New pyrrol derivative having ureide and aminocarbonyl groups as substitutes

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrrol derivatives of formula (1): or a pharmaceutically acceptable salt thereof wherein the values A, R1-R3, n are specified in clause 1 of the patent claim.

EFFECT: compounds (1) inhibit activity against the interleukin IL-6 production that allows using them both in pharmaceutical compositions, and in a prophylactic drug for ocular inflammatory disease.

23 cl, 2 tbl, 22 ex

 

The text descriptions are given in facsimile form.

1. The compound of General formula (1) or its pharmaceutically acceptable salt:
,
where ring a is a benzene ring or a mononuclear aromatic heterocycle having a ring one or more heteroatoms selected from the atoms N, O and S;
R1represents a halogen atom, a hydrogen atom, a lower alkyl group, a lower alkyl group substituted by a hydroxy-group, a lower alkyl group, a substituted lower alkoxygroup, a lower alkyl group substituted by-NRh1Rh2, formyl group or a lower alkylcarboxylic group;
R2represents a halogen atom, a lower alkyl group which may have a Deputy, lower alkenylphenol group, lower alkylamino group which may have a Deputy, lower cycloalkyl group, phenyl group, saturated or unsaturated single-a heterocycle having a ring one or more heteroatoms selected from the atoms N, O and S, hydro is the system of groups, the lower alkoxygroup, which may have a Deputy, the lower alkenylacyl, lower alkyloxy, lower cycloalkylation, fenoxaprop, fenoxaprop substituted by a nitro-group, formyl group, lower alkylcarboxylic group, phenylcarbonylamino group, carboxypropyl, lower alkoxycarbonyl group, phenoxycarbonyl group, a lower alkylcarboxylic, phenylcarbonylamino, mercaptopropyl, lower allylthiourea, lower allylthiourea substituted by cyano, phenylthiourea, phenylthiourea substituted by a nitro-group, a cyano, a nitro-group, -NRalRa2or-OCONRe1Re2;
provided that when R2represents a lower alkyl group which may have a Deputy, the lower alkyl group represents a group which may be substituted by one or more groups selected from the group consisting of halogen atom, hydroxy-group, the lower alkoxygroup, mercaptopropyl, low ancilliary and-NRi1Ri2;
provided that when R2represents the lowest alkylamino group which may have a Deputy, lower Alchemilla group represents a group which may be substituted by one or more groups selected from the group consisting of lower cycloalkyl group, f is Niley group, hydroxy-group, the lower alkoxygroup, low cycloalkylcarbonyl, fenoxaprop and - NRj1Rj2;
provided that when R2represents a lower alkoxygroup, which may have a Deputy, the lowest alkoxygroup represents a group which may be substituted by one or more groups selected from the group consisting of halogen atom, lower cycloalkyl group, phenyl group, saturated or unsaturated single-heterocycle or dual core condensed heterocycle having a ring one or more heteroatoms selected from the atoms N, O and S, saturated or unsaturated single-heterocycle or dual core condensed heterocycle having a ring one or more heteroatoms selected from the atoms N, O and S, substituted lower alkyl group, saturated or unsaturated single-heterocycle or dual core condensed heterocycle having a ring one or more heteroatoms selected from the atoms N, O and S, substituted hydroxy-group, saturated or unsaturated single-heterocycle or dual core condensed heterocycle having a ring one or more heteroatoms selected from the atoms N, O and S, substituted lower alkoxygroup, hydroxy-group, the lower alkoxygroup, Issa alkoxygroup, substituted lower cycloalkyl group, lower alkoxygroup, substituted phenyl group, lower alkoxygroup, substituted lower alkoxygroup, low cycloalkylcarbonyl, fenoxaprop, saturated or unsaturated core of heterozygosity having in the ring one or more heteroatoms selected from the atoms N, O and S, formyl group, lower alkylcarboxylic group, phenylcarbonylamino group, phenylcarbonylamino group substituted by a halogen atom, a saturated single-heterocyclimamines group having in the ring one or more heteroatoms selected from the atoms N, O and S, carboxypropyl, lower alkoxycarbonyl group, mercapto group, lower allylthiourea, phenylthiourea, ceanography and-NRf1Rf2;
R3represents a hydrogen atom or a lower alkyl group;
Ra1, Ra2, Re1and Re2are the same or different and represent hydrogen atoms or lower alkyl groups;
Rf1and Rf2are the same or different and represent hydrogen atoms, lower alkyl groups, lower alkyl groups, substituted phenyl group, lower alkyl groups, substituted saturated mononuclear heterocyclic group having in the ring one or more heteroatoms selected from the atoms N, O and S, lower alkyl group substituted by a hydroxy-group, lower alkyl groups, substituted lower alkoxygroup, a lower alkyl group substituted by-NRg1Rg2or lower cycloalkyl group, and, in addition, Rf1and Rf2can be connected to each other to form nitrogen-containing heterocycle;
Rg1and Rg2are the same or different and represent hydrogen atoms or lower alkyl groups;
Rh1and Rh2are the same or different and represent hydrogen atoms or lower alkyl groups;
Ri1and Ri2are the same or different and represent hydrogen atoms, lower alkyl groups, lower alkyl groups, substituted phenyl group, lower alkyl group substituted by a hydroxy-group, or a lower alkyl group, a substituted lower alkoxygroup;
Rj1and Rj2are the same or different and represent hydrogen atoms or lower alkyl groups;
n is 0, 1, 2 or 3; and
provided that when n is 2 or 3, R2may be the same or different.

