Substituted hydantoins for treating cancer

FIELD: chemistry.

SUBSTANCE: formula (I) compounds, radicals of which are defined in the formula of invention, are described. A pharmaceutical composition containing formula (I) compounds is also described.

EFFECT: obtaining compounds which have inhibitory activity on protein kinase MEK1/2 and are meant for use as a therapeutically active substance which is useful for treating MEK1/2 mediated diseases.

13 cl, 18 ex

 

The text descriptions are given in facsimile form.

1. The compound of the formula

where R1means COR5,
R2means hydrogen,
R3selected from the group including (ness.)alkyl and cycloalkyl containing from 3 to 10 carbon atoms which may be substituted (ness.)alkylthio, (ness.)alkylsulfonyl or phenyl; tetrahydropyranyl; aryl represents monocyclic or bicyclic 6-10-membered aromatic system, which may be substituted by 1-2 substituents selected from the group comprising hydroxyl, (ness.)alkyl, (ness.)alkoxy, halogen, amino, di(ness.)alkylamino, nitro, cyano, phenyl, trifluoromethyl, carbarnoyl, methylsulfonylamino, ethoxycarbonylmethoxy; and heteroaryl represents an aromatic heterocyclic 5-9-membered ring system containing up to two cycles, in which 1-2 carbon atoms replaced by a heteroatom selected from nitrogen, oxygen and sulfur, which may be substituted (ness.)by alkyl;
R4selected from the group comprising naphthyl; phenyl which may be substituted by 1-2 substituents selected from the group comprising hydroxyl, (ness.)alkoxy, hydroxy(ness.)alkoxy, methoxyethoxy, methoxypropane, 2,3-dihydroxypropane, pyrrolidinyloxy, (ness.)alkylthio, (ness.)alkylsulfonyl, (ness.)alkyl, halogen, trifluoromethyl and di(ness.)alkylamino, and several deputies can about razvivat second cycle, condensed with the phenyl cycle, such as [2,3]dihydrobenzofuranyl, [2,2]difterent[1,3]dioxole, benzo[1,3]dioxole, dihydrobenzo[1,4]dioxines; furanyl; thienyl; and benzimidazolyl, substituted (ness.)by alkyl;
R5selected from the group including (ness.)alkyl, (ness.)alkoxy or amine, and independently replaced by Deputy selected from the group comprising hydrogen, (ness.)alkyl and (ness.)alkoxy; optionally in form of its racemates, enantiomers, diastereomers and mixtures thereof, or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which R1means COR5where R5means (ness.)alkoxy.

3. The compound according to claim 1 or 2, in which R3means phenyl.

4. The compound according to claim 1 or 2, in which R3mean 2-propyl.

5. The compound according to claim 1 or 2, in which R4means phenyl.

6. The compound according to claim 1, in which R1means COR5where R5means (ness.)alkoxy, and R3selected from the group comprising phenyl and 2-propyl.

7. The compound according to claim 1, in which R1means COR5where R5means (ness.)alkoxy, and R4means phenyl.

8. The compound according to claim 1 or 2, in which R5means methoxy.

9. The compound according to claim 1, in which R1means COR5where R5means (ness.)alkoxy, R3means substituted aryl or substituted heteroaryl ka is defined in claim 1, and R4means substituted phenyl as defined in claim 1, or benzimidazolyl, substituted (ness.)the alkyl.

