Cyclin-dependent kinase inhibitors and their application

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds for cyclin-dependent kinase inhibition, in particular, chromenone derivatives by formula Ic: (la) where R1, R2, R3, R4, R5, R6, R7 and A take on values specified in formula of invention. Invention also refers to technology of these compounds, as well as to application of these compounds for medicines intended for cyclin-dependent kinase inhibition and cell proliferation inhibition, used for treatment and prevention of various proliferative diseases. Invention also concerns compositions containing these compounds alone or in combination with other active agent, mixed or otherwise reacted with inert carrier, in particular, pharmaceutical compositions containing these compounds alone or in combination with other active agent, together with pharmaceutically acceptable carriers and adjuvants.

EFFECT: production of new compounds for cyclin-dependent kinase inhibition used for cyclin-dependent kinase inhibition and cell proliferation inhibition used for treatment and prevention of various proliferative diseases.

21 cl, 6 dwg, 2 tbl, 149 ex

 

The text descriptions are given in facsimile form.

1. The compound of General formula Ic

where R1means aryl, unsubstituted or replacement of the military, at least one Deputy, selected from halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, nitro, NR9R10, trifloromethyl, hydroxyl, cyano, a saturated, partially unsaturated, or aromatic heterocycle containing 1, 2, 3 or 4 identical or different heteroatoms, selected from nitrogen and sulfur, and the heterocycle is unsubstituted or substituted with halogen;

R2is hydrogen, C1-C6-alkyl; aryl, unsubstituted or substituted by at least one Deputy chosen from:1-C4-alkyl, C1-C4-alkoxy;

R3, R4and R5each independently selected from hydrogen; OR11;

R6- C1-C4-OR11;

R9and R10each independently selected from hydrogen; C1-C6-alkyl;

R11is hydrogen; C1-C6-alkyl; C1-C4-alkanoyl or1-C4-alkoxycarbonyl;

Z is an oxygen atom;

A - saturated or unsaturated 5-membered ring represented by the following General structures (i)to(v):

in which X1and X2each independently selected from a carbon atom and a nitrogen atom, provided that in structures (i), (iii) and (iv)at least one of X1and X2assetstotal nitrogen, which, at least, monogamist R13where R13selected from hydrogen; C1-C6-alkyl; aryl, unsubstituted or substituted by at least one Deputy, selected from C1-C4-alkyl, C1-C4-alkoxy, cyano;

R6is defined above Deputy, at least one carbon atom in the ring;

R7is hydrogen, C1-C4-alkyl;

p is an integer 1 or 2, and

its tautomeric forms, stereoisomers, optical isomers, pharmaceutically acceptable salt, pharmaceutically acceptable solvate.

2. The compound according to claim 1 of the formula Ic, in which

R1is phenyl, unsubstituted or substituted 1, 2 or 3 identical or different substituents selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, trifloromethyl, hydroxyl, cyano or heterocycle representing a saturated, partially unsaturated or aromatic ring containing 5 or 6 atoms in the ring, of which 1, 2 or 3 presents the same or different heteroatoms, selected from nitrogen and sulfur, and a heterocycle unsubstituted or substituted 1, 2 or 3 halogen atoms;

R2is hydrogen; C1-C6-alkyl; phenyl, unsubstituted or substituted 1, 2 or 3 identical or different substituents, select the reference from the 1-C4-alkyl or C1-C4-alkoxy;

R3, R4and R5each independently selected from hydrogen OR11;

Z is an oxygen atom;

A - saturated or unsaturated 5-membered ring represented by one of the General structures (i) to (v)as claimed in claim 1, in which X1and X2each independently selected from a carbon atom and a nitrogen atom, provided that in structures (i), (iii) and (iv)at least one of X1and X2is nitrogen, which is at least monogamist R13where R13selected from hydrogen, C1-C6-alkyl and phenyl, which is unsubstituted or substituted by at least one Deputy, selected from C1-C4-alkyl, C1-C4-alkoxy, a R7is hydrogen;

R9and R10each independently selected from hydrogen, C1-C4-alkyl;

R11is hydrogen, C1-C4-alkyl, C1-C4-alkanoyl or1-C4-alkoxycarbonyl.

3. The compound according to claim 1 or 2, the General formula Ic, in which a 5-membered, saturated or unsaturated ring represented by one of the General structures (i)to(iv):

in which X1means a carbon atom or nitrogen, a R6and R13defined above.

4. The compound according to claim 1 of General formula Ic, in which R1about the means phenyl, unsubstituted or substituted by 1, 2 or 3 odinakovimi or different substituents selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, trifloromethyl, hydroxyl, cyano, carboxy, C1-C4-alkoxycarbonyl and C1-C4-alkylenedioxy; or a heterocycle, which represents a saturated, partially unsaturated or aromatic ring containing 6 atoms in the ring, of which 1, 2 or 3 presents identical or different heteroatoms, selected from nitrogen and sulfur, and the heterocycle unsubstituted or substituted 1, 2 or 3 halogen atoms;

R2and R4submitted by hydrogen and

R3and R5each independently selected from hydroxyl, C1-C4-alkoxyl and C1-C4-alkylcarboxylic.

5. The compound according to claim 1 of General formula Ic, in which R1means phenyl or pyridinyl, substituted by 1, 2 or 3 identical or different substituents selected from halogen and nitro, R2and R4represented by hydrogen; R3and R5submitted by hydroxyl, And - saturated 5-membered ring represented by one of the General structures (i)to(v)in which X1, X2, R6and R13defined above.

