR8, -O-C(O)R8, NR8R9, NHC(O)R8, C(O)NR8R9, NHC(S)R8, C(S)NR8R9, SR8, S(O)R8, SO2R8, NHSO2R8, SO2NR8R9, -O-SO2R8, -SO2-O-R8, trifluoromethyl, tripterocarpa, (C1-C6)alkyl, (C1-C6)alkoxyl, aryl, aryl(C1-C6)alkyl, heteroaryl, heteroaryl(C1-C6)alkyl, a heterocyclic residue, cycloalkyl, alkenyl, quinil, substituted, politically, and these radicals can be substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR10, COOH, C(O)OR10, -O-C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10, SO2R10, NHSO2R10, SO2NR10R11, -O-SO2R10, -SO2-O-R10, aryl, heteroaryl, formyl, trifloromethyl, cryptometer, (C1-C6)alkyl;

R1, R2, R8, R9, R10, R11, independently of one another, mean a hydrogen atom, (C1-C6)alkyl, aryl, alkenyl, quinil, heteroaryl, and they may themselves be substituted by one or more substituents selected among halogen, (C1-C6)alkyl, (C1-C6)alkoxyl, CN, NO2, NH2, OH, COOH, Coulcil, CONH2, formyl, trifloromethyl, cryptometer;

R1 Is R2, or R8 and R9, or R10 and R11 may form a 5 - or 6-membered cycle, with or without heteroatom such as O, S, N;

and when R3 means a 6-membered nitrogen containing heteroaryl, or thiazolyl, or imidazolyl, or oxazolyl, then at least one of R5, R6 denotes aryl which may be substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR10, COOH, C(O)R10, -O-C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10, SO2R10, NHSO2R10, SO2NR10R11, -O-SO2R10, -SO2-O-R10, aryl, heteroaryl, formyl, trifloromethyl, cryptometer, (C1-C6)alkyl;

their racemates, enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts.

In particular, the present invention relates to the use as a medicinal product derived aminoindazole formula (I)in which:

R3 means (C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, heteroaryl, heteroaryl(C1-C6)alkyl, condensed with (C1-C10)cycloalkyl aryl or heteroaryl, heterocyclic residue, heteroseksualci, cycloalkyl, substituted, politically, alkenyl, quinil, CONR1R2, CSNR1R2, COOR1, SO2R1, C(=NH)NR1, and these radicals can be substituted by one or more substituents selected among halogen, CN, NO2,NH 2, OH, OR1, COOH, C(O)R1, -O-C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2, SR1, S(O)R1, SO2R1, NHSO2R1, SO2NR1R2, C(S)NR1R2, NHC(S)R1, -O-SO2R1, -SO2-O-R1, aryl, heteroaryl, formyl, carbonyl group, trifloromethyl, cryptomelane, cryptometer, (C1-C6)alkyl;

R5 denotes aryl, possibly substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR10, COOH, C(O)OR10, -O-C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10, SO2R10, NHSO2R10, SO2NR10R11, -O-SO2R10, -SO2-O-R10, aryl, heteroaryl, formyl, trifloromethyl, cryptometer, (C1-C6)alkyl;

R6 means a halogen atom, methyl, cyclopropyl, CN, OH, methoxy group, trifluoromethyl, Etiler, acetylenyl, trifloromethyl, NO2, NH2N(CH3)2;

R1, R2 independently of one another, mean a hydrogen atom, (C1-C6)alkyl, aryl, alkenyl, quinil, heteroaryl, and they may themselves be substituted by one or more substituents selected among halogen, (C1-C6)alkyl, (C1-C6)alkoxyl, CN, NO2, NH2, OH, COOH, Coulcil, CONH2, formyl, carbonyl group, trifloromethyl, cryptometer;

R1 and R2 may form a 5 - or 6-membered cycle, with or without heteroatom such as O, S, N;

their racemates, enantiomers, diastereoisomers and their mixtures, is of autokarow and their pharmaceutically acceptable salts.

Preferably, the present invention relates to the use as a medicinal product derived aminoindazole formula (I)in which:

R3 means (C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, heteroaryl, heteroaryl(C1-C6)alkyl, condensed with (C1-C10)cycloalkyl aryl or heteroaryl, heterocyclic residue, heteroseksualci, cycloalkyl, substituted, politically, alkenyl, quinil, CONR1R2, COOR1, SO2R1, C(=NH)R1, C(=NH)NR1, and these radicals can be substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR1, COOH, C(O)OR1, -O-C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2, SR1, S(O)R1, SO2R1, NHSO2R1, SO2NR1R2, C(S)NR1R2, NHC(S)R1, -O-SO2R1, -SO2-O-R1, aryl, heteroaryl, formyl, trifloromethyl, cryptomelane, cryptometer, (C1-C6)alkyl;

R5 denotes phenyl;

R6 denotes chlorine;

R1, R2 independently of one another, mean a hydrogen atom, (C1-C6)alkyl, aryl, alkenyl, quinil, heteroaryl, and they may themselves be substituted by one or more substituents selected among halogen, (C1-C6)alkyl, (C1-C6)alkoxyl, CN, NO2, NH2, OH, COOH, Coulcil, CONH2, formyl, trifloromethyl, cryptometer;

their isomers, their mixtures, their racemates, ananti the Mer, diastereoisomers, tautomers and their pharmaceutically acceptable salts.

Derivatives of formula (I) can be obtained from the corresponding 3-amino-derivatives of the formula (V), in which the nitrogen in position 1, if necessary, protected by the Pr group. Pr means trimethylsilylethynyl, tosyl, mesyl, benzyl or a group known to protect the group NH - aromatic heterocycles, as specified in the manual T.W. GREENE, "Protective groups in organic Synthesis", J. Wiley-Interscience Publication (1999).

3-amino-1H-indazols formula (II) can be obtained by reaction of 2-perbenzoate with hydrazinehydrate or hydrazinecarboxamide boiling under reflux for 2-18 hours in alcohol type ethanol or n-butanol (according R.F. KALTENBACH, Bioorg. Med. Chem. Lett.,9(15), 2259-2262 (1999)):

Compounds in which R5, R6, independently of one another, chosen from the following radicals: hydrogen atom, halogen atom, CN, NO2, NH2, OH, COOH, C(O)OR8, -O-C(O)R8, NR8R9, NHC(O)R8, C(O)NR8R9, NHC(S)R8, C(S)NR8R9, SR8, S(O)R8, SO2R8, NHSO2R8, SO2NR8R9, -O-SO2R8, -SO2-O-R8, trifluoromethyl, tripterocarpa, (C1-C6)alkyl, (C1-C6)alkoxyl, aryl, aryl(C1-C6)alkyl, heteroaryl, heteroaryl(C1-C6)alkyl, cycloalkyl, alkenyl, quinil, substituted, and these radicals could the t to be substituted by one or more substituents, chosen among halogen, CN, NO2, NH2, OH, OR10, COOH, C(O)OR10, -O-C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10, SO2R10, NHSO2R10, SO2NR10R11, -O-SO2R10, -SO2-O-R10, aryl, heteroaryl, formyl, trifloromethyl, cryptometer, (C1-C6)alkyl; can be obtained by reactions used in the chemistry of palladium: Suzuki (A. SUZUKI, Pure Appl. Chem.,63, 419-422 (1991)), Stille (J. STILLE, Angew. Chem. Int. Ed.,25, 508-524 (1986)), Heck (R.F. HECK, Org. React.,27, 345-390 (1982)), Sonogashira (K. SONOGASHIRA, Synthesis, 777 (1977)), Buckwald (S.L. BUCKWALD, Acc. Chem. Re.,31, 805 (1998)), on the basis of the corresponding halogen derivatives.

For this purpose it is necessary to protect reactive functional groups. Thus, functional groups, HE, SH, COOH, NH2must be protected prior to introduction into the reaction link. The protective group is administered according to any known specialist methods and, in particular described in T.W. GREENE, "Protective groups in Organic Synthesis", J. Wiley-Interscience Publication (1999). Preferred is the protection of the nitrogen in position 1 with the help of groups such as tertbutoxycarbonyl, or silicone derivatives. Preferably choose Siciliano group, as tributylammonium, triisopropylsilyl, which can be removed using foranyone or with acetic acid, and, in particular, trimethylsilylethynyl, ottsepleny with tetrabutylammonium is and boiling under reflux in a solvent, such as tetrahydrofuran, dioxane (J.P. WHITTEN, J. Org. Chem.,51, 1891 (1986); B.H. LIPSHUTZ, Tetrahedron Lett., 4095 (1986)), or by using a 2n solution of hydrogen chloride in methanol or ethanol at boiling under reflux.

Derivatives, secured in position 1 trimethylsilylamodimethicone group obtained by introducing into the interaction of the parent compounds with trimethylsilylamodimethicone in the presence of sodium hydride in a solvent such as dimethylformamide, at room temperature (J.P. WHITTEN, J. Org. Chem.,51, 1891 (1986); M.P. EDWARDS, Tetrahdron,42, 3723 (1986)).

Similarly, the nitrogen-containing functional group 1-NH indazole protecting groups, such as tosyl, urethane group, benzyl, or groups similarbank derivatives. For example, in the case when you want to bind palladium with halogenated in position 6 derived, it is necessary to protect the nitrogen in position 1, as shown below (X=Cl, Br, I):

The removal of the protective groups is carried out according to methods known to the expert and described in the manual T.W. GREENE, "Protective groups in Organic Synthesis", J. Wiley-Interscience Publication (1999). For example, if the protective group at position 1 is trimethylsilylethynyl, then it can be removed by introducing the interaction with tetrabutylammonium, as shown below:

COH is but one of the groups R5, R6 involved in binding assays used in the chemistry of palladium, itself contains a reactive functional group such as hydroxyl, amino, Tolna group, acid group, or, generally, includes a heteroatom, these latter also must be protected prior to binding with palladium. For example, the phenolic group is introduced into a protected form (as, for example, O-benzyl), when coming from a derivative containing chlorine and protected, as indicated earlier, the nitrogen in position 1:

The benzyl group is then removed, for example, by treatment with trimethylsilylimidazole by boiling under reflux in acetonitrile. Protection can also be accomplished using trimethylsilylamodimethicone group, tsepliaeva using tetrabutylammonium by boiling under reflux in a solvent such as tetrahydrofuran, dioxane (J.P. WHITTEN, J. Org. Chem.,51, 1891 (1986); B.H. LIPSHUTZ, Tetrahedron Lett., 4095 (1986)), or by using a 2n solution of hydrogen chloride in methanol or ethanol at boiling under reflux.

