Tetraline and indan derivatives and application thereof


FIELD: medicine, pharmaceutics.

SUBSTANCE: there is described a compound of formula I: or its pharmaceutically acceptable salt, where R2 represents (CR3R4)n-NR5R6 and m, p, q, Ar, R1, R3, R4, R5 and R6 are those as specified in the patent claim and defined as selective 5-NT6 and/or 5-NT2A antagonists. There is also described a pharmaceutical composition containing this compound, and application thereof in preparing drugs for treating diseased conditions of central nervous system chosen from psychoses, schizophrenia, manic depressions, neural disorders, memory impairment, attention deficient syndrome, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, malnutrition and Huntington's disease.

EFFECT: preparation of the compounds which can find application in treatment of a diseased condition of central nervous system.

27 cl, 1 tbl, 29 ex

 

The text descriptions are given in facsimile form.

1. The compound of formula I:

or its pharmaceutically acceptable salt,
where m is from 0 to 1;
p is from 1 to 2;
q is 2;
Ar represents phenyl, possibly substituted by the Deputy, is selected from C1-12-alkoxy, halogen, cyano, hydroxy and C1-12-alkylsulfonyl, or heteroaryl, meaning monocyclic or bicyclic monovalent radical of 5-9 ring atoms having an aromatic ring containing one or two nitrogen atom, possibly substituted C1-12-alkyl, halogen;
each R1independently represents halogen or C1-12-alkoxy;
;
R2represents a
n is from 1 to 3;
R3and R4each independently represents hydrogen, or R3and R4can together form =O or =NRfwhere Rfrepresents hydrogen; and
one of R5and R6represents hydrogen or C1-12-alkyl and the other is: hydrogen; C1-12-alkyl; amidine; aminocarbonyl; C1-12-alkylaminocarbonyl; di(C1-12-alkyl)aminocarbonyl; C1-12-alkylsulphonyl; C1-12-alkoxycarbonyl; aminocarbonyl-C1-12-alkyl; C1-12-alkylaminocarbonyl-C1-12-alkyl; amino-C1-12-alkali boil; C1-12-alkylamino-C1-12-alkylsulphonyl; di(C1-12-alkyl)amino-C1-12-alkylsulphonyl; C1-12-alkoxycarbonyl-C1-12-alkyl;
imidazolines; imidazolyl; imidazolidinyl; pyrrolidinone;
pyrrolidinylcarbonyl; N-cyanoaniline; C1-12-alkylsulfonyl; hydroxy-C1-12-alkylsulphonyl; aminosulfonyl; hydroxy-C1-12-alkyl;
or maybe substituted C1-12the alkyl heteroaryl, meaning monocyclic or bicyclic monovalent radical of 5-9 ring atoms, having at least one aromatic ring or a partially saturated, containing two ring atoms selected from N and S, the remaining ring atoms are carbon;
or R5and R6together with the nitrogen atom to which they are attached, can form a group amidines, (C1-12-alkyl)amidines; three(C1-12-alkyl)amidines, the group of N-alkyl-N-phenyl-guanidine or 5-membered ring heteroaryl, possibly substituted C1-12-alkyl and which may include additional nitrogen heteroatom; or
one of R5and R6and one of R3and R4together with the atoms to which they are attached, may form a 5-membered ring, which includes an additional heteroatom n

2. The compound according to claim 1, where R3and R4represent hydrogen.

3. Soy is inania according to claim 2, where R5and R6represent hydrogen.

4. The compound according to claim 2, where one of R5and R6represents hydrogen and the other represents C1-12-alkyl.

5. The compound according to claim 2, where one of R5and R6represents hydrogen or C1-12-alkyl and the other is: hydrogen; C1-12-alkyl; amidine; aminocarbonyl; C1-12-alkylsulphonyl; C1-12-alkoxycarbonyl; aminocarbonyl-C1-12-alkyl; amino-C1-12-alkylsulphonyl; C1-12-alkoxycarbonyl-C1-12-alkyl; imidazolyl; imidazolidinyl; pyrrolidinone; pyrrolidinylcarbonyl; N-cyanoaniline; C1-12-alkylsulfonyl; hydroxy-C1-12-alkylsulphonyl; aminosulfonyl; hydroxy-C1-12-alkyl; or perhaps substituted 5 - or 6-membered heteroaryl.

6. The compound according to claim 2, where one of R5and R6represents hydrogen and the other is: hydrogen; C1-12-alkyl; amidine; aminocarbonyl; C1-12-alkylsulphonyl; C1-12-alkoxycarbonyl; aminocarbonyl-C1-12-alkyl; amino-C1-12-alkylsulphonyl; C1-12-alkoxycarbonyl-C1-12-alkyl; C1-12-alkylsulfonyl or hydroxy-C1-12-alkylsulphonyl.

7. The compound according to claim 2, where R5and R6together with the nitrogen atom to which they are attached, form a group amidines.

8. The connection p is 1, where R3and R4together form: =NRfwhere Rfrepresents a hydrogen, and where R5and R6represent hydrogen.

9. The compound according to claim 1, where R3and R4together form =O.

10. The compound according to claim 1, where one of R5and R6and one of R3and R4together with the atoms to which they are attached, form a ring imidazolines.