6. The compound according to claim 5, in which X1- carbon, X2is nitrogen, R6- C1-C4-Ala is lanhydrock, R13- C1-C4-alkyl.

7. The compound according to claim 1 of General formula IC, which is:

(+/-)-TRANS-2-(2-chlorophenyl)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+)-TRANS-2-(2-chlorophenyl)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+)-TRANS-2-(2-chlorophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(-)-TRANS-2-(2-chlorophenyl)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(-)-TRANS-2-(2-chlorophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+)-TRANS-2-(2-bromophenyl)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+)-TRANS-2-(2-bromophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+)-TRANS-2-(4-bromophenyl)-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+)-TRANS-2-(4-bromophenyl)-5-hydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-7-methoxypropan-4-one;

(+)-TRANS-2-(4-bromophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+)-TRANS-2-(3-chlorophenyl)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+)-TRANS-2-(3-chlorophenyl)-5-hydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-7-methoxypropan-4-one;

(+)-TRANS-2-(3-chlorophenyl)-5,7-digit the STI-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+)-TRANS-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-2-(2-itfinal)-5,7-dimethoxyfuran-4-one;

(+)-TRANS-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-2-(2-itfinal)-chromen-4-one;

(+)-TRANS-2-(2-forfinal)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+)-TRANS-2-(2-forfinal)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+)-TRANS-2-(3-forfinal)-5,7-dimethoxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+)-TRANS-2-(3-forfinal)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+)-TRANS-2-(2,6-differenl)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+)-TRANS-2-(2,6-differenl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+/-)-TRANS-4-[8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxy-4-oxo-4H-chromen-2-yl]-benzonitrile;

(+/-)-TRANS-4-[5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-4-oxo-4H-chromen-2-yl]-benzonitrile;

(+)-TRANS-4-[8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxy-4-oxo-4H-chromen-2-yl]-benzonitrile;

(+)-TRANS-4-[5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl-4-oxo-4H-chromen-2-yl]-benzonitrile;

(+/-)-TRANS-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxy-2-(4-triptoreline)-chromen-4-one;

(+/-)-Tran is -5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl-)-2-(4-triptoreline)-chromen-4-one;

(+)-TRANS-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxy-2-(4-triptoreline)-chromen-4-one;

(+)-TRANS-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-2-(4-triptoreline)-chromen-4-one;

(-)-TRANS-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxy-2-(4-triptoreline)-chromen-4-one;

(-)-TRANS-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-2-(4-triptoreline)-chromen-4-one;

(+)-TRANS-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxy-2-phenylpropen-4-one;

(+)-TRANS-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-2-phenylpropen-4-one;

(+)-TRANS-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxy-2-thiophene-2-ilhame-4-one;

(+)-TRANS-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-2-thiophene-2-ilhame-4-one;

(+)-TRANS-4-[5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-4-oxo-4H-chromen-2-yl]-3-methylbenzonitrile;

(+)-TRANS-4-[8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxy-4-oxo-4H-chromen-2-yl]-3-methylbenzonitrile;

(+/-)-TRANS-2-[2-bromo-5-methoxyphenyl)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+/-)-TRANS-2-[2-bromo-5-methoxyphenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+)-TRANS-2-[2-bromo-5-methoxyphenyl)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)]-5,7-dimethoxy the Myung-4-one;

(+)-TRANS-2-(2-bromo-5-methoxyphenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+/-)-TRANS-2-(2-bromo-5-hydroxyphenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+)-TRANS-2-(2-bromo-5-hydroxyphenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+/-)-TRANS-2-[(3,5-bis-trifluoromethyl)-phenyl]-8-[2-hydroxymethyl-1-methylpyrrolidine-3-yl]-5,7-dimethoxyfuran-4-one;

(+/-)-TRANS-2-[(3,5-bis-trifluoromethyl)-phenyl]-5,7-dihydroxy-8-[2-hydroxymethyl-1-methylpyrrolidine-3-yl]-chromen-4-one;

(+)-TRANS-2-(2-chloro-5-were)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+)-TRANS-2-(2-chloro-5-were)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+)-TRANS-2-[2-bromo-5-nitrophenyl]-8-[2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+/-)-TRANS-2-[2-bromo-5-nitrophenyl]-8-[2-hydroxymethyl-1-methylpyrrolidine-3-yl]-5,7-dihydroxyfuran-4-one;

(+/-)-TRANS-2-(2-chloropyridin-3-yl)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+/-)-TRANS-2-(2-chloropyridin-3-yl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+/-)-TRANS-2-[2-bromo-5-nitrophenyl]-8-[2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+)-TRANS-2-(2-chloropyridin-3-yl)-5,7-dihydrox is-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+/-)-TRANS-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxy-2-(4-nitrophenyl)-chromen-4-one;

(+/-)-TRANS-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-2-(4-nitrophenyl)-chromen-4-one;

(+)-TRANS-2-(4-AMINOPHENYL)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+/-)-TRANS-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxy-2-(2-methoxyphenyl)-chromen-4-one;

(+/-)-TRANS-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-2-(2-hydroxyphenyl)-chroman-4-one;

(+)-TRANS-3-chloro-4-[8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxy-4-oxo-4H-chromen-2-yl]-benzonitrile;

(+)-TRANS-3-chloro-4-[5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxy-4-oxo-4H-chromen-2-yl]-benzonitrile;

