Pyridazine derivatives

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula I: and their pharmaceutically acceptable salts, in which R1-R4 have values, given in item 1 of invention formula. Said compounds possess inhibiting activity with respect to 11-beta-hydroxysteroid-dehydrogenase and can be applied for production of medications, intended for treatment and prevention of diabetes, especially, diabetes of II type, obesity, malnutrition and hypertension.

EFFECT: development of efficient method of obtaining formula I compounds and based on them pharmaceutical composition.

25 cl, 1 tbl, 149 ex

 

The text descriptions are given in facsimile form.

1. The compounds of formula

in which R1denotes cycloalkyl;
R2denotes cycloalkyl; or
R1and R2together with the carbon atoms Caand Cbto which they are attached, form fragments
,,,,
,or;
R3denotes hydrogen or alkyl;
R4denotes benzyl, cycloalkyl, phenylcyclohexyl, substituted, phenyl, indolyl, pyrazolyl, pyrrolyl or thiazolyl, where benzyl, cycloalkyl, phenylcyclohexyl, phenyl, indolyl, pyrazolyl, pyrrolyl and thiazolyl optionally contains 1-3 substituent, independently selected from the group comprising alkyl, cycloalkyl, alkoxygroup, the hydroxy-group, halogen, trifluoromethyl, cryptometer, benzyl, phenyl and phenyl containing 1-3 substituent, independently selected from the group comprising alkyl, halogen and trifluoromethyl;
R5denotes hydrogen or alkyl;
R6denotes ogorodili alkyl;
R7denotes hydrogen or alkyl;
and their pharmaceutically acceptable salts; provided that if R4denotes unsubstituted phenyl, at least one of R5, R6and R7does not denote hydrogen or methyl.

2. Compounds according to claim 1, in which R4denotes cycloalkyl, phenylcyclohexyl, substituted, phenyl, indolyl, pyrazolyl, pyrrolyl or thiazolyl where phenylcyclohexyl, phenyl, indolyl, pyrazolyl, pyrrolyl or thiazolyl optionally contains 1-3 substituent, independently selected from the group comprising alkyl, alkoxygroup, the hydroxy-group, halogen, trifluoromethyl, phenyl and phenyl containing 1-3 substituent, independently selected from the group comprising alkyl, halogen and trifluoromethyl.

3. Compounds according to claim 1 or 2, in which R3denotes hydrogen.

4. Compounds according to claim 1 or 2, in which R3denotes methyl.

5. Compounds according to claim 1, in which R4denotes benzyl, cyclopropyl, methylcyclopropyl, cyclobutyl, vinylcyclopropyl, phenylcyclohexyl, substituted, phenyl, indolyl, pyrazolyl, pyrrolyl or thiazolyl, where benzyl, cyclopropyl, vinylcyclopropyl, phenylcyclohexyl, phenyl, indolyl, pyrazolyl, pyrrolyl and thiazolyl optionally contains 1-3 substituent, independently selected from the group comprising alkyl, cycloalkyl, alkoxygroup, halogen, trifluoromethyl, triptoreline the PU, benzyl, phenyl and phenyl containing 1-3 substituent, independently selected from the group comprising alkyl, halogen and trifluoromethyl.

6. Compounds according to claim 1, in which R2denotes cyclopropyl.

7. Compounds according to claim 1, in which R1denotes cyclopropyl.

8. Compounds according to claim 1, in which R1and R2together with the carbon atoms Caand Cbto which they are attached, form fragments
,,,
,or.

9. Compounds according to claim 1, in which R1and R2together with the carbon atoms Caand Cbto which they are attached, form a fragment
.

10. Compounds according to claim 1, in which R1and R2together with the carbon atoms Caand Cbto which they are attached, form a fragment