11. The compound according to claim 2, where Ar represents a phenyl, possible substitutions Deputy, selected from C1-12-alkoxy, halogen, cyano, hydroxy and C1-12-alkylsulfonyl.

12. The compound according to claim 2, where Ar represents a 5 - or 6-membered heteroaryl selected from indolyl, pyrrolyl, imidazolyl, pyrazolyl, benzimidazolyl, each of which may substituted With1-12-alkyl, halogen.

13. The compound according to claim 1, where one of R5and R6and one of R3and R4together with the atoms to which they are attached, form a ring imidazolines.

14. The compound according to claim 1, where R2represents an amino-C1-3-alkyl, C1-12-alkylamino-C1-3-alkyl, di(C1-12-)alkylamino-C1-3-alkyl, imidazolidinone-C1-3-alkyl, imidazolyl-C1-3-alkyl, guanidino-C1-3-alkyl, tetrahydropyrimidine-C1-3-alkyl, amidine-C1-3-alkyl, ur-C1-3-alkyl, pyrimidinyl-amino-C1-3-alkyl, them is azolylamines-C 1-3-alkyl, guanidiniocarbonyl-C1-3-alkyl, imidazolylidene-C1-3-alkyl, imidazoledicarbonitrile-C1-3-alkyl, aminocarbonyl-C1-3-alkyl, pyrrolidinedione-C1-3-alkyl, amino-C1-12-alkylcarboxylic-C1-3-alkyl, C1-12-alkoxycarbonyl-C1-12-alkylamino-C1-3-alkyl, N-cyanoguanidine-C1-3-alkyl, C1-12-alkylcarboxylic-C1-3-alkyl, aminocarbonyl-C1-12-alkylamino-C1-3-alkyl,
pyrrolidinylcarbonyl-C1-3-alkyl, C1-12-alkylsulfonamides-C1-3-alkyl, aminosulfonyl-C1-3-alkyl, C1-12-alkoxycarbonyl-C1-3-alkyl, hydroxy-C1-12-alkylcarboxylic-C1-3-alkyl, hydroxy-C1-12-alkylamino-C1-3-alkyl.

15. The compound according to claim 1, where R2represents an amino-C1-12-alkyl, C1-12-alkylamino-C1-12-alkyl, di(C1-12-)alkylamino-C1-12-alkyl, guanidino-C1-12-alkyl, amidine-C1-12-alkyl, ur-C1-12-alkyl, amidines, guanidiniocarbonyl-C1-12-alkyl, aminocarbonyl-C1-12-alkyl, amino-C1-12-alkylcarboxylic-C1-12-alkyl, C1-12-alkylcarboxylic-C1-12-alkyl, aminocarbonyl-C1-12-alkylamino-C1-12-alkyl or C1-12-alkoxycarbonyl-C1-12-alkyl.

16. The compound according to claim 1, where R2 is:
;;;;;;
;;;;;;
;;;;;;
;;;;;
;;;;or
where Rgrepresents hydrogen, C1-12-alkyl, phenyl or pyrimidinyl, Rh, Ri, Rjand Rkindependently in each case represent hydrogen or C1-12-alkyl and Rmrepresents hydrogen, alkyl or-NRhRi.

17. The compound according to claim 1, where R2is:
;;;;or
where Rg, Rh, Riand Rjeach independently represents hydrogen or methyl.

18. The compound according to claim 1, where R3and R4represent hydrogen, R5represents hydrogen or methyl and R6is:
;;;;;;
;;;;;
;;;;or;
where Rgrepresents hydrogen, C1-12-alkyl, phenyl or pyrimidinyl, Rh, Ri, Rjand Rkindependently in each case represent hydrogen or C1-12-alkyl and Rmrepresents hydrogen, alkyl or-NRhRi.

19. The compound according to claim 1, where R3and R4represent hydrogen, R5represents hydrogen or methyl and R6is:
;;;or;
where R g, Rh, Riand Rjeach independently represents hydrogen or methyl.

20. The compound according to claim 1, where the specified compound has the formula II:
;
where m, Ar, R1and R2are as set forth in claim 1.

21. The compound according to claim 1, where the specified compound has the formula IIIa:
;
where s is from 0 to 1;
each R7independently represents halogeno,1-12-alkoxy, cyano, -S(O)rRawhere r is 2, R3represents a C1-12-alkyl; and
m, n, R1, R3, R4, R5and R6are as set forth in claim 1.

22. Connection item 21, where the aforementioned compound has formula IVa:
;
and where m, n, s, R1, R5, R6and R7are as set out in item 21.

23. Connection p.22, where m is 0 or 1, s is 0 or 1 and R1and R7represent halogeno.

24. Connection item 23, where one of R5and R6represents hydrogen and the other is: hydrogen; C1-12-alkyl; amidine; aminocarbonyl; C1-12-alkylsulphonyl; C1-12-alkoxycarbonyl; aminocarbonyl-C1-12-alkyl; amino-C1-12-alkylsulphonyl; C1-12-alkoxycarbonyl-C1-12-alkyl; C1-12-alkylsulfonyl or hydroxy-C1-12-alkylsulphonyl.