(+)-TRANS-2-(4-bromo-2-chlorophenyl)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+)-TRANS-2-(4-bromo-2-chlorophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+/-)-TRANS-2-(2-chlorodimethylsilyl)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+/-)-TRANS-2-(2-chlorotoluidines)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+/-)-TRANS-2-(2-chloro-4-methoxyphenyl)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+/-)-TRANS-2-(2-chloro-4-hydroxyphenyl)-5,7-dihydro the C-8-[2-hydroxymethyl-1-methylpyrrolidine-3-yl]-chromen-4-one;

(+/-)-TRANS-2-(2-chloro-5-forfinal)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+/-)-TRANS-2-(2-chloro-5-forfinal)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+/-)-TRANS-2-(2-chloro-5-methoxyphenyl)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+/-)-TRANS-2-(2-chloro-5-hydroxyphenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+/-)-TRANS-2-(2-chloro-5-methoxyphenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+/-)-TRANS-8-(2-azidomethyl-1 methylpyrrolidine-3-yl)-2-(2-chlorophenyl)-5,7-dimethoxyfuran-4-one;

(+/-)-TRANS-8-(2-aminomethyl-1 methylpyrrolidine-3-yl)-2-(2-chlorophenyl)-5,7-dimethoxyfuran-4-one;

(+/-)-TRANS-8-(2-aminomethyl-1 methylpyrrolidine-3-yl)-2-(2-chlorophenyl)-5,7-dihydroxyfuran-4-one;

(+/-)-TRANS-3-{[2-(2-chlorophenyl)-5,7-dimethoxy-4-oxo-4H-chromen-8-yl]-1-methylpyrrolidine-2-yl}-acetonitrile;

(+/-)-TRANS-{3-[2-(2-chlorophenyl)-5,7-dihydroxy-4-oxo-4H-chromen-8-yl]-1-methylpyrrolidine-2-yl}-acetonitrile;

(+/-)-TRANS-3-[2-(2-chlorophenyl)-5,7-dimethoxy-4-oxo-4H-chromen-8-yl]-1-(4-methoxyphenyl)-pyrrolidin-2-ymetray ether acetic acid;

(+/-)-TRANS-2-(2-chlorophenyl)-8-[2-hydroxymethyl-1-(4-methoxyphenyl)-pyrrolidin-3-yl]-5,7-dimethoxyfuran-4-one;

(+/-)-TRANS-2-(2-chlorophenyl)-5,7-dihydroxy-8-[2-hydroxym the Teal-1-(4-phenyl)pyrrolidin-3-yl]-chromen-4-one;

(+/-)-TRANS-3-[2-(2-chlorophenyl)-5,7-dimethoxy-4-oxo-4H-chromen-8-yl]-1-propylpyrrolidine-2-ymetray ether acetic acid;

(+/-)-TRANS-2-(2-chlorophenyl)-8-(2-hydroxymethyl-1-propylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+/-)-TRANS-2-(2-chlorophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-propylpyrrolidine-3-yl)-chromen-4-one;

(+/-)-TRANS-2-(2-chloro-4-nitrophenyl-5,7-dihydroxy-8-2-hydroxymethyl-1-propylpyrrolidine-3-yl)-chromen-4-one;

(+/-)-TRANS-2-(2-bromo-4-nitrophenyl-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+/-)-TRANS-3-chloro-4-[5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-4-oxo-4H-chromen-2-yl]-benzoic acid;

(+/-)-TRANS-3-bromo-4-[5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-4-oxo-4H-chromen-2-yl]-benzoic acid;

(+/-)-TRANS-2-(2-chloro-4-forfinal)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+/-)-TRANS-2-(4-amino-2-chlorophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+/-)-TRANS-2-(2-bromo-4-forfinal)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+/-)-TRANS-2-(4-amino-2-bromophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+/-)-TRANS-4-chloro-3-[5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-4-oxo-4H-chromen-2-yl]-benzoic acid;

(+/-)-TRANS-4-bromo-3-[5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-4-oxo-4H-chromen-2-yl]-N-hydroxybenzamide;

(+/-)-TRANS-4-chloro-3-[5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-4-oxo-4H-chromen-2-yl]-N-hydroxybenzamide;

(+/-)-TRANS-3-chloro-4-[5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-4-oxo-4H-chromen-2-yl]-N-hydroxybenzamide;

(+/-)-TRANS-3-bromo-4-[5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-4-oxo-4H-chromen-2-yl]-N-hydroxybenzamide;

(+/-)-TRANS-2-(2,4-differenl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+)-TRANS-2-(2-chloro-3-forfinal)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+)-TRANS-2-(2-chloro-3-forfinal)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+)-TRANS-2-(2-bromo-3-forfinal)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+)-TRANS-2-(2-bromo-3-forfinal)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+)-TRANS-2-(2-bromo-5-forfinal)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+)-TRANS-2-(2-bromo-5-forfinal)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+-TRANS-2-(2-chloro-5-itfinal)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+)-TRANS-2-(2-chloro-5-itfinal)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+)-TRANS-2-(2-bromo-5-chlorophenyl)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+)-TRANS-2-(2-bromo-5-chlorophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+/-)-TRANS-2-(2-chlorophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methoxypyridine-3-yl)-chromen-4-one;

(+)-TRANS-2-(2-bromo-4-nitrophenyl)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+)-TRANS-2-(2-bromo-4-nitrophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+)-TRANS-2-(4-amino-2-bromophenyl)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+)-TRANS-2-(4-amino-2-bromophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+)-TRANS-2-(2-bromo-4-methoxyphenyl)-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one;

(+)-TRANS-2-(2-bromo-4-methoxyphenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+)-TRANS-2-(2-bromo-4-hydroxyphenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one;

(+)-TRANS-8-(2-acetoxymethyl-1 methylpyrrolidine-3-yl)-5-hydroxy-2-(4-nitrophenyl)-4-oxo-4H-chromen-7-silt ether acetic acid;

(+)-TRANS-2-(2,4-dichloro-5-forfinal)-8-(2-what hydroxymethyl-1 methylpyrrolidine-3-yl)-5,7-dimethoxyfuran-4-one

(+)-TRANS-2-(2,4-dichloro-5-forfinal-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidine-3-yl)-chromen-4-one.