11. Compounds according to claim 1, in which R5, R6and R7denote hydrogen.

12. Compounds according to claim 1, selected from the group including
(1S,8R)-1,11,11-trimethyl-5-(5-methyl-1-phenyl-1H-pyrazole-4-yl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(1S,8R)-1,11,11-trimethyl-5-(2-triptoreline)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(1S,8R)-1,11,11-trimethyl-5-(1-phenyl-5-trifluoromethyl-1H-feast of the ol-4-yl)-3,4-diazatricyclo[6.2.1.0 2,7]undeca-2(7),3,5-triene;
(1S,8R)-5-adamantane-1-yl-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-[2-(3-chlorophenyl)-thiazol-4-yl]-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1R,8S)-5-(2-chlorophenyl)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-1,11,11-trimethyl-5-phenyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1R,8S)-1,11,11-trimethyl-5-phenyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1R,8S)-1,11,11-trimethyl-5-(2-triptoreline)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1R,8S)-1,11,11-trimethyl-5-(4-triptoreline)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-(4-forfinal)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-[1-(4-chlorophenyl)-5-trifluoromethyl-1H-pyrazole-4-yl]-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-(2-chlorophenyl)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1R,8S)-1,11,11-trimethyl-5-(1-phenyl-5-trifluoromethyl-1H-pyrazole-4-yl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1R,8S)-5-[1-(4-chlorophenyl)-5-trifluoromethyl-1H-pyrazole-4-yl]-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1R,8S)-1,11,11-trimethyl-5-(5-methyl-1-phenyl-1H-pyrazole-4-yl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-(2,4-differenl)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-(2-forfinal)-1,1,11-trimethyl-3,4-diazatricyclo[6.2.1.0 2,7]undeca-2,4,6-triene;
(1S,8R)-5-(2,5-differenl)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-1,11,11-trimethyl-5-(1-phenyl-5-propyl-1H-pyrazole-4-yl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(1S,8R)-1,11,11-trimethyl-5-(1-methyl-1H-indol-3-yl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(1S,8R)-5-[1-(4-chlorophenyl)-cyclopropyl]-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-[1-(4-chlorophenyl)-cyclobutyl]-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
3-adamantane-1-yl-5,6,7,8-tetrahydroquinolin;
3-(1-phenyl-5-trifluoromethyl-1H-pyrazole-4-yl)-5,6,7,8-tetrahydroquinolin;
3-[1-(4-chlorophenyl)-cyclopropyl]-5,6,7,8-tetrahydroquinolin;
3-[1-(4-chlorophenyl)-cyclobutyl]-5,6,7,8-tetrahydroquinolin;
3-(2-triptoreline)-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
3-[1-(4-chlorophenyl)-5-trifluoromethyl-1H-pyrazole-4-yl]-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
3-[1-(4-chlorophenyl)-cyclopropyl]-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
3-[1-(4-chlorophenyl)-cyclobutyl]-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
3-(5-fluoro-2-triptoreline)-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
(1S,8R)-5-[1-(4-forfinal)-5-trifluoromethyl-1H-pyrazole-4-yl]-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(1S,8R)-5-cyclopropyl-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
3,4-dicyclopropyl-6-(5-methyl-phenyl-1H-pyrazole-4-yl)-pyridazin;
3,4-dicyclopropyl-6-(2-triptoreline)-pyridazin;
6-[1-(4-chlorophenyl)-cyclopropyl]-3,4-Dicyclopentadiene;
6-[1-(4-chlorophenyl)-cyclobutyl]-3,4-Dicyclopentadiene;
(1SR,8RS)-5-(5-methyl-1-phenyl-1H-pyrazole-4-yl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(1SR,8RS)-5-(2-triptoreline)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
3-(2-triptoreline)-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
(1S,8R)-5-(3-fluoro-2-triptoreline)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
3-(3-fluoro-2-triptoreline)-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
(1SR,8RS)-5-[1-(4-forfinal)-5-trifluoromethyl-1H-pyrazole-4-yl]-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1SR,8RS)-5-(2,4-differenl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1SR,8RS)-5-(2-forfinal)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1SR,8RS)-5-(4-fluoro-2-triptoreline)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
3-(3-trifluoromethyl-1H-pyrazole-4-yl)-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
3-(4-fluoro-2-triptoreline)-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
3-(2-forfinal)-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
(1S,8R)-5-(5-methoxy-2-triptoreline)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
3-(5-methyl-1-phenyl-1H-pyrazole-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
(1S,8R)-5-(4-fluoro-2-triptoreline)-111,11-trimethyl-3,4-diazatricyclo[6.2.1.0 2,7]undeca-2,4,6-triene;
3-(2,5-differenl)-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
3-[1-(4-forfinal)-5-trifluoromethyl-1H-pyrazole-4-yl]-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
3-(2,4-differenl)-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
3-(2-forfinal)-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
(1S,8R)-1,11,11-trimethyl-5-(3-trifluoromethyl-1H-pyrazole-4-yl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
3-[1-(4-chlorophenyl)-cyclopropyl]-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
(1S,8R)-5-(5-butoxy-1-methyl-1H-pyrazole-4-yl)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
3-(1-phenyl-5-propyl-1H-pyrazole-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
3-[1-(4-chlorophenyl)-cyclobutyl]-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
3,4-dicyclopropyl-6-(1-phenyl-5-propyl-1H-pyrazole-4-yl)-pyridazin;
3-(4-fluoro-2-triptoreline)-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin; and
3-(1-methyl-5-trifluoromethyl-1H-pyrazole-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[with] pyridazin.

