Novel pyrimidine derivatives and their application in therapy, as well as application of pyrimidine derivatives in manufacturing medication for prevention and/or treatment of alzheimer's disease

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel pyrimidine derivatives or their pharmaceutically acceptable salts, possessing inhibiting activity with respect to glycogensintase kinase-3 (GSK3). In compound of formula I: R1 is selected from hydrogen, cyano, C1-3alogenoalkinyl, SO2NRbRc, C0-2alkyl(O)NRbRc, C1-4alkylNBbRc, SO2Ri, C(O)ORa, CH(OH)Rj and C(O)Rj; R2 and R4 are independently selected from hydrogen, halogeno, cyano, NO2, C1-4alkyl, C1-3ahalogenoalkyl, ORa, C(O)NRbRc, SO2Ri, and C(O)ORa; or R1 and R2 together with atoms, to which they are bound, are bound with formation of 5- or 6-member heterocyclic ring, which contains one S, any of the hydrogen atoms of group CH2 in said heterocyclic ring can be substituted by oxo, hydroxy, and sulphur atom in said heterocyclic ring is probably oxydised to -SO2-; R3 and R5 represent hydrogen; R6 represents tetrahydropyran; R7 is selected from hydrogen, C1-3alkyl, cyano and C1-3halogenoalkyl; R8 represents hydrogen; Ra is selected from C1-3alkyl and C1-3halogenoakryl. Other radicals are given in formula of invention.

EFFECT: compounds can be applied in manufacturing medication for prevention and/or treatment of predemential states, moderate cognitive failure and type II diabetes, Alzheimer's disease and Parkinson disease, as well as bone-associated malfunctions.

40 cl, 3 dwg, 1 tbl, 122 ex

 

The text descriptions are given in facsimile form.

1. The compound of the formula I

where R1selected from hydrogen, cyano, C1-3halogenoalkane, SO2NRbRc,
C0-2alkyls(O)NRbRcC1-4RbRc, SO2RiC(O)ORaCH(OH)Rjand C(O)Rj;
R2and R4independently selected from hydrogen, halogeno, cyano, NO2With1-4of alkyl, C1-3halogenoalkane, ORaC(O)NRbRc, SO2Riand C(O)ORa; or
R1and R2together with the atoms to which they are attached, are connected with the formation of 5 - or 6-membered heterocyclic ring containing one S and ubai of the hydrogen atoms of the groups CH 2in the specified heterocyclic ring may be substituted by oxo, hydroxy, and the sulfur atom in the specified heterocyclic ring may oxidized to the SO2-;
R3and R5represent hydrogen;
R6represents tetrahydropyran;
R7selected from hydrogen, C1-3of alkyl, cyano and C1-3halogenoalkane;
R8represents hydrogen;
R9independently selected from hydrogen, fluorescent;
Raselected from hydrogen, C1-3the alkyl and C1-3halogenoalkane;
Rband Rcindependently selected from hydrogen, C1-6of alkyl, 5-7 membered heterocyclyl having 1-2 heteroatoms in the ring selected from nitrogen and oxygen, where indicated With1-6alkyl and heterocyclyl possibly substituted by one or more1-4the alkyl, C1-4halogenoalkanes, halogeno, cyano, a group methanesulfonyl-, ORaor NRdRe; or
Rband Rctogether with the atom to which they are attached, may form a 4-7-membered mono - or bicyclic heterocyclic ring having 1-2 heteroatom selected from nitrogen and oxygen, which may be substituted by one or more than one halogen, hydroxy, di-(C1-4alkyl)amino, C1-6the alkyl or C1-3halogenoalkanes where specified With1-6alkyl or C1-3halogenoalkane possible dopolnitelnost one or more 1-3alkoxy or ora;
Rdand Reindependently selected from hydrogen, C1-6of alkyl; or
Rdand Retogether with the atom to which they are attached, may form a 5 - or 6-membered heterocyclic ring having 1-2 heteroatom selected from nitrogen or oxygen, which may be substituted by one or more than one halogen;
Riselected from C1-6the alkyl or 6-membered heterocyclic ring having one heteroatom of oxygen, where indicated With1-6alkyl possibly substituted by one di-(C1-4alkyl)amino or ora;
Rjrepresents a 6-membered heteroaryl ring having one nitrogen heteroatom;
in free base form or pharmaceutically acceptable salt.