25. The compound according to claim 1, where the specified connection is selected:
2-(5-Benzazolyl-indan-1-yl)-ethylamine;
[2-(5-Benzazolyl-indan-1-yl)-ethyl]-(4,5-dihydro-1H-imidazol-2-yl)-amine;
1-[2-(5-Benzazolyl-indan-1-yl)-ethyl]-1-methyl-1H-pyrrole iodide;
[2-(5-Benzazolyl-indan-1-yl)-ethyl]-methylamine;
3-(5-Benzazolyl-indan-1-yl)-Propylamine;
With-(7-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-methylamine;
N-[2-(7-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-ethyl]-guanidine;
C-[7-(4-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-yl]-methylamine;
(7-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl)-(5,5-dimethyl-1,4,5,6-tetrahydro-pyrimidine-2-yl)-amine;
2-(7-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-acetamidine;
2-(7-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-ethylamine;
(6-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl)-(4,5-dihydro-1H-imidazol-2-yl)-amine;
N-(7-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl)-N'-methyl-N"-phenyl-guanidine;
N-(6-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl)-guanidine;
N-(7-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl)-guanidine;
1-[2-(7-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-ethyl]-1H-imidazole;
[2-(7-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-ethyl]-pyrimidine-2-yl-amine;
N'-[2-(7-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-ethyl]-N,N-dimethyl-ACET is Medina;
3-(6-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-propionamide;
[2-(6-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-ethyl]-dimethyl-amine;
C-(6-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-methylamine;
S-[6-(3-Chloro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-yl]-methylamine;
(6-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl)-methyl-amine;
(6-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl)-pyrimidine-2-yl-amine;
N-(6-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl)-acetamidine;
2-(6-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-ethylamine and
2-[6-(2-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-yl]-ethylamine,
[6-(3-Chloro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-methylamine;
S-[6-(2-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-yl]-methylamine;
1-[2-(6-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-ethyl]-1H-imidazole;
3-[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-yl]-Propylamine;
C-(6-Benzazolyl-7-methoxy-1,2,3,4-tetrahydro-naphthalene-1-yl)-methylamine;
(6-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl)-dimethyl-amine;
(6-Benzazolyl-7-methoxy-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl)-methylamine;
[2-(6-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-ethyl]-dimethyl-amine;
(R)-(6-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl)-methyl-amine;
(S)-(6-Benzazolyl-1,2,34-tetrahydro-naphthalene-1-ylmethyl)-methyl-amine;
(6-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl)-urea;
2-(6-Benzazolyl-7-methoxy-1,2,3,4-tetrahydro-naphthalene-1-yl)-ethylamine;
S-[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-yl]-methylamine;
[2-(6-Benzazolyl-7-methoxy-1,2,3,4-tetrahydro-naphthalene-1-yl)-ethyl]-methylamine;
N-[2-(6-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-acetyl]-guanidine;
[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-methylamine;
Ethyl-[6-(3-fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-amine;
(R)-S-(6-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-methylamine;
(R)-S-[6-(3-Methoxy-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-yl]-methylamine;
(R)-[6-(3-Methoxy-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-methylamine;
(R)-S-[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-yl]-methylamine;
(R)-3-(5-Aminomethyl-5,6,7,8-tetrahydro-naphthalene-2-sulfonyl)-benzonitrile;
(R)-[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-urea;
(R)-S-[6-(1H-Indol-3-sulfonyl)-1,2,3,4-tetrahydro-naphthalene-1-yl]-methylamine;
(R)-2-{[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-amino} - for 3,5-dihydro-imidazol-4-it;
(R)-S-(6-Benzazolyl-8-fluoro-1,2,3,4-tetrahydro-naphthalene-1-yl)-methylamine;
(R)-N-{2-[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-yl]-acetyl}-guanidine;
(R)-(6-Benzazolyl-1,2,3,4-tet is ahydro-naphthalene-1-ylmethyl)-urea;
(R)-S-[6-(1H-Pyrrol-3-sulfonyl)-1,2,3,4-tetrahydro-naphthalene-1-yl]-methylamine;
(R)-(6-Benzazolyl-8-fluoro-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl)-methylamine;
(R)-1H-Imidazole-2-carboxylic acid [6-(3-fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-amide;
(R)-2-(6-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-ndimethylacetamide;
(R)-1H-Pyrrole-2-carboxylic acid [6-(3-fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-amide;
(R)-S-(6-Benzazolyl-5-fluoro-1,2,3,4-tetrahydro-naphthalene-1-yl)-methylamine;
(R)-S-[6-(3-Methanesulfonyl-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-yl]-methylamine;
(R)-2-Amino-N-[6-(3-fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-ndimethylacetamide;
(R)-S-[6-(1H-Pyrazole-4-sulfonyl)-1,2,3,4-tetrahydro-naphthalene-1-yl]-methylamine;
(R)-S-[6-(6-Fluoro-3H-benzimidazole-4-sulfonyl)-1,2,3,4-tetrahydro-naphthalene-1-yl]-methylamine;
(R)-C-[6-(1-Methyl-1H-imidazol-2-sulfonyl)-1,2,3,4-tetrahydro-naphthalene-1-yl]-methylamine;
(R)-N-[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-2-methylamino-ndimethylacetamide;
(R)-1-[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-3-methyl-urea;
(R)-{[6-(2-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-amino}-acetic acid ethyl ester;
(R)-Methyl-[6-(1H-pyrrol-3-sulfonyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-amine;
(R)-N-[6-(2-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-Naftali is-1-ylmethyl]-N'-cyano-guanidine;
(R)-N-[6-(1H-Indol-3-sulfonyl)-1,2,3,4-tetrahydro-naphthalene-ylmethyl]-ndimethylacetamide;
(R)-N-(6-Benzazolyl-8-fluoro-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl)-ndimethylacetamide;
(R)-2-{[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-amino}-ndimethylacetamide;
(R)-2-Dimethylamino-N-[6-(3-fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-ndimethylacetamide;
(R)-S-[6-(5-fluoro-1H-indol-3-sulfonyl)-1,2,3,4-tetrahydro-naphthalene-1-yl]-methylamine;
(R)-Pyrrolidin-2-carboxylic acid (6-benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl)-amide;
(R)-2-{[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-amino}-N-methyl-ndimethylacetamide;
(R)-Pyrrolidin-2-carboxylic acid [6-(3-fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-amide;
(R)-2-{[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-methylamino}-ndimethylacetamide;
(R)-N-[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-methanesulfonamide;
(R)-3-[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-1,1-dimethyl-urea;
(R)-N-[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-ndimethylacetamide;
(R)-1-[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-1-methyl-urea;
(R)-[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-carbamino acid methyl ester;
(R)-Methyl-[6-(1-methyl-lH-pyrrol-3-sulfonyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-amine;
(R)-3-(5-Aminomethyl-5,6,7,8-tetrahydro-naphthalene-2-sulfonyl)-phenol;
(R)-N-[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-2-hydroxy-ndimethylacetamide;
(R)-N-[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-N-methyl-ndimethylacetamide;
6-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid amide;
(R)-6-Benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid amide
and
(R)-2-{[6-(3-Fluoro-benzazolyl)-1,2,3,4-tetrahydro-naphthalene-1-ylmethyl]-amino}-ethanol.