13. Compounds according to claim 1, selected from the group including
3-[1-(4-forfinal)-5-trifluoromethyl-1H-pyrazole-4-yl]-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
(1SR,8RS)-5-(3-fluoro-2-triptoreline)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1SR,8RS)-5-cyclopropyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1SR,8RS)-5-(5-fluoro-2-triptoreline)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-three is n;
(1SR,8RS)-5-(1-methyl-3-trifluoromethyl-1H-pyrazole-4-yl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-(2-chloro-4-forfinal)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
3-(3-fluoro-2-triptoreline)-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
3-(5-fluoro-2-triptoreline)-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
(1S,8R)-5-(2-chloro-4-fluoro-5-methoxyphenyl)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-(2-chloro-4,5-differenl)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
3-cyclopropyl-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
3-(5-chloro-2-triptoreline)-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
(1SR,8RS)-5-(2-chloro-4-forfinal)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(1SR,8RS)-5-(5-chloro-2-triptoreline)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(lSR,8RS)-5-(2-chloro-4,5-differenl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
3-(1-phenyl-5-trifluoromethyl-1H-pyrazole-4-yl)-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
(1S,8R)-1,11,11-trimethyl-5-(4-methyl-2-phenylthiazol-5-yl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
3-(4-methyl-2-phenylthiazol-5-yl)-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
(1SR,8RS)-5-(2-methoxyphenyl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1SR,8RS)-5-o-tolyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-(2-methoxyphenyl)-1,11,11-trimethyl-3,4-Diaz is tricyclo[6.2.1.0 2,7]undeca-2,4,6-triene;
(1S,8R)-1,11,11-trimethyl-5-o-tolyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
3-(2-methoxyphenyl)-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
3-(2-methoxyphenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
3-o-tolyl-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
3-(4-chloro-2-were)-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
3-(4-chloro-2-were)-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
(1S,8R)-5-(4-chloro-2-were)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(1S,8R)-1,11,11-trimethyl-5-(1-methyl-1H-pyrrol-2-yl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
3-(1-methyl-1H-pyrrol-2-yl)-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
3-(1-methyl-1H-pyrrol-2-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
(1SR,8RS)-5-(1-methyl-1H-pyrrol-2-yl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-(4-chloro-2-were)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
3-(1-methylcyclopropyl)-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
(1SR,8RS)-5-(4-fluoro-2-were)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
6,6-dimethyl-3-(5-methyl-1-phenyl-1H-pyrazole-4-yl)-6,7-dihydro-5H-cyclopent[C]pyridazin;
(1S,8R)-5-(5-fluoro-2-methoxyphenyl)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1SR,8RS)-5-(5-fluoro-2-methoxyphenyl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
6,6-dimethyl-3-(2-triptoreline)-6,7-dihydro-5 is-cyclopent[C]pyridazin;
(1S,8R)-5-(4-fluoro-2-were)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
3-(2-chlorophenyl)-6,6-dimethyl-6,7-dihydro-5H-cyclopent[C]pyridazin;
3-(2,4-differenl)-6,6-dimethyl-6,7-dihydro-5H-cyclopent[C] pyridazin;
(1SR,8RS)-5-(1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-yl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-(1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-yl)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(1SR,8RS)-5-(2-trifloromethyl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-1,11,11-trimethyl-5-(1-methylcyclopropyl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-1,11,11-trimethyl-5-(2-trifloromethyl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-(1-tert-butyl-5-methyl-1H-pyrazole-4-yl)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1SR,8RS)-5-(1-tert-butyl-5-methyl-1H-pyrazole-4-yl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
6,6-dimethyl-3-(2-trifloromethyl)-6,7-dihydro-5H-cyclopent[C]pyridazin;
3-(1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-yl)-6,6-dimethyl-6,7-dihydro-5H-cyclopent[C]pyridazin;
(1SR,8RS)-5-(1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-yl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-(1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-yl)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
3-(5-chloro-2-triptoreline)-6,6-dimethyl-6,7-dihydro-5 is-cyclopent[C]pyridazin;
(1S,8R)-5-(5-cyclopropyl-1-methyl-1H-pyrazole-4-yl)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1SR,8RS)-5-(5-cyclopropyl-1-methyl-1H-pyrazole-4-yl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
3-(5-cyclopropyl-1-methyl-1H-pyrazole-4-yl)-6,6-dimethyl-6,7-dihydro-5H-cyclopent[C] pyridazin;
(1S,8R)-5-cyclobutyl-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1SR,8RS)-5-cyclobutyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
3-(1-tert-butyl-5-methyl-1H-pyrazole-4-yl)-6,6-dimethyl-6,7-dihydro-5H-cyclopent[C]pyridazin;
(1S,8R)-5-(1,3-dimethyl-1H-pyrazole-4-yl)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-1,11,11-trimethyl-5-(1-methyl-5-trifluoromethyl-1H-pyrazole-4-yl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-(1-benzyl-5-trifluoromethyl-1H-pyrazole-4-yl)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-(1-benzyl-5-methyl-1H-pyrazole-4-yl)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-(1-benzyl-3-methyl-1H-pyrazole-4-yl)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1SR,8RS)-5-cyclopropyl-6-methyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-cyclopropyl-1,6,11,11-tetramethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-(1-tert-butyl-5-phenyl-1H-pyrazole-4-yl)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-(4-chlorbenzyl)-1,11,11-dimetil-3,4-diazatricyclo[6.2.1.0 2,7]undeca-2,4,6-triene;
(1S,8R)-1,11,11-trimethyl-5-(1-cryptomaterial)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
3-(4-fluoro-2-triptoreline)-6,6-dimethyl-6,7-dihydro-5H-cyclopent[C]pyridazin;
(1R,8S)-5-cyclopropyl-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
3-(3-fluoro-2-triptoreline)-6,6-dimethyl-6,7-dihydro-5H-cyclopent[C]pyridazin;
(1SR,8RS)-5-(2,5-dichlorophenyl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(1SR,8RS)-5-(2,3-dimetilfenil)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
3-(2,5-dichlorophenyl)-6,6-dimethyl-6,7-dihydro-5H-cyclopent[C]pyridazin;
3-(2,3-dimetilfenil)-6,6-dimethyl-6,7-dihydro-5H-cyclopent[C]pyridazin;
(1SR,8RS)-5-(2,4-dichlorophenyl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(1SR,8RS)-5-(2,3-dichlorophenyl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(1SR,8RS)-5-(2,4-dimetilfenil)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(1R,8S)-5-cyclopropyl-8,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene and (1S,8R)-5-cyclopropyl-8,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene.