When R5 and R6, independently from each other represent an aryl and a halogen atom, aryl group injected from a connection of palladium in the position of the bromine atom and the nitrogen in positions 1 and 3 protect accordingly. Preferably, Pr means three is ethyltrimethoxysilane and Pr' means n-butylcarbamoyl, which together with n forms an n-butylamide. The stage of removal of the protective group of the amide is carried out in the presence of ethanolamine by boiling under reflux in the course of a week in dimethylformamide. This cleavage can also be implemented using chloride of divalent tin in ethanol (R.J. Griffin, J. Chem. Soc. Perkin I, 1811-1819 (1992)), or by means of sodium methylate in methanol (Y. Furukawa, Chem. Pharm. Bull.,16, 1076 (1968)), or using any other alcoholate in the corresponding alcohol.

The compounds of formula (II) are used as starting compounds to obtain a large variety of products obtained by reaction of the primary amino group 3-aminoindazole all the classic reactions of this functional group, such as alkylation, acylation, reaction with carbonylcyanide derivative, followed by reduction, sulfonation, conversion into urea or carbamates, atilirovanie (reaction Castro or Buchwald), etc.

Recovery of amino derivatives of General formula (I), where R3 denotes H when Pr means trimethylsilylethynyl, can be carried out using boron derivatives, such as triacetoxyborohydride sodium in dichloromethane in the presence of aldehyde type R1CHO in the conditions described in "Organic Reactions", volume 59, 1-714 (E. Baxter, A. Reitz), or using other was the of vitela, usually used to restore Iminov, with the formation of products, where R3 denotes (C1-C6)alkyl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, heteroseksualci, cycloalkyl, politically, and these radicals can be substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, OR1, COOH, C(O)R1, -O-C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2, SR1, S(O)R1, SO2R1, NHSO2R1, SO2NR1R2, C(S)NR1R2, NHC(S)R1, -O-SO2R1, -SO2-O-R1, aryl, heteroaryl, formyl, trifloromethyl, cryptomelane, cryptometer, (C1-C6)alkyl.

The condensation reaction using derivatives of General formula (I), where R3 denotes H, with isocyanates of the type OCNR1, in particular, can be carried out in tetrahydrofuran and in accordance with the examples described in the book "Comprehensive Organic functionnal Group Transformations, volume 6 (Katritzky, Meth-Cohn, Rees, 1995), with the formation of products, where R3 means CONR1R2; R1, R2, independently of one another, mean a hydrogen atom, (C1-C6)alkyl, aryl, alkenyl, quinil, heteroaryl, and they may themselves be substituted by one or more substituents selected among halogen, (C1-C6)alkyl, (C1-C6)alkoxyl, CN, NO2, NH2, OH, COOH, Coulcil, CONH2, formyl, trifloromethyl, cryptometer.

The sulphonation derivatives total is ormula (I), where R3 denotes H, can be carried out on the basis of sulphonylchloride type R1SO2Cl in the presence of a base (in particular, in the presence of tertiary amines such as triethylamine, or aromatic compounds such as pyridine) in a conventional solvent such as, for example, dichloromethane, education products, where R3 is SO2R1 and R1 means a hydrogen atom, (C1-C6)alkyl, aryl, alkenyl, quinil, heteroaryl, and they may themselves be substituted by one or more substituents selected among halogen, (C1-C6)alkyl, (C1-C6)alkoxyl, CN, NO2, NH2, OH, COOH, Coulcil, CONH2, formyl, trifloromethyl, cryptometer.

The compound of formula (IV), where Pr denotes trimethylsilylethynyl, is a 3-amino-5-phenyl-6-chloro-1-[(2-trimethylsilyloxy)methyl]indazole, and it is derived as follows:

3-amino-5-phenyl-6-chloro-1-[(2-trimethylsilyloxy)methyl]indazol

To 2.4 g of N-[[5-phenyl-6-chloro-1-[(2-trimethylsilyloxy)methyl]indazol-3-yl]]butanamide described below 75 cm3of dimethylformamide add 1,63 cm3ethanolamine, then 2.24 g of potassium carbonate and refluxed during the week. Reaction medium was concentrated to dryness under reduced pressure and treated with 250 cm3ethyl acetate and 100 cm3water. About the organic phase is decanted and washed successively with 2 times 100 cm 3water and 75 cm3the brine. The organic phase is dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2 kPa, 50°C). The resulting crude oil is purified by chromatography under a pressure of argon of 50 kPa on a column of silica gel (grain size distribution of 40-60 μm; diameter 4 cm), elwira with a mixture of cyclohexane and ethyl acetate (ratio 80:20 by volume) and collecting fractions of 35 cm3. The fractions containing the desired product are pooled and evaporated under reduced pressure (2 kPa; 50°C). After drying (90 PA; 45°C) gain of 0.43 g of 3-amino-5-phenyl-6-chloro-1-[(2-trimethylsilyloxy)methyl]indazole in the form of a yellow oil.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6(ppm): -0,05 (N, C); 0,83 (2H, t, J=8 Hz); to 3.52 (2H, t, J=8 Hz); 5,49 (2H, s); of 5.75 (2H, ush. C); from 7,30 to 7.55 (5H, m); to 7.77 (1H, s); 7,81 (1H, s).

N-[[5-phenyl-6-chloro-1-[(2-trimethylsilyloxy)methyl]indazol-3-yl]]butanamide receive the following way:

To 2 g of N-[[5-bromo-6-chloro-1-[(2-trimethylsilyloxy)methyl]indazol-3-yl]]butanamide described below 180 cm3dioxane add 821 mg of phenylboronic acid, 1,14 g of sodium carbonate in 30 cm3distilled water and, finally, 347 mg of tetrakis(triphenylphosphine)palladium. Refluxed for 90 minutes, then stand up to return the temperature to 20°C add 100 cm3ethyl acetate and 100 cm3dis is illirians water. The organic phase is washed with 100 cm3aqueous saturated solution of sodium chloride, then decanted and dried over magnesium sulfate. After filtration through a sintered glass filter, the filtrate is concentrated to dryness under reduced pressure (2 kPa, 50°C). The residue is purified by chromatography under a pressure of argon of 50 kPa on a column of silica gel (grain size distribution of 40-60 μm; diameter 4.5 cm), elwira with a mixture of cyclohexane and ethyl acetate (ratio 80:20 by volume) and collecting fractions of 35 cm3. The fractions containing the desired product are pooled and evaporated under reduced pressure (2 kPa; 50°C). After drying (90 PA; 45°C), thus, receive 2 g of N-[[5-phenyl-6-chloro-1-[(2-trimethylsilyloxy)methyl]indazol-3-yl]]butanamide in the form of a yellow oil.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6(ppm): -0,05 (N, C); 0,85 (2H, t, J=8 Hz); to 0.92 (3H, t, J=7.5 Hz); and 1.63 (2H, m); of 2.38 (2H, t, J=7.5 Hz); of 3.56 (3H, t, J=8 Hz); 5,70 (2H, s); from 7,30 to 7.55 (5H, m); to $ 7.91 (1H, s); 7,99 (1H, s); 10,59 (1H, ush.).

N-[[5-bromo-6-chloro-1-[(2-trimethylsilyloxy)methyl]indazol-3-yl]butanamide receive the following way:

To 1 g of N-[[6-chloro-1-[(2-trimethylsilyloxy)methyl]indazol-3-yl]]butanamide described below 15 cm3chloroform add to 0.22 cm3pyridine, then add to 0.14 cm3bromine. Stirred for 24 hours at 20°C, then add 50 cm3 dichloromethane and 50 cm 3aqueous saturated solution of sodium sulfate. After stirring for 10 minutes, the insoluble portion removed by filtration through a porous glass filter and the organic phase is washed with 50 cm3aqueous saturated solution of sodium chloride. The organic phase is decanted, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2 kPa; 50°C). The residue is purified by chromatography under a pressure of argon of 50 kPa on a column of silica gel (grain size distribution of 40-60 μm; diameter 3.5 cm), elwira a mixture of ethyl acetate and cyclohexane (in a ratio of 20:80 by volume) and collecting fractions of 35 cm3. The fractions containing the desired product are pooled and evaporated under reduced pressure (2 kPa; 50°C). After drying (90 PA; 45°C) gain of 0.94 g of N-[[5-bromo-6-chloro-1-[(2-trimethylsilyloxy)methyl]indazol-3-yl]]butanamide in a solid white color, melting at 130°C.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6(ppm): -0,08 (N, C); 0,82 (2H, t, J=8 Hz); of 0.95 (3H, t, J=7.5 Hz); of 1.66 (2H, m); 2.40 a (2H, t, J=7.5 Hz); 3,52 (3H, t, J=8 Hz); to 5.66 (2H, s); 8,13 (1H, s); a 8.34 (1H, s); 10,67 (1H, ush.).

N-[[6-chloro-1-[(2-trimethylsilyloxy)methyl]indazol-3-yl]]butanamide receive the following way:

To 606 mg of 60%sodium hydride in 20 cm3of dimethylformamide, add 3 g of N-(6-chloro-1H-indazol-3-yl)butanamide in the form of a solution in 0 cm 3of dimethylformamide. After cooling to a temperature of 5°C type of 2.68 cm32-(trimethylsilyl)ethoxymethylene 10 cm3of dimethylformamide. Stand to return the temperature to 21°C and stirred for 2 hours. Reaction medium was then evaporated under reduced pressure (2 kPa; 45°C). The residue is treated with 200 cm3ethyl acetate and 100 cm3of distilled water. Again washed with 2 times 100 cm3distilled water and 100 cm3aqueous saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate, filtered through a porous glass filter, and then evaporated under reduced pressure (2 kPa; 50°C). The residue is purified by chromatography under a pressure of argon of 50 kPa on a column of silica gel (grain size distribution of 40-60 μm; diameter 4.5 cm), elwira with a mixture of cyclohexane and ethyl acetate (ratio 80:20 by volume) and collecting fractions of 100 cm3. The fractions containing the desired product are pooled and evaporated under reduced pressure (2 kPa; 50°C). After drying (90 PA; 50°C) obtain 3 g of N-[[6-chloro-1-[(2-trimethylsilyloxy)methyl]indazol-3-yl]]butanamide in the form of a yellow oil.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6(ppm): -0,08 (N, C); 0,83 (2H, t ush., J=8 Hz); of 0.96 (3H, t, J=7.5 Hz); 1,67 (2H, m); 2.40 a (2H, t, J=7.5 Hz); of 3.53 (2H, t, J=8 Hz); to 5.66 (2H, s); 7,16 (1H, DD, J=9 and 2 Hz); 7,86 (1H, d, J=2, G is); 7,88 (1H, d, J=9 Hz); 10,53 (1H, array).