2. The compound or its pharmaceutically acceptable salt according to claim 1, where in the General formula (1)
ring a represents a benzene ring or a mononuclear aromatic heterocycle having one ring or several is about heteroatoms, selected from the atoms N, O and S;
R1represents a halogen atom, a hydrogen atom, a lower alkyl group, a lower alkyl group substituted by a hydroxy-group, the lower alkyl group is replaced with-NRh1Rh2or formyl group;
R2represents a halogen atom, a lower alkyl group which may have a Deputy, lower alkenylphenol group, lower alkylamino group which may have a Deputy, phenyl group, saturated or unsaturated mononuclear heterocyclic group having in the ring one or more heteroatoms selected from the atoms N, O and S, a hydroxy-group, the lower alkoxygroup, which may have a Deputy, the lower alkenylacyl, lower alkyloxy, fenoxaprop substituted by a nitro-group, formyl group, lower alkylcarboxylic group, a lower alkylcarboxylic, lower allylthiourea, lower allylthiourea substituted by cyano, phenylthiourea substituted by a nitro-group, a cyano the nitrogroup, -NRa1Ra2or-OCONRe1Re2;
provided that when R2represents a lower alkyl group which may have a Deputy, the lower alkyl group represents a group which may be substituted by one or more groups selected from the group consisting of atom Gal is gene hydroxy-group, the lower ancilliary and-NRi1Ri2;
provided that when R2represents the lowest alkylamino group which may have a Deputy, lower Alchemilla group represents a group which may be substituted by one or more groups selected from the group consisting of phenyl groups, hydroxy-group, and-NRj1Rj2;
provided that when R2represents a lower alkoxygroup, which may have a Deputy, the lowest alkoxygroup represents a group which may be substituted by one or more groups selected from the group consisting of halogen atom, lower cycloalkyl group, phenyl group, saturated or unsaturated single-heterocycle or dual core condensed heterocycle having a ring one or more heteroatoms selected from the atoms N, O and S, saturated or unsaturated single-heterocycle or dual core condensed heterocycle having a ring one or more heteroatoms selected from the atoms N, O and S, substituted lower alkyl group, saturated or unsaturated single-heterocycle or dual core condensed heterocycle having a ring one or more heteroatoms selected from the atoms N, O and S, substituted HYDR what syruppy, hydroxy-group, the lower alkoxygroup, low alkoxygroup, substituted phenyl group, lower alkoxygroup, substituted lower alkoxygroup, fenoxaprop, saturated or unsaturated core of heterozygosity having in the ring one or more heteroatoms selected from the atoms N, O and S, phenylcarbonylamino group substituted by a halogen atom, a saturated single-getrollbackonly group having in the ring one or more heteroatoms selected from the atoms N, O and S, the lower alkoxycarbonyl group, lower allylthiourea, ceanography and-NRf1Rf2;
R3represents a hydrogen atom;
Ra1and Ra2represent hydrogen atoms;
Re1and Re2are the same or different and represent hydrogen atoms or lower alkyl groups;
Rf1and Rf2are the same or different and represent hydrogen atoms, lower alkyl groups, lower alkyl groups, substituted phenyl group, lower alkyl groups, substituted saturated mononuclear heterocyclic group having in the ring one or more heteroatoms selected from the atoms N, O and S, a lower alkyl group substituted by a hydroxy-group, the lower alkyl group is replaced with - NRg1Rg2or lower cycloalkyl group, and in addition, Rf1and Rf2can be connected to each other to form nitrogen-containing heterocycle;
Rg1and Rg2represent a lower alkyl group;
Rh1and Rh2are the same or different and represent hydrogen atoms or lower alkyl groups;
Ri1and Ri2are the same or different and represent hydrogen atoms, lower alkyl groups, lower alkyl groups, substituted phenyl group, or a lower alkyl group substituted by a hydroxy-group;
Rj1and Rj2represent a lower alkyl group;
n is 0, 1, 2 or 3; and
provided that when n is 2 or 3, R2may be the same or different.