10. The connection according to claim 9, where R5means methoxy.

11. The compound according to claim 1, selected from the group including
methyl ester 2-[(S)-2-((S)-2,5-dioxo-4-phenylimidazoline-1-yl)-4-methylpentylamino]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-3-cyclohexyl-2-((5)-2,5-dioxo-4-phenylimidazoline-1-yl)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-((S)-2,5-dioxo-4-phenylimidazoline-1-yl)hexanamide]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-((S)-2,5-dioxo-4-phenylimidazoline-1-yl)-2-phenylacetylamino]thiazole-4-carboxylic acid,
methyl ester 2-[(R)-2-((S)-2,5-dioxo-4-phenylimidazoline-1-yl)-3-(4-hydroxyphenyl)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-((S)-2,5-dioxo-4-phenylimidazoline-1-yl)-4-methylsulfonylamino]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-((S)-2,5-dioxo-4-phenylimidazoline-1-yl)-3-thiophene-2-ylpropionic]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-((S)-2,5-dioxo-4-phenylimidazoline-1-yl)-4-phenylbutyramide]thiazole-4-carboxylic acid,
methyl ester 2-[(R)-2-((S)-2,5-dioxo-4-phenylimidazoline-1-yl)pentanediamine]thiazole-4-carboxylic acid,
methyl ester 2-[(R)-2-((S)-2,5-dioxo-4-phenylimidazoline-1-yl)-4-methylpentylamino]thiazole-4-ka is oil acid,
methyl ester 2-[(S)-2-((S)-2,5-dioxo-4-phenylimidazoline-1-yl)-3-phenylpropionylamino]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-((R)-2,5-dioxo-4-phenylimidazoline-1-yl)-4-methylpentylamino]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-((S)-2,5-dioxo-4-phenylimidazoline-1-yl)-3-naphthalene-2-ylpropionic]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-3-biphenyl-4-yl-2-((S)-2,5-dioxo-4-phenylimidazoline-1-yl)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(2,5-dioxo-4-(2-were)imidazolidin-1-yl)-4-methylpentylamino]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(4-furan-2-yl-2,5-dioxoimidazolidin-1-yl)-3-phenylpropionylamino]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(4-naphthalene-2-yl-2,5-dioxoimidazolidin-1-yl)-3-phenylpropionylamino]thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(4-hydroxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(3-hydroxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[2,5-dioxo-4-(4-triptoreline)imidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(2-chlorophenyl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(3-methoxyphenyl-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino} thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(2,5-dioxo-4-(3-were)imidazolidin-1-yl)-3-phenylpropionylamino]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(2,5-dioxo-4-(4-were)imidazolidin-1-yl)-4-methylpentylamino]thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(4-isopropylphenyl)-2,5-dioxoimidazolidin-1-yl]-4-methylpentylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(4-chlorophenyl)-2,5-dioxoimidazolidin-1-yl]-4-methylpentylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-4-methylpentylamino}thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(4-furan-2-yl-2,5-dioxoimidazolidin-1-yl)-4-methylpentylamino]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-4-methyl-2-(4-naphthalene-2-yl-2,5-dioxoimidazolidin-1-yl)pentanediamine]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(2,5-dioxo-4-thiophene-3-elimination-1-yl)-4-methylpentylamino]thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(4-forfinal)-2,5-dioxoimidazolidin-1-yl]-4-methylpentylamino}thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-4-methylpentylamino]thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(3-itfeel)-2,5-dioxoimidazolidin-1-yl]-4-methylpentylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(4-hydroxide who yl)-2,5-dioxoimidazolidin-1-yl]-4-methylpentylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(3-hydroxyphenyl)-2,5-dioxoimidazolidin-1-yl]-4-methylpentylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[2,5-dioxo-4-(3-triptoreline)imidazolidin-1-yl]-4-methylpentylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(2-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-4-methylpentylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(2-chlorophenyl)-2,5-dioxoimidazolidin-1-yl]-4-methylpentylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(2-forfinal)-2,5-dioxoimidazolidin-1-yl]-4-methylpentylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(3-forfinal)-2,5-dioxoimidazolidin-1-yl]-4-methylpentylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(3-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-4-methylpentylamino}thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(2,5-dioxo-4-(3-were)imidazolidin-1-yl)-4-methylpentylamino]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(2,5-dioxo-4-(4-were)imidazolidin-1-yl)-3-phenylpropionylamino]thiazole-4-carboxylic acid,
methyl ester 2-[2-(2,5-dioxo-4-thiophene-3-elimination-1-yl)-3-phenylpropionylamino]thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(3-fluoro-4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid.