26. Pharmaceutical composition having the activity of a selective antagonist of 5-HT6and/or 5-HT2Acontaining an effective amount of a compound according to claim 1 in a mixture with a pharmaceutically acceptable carrier.

27. The use of the compounds of formula 1 according to any one of claims 1 to 25 in the manufacture of medicaments useful for the treatment of painful conditions of the Central nervous system selected from psychoses, schizophrenia, manic depressions, neurological disorders, memory disorders, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, eating disorders and Huntington's disease.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula

, where R1 is a

or or or group, R2 is morpholine or OR' or N(R")2; R' is a lower alkyl, a lower alkyl substituted with a halogen, or -(CH2)n-cycloalkyl; R" is a lower alkyl; R is NO2 or SO2R'; R4 is hydrogen, hydroxy, halogen, NO2, lower alkoxy, SO2R' or C(O)OR"; R5/R6/R7 denote hydrogen, halogen, lower alkyl; X'/X1 denote CH or N, provided that X1 /X1' are not CH at the same time; X2 is O or S; n equals 0 or 1, and to their pharmaceutically active acid-addition salts. The invention also relates to a drug.

EFFECT: obtaining novel biologically active compounds which are active as glycine transporter 1 inhibitors.

11 cl, 24 ex, 1 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; medicine.

SUBSTANCE: invention relates to 3-phenylpropionic acid derivatives of formula (I) as ligand of peroxisome proliferator-activated gamma-receptor (PPARγ), to their pharmaceutically acceptable salts, as well as to their application, treatment method and based on them pharmaceutical composition. Compounds can be applied for treatment and prevention of diseases mediated by peroxisome proliferator-activated gamma-receptor (PPARγ), for instance type 2 diabetes, insulin-resistance, metabolic syndrome, complications resulting from or connected with diabetes, cardio-vascular dysfunctions, atherosclerosis, obesity, cognition disturbances and lipid metabolism derangements. In general formula (I): W represents COOH or -COO-C1 - C4-alkyl group; Y represents NH; Z represents S or O; X represents O; R1 - R8 each independently represents hydrogen atom or halogen atom; A represents mono-, bi- or tri-cyclic 5-13-member heteroaryl with 1 or 2 heteroatoms selected from N, S or O, aryl, selected from phenyl and naphtyl, or -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, where heteroaryl is optionally substituted with 1-3 substituents, independently selected from group, consisting of C1-C4-alkyl, CN, phenyl halogen and phenyl, optionally substituted with 1-3 substituents, independently selected from C1-C4alkoxy, halogen and ethylenedioxy-group; and n represents integer number from 0 to 3 including; and their pharmaceutically acceptable salts.

EFFECT: increased efficiency of composition and treatment method.