N-(6-chloro-1H-indazol-3-yl)butanamide

To 750 mg of 3-amino-6-chloro-1H-indazole 10 cm3pyridine, after cooling the reaction medium to a temperature of 3°C, add 0,47 cm3butyrylcholine. Then incubated for 14 hours when returning the environment to a temperature of 19°C. the Reaction medium is evaporated to dryness under reduced pressure (2 kPa; 40°C). The residue is treated with 50 cm3ethyl acetate, 50 cm3of tetrahydrofuran and 50 cm3of distilled water. The organic phase is again washed with 50 cm3distilled water and 50 cm3aqueous saturated solution of sodium chloride, then dried over magnesium sulfate, filtered through a porous glass filter and evaporated under reduced pressure. The resulting residue is purified by chromatography under a pressure of argon of 50 kPa on a column of silica gel (grain size distribution of 40-60 μm; diameter 2.5 cm), elwira with a mixture of cyclohexane and ethyl acetate (in the ratio of 70:30 by volume) and collecting fractions of 25 cm3. The fractions containing the desired product are pooled and evaporated under reduced pressure (2 kPa; 40°C). After drying (90 PA; 45°C) receive 200 mg of N-(6-chloro-1H-indazol-3-yl)butanamide in a solid white color, melting at 230°C.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6(in ppm: 0,98 (3H, t, J=7 Hz); 1,67 (2H, m); 2.40 a (2H, t, J=7 Hz); was 7.08 (1H, DD, J=9 and 2 Hz); 7,52 (2H, d, J=2 Hz); to 7.84 (1H, d, J=9 Hz); accounted for 10.39 (1H, array); between 12.50 to 13.00 (1H, array ush.).

3-amino-6-chloro-5-phenyl-1H-indazol obtained from 3-amino-5-phenyl-6-chloro-1-[(2-trimethylsilyloxy)methyl]indazole.

To 108,3 mg 3-amino-5-phenyl-6-chloro-1-[(2-trimethylsilyloxy)methyl]indazole 4.7 ml of methanol, add 300 μl of 2n HCl. The reaction mixture is exposed to microwave radiation for 150 seconds at a temperature of 140°C. was Poured into a saturated solution KN2RHO4and extracted with ethyl acetate. The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting crude product was then purified on silica and get 63.5 mg 3-amino-6-chloro-5-phenyl-1H-indazole.

The compounds of formula (I) allocate and they can be cleaned by the usual known methods, for example by crystallization, chromatography or extraction.

The compounds of formula (I), if necessary, can be transformed into additive salts of inorganic or organic acids by exposure to this acid in an organic solvent, such as alcohol, ketone, simple ether or a chlorinated solvent. These salts also form part of the invention.

As examples of pharmaceutically acceptable salts can be mentioned the following salts: bansilalpet, hydrobromide, hydrochloride, is itrat, econsultant, fumarate, gluconate, Iodate, maleate, isetionate, methanesulfonate, methylene-bis-β-xinafoate, nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophyllinate and p-toluensulfonate.

The compounds of formula (I) are inhibitors of kinases, and thus suitable for the prevention and treatment of neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, frontoparietal dementia, corticobasal degeneration, diseases of the Peak, cerebrovascular complications, cranial and spinal traumas and peripheral neuropathies, obesity, essential hypertension, atherosclerotic cardiovascular diseases, polycystic ovary syndrome, syndrome X, immunodeficiency and cancer.

Their activity was determined by measuring the inhibition of phosphorylation of tau protein in slices of cerebral cortex of adult rats.

Slices of the cerebral cortex thickness of 300 μm prepared using male OFA rats (Iffa-Credo) at the age of 8-10 weeks, murdered by decapitate. They were incubated in 5 ml of modified according to the method of Dulbecco eagle medium (DMEM)containing pyruvate and glucose at a concentration of 4.5 g/l, at 37°C for 40 minutes. The slices were then washed 2 times with medium, distributed in a microtube (50 ál 500 ál medium with the test compounds Il is without them), and incubated at 37°C under stirring. Two hours later, the experiment was stopped by centrifugation. Sections were literally, was treated with ultrasound and centrifuged with acceleration 18300 g for 15 minutes at 4°C. the protein Concentration in the supernatant was determined by a commercially available device for the quantitative determination (ICA Protein Assay, Pierce)based on the Lowry method.

The samples, previously denatured for 10 minutes at 70°C, separated on a vertical gel 4-12% Bis-Tris, in the presence of buffer MOPS-SDS and subjected to electroblotting on the nitrocellulose. Immunomarkers was performed using monoclonal antibody AD2, which specifically recognize phosphorylated epitopes Ser396/404 tau protein. Immunoreactions proteins were visualized by adding a second antibody directed against mouse IgG and conjugated to peroxidase and chemiluminescent substrate. Received autoradiogram finally quantitatively evaluated using the software package "GeneTools" Syngene (GeneGnome, Ozyme) to determine premaxillae inhibitory concentration (CI50).

The compounds of formula (I) have an interest, activity, and, in particular, some compounds have CI50 below 100 µmol.

Conditions of analysis products according to liquid chromatography/mass spectrometry (LC/MS) implemented in Waters Alliance 2695 for part of liquid chromatography and Waters-Micromass Platform II mass spectral part.

The following examples explain the invention without limiting its scope.

Example A1

N-Butyl-6-chloro-5-phenyl-1H-indazol-3-amine

Stage 1:

24 mg of n-Butyraldehyde and 113 mg of triacetoxyborohydride sodium are added to a solution of 100 mg 3-amino-5-phenyl-6-chloro-1-[(2-trimethylsilyloxy)methyl]indazole 5 cm3dichloromethane. After incubation for 3 hours at room temperature the reaction environment hydrolyzing, then extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and viparivartate crude product by chromatography on silica (eluting agent: ethyl acetate/hexane (in a ratio of 80:20./about.)) allows to obtain 21 mg butyl[6-chloro-5-phenyl-1-(2-trimethylsilylethynyl)-1H-indazol-3-yl]amine (solid yellow).

Mass spectrum: 432 [M+H]+; retention time: 5,26 minutes.

1H-NMR [DMSO-d6], δ, ppm: 7,83 (1H, s); 7,73 (1H, s); 7,35 is 7.50 (5H, m); and 6.25 (1H, t, J=6 Hz); 5,49 (2H, s); to 3.52 (2H, t, J=8 Hz); 3,24 (2H, m)and 1.60 (2H, m); of 1.39 (2H, m); of 0.91 (3H, t, J=7 Hz); 0,81 (2H, t, J=8 Hz); -0,07 (N, C).

Stage 2:

0.7 ml of 2n HCl are added to a solution of 21 mg butyl[6-chloro-5-phenyl-1-(2-trimethylsilylethynyl)-1H-indazol-3-yl]amine 0.3 cm3of methanol. The reaction medium is stirred at room temperature for 48 hours, within 1 hour, refluxed, and then evaporated. P the obtained solid is dried in vacuum, receiving 16 mg of N-butyl-6-chloro-5-phenyl-1H-indazol-3-amine (solid yellow).

Mass spectrum: 300 [M+H]+; retention time: 4.25 minutes.

1H-NMR [DMSO-d6], δ, ppm: 7,52 (1H, s); of 7.95 (1H, s); 7,35 is 7.50 (5H, m); 3,30 (2H, t, J=7 Hz); of 1.61 (2H, m); of 1.40 (2H, m); to 0.92 (3H, t, J=7 Hz).

Example A2

3-(6-chloro-5-phenyl-1H-indazol-3-ylamino)thiophene-2-carbonitrile

To 52 mg of 3-amino-5-phenyl-6-chloro-1-[(2-trimethylsilyloxy)methyl]indazole in 0.5 ml of 1-methyl-2-pyrrolidone (NMP) is added 38 mg of 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 20 mg of Tris(dibenzylideneacetone)diplodia-(0) (Pd2dba3), 52 mg of 2-cyano-3-bromothiophene, 23 mg of trebuchet sodium. The reaction mixture is exposed to microwave radiation for 3 minutes at a temperature of 140°C. After the usual treatments of the crude product is treated with 2n solution of hydrogen chloride in methanol, receiving, after cleaning, and 8.4 mg of 3-(6-chloro-5-phenyl-1H-indazol-3-ylamino)thiophene-2-carbonitrile.

Mass spectrum: 351 [M+H]+; retention time: 4,19 minutes.

1H-NMR [DMSO-d6], δ, ppm: 7,40 (1H, m); of 7.48 (3H, m); 7,53 (3H, m), 7,81 (1H, s); of 8.09 (1H, s); of 8.27 (1H, d, J=5.5 Hz); 8,91 (2H, s).

Examples A3 - A5

Compounds of the following examples to get an equivalent method according to example A2.

No.Name The original productRetention time and[M+H]+NMR (DMSO-d6)a)
A3(6-chloro-5-phenyl-1H-indazol-3-yl)pyridin-2-ylamine2-bromopyridin2,89/3217,07 ppm (1H, ush.); from of 7.36 ppm to 7.50 ppm (5H, m); at 7.55 ppm (1H, ush.); to 7.67 ppm (1H, s); 7,87 ppm (s, 1H); TO 7.95 (1H, ush.); 8,21 ppm (1H, ush.) in CH3D
A4(6-chloro-5-phenyl-1H-indazol-3-yl)-(5-nitropyridine-2-yl)Amin2-bromo-5-nitropyridine4,58/366From 7,42 ppm to 7,52 ppm (5H, m); 7,63 ppm (1H); of 7.65 ppm (1H, s); 7,94 ppm (1H, d, J=9 Hz); 8,43 ppm (1H, DD, J=2.5 to 9 Hz); 9,13 ppm (1H, d, J=2.5 Hz); to 7.77 ppm (1H, ush.); of 9.55 ppm (1H, ush.)
A5(6-chloro-5-phenyl-1H-indazol-3-yl)-(6-methoxypyridine-2-yl)-
Amin
2-bromo-6-methoxypyridinea 3.87 ppm (3H, s); of 6.31 ppm (1H, d, J=7.5 Hz,); of 7.36 ppm (1H, d ush., J=7.5 Hz,); of 7.35 to 7.50 ppm ppm (5H, m); of 7.36 ppm (1H, t, J=7.5 Hz,); rate of 7.54 ppm (1H, s); of 7.69 ppm (1H, ush.) in CDCl3
a): unless otherwise indicated;

Example B1

-(6-chloro-5-phenyl-1H-indazol-3-yl)-N'-prilocaine

Stage 1:

39 μl of phenylisocyanate added to the solution to 102.2 mg 3-amino-5-phenyl-6-chloro-1-[(2-trimethylsilyloxy)methyl]indazole 2.5 cm3tetrahydrofuran (THF). The reaction medium is stirred for 24 hours at room temperature, then evaporated. Purification of the crude product by chromatography on silica (eluting agent: dichloromethane/acetone (in a ratio of 98:2.about.)) lets get 122,5 mg 1-[6-chloro-5-phenyl-1-(2-trimethylsilylethynyl)-1H-indazol-3-yl]-3-phenylacetone (colorless solid).