methyl ester 2-{(S)-2-[4-(2,3-dihydrobenzofuran-5-yl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(3,4-acid)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(2,3-differenl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(2,4-differenl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(3-chloro-4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(3,5-differenl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(2,6-differenl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(5-fluoro-2-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(2-fluoro-4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(4-dimethylaminophenyl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropyl is ylamino}thiazole-4-carboxylic acid,
methyl ester 2-[2-(4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-3-(4-cyanophenyl)propionamide]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-3-(4-carbamoylphenoxy)propionamido]thiazole-4-carboxylic acid,
methyl ester of 2-((S)-2-{2,5-dioxo-4-[4-(2-pyrrolidin-1 ylethoxy)phenyl]imidazolidin-1-yl}-3-phenylpropionylamino)thiazole-4-carboxylic acid,
methyl ester of 2-((S)-2-{(R)-4-[4-(3-methoxypropane)phenyl]-2,5-dioxoimidazolidin-1-yl}-3-phenylpropionylamino)thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(1-methyl-1H-benzimidazole-5-yl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-3-(2-triptoreline)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(4-methylsulfinylphenyl)-2,5-dioxoimidazolidin-1-yl]-3-(2-triptoreline)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-[4-(4-methanesulfonyl)-2,5-dioxoimidazolidin-1-yl]-3-(2-triptoreline)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(2,5-dioxo-4-thiophene-2-elimination-1-yl)-3-phenylpropionylamino]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-(1H-indol-3-yl)propionamido]thiazole-4-carb is a new acid,
methyl ester 2-{(S)-2-[4-(2,2-debtorrent[1,3]dioxol-5-yl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(3,5-acid)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-3-pyridin-3-ylpropionic]thiazole-4-carboxylic acid,
methyl ester 2-[2-(4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-3-(tetrahydropyran-4-yl)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-3-(1-methyl-1H-imidazol-4-yl)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-(4-methanesulfonylaminoethyl)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-3-phenylpropionylamino]thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(2-fluoro-4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-4-methylpentylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(2,3-differenl)-2,5-dioxoimidazolidin-1-yl]-4-methylpentylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(2-fluoro-4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-4-methylpentylamino}thiazole-4-carboxylic acid,
methyl is the ester of 2-{3-cyclopentyl-(S)-2-[4-(3-fluoro-4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]propionamide}thiazole-4-carboxylic acid,
methyl ester of (S)-2-[2-(4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-3-cyclopentylpropionyl]thiazole-4-carboxylic acid,
methyl ester of (S)-2-[2-(4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-3-cyclopropylamino]thiazole-4-carboxylic acid,
methyl ester of (S)-2-[2-(4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-4-methysulfonylmethane]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-3-(3-chlorophenyl)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-3-(2-chlorophenyl)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-(2-methoxyphenyl)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-3-(3-methoxyphenyl)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-[4-(3-fluoro-4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-(2-methoxyphenyl)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-3-(4-methoxyphenyl)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-3-ortho-Tripropylamine]thiazole-4-carboxylic acid
methyl ester 2-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-indan-1-ylpropionic}thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-(2-forfinal)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-(3,4-acid), propionamido]thiazole-4-carboxylic acid,
methyl ester 2-[(2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-(3-methoxycarbonylaminophenyl)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-{(S)-3-benzoxazol-5-yl-2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]propionamide}thiazole-4-carboxylic acid, isomer 1,
methyl ester 2-{(S)-3-benzoxazol-5-yl-2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]propionamide}thiazole-4-carboxylic acid, isomer 2,
methyl ester 2-[(S)-2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-(4-dimethylaminophenyl)propionamido]thiazole-4-carboxylic acid, isomer 1,
methyl ester 2-[(S)-2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-(4-dimethylaminophenyl)propionamido]thiazole-4-carboxylic acid, isomer 2,
methyl ester 2-{(S)-2-[4-(3-fluoro-4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-thiazol-4-ylpropionic}thiazole-4-Carbo the OIC acid,
methyl ester 2-[(S)-2-(4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-3-thiazol-4-ylpropionic]thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-thiazol-4-ylpropionic}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(3-fluoro-4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-furan-2-ylpropionic}thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-3-(3-methyl-3H-imidazol-4-yl)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-pyridin-3-ylpropionic}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[(R)-4-(3-fluoro-4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[(S)-4-(3-fluoro-4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[(R)-4-(3-chloro-4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[(R)-4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[(R)-4-(3,5-differenl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl Efir-{(S)-2-[(R)-4-(3-fluoro-4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-(2-methoxyphenyl)propionamido}thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-((R)-4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-3-cyclopropylamino]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-((R)-4-benzo[1,3]dioxol-5-yl-2,5-dioxoimidazolidin-1-yl)-3-cyclopentylpropionyl]thiazole-4-carboxylic acid,