2. The compound of formula Ib according to claim 1

where R1selected from hydrogen, cyano, C1-3halogenoalkane, SO2NRbRc,
C(O)NRbRcCH2NRbRc, SO2Riand C(O)Rj;
R2and R4independently selected from hydrogen, halogeno, cyano, NO2With1-3halogenoalkane, ORaC(O)NRbRcand SO2Ri,
R3and R5represent hydrogen;
R6represents tetrahydropyran;
R7selected from C1-3the alkyl and C1-3halogenoalkane;
R8is own the th hydrogen;
R9represents hydrogen or fluorescent;
Rarepresents a C1-3alkyl or C1-3halogenoalkane;
Rband Rcindependently selected from hydrogen and C1-6of alkyl, possibly substituted by one or more than one ORa; or
Rband Rctogether with the atom to which they are attached, may form a 4-, 5 - or 6-membered heterocyclic ring containing one or two heteroatoms selected from N or O, which may be substituted by one or more than one halogen or C1-3by alkyl;
Rirepresents a C1-3alkyl;
Rjrepresents a 6-membered heteroaryl ring having one nitrogen atom;
in free base form or pharmaceutically acceptable salt.

3. The compound according to claim 1, where
R1selected from hydrogen, cyano, C1-3halogenoalkane, SO2NRbRc,
With0-2alkyls(O)NRbRcWith1-4NRbRc, SO2RiC(O)ORaCH(OH)Rjand
C(O)Rj;
R2and R4independently selected from hydrogen, halogeno, cyano, NO2With1-4of alkyl, C1-3halogenoalkane, ORa, SO2RiC(O)NRbRcand C(O)ORa; or
R1and R2together with the atoms to which they are attached, are connected with the formation of 5-or 6-membered heterocyclic ring, terasawa one S, moreover, any of the hydrogen atoms of the groups CH2in the specified heterocyclic ring may be substituted with oxo, hydroxy or halogen, and any sulfur atom in the specified heterocyclic ring may oxidized to the SO2-;
R3and R5represent hydrogen;
R6represents tetrahydropyran;
R7selected from C1-3of alkyl, cyano and C1-3halogenoalkane;
R8represents hydrogen;
R9represents hydrogen or fluorescent;
Raselected from hydrogen, C1-3the alkyl and C1-3halogenoalkane where specified With1-3alkyl possibly substituted by one or more than one C1-3alkoxy;
Rband Rcindependently selected from hydrogen, C1-6the alkyl and a 5-7 membered heterocyclyl having 1-2 heteroatoms in the ring selected from nitrogen and oxygen, where indicated With1-6alkyl, heterocyclyl possibly substituted by one or more cyano, ORaor NRdRe; or
Rband Rctogether with the atom to which they are attached, can
to form a 4-7-membered mono - or bicyclic heterocyclic ring having 1-2 heteroatom selected from nitrogen and oxygen, which may be substituted by one or more than one halogen, hydroxy, di-(C1-4alkyl)amino, C1-6the alkyl or C1-3halogenoalkanes where specified With 1-6alkyl or C1-3halogenoalkane may additionally substituted by one or more than one C1-3alkoxy or ora;
Rdand Reindependently selected from C1-6of alkyl; or
Rdand Retogether with the atom to which they are attached, may form a 5 - or 6-membered heterocyclic ring having 1-2 heteroatom selected from nitrogen or oxygen, which may be substituted by one or more than one halogen;
Riselected from C1-6the alkyl or 6-membered heterocyclic ring having one heteroatom of oxygen, where indicated With1-6alkyl possibly substituted by one di-(C1-4alkyl)amino or ora,
Rjrepresents a 6-membered heteroaryl ring having one nitrogen heteroatom;
in free base form or pharmaceutically acceptable salt.