14. Compounds according to claim 1, selected from the group including
(1S,8R)-1,11,11-trimethyl-5-(5-methyl-1-phenyl-1H-pyrazole-4-yl)-3,4-
diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(18,8R)-1,11,11-trimethyl-5-(2-triptoreline)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(18,8R)-1,11,11-trimethyl-5-(1-phenyl-5-reformer-1H-pyrazole-4-yl)-3,4-diazatricyclo[6.2.1.0 2,7]undeca-2(7),3,5-triene;
(1S,8R)-1,11,11-trimethyl-5-phenyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-[1-(4-chlorophenyl)-5-trifluoromethyl-1H-pyrazole-4-yl]-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-(2-chlorophenyl)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-(2-forfinal)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-1,11,11-trimethyl-5-(1-phenyl-5-propyl-1H-pyrazole-4-yl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(1S,8R)-5-[1-(4-chlorophenyl)-cyclopropyl]-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-[1-(4-chlorophenyl)-cyclobutyl]-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
3-[1-(4-chlorophenyl)-cyclopropyl]-5,6,7,8-tetrahydroquinolin;
3-[1-(4-chlorophenyl)-cyclobutyl]-5,6,7,8-tetrahydroquinolin;
3-(2-triptoreline)-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
3-[1-(4-chlorophenyl)-5-trifluoromethyl-1H-pyrazole-4-yl]-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
3-(5-fluoro-2-triptoreline)-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
(1S,8R)-5-cyclopropyl-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(1SR,8RS)-5-(2-triptoreline)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
3-(2-triptoreline)-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
3-(3-fluoro-2-triptoreline)-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin;
(1SR,8RS)-5-[1-(4-forfinal)-5-trifluoromethyl-1H-pyrazole-4-yl]-3,4-diazatricyclo[6.2.1.0 2,7]undeca-2,4,6-triene;
(1SR,8RS)-5-(4-fluoro-2-triptoreline)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
3-(4-fluoro-2-triptoreline)-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
(1S,8R)-5-(4-fluoro-2-triptoreline)-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
3-(4-fluoro-2-triptoreline)-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin; and
3-(1-methyl-5-trifluoromethyl-1H-pyrazole-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[with]pyridazin.

15. Compounds according to claim 1, selected from the group comprising (1S,8R)-5-cyclopropyl-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(1SR,8RS)-5-(2-triptoreline)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
3-(2-triptoreline)-5,6,7,8,9,10-hexahydrocyclooct[with]pyridazin;
(1SR,8RS)-5-(5-chloro-2-triptoreline)-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(1S,8R)-1,11,11-trimethyl-5-(1-methylcyclopropyl)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-5-cyclopropyl-1,6,11,11-tetramethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
(1S,8R)-1,11,11-trimethyl-5-(1-cryptomaterial)-3,4-diazatricyclo[6.2.1.02,7]undeca-2,4,6-triene;
3-(4-fluoro-2-triptoreline)-6,6-dimethyl-6,7-dihydro-5H-cyclopent[C]pyridazin and
(1R,8S)-5-cyclopropyl-1,11,11-trimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene.

16. The compound according to claim 1, which represents the (1S,8R)-5-cyclopropyl-1,11,11-trimethyl-3,-diazatricyclo[6.2.1.0 2,7]undeca-2(7),3,5-triene.

17. A method of obtaining a compound according to any one of claims 1 to 15, including the interaction of the compounds of formula

with hydrazine, where the values of R1-R4defined in claim 1.

18. Compounds according to claim 1, intended for use as therapeutically active substances for the treatment or prophylaxis of diabetes type II.

19. Compounds according to claim 1, intended for the preparation of pharmaceuticals for the prevention and treatment of diseases that are caused by disorders associated with enzyme 11-beta-hydroxysteroiddehydrogenase 1.

20. The pharmaceutical composition intended for the treatment or prevention of type II diabetes, comprising a compound according to any one of claims 1 to 16 and a therapeutically inert carrier.

21. The use of compounds according to any one of claims 1 to 16 for the preparation of drugs intended for the treatment and prevention of diabetes, obesity, eating disorders, dyslipidemia and hypertension.

22. The use of compounds according to any one of claims 1 to 16 for the preparation of drugs intended for the treatment and prevention of type II diabetes.

23. The compound according to claim 1, obtained by reacting compounds of the formula

with hydrazine, where the values of R1-R4defined in claim 1.

24. The way Le is to be placed and prevention of diabetes, obesity, eating disorders, dyslipidemia and hypertension, comprising introducing an effective amount of a compound according to any one of claims 1 to 16.

25. Method for the treatment and prevention of type II diabetes, comprising introducing an effective amount of a compound according to any one of claims 1 to 16.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) in form of base or a pharmaceutically acceptable addition salt with an acid. The disclosed compounds have β-amyloid peptide(β-A4) formation inhibiting properties. In formula (I), R1 denotes: C1-6-alkyl or phenyl; where said phenyl groups are substituted with two substitutes selected from halogen atoms; R1 and R2' independently denote a hydrogen atom or a hydroxy group; R3 denotes C1-6-alkyl; one or another of radicals R4 and R5 is a group Z and one or another of radicals R4 and R5 is a -C(X)R6 group; G denotes a single bond; Y denotes a single bond, an oxygen atom, a sulphur atom, a C1-4-alkylene group; A and B independently denote a hydrogen atom, a halogen, trifluoromethyl, trifluoromethoxy group; provided that if Y denotes a single bond or an oxygen atom and if group Z is a type group, A does not denote a hydrogen atom; X denotes an oxygen atom; R6 denotes a C1-6alkoxy group. The invention also relates to a method for synthesis of formula (I) compounds, to a medicinal agent and a pharmaceutical composition based on said compounds, and to use of formula (I) compounds in preparing the medicinal agent.

EFFECT: increased effectiveness of using said derivatives.