3. The compound or its pharmaceutically acceptable salt according to claim 1, where in the General formula (1)
ring a represents a benzene ring or a mononuclear aromatic heterocycle having a ring one or more heteroatoms selected from the atoms N, O and S;
R1represents a halogen atom, a hydrogen atom, a lower alkyl group, a lower alkyl group substituted by a hydroxy-group, the lower alkyl group is replaced with-NRh1Rh2or formyl group;
R2represents a halogen atom, a lower alkyl group which may have a Deputy, lower alkenylphenol group, issuu alkylamino group, lower alkylamino group substituted by a hydroxy-group, phenyl group, saturated or unsaturated single-a heterocycle having a ring one or more heteroatoms selected from the atoms N, O and S, a hydroxy-group, the lower alkoxygroup, which may have a Deputy, the lower alkenylacyl, lower alkyloxy, lower alkoxycarbonyl group, a lower alkylcarboxylic, lower allylthiourea, a cyano, a nitro-group, -NRa1Ra2or-OCONRe1Re2;
provided that when R2represents a lower alkyl group which may have a Deputy, the lower alkyl group represents a group which may be substituted by one or more groups selected from the group consisting of halogen atom, hydroxy-group and lowest ancilliary;
provided that when R2represents a lower alkoxygroup, which may have a Deputy, the lowest alkoxygroup represents a group which may be substituted by one or more groups selected from the group consisting of halogen atom, lower cycloalkyl group, saturated or unsaturated single-heterocycle or dual core condensed heterocycle having a ring one or more heteroatoms selected from the atoms N, O and S, the saturated and the unsaturated mononuclear heterocycle or dual core condensed heterocycle, having in the ring one or more heteroatoms selected from the atoms N, O and S, substituted lower alkyl group, a hydroxy-group, the lower allylthiourea, ceanography and - NRf1Rf2;
R3represents a hydrogen atom;
Ra1and Ra2represent hydrogen atoms;
Re1and Re2are the same or different and represent hydrogen atoms or lower alkyl groups;
Rf1and Rf2are the same or different and represent hydrogen atoms, lower alkyl groups, lower alkyl groups substituted by a hydroxy-group, or a lower cycloalkyl group, and, in addition, Rf1and Rf2can be connected to each other to form nitrogen-containing heterocycle;
Rh1and Rh2are the same or different and represent hydrogen atoms or lower alkyl groups;
n is 0, 1, 2 or 3; and
provided that when n is 2 or 3, R2may be the same or different.

4. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 3, where in the General formula (1)
ring a represents a benzene, pyridine, pyrazin or thiophene.

5. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 3, where in the General formula (1)
ring a represents a benzene, pyridine or thiophene.

6. Connection of the giving or its pharmaceutically acceptable salt according to any one of claims 1 to 3, where in the General formula (1)
ring a represents a benzene.

7. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 3, where in the General formula (1)
R1represents a hydrogen atom; and
R3represents a hydrogen atom.

8. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 3, where in the General formula (1)
n is 0, 1 or 2.

9. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 3, where in the General formula (1)
n is 1 or 2.

10. The compound or its pharmaceutically acceptable salt according to claim 1, where in the General formula (1)
ring a represents a benzene ring;
R1represents a hydrogen atom;
R2represents a halogen atom, a lower alkylamino group, a hydroxy-group, the lower alkoxygroup, which may have a Deputy, the lower allylthiourea, which may have a Deputy, or cyano;
provided that when R2represents a lower alkoxygroup, which may have a Deputy, or lower allylthiourea, which may have a Deputy, the lowest alkoxygroup or lower allylthiourea represents a group which may be substituted by one or more groups selected from the group consisting of hydroxy-group, the lower alkoxygroup, mercaptopropyl, low ancilliary and tzia is gruppy;
R3represents a hydrogen atom;
n is 0, 1 or 2; and
provided that when n is 2, R2may be the same or different.

11. The compound or its pharmaceutically acceptable salt according to claim 1, where in the General formula (1)
ring a represents a benzene ring;
R1represents a hydrogen atom;
R2represents a halogen atom, a lower alkylamino group, a hydroxy-group, the lower alkoxygroup, lower alkoxygroup, substituted hydroxy-group, the lower alkoxygroup substituted by cyano, lower allylthiourea or cyano;
R3represents a hydrogen atom;
n is 0, 1 or 2; and provided that when n is 2, R2may be the same or different.

12. The compound or its pharmaceutically acceptable salt according to claim 1, where in the General formula (1)
ring a represents a benzene ring;
R1represents a hydrogen atom;
R2represents a fluorine atom, a chlorine atom, a bromine atom, etinilnoy group, a hydroxy-group, a methoxy group, ethoxypropan, propoxylate, hydroxyethylacrylate, cinematograp or cyano;
R3represents a hydrogen atom;
n is 1 or 2; and
provided that when n is 2, R2may be the same or different.