methyl ester 2-{3-cyclopentyl-(S)-2-[(R)-4-(3-fluoro-4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]propionamide}thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-((S)-2,5-dioxo-4-thiophene-3-elimination-1-yl)-3-phenylpropionylamino]thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[(R)-4-(4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-thiazol-2-ylpropionic}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[(R)-4-(2-fluoro-4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-(2,5-dioxo-(R)-4-phenylimidazoline-1-yl)-3-phenylpropionylamino]thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[(R)-4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[(R)-4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-(4-forfinal)propionamido}thiazole-4-carboxylic acid,
methyl ester 2-{3-(3,5-differenl)-(S)-2-[(R)-4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]propionamide}thiazole-4-carboxylic acid,
methyl ester 2[(S)-2-[(R)-4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-(2-forfinal)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[(R)-4-(4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{3-(2-methoxyphenyl)-(S)-2-[(R)-4-(4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]propionamide}thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-[(R)-4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-(3-forfinal)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-{3-(3,4-differenl)-(S)-2-[(R)-4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]propionamide}thiazole-4-carboxylic acid,
methyl ester of 2-((S)-2-{(R)-4-[4-(2-hydroxyethoxy)phenyl]-2,5-dioxoimidazolidin-1-yl}-3-phenylpropionylamino)thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[(R)-4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-thiophene-2-ylpropionic}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[(R)-4-(4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-thiazol-4-ylpropionic}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[(R)-4-(4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-thiazol-2-ylpropionic}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[(R)-4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-thiazol-4-ylpropionic}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[(R)-4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-thiophene-3-ylpropionic}t is evil-4-carboxylic acid,
methyl ester 2-{(S)-2-[(R)-4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2,5-dioxoimidazolidin-1-yl]-3-pyrazole-1-ylpropionic}thiazole-4-carboxylic acid,
methyl ester 2-{(R)-2-[(R)-4-(4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[(S)-4-(4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester of 2-((S)-2-{(R)-4-[4-(2-methoxyethoxy)phenyl]-2,5-dioxoimidazolidin-1-yl}-3-phenylpropionylamino)thiazole-4-carboxylic acid,
methyl ester 2-[2-[(R)-4-(4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-(3-nitrophenyl)propionamide]thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-[(R)-4-(4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-(4-nitrophenyl)propionamide]thiazole-4-carboxylic acid,
methyl ester 2-{(S)-3-(4-AMINOPHENYL)-2-[(R)-4-(4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]propionamide}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-3-(4-dimethylaminophenyl)-2-[(R)-4-(4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]propionamide}thiazole-4-carboxylic acid,
methyl ester 2-[(S)-2-{4-[4-(2-methoxyethoxy)phenyl]-2,5-dioxoimidazolidin-1-yl}-3-(2-methoxyphenyl)propionamido]thiazole-4-carboxylic acid,
methyl ester 2-{(S)-3-(2-cyanophenyl)-2-[(R)-4-(4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]propionamide}thiazole-4-carboxylic acid,
methyl ester of 2-((S) - 3-(2-cyanophenyl)-2-{4-[(R)-4-(2-methoxyethoxy)phenyl]-2,5-dioxoimidazolidin-1-yl}propionamide)thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-((R)-(4-ethoxyphenyl))-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester of 2-((S)-2-{(R)-4-[4-((R)-2,3-dihydroxypropane)phenyl]-2,5-dioxoimidazolidin-1-yl}-3-phenylpropionylamino)thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(4-methoxy-3-were)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(3-isopropyl-4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methyl ester 2-{(S)-2-[4-(3-ethyl-4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
methoxyethylamine 2-{(S)-2-[(R)-4-(4-methoxyphenyl)-2,5-dioxoimidazolidin-1-yl]-3-phenylpropionylamino}thiazole-4-carboxylic acid,
(S)-N-(4-acetylthiazole-2-yl)-2-(2,5-dioxo-4-phenylimidazoline-1-yl)-3-phenylpropionamide,
amide 2-[(S)-2-(2,5-dioxo-4-phenylimidazoline-1-yl)-3-phenylpropionylamino]thiazole-4-carboxylic acid,
dimethylamide 2-[(S)-2-(2,5-dioxo-4-phenylimidazoline-1-yl)-3-phenylpropionylamino]thiazole-4-carboxylic acid.