8. The use of compounds according to any one of claims 1 to 7 General formula IC or their pharmaceutically acceptable salts for the manufacture of medicaments intended for the inhibition of cyclin-dependent kinases.

9. The use of compounds according to any one of claims 1 to 7 General formula IC or their pharmaceutically acceptable salts for the manufacture of medicaments intended for the treatment or prevention of proliferative diseases.

10. The use of compounds according to any one of claims 1 to 7 General formula IC or their pharmaceutically acceptable salts for the manufacture of medicaments intended for the treatment or prevention of cancer.

11. Pharmaceutical composition useful as an inhibitor of cyclin-dependent kinase, comprising a therapeutically effective amount of at least one of the compounds of General formula IC according to any one of claims 1 to 7 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

12. Pharmaceutical composition useful as an inhibitor of cyclin-dependent kinase, comprising a therapeutically effective amount of at least one of the compounds of General formula IC according to any one of claims 1 to 7 or its pharmaceutically acceptable salt and at least one pharmacy is is automatic active compound together with a pharmaceutically acceptable carrier.

13. The use of compounds of General formula Ic according to any one of claims 1 to 7 or of their pharmaceutically acceptable salts for the manufacture of medicaments intended for the treatment or prevention of diseases associated with excessive cell proliferation, and the drug is used either alternately or simultaneously with at least one pharmaceutically active compound.

14. The method of obtaining compounds of General formula Ic according to any one of claims 1 to 7 or its pharmaceutically acceptable salts, including:

(a) carrying out the reaction between benzopyranones formula II

where R1, R2, R3, R4, R5and Z take on the values defined in any one of claims 1 to 6, and R is a functional group,

and a compound according to formula III

where And substituted R6and R7and A, R6and R7take the values defined in claims 1 to 6, except that a is not 5-membered ring of the above General structure (ii) or (v), and Q represents a functional group attached to a saturated or unsaturated carbon atom in the ring And, in addition:

i) if Q forms a link to the unsaturated carbon atom, the reaction is carried out in the presence of a metal catalyst, organic is whether inorganic bases and organic or inorganic solvent, this forms a bond With-between the respective carbon atoms, with associated P and Q, followed by treatment with reducing agent to restore the double bond between positions 1 and 2 or 1 and 5 in the 5-membered ring And with the formation of the compounds of formula Ic,

ii) when Q forms a link to the saturated carbon atom, the reaction is carried out in the presence of an appropriate ligand or catalyst and tsepliaeva group, this forms a bond With-between the respective carbon atoms, with associated P and Q, with the formation of the compounds of formula Ic,

and, if necessary, converting the resulting compound in pharmaceutically acceptable salt; or

(b) conducting the reaction between benzopyranones formula II

where R1, R2, R3, R4, R5and Z take values defined in claims 1 to 6, and R is a functional group,

and the compound of the formula IIIA

where X2and R6take the values defined in claims 1 to 6,

in the presence of a metal catalyst, an organic or inorganic bases and organic or inorganic solvent with the formation of N-C between the carbon of the compounds of formula II, is attached to the group R, and azo what Ohm the compounds of formula IIIA and if necessary, conversion of the resulting compound of the formula Ic in pharmaceutically acceptable salt.

15. The method of obtaining compounds of General formula Ic according to any one of claims 1 to 7 or its pharmaceutically acceptable salts, where Z is an oxygen atom, R7is hydrogen, R1, R2, R3, R4, R5, R6and As defined above, including

carrying out the reaction between the compound of formula HA

or a compound of formula XIIA

where in both cases, R1, R2, R3, R4, R5, R6, R7and As defined above,

with an organic or inorganic base and then adding to the reaction mixture acid capable of cyclization, and then add organic or inorganic base and, if necessary, transform the resulting compound of the formula Ic in pharmaceutically acceptable salt.

16. The method according to item 15, in which the compound of the formula XIIA is obtained by reaction of compounds of formula XIA

where R1, R2, R3, R4, R5, R6, R7and As defined above,

ether carboxylic acids, galogenangidridy or activated ester in the presence of organic sludge is an inorganic base in an organic or inorganic solvent.

17. The method according to item 15 or 16, in which a is selected from a, b, C and d:

and

where R11and R13defined above.

18. The method according to claim 19, in which R11- hydrogen and/or R13is methyl.

19. The method of obtaining the compounds of formula XIIIA or its pharmaceutically acceptable salt:

where R1, R2, R3, R4, R5, R13and Z defined in claims 1 to 6,

comprising carrying out the reaction between the compound of the formula VIIA

where R1, R2, R3, R4, R5, R13and Z defined in claims 1 to 6,

with a reagent capable of replacing the group-HE piperidinium ring tsepliaeva group, in the presence of an organic or inorganic base followed by the addition of a suitable organic base in the presence of a suitable organic solvent for the implementation of the circuit piperidino rings and, if necessary, conversion of the resulting compound of formula XIIIA in pharmaceutically acceptable salt.

