Pyrazole-pyrimidine derivatives as mglur2 antagonists

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazole-pyrimidine derivatives having metabotropic glutamate receptor (mGluR2) antagonist properties and having formula (1): , where A is selected from a group consisting of: Ra is H, halogen or C1-6-alkyl; R1 is II, halogen, C1-6-alkoxy, C1-6-alkyl, C1-6-haloalkyl, C1-6-haloalkoxy; R2 is a halogen, C1-6-haloalkyl; R3 is NRbRc, where Rb and Rc are independently selected from a group consisting of H and C1-6-alkyl which is possibly substituted with one or more substitutes selected from a group consisting of hydroxy and -NRb'Rc', where Rb' and Rc' are independently selected from a group consisting of H and C1-6-alkyl; or Rb and Rc together with the nitrogen atom to which they are bonded form a possibly substituted heterocyclic group containing 5-6 ring atoms, possibly containing an additional N heteroatom, where the substitutes are selected from a group consisting of hydroxy and C1-6-alkyl, R4 is C1-6-haloalkyl or C3-4-cycloalkyl; as well as to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition and use of the compounds in preparing a medicinal agent for treating or preventing diseases and conditions in which mGluR2 activation plays a role.

EFFECT: improved properties of compounds.

10 cl, 2 dwg, 1 tbl, 129 ex

 

The text descriptions are given in facsimile form.

1. The compound according to formula (I)

where a is selected from the group consisting of:

Rarepresents H, halogen or C1-6-alkyl;
R1represents H, halogen, C1-6-alkoxy, C1-6-alkyl, C1-6-haloalkyl, C1-6-haloalkoxy;
R2is the battle halogen, C1-6-haloalkyl;
R3represents NRbRc,
where Rband Rcindependently from each other selected from the group consisting of N and C1-6-alkyl, which is possibly substituted by one or more than one Deputy, selected from the group consisting of hydroxy, and-NRb'Rc'where Rb'and Rc'independently from each other selected from the group consisting of N and C1-6-alkyl;
or Rband Rctogether with the nitrogen atom to which they are connected, form a possibly substituted heterocyclic group comprising 5 to 6 ring atoms, possibly containing additional N heteroatom, where the substituents selected from the group consisting of hydroxy and C1-6-alkyl;
R4represents a C1-6-haloalkyl or3-4-cycloalkyl;
as well as its pharmaceutically acceptable salt.

2. The compound of formula (I) according to claim 1, where:
And selected from the group consisting of:

where Rarepresents H, halogen or C1-6-alkyl;
R1represents H, halogen, C1-6-alkoxy, C1-6-alkyl, C1-6-haloalkyl, C1-6-haloalkoxy;
R2represents halogen, C1-6-haloalkyl;
R3represents NRbRcwhere Rband Rcindependent is from each other selected from the group consisting of:
H, C1-6-alkyl, which is possibly substituted by one or more than one Deputy, selected from the group consisting of hydroxy, and-NRb'Rc'where Rb'and Rc'independently from each other selected from the group consisting of N and C1-6-alkyl;
R4represents a C1-6-haloalkyl or3-4-cycloalkyl; and its pharmaceutically acceptable salts.

3. The compound of formula (Ia) according to any one of claims 1 or 2:

where Ra, R1, R2, R3and R4are as defined in any one of claims 1 or 2, its pharmaceutically acceptable salt.