13. The compound or its pharmaceutically who ramlila salt, selected from the group which includes
2 aminocarbonyl-5-(4-bromophenyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(pyridin-2-yl)pyrrol-3-carboxamide;
2 aminocarbonyl-5-phenylpyrrole-3-carboxamide;
2 aminocarbonyl-5-(4-biphenyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(3-nitrophenyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(4-forfinal)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(2-methoxyphenyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(4-were)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(2-triptoreline)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(4-cyanophenyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(thiophene-2-yl)pyrrol-3-carboxamide;
2 aminocarbonyl-5-(2,5-acid)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(5-fluoro-2-methoxyphenyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(4-bromophenyl)-4-methylpyrrole-3-carboxamide;
2 aminocarbonyl-5-(5-chloro-2-methoxyphenyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(5-chloro-2-methoxy-4-were)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(3-chlorophenyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(2,5-dichlorophenyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(3-forfinal)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(5-chloro-2-methoxyphenyl)-1-methylpyrrole-3-carboxamide;
2 aminocarbonyl-5-(4-this is kscarberry)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(3-chloro-4-forfinal)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(3-chloro-4-methoxyphenyl)pyrrol-3-carboxamide;
2 aminocarbonyl-5-(3-cyanophenyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(2-chlorophenyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(5-methylthiophene-2-yl)pyrrol-3-carboxamide;
2 aminocarbonyl-5-(2-were)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(3-methylthiophenyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(3-ethylthiophene)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(2-forfinal)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(5-chlorothiophene-2-yl)pyrrol-3-carboxamide;
2 aminocarbonyl-5-(2,5-dimethylthiophene-3-yl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(2,4,5-tryptophanyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(2,5-differenl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(4-AMINOPHENYL)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(2-hydroxyphenyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(5-fluoro-2-hydroxyphenyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(5-chloro-2-hydroxyphenyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(2-cyanoethylidene)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(2-proproxyphene)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(3-cyanoethylidene)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(2-etox is phenyl)pyrrol-3-carboxamide;
2 aminocarbonyl-5-[2-(pyridine-3-ylmethylene)phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-(2-cyclopropylmethoxy)pyrrole-3-carboxamide;
2 aminocarbonyl-5-[2-(3-forproposals)phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-[2-[2-(piperidine-1-yl)ethyloxy]phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-[2-(3-dimethylaminopropoxy)phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-[2-(2-dimethylaminoethoxy)phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-[2-[2-(1-methylpyrrolidine-2-yl)ethyloxy]phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-(5-fluoro-2-proproxyphene)pyrrole-3-carboxamide;
2 aminocarbonyl-5-[5-fluoro-2-(3-hydroxypropoxy)phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-(5-chloro-2-proproxyphene)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(5-chloro-2-cyanoethylidene)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(5-fluoro-2-ethoxyphenyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(5-chloro-2-ethoxyphenyl)pyrrole-3-carboxamide;
5-(2-allyloxy-5-chlorophenyl)-2-(aminocarbonyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-[5-chloro-2-(2-propenyloxy)phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-[5-fluoro-2-(2-hydroxyethyloxy)phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-(2-acetoxyphenyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(2-propylamino ebonyocean)pyrrole-3-carboxamide;
2 aminocarbonyl-4-chloro-5-(4-forfinal)pyrrole-3-carboxamide;
2 aminocarbonyl-5-[2-[3-(pyrrolidin-1-yl)propyloxy]phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-[2-[2-(4-methylpiperazin-1-yl)ethyloxy]phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-[2-[2-(morpholine-4-yl)ethyloxy]phenyl]pyrrole-3-carboxamide;
2-aminocarbonyl-5-[2-[2-(pyrrolidin-1-yl)ethyloxy]phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-[2-[2-(4-methylpiperidin-1-yl)ethyloxy]phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-[2-[2-[N-(2-hydroxyethyl)-N-methylamino]ethyloxy]phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-[5-fluoro-2-[2-(pyrrolidin-1-yl)ethyloxy]phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-[5-fluoro-2-[2-(4-methylpiperidin-1-yl)ethyloxy]phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-[5-chloro-2-[2-(piperidine-1-yl)ethyloxy]phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-[5-chloro-2-[2-(4-methylpiperazin-1-yl)ethyloxy]phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-[5-chloro-2-[2-(4-hydroxyethylpiperazine-1-yl)ethyloxy]phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-[5-fluoro-2-[2-[N-(2-hydroxyethyl)-N-methylamino]ethyloxy]phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-[5-fluoro-2-(2-methylthioethyl)phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-[2-[2-(N-cyclohexyl-N-methylamino)ethyloxy]-5-forfinal] pyrrol-3-carboxamide;br/> 2 aminocarbonyl-5-(4-vinylphenol)pyrrole-3-carboxamide;
2 aminocarbonyl-5-[4-(furan-3-yl)phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-[3-(3-hydroxypropyl)phenyl]pyrrole-3-carboxamide;
2 aminocarbonyl-5-(3-ethynylphenyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(3-hydroxymethylene)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(3-methylthiomethyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(3-chlorophenyl)-4-formylphenol-3-carboxamide;
2 aminocarbonyl-5-(3-chlorophenyl)-4-(hydroxymethyl)pyrrole-3-carboxamide;
2 aminocarbonyl-5-(3-chlorophenyl)-4-(methylaminomethyl)pyrrole-3-carboxamide and
2 aminocarbonyl-5-[2-(2-methylaminomethyl)phenyl]pyrrole-3-carboxamide.