4. The compound according to any one of claims 1 to 3, where R7represents methyl or trifluoromethyl.

5. The compound according to any one of claims 1 to 4, where R4selected from hydrogen, halogeno, NO2C1-4of alkyl, C1-3halogenoalkane, ORa, SO2RiC(O)NRbRcC(O)ORa.

6. The compound according to claim 5, where R4represents C(O)NRbRcand where Rband Rcindependently selected from hydrogen and C1-6of alkyl, where specified With1-6alkyl possibly substituted by one or more the than one OR aand where Rarepresents a C1-3alkyl.

7. The compound according to claim 5, where R4represents trifluoromethyl.

8. The compound according to claim 5, where R4represents chloro.

9. The compound according to claim 5, where R3represents trifluoromethyl.

10. The compound according to any one of claims 1 to 5, where R2represents hydrogen, halogeno,1-3alkyl or ora.

11. The connection of claim 10, where R2represents chloro.

12. The connection of claim 10, where R1selected from hydrogen, cyano, C1-3halogenoalkane, SO2NRbRcC0-2alkyls(O)NRbRcC1-4NRbRc, SO2RiC(O)ORaCH(OH)Rjand C(O)Rj.

13. The connection section 12, where R1represents a C0-2alkyls(O)NRbRcand
Rband Rcindependently selected from hydrogen, C1-6of alkyl, 5-7 membered heterocyclyl having 1-2 heteroatoms in the ring selected from nitrogen and oxygen, where indicated With1-6alkyl and heterocyclyl possibly substituted by one or more1-4the alkyl, C1-4halogenoalkanes, halogeno, cyano, a group methanesulfonyl-, ORaor NRdReor
Rband Rctogether with the atom to which they are attached, may form a 4-7-membered mono - or bicyclic heterocyclic ring having 1-2 heteroatom is a, selected from nitrogen and oxygen, which may be substituted by one or more than one halogen, hydroxy, di-(C1-4alkyl)amino, C1-6the alkyl or C1-3halogenoalkanes where specified With1-6alkyl or C1-3halogenoalkane may be additionally substituted by one or more1-3alkoxy or ora.

14. The connection indicated in paragraph 13, where Rband Rctogether with the atom to which they are attached, form a 4-7-membered mono - or bicyclic heterocyclic ring having 1-2 heteroatom selected from nitrogen and oxygen, which may be substituted by one or more than one halogeno,1-6the alkyl or C1-3halogenoalkanes where specified With1-6alkyl or C1-3halogenoalkane may additionally substituted by one or more than one C1-3alkoxy or ora.

15. The connection 14, where the specified 4-7-membered mono - or bicyclic heterocyclic ring substituted stands.

16. The connection section 12, where R1represents a C1-4alkyl NRbRcand Rband Rctogether with the atom to which they are attached, form a 4-7-membered mono - or bicyclic heterocyclic ring having 1-2 heteroatom selected from nitrogen and oxygen.

17. The connection section 12, where R1represents the SO2Riand Rirepresents a C alkyl, where specified With1-6alkyl possibly substituted by one or more than one ORa.

18. The connection 17, where Rirepresents methyl.

19. The connection section 12, where R1represents the SO2NRbRcand Rband Rcindependently selected from hydrogen, C1-6of alkyl, 5-7 membered heterocyclyl having 1-2 heteroatoms in the ring selected from nitrogen and oxygen, where indicated With1-6alkyl and heterocyclyl possibly substituted by one or more1-4the alkyl, C1-4halogenoalkanes, halogeno, cyano, a group methanesulfonyl-, ORaor NRdRe; or
Rband Rctogether with the atom to which they are attached, may form a 4-7-membered mono - or bicyclic heterocyclic ring having 1-2 heteroatom selected from nitrogen and oxygen, which may be substituted by one or more than one halogen, hydroxy, di-(C1-4alkyl)amino, C1-6the alkyl or C1-3halogenoalkanes where specified With1-6alkyl or C1-3halogenoalkane may be additionally substituted by one or more1-3alkoxy or ora.