4. The compound of formula (Ia) according to claim 3 where the compound is selected from the group consisting of:
(2-chloro-5-sulfamoyl-thiophene-3-yl)-amide-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
(2-chloro-5-sulfamoyl-thiophene-3-yl)-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-thiophene-3-yl]-amide-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-thiophene-3-yl]-amide-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
(2-chloro-5-sulfamoyl-thiophene-3-yl)-amide 5-(4-chloro-phenyl)-7-trifluoromethyl-PI is azolo[1,5-a]pyrimidine-3-carboxylic acid;
(2-chloro-5-sulfamoyl-thiophene-3-yl)-amide 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
(2-chloro-5-sulfamoyl-thiophene-3-yl)-amide 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a] pyrimidine-3-carboxylic acid;
[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-thiophene-3-yl]-amide 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-thiophene-3-yl]-amide 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-thiophene-3-yl]-amide 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-thiophene-3-yl]-amide 5-[3-(2,2,2-Cryptor-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-thiophene-3-yl]-amide 5-(3-chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[2-chloro-5-(2-hydroxy-1-hydroxymethyl-ethylsulfanyl)-thiophene-3-yl]-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[2-chloro-5-(2-hydroxy-1-hydroxymethyl-ethylsulfanyl)-thiophene-3-yl]-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]feast midin-3-carboxylic acid;
{5-[bis-(2-hydroxy-ethyl)-sulfamoyl]-2-chloro-thiophene-3-yl}-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
{5-[bis-(2-hydroxy-ethyl)-sulfamoyl]-2-chloro-thiophene-3-yl}-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[2-chloro-5-(2-hydroxy-ethylsulfanyl)-thiophene-3-yl]-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[2-chloro-5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfanyl)-thiophene-3-yl]-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[2-chloro-5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfanyl)-thiophene-3-yl]-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo(1,5-a]pyrimidine-3-carboxylic acid;
[2-chloro-5-(2-hydroxy-ethylsulfanyl)-thiophene-3-yl]-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
(2-methyl-5-sulfamoyl-thiophene-3-yl)-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
(2-methyl-5-sulfamoyl-thiophene-3-yl)-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-2-methyl-thiophene-3-yl]-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-1,1-dimethyl-atlanfa the oil)-2-methyl-thiophene-3-yl]-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[2-chloro-5-(2-dimethylamino-ethylsulfanyl)-thiophene-3-yl]-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[2-chloro-5-(2-dimethylamino-ethylsulfanyl)-thiophene-3-yl]-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[2-chloro-5-(2-hydroxy-ethylsulfanyl)-thiophene-3-yl]-amide 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-thiophene-3-yl]-amide 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-amino-ethylsulfanyl)-2-chloro-thiophene-3-yl]-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[(RS)-2-chloro-5-(3-hydroxy-pyrrolidin-1-sulfonyl)-thiophene-3-yl]-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[(RS)-2-chloro-5-(3-hydroxy-pyrrolidin-1-sulfonyl)-thiophene-3-yl]-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
{2-chloro-5-[(2-hydroxy-ethyl)-methyl-sulfamoyl]-thiophene-3-yl}-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[2-chloro-5-(4-methyl-piperazine-1-sulfonyl)-thiophene-3-yl]-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[2-chloro-5-(4-methyl-piperazine-1-Sul who were radioactive)-thiophene-3-yl]-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
{2-chloro-5-[(2-hydroxy-ethyl)-methyl-sulfamoyl]-thiophene-3-yl}-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and
[5-(2-amino-ethylsulfanyl)-2-chloro-thiophene-3-yl]-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid.

5. The compound of formula (1B) according to any one of claims 1 or 2:

where R1, R2, R3and R4are as defined in any one of claims 1 or 2, its pharmaceutically acceptable salt.

6. The compound of formula (1B) according to claim 5, where the compound is selected from the group consisting of:
(5-sulfamoyl-[1,3,4]thiadiazole-2-yl)-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and
(5-sulfamoyl-[1,3,4]thiadiazole-2-yl)-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid.

7. The compound of formula (IB) according to any one of claims 1 or 2:

where Ra, R1, R2, R3and R4are as defined in any one of claims 1 or 2, its pharmaceutically acceptable salt.