14. The pharmaceutical composition inhibiting activity against the production of interleukin IL-6, comprising the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 13 and a pharmaceutically acceptable additive.

15. The inhibitor of the production of IL-6, comprising the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 13 as an active ingredient.

16. Prophylactic or therapeutic agent against ocular inflammatory diseases associated with IL-6, comprising the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 13 as an active ingredient.

17. Profile is static or therapeutic agent according to item 16, where the ocular inflammatory disease is age-related macular degeneration, diabetic retinopathy, diabetic macular edema, keratitis, conjunctivitis or uveitis.

18. Prophylactic or therapeutic agent against diseases of the retina, comprising the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 13 as an active ingredient.

19. Preventive or therapeutic agent for p, where disease of the retina is age-related macular degeneration, diabetic retinopathy or diabetic macular edema.

20. The method of prevention or treatment of ocular inflammatory diseases associated with IL-6, including the introduction of the patient pharmaceutically effective amount of the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 13.

21. The method of prevention or treatment according to claim 20, where the ocular inflammatory disease is age-related macular degeneration, diabetic retinopathy, diabetic macular edema, keratitis, conjunctivitis or uveitis.

22. The method of prevention or treatment of retinal diseases, including the introduction of the patient pharmaceutically effective amount of the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 13.

23. The method of prevention or treatment according to article 22, where the disease of the retina is the tsya age-related macular degeneration, diabetic retinopathy or diabetic macular edema.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted pyrimidin-5-yl carboxylic acids of formula I and can be used in organic chemistry. The method is realised by reacting N-substituted guanidines and hetarylamidines with ethoxymethylene derivatives of 1,3-ketoesters according to a scheme given below (where the substitutes are as defined in the claim).

EFFECT: improved method of producing substituted pyrimidin-5-yl carboxylic acids of formula I.

2 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to a method of producing M-(1,5,3-dithiazepan-3-yl)amides of general formula (1) where R = p-C5H4N (a), (CH3)3CO (b), o-CH3OC6H4 (c), which involves reaction of N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine with a hydrazide of general formula RC(O)NHNH2 [R is as described above] in the presence of a samarium nitrate crystalline hydrate Sm(NO3)3·6H2O catalyst with molar ratio N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine:RC(O)NHNH2:Sm(NO3)3·6H2O=10:10:(0.3-0.7) at temperature of 65-75°C and atmospheric pressure in the mixture of solvents - ethyl alcohol and chloroform for 20-28 hours.

EFFECT: method of producing N-(1,5,3-dithiazepan-3-yl)amides with high selectivity and output, which can be used as biologically active compounds, selective sorbents and extractants of noble and precious metals.

1 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds for treating cell-proliferative disorders having formula (II): wherein the values R1,R2, X, A, B, R6, R7, R9 are specified in cl. 1 of the patent claim with the exception of the compound of formula: .

EFFECT: there are presented compounds possessing anticancer activity.

95 cl, 27 dwg, 11 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to a method of producing N-(1,5,3-dithiazepinan-3-yl)amides of general formula (1): where R = p-C5H4N (a), (CH3)3CO (b), o-CH3OC6H4 (c) which involves reaction of t-butyl-1,5,3-dithiazepinane with a hydrazide of general formula RC(O)NHNH2 [R is as described above] in the presence of an iron chloride crystalline hydrate catalyst FeCl3-6H2O in molar ratio t-butyl-1,5,3-dithiazepinane:RC(O)NHNH2:FeCl3-6H2O=10:10:(0.3-0.7) at temperature of 65-75°C and atmospheric pressure of a mixture of solvents - ethyl alcohol-chloroform for 40-48 hours.

EFFECT: novel method of producing N-(1,5,3-dithiazepinan-3-yl)amides with high selectivity and output, which can be used as biologically active compounds, selective sorbents and extractants of noble and precious metals.

1 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I), wherein A represents a pyrrole group or a pyrazole group, and X represents a carbon atom or a nitrogen atom; R1 represents a carboxy group; R2 independently represents a group specified in a substitute group α; R3 independently represents phenyl(C1-C6alkyl)group substituted by, phenyl(C1-C6alkyl)group (wherein the substitute(s) represents (represent) 1-4 groups independently specified in the substitute group α); m is equal to 0, 1, 2 or 3, n is equal to 0 or 1; each of R4, R5, R6 and R7 independently represents a hydrogen atom, C1-C6alkyl group or a halogen atom; B represents a substituted naphthyl group (wherein the substitute(s) represents (represent) 1-4 groups independently specified in the substitute group α), or the group represented by formula (II), wherein B1, B2 and α are those as specified in the patent claim. Also, the invention refers to a pharmaceutical composition possessing lipolysis inhibiting activity, to the use of the compounds of formula (I) in preparing a drug preparation for treating hyperlipidemia, dislipidemia, abnormal lipid metabolism, arteriosclerosis or type II diabetes mellitus and to a method of treating or preventing the mentioned diseases.