12. The compound according to claim 1, intended for use as therapeutically active substances useful for treating diseases mediated MEK/2.

13. Pharmaceutical composition having inhibitory activity against protein kinases MEK/2, VK is causa compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (XXI) where values of R1, Y, Ra and Rb are given in subparagraphs 1 and 2 of the formula of invention, as phosphatidylinositol-3-kinase inhibitors, a pharmaceutical composition based on said compounds and their use.

EFFECT: compounds can be used for treating and preventing diseases mediated by phosphatidylinositol-3-kinase.

5 cl, 5 tbl, 146 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I)

Values of radicals R1-R6 are given in the formula of invention. The compounds inhibit protein kinase MEK1/2. Also described is a pharmaceutical composition for administration in diseases mediated by MEK1/2.

EFFECT: compounds are highly efficient.

16 cl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

or

or to their pharmaceutically acceptable salts, where ring A, R2, R3, R4 and X are as defined in the description. The disclosed compounds are useful as 11βHSD1 inhibitor. The invention also relates to a pharmaceutical composition, an agent for treating or preventing pathology related to glucocorticoids, a 11βHSD1 inhibitor containing the disclosed compound or its pharmaceutically acceptable salt, and use of the disclosed compounds.

EFFECT: compounds are highly effective.

40 cl, 48 tbl, 191 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula and their pharmaceutically acceptable salts and esters. The disclosed compounds have cdk4 inhibition properties. In formula (I) n equals 0 or 1; R1 and R2 are each independently selected from a group consisting of H, lower alkyl, CO2R5, SO2R6 and COR6; or alternatively, R1 and R2 can form a ring containing 5-6 atoms in the ring, where the said ring contains carbon atoms, where the said carbon atoms are optionally substituted with oxygen, and the said atoms in the ring are optionally substituted with OR6; R3 is selected from a group consisting of H, lower alkyl, O-lower alkyl, halogen, OH, CN, NO2 and COOH; R4 is selected from a group consisting of H, lower alkyl, C3-C6-cycloalkyl, O-lower alkyl, halogen, NO2, S-lower alkyl, NR5R6, CONR7R8, OH and CN; or alternatively R3 and R4, together with two carbon atoms and the bond between them from the benzene ring, to which R3 and R4 are bonded, can form a ring containing 5-7 atoms, where the said 5-7-member ring contains carbon atoms, where the said carbon atoms are optionally substituted with one or two heteroatoms selected from O and N, and the said atoms in the ring are optionally substituted with CO2R6; R4 represents H or halogen; R5 and R6 are each independently selected from a group consisting of H and lower alkyl; R7 and R8 each represents H. The invention also relates to a pharmaceutical composition for treating or controlling diseases progression of which can be enhanced by inhibiting cdk4, containing an effective amount of the disclosed compound as an active ingredient, to use of disclosed compounds for preparing medicinal agents and method of producing said compounds.

EFFECT: more effective treatment.

30 cl, 1 tbl, 142 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I: where A,Y,R and R2 assume values given in the description. The invention also relates to methods of producing compounds of formula I and their intermediate compounds, pharmaceutical compositions and methods of using the compounds and their pharmaceutical compositions for inhibiting caspase.

EFFECT: novel compounds have useful biological properties.

44 cl, 5 tbl, 66 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: claimed compounds show effect on receptor activated by peroxysome proliferate δ (PPARδ). In formula I: [Formula I] , [Formula VII] , [Formula VI] , A is R1 is C1-4alkyl group; R3 groups are different and denote halogen atom or C1-4alkyl group substituted or unsubstituted by halogen; R4 is R5 is hydrogen atom or hydroxyl group; the other radicals are as defined in the invention claim. Also invention refers to methods of compound I obtainment, to intermediary compounds VI, VII and methods of their obtainment, to medicines of diabetes, obesity, atherosclerosis, hyperlipidemia treatment and prevention, containing thiazole derivative of the formula I as active component.

EFFECT: enhanced activity of derivatives.