8. The compound of formula (IB) according to claim 7 where the compound is selected from the group consisting of:
(4-methyl-5-sulfamoyl-thiazol-2-yl)-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
(4-methyl-5-sulfamoyl-thiazol-2-yl)-amide 7-reformer-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-4-methyl-thiazol-2-yl]-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-4-methyl-thiazol-2-yl]-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
(4-methyl-5-sulfamoyl-thiazol-2-yl)-amide 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
(4-methyl-5-sulfamoyl-thiazol-2-yl)-amide 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
(4-methyl-5-sulfamoyl-thiazol-2-yl)-amide 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-4-methyl-thiazol-2-yl]-amide 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-4-methyl-thiazol-2-yl]-amide 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-4-methyl-thiazol-2-yl]-amide 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
(4-methyl-5-sulfamoyl-thiazol-2-yl)-amide 5-(3-chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
(4-methyl-5-sulfamoyl-thiazol-2-yl)-amide 5-(3,4-dichloro-dryer is l)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
(4-methyl-5-sulfamoyl-thiazol-2-yl)-amide 5-[3-(2,2,2-Cryptor-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-4-methyl-thiazol-2-yl]-amide 5-(3-chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-4-methyl-thiazol-2-yl]-amide 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-4-methyl-thiazol-2-yl]-amide 5-[3-(2,2,2-Cryptor-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
(4-methyl-5-sulfamoyl-thiazol-2-yl)-amide 7-deformity-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-4-methyl-thiazol-2-yl]-amide 7-deformity-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
{5-[bis-(2-hydroxy-ethyl)-sulfamoyl]-4-methyl-thiazol-2-yl}-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
{5-[bis-(2-hydroxy-ethyl)-sulfamoyl]-4-methyl-thiazol-2-yl}-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfanyl)-4-methyl-thiazol-2-yl]-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[15-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfanyl)-4-methyl-thiazol-2-yl]-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-ethylsulfanyl)-4-methyl-thiazol-2-yl]-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-ethylsulfanyl)-4-methyl-thiazol-2-yl]-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
(5-sulfamoyl-thiazol-2-yl)-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
(5-sulfamoyl-thiazol-2-yl)-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfanyl)-4-methyl-thiazol-2-yl]-amide 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-dimethylamino-ethylsulfanyl)-4-methyl-thiazol-2-yl]-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-dimethylamino-ethylsulfanyl)-4-methyl-thiazol-2-yl]-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-thiazol-2-yl]-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-enous the l-2-yl]-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-1,1-dimethyl-ethylsulfanyl)-4-methyl-thiazol-2-yl]-amide 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-1-hydroxymethyl-ethylsulfanyl)-4-methyl-thiazol-2-yl]-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[5-(2-hydroxy-1-hydroxymethyl-ethylsulfanyl)-4-methyl-thiazol-2-yl]-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-yl]-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-yl]-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
{5-[(2-hydroxy-ethyl)-methyl-sulfamoyl]-4-methyl-thiazol-2-yl}-amide 7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
{5-[(2-hydroxy-ethyl)-methyl-sulfamoyl]-4-methyl-thiazol-2-yl}-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
[(RS)-5-(3-hydroxy-pyrrolidin-1-sulfonyl)-4-methyl-thiazol-2-yl]-amide (RS)-7-deformity-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and
[(RS)-5-(3-hydroxy-pyrrolidin-1-sulfonyl)-4-methyl-thiazol-2-yl]-amide 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbon is acid.

9. Pharmaceutical composition having the properties of an antagonist of metabotropic glutamate receptor (mGluR2), containing an effective amount of a compound according to any one of claims 1 to 8.

10. The use of the compounds of formula (I), (Ia), (IB) or (IB) according to any one of claims 1 to 8 for the manufacture of a medicinal product for the treatment or prevention of a disease or condition in which it is involved, or plays the role of activation of mGluR2.



 