EFFECT: preparing the compounds of formula (I) possessing lipolysis inhibiting activity.

36 cl, 1 dwg, 1 tbl, 69 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound selected from a group consisting of: 4-[(2-{[(2S)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-[(2-{[(2R)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-{[(6-{[(2R)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl} benzoic acid, 4-[(5-chlor-2-{[(2S)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-4-methylphenoxy)methyl]benzoic acid, 4-[(5-chlor-2-{[(2R)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-4-methylphenoxy)methyl]benzoic acid, 4-[(2-{[(2R)-3-fluor-2- methylpropyl](pyridin-2-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-[(2-{[(2S)-3-fluor-2- methylpropyl](pyridin-2-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-{[(6-{[(2R)-2-fluorobutyl](pyridin-2-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl} benzoic acid, 4-{[(6-{[(2S)-2-fluorobutyl](pyridin-2-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl}benzoic acid, 4-[(5-chlor-2-{[(2R)-2-fluoropropyl] (pyridin-3-ylsulfonyl)amino}-4-methylphenoxy)methyl]benzoic acid, 4-[(5-chlor- 2-{[(2S)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-4-methylphenoxy)methyl] benzoic acid, 4-[(2-{[(2S)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-[(2-{[(2R)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl] benzoic acid, 4-{[(6-{[(2S)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl} benzoic acid and 4-{[(6-{[(2R)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl}benzoic acid, or a pharmaceutically acceptable salt thereof. These compounds have an EP1 receptor antagonist effect and may be used for treating the dysfunction pollakiuria.

EFFECT: preparing the sulfonamide compounds with a strong EP1 receptor antagonist effect.

23 cl, 24 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrimidine derivatives and their pharmaceutically acceptable salts possessing the properties of a HIV replication inhibitor. In formula (I'): , R1 means a hydrogen atom; R7 means a hydrogen atom; C1-6alkyl; R8 means a hydrogen atom; C1-6alkyl; R4 means cyano; R9 means -CH=CH-CN; R5 means C3-7cycloalkyl; C1-6alkyloxy; aryl; Het; C1-6alkyl substituted by a radical specified in hydroxy, C1-6alkyloxy, cyano, amino, mono- and di-C1-6alkylamino, C1-6alkylcarbonylamino, aryl, Het, dioxoalanine optionally substituted by one or two C1-6alkyl radicals, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl optionally substituted by C1-6alkyl or C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, aryl C1-6alkyloxycarbonyl and C3-7cycloalkyl; or R5 means C1-6alkyl substituted by two C1-6alkyloxy radicals; R6 means a hydrogen atom or C1-6alkyl; X means -NR1- or -O; the values of Het are presented in the patent claim. The invention also refers to a pharmaceutical composition containing said compounds.

EFFECT: preparing the pharmaceutically acceptable salts possessing the properties of a HIV replication inhibitor.

9 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2,2'-dibenzthiazolyl-disulphide via electrochemical oxidation of an alkaline solution of 2-mercaptobenzthiazole at temperature of 70°C and current density of 1 A/cm2, wherein the process is carried out on alternating current with frequency of 55…575 Hz, preferably 100…120 Hz and more preferably 105…115 Hz. The highest current output is achieved using alternating current with frequency of 110 Hz.

EFFECT: high efficiency of the electrolysis cell, reduced electric power consumption, avoiding use of toxic and expensive reagents.

2 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (1) and pharmaceutically acceptable salts thereof, which exhibit inhibitory activity on phospholipase A2 enzyme and therefore have prostaglandin and/or leucotriene production suppressing action. In formula X is a halogen atom, cyano group, C1-C3 alkyl group, which can be substituted with halogen atoms, C1-C3 alkoxy group or hydroxy group, C2-C4 alkenyl group, C1-C3 alkoxy group or hydroxy group; Y is a hydrogen atom or C1-C3 alkyl group; Z is C1-C3 alkyl group; G is selected from formulae and , where in formulae (G2) and (G5) R4 is a hydrogen atom or C1-C6 alkyl group which can be substituted with halogen atoms; D is -NR10C(O)-, -C(O)NR10-, -S(O)2NR10- or -N(R11)-; R10 is a hydrogen atom; R11 is a hydrogen atom or C1-C3 alkyl group; A is a single bond, C1-C6 alkylene, which can be substituted with a phenyl group, or C2-C4 alkenylene; Q is a phenyl group or a 5-6-member aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, S, optionally substituted with a benzene ring; R5, R6 and R7 all or independently denote a hydrogen atom, a halogen atom, C1-C6 alkyl group which can be substituted with halogen atoms, C1-C6 alkoxy group which can be substituted with halogen atoms, phenyloxy group, phenyl group or a 5-6-member aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, where said phenyl group and 5-6-member aromatic heterocyclic group can be substituted with a C1-C3 alkyl group which can be substituted with halogen atoms or a C1-C3 alkoxy group. The invention also relates to specific compounds, a medicinal agent, a pharmaceutical composition, a phospholipase A2 enzyme activity inhibitor and a treatment method.