6 cl, 1 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula

, in which A is a counter ion, a=1-3, b=0-3, X=1-6C alkyl, R1=1-6C alkyl, one or R2 and R3 is 1-6C alkyl and the other is XN+Hb(R1)3-b, or R2 and R3 form a methylenedioxy group, one or R4 and R5 is a halogen and the other is a halogen-substituted 1-6C alkyl, or R4 and R5 are bonded to form a 6-10C aromatic ring or a substituted 6-10C aromatic ring in which the substitute is selected from 1-6C alkoxy, halogen and halogen-substituted 1-6C alkyl. The invention also relates to a method of measuring content of analysed substance capable of ensuring proportional colour change as a result of a reaction in a biological fluid, involving the following steps: ensuring availability of the disclosed tetrazolium salt as an indicator and determination of concentration of the said analysed substance in the biological fluid using the said tetrazolium salt which is used as an indicator.

EFFECT: agents are highly effective.

24 cl, 7 dwg, 1 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula I and to their pharmaceutically acceptable acid addition salts. The compounds of the present invention exhibit the properties of glycine carrier 1 (GlyT-1) inhibitors. In formula I , R1 represents -OR1', -SR1' or morpholinyl; R1' represents lower alkyl, halogen-substituted lower alkyl, or represents -(CH2)n-lower cycloalkyl; R2 represents -S(O)2-lower alkyl, -S(O)2NH-lower alkyl, NO2 or CN; X1 represents CR3 or N; X2 represents CR3' or N; R3/R3' independently represent hydrogen, halogen, lower alkyl, CN, NO2, -S(O)2-phenyl, -S(O)2-lower alkyl, -S(O)2-pyridine-2, 3 or 4-yl, phenyl optionally substituted with one or two substitutes specified from the group consisting of NO2 or halogen, or represent halogen-substituted lower alkyl, or represent -C(O)-lower alkyl; n has a value of 0, 1 or 2. The invention also concerns a drug containing one or more compounds of the invention and pharmaceutically appropriate excipients.

EFFECT: preparation of the compounds exhibiting the properties of glycine carrier inhibitors.

20 cl, 1 tbl, 133 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where R1 is selected from group, including: phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, lower alkoxy group, halogen or lower halogenalkyl; naphtyl; tetrahydronaphtyl; C3-7cycloalkyl; -(CHR3)m-phenyl, where m stands for 1, 2, or 3; and phenyl is unsubstituted or mono-, di- or tri-substituted with lower alkoxy group, and where R3 is independently selected from hydrogen and lower alkyl; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur, and heteroaryl is mono-, di- or tri-substituted independently with lower alkoxy group; and R2 is selected from group including: n-butyl; phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, halogen or lower alkoxy group; heteroaryl, where term "heteroaryl" relates to aromatic 5-member ring, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; unsubstituted or mono-, di- or tri-substituted independently with lower alkoxy group; -C(O)-NR4R5; where R4 and R5 stand for lower alkyl or together with nitrogen atom, to which they are bound, form 5-member heterocycle, which can additionally contain heteroatom, selected from N or S, and to their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, able to inhibit DPP-IV.

13 cl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel benzothiazinone derivatives of formula (I) and their use as antibacterial agents in infectious diseases caused by bacteria, especially mycobacterium tuberculosis (TB) and leprosy, in which R1 and R2 independently denote NO2, CN, CONR7R8, COOR9 CHO, halogen, SO2NR7R8, OCF3, trifluromethyl; R3 and R4 independently denote H or methyl; R5 and R6 independently denote a straight or branched aliphatic radical having 1-8 members in the chain, or R5 and R6 together denote a divalent radical -(CR92)m- or R5 and R6 together denote a divalent radical: R7, R8 and R9 independently denote H or a straight or branched aliphatic radical having 1-7 members in the chain, or phenyl.

EFFECT: design of an efficient method of obtaining benzothiazinone derivatives, a pharmaceutical composition having anti-mycobacterial activity.

12 cl, 6 tbl, 12 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: medicine.

SUBSTANCE: there is described thiomorpholine compound presented by formula (I) wherein the ring A represents benzene ring; the ring B represents benzene ring; R1 represents hydrogen atom, R2 represents C1-6-alkyl group; R3a and R3b are identical or different, each representing hydrogen atom or C1-6-alkyl group, and n represents an integer equal to 2, or its pharmaceutically acceptable salt. There is also described method for making the compound of formula (1), a pharmaceutical composition and application of the compound of formula (1) for making a medical product used for treatment and prevention of the disease chosen from inflammation, allergic diseases, pain, migraine, neuralgia, itch, cough, central nervous system diseases, alimentary organ diseases, nausea, vomiting and urological disorders.

EFFECT: compounds exhibits affinity to neurokinine-1 receptor.

6 cl, 4 tbl, 16 ex

Gsk-3 inhibitors // 2379300

FIELD: medicine.

SUBSTANCE: invention concerns GSK-3 inhibitors of general formula (I), method for making thereof and based pharmaceutical compositions which can be used in medicine: formula I, where R1 means an organic group containing at least 8 atoms, chosen of C or O, including aromatic ring of phenyl, naphthyl or methylene dioxypjenyl, which is not bound directly with N through -C(O)- or oxygen; Ra, Rb, Rz, R3, R4, R5 and R6 represent hydrogen.

EFFECT: production of new biologically active compounds for treatment of GSK-3 mediated diseases.