20. The method of obtaining the compounds of formula XXXVII or its pharmaceutically acceptable salt:

where R1, R2, R3, R 4, R5and Z defined in claims 1 to 6,

comprising carrying out the reaction between the compound of formula XXXVI

where R1, R2, R3, R4, R5, R13and Z defined in claims 1 to 6,

and a reducing agent capable of reduction of the ester group-C(O)OEt on imidazolinium ring in group-CH2OH, and, if necessary, converting the resulting compound of formula XXXVII in pharmaceutically acceptable salt.

21. The method according to claim 20, in which the compound of formula XXXVI get in the reaction of compounds of formula XXXV

where R1, R2, R3, R4, R5and Z defined in claims 1 to 6,

with isocyanides in the presence of an inorganic base in an organic solvent.

22. The method of obtaining the compounds of formula XIII

where R1, R2, R3, R4, R5and R13defined in claims 1 to 6,

comprising carrying out the reaction between racemic compound of formula VIII

where R3, R4, R5and R13defined in claims 1 to 6,

and chiral auxiliary reagent in the presence of a solvent to form diastereomeric salts of the compounds of formula VIII, crystallize the Oia desired diastereoisomer salts and subsequent treatment with base to obtain the desired enantiomer of the compounds of formula VIII, treatment of compounds of formula VIII allermuir reagent or an activated form of the acid in the presence of a catalyst of the type of Lewis acid to obtain the acylated compounds of formula IX

where R2, R3, R4, R5and R13defined in claims 1 to 6,

treatment of compounds of formula IX

(a) the acid chloride of the type R1COCl, anhydride type (R1CO)2O or ether type R1COOCH3where R1defined above, or

(b) acid type R1COOH, where R1defined above, and phosphorus oxychloride in the presence of the absorber acid to obtain the acid chloride in situ in neutral conditions, or

(c) R1COOH, where R1defined above,

together with polyphosphoric acid,

with the formation of the compounds of formula X

where R1, R2, R3, R4, R5and R13defined in claims 1 to 6,

treatment of compounds of formula X base, then treated with a strong acid capable of cyclization, and then a weak base with the formation of the desired compounds of formula XIII, and need not make this connection in pharmaceutically acceptable salt;

alternatively, the compound of the above formula is IX is subjected to hydrolysis of its ester linkages in the processing base in aqueous ethanol or methanol to form compounds of formula XI

where R2, R3, R4, R5and R13defined in claims 1 to 6,

the compound of formula XI is treated with ether carboxylic acid, acid chloride or activated ester in the presence of a base in a solvent to form compounds of formula XII

where R1, R2, R3, R4, R5and R13defined in claims 1 to 6,

and the compound of formula XII is treated with a strong acid capable of cyclization, and then a weak base with the formation of the desired compounds of formula XIII, and need not make this connection in pharmaceutically acceptable salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to the compound of formula I: , where R1, R2 and R3 are equal or different and represent hydrogen, halogen, alkyl, aloxy, hydroxyl, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group, R4 represents hydrogen, alkyl or alkylaryl group; X represents CH2, oxygen atom and sulphur atom; n represents 2 or 3, and individual (R)- and (S)-enantiomers or the mixture of enantiomers and its pharmaceutically acceptable salts; where alkyl termine denotes straight and branched hydrocarbon chains, containing fro one to six atoms of carbon, optionally substituted by aryl, alkoxy, halogen, alkoxycarbonyl or hydroxycarbonyl groups, termine aryl denotes phenyl or naphtyl group, optionally substituted alkyloxy group, halogen or nitro group, termine halogen denotes fluorine, chlorine, bromine or iodine. The compounds have valuable pharmaceutical properties and perspectives for the treatment of cardiovascular disorder, such as hypertension and chronic heart failure. The method of production of individual (R)- and (S)-enantiomers or the mixture of enantiomers and pharmaceutically acceptable salts of the compound of formula I, pharmaceutical composition having inhibitor dophamine-β-hydrolaze potency, containing therapeutic effective volume of the compound of formula I, different variants of formula I compound application and intermediate compounds are described.

EFFECT: production of new compounds, imidazole derivatives having useful biological properties.

21 cl, 2 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the general formula: , where R1 is an inferior alkyl, -(CH2)n-aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluormethyl, or pyridine; R2 is an inferior alkyl, -(CH2)n- aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluoromethyl, nitro-, cyano-, -NR'R", hydroxy-, or heteroaryl group that is a monovalent heterocyclic 5- or 6-membered aromatic radical with N atoms, either R2 is a heteroaryl that is monovalent heterocyclic 5- or 6-membered aromatic radical where heteroatoms are chosen from N, O or S group, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl or halogen; R3 is pyridine or aryl, unsubstituted or substituted by a halogen or inferior alkyl; R4 is hydrogen or hydroxy-. A is -S(O)2- or -C(O)-; X, Y are -CH2- or -O- independently from each other, though both X and Y should not be -O- at the same time; R'R" are hydrogen or inferior alkyl independently from each other; n is 0, 1 or 2. Also the invention concerns pharmaceutically acceptable additive salts and acids of the compounds, and a medicine based on it.

EFFECT: new biologically active compounds show inhibition effect in glycine absorption.