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1 cl, 1 ex, 1 tbl

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10 cl, 2 tbl, 6 ex

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12 cl, 3 tbl, 2 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrolotriazines of formula (I) , where R1 is selected from a group which includes phenyl, naphthyl, benzyl and heteroaryl, which denotes a mono- or bicyclic radical containing 5-10 ring atoms and up to 2 heteroatoms selected from a group consisting of nitrogen, oxygen and sulphur, at least one ring of which is aromatic, where, if necessary, phenyl and heteroaryl may be substituted with 0, 1 or 2 substitutes independently selected from a group consisting of -(C1-C4)alkyl, where -(C1-C4)alkyl can be substituted with 0, 1, 2 or 3 halogens, 0 or 1 pyrrolidine, -(C1-C3)alkoxy group, where, if necessary, the (C1-C3)alkoxy group may be substituted with a (C1-C3)alkylamino group, halogen, trifluoromethyl, trifluoromethoxy group, phenyl, if necessary substituted with 1 or 2 halogens, - , where X denotes O, nitro group, - (C1-C3)alkylthio group, trifluoromethylthio group, - (C1-C3)alkylcarbonyl, - (C1-C6)alkoxycarbonyl, and a phenoxy group, and where the benzyl can be substituted with 0, 1, 2 or 3 groups selected from a group which includes halogen; R2 is selected from a group consisting of hydrogen, halogen; R3 is selected from a group consisting of carboxyl, - (C1-C6)alkylcarbonyl, - (C3-C6)cycloalkylcarbonyl, - (C1-C6)alkoxycarbonyl, if necessary substituted with 0, 1, 2 or 3 groups selected from a group which includes amino group and (C1-C6)alkoxycarbonyl; aminocarbonyl, -(C1-C6)alkylaminocarbonyl, where (C1-C6)alkylaminocarbonyl which, if necessary, can be substituted with 0, 1, 2 or 3 substitutes independently selected from a group consisting of (C3-C6)cycloalkyl, halogen, amino group, (C1-C6)alkylamino group, hydroxy group, (C1-C6)alkoxy group, (C1-C6))alkoxycarbonyl, (C1-C6)alkylthio group, (C1-C6)alkoxycarbonylamino group,and where, if necessary, (C1-C6)alkylaminocarbonyl may be substituted with 0 or 1 heterocyclyl, which denotes a monocyclic, non-aromatic radical containing 5-8 ring atoms and up to 2 heteroatoms selected from nitrogen and oxygen, where, if necessary, the hetecyclyl may be substituted with 0 or 1 (C1-C6)alkyl, heterocyclylcarbonyl, if necessary substituted with 0 or 1 (C1-C6)alkylamino group, cycloalkyl or (C1-C6)alkyl,where, if necessary, (C1-C6)alkyl may be substituted with 0 or 1 (C1-C6)alkylamino group, and where heterocyclyl denotes a monocyclic, non-aromatic radical containing 5-8 ring atoms and up to 2 heteroatoms selected from nitrogen and oxygen, -(C1-C6)alkyl if necessary substituted with 0, 1 or 2 substitutes independently selected from a group consisting of a) hydroxyl, b) (C1-C6)alkylamino group, where (C1-C6)alkylamino group may be substituted with 0, 1 or 3 substitutes independently selected from a group consisting of halogen, alkylamino group, methoxy group, methylthio group and methylsulphonyl, c) phenylamino group, where the phenylamino group may be substituted with 0, 1 or 2 substitutes independently selected from a group consisting of (C1-C6)alkoxy group and trifluoromethyl, d) heterocyclyl, where heterocyclyl denotes a monocyclic, non-aromatic radical containing 5-8 ring atoms and up to 2 heteroatoms selected from nitrogen and oxygen, and where the heterocyclyl may be substituted with 0 or 1 (C1-C6)alkyl, where (C1-C6)alkyl may be substituted with 0 or 1 methoxy groups or pyridyls, e) imidazolyl, f) pyridylamino group, g) (C1-C3)alkoxy group, if necessary substituted with fluorine or piperidine,where, if necessary, the piperidine may be substituted with 0 or 1 (C1-C6)alkyl, h) (C1-C3)alkoxy(C2-C3)alkoxy group, and i) (C1-C6)alkoxycarbonyl, j) (C3-C6)cycloalkyl, k) cyano group, - (C3-C6)cycloalkylaminocarbonyl, cyano group, heteroaryl, where heteroaryl denotes a monocyclic radical containing 5-6 ring atoms and up to 3 heteroatoms selected from a group consisting of nitrogen and oxygen, the ring of which is aromatic, where the heteroaryl may be substituted with 0, 1 or 2 groups independently selected from a group consisting of q) (C1-C6)alkyl, where the (C1-C6)alkyl may be substituted with 0 or 1 morpholine or 0 or 1 hydroxy group, r) (C1-C6)alkoxycarbonyl, thiophene carbonyl, and R4 is selected from a group consisting of hydrogen; to a pharmaceutically acceptable salt thereof. The invention also pertains to methods of obtaining said compounds.

EFFECT: obtaining novel compounds which can be used in medicine for preventing or treating hyper-proliferative disorders and diseases associated with angiogenesis.

5 cl, 313 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a crystalline form of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one, which exhibits characteristic peaks on an X-ray powder diffraction pattern expressed in two-theta degrees, selected from approximately 7.1, approximately 12.1 and approximately 16.1; or approximately 7.1, approximately 12.1 and approximately 17.5; or approximately 7.1, approximately 12.1 and approximately 23.5; or approximately 12.1, approximately 16.1 and approximately 17.5; or approximately 12.1, approximately 16.1 and approximately 23.5; or approximately 16.1, approximately 17.5 and approximately 23.5; or approximately 7.1, approximately 17.5 and approximately 23.5; or approximately 7.1, approximately 12.1 and approximately 23.5; or approximately 7.1, approximately 16.1 and approximately 23.5, and to a pharmaceutical composition based on said compound, which can be used in medicine to prepare a medicinal agent which acts on the hepatitis C virus (HCV) in HCV-infected mammals.