20 cl, 14 dwg, 10 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of formula (I) and its pharmaceutically acceptable salts and esters. Compounds of the present invention are characterised with properties of DGAT-1 inhibitor. In general formula (I) , Q represents O, S or NR5; A represents a linker chosen from where p is equal to 1 or 2, and , where m is equal to 0, and n is equal to 1, 2, 3 or 4, or m is equal to 1, while n is equal to 1, 2 or 3, where specified linker is optionally substituted with one or two groups R8; R1 and R2 are independently chosen from hydrogen, haloid; R3 is chosen from hydrogen, (C1-C6)alkyl optionally substituted with hydroxyl and phenyl optionally substituted with haloid; R4 is chosen from hydrogen, nitro and (C1-C6)alkyl; or R3 and R4 together with carbon atoms whereto attached, can form benzene ring optionally substituted with 1-2 substitutes. The invention also concerns compounds of formula (Ia) and (Ib) with structural formulas presented in the patent claim, and also to a pharmaceutical composition, a medical product, to application of compounds for making a medical product and compound process.

EFFECT: new compounds possess useful biological activity.

19 cl, 2 tbl, 7 dwg, 215 ex

FIELD: chemistry.

SUBSTANCE: invention concerns benzothiazole derivatives of general formula (I) and their pharmaceutically acceptable salts as adenosine receptor ligands and based medicinal product. Compounds can be applied in treatment and prevention of diseases mediated by A2A adenosine receptors, such as Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease. In the general formula (I) , R1 is C5-C6-cycloalkyl substituted by CF3 group, lower alkyl, -(CH2)nOH or -(CH2)n-O- lower alkyl, or is 1-bicyclo[2,2,1]hept-2-yl, 1-(7-oxa-bicyclo[2,2,1]hept-2-yl, 1-(5-exo-hydroxybicyclo[2,2,1]hept-2-exo-yl, 1-(5-exo-hydroxybicyclo[2,2,1]hepto-2-endo-yl, or is 1-adamantane-1-yl; R2 is lower alkyl; or R1 and R2 together with N atom form 8-oxa-3-aza-bicyclo[3,2,1]octane group, n is 0 or 1.

EFFECT: improved efficiency of treatment.

9 cl, 2 dwg, 15 ex

FIELD: chemistry.

SUBSTANCE: invention concerns benzothiazole derivatives of general formula (1) and their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands with high affinity to A2A adenosine receptor, and based medicine. Compounds can be applied in treatment and prevention of diseases mediated by A2A adenosine receptors, such as Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease. In general formula (I) , R is C5-C6-cycloalkyl non-substituted or substituted by hydroxy group, or is ethyl or isobutyl, or is tetrahydropyrane-4-yl or -(CH2)n-tetrahydrofurane-2 or 3-yl or is 5-hydroxybicyclo[2,2,1]hept-2-yl; X is CH or N; n is 0 or 1.

EFFECT: enhanced efficiency of composition and treatment method.

12 cl, 2 dwg, 14 ex

FIELD: chemistry.

SUBSTANCE: this invention refers to new compounds of formula (Ia) and to their pharmaceutically acceptable salts. Compounds of this invention are characterised by CB1 receptor antagonist properties. In formula (Ia) , R1 means phenyl independently mono-, di- or tri-substituted with haloid, (lower)alkoxy, (lower)alkyl, halogenated (lower)alkoxy or di(lower)alkylamino; R2 means phenyl, independently mono-, di- or tri-substituted with haloid, halogenated (lower)alkyl, nitro or cyano; R3 means hydrogen, nitro, amino, -NHSO2-R3a or -NHCO-R3b; R3a means (lower)alkyl, di(lower)alkylamino, benzyl, phenyl or phenyl monosubstituted with (lower)alkyl; R3b means benzyl or phenyl monosubstituted with (lower)alkyl.

EFFECT: application of compounds thereof as therapeutically active substance with CB1 receptor agonist properties and to relevant pharmaceutical composition.

18 cl, 1 dwg, 5 tbl, 70 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula II as neuropeptide FF receptor antagonist, their pharmaceutically acceptable acid-additive salts, medication based on them, as well as their application. Compounds can be applied for treatment and prevention of diseases mediated by activity of neuropeptide FF receptor, such as pain, hyperalgesia, enuresis, for elimination of syndromes arising in case of alcohol, psychotropic and nicotine addiction, for regulation of insulin release, digestion, memory functions, blood pressure or electrolytic and energy exchange. In general formula II , A together with thiazole ring forms 4,5,6,7-tetrahydrobenzothiazole, 5,6,7,8-tetrahydro-4H-cycloheptathiazole, 5,6-dihydro-4H-cyclopentathiazole fragments; R1 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tret-butyl, 1,1-dimethylpropyl or phenyl; R2-R6 each represents hydrogen or methyl.

EFFECT: obtaining solutions, which ca be used for treatment and prevention of diseases, mediated by activity of neuropeptide FF receptor.