21 cl, 10 tbl, 102 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I): , where R1 is C1-C8alkyl optionally substituted with one to three substitutes selected out of substitute group A; R2 is C1-C6alkyl or C1-C6alkoxyC1-C6alkyl; R3 is C1-C6alkyl or C1-C6alkoxy; or R2 and R3 together with adjoining carbon atoms form optionally substituted non-aromatic 5-10-member carbon ring; R4 is hydrogen; G is group represented by the formula: or the rest as provided in the invention claim; and to pharmaceutical composition, application of claimed compounds, and method of atopic dermatitis prevention or treatment.

EFFECT: novel compounds useful as atopic dermatitis treatment medication and antipruritic medicines.

24 cl, 75 ex, 290 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to cyclic derivatives of aminobenzoic acid and to their pharmaceutically acceptable salts of general formula , in which ring Ar is a phenyl group, a 5-member aromatic heterocyclic group containing 1-2 heteroatoms selected from nitrogen, sulphur and oxygen, or a benzothiazolyl group; where the said groups can have 1-2 substitutes selected from a group comprising lower alkyl; a phenyl group; a phenyl group substituted with 1-2 halogens; a phenyl group substituted with a lower alkoxy group; a phenyl group substituted with a halogen-substituted lower alkyl group; a phenoxy group substituted with a halogen; a halogen; Z is an oxygen atom or -(CH2)-n (where n equals 0, 1 or 2); Y is C1-C4 alkylene, C2-C4 alkenylene or general formula (2) -T-A-U- (2) in which T is a single bond, C1-C4 alkylene or C2-C4 alkenylene; U is single bond, C1-C4 alkylene; values of the rest of radicals are given in the formula of invention.

EFFECT: obtaining a PPARα, agonist which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid, and an agent which reduces the level of lipids which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid.

12 cl, 16 tbl, 184 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula 1 , where R1, R2, R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, halogen, alkylcarboxylate, alkyl, alkenyl, cycloalkyl, nitro, sulfonyl chloride, sufonyl hydrazide, alkyl sulfonyl, heterocycylsulfonyl, heteroarylsufonyl, sulfonamide, alkyl-NH-SO2-, cycloalkyl-NH-SO2-, heterocyclyl-NH-SO2-, heteroalkyl-NH-SO2-, heteroarylalkyl-NH-SO2-, heterocyclyl, heteroaryl, guanidinocarbonyl, guanidine, -NR'R" and N=R'"; R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, halogenalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, aminoalkyl, mono- or dialkyl substituted aminoalkyl, cycloalkylaminoalkyl, aralkylaminoalkyl, alkoxyaralkylaminoalkyl, heterocyclylalkyl, heterocyclylaminoalkyl, heterocyclylalkylaminoalkyl, heterocyclylalkyl-N(alkyl) alkyl, heteroarylalkyl, heteroaralkylaminoalkyl, alkoxyaralkyl-N(alkyl)alkyl, aralkyl-N(alkyl)alkyl, alkoxycarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl alkylcarbonyl; R'" is selected from heterocyclyl, cycloalkyl and alkyl; where the alkyl is unsubstituted or substituted with 1, 2 or 3 identical or different substitutes selected from halogen, halogen alkyl, hydroxy, alkoxy, alkylamino, carbonyl, cycloalkylamino, nitro, cycloalkyl, aryl, heteroaryl and heterocyclyl; aryl is (C6-C10)aryl which is unsubstituted or substituted with 1-2 identical or different substitutes selected from nitro, alkyl, alkoxy, halogen, halogenalkyl, amino and mono or dialkylamino-; heteroaryl is a 5- or 6-member ring system containing 1, 2 or 3 atoms in the ring selected from N, O and S, which is unsubstituted or substituted with 1-2 identical or different groups selected from halogen, nitro, amino, alkylamino, alkyl, alkoxy and cycloalkyl; heterocyclyl is a 5- or 6-member ring system containing 1, 2 or 3 atoms in the ring selected from N, O and S, which is unsubstituted or substituted with 1-2 identical or different groups selected from alkyl, cycloalkyl, hydroxyalkyl, alkylaminoalkyl, cycloalkylalkyl, cycloalkylcarbonyl, heterocyclylalkyl, heteroarylalkyl, heteroarylcarbonyl, arylalkyl and oxo; and guanidino and guanidinocarbonyl are unsubstituted or substituted with 1, 2 or 3 identical or different groups selected from alkyl and alkylcarbonyl; provided that at least one of R1, R2, R3, R4, R5, R6, R7 or R8 is guanidine or guanidine carbonyl; U is C(O), CRaRb, O or NRa; V is CRaRb or NRa; and W is S(O)m; where Ra is H, alkyl, cycloalkyl or alkenyl; Rb is H, alkyl, OH or ORa, and m equals 1 or 2; or to pharmaceutically acceptable salts thereof. The invention also relates to a method of obtaining formula 1 compounds, to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining new biologically active compounds which are sodium/proton exchange (Na+/H+) (NHE) inhibitors.