EFFECT: improved properties of derivatives.

12 cl, 1 tbl, 3 dwg, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted tetracyclic derivatives of tetrahydropyran, pyrrolidine and tetrahydrothiophene of general formula (I), their pharmaceutically acceptable addition salts, their stereochemically isomeric forms, their N-oxide forms, in which all substitutes are defined in claim 1 of the formula of invention. These compounds have binding affinity to serotonin receptors, particularly 5-HT2A and 5-HT2C receptors, and to dopamine receptors particularly D2 dopamine receptors, and have norepiniphrine reuptake inhibition properties. The invention also relates to a pharmaceutical composition containing said compounds, method of preparing said composition and use of said compounds as medicinal agents, particularly for preventing and/or treating several psychiatric and neurological disorders.

EFFECT: new compounds have useful biological properties.

12 cl, 3 tbl, 49 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-alkylamino-3-sulfonyl-pyrazolo[1,5-a]pyrimidines, their pharmaceutically acceptable salts and/or hydrates which have serotonin 5-HT6 receptor antagonist properties and can be used in treating or preventing development of various central nervous system diseases, whose pathogenesis is related to 5-HT6 receptors, particularly Alzheimer's disease, Parkinson's disease, Huntington disease, schizophrenia, other neurodegenerative diseases, cognitive and anxiety disorders and obesity. In general formula (I):

R1 and R3 independently denote optionally identical C1-C3alkyl, R2 is a -(CH2)nX group or R1 and R3 independently denote different substitutes selected from C1-C3 alkyl or a -(CH2)nX group, and R2 is a hydrogen atom or C1-C3alkyl; R4 is C1-C3alkyl; Ri5 is a hydrogen atom, one or two identical or different halogen atoms, C1-C3alkyl; i is equal to 0, 1 or 2; n is equal to 0, 1, 2 or 3; X is a carboxyl CO2H, C1-C3alkyloxycarbonyl, aminocarbonyl CONR6R7 or a NR6R7 amino group; R6 and R7 denote optionally identical hydrogen atom, optionally substituted C1-C3 alkyl, C3-C7cycloalkyl or an optionally substituted 5-7-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitutes are selected from C1-C3alkyl; or R6 and R7 together with the nitrogen atom to which they are bonded form an optionally substituted 5-6-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitutes are selected from C1-C3alkyl.

EFFECT: obtaining new biologically active compounds.

26 cl, 12 dwg, 4 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of novel derivatives of benzo[7,8]azonino[5,4-b]indoles, 7,9-etheno-azecino[5,4-b]indoles and 7,9-ethano-azecino[5,4-b]indoles with general structural formulae: , , , I, IV, VII X=H,Y=CO2Me; II, V, VIII X=H, Y=COMe; III, VI, IX X=Y=CO2Me, which have proved to be cytostatic and cytotoxic compounds. The method involves dissolving 3,8,13,13b-tetrahydro-5H-benzo[1,2]indolysino[8,7-b]indole, ethyl eburnamenine-14-carboxylate or methyl (3-α, 14-β, 16α)-14-hydroxy-14,15-dihydro eburnamenine -14-carboxylate in methanol and then reaction with excess dimethyl acetylenedicarboxylate (ADCX) or methyl propiolate or acetyl acetylene, while stirring at +40-+50°C, with subsequent removal of the solvent and grinding the residue in hexane or a mixture of hexane with ethylacetate (ether) or purified using column chromatography on aluminium oxide.

EFFECT: design of an efficient method of obtaining hazardous compounds.

9 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel compounds of general formula: , where R1 - C1-C6alkyl, C1-C6alkoxy, halogen, CN, C(O)NH2 or OCH2CH2OCH3; R2-C1-C6alkyl, possibly substituted with halogen, a halogen, C1-C6alkoxy, phenyl, N(R6)2, (OCH2CH2)nOCH3, O(CH2)mNR7R8, where n equals 1 or 2; m equals 2 or 3; R6 -R7 -C1C6alkyl, and R8 -OCH2CH2OCH3; or R7 and R8 together with the nitrogen atom to which they are bonded form a 6-member heterocycle which additionally contains one oxygen atom or one nitrogen atom, which in the latter case is substituted with C1-C4alkyl; or R1 and R2 together form a 5-member heterocyclic ring system containing two oxygen atoms as heteroatoms; R3 - hydrogen or C1-C6alkyl; R4 - hydrogen, halogen or C1-C6alkoxy; or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing these compounds.