6 cl, 4 tbl, 106 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole. Method involves the following successive steps: (i) interaction of bromine with 4-acetamidocyclohexanone an aqueous solution to yield 2-bromo-4-acetamidocyclohexanone; (ii) addition of thiourea to yield 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzothiazole; (iii) addition of hydrobromic acid an aqueous solution to yield 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole without isolation of 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzothiazole synthesized at stage (ii); (iv) isolation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole and if necessary separation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole isolated at stage (iv) for R-(+)- and S-(-)-enantiomers, and isolation of R-(+)- and/or S-(-)-enantiomer. 2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole is used for synthesis of pramipexole. Also, invention relates to a method for synthesis of pramipexole by synthesis of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole by using the method said and its conversion to pramipexole and if necessary by separation of pramipexole for its R-(+)- and S-(-)-enantiomers and isolation of R-(+)- and/or S-(-)-enantiomer.

EFFECT: improved method of synthesis.

15 cl, 1 sch, 3 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds that possess affinity for adenosine A2A-receptors and represent compounds of the general formula: wherein R1 and R2 represent independently hydrogen atom, lower alkyl, tetrahydropyrane-2,3- or 4-yl, -(CH2)n-O-lower alkyl, -C(O)-lower alkyl, -(CH2)n-C(O)-lower alkyl, -(CH2)n-C(O)-NR'R'', -(CH2)n-phenyl substituted optionally with lower alkyl, lower alkoxy-group or -(CH2)n-pyridinyl, -(CH2)n-tetrahydropyrane-2,3- or 4-yl, -C(O)-piperidine-1-yl; or R1 and R2 in common with nitrogen atom (N) to which they are added form the ring 2-oxa-5-azabicyclo[2,2,1]hept-5-yl; R3 represents lower alkoxy-group, phenyl substituted optionally with halogen atom, -(CH2)n-halogen or -(CH2)n-N(R')-(CH2)n+1-O-lower alkyl, or represents pyridinyl substituted optionally with lower alkyl, halogen atom or morpholinyl; n means 1 or 2; R'/R'' represent independently of one another hydrogen atom or lower alkyl, and their pharmaceutically acceptable acid-additive salt. Except for, invention relates to a medicinal agent showing affinity to adenosine A2A-receptors containing one or some compounds by any claims 1-11, and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of compounds and agents.

13 cl, 38 ex

FIELD: medicine.

SUBSTANCE: invention refers to compound of formula I wherein X represents -S- or -NH-; R1 represents C1-12alkyl, C2-12alkenyl, phenyl C1-12alkel, phenyl C2-12alkenyl or phenyl-O-C1-12alkyl and wherein said phenyl groups are optionally substituted with one or two assistants chosen from the group consisting of lower C1-7alkyl, C C1-7alkoxy and halogen C1-7alkyl; R2 represents hydrogen, lower C1-7alkyl or C3-6cycloalkyl; R3/R4 together with N-atom whereto attached, form nonaromatic 5,6-members heterocyclic ring system which optionally contains in addition to N-atom one additional heteroatom chosen from the group, consisting of O or N and where the ring system is optionally substituted group lower C1-7alkyl, lower C1-7alkoxy, -NR2, -CONR2; or R3/R4 together with N-atom whereto attached, can form heterocyclic ring system which contains at least two rings and which optionally contains one or two additional heteroatoms chosen from group, consisting of N and O; R represents hydrogen or lower C1-7alkyl; R5 represents hydrogen or lower C1-7alkyl; or to pharmaceutically acceptable additive salts with acid of this compound. The invention also concerns a medical product.

EFFECT: improved clinical effectiveness.

16 cl, 4 dwg, 3 tbl, 43 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treatment and prevention of diseases associated with activity of specified enzyme, such as diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension. In general formula (I) , R1 represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropyl methoxymethyl, 2-methyl thiazolyl, morpholinyl methyl or phenyl; R2 represents hydrogen, C1-4alkyl or phenyl; R3 represents hydrogen, C1-4alkyl or phenyl; R4 represents phenyl, naphthyl, thiophenyl, quinolyl or piperidyl where phenyl, naphthyl, thiophenyl, quinolyl and piperidyl are optionally substituted with one to three substitutes independently chosen of C1-4alkyl, halogen, C1-4alkoxy, cyano, trifluoromethyl, phenyl, phenyls C1-4alkyl, phenyloxy, oxasolyl and pyridinyl; R5 represents hydrogen, C1-4alkyl, phenyl-C1-4alkyl, C3-6dicloalkyl-C1-4alkyl or aminocarbonylC1-4alkyl.

EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

FIELD: chemistry.

SUBSTANCE: object of present invention is the following compounds: thiazol-2-ylamide 2-(3,4-dichlorophenoxy) hexanoic acid, 2-(4-fluorophenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-K-pyridin-2-ylhexaneamide, 2-(3,4-dichlorophenoxy)-4-methyl-N,3-thiazol-2-ylpentaneamide, 2-(1,1'-biphenyl-4-yloxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-isopropylphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(3-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, and others, named in the formula of invention. Present invention also relates to a pharmaceutical composition, which contains the invented compound as an active ingredient and use of compounds in preparing a medicinal agent which increases activity of glucose. The invention also pertains to a compound of formula (I) where G is -C(O)-; L1 is a direct bond, A is >N-, X is a direct bond, R1 is cyclohexyl, R3 is cyclohexyl, substituted with R34, R4 is hydrogen; R5 is thiazol-5-yl, substituted with R48.