Mass spectrum: 493 [M+H]+; retention time: 6,02 minutes.

1H-NMR [DMSO-d6], δ, ppm: of 9.89 (1H, ush.); 9,86 (1H, ush.); to 8.20 (1H, s); 8,07 (1H, s); 7,35 is 7.50 (5H, m); of 5.81 (2H, s); 3,66 (2H, t, J=8 Hz); 0,92 (2H, t, J=8 Hz); -0,12 (N, C).

Stage 2:

1 ml of 2n HCl are added to a solution of 106 mg of 1-[6-chloro-5-phenyl-1-(2-trimethylsilylethynyl)-1H-indazol-3-yl]-3-phenylacetone 12 cm3of methanol. The reaction medium is stirred at room temperature for 48 hours, refluxed for 5 hours, then evaporated. The obtained solid is dried in vacuum, obtaining 82 mg of N-(6-chloro-5-phenyl-1H-indazol-3-yl)-N'-phenylacetone (colorless solid).

Mass spectrum: 363 [M+H]+; retention time: 5.15 min.

1H-NMR [DMSO-d6], δ, ppm: 12,64 (1H, ush.); to 9.70 (1H, ush.); 9,59 (1H, ush.); 8,07 (1H, s); to 7.64 (1H, s); to 7.50 (7H, m); 7,30 (2H, m); 7,00 (1H, m).

Example B2

1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(4-ethoxyphenyl)urea

To 80 mg 3-amino-5-phenyl-6-chloro-1-[(2-trimethylsilyloxy)methyl]indazole in 1 ml of tetrahydrofuran type of 36.4 mg 4-ethoxypropionate. Heated at 50°C for 1 hour, and then hydrolyzing in a saturated solution KN2RHO4and extracted with dichloromethane. After drying and evaporation the crude product is purified by chromatography on silica using a mixture of ethyl acetate and hexane. From the resulting product to remove the protective group by boiling under reflux for 3 hours in 2 ml of a mixture of methanol and 2n HCl in a 1:1 ratio. Get 62,5 mg 1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(4-ethoxyphenyl)urea.

Mass spectrum: 407 [M+H]+; retention time: 4.36 minutes.

1H-NMR [DMSO-d6], δ, ppm: 1,3 (1H, t, J=7 Hz); 3,98 (2H, square, J=7 Hz); 6.87 in and of 7.36 (4H, AA'-BB'); OF 7.36-TO 7.50 (5H, m); 7,63 (1H, s); 8,08 (1H, s); at 9.53 (2H, s); of 12.53 (1H, s).

Examples B3-B13

Products B3-B13 get the equivalent for receipt of the product B2 method.

No.NameThe original productRetention time and [M+H]+NMR (DMSO-d6)
B31-(6-chloro-5-phenyl-1H-indazol-3-yl)-(3,4-dichlorophenyl)urea3,4-dichloro-phenylisocyanate4,75/407[M-H]From 7,38 ppm up of 7.48 ppm (6N, m); 7,53 ppm (1H, d, J=8.5 Hz); 7,66 ppm (1H, s); of 7.90 ppm (1H, d, J=2.5 Hz); 8,01 ppm (1H, s); 9,70 ppm (1H, s); 9,84 ppm (1H, s); 12,72 ppm (1H, ush.)
B4methyl ester of 3-[3-(6-chloro-5-phenyl-1H-indazol-3-yl)ureido]propionic acidgeneticization3,71/373of 2.56 ppm (2H, t, J=6.5 Hz); 3,44 ppm (2H, m); 3,61 ppm (3H, s); of 7.36 ppm to 7.50 ppm (5H, m); 7,58 ppm (1H, s); 7,81 ppm (1H, ush.); 8,08 ppm (1H, s); 9,48 ppm (1H, s); to 12.52 ppm (1H, ush.)
B51-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(4-dimethylaminophenyl)urea4-dimethylaminophenyl-isocyanate3,26/4063,10 ppm (6N, C); 7,38 ppm to 7.50 ppm (5H, m); of 7.64 ppm (4H, ush.); 7,66 ppm (1H, s); 8,03 ppm (1H, s); 9,70 ppm (1H, s); 9,95 ppm (1H, s); 12,72 ppm (1H, ush.)
B61-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-isopropylaminoisopropyltoluene3,95/329to 1.16 ppm (6N, d, J=6.5 Hz); of 3.85 ppm (1H m); from 7,38 ppm to 7.50 ppm (5H, m); 7,58 ppm (1H ush.); of 7.60 ppm (1H, s); 8,10 ppm (1H, s); 9,36 ppm (1H, s); 12,48 ppm (1H with ush.)
V71-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-cyclohexylaminocyclohexylsulfamate4,37/369From 1.3 ppm to 1.9 ppm (10H, m); to 3.58 ppm (1H, m); 7,38 ppm to 7.49 ppm (5H, m); EUR 7.57 ppm (1H, s); 7.68 per ppm (1H, d ush., J=5,5 Hz); 8,10 ppm (1H, s); 9,38 ppm (1H, s); 12,48 ppm (1H, ush.)
B81-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(3-triptoreline)urea3 trifter-methylphenylsulfonylbr4.61/4317,34 ppm (1H, d ush., J=8 Hz); 7,38 ppm to 7.49 ppm (5H, m); 7,53 ppm (1H, t, J=8 Hz); 7,66 ppm (1H, s); of 7.69 ppm (1H, d ush., J=8 Hz);7,98 ppm (1H, ush.); 8,03 ppm (1H, s); 9,71 ppm (1H, s); 9,96 ppm (1H, s); 12,76 ppm (1H, ush.)
B91-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(2-thiophene-2-yl-ethyl) - urea2-thiophene-2-yatiletie-
NAT
4,2/397to 3.02 ppm (2H, t, J=7 Hz); 3.46 in ppm (2H, m); 6,92 ppm (1H, DD, J=1.5-to 3.5 Hz); 6,95 ppm (1H, DD, J=3,5-5 Hz); to 7.32 ppm (1H, DD, J=1.5 to 5 Hz); 7,37 ppm to 7.49 ppm (5H, m); 7,58 ppm (1H, s); 7,80 ppm (1H, t ush., J=6 Hz); 8,08 ppm (1H, s); 9,50 ppm (1H, s); 12,48 ppm (1H, ush.)
101-benzo[1,3]dioxol-5-yl-3-(6-chloro-5-phenyl-1H-indazol-3-yl)-urine-
wine
1-benzo[1,3]dioxol-5-isocyanate4,19/4075,97 ppm (2H, s); for 6.81 ppm (1H, DD, J=2,5-8,5 Hz); at 6.84 ppm (1H, d, J=8.5 Hz); 7,22 ppm (1H, d, J=2.5 Hz); of 7.35 to 7.50 ppm ppm (5H, m); the 7.65 ppm (1H, s); 8,05 ppm (1H, s); by 9.56 ppm (1H, s); and 9.6 ppm (1H, s); 12,65 ppm (1H, ush with.)
B111-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(3,5-dimethylisoxazol-4-yl)urine-wine3,5-dimethylisoxazol-4-
isocyanate
3,76/3822,13 ppm (3H, s); to 2.29 ppm (3H, s); of 7.36 ppm to 7.50 ppm (5H, m); of 7.64 ppm (1H, s); 8,03 ppm (1H, s); rate of 8.75 ppm (1H, s); 9,74 ppm (1H, s); 12,68 ppm (1H, ush.)
B121-benzyl-3-(6-chloro-5-phenyl-1H-indazol-3-yl)ureabenzylsuccinic4,2/3774,43 ppm (2H, d, J=6 Hz); 7.20 to 7.50 ppm ppm (10H, m); 7,58 ppm (1H, s); 8,10 ppm (1H with ush.); to 9.57 ppm (1H, s); 12,50 ppm (1H, s)
B131-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-penetrtiongeneticisation2,96 ppm (2H, t, J=7.0 Hz); 3,86 ppm (2H, dt, J=5.5 and 7.0 Hz); about what to 7.15 ppm to 7.35 ppm (5H, m); of 7.35 to 7.50 ppm ppm (5H, m); of 7.64 ppm (1H, s); of 8.37 ppm (1H, s); 10,14 ppm (1H, t, J=5.5 Hz); 10,97 ppm (1H, s); of 12.73 ppm (1H, ush.)

Example C1

1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-[3-(4-methylpiperazin-1-yl)propyl]urea

Stage 1:

to 387,8 mg 3-amino-5-phenyl-6-chloro-1-[(2-trimethylsilyloxy)methyl]indazole in 2 ml of dichloromethane added sequentially 62 μl of pyridine and 125 ál ethylchloride. After 75 minutes the reaction ends. After hydrolysis, extraction and evaporation receive 571 mg of the crude carbamate: ethyl ether (6-chloro-5-phenyl-1H-indazol-3-yl)carbamino acid.

Stage 2:

to 106 mg videolooking carbamate in 2.5 ml of triptoreline add 377 mg of 3-aminopropyl-1-methylpiperazine and the reaction is carried out under the influence of microwave radiation for 20 minutes at 200°C. After purification using preparative liquid chromatography with mass spectrometry (acetonitrile/buffer, pH 9) receive 60 mg of 1-[6-chloro-5-phenyl-1-(2-trimethylsilylethynyl)-1H-indazol-3-yl]-3-[3-(4-methylpiperazin-1-yl)propyl]urea.

Stage 3:

visaelectron connection is treated with 2 ml of a mixture of methanol and 2n HCl in a ratio of 1:1 and refluxed for 3 hours.

1H-NMR [DMSO-d6], δ, ppm: 1,63 (2H, m); to 2.18 (3H, s); 2,33 (10H, m); is 3.21 (2H, m); of 7.36-of 7.48 (5H, m); 7,58 (1H, s); 7,66 (1H, t, J=5.5 Hz); 8,08 (1H,s); 9,37 (1H, s); 12,70 (1H, s).

Examples of C2 - C19

Products C2-C19 get the equivalent for receipt of the product S1 method.