EFFECT: improved method.

21 cl, 56 tbl, 561 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-hydroxylsulphonamide derivatives of formula or , where R1 is H; R2 is H; n is 0; b is an integer in the range of 1-4; R3, R4, R5, R6 and R7 are independently selected from H, halogen, carboxyl, carboxyl ester selected from a group including -C(O)O-morpholino, -C(O)O-C1-C8alkyl and -C(O)O-substituted C1-C8alkyl, where the substitute is morpholino; acylamino, which is a -C(O)NRaRb group, where Ra and Rb are independently C1-C8alkyl, or Ra and Rb together with a nitrogen atom to which they are bonded form morpholino; and sulphonylamino, which is a SO2NR2 group, where two groups R, together with a nitrogen atom to which they are bonded, form morpholino; R8 is selected from halogen and carbonylamino, selected from a -CONH-substituted C1-C8alkyl, where the substitute is morpholino; and -CONR2, where two groups R, together with a nitrogen atom to which they are bonded, form morpholino; C is a heteroaromatic ring which contains cyclic fragments Q9, Q10, Q11, Q12, Q13 and Q14, which are independently selected from C, CH and S, under the condition that at least one of the fragments Q9, Q10, Q11, Q12, Q13 and Q14 is S. The invention also relates to a method of modulating nitroxyl levels, a method of treating diseases which respond to treatment with nitroxyl, a treatment set and a pharmaceutical composition containing compounds of formula (I) or (III).

EFFECT: compounds of formula (I) or (III) for treating diseases which respond to treatment with nitroxyl.

20 cl, 5 ex, 4 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted pyrimidin-5-yl carboxylic acids of formula I and can be used in organic chemistry. The method is realised by reacting N-substituted guanidines and hetarylamidines with ethoxymethylene derivatives of 1,3-ketoesters according to a scheme given below (where the substitutes are as defined in the claim).

EFFECT: improved method of producing substituted pyrimidin-5-yl carboxylic acids of formula I.

2 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to isoxazole-pyridine derivatives of formula , where X; R1; R2, R3, R4, R5 and R6 are as described in claim 1 of the invention and a pharmaceutically acceptable salt thereof. The invention also relates to a medicinal agent for treating diseases associated with the binding site of the GABA A α5 receptor based on compounds of formula I and use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds are active towards the binding site of said receptor and are useful in treating cognitive disorders such as Alzheimer's disease.

22 cl, 372 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I), wherein A represents a pyrrole group or a pyrazole group, and X represents a carbon atom or a nitrogen atom; R1 represents a carboxy group; R2 independently represents a group specified in a substitute group α; R3 independently represents phenyl(C1-C6alkyl)group substituted by, phenyl(C1-C6alkyl)group (wherein the substitute(s) represents (represent) 1-4 groups independently specified in the substitute group α); m is equal to 0, 1, 2 or 3, n is equal to 0 or 1; each of R4, R5, R6 and R7 independently represents a hydrogen atom, C1-C6alkyl group or a halogen atom; B represents a substituted naphthyl group (wherein the substitute(s) represents (represent) 1-4 groups independently specified in the substitute group α), or the group represented by formula (II), wherein B1, B2 and α are those as specified in the patent claim. Also, the invention refers to a pharmaceutical composition possessing lipolysis inhibiting activity, to the use of the compounds of formula (I) in preparing a drug preparation for treating hyperlipidemia, dislipidemia, abnormal lipid metabolism, arteriosclerosis or type II diabetes mellitus and to a method of treating or preventing the mentioned diseases.

EFFECT: preparing the compounds of formula (I) possessing lipolysis inhibiting activity.

36 cl, 1 dwg, 1 tbl, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyrazinone derivatives of formula (I):

, where R1, R2, R3, R4, R5, R and R7 are as defined in claim 1 of the invention. The invention also describes a crystalline form, compounds of formula I, use of the compound of formula I in producing a medicinal agent for treating chronic obstructive pulmonary disease. A pharmaceutical composition and a pharmaceutical product are also described. Methods of obtaining compounds of formula I are also described.

EFFECT: novel compounds which can be used in therapy are obtained and described.