19 cl, 203 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I)

Values of radicals R1-R6 are given in the formula of invention. The compounds inhibit protein kinase MEK1/2. Also described is a pharmaceutical composition for administration in diseases mediated by MEK1/2.

EFFECT: compounds are highly efficient.

16 cl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula and their pharmaceutically acceptable salts and esters. The disclosed compounds have cdk4 inhibition properties. In formula (I) n equals 0 or 1; R1 and R2 are each independently selected from a group consisting of H, lower alkyl, CO2R5, SO2R6 and COR6; or alternatively, R1 and R2 can form a ring containing 5-6 atoms in the ring, where the said ring contains carbon atoms, where the said carbon atoms are optionally substituted with oxygen, and the said atoms in the ring are optionally substituted with OR6; R3 is selected from a group consisting of H, lower alkyl, O-lower alkyl, halogen, OH, CN, NO2 and COOH; R4 is selected from a group consisting of H, lower alkyl, C3-C6-cycloalkyl, O-lower alkyl, halogen, NO2, S-lower alkyl, NR5R6, CONR7R8, OH and CN; or alternatively R3 and R4, together with two carbon atoms and the bond between them from the benzene ring, to which R3 and R4 are bonded, can form a ring containing 5-7 atoms, where the said 5-7-member ring contains carbon atoms, where the said carbon atoms are optionally substituted with one or two heteroatoms selected from O and N, and the said atoms in the ring are optionally substituted with CO2R6; R4 represents H or halogen; R5 and R6 are each independently selected from a group consisting of H and lower alkyl; R7 and R8 each represents H. The invention also relates to a pharmaceutical composition for treating or controlling diseases progression of which can be enhanced by inhibiting cdk4, containing an effective amount of the disclosed compound as an active ingredient, to use of disclosed compounds for preparing medicinal agents and method of producing said compounds.

EFFECT: more effective treatment.

30 cl, 1 tbl, 142 ex

Organic compounds // 2382783

FIELD: chemistry.

SUBSTANCE: invention relates to a compound which is 1-[2-(2-ethyl-2H-tetrazol-5-yl)ethyl]-3-[5-(3-fluoro-4-methanesulfonylphenyl)-4-methylthiazol-2-yl]urea in free form or in form of a pharmaceutically acceptable salt.

EFFECT: composition has inhibitory activity on phosphatidylinositol-3-kinase, which contains the disclosed compound as an active ingredient, to use of the compound to prepare a pharmaceutical composition for treating diseases mediated by phosphatidylinositol-3-kinase and synthesis method thereof.

6 cl, 9 tbl, 154 ex

FIELD: chemistry.

SUBSTANCE: novel 1,2,4-triazole derivatives - protein kinase inhibitors of formula (I) are described, where X - N; Y - CH2, NH, NR or 0; R1 and R2 each independently denote hydrogen; R3 is phenyl, substituted with -CN, 6-member heteroaryl containing 1-2 N atoms, possibly substituted with a 7-member heterocyclyl containing 2 nitrogen atoms, which in turn is substituted with C1-6alkylcarbonyl; R4 is hydrogen; R5 is hydrogen or -CN; and R is a C1-6alkyl group, C1-6alkylcarbonyl group substituted with -CN, or a C3-6cycloalkyl group, a method of inhibiting FLT-3 or c-KIT protein kinase.

EFFECT: obtaining novel compounds and their use in making a medicinal agent for treating or relieving acute myelogenic leucosis.

11 cl, 1 tbl, 13 ex

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