No.NameThe original productRetention time and[M+H]+NMR (DMSO-d6)
C21-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(3-imidazol-1-ylpropyl)
urea
3-imidazolyl-1-
Amin
3/395is 2.05 ppm (2H, m); 3.24 in ppm (2H, m); 4.25 in ppm (2H, t, J=6 Hz); 7,38 ppm to 7.49 ppm (5H, m); to 7.61 ppm (1H, s); of 7.69 ppm (1H, ush.); 7,76 ppm (1H, d, J=5.5 Hz); 7,83 ppm (1H, ush.); 8,08 ppm (1H, s); 9,19 ppm (1H, s); at 9.53 ppm (1H, s); 12,53 ppm (1H, ush.)
C41-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(2-hydroxyethyl)ureaEthanolamine3,36/331with 3.27 ppm (2H, m); 3,49 ppm (2H, t, J=6.5 Hz); 7,38 ppm to 7.50 ppm (5H, m); to 7.59 ppm (1H, s); 7,83 ppm (1H, ush.); 8,10 ppm (1H, s); 9,49 ppm (1H, s); 12,50 ppm (1H, ush.)
C51-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-[3-(4-methylpiperazin-1-yl)propyl]urea(4-methyl who piperazin-1-yl)
Propylamine
2,52/427
C6(6-chloro-5-phenyl-1H-indazol-3-yl)-amide pyrrolidin-1-carboxylic acidPyrrolidin4/340of 1.84 ppm (4H, m); 3,37 ppm (4H, m); 7,37 ppm to 7.49 ppm (5H, m); to 7.61 ppm (1H, s); 7,72 ppm (1H, s); 8,80 ppm (1H, s); br12.62 ppm (1H, s)
C7methyl ester (6-chloro-5-phenyl-1H-indazol-3-yl)carbamino acidmethylchloroform4,1/3023,66 ppm (3H, s); 7,33 ppm to 7.49 ppm (5H, m); the 7.65 ppm (1H, s); 7,78 ppm (1H, s); a 10.1 ppm (1H, s); 12,80 ppm (1H, s)
C8(6-chloro-5-phenyl-1H-indazol-3-yl)ureathe ammonium hydroxide3,39/2876,89 ppm (2H, ush.); from 7,37 ppm to 7.49 ppm (5H, m); to 7.59 ppm (1H, s); of 8.09 ppm (1H, s); 9,37 ppm (1H, s); 12,51 ppm (1H, ush.)
C9benzyl ether(6-chloro-5-phenyl-1H-
indazol-3-yl)carbamino acid
benzylchloride4,5/3785,14 ppm (2H, s); 7,29 ppm to 7.49 ppm (10H, m); the 7.65 ppm (1H, s); 7,76 ppm (1 is, C); 10,08 ppm (1H, ush.); 10,77 ppm (1H, ush.)
C10allyl ether(6-chloro-5-phenyl-1H-
indazol-3-yl)carbamino acid
allylchloroformate4,4/328br4.61 ppm (2H, d ush., J=5 Hz); a total of 5.21 ppm (2H, d ush., J=11 Hz); of 5.34 ppm (1H, d ush., J=17.5 Hz); 5,96 ppm (1H, m); from 7,39 ppm to 7.49 ppm (5H, m); the 7.65 ppm (1H, s); 7,78 ppm (1H, s); 10,06 ppm (1H, ush.); 12,76 ppm (1H, ush.)
C11isobutyl ether (6-chloro-5-phenyl-1H-indazol-3-yl)carbamino acidisobutylparaben4,55/344of 0.90 ppm (6N, d, J=6.5 Hz); 1,90 ppm (1H, m); 3,86 ppm (2H, d, J=6.5 Hz); 7,38 ppm to 7.49 ppm (5H, m); 7,66 ppm (1H, s); 7,79 ppm (1H, s); to 9.93 ppm (1H, ush.); 12,93 ppm (1H, ush.)
C12(6-chloro-5-phenyl-1H-indazol-3-yl)amide piperidine-1-carboxylic acidpiperidineto 3.92/355of 1.40 ppm (4H, m)and 1.60 ppm (2H, m); 3,43 ppm (4H, m); 7,37 ppm to 7.50 ppm (5H, m); to 7.61 ppm (1H, s); a 7.62 ppm (1H, s); 9,07 ppm (1H, s); br12.62 ppm (1H, s)
C131-(3-azetidin-1-yl-propyl)-3-(6-chloro-5-phenyl-1H-indazol-3-yl)ureaazetidin (double prisoedinenie) of 1.50 ppm (2H, m); 2,02 ppm (1H, m); 3,20 ppm (2H, m); of 2.54 ppm (2H, masqué); with 3.27 ppm (4H, mascqué); of 7.35 to 7.50 ppm ppm (5H, m); to 7.59 ppm (1H, s); 7,72 ppm (1H, t ush., J=6 Hz); of 8.09 ppm (1H, s); 9,44 ppm (1H, s); 12,50 ppm (1H, s)
C141-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(3-chlorpropyl)ureaazetidin (disclosure, HCl)4.26 deaths/363of 1.94 ppm (2H, m); 3,30 ppm (2H, masqué); of 3.60 ppm (2H, t, J=6.5 Hz); 7,38 ppm to 7.50 ppm (5H, m); 7,58 ppm (1H, s); 7,60 ppm (1H, t ush., J=6 Hz); 8,07 ppm (1H, s); 9,40 ppm (1H, s); 12,41 ppm (1H, s)
C151-(6,7-debtor-5-phenyl-1H-
indazol-3-yl)-3-(3-imidazol-1-ylpropyl)
urea
3-imidazol-1-ylpropyl
Amin
of 1.94 ppm (2H, m); 3,18 ppm (2H, square, J=6.5 Hz); as 4.02 ppm (2H, t, J=6.5 Hz); 6.89 in ppm (1H, s); 7,21 ppm (1H, s); 7,42 ppm (1H, t ush., J=7.5 Hz); 7,50 ppm (2H, t ush., J=7.5 Hz); at 7.55 ppm (1H, d ush., J=7.5 Hz); the 7.65 ppm (1H, s); 7,73 ppm (1H, t ush., J=6.5 Hz); 8,05 ppm (1H, d, J=6.0 Hz); 9,58 ppm (1H, s)
C161-(3-aminopropyl)-3-(6-chloro-5-phenyl-1H-indazol-3-yl)urea3-aminopropylene2,74/344to 1.77 ppm (2H, m); 2,81 ppm (2H, m); for 3.28 ppm (2H, m); 7,38 m is. to 7.50 ppm (5H, m); 7,60 ppm (1H, s); 7,81 ppm (3H, m); 8,08 ppm (1H, s); 9,54 ppm (1H, s); 12,54 ppm (1H, ush.)
C171-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-[4-(4-pyridine-3-eliminator-1-yl)butyl]urea4-(4-pyridine-3-eliminator-1-yl)butylamine2,95/486is 1.51 ppm (2H, m); 1,90 ppm (2H, m); 3,26 ppm (2H, m); to 4.23 ppm (2H, t, J=7 Hz); 7,37 ppm to 7.49 ppm (5H, m); 7,58 ppm (1H, s); of 7.75 ppm (2H, m); 8,08 ppm (1H, s); of 8.37 ppm (1H, d, J=2 Hz); of 8.47 ppm (1H, m); 8,69 ppm (1H, DD, J=1.5 to 5 Hz); 9,00 ppm (1H, ush.); 9,12 ppm (1H, d, J=2 Hz); 9,48 ppm (1H, s); 12,40 ppm (1H, ush.)
C181-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(2-pyrrolidin-1-retil)
urea
(2-pyrrolidin-1-retil)
Amin
2,8/384to 1.83 ppm (2H, m); 1,99 ppm (2H, m); 3,03 ppm (2H, m); for 3.28 ppm (2H, m); of 3.56 ppm (4H, masqué); of 7.36 ppm to 7.49 ppm (5H, m); to 7.61 ppm (1H, s); 7,80 ppm (1H, t ush., J=5.5 Hz); 8,08 ppm (1H, s); 9,65 ppm (1H, s); 10,02 ppm (1H, ush.); br12.62 ppm (1H, ush.)
C19(6-chloro-5-phenyl-1H-indazol-3-yl)amide 2,5-dimethylpyridin-1-
carboxylic acids
2,5-dimethylpyridin4,08/3691,10 and to 1.21 ppm (6N, d, J=7 Hz); 1.50 for and 1.61 ppm (2H, m); 1.99 and a 2.12 ppm (2H, m); 4,03 4,15 ppm (2H, m); of 7.36 ppm to 7.49 ppm (5H, m); 7,60 ppm (1H, s); to 7.67 and 7.69 ppm (1H, s); charged 8.52 and 8,66 ppm (1H, s); 12,60 ppm (1H, ush.)

Example D1

N-(6-chloro-5-phenyl-1H-indazol-3-yl)acetamide

To 50 mg of 3-amino-6-chloro-5-phenyl-1H-indazole in 3 ml of acetonitrile and 12 mg of acetic acid are added 33 mg of methylacetanilide. The reaction mixture is exposed to microwave radiation for 5 minutes at 180°C. After the usual treatment and purification on silica obtain 35 mg of N-(6-chloro-5-phenyl-1H-indazol-3-yl)acetamidine.

Examples D2 - D4

The following products will receive the equivalent for receipt of the product D1 method.

No.NameThe original productRetention time and[M+H]+NMR (DMSO-d6)
D21N-(6-chloro-5-phenyl-1H-indazol-3-yl)-6-methoxypyrazine-2-
carboxamidine
6-methoxypyrazine-2-toximia3,61/3794,08 ppm (3H, s); 7,40 ppm to 7.50 ppm (5H, m); 7.68 per ppm (1H, s); of 7.93 ppm (1H, s); 8,24 ppm (1H, ush.); 8,43 ppm (1H, s); 8,69 ppm (1H, ush.); 9,27 ppm (1H, s); 12,80 ppm (1H, s)
D3generationid3,42/347From of 7.36 ppm to 7.50 ppm (8H, m); of 7.64 ppm (1H, s); 7,80 ppm (1H, s); 8,12 ppm (2H, m); 8,24 ppm (1H, ush.); 8,76 ppm (1H, ush.); 8,76 ppm (1H, ush.); 12,60 ppm (1H, ush.)
D4N-(6-chloro-5-phenyl-1H-indazol-3-yl)pyridine-2-carboxamidepyridyl-2-toximiaFrom of 7.35 to 7.50 ppm ppm (5H, m); rate of 7.54 ppm (1H, DD, J=5.0 and 7.5 to); to 7.67 ppm (1H, s); 7,87 ppm (1H, s); 7,94 ppm (1H, dt, J=1.5 and 7.5 Hz); 8,30 ppm (1H, ush.); 8,58 ppm (1H, d, J=7.5 Hz); 8,64 ppm (1H, ush.); 8,58 ppm (1H, DD, J=1.5 and 5.0 Hz); 12,70 ppm (1H, ush.)