EFFECT: obtaining compounds which can be used for preparing a medicinal agent which can be used for treating diseases caused by glucokinase deficiency, for preparing a medicinal agent for treating diseases where increased activity of glucokinase is favourable.

6 cl, 143 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing rosuvastatin calcium salt (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, which is useful as inhibitor of HMG-CoA-reductase. The method involves: a) acid hydrolysis of the acetal protective group in compound with formula ,

where A is an acetal or ketal protective group and R is (2-6C)alkyl, and separation of the obtained crystalline compound with formula ; b) possible recrystallisation of formula (8) compound; c) hydrolysis of the ester group in formula (8) compound, obtaining hydroxycarboxylate derivative (9) (where M is hydrogen or metal counter ion, different from calcium) or compound with formula (1); and , .

EFFECT: invention also relates to crystalline intermediate compounds with formulae 7, 8 and 10.

17 cl, 11 dwg

FIELD: chemistry.

SUBSTANCE: according to the invention the new hydrate and dehydrate polymorphic forms of calcium salt of bis-[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulphonyl)amino]-pyrimidin-5-yl](3R, 5S)-3, 5-dihydroxyhept-6-enoic acid general formula are proposed. They can be used for treatment of the diseases demanding of inhibition of the ferment HMG-CoA of 3-dihydroxy-3-methylglutaryl-coenzyme A-reductase), in particular such diseases as hyperlipedimia, hyperholesterinemia, atherosclerosis et al., and to the methods of preparation and application thereof. The crystalline hydrate form B of the said compound has the X-ray diffraction pattern on the powder obtained with the Cu-radiation source featured with the angles 2θ equal to 8.8, 13.1 and 21.5°. The crystalline dehydrate form B1 of the said compound has the X-ray diffraction pattern on the powder obtained with the Cu-radiation source characterised by the angles 2θ equal to 4.4, 7.7, 9.0 and 20.7°.

EFFECT: invention refers also to amorphous form.

16 cl, 4 dwg, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine derivatives with general formula (I), their tautomeric or stereoisomeric form, in free form, in form of pharmaceutically acceptable salt or C1-6alkyl ester which are effective antagonists of CRTH2 (G-protein-associated chemoattractant receptor, ex prone on Th2 cells) and can be used for preventing and treating diseases related to CRTH2 activity, particularly in treatment of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, diseases related to eosinophil. In formula (I) R1 is hydrogen, or in which n is an integer from 0 to 6; -Q1- is -NH-, -N(C1-6alkyl)- or -O; Y is hydrogen, C1-6alkyl, C3-6cycloalkyl, optionally substituted with C1-6alkyl, C3-6cycloalkyl, condensed with a benzene ring, phenyl, naphthyl or 5-6-member heteroaryl, possibly condensed with a benzene ring, and containing at least one heteroatom, chosen from a group consisting of oxygen and nitrogen, where the said phenyl, naphthyl or heteroaryl are optionally substituted on the displaceable position with one or several substitutes, chosen from a group consisting of cyano, halogen, nitro, guanidine, pyrroyl, sulfamoyl, phenyloxy, phenyl, di(C1-6)alkylamino, C1-6alkanoylamino, C1-6alkyl, optionally mono-, di- or tri-substituted with halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen and C1-6alkylthio, optionally mono-, di- or tri-substituted with halogen; or phenyl, condensed with 1,3-dioxolane; R2 is hydrogen or C1-6alkyl; R3 is a halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen, or , R3a and R3b are independently C3-8cycloalkyl or C1-6alkyl, this C1-6alkyl is optionally substituted with hydroxyl, carboxy, C3-6cycloalkylcarbamoyl, C5-6heterocyclocarbonyl containing a heteroatom in form of nitrogen, or C1-6alkoxy, q is an integer from 1 to 3; R3c is hydrogen, hydroxyl or carboxy; Xa is -O-; R4 is hydrogen, halogen, di(C1-6alkyl) amino or C1-6alkyl, optionally substituted C1-6alkoxy or mono- , di- or tri-substituted with halogen; R5 is hydrogen or C1-6alkyl; and R6 is carboxy, carboxamide, nitrile or tetrazolyl.

EFFECT: wider field of use of compounds.

32 cl, 9 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing calcium salt (E)-7[4(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid (rosuvastatin calcium salt), suitable for making a pharmaceutical drug, useful in treatment of, among others, hypercholesteremia, hyperlipoproteinemia and atherosclerosis. The method involves stages (a)-(g): a) reaction of (1-6C)alkyl ester (E)-(6-{2-[4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxin-4-yl)acetic acid in an organic solvent mixed with water with aqua acid at high temperature; b) reaction of the obtained solution with aqueous hydroxide of an alkali metal and, possibily, washing the obtained aqueous solution of salt of the alkali metal with a suitable organic solvent; c) bringing the pH of the obtained solution to approximately pH 9-10.5 by adding aqueous hydrochloric acid; d) removal of the organic solvent mixed with water; e) possible filtration of the obtained mixture; f) addition of water soluble calcium salt to the filtrate so that, calcium salt (E)-7[4(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(1R,5S)-3,5-dihydroxyhept-6-enoic acid is formed; and g) extraction of product of stage (f). The preferred organic solvent mixed with water is acetonitrile. Aqua acid on stage (a) is hydrochloric acid. Stage (b) involves reaction of the obtained solution with aqueous sodium hydroxide and washing the obtained aqueous solution of sodium salt with a suitable hydrocarbon, ester or ether solvent, for example, toluene, xylol, MTBE (methyl-tert-butyl ether) or ethyl acetate.