21 cl, 214 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the compound with the formula (1): where R1 is C1-C12 alkyl group, which can have the substitute, or C2-C12 alkenyl group, which can have the substitute represented with the C6-C14 aryl group, which can be substituted with the halogen atoms; each of R2 and R3 represent the hydrogen atom, alkyl group, hydroxyalkyl group, dihydroxyalkyl group, or R2 and R3 form with the adjacent nitrogen atoms the 5-membered, 6-membered, or 7-membered nitrogen-containing saturated heterocyclic group, which can be substituted with the alkyl group; (the dotted line means the possible double bind), or its salt, as well as to the pharmaceutical composition containing the said compound, and to its application as a pharmaceuticals and to the treatment method.

EFFECT: invented compound demonstrates inhibiting activity against the tumor necrosis factor production (TNF-α) and improved absorbability after oral administration.

16 cl, 1 tbl, 18 dwg, 1 ex

FIELD: chemistry; obtaining of medicinal preparations.

SUBSTANCE: description is given of a compound with general formula where R1 represents a halogen, C1-C6alkyl, CF3, CF2H or cyano, R2 represents C1-C6alkyl, R3 represents 5- or 6 - member hetero-aryl, optionally substituted with one, two or three substitutes, chosen from a group, consisting of a halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylhalogen, C1-C6alkoxy, NR'R", or substituted with a 1-morpholinyl group or substituted with thiomorpholinyl groups, 1-oxothiomorpholinyl or 1,1-dioxothiomorpholinyl; R', R" independently represent hydrogen, C1-C6alkyl, (CH2)0,1-(C3-C6)cycloalkyl, R represents hydrogen as well as its pharmaceutical salts and the method of obtaining them. The invention also relates to use of the given amidazole derivatives for obtaining medicinal preparations and to medicinal preparations containing them, meant for prevention or treatment of damages, through the mGluR5 receptor, such as acute and/or chronic neurologic damages, primarily shock pain, or for treatment of chronic and sharp pain.

EFFECT: obtaining of new compounds, with useful biological properties.

40 ex

FIELD: organic chemistry, medicine, pharmacy, chemical technology.

SUBSTANCE: invention relates to novel substituted esters of 1H-indol-3-carboxylic acids of the general formula (1): or their racemates, or their optical isomers, or their pharmaceutical acceptable salts and/or hydrates. Compounds can be used in treatment of such diseases as infectious hepatitis, human immunodeficiency, atypical pneumonia and avian influenza. In compound of the general formula (1) R1, R41 and R42 each represents independently of one another a substitute of amino group chosen from hydrogen atom, optionally linear or branched alkyl comprising 3-12 carbon atoms, optionally substituted cycloalkyl comprising 3-10 carbon atoms, optionally substituted aryl or optionally substituted and possibly an annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 carbon atom in ring with one or some heteroatoms chosen from nitrogen oxygen or sulfur atoms; or R41 and R42 in common with nitrogen atom to which they are bound form 5-10-membered azaheterocycle or guanidyl through R41 and R42; R2 represents an alkyl substitute chosen from hydrogen atom, optionally substituted mercapto group, optionally substituted amino group, optionally substituted hydroxyl; R3 represents lower alkyl; R5 represents a substitute of cyclic system chosen from hydrogen atom, halogen atom, cyano group, optionally substituted aryl or optionally substituted and possibly an annelated heterocycle that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms. Also, invention relates to methods for treatment, drugs and pharmaceutical compositions using compounds of this invention.

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

22 cl, 3 tbl, 8 dwg, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds, namely, to N-substituted derivatives of piperidine of the formula (I): or their pharmaceutically acceptable salts, amides, esters wherein values R1, R, R3, m, X, n, W, Ar1 and Ar2 are disclosed in the invention claim. Also, invention relates to methods for inhibition of activity and methods for inhibition of activation of monoamine receptors. Methods involve contacting monoamine receptors or system comprising monoamine receptors with the effective amount of one or some compounds of the formula (I). Except for, invention relates to using compounds of the formula (I) in treatment of psychotic diseases.

EFFECT: valuable medicinal properties of compounds.

35 cl, 1 tbl

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel derivatives of 1,2,4-triazole of the general formula (I): wherein A and b can be taken separately or in common being when they are taken separately then A means (C1-C6)-alkyl or phenyl, and B means (C1-C6)-alkyl; A and B taken in common mean (C2-C5)-alkanediyl, and they form with C-atoms 3-6-membered cycle optionally substituted with (C1-C4)-alkylene, oxo, ethylenedioxy group, (C1-C4)-alkyl, 1-2 halogen atoms, (C1-C3)-alkoxy-(C1-C3)-alkoxy or hydroxy group; each R1 means independently hydrogen atom, -OH, halogen atom, (C3-C6)-cycloalkyl, (C1-C6)-alkyl optionally substituted with 1-3 halogen atoms; or two R1 groups near adjacent carbon atoms form 6-membered aryl cycle; R2 and R3 can be taken in common or separately, and when they are taken in common then they represent (C3-C8)-alkanediyl that forms condensed 5-10-membered nonaromatic cycle; when R2 and R3 are taken separately then R2 means (C1-C6)-alkyl possibly substituted with 1-3 halogen atoms or cyclopropyl, and R3 means cyclopropyl possibly substituted with (C1-C4)-alkyl, naphthyl, phenyl possibly substituted with halogen atom, -OH, (C1-C6)-alkyl wherein indicated (C1-C6)-alkyl is optionally substituted with 1-3 halogen atoms, -O-(C1-C6)-alkyl wherein indicated -O-(C1-C6)-alkyl is optionally substituted with 1-3 halogen atoms, phenyl or benzyloxy group, dihydrobenzofuranyl, benzothiadiazolyl or benzoimidazolyl possibly substituted with (C1-C6)-alkyl, their pharmaceutically acceptable salts or solvates, and pharmaceutical composition based on thereof. Proposed compounds are inhibitor of 11β-hydroxysteroid dehydrogenase I, and can be used in medicine in treatment of diabetes mellitus, obesity and dyslipidemia.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