EFFECT: obtaining novel compounds with kinase inhibiting properties, particularly CDK2, or angiogenesis inhibiting properties and can be used in treating malignant growths, particularly in mammary glands, large intestines, lungs and prostate glands.

60 cl, 7 tbl, 101 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): or pharmaceutically acceptable salts thereof, where X is CH; R1 is phenyl or a 6-member heteroaryl which contains 1 or 2 nitrogen atoms as heteroatoms, independently and optionally substituted with up to five groups J; R2 and R3 each independently represents hydrogen, halogen, -V-R or -V-Ra; R5 is R; R is H or an optionally substituted C1-6aliphatic group, where the substitutes are selected from -OR0, phenyl, substituted R0, -N(R0)2; where each independent R0 is selected from hydrogen, halogen, C1-6aliphatic group; Ra is morpholine, V is a bond or Q; Q is -NR5-; each J group independently represents a halogen, -N(R5)2. The invention also relates to a pharmaceutical composition with protein kinase inhibiting properties, and to methods of inhibiting Aurora A protein kinase using the said compounds.

EFFECT: obtaining novel compounds and pharmaceutical compositions based on the said compounds, which can be used in medicine to treat or alleviating a proliferative disorder, such as cancer, in a patient.

25 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention describes an amide of formula:

where A and B are independently selected from CH or N; D is H; Z is selected from hydrogen, unsubstituted C1-8alkyl, each L is independently selected from -CraRb-, -CRa=, -CO-, -O- or -NRa-; k, m, n, q, x and w are integers independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, provided that k+m+n+q+x+w equals at least 4; R1-R6 are independently selected from hydrogen, CN or halogen; Ra and Rb are independently selected from hydrogen, unsubstituted C1-8alkyl, or its pharmaceutically acceptable salt. The invention describes a pharmaceutical composition, use of the compounds to treat AChE-mediated diseases, a treatment method, as well as an amide synthesis method and use of the formula (I) amide as a chemical agent for inhibiting acetylcholinesterase in biological research.

EFFECT: compounds have high acetylcholinesterase or butyrylcholinesterase inhibiting activity.

24 cl, 27 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel malonamide derivatives of general formula , to their pharmaceutically acceptable salts of acid bonding and to all forms of their optically pure enantiomers, racemates or diastereomers and diastereomer mixtures, possessing inhibiting activity with respect to γ-secretase, as well as to pharmaceutical preparation, containing one or more than one of claimed compounds, and to application of claimed compounds for manufacturing of drugs. Values of substituents R, R1, R2, R3, as well as X, n are given in invention formula.

EFFECT: obtaining compounds that can be applied in treatment of Alzheimer's disease.

19 cl, 6 dwg, 111 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, ophthalmology, and can be used for treatment of optic atrophy in children of age from 1 to 6 months. For this purpose regions of large and small fontanelles of head and upper sympathetic ganglia at the level of cervical spine at C1-C2 level are exposed to polarised light of apparatus "Bioptron". Exposures to light are carried out daily during 10 days in therapeutic dose 12 J/cm2 from the distance 5 cm from skin surface with light spot diametre 5 cm, irradiation intensity 40 mW/cm2 exposure duration 30 seconds on region of fontanelles and 1 minute on regions of ganglia. On finishing light impact nootropic medications cortexin and/or actovegin or cerebrolisin are introduced in age dose. Courses of treatment are carried out from 1 month to 6 month age until desired therapeutic effect is obtained.

EFFECT: method allows to improve cerebral and intraocular blood supply and metabolic processes of brain and optic nerve, improve delivery of nootropic medications to optic analyser, obtain therapeutic concentrations of medications without side effects.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention is aimed at dipyrazole compounds of formula I and their pharmaceutically acceptable salts, where radicals and groups are defined in claim 1 of the formula of invention. Disclosed compounds modulate AMPA and NMDA receptor functioning. A pharmaceutical composition based on formula I compounds and separate dipyrazole compounds are also part of the subject of invention.

EFFECT: possibility of using compounds as pharmaceutical agents, mainly for treating psychoneurological diseases.