28 cl, 13 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medication, reducing desire for alcohol, which represents substituted 1H-benzimidazoles of general formula 1 or their pharmaceutically acceptable salts and/or hydrates, pharmaceutical composition, and medication on their basis. Compounds can be applied in treatment of alcohol abuse with application of ethanol-containing products, if necessary, together with antidepressants. In compounds of general formula 1 , where: W represents sulfur atom or group S=O; R1 represents one or more substituents, selected from hydrogen, halogen, C1-C4alkyl, C1-C4alkyloxy, optionally substituted 5-6-member azaheterocyclyl with 1-2 atoms of nitrogen and/or oxygen in cycle; R2 represents atom of hydrogen or optionally substituted C1-C4alkyl; R3 and R4 independently on each other represent optionally similar substituents, selected from hydrogen, optionally substituted C1-C4alkyl, C3-C6cycloalkyl; R5 represents alkyl substituent, selected from hydrogen or optionally substituted C1-C7alkyl, C1-C7alkenyl, C1-C4alkynyl, optionally substituted phenyl, optionally substituted 5-6-member heterocyclyl with 1-3 heteroatoms, selected from nitrogen, oxygen and sulfur, possibly condensed with benzene ring; C1-C4-alkoxycarbonyl, optionally substituted amino carbonyl, or group CR3R4R together stands for group , where Alk stands for C1-C4alkyl.

EFFECT: medication allows to reduce symptoms of alcohol abuse considerably as compared with earlier known compounds and does not produce unfavorable effect on liver function.

12 cl, 3 tbl, 2 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), specifically compounds of formula (Ia) which have inhibiting activity during activity of kinase selected from Abl, BCR-AbI, PDGF-R, trkB, c-SRC, BMX, FGFR3, b-RAF, SGK, Tie2, Lck, JNK2a2, MKK4, c-RAF, MKK6, SAPK2a and SAPK2P and pharmaceutical compositions containing such compounds. In the compound of formula I, Ia, m and n are equal to 0; R1 denotes XNR5R6, where X denotes a bond; R5 is selected from hydrogen, C1-6alkyl, phenyl, C5-10heteroaryl-C0-4alkyl, C3-6cycloalkyl and C3-10heterocycloalkyl-C0-4alkyl, where the heteroaryl and heterocycloalkyl contain 1-2 heteroatoms selected from nitrogen and oxygen; and R6 is selected from hydrogen and C1-6alkyl; or R5 and R6 together with the nitrogen atom with which both are bonded form a heteroaryl or heterocycloalkyl; where any of phenyl, heteroaryl, cycloalkyl and heterocycloalkyl, R5 or a combination of R5 and R6 can be optionally substituted with 1-3 radicals independently selected from a halogen group, C1-6alkyl, C1-6alkoxy group, halogen-substituted alkyl, -XNR7R8, -XOR7, -XR8, -XC(O)NR7R8, -XC(O)NR7XNR7R8, -XNR7C(O)R8, -XR9; where X denotes a bond or C1-4alkylene; R7 and R8 are independently selected from a group consisting of hydrogen and C1-4alkyl;and R8 is selected form C5-6heterocycloalkyl and C5-6heteroaryl; where said heterocycloalkyl or heteroaryl contain 1-2 heteroatoms selected from nitrogen and oxygen, and said heterocycloalkyl or heteroaryl in R8 is optionally substituted with a radical selected from a group consisting of C1-4alkyl and XOR7; R3 denotes -NR10R11; where R10 denotes hydrogen; R11 denotes phenyl; where phenyl in R11 is optionally substituted with 1-3 radicals selected from a halogen group, C1-6alkyl, C1-6alkoxy group, halogen-substituted alkyl, halogen-substituted alkoxy group, -NR12C(O)R13, -NR12C(O)NR12R13 and -NR12S(O)0-2R13; where R12 denotes hydrogen; R13 is selected from phenyl, C5-6heteroaryl and C5-6heterocycloalkyl; where any of phenyl, heteroaryl, cycloalkyl or heterocycloalkyl contains 1-2 heteroatoms selected from nitrogen and oxygen, and said heterocycloalkyl or heteroaryl in R13 is substituted with 1-3 radicals independently selected from a halogen group, C1-6alkyl, halogen-substituted C1-6alkyl, C1-6alkoxy group, halogen-substituted C1-6alkoxy group, -XNR7R8, phenyl-C0-4alkyl, C5-6heteroaryl-C0-4alkyl, C5-6heterocycloalkyl-C0-4alkoxy group and C5-6heterocycloalkyl-C0-4alkyl; where X, R7 and R8 are described above, and where any of the phenyl, heteroaryl or heterocycloalkyl fragments contain 1-2 heteroatoms selected from nitrogen and oxygen, and said heterocycloalkyl or heteroaryl in R13 optionally further substituted with 1-3 radicals independently selected from a halogen group, C1-6alkyl, halogen-substituted C1-6alkyl, hydroxy-substituted C1-6alkyl, C1-6alkoxy group; R15 and R16 are selected from phenyl substitutes given in values of R11 and R12 for formula I compounds.

EFFECT: compounds can be used to treat or prevent such diseases as proliferative disorders, and diseases resulting from anomalous activation of the immune and nervous systems.

8 cl, 1 tbl, 1 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 1-substituted-3-[(1E)-1-alkenyl]-4-(5-alkoxy-1,2-dimethyl-1H-indol-3-yl)-1H-pyrrole-2,5-diones of general formula

, where R1=C1-C6alkyl, R2=C1-C6 alkyl, R3=CH2C6H5, C6H5.