19 cl, 17 tbl, 4 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes novel derivatives if 1,3,5-triazine of the general formula (1): wherein R1 means halogen atom, (C1-C3)-alkyl, (C1-C3)-alkoxy-group, N-(di)-(C1-C3)-alkyl, NH-(C2-C3)-alkynyl, N,N-(C1-C3)-alkyl, (C2-C3)-alkynyl or 1-pyrrolidinyl, 1-piperidinyl or 1-morpholinyl group; R2 means hydrogen atom (H), (C1-C3)-alkyl possibly substituted with hydroxy-, (C1-C3)-alkoxy- or phenoxy-group; R3 means H, -CF3, (C1-C3)-alkyl possibly substituted with hydroxy-, (C1-C3)-alkoxy-, phenoxy-group or 1-morpholinyl group; or R2 and R3 in common with phenyl group to which they are bound form benzodioxolane or naphthalene cyclic system; R4 means H, -CF3 or (C1-C3)-alkoxy-group; X means -NH, N-(C1-C3)-alkyl, -CH2, oxygen atom (O) or a bond carbon-carbon; Y means group of the general formula (A) , (B) or (C) wherein R5 means -OH or -CH2OH; R6 means H or phenyl; n = 0 or 1; R7 means (C1-C3)-alkyl; R8 means H, -OH or (C1-C3)-alkoxy-group; R9 means H or (C1-C3)-alkoxy-group; R10 and R11 mean independently H or (C1-C3)-alkyl; Z means -NOH or O, or their pharmacologically acceptable salts, pharmaceutical composition possessing (ant)agonistic activity to adenosine-A3 receptors and using novel compounds in treatment of such diseases as chronic pains, arthritis, cerebrospinal sclerosis, asthma, psoriasis and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 4 tbl, 2 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a compound of the formula (I): , wherein carbon atom designated as * is in (R)- or (S)-configuration; R1 represents (C1-C6)-alkyl; R2 represents hydrogen atom (H), (C1-C6)-alkyl or (C1-C6)-halogenalkyl; R3 represents H or halogen atom; R4 represents phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl, isoxazolyl, pyrazolyl or pyrazinyl wherein R4 group is substituted optionally with 1-4 R14-substitutes; each among R5, R6 and R7 is chosen independently from the following group: H, halogen atom, -OR11, -CN, (C1-C4)-halogenalkyl or (C1-C6)-alkyl; or R5 and R6 taken in common can represent -O-C-(R12)2-O-; R8 represents H; R11 represents H or (C1-C4)-alkyl; R12 represents (C1-C4)-alkyl; R12 is chosen independently in each case from a substitute chosen from the following group: halogen atom, -OR11, -NR11R12, morpholinyl, (C1-C6)-alkyl and (C1-C4)-halogenalkyl, or its pharmaceutically acceptable salt or solvate. Also, invention describes a pharmaceutical composition used in blocking in reuptake of norepinephrine, dopamine and serotonin based on compounds of the formula (I). Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties, improved method of treatment.

39 cl, 2 tbl, 49 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of formula (I) as well as to synthesis procedure and application for treatment of various disorders, including inflammatory and autoimmune disorders, and disorders caused by malignant growths or by increased angiogenesis where R1-R11, t, X, Y, Z and n have values specified in the description.

EFFECT: production of macrocyclic compounds used for treatment of various disorders, including inflammatory and autoimmune disorders, and disorders caused by malignant growths or by increased angiogenesis.

41 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: anti-tumour remedy includes, as active ingredients, tegafur in therapeutically efficient amount, gimeracil in amount efficient for enhancing anti-tumour effect, potassium oteracil in amount efficient for inhibiting side-effect, and at least one element selected from the group consisting of pholinic acid and its pharmacologically acceptable salts in amount efficient for enhancing anti-tumour effect. Molar ratio of tegafur: gimeracil: potassium oteracil: at least one element selected from group consisting of folinic acid and its pharmacologically acceptable salts is 1:0.4:1: 0.01 to 10. Application of combined medication tegafur/gimeracil/potassium oteracil in combination with potassium folinate essentially increases anti-tumour activity without aggravating toxicity.

EFFECT: enhanced anti-tumour effect.

13 cl, 3 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns chemical pharmaceutical industry, particularly a combination including selective cyclooxygenase-2 (COX-2) inhibitor and epothilone. COX-2 inhibitor can be 5-methyl-2-(2'-chlor-6'-fluoranilino)phenylacetic acid or its pharmaceutically acceptable salt. The combination can be applied in treatment of precancerous colon lesions or colon cancer as well as other malignant diseases. The invention also claims consumer package including cyclooxygenase-2 inhibitor and epothilone with manual for simultaneous, separate or alternating application of the medications for proliferative disease treatment.

EFFECT: reduction of side effects during epothilone treatment.

12 cl, 8 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts; where n is an integer independently equal to 1 or 2; X is a halogen; R1 is selected out of a group including hydrogen, carbonyl, sulfonyl, low alkyl and low alkyl substituted for hydroxyl group; R12 is selected out of a group including alkyl and alkenyl containing ca. 1 to 5 carbon atoms, and where R7-R11 are independently selected out of a group including hydrogen, halogen, -CN, -NO2, CF3, -OCH3, -COOCH3 and -C6H5; R2-R6 are independently selected out of a group including hydrogen, halogen, low alkyl, -C(CH3)3, CF3, -OCH3, -NO2 and -CN; and if R12 is alkyl or alkenyl containing ca. 1 to 5 carbon atoms then R2-R6 are hydrogen. The invention also concerns pharmaceutical composition.