20 cl, 334 ex, 15 tbl, 12 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (1) and pharmaceutically acceptable salts thereof, which exhibit inhibitory activity on phospholipase A2 enzyme and therefore have prostaglandin and/or leucotriene production suppressing action. In formula X is a halogen atom, cyano group, C1-C3 alkyl group, which can be substituted with halogen atoms, C1-C3 alkoxy group or hydroxy group, C2-C4 alkenyl group, C1-C3 alkoxy group or hydroxy group; Y is a hydrogen atom or C1-C3 alkyl group; Z is C1-C3 alkyl group; G is selected from formulae and , where in formulae (G2) and (G5) R4 is a hydrogen atom or C1-C6 alkyl group which can be substituted with halogen atoms; D is -NR10C(O)-, -C(O)NR10-, -S(O)2NR10- or -N(R11)-; R10 is a hydrogen atom; R11 is a hydrogen atom or C1-C3 alkyl group; A is a single bond, C1-C6 alkylene, which can be substituted with a phenyl group, or C2-C4 alkenylene; Q is a phenyl group or a 5-6-member aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, S, optionally substituted with a benzene ring; R5, R6 and R7 all or independently denote a hydrogen atom, a halogen atom, C1-C6 alkyl group which can be substituted with halogen atoms, C1-C6 alkoxy group which can be substituted with halogen atoms, phenyloxy group, phenyl group or a 5-6-member aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, where said phenyl group and 5-6-member aromatic heterocyclic group can be substituted with a C1-C3 alkyl group which can be substituted with halogen atoms or a C1-C3 alkoxy group. The invention also relates to specific compounds, a medicinal agent, a pharmaceutical composition, a phospholipase A2 enzyme activity inhibitor and a treatment method.

EFFECT: improved method.

21 cl, 56 tbl, 561 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylpyrrolidinyl methylpyrrolidine amides of formula , where R, R1, R2 and R3 are identical or different and independently denote H, (C1-C4)alkyl, CF3; R4 denotes phenyl, cyclohexyl, pyridinyl, furanyl, isoxazolyl, quinolinyl, naphthyridinyl, indolyl, benzoimidazolyl, benzofuranyl, chromanyl, 4-oxo-4H-chromenyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxolyl and 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e]][1,4]diazepinyl; where said R4 is optionally substituted one to more times with a substitute selected from halogen, hydroxy, (C1-C4) alkyl, (C1-C4) alkoxy, CF3, hydroxymethyl, 2-hydroxyethylamino, methoxyethylamide, benzyloxymethyl, piperidinyl, N-acetylpiperidinyl, pyrrolyl, imidazolyl, 5-oxo-4,5-dihydropyrazolyl; or pharmaceutically acceptable salt thereof or enantiomer or diastereomer thereof.

EFFECT: compounds have modulating activity on histamine H3 receptor, which enables use thereof to prepare a pharmaceutical composition.

10 cl, 3 dwg, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylbipyrrolidine carboxamides of formula , where R denotes (C1-C4)-alkyl; R1 and R2 are identical or different and independently denote H, (C1-C4)-alkyl, CF3; R3 denotes H; R4 denotes cyclopropyl, cyclopentyl, cyclohexyl, bicyclo[2,2,1]heptyl, cyclopentylmethyl, tetrahydropyranyl, furanyl, oxazolyl, isoxazolyl and pyrazolyl; where R4 is optionally substituted one or more times by a substitute selected from methyl, ethyl, pyridinyl, 2-oxo-2H-pyridin-1-yl; or a pharmaceutically acceptable salt thereof, an enantiomer or a diastereomer thereof.

EFFECT: compounds have activity which binds to the H3 ligand, which allows use thereof to prepare a pharmaceutical composition for treating central nervous system diseases.

10 cl, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to (R)-4-(heteroaryl)phenyl compounds of formula ,

where X represents heteroatom, selected from -S or O, Y represents H or residue, selected from group, consisting of - linear or branched C1-C4-alkyl, halogen-C1-C3-alkyl; Z represents heteroaryl ring, selected from group, consisting of unsubstituted tetrazole and triazole, pyrazole, thiazole, isoxazole, isothiazole, thiadiazole and oxadiazole, substituted with one hydroxyl group and optionally additionally substituted with linear C1-C4-alkyl. (R)-4-(heteroaryl)phenylethyl derivatives of formula (I), which can be used for application in treatment of diseases, into which C5a-induced human PMN-chemotaxis is involved. Formula (I) compounds, where Z represents tertazole, is obtained by interaction of formula

compound with trimethylsililazide.

EFFECT: obtaining (R)-4-(heteroaryl)phenylethyl derivatives, possessing high selectivity and activity in inhibition of C5a-induced chemotaxis of neutrophils.

7 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted pyrimidin-5-yl carboxylic acids of formula I and can be used in organic chemistry. The method is realised by reacting N-substituted guanidines and hetarylamidines with ethoxymethylene derivatives of 1,3-ketoesters according to a scheme given below (where the substitutes are as defined in the claim).

EFFECT: improved method of producing substituted pyrimidin-5-yl carboxylic acids of formula I.

2 tbl, 14 ex

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