EFFECT: obtaining novel compounds which can be used as fluorescent photochromes.

4 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of existing and novel N-sulfamoyl- N'-arylpiperazines and their physiologically compatible acid-addition salts of formula I , where Ar denotes a monocyclic or bicyclic C6-C10aryl in which ring carbon atoms are optionally substituted with 1-3 nitrogen or oxygen atoms, and/or where the C6-C10aryl ring system optionally contains 3-5 double bonds, and/or where the C6-C10aryl ring system is optionally substituted with 1 or 2 substitutes which can be identical or different and which can be selected from a group containing halogen, trifluoromethyl, cyano group, nitro group, C1-C4alkyl, C1-C4alkoxy group, C1-C4alkylsulfonyl; and two oxygen atoms which are bonded to two neighbouring carbon atoms of the C6-C10aryl ring system and are bonded by a C1-C2alkylene bridge; or where the C6-C10aryl ring system is substituted with phenyl which can optionally be substituted in the phenyl ring by one substitute which can be selected from a group containing halogen; for preventing or treating obesity and related diseases.

EFFECT: design of a method of obtaining the said compounds and a pharmaceutical composition based on the said compounds.

25 cl, 9 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a compound having the structural formula I , or its pharmaceutically acceptable salt, ester or amide, where A has the structure , where each bond in A, represented by a dotted and a solid line, represents a carbon-carbon single bond; each of a, b and c is a carbon atom; each of e, f, g and h is a carbon atom; X is nitrogen; X' is C; L is absent; each n equals 1; Y is nitrogen; W is nitrogen; R1 is hydrogen; each of R2, R3 and R4 is a hydrogen atom; each of R6, R8 and R9 is a hydrogen atom; R5 is selected from a group consisting of halogen, C1-6alkyl, optionally substituted with a hydroxy group, and C1-6alkoxy; R7 is selected from a group consisting of halogen, C1-6alkyl and perhalogenalkyl; Z is selected from a group consisting of NR11, oxygen and CH2; R11 is hydrogen; and each bond in formula I, represented by a dotted and a solid line, is a carbon-carbon double bond. The invention also relates to a method for synthesis of a formula V compound, a pharmaceutical composition based on a formula I compound, methods of treating psychoneurological disorders, a pharmaceutical composition containing a formula I compound and a psychoneurological agent.

EFFECT: obtaining novel compounds useful for modulating muscarine receptor activity.

37 cl, 1 tbl, 141 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to phenylalanine derivatives and their pharmaceutically acceptable salts. In formula (1) R11 is a hydroxyl group, an alkoxyl group having 1-6 carbon atoms, which can be substituted with a methoxy group, cycloalkoxyl group having 3-6 carbon atoms, or a benzyloxy group; R12 and R13 each independently represents a hydrogen atom, alkyl group having 1-6 carbon atoms, cycloalkyl group having 3-6 carbon atoms, acetyl group or methyloxycarbonyl group, or N(R12)R13 is a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group; R14 is a methyl group; R1' is a hydrogen atom, fluorine atom; X1 is -CH(R1a)-, -CH(R1a)CH(R1b)-, -CH(R1a)CH(R1b)CH(R1c)-, -N(R1a)CH(R1b)CH(R1c)-, -OCH(R1a)CH(R1b)-, -OCH(R1a)CH(R1b)CH(R1c)- or 1,3-pyrrolidinylene, where R1a, R1b, each independently represents a hydrogen atom or a methyl group, and R1c is a hydrogen atom; Y11 and Y12 represent any of the combinations (CI, Cl), (CI, Me), (CI, F). Invention also relates to phenylalanine derivatives of formulae (2)-(14), given in the formula of invention.

EFFECT: obtaining a pharmaceutical composition having antagonistic effect on α4-integrin, containing a phenylalanine derivative as an active ingredient, a α4-integrin antagonist and a therapeutic agent.

65 cl, 51 tbl, 244 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula Ia: and its pharmaceutically acceptable salt, where: p equals 0 or 1; n assumes values from 1 to 3, q equals 1; R5 is selected from hydrogen, -XNR7R8, pyrimidine-C0-4alkyl, pyridine-C0-4alkyl, phenyl, C3-10cycloalkyl-C0-4alkyl and C3-6heterocycloalkyl-C0-4alkyl, where C3-6heterocycloalkyl is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is hydrogen or C1-4alkyl; R7 and R8 represent C1-4alkyl; R6 denotes hydrogen; or R5 and R6 together with a nitrogen atom to which they are both bonded form morpholine or piperidine; where any piperdine-C0-4alkyl, piperidine-C0-4alkyl or C3-10cycloalkyl-C0-4alkyl of substitute R5 or a combination of radicals R5 and R6 can be optionally substituted with 1-2 radicals which are independently selected from -XNR7R8 and -XOR7, the said phenyl of substitute R5 is substituted with a -XR9 group, the said C3-6heterocycloalkyl-C0-4alkyl of substitute R5 is optionally substituted with a -XOR7 group, where X is a single bond or C1-4alkylene; R7 and R8 are independently selected from hydrogen and C1-4alkyl; R9 is selected from C3-10heterocycloalkyl which is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is as given above; R10 denotes hydrogen; R15 is selected from halogen, C1-6alkyl and C1-6alkoxy; and R16 is selected from halogen, methoxy, nitro, -NR12C(O)R13, -C(O)NR12R12, -NR12R12, -C(O)OR12 and -C(O)NR12R13; each R12 is selected from hydrogen and C1-6alkyl; R13 is selected from phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl, where any phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl of substitute R13 can be optionally substituted with 1-2 radicals which are independently selected from halogen, C1-6alkyl, halogen-substituted C1-6alkyl, imidazole-C0-4alkyl, C3-10cycloalkyl, C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl; where the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl each represent a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R assumes values given above; and the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl can each be optionally substituted with 1 radical independently selected from C1-6alkyl, hydroxyl-substituted C1-6alkyl and NR7R8, where R7 and R8 assume values given above. The invention also relates to pharmaceutical compositions containing the said compounds.