EFFECT: improved method.

FIELD: chemistry, medicine.

SUBSTANCE: invention refers to the new method for the preparation of the compound of following formula (S1): , including the reaction of disilyloxydiene of formula (II) with aldehyde of following formula (Q1): , in the presence of catalyst based on titanium (IV) of formula (IV) in the inert solvent with obtaining of 5(S)hydroxy-3-ketoester of formula (S1) where R1 is possibly substituted alkyl, cycloalkyl or aralkyl, and R2, R3, R4, R5, R6 and R7 independently represent hydrogen or halogen atoms, hydroxyl, possibly substituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaralkyl, possibly substituted alkoxy-, aryloxy-, aralkoxy-, heterocyclooxy or heteroaralkoxy groups; R8 represents lower alkyl; the binaphtyl radical has the S-configuration; R and R' independently represent lower alkyl. The reaction is carried out at the temperature range from 10 to 60°C, preferentially from 15 to 55°C. The invention refers also to the method for preparation of the 3(R), 5(S) dihydroxy ester of formula (V1), to the methods for preparation of the calcium salts of the following formula (W1) as well as to the method for preparation of the alkali metal salt of formula (X1).

EFFECT: new method for the preparation of the compound of formulas (S1), (V1), (W1) and (X1).

27 cl, 10 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention is related to derivatives of nitrosulfobenzamide of formula (I) , in which R1 - alkyl with 1 - 6 carbon atoms, R2 - alkyl with 1 - 6 carbon atoms; Q - is hydrogen or cation of alkaline metal, and also to method of their preparation by interaction of amine of formula NHR1R2 or its salt, with diacid of formula (III) or its salt, where Q1 and Q2 are identical or different and stand for hydrogen or alkali metal cation.

EFFECT: compounds according to the present invention may be useful for production of sulfonylureas and their precursors, such as for instance sulfochlorides or sulfonamides.

10 cl, 5 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: invention refers to new pyrimidine compounds of formula (I) with selective inhibition of "КДР" and "ФРФР" kinase. These compounds and their pharmaceutically acceptable salts are antiproliferative agents. In formula (I) , where R1 is chosen from series including -H, -(CH2)n -5-6-merous heterocycle containing 1-2 heteroatoms chosen from nitrogen, sulphur oxygen or dioxide, (C1-C6)alkyl, (C3-C6)cycloalkyl where n stands for 0, and each groups including heterocycle, alkyl, cycloalkyl is independently optionally substituted to three groups chosen from: -OR9, -COR10, -CO2R10, -CONR10R11 and -CN; R2 stands for -H or -OCH3; R3 stands for -H, -F or -OCH3; R4, R5 and R7 stand for -H, R6 means (C1-C6)alkyl or OR12; R8 stands for -H or -F; R9 stands for -H and (C1-C6)alkyl, (C1-C6)alkoxide R10 and R11 independently are chosen from -H and (C1-C6)alkyl, (C1-C6)alkoxy, and R12 stands for -H and (C1-C6)alkyl.

EFFECT: can be used for treating and preventing solid cancers, specifically breast, rectum, lung and prostate cancer.

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein Ar represents phenyl substituted with a group taken among isobutyl, benzoyl, isopropyl, styryl, pentyl, (2,6-dichlorophenyl)-amino-group, α-hydroxyethyl, α-hydroxybenzyl, α-methylbenzyl and α-hydroxy-α-methylbenzyl; R represents hydrogen atom; X means linear (C1-C6)-alkylene, (C4-C6)-alkenylene, (C4-C6)-alkynylene optionally substituted with group -CO2R3 wherein R3 means hydrogen atom, group (CH2)m-B-(CH2)n wherein B means oxygen atom; m = 0; n means a whole number 2; or B means group -CONH; m means a whole number 1; n means a whole number 2 and so on; R1 and R2 are taken independently among group comprising hydrogen atom, linear (C1-C4)-alkyl, hydroxy-(C2-C3)-alkyl and so on. Invention proposes a method for preparing compounds of the formula (I). Invention proposes inhibitors of C5-induced hemotaxis of polymorphonuclear leukocytes and monocytes representing (R)-2-arylpropionic acid omega-aminoalkylamides of the formula (I). Also, invention relates to a pharmaceutical composition possessing inhibitory activity with respect to hemotaxis of polymorphonuclear leukocytes and monocytes and comprising compounds of the formula (I) in mixture with suitable carrier. Proposes (R)-2-arylpropionic acid omega-alkylamides are useful for inhibition of hemotaxic activation induced C5a and other hemotaxic proteins.

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

18 cl, 3 tbl, 23 ex

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