EFFECT: obtaining new biologically active compounds and pharmaceutical composition based on there, with inhibition effect on MDM2-p53.

29 cl, 97 ex

FIELD: medicine; pharmacology.

SUBSTANCE: derivatives possess antiproliferative activity and stimulate an apoptosis in cells where absence of normal regulation of development of a cell and its destruction is observed. The derivatives are applied as a part of pharmaceutical compositions in combination with pharmaceutically acceptable mediums. The pharmaceutical compositions can be applied for treatment of diseases caused by hyperproliferation, including tumour growth, lymphoproliterative diseases and angiogenesis. Invention compounds pertain to the group of replaced pyrazoles and Pyrazolinums characterised by the formula of the invention.

EFFECT: derivatives possess useful biological properties.

56 cl, 115 ex

FIELD: medicine; oncology.

SUBSTANCE: method consists in a combined treatment using bisphosphonates for 5-10 days and mustophorane, mustophorane being injected intravenously driply once a week for 2-3 weeks in the quantity of 208 mg per one injection, 3-5 days after injection of bisphosphonates. Such courses of treatment by a combination of bisphosphonates and mustophorane are repeated in 6-8 weeks under control of indicants of peripheric blood.

EFFECT: increased efficiency of palliative treatment and a possibility to relieve a painful syndrome and improve quality of a life of patients with plural osteal metastasises of mammary gland cancer.

2 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to cyclodextrin-containing polymeric compounds, which are carriers for delivery of therapeutics, and pharmaceutical preparations based on them. Invention also relates to method of treating subjects with therapeutically effective quantity of said cyclodextrin-containing polymeric compound. Claimed cyclodextrin-containing polymers improve medication stability, increase its solubility and reduce toxicity of therapeutics when used in vivo. Furthermore, by selecting from a variety of linker groups and targeting ligands of said polymers it is possible to realise controlled delivery of therapeutic agents.

EFFECT: obtaining cyclodextrin-containing polymer compounds, improving medication stability, increasing its solubility and reducing toxicity of therapeutics when used in vivo.

56 cl, 13 dwg, 7 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new pyrazole derivatives of formula (IIa) or their pharmaceutically acceptable salts, where: Rx and Ry banded with intervening atoms while deriving benzol or cyclohexylene rings, optionally substituted by R3; R1 represents T-(ring D); ring D represents phenyl, optionally substituted by 1-2 groups R5, or naphtyl or imidazolyl or benzymidazolyl, optionally substituted by C1-C6alkyl group; T represents the linking; R2 represents hydrogen, C1-C6alkyl or C3-C6cycloalkyl; R2' represents hydrogen, or R2 and R2' is banded with their intervening atoms while deriving phenyl ring; R3 is selected from C1-C6alkyl, hydrogen, halogen, -OH, -NH2, -NHOH, -NO2, C1-C6alkoxy, optionally substituted -N(R4)2; each R4 independently selected from C1-C6alkyl, -CO2C1-C6alkyl or two R4 at the same nitrogen atom joined with nitrogen atom while deriving morpholine ring; each R5 represents one or two substitutes, independently selected from C1-C6alkyl, halogen, OH, -NH2, -CF3, C1-C6alkoxy, -COOH, -CO2C1-C6alkyl, -NHCO-C1-C6aliphatic group, NHCO(C1-C6alkyl)N(R4)2, -CONHC1-C6alkyl, -CONH(C1-C6alkyl)N(R4)2, and -NHSO2C1-C6alkyl. The compounds are useful as inhibitors of protein kinase, in particular as inhibitors Aurora-2 and GSK-3 for the treatment of cancer, diabetes and Alzheimer's disease. The subjects matter is also pharmaceutical composition on basis of their compounds and methods of the treatment of diseases mediated by the protein kinase.

EFFECT: production of new pyrazole derivatives - inhibitors of protein kinase.

25 cl, 12 tbl, 292 ex

FIELD: medicine; oncology.

SUBSTANCE: invention can be applied in treatment of squamous cell carcinoma of oral mucosa. Chemioradiation therapy is used for that purpose, with simultaneous intramuscular injection of 2 ml of 12.5% cyclopheron solution on the pattern of 1st, 3rd, 6th, 9th and 12th day. Additionally, since the first day of chemioradiation therapy cyclopheron applications are applied to the oral mucosa for 20 days twice per day.

EFFECT: reduction of radiation stomatitis and increased total efficiency of treatment.

1 ex

FIELD: medicine; oncology.

SUBSTANCE: before lymphatic nodes and vessels selection Klein's solution in the dose of 2-2.5 ml per 1 cm2 of wound is injected into cellular space of regional metastasis areas. The invention enables cancer metastasis prevention due to anatomical vasospasm and prevention of tumour emboli entering larger lymphatic vessels and venules.

EFFECT: improved prevention efficiency.

FIELD: medicine; pharmacology.

SUBSTANCE: composition is intended for treatment or prevention of insulin resistance of susceptible warm-blooded animals, including humans, and contains selective modulator of estrogen receptor EM-652-HC1, taken in amount determined by therapeutic efficiency.

EFFECT: effective treatment of prevention of insulin resistance development for warm-blooded mammals.

5 cl, 20 ex, 12 tbl, 8 dwg

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