EFFECT: obtaining novel compounds and compositions based on the said compounds which can be used in medicine for treating and preventing diseases or disorders associated with abnormal or uncontrolled kinase activity, particularly diseases or disorders associated with abnormal activity of kinase c-Src, FGFR3, KDR and/or Lck.

12 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) which are protein tyrosine kinase 1B(PTP-1B) inhibitors and can be used in medicinal preparations for treating and preventing diseases related to high concentration of glucose in blood, for example diabetes and obesity. In formula (I) X is a X-1 group or X-2: , where R1 and R2 are each independently selected from a group consisting of hydrogen, lower alkyl, alkoxy-lower alkyl and hydroxyl-lower alkyl, under the condition that, R1 and R2 both represent hydrogen; R3, R4, R6 and R7 are each independently selected from a group consisting of hydrogen, lower alkyl; lower alkyl substituted with halogen or hydroxy; lower alkoxy; lower alkoxy substituted with halogen, hydroxy or lower alkoxy; hydroxyl, halogen, lower alkylthio, lower alkylsufanyl, lower alkylsufanyl, aminosufonyl, cyano, nitro, carbamoyl, lower mono- or dialkylcarbamoyl, lower alkanoyl, benzoyl, phenyl, phenyl substituted with halogen, phenyloxy, lower mono- or dialkylamino, hydroxy-substituted lower alkylamino, lower alkanoylamino, lower alkylsulfonylamino, heterocycloalkyl, hydroxy-substituted heterocycloalkyl, heterocyclyloxy, heterocyclylcarbonyl; where each heterocycloalkyl in the said values represents a 5-6-membr ring containing 1-2 heteroatoms selected from nitrogen and oxygen, and which can be substituted with lower alkyl or phenyl-lower alkyl; carboxyl, lower alkoxycarbonyl and a substitute of formula: ; R8 is selected from a group consisting of hydrogen, lower alkylthio, halogen, alkoxy-lower alkoxy, lower alkoxy, halogen-lower alkyl, hydroxy-lower alkyl; represents a 5-member heteroaromatic ring containing 1 or 2 heteroatoms selected from a group consisting of hydrogen, sulphur and nitrogen; R8 and R9 each independently represents hydrogen or lower alkyl.

EFFECT: novel compounds have useful biological properties.

31 cl, 7 dwg, 152 ex

FIELD: medicine.

SUBSTANCE: invention covers compound 6-amino-4-chloropyrazolo[3,4-d]pyrimidine. Offered compound is made of 2-amino-4,6-dichloropyrimidine by the two-staged method based on a common reaction of selective replacement of hydroxyl group with chlorine atom (chlorodehydroxylation) and replacement of hydrogen atom with carbonyl group followed with ring closure of the product with hydrazine. The declared compound provides a specific inhibiting action on human 8-oxoguanine-DNA-glycosylase enzyme (hOggl).

EFFECT: low-price and available compound, extended range of specific inhibitors of said enzyme and possibility for effective application in medicine.

2 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to derivatives of substituted pyridazinylamine of formula or to their pharmaceutically acceptable salts or hydrates, where X is C or N; Y is O or S; W is C or N; R1, R2, R3 each independently represents hydrogen or halogen; R4, R5, R6 each independently represents hydrogen, halogen, C1-C8-straight or branched alkyl, C1-C8-straight or branched alkoxy, nitro, cyano, -COOR7, -CH2COOR7, -COR7; R7 independently represents hydrogen or C1-C8-straight or branched alkyl. The invention also relates to a method of producing said compounds, to pharmaceutical compositions containing said compounds and to use of the said compounds as picornavirus inhibitors for preventing and/or treating diseases caused by pircornaviruses.

EFFECT: novel compounds have useful biological properties.

10 cl, 1 tbl, 33 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention can be used in medicine and pharmaceutical industry and relates to the cell proliferation inhibitor and to the anti-tumor agent, which contains the 3-phenylcinnolin analogue as an active component, and has the formulas , where J presents the A-C-B, where C is carbon, A is alcoxy, OH, acyloxy or amino acid residue, B is hydrogen, alkyl group, carbonyl group or = N-NH2 together with A, K - (CH2)q; L - N-W, where N -nitrogen atom, or W-C-W′, where C - carbon atom; W - alkyl group or hydrogen atom; W′ - alkyl, phenyl, carboxyl or alcoxycarbonyl group or hydrogen; J-K-L-M corresponds to C(O-Y)=CH-C(W)=CH or M - group (CH2)m; Z - oxygen; X - alcoxyl group, halogenated alkyl group, nitrogroup, cyanogroup or halogen; X' - halogen or hydrogen; m and q = 1, n and n' = 0 or 1, and (n + n') less than 2.

EFFECT: improved anti-tumor agent is available based on described compound.

82 ex

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