Example E1

N-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-methoxybenzenesulfonamide

Stage 1:

0,236 cm3pyridine and 26.5 mg 3-methoxyphenylacetonitrile added to a solution of 54.1 mg 3-amino-5-phenyl-6-chloro-1-[(2-trimethylsilyloxy)methyl]indazole 2 cm3dichloromethane. The reaction medium is stirred for 24 hours at room temperature, then evaporated. Purification of the crude product by chromatography on silica gel (buywise tool: dichloromethane/acetone (in a ratio of 98:2.about.)) allows to obtain 70 mg 1N-[6-chloro-5-phenyl-1-(2-trimethylsilylethynyl)-1H-indazol-3-yl]-3-methoxybenzenesulfonamide (beszvetnaya).

Mass spectrum: 546 [M+H]+; retention time: 4,24 minutes.

1H-NMR [DMSO-d6], δ, ppm: 7,37 (1H, s); 7,58 (1H, s); 7,30-of 7.55 (8H, m); 7,17 (1H, DD); 5,63 (2H, s); 3,74 (3H, s); to 3.38 (2H, t, J=8 Hz); 0,74 (2H, t, J=8 Hz); -0,12 (N, C).

Stage 2:

1 cm32n HCl are added to a solution 10,8 mg 1N-[6-chloro-5-phenyl-1-(2-trimethylsilylethynyl)-1H-indazol-3-yl]-3-methoxybenzenesulfonamide 1 cm3of methanol. The reaction medium is stirred at room temperature for 48 hours, refluxed for 1 hour, then viparivartate the solid is dried in vacuum, receiving 8 mg of N-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-methoxybenzenesulfonamide (colorless solid).

Mass spectrum: 414 [M+H]+; retention time: 4,04 minutes.

1H-NMR [DMSO-d6], δ, ppm: 12,90 (1H, ush.); a 10.74 (1H, ush.); to 7.67 (1H, s); 7,31-7,56 (10H, s); then 7.20 (1H, DD); of 3.77 (3H, s).

The pharmaceutical compositions according to the invention is formed by a compound of the formula (I) or the salt of such compounds in a pure state or in the form of a composition in which it associated with any other pharmaceutically acceptable product, which can be inert or physiologically active. Medicinal product according to the invention can be administered orally, parenterally, rectally or locally.

As solid compositions for administration orally can be and is used tablets pills, powders (gelatin capsules, starch wafers or pellets. In these compositions, the active principle according to the invention are mixed in a stream of argon with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica. These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a protective coating (coated tablets) or a varnish.

As liquid compositions for oral administration can be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. These compositions can comprise substances other than diluents, for example wetting, sweetening, thickening agents, flavoring agents or stabilizers.

Sterile compositions for parenteral administration can be a preferably aqueous or nonaqueous solutions, suspensions or emulsions. As a solvent or excipient you can use water, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, suitable for injectable organic esters, such as, for example, etiloleat, or other acceptable organic is such solvents. These compositions can also contain additives, in particular wetting, isotonic components, emulsifiers, dispersing agents and stabilizers. Sterilization may be accomplished in several ways, for example by asamisimasa filtration, by incorporating in the composition of sterilizing agents, by irradiation or by heating. They can also be obtained in the form of sterile solid compositions, which at the time of use can be dissolved in sterile water or any other sterile environment for injection.

Compositions for rectal injection are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Compositions for local application can be, for example, creams, lotions, lotions for the eyes, the liquid for rinsing the mouth and appliques on the gums, nasal drops or aerosols.

The object of the invention is aminoindazole formula (I) and their pharmaceutically acceptable salts, used to obtain pharmaceutical compositions intended for the prevention and treatment of diseases that can arise from abnormal activity of kinases, such as protein kinases involved in neurodegenerative diseases, diseases And is of lzgamer, Parkinson's disease, frontoparietal dementia, corticobasal degeneration, diseases of the Peak, cerebrovascular complications, cranial and vertebral traumas and peripheral neuropathies, obesity, metabolic diseases, type II diabetes, essential hypertension, atherosclerotic cardiovascular diseases, polycystic ovary syndrome, syndrome X, immunodeficiency and cancer.

As abnormal activity of the kinase can be called, for example, such RK, AkT, GSK3-β, CDK's...

In human therapy, the compounds according to the invention is particularly suitable for the treatment and/or prevention of neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, frontoparietal dementia, corticobasal degeneration, diseases of the Peak, cerebrovascular complications, cranial and spinal traumas and peripheral neuropathy, obesity, metabolic diseases, type II diabetes, essential hypertension, atherosclerotic cardiovascular diseases, polycystic ovary syndrome, syndrome X, immunodeficiency and cancer.

Doses depend on the desired effect, the duration of treatment and the route of administration; they typically range from 5 mg to 1000 mg per day orally for an adult with single doses of 1 mg to 250 mg of active substance.

In General, the physician determines correspond to the second dosage depending on the age, weight and all other factors inherent to the patient.

The following examples illustrate compositions according to the invention.

An example of a

Prepared according to conventional methods, gelatin capsules with doses of 50 mg of active start having the following composition:

the compound of formula (I)50 mg
cellulose18 mg
lactose55 mg
the gel of silicic acid1 mg
sodium salt of carboxymethyl amylum10 mg
talc10 mg
magnesium stearate1 mg

The EXAMPLE IN

Prepared according to conventional methods, pills with doses of 50 mg of active start having the following composition:

the compound of formula (I)50 mg
lactose104 mg
cellulose40 mg
pariston10 mg
sodium salt of carboxymethyl amylum22 mg
talc10 mg
magnesium stearate2 mg
the gel of silicic acid2 mg
a mixture of hydroxymethylcellulose, glycerin,
titanium dioxide (72-3,5-24,5), enough for 1 tablet, coated with a thin film, with the ultimate weight
245 mg

EXAMPLE WITH

Prepare a solution for injection containing 10 mg of active product of the following composition:

the compound of formula (I)10 mg
benzoic acid80 mg
benzyl alcohol : 0.06 ml
sodium benzoate80 mg
ethanol, 95%0.4 ml
sodium hydroxide24 mg
propylene glycol1.6 ml
water to a total volume4 ml

The present invention relates also to a method for prevention and treatment of diseases in which occur the phosphorylation of Tau protein by introducing the compounds of formula (I) and its pharmaceutically acceptable salts.

1. The compounds of formula (I)

in which R5 represents aryl, aryl(C1-C6)alkyl;
R6 represents halogen;
R3 means (C1-C6)alkyl, possibly substituted by substituents selected from halogen, HE, NH2azetidine; or monocyclic aryl or heteroaryl, such as thiophene, pyridine, possibly substituted by substituents selected from the NO2CN, (C1-C6)alkoxy, (C1-C6)alkyl; or CONR1R2, SO2Ra, C(=NH)R1b, COOR1c;
R1, R2 independently from each other represent a hydrogen atom, possibly substituted by one halogen atom (C1-C6)alkyl, monocyclic aryl or monocyclic 5 - or 6-membered heteroaryl comprising 1 to 2 heteroatoms, such as S, O, N, possibly substituted by one or more substituents selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxyl, trifloromethyl, N(CH3)2; or
R1 and 2 may form a 5 - or 6-membered cycle, optionally containing heteroatom, such as N;
R1adenotes aryl, possibly substituted (C1-C6)alkoxyl;
R1bmeans (C1-C6)alkyl, possibly substituted aryl or 6-membered heteroaryl containing 1 or 2 N atom, where the Deputy is a (C1-C6)alkoxyl;
R1cmeans (C1-C6)alkyl, (C2-C6)alkenyl;
and their pharmaceutically acceptable salts.

2. The compound according to claim 1, characterized in that it is chosen from the group consisting of:
N-butyl-6-chloro-5-phenyl-1H-indazol-3-amine;
3-(6-chloro-5-phenyl-1H-indazol-3-ylamino)thiophene-2-carbonitrile;
(6-chloro-5-phenyl-1H-indazol-3-yl)pyridine-2-ylamine;
(6-chloro-5-phenyl-1H-indazol-3-yl)-(5-nitropyridine-2-yl)amine;
(6-chloro-5-phenyl-1H-indazol-3-yl)-(6-methoxypyridine-2-yl)amine;
N-(6-chloro-5-phenyl-1H-indazol-3-yl)-N'-prilocaine;
1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(4-ethoxyphenyl)urea;
1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(3,4-dichlorophenyl)urea;
1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(4-dimethylaminophenyl)urea;
1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-Isopropylamine;
1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(3-triptoreline)urea;
1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(3,5-dimethylisoxazol-4-yl)urea;
(6-chloro-5-phenyl-1H-indazol-3-yl)amide, pyrrolidin-1-carboxylic acid;
methyl ester(6-chloro-5-phenyl-1H-indazol-3 and is)carbamino acid;
(6-chloro-5-phenyl-1H-indazol-3-yl)urea;
allyl ether(6-chloro-5-phenyl-1H-indazol-3-yl)carbamino acid;
isobutyl ether(6-chloro-5-phenyl-1H-indazol-3-yl)carbamino acid;
(6-chloro-5-phenyl-1H-indazol-3-yl)amide piperidine-1-carboxylic acid;
1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(3-chlorpropyl) urea;
N-(6-chloro-5-phenyl-1H-indazol-3-yl)acetamidine;
N-(6-chloro-5-phenyl-1H-indazol-3-yl)-6-methoxypyrazine-2-carboxamidine;
N-(6-chloro-5-phenyl-1H-indazol-3-yl)benzamidine;
N-(6-chloro-5-phenyl-1H-indazol-3-yl)pyridine-2-carboxamidine;
N-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-methoxybenzenesulfonamide;
and their pharmaceutically acceptable salts.

3. The compound according to any one of claims 1 or 2, is used to obtain a drug that inhibits the phosphorylation of protein tai.

4. Pharmaceutical composition having inhibitory activity against protein tai, characterized in that it contains, in a pharmaceutically acceptable medium, a compound according to any one of claims 1 and 2.

5. The method of obtaining compounds of formula (I), such as specified in claim 1, where R3 denotes (C1-C6)alkyl, and R1 denotes a (C1-C6)alkyl based on a derivative of formula (I), where R3 denotes H, derived R1CHO and triacetoxyborohydride sodium in dichloromethane.