16 cl, 2 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-alkylamino-3-sulfonyl-pyrazolo[1,5-a]pyrimidines, their pharmaceutically acceptable salts and/or hydrates which have serotonin 5-HT6 receptor antagonist properties and can be used in treating or preventing development of various central nervous system diseases, whose pathogenesis is related to 5-HT6 receptors, particularly Alzheimer's disease, Parkinson's disease, Huntington disease, schizophrenia, other neurodegenerative diseases, cognitive and anxiety disorders and obesity. In general formula (I):

R1 and R3 independently denote optionally identical C1-C3alkyl, R2 is a -(CH2)nX group or R1 and R3 independently denote different substitutes selected from C1-C3 alkyl or a -(CH2)nX group, and R2 is a hydrogen atom or C1-C3alkyl; R4 is C1-C3alkyl; Ri5 is a hydrogen atom, one or two identical or different halogen atoms, C1-C3alkyl; i is equal to 0, 1 or 2; n is equal to 0, 1, 2 or 3; X is a carboxyl CO2H, C1-C3alkyloxycarbonyl, aminocarbonyl CONR6R7 or a NR6R7 amino group; R6 and R7 denote optionally identical hydrogen atom, optionally substituted C1-C3 alkyl, C3-C7cycloalkyl or an optionally substituted 5-7-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitutes are selected from C1-C3alkyl; or R6 and R7 together with the nitrogen atom to which they are bonded form an optionally substituted 5-6-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitutes are selected from C1-C3alkyl.

EFFECT: obtaining new biologically active compounds.

26 cl, 12 dwg, 4 tbl, 14 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely for teacheability and memory improvement in mammals. An infant takes a milk formula containing casein glycomacropeptide in amount sufficient to ensure introducing at least 100 mg/kg of sialic acid a day.

EFFECT: method extends the range of products for teacheability and memory improvement in an infant.

11 cl, 14 tbl, 13 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to bioorganic chemistry and medicine and can be used to prepare medicinal agents with neurotropic activity. The technical result is achieved due to creation of a peptide with neurotropic activity and having general formula: Ac-X-Met-Pro-Arg-Gly-NH2, where X-Met - L-Met or DL-Met.

EFFECT: obtaining a novel compound - analogues of the C-terminal end of vasopressin which are capable of selectively bonding with different subtypes of vasopressin receptors and, as a result, have different types of neurotropic activity, have low toxicity and are suitable for simple intranasal administration.

5 ex

FIELD: medicine.

SUBSTANCE: there is claimed application of dipeptidyl peptidase IV inhibitor (DPP-IV inhibitor), vildagliptin or its salt for production of medication for prevention, retardation of progress or treatment of peripheral diseases such as peripheral neuropatia, neurodegenerative disorders, cognitive disorders, as well as for improvement of memory and ability to learn, and pharmaceutical composition for the same purpose. It is demonstrated: vildagliptin increases stage of wakefulness and response to external stimuli, increases REM sleep phase.

EFFECT: combination of vildagliptin with donepezil considerably improves disturbed ability to learn.

23 cl, 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: medicine.

SUBSTANCE: invention refers to psychoneurology, particularly to an agent for treating multiple sclerosis. A composition (solid or liquid dosage form) contains triiodide 1,3-diethylbenzimidazolium as an agent, low-molecular surgical polyvinylpyrrolidone, presented as a solubiliser, and an agent stabiliser, and in addition in the liquid dosage form - ethanol as a solvent.

EFFECT: composition under the invention exhibits high therapeutic effectiveness in treating multiple sclerosis, and is characterised by relieving undesirable by-effects.

2 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a crystalline form of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one, which exhibits characteristic peaks on an X-ray powder diffraction pattern expressed in two-theta degrees, selected from approximately 7.1, approximately 12.1 and approximately 16.1; or approximately 7.1, approximately 12.1 and approximately 17.5; or approximately 7.1, approximately 12.1 and approximately 23.5; or approximately 12.1, approximately 16.1 and approximately 17.5; or approximately 12.1, approximately 16.1 and approximately 23.5; or approximately 16.1, approximately 17.5 and approximately 23.5; or approximately 7.1, approximately 17.5 and approximately 23.5; or approximately 7.1, approximately 12.1 and approximately 23.5; or approximately 7.1, approximately 16.1 and approximately 23.5, and to a pharmaceutical composition based on said compound, which can be used in medicine to prepare a medicinal agent which acts on the hepatitis C virus (HCV) in HCV-infected mammals.

EFFECT: improved properties of derivatives.

12 cl, 1 tbl, 3 dwg, 11 ex

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