6. The method of obtaining compounds of formula (I), such as specified in claim 1, ihde R3 means CONR1R2; R1, R2 independently from each other, represent a hydrogen atom, possibly substituted by one halogen atom (C1-C6)alkyl, monocyclic aryl or monocyclic 5 - or 6-membered heteroaryl comprising 1 to 2 heteroatoms, such as S, O, N, possibly substituted by one or more substituents selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxyl, trifloromethyl; based on OCNR1 and derivative of the formula (I), where R3 denotes H, in tetrahydrofuran.

7. The method of obtaining compounds of formula (I), such as specified in claim 1, where R3 is SO2R1, and R1 denotes a monocyclic aryl, possibly substituted (C1-C6)alkoxyl; based on sulphonylchloride R1SO2Cl and derivative of the formula (I), where R3 denotes H, in dichloromethane in the presence of a base.

8. Compounds selected from the group consisting of:
3-amino-5-phenyl-6-chloro-1-[(2-trimethylsilyloxy)methyl]indazol;
N-[[5-phenyl-6-chloro-1-[(2-methylcellulose)methyl]indazol-3-yl]]butanamide;
N-[[5-bromo-6-chloro-1-[(2-trimethylsilyloxy)methyl]indazol-3-yl]]butanamide;
N-[[6-chloro-1-[(2-trimethylsilyloxy)methyl]indazol-3-yl]]butanamide,
as intermediate products for use in the method according to any of pp.5-7.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of benzoindazole of formula I , where radicals A1, A2, A3, R1, R2, R3, R4 and n have values mentioned in formula of invention, and their pharmaceutically acceptable salts, and also to application of these compounds for production of medicinal agent intended for modulation of α2-subsort of GABA receptor, and pharmaceutical composition that contains it.

EFFECT: application of compounds for preparation of medicinal agent intended for treatment of depression, disorder in the form of anxiety, psychic disorder, disturbed ability to learning and cognition, sleep disturbance, disorder in the form of cramps or fits or pain.

16 cl, 5 tbl, 40 ex

FIELD: medicine.

SUBSTANCE: invention is related to compounds with common formulae I , III , IV and V , value of radicals such as given in formula of invention. Also suggested invention is related to pharmaceutical composition in the basis of above-mentioned compounds, to their use, and also to method of frequent urination treatment, enuresis and increased activity of urinary bladder.

EFFECT: increased efficiency of diseases treatment, in particular for treatment of frequent urination and enuresis, increased activity of urinary bladder and pain.

16 cl, 406 ex, 73 tbl

V:

FIELD: medicine.

SUBSTANCE: there are described derivatives of 1,3,4-oxadiazol-2-one of formula I and their pharmaceutically acceptable salts wherein ARYL represents phenyl which can have one substitute chosen from halogen; W represents chain or (CH2)m where m designates an integer 1 to 4; Z represents -O(CH2)n-, -(CH2)n-Y-(CH2)n- where Y designates O, n independently means an integer 1 to 5; X represents O or S; R1 represents C1-6 alkyl; R2 represents substituted phenyl where substitutes are chosen from the group including C1-6alkyl, C1-4perfluoralkyl. There are also described pharmaceutical composition, and method of treating a disease in mammal wherein said disease can be modulated by PPAR-delta receptor binding activity.

EFFECT: compounds possess agonist or antagonist activity with respect to PPAR-delta receptor.

9 cl, 2 tbl, 34 ex

Amide derivatives // 2375352

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I, to its pharmaceutically acceptable salts exhibiting properties of inhibitors of cytokine production, such as TNF (tumour necrosis factor) and various members of interleukins (IL) family, and properties of kinase inhibitors, particularly p38α kinase. The invention also concerns methods for producing; pharmaceutical compositions and application thereof for making the medicines for treating diseases affected by the compound of the invention with specified activity. In formula I , m represents 0, 1 or 2; R1 represents halogeno, hydroxy, (1-6C) alkyl, (1-6C)alkoxy, (2-6C)alkenyl, (2-6C) alkinyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, amino-(2-6C) alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, N-(1-6C)alkylcarbamoyl - (1-6C)alkoxy, di[(1-6C) alkyl]amino-(1-6C)alkyl, hydroxy-(2-6C)alkylamino, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclyloxy and heterocyclyl-(1-6C)alkoxy and wherein any heteroaryl or heterocyclyl group in substitute representing R1, can probably have 1 or 2 substitutes chosen from hydroxy, halogeno, (1-6C) alkyl, (2-6C)alkinyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxycarbonyl, (2-6C) alkanoyl, halogen-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, carboxy- (1-6C)alkyl and methylsulphonyl and wherein any said substitute representing R1 which contains group CH2 attached to 2 carbon atoms, or group CH3 attached to carbon or nitrogen atom, can probably have with each specified group CH2 or CH3, one or two substitutes chosen from halogeno, hydroxy, amino, triflouromethyl, oxo, carboxy, acetamido, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkyamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, halogen-(1-6C)alkyl, (1-6C)alkoxycarbonyl, carbamoyl, N, N-di-[(1-6)alkyl]carbamoyl, (1-6C)alkylsulphonyl, heteroaryl, heteroaryl-(1-6)alkyl and heterocyclyloxy and wherein any heterocyclyl group in substitute representing R1, can probably have 1 oxo-subsitute; R2 represents trifluoromethyl or (1-6C)alkyl; R3 represents hydrogen or (1-6C)alkyl; and R4 represents (3-6C)cycloalkyl, and R4 can be optionally substituted with one or more substitutes chosen from (1-6C)alkyl; and wherein heteroaryl represents aromatic 5- or 6-merous monocyclic ring containing one or two heteroatoms chosen from oxygen, nitrogen and sulphur; heterocyclyl represents saturated 3-10-merous monocyclic or bicyclic ring, each containing one or two heteroatoms chosen from oxygen, nitrogen and sulphur.

EFFECT: improved efficiency.

24 cl, 16 tbl, 66 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treatment and prevention of diseases associated with activity of specified enzyme, such as diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension. In general formula (I) , R1 represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropyl methoxymethyl, 2-methyl thiazolyl, morpholinyl methyl or phenyl; R2 represents hydrogen, C1-4alkyl or phenyl; R3 represents hydrogen, C1-4alkyl or phenyl; R4 represents phenyl, naphthyl, thiophenyl, quinolyl or piperidyl where phenyl, naphthyl, thiophenyl, quinolyl and piperidyl are optionally substituted with one to three substitutes independently chosen of C1-4alkyl, halogen, C1-4alkoxy, cyano, trifluoromethyl, phenyl, phenyls C1-4alkyl, phenyloxy, oxasolyl and pyridinyl; R5 represents hydrogen, C1-4alkyl, phenyl-C1-4alkyl, C3-6dicloalkyl-C1-4alkyl or aminocarbonylC1-4alkyl.

EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (ZP) , in which U is a CH group, V is an oxygen atom, W is a hydroxyl-substituted heterocycloalkylene group which contains 5 to 7 atoms in the ring, including an N atom as a heteroatom, X is an oxygen atom, Y is , Z is C1-C6-alkylene group. Invention also relates to use of invented compounds to produce compounds of formula (I) , in which A is a nitrogen atom or CH group.

EFFECT: wider field of use of compounds.

6 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted 2-[2-(3-oxomorpholin-4-yl)ethylthio]benzimidazoles of general formula: , where R1, R2, R3, R4, R5 are identical or different: H, lower alkyls or alkoxy groups.

EFFECT: obtaining new compounds with anxiolytic properties, which allows for their potential use in medicine for treating neuropsychic disorders.

2 cl, 4 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I), compounds, , their pharmacologically acceptable salt, solvate and hydrate, where A is an alkylene group, alkenyl group, alkynyl group, heteroalkylene group, cycloalkylene group, heterocylcoalkylene group, arylene group or heteroarylene group, where each of the said groups can be substituted, Q is CR4, X is CR7 or N, Y is CR6 or N, n equals 1, 2 or 3, m equals 1, 2 or 3, R1 is H, F, Cl, Br, I, OH, NH2, alkyl group or heteroalkyl group, R is H, F or Cl, R3 is H, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkylaryl group or heteroarylalkyl group, where each of the said groups can be substituted with one, two or more halogen atoms or amino groups, R4 is hydroxy, a group with formula OPO3R92 or OSO3R10 or a heteroalkyl group, containing at least one OH, NH2, SO3R10, PO3R92 or COOH group or ester group of natural amino acid or its derivative, where R9 groups independently represent H, alkyl, cycloalkyl, aryl or aralkyl, and R10 is H, alkyl, cycloalkyl, aryl or aralkyl, and further values of R5, R6, R7 and R8 are given in the formula of invention. The invention also relates to pharmaceutical compositions with antibacterial activity, containing compounds described above, as well as to use of formula (I) compounds and a pharmaceutical composition for treating bacterial infection.

EFFECT: new compounds are obtained and described, which can be used as antibacterial agents and which are effective against multi-drug resistant bacteria.

18 cl, 32 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel sulphonamide derivatives of general formula (I) , where R1 is phenyl, thiophenyl or furanyl, unsubstituted or substituted with one or two substitutes selected from a group consisting of halogen, lower alkyl, lower alkyl substituted with halogen, -O-lower alkyl substituted with halogen, NO2 or CN; R2-R4 and R2'-R4' is hydrogen, lower alkyl, phenyl or lower alkyl substituted with halogen; R5 is phenyl, pyridinyl, benzo[1,3]dioxolyl or benzofuranyl, unsubstituted or substituted with 1-3 substitutes selected from a group consisting of halogen, lower alkyl, lower alkyloxy, CN, nitro, amino, hydroxy, lower alkyl substituted with hydroxy, lower alkyl substituted with halogen, or substituted with -C(O)-NR"2, -(CR2)m-C(O)-R', -(CH2)m-heteroaryl, unsubstituted or monosubstituted -(CH2)m-lower alkoxy, lower alkyl, -(CH2)m-O-benzene or CH2OH, -O-C(O)-lower alkyl, -O-C(O)-NR2, -O-(CH2)m-C(O)OH, -O-lower alkynyl, -O-lower alkyl, substituted with halogen, -O-(CH2)m-heterocyclyl, -O-(CH2)m-phenyl, unsubstituted or monosubstituted hydroxy, -O-(CH2)m-heteroaryl, unsubstituted or monosubstituted with lower alkyl, -(CH2)m-NH-C(O)R', -(CH2)m-NH-S(O)2-R', -S(O)2-lower alkyl, -S(O)2-heterocyclyl, -S(O)2NH-cycloalkyl, or is C3-6cycloalkyl; R' is hydrogen, lower alkyl, lower alkynyloxy, hydroxy, C3-6cycloalkyl, heterocyclyl, which is unsubstituted or substituted with one or two substitutes selected from COOH, -C(O)O-lower alkyl, halogen or lower alkyl, or is phenyl, benzyl, heteroaryl, -(CH2)m-lower alkoxy or -(CHR)m-C(O)O-lower alkyl; R" is hydrogen, C3-6cycloalkyl, which is unsubstituted or substituted with one or two substitutes selected from halogen, or is lower alkyl, lower alkyl substituted with halogen, lower alkyl substituted with hydroxy, -(CH2)m-heterocyclyl, -NR2, heteroaryl, benzyl or -(CHR)m-C(O)O-lower alkyl; R is hydrogen or lower alkyl; X is -CHR-; m equals 0, 1, 2 or 3; and its pharmaceutically acceptable salts of an acid compound, optically pure enantiomers, racemates or diastereomeric mixtures. The invention also relates to medicine containing a formula I compound.

EFFECT: obtaining novel compounds which inhibit γ-secretase.

16 cl, 230 ex

FIELD: medicine.

SUBSTANCE: invention is related to compound of formula (I) , where

R1 -C1-8alkyl; R2 - pyridynyl, unnecessarily substituted with C1-8alkyl, quinolyl or isoquinolyl; R3 - hydrogen or C1-8alkylcarbonyl; R4 means group of formula G-L1-(CRR')n-, in which n is integer number from 0 to 3; R and R' are independently selected from group that includes atoms of hydrogen and lower alkyl groups; L1 means connection group, selected from group, which includes direct connection, groups -O-, -CO-, -NR"-, -O(CO)O-, -O-(CO)-, -(CO)O- and -NR"-(CO)-, where R" is lower alkyl; G is selected from group, including atoms of hydrogen, C1-8alkyl, C2-8alkenyl, C3-7dicloalkyl, phenylC1-8alkyl, pyridinyl, thiophenyl or residue of indan, and also phenyl, unnecessarily substituted with atom of halogen, C1-8alkoxy, cyano- or C1-8alkyl, which, in its turn, unnecessarily contains one or more atoms of halogen. Specified compounds are active and selective inhibitors of phosphodiesterase 4 (FDE4), therefore, they are applicable for treatment, prevention or suppression of pathological conditions, diseases or disorders, for which it is known that their behavior is relieved by inhibition of FDE4, such as asthma, chronic obstructive lung disease, rheumatoid arthritis, atopic dermatitis, psoriasis or syndrome of sore large gut. Invention is related also to pharmaceutical compositions on the basis of mentioned compounds, application of compounds, method for treatment of subject, when efficient amount of specified compounds is introduced to them. Besides invention is related to combined product for treatment or prevention of pathological condition or disease, behavior of which is relieved by inhibition of phosphodiesterase 4, including specified compound and another compound, selected from the group that includes (a) steroids, (b) immunosuppressive agents, (c) blockers of T-cells receptors, (d) anti-inflammatory medicinal agents, (e) β2-adrenergic agonists and (f) antagonists of muscarine receptors M3, for single-time, separate or serial use.

EFFECT: improved efficiency of compounds use.

11 cl, 2 tbl, 77 ex

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of common formula IC1: , where A represents cyano; B represents hydrogen; R1, R2, R3 and R4 independently represent hydrogen; alkyl; halogen or nitro; R5 and R6 independently represent hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; heteroaryl; heteroarylalkyl; alkenyl; carboxyalkyl; cyanoalkyl; diphenylalkyl; aryl, arylalkoxyaryl, arylalkyl, arylalkylaryl, arylcarbonylaryl or aryloxyaryl, or R5 and R6, together with atom of nitrogen, to which they are connected, create heterocyclic ring system; or to salts of such compound; at the same time "heteroaryl" used separately or in combination, is related to mono-, bi- or tricyclic aromatic ring system, which contains up to 14 atoms included in ring, in which at least one ring contains at least one heteroatom, independently chosen from nitrogen, oxygen or sulfur, besides specified heteroaryl group may be unsubstituted or substituted with one to three substituents, independently selected from alkyl and alkoxy; "diphenylalkyl" is related to alkyl group, where each of two atoms of hydrogen is substituted with unsubstituted phenyl group; "aryl" is related to carbocyclic group, selected from group, which consists of phenyl, biphenyl, 1,2,3,4-tetrahydronaphthyl, naphthyl, antryl, phenantryl, fluorenyl, indanyl, 2,3-dihydrobenzo[1,4]dioxynyl and benzo[1,3]dioxolyl group, besides specified aryl group may be unnecessarily substituted with functional groups in number from one to three, which are separately and independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, cyano, halogen, halogenlkoxy, halogenalkyl and nitro groups, where in certain specific cases, if aryl group represents condensed system from several rings, in which not all the rings are aromatic, one of carbon atoms of which is not included into aromatic ring may be in oxidised condition, and according fragment of ring -CH2- will be substituted by fragment-C(O); "arylalkoxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkoxygroup, where aryl group is unsubstituted; "arylalkyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkyl group, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "aryloxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via oxygen bridge, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "arylcarbonyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via carbonyl group, where aryl group is unsubstituted; "heterocyclic ring system", used separately or in combination, is related to monocyclic, bicyclic or polycyclic ring system, which contains up to 15 atoms included into ring, at least one of which represents heteroatom, independently selected from nitrogen, oxygen or sulfur, besides specified ring system may be saturated, partially unsaturated, unsaturated or aromatic, where specified heterocyclic fragment may be unnecessarily substituted with one or more substituents, every of which separately and independently is selected from group made of halogen and halogenalkyl, excluding the following compounds: {3-[(E)-2-cyano-2-(4-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-m-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(3-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-phenylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-benzylcarbamoyl-2-cyanovinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-o-tolylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-t-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(4-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-ethylphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2~cyano-2-(4- ethoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-isopropylcarbamoylvinyl)indole-1-yl]acetic acid; {3-[(E)-2-cyano-2-(3-etoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-[[2-(1H-indole-3-yl)ethyl]amino]-3-oxo-1-propenyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-chlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-(4-methyl-piperidine-1-yl)-3-oxopropenyl]indole-1-yl}acetic acid; {3-[(E)-2-(3-chloro-4-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(3-phenylpropylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2,3-dichlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-(5-chloro-2-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxybenzylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; and {3-[(E)-2-cyano-3-oxo-3-(4-phenyl-piperazine-1-yl)propenyl]indole-1-yl}acetic acid. Invention is also related to pharmaceutical composition, and also to application of compounds of clause 1.

EFFECT: production of biologically active compounds, which have activity of antagonist coupled with G-protein of chemoattractant receptor of molecules homologue released by Th2-cells.

11 cl, 156 ex, 8 tbl

FIELD: medicine.

SUBSTANCE: compounds can be used for treatment and prevention of diseases associated with activity of specified enzyme, such as diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension. In general formula (I) , R1 represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropyl methoxymethyl, 2-methyl thiazolyl, morpholinyl methyl or phenyl; R2 represents hydrogen, C1-4alkyl or phenyl; R3 represents hydrogen, C1-4alkyl or phenyl; R4 represents phenyl, naphthyl, thiophenyl, quinolyl or piperidyl where phenyl, naphthyl, thiophenyl, quinolyl and piperidyl are optionally substituted with one to three substitutes independently chosen of C1-4alkyl, halogen, C1-4alkoxy, cyano, trifluoromethyl, phenyl, phenyls C1-4alkyl, phenyloxy, oxasolyl and pyridinyl; R5 represents hydrogen, C1-4alkyl, phenyl-C1-4alkyl, C3-6dicloalkyl-C1-4alkyl or aminocarbonylC1-4alkyl.

EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

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

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: present invention relates to novel sulphonamide derivatives of general formula (I) , where R1 is phenyl, thiophenyl or furanyl, unsubstituted or substituted with one or two substitutes selected from a group consisting of halogen, lower alkyl, lower alkyl substituted with halogen, -O-lower alkyl substituted with halogen, NO2 or CN; R2-R4 and R2'-R4' is hydrogen, lower alkyl, phenyl or lower alkyl substituted with halogen; R5 is phenyl, pyridinyl, benzo[1,3]dioxolyl or benzofuranyl, unsubstituted or substituted with 1-3 substitutes selected from a group consisting of halogen, lower alkyl, lower alkyloxy, CN, nitro, amino, hydroxy, lower alkyl substituted with hydroxy, lower alkyl substituted with halogen, or substituted with -C(O)-NR"2, -(CR2)m-C(O)-R', -(CH2)m-heteroaryl, unsubstituted or monosubstituted -(CH2)m-lower alkoxy, lower alkyl, -(CH2)m-O-benzene or CH2OH, -O-C(O)-lower alkyl, -O-C(O)-NR2, -O-(CH2)m-C(O)OH, -O-lower alkynyl, -O-lower alkyl, substituted with halogen, -O-(CH2)m-heterocyclyl, -O-(CH2)m-phenyl, unsubstituted or monosubstituted hydroxy, -O-(CH2)m-heteroaryl, unsubstituted or monosubstituted with lower alkyl, -(CH2)m-NH-C(O)R', -(CH2)m-NH-S(O)2-R', -S(O)2-lower alkyl, -S(O)2-heterocyclyl, -S(O)2NH-cycloalkyl, or is C3-6cycloalkyl; R' is hydrogen, lower alkyl, lower alkynyloxy, hydroxy, C3-6cycloalkyl, heterocyclyl, which is unsubstituted or substituted with one or two substitutes selected from COOH, -C(O)O-lower alkyl, halogen or lower alkyl, or is phenyl, benzyl, heteroaryl, -(CH2)m-lower alkoxy or -(CHR)m-C(O)O-lower alkyl; R" is hydrogen, C3-6cycloalkyl, which is unsubstituted or substituted with one or two substitutes selected from halogen, or is lower alkyl, lower alkyl substituted with halogen, lower alkyl substituted with hydroxy, -(CH2)m-heterocyclyl, -NR2, heteroaryl, benzyl or -(CHR)m-C(O)O-lower alkyl; R is hydrogen or lower alkyl; X is -CHR-; m equals 0, 1, 2 or 3; and its pharmaceutically acceptable salts of an acid compound, optically pure enantiomers, racemates or diastereomeric mixtures. The invention also relates to medicine containing a formula I compound.

EFFECT: obtaining novel compounds which inhibit γ-secretase.

16 cl, 230 ex

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