20. The connection according to claim 19, where Rband Rctogether with the atom to which they are attached, form a 4-7-membered mono - or bicyclic heterocyclic ring having 1-2 heteroatom selected from nitrogen and oxygen, which may be substituted by one or more than one halogeno,1-6the alkyl or C1-3halogenoalkanes.

21. Connection claim 20, where the aforementioned heterocyclic ring substituted C1-6the alkyl.

22. Connection item 21, where specified With1-6alkyl represents methyl.

23. The compound according to claim 1 or 2, which is selected from:
hydrochloride 5-fluoro-N-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
hydrochloride 5-fluoro-N-{3-methoxy-4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
hydrochloride 5-fluoro-N-[4-[(4-methylpiperazin-1-yl)carbonyl]-3-(methylsulphonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1N-imidazol-5-yl]pyrimidine-2-amine;
hydrochloride 5-fluoro-N-[4-[(4-methylpiperazin-1-yl)sulfonyl]-3-(triptoreline)phenyl]-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
hydrochloride 5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]-N-[4-(pyrrolidin-1-ylsulphonyl)phenyl]pyrimidine-2-amine;
hydrochloride 5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]-N-[4-(morpholine-4-ylsulphonyl)phenyl]pyrimidine-2-amine;
hydrochloride [4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-yl}amino)phenyl](pyridin-2-yl)methanone;
hydrochloride 5-fluoro-4-[2-methyl-1-(tetr the hydro-2H-Piran-4-yl)-1H-imidazol-5-yl]-N-[4-(piperidine-1-ylcarbonyl)phenyl]pyrimidine-2-amine;
hydrochloride 5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]-N-[4-(trifluoromethyl)phenyl]pyrimidine-2-amine;
hydrochloride 3-fluoro-N-[3-(methylsulphonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
hydrochloride 5-fluoro-N-[4-(methylsulphonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
hydrochloride 3-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-yl}amino)benzonitrile;
hydrochloride 4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-yl}amino)benzonitrile;
hydrochloride 5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]-N-[4-(piperazine-1-ylsulphonyl)phenyl]pyrimidine-2-amine and
hydrochloride 5-fluoro-N-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[1-(tetrahydro-2H-Piran-4-yl)-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidine-2-amine.

24. The compound according to claim 1 or 2, which is selected from:
N-{4-[(dimethylamino)methyl]phenyl}-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]-N-[4-(1-morpholine-4-retil)phenyl]pyrimidine-2-amine;
N-[4-(1-azetidin-1-retil)phenyl]-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]-N-[4-(2-morpholine-4-retil)phenyl]pyrimidine-2-amine;
[4-(metals hanil)phenyl]-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
N-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
N-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]-N-[4-(morpholine-4-ylmethyl)phenyl]pyrimidine-2-amine;
4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]-N-[4-(morpholine-4-ylsulphonyl)phenyl]pyrimidine-2-amine;
N-(4-{[4-(2-methoxyethyl)piperazine-1-yl]sulfonyl}phenyl)-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
N-{4-[(4-isopropylpiperazine-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]-N-[4-(pyrrolidin-1-ylsulphonyl)phenyl]pyrimidine-2-amine;
N-(1-methylpiperidin-4-yl)-4-({4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-yl}amino)benzosulfimide;
N-{4-[(4-methyl-14-diazepan-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
N,N-diethyl-4-({4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-yl}amino)benzosulfimide;
N-[4-(azetidin-1-ylsulphonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
N-{3-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidin-amine;
N-{3-chloro-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-
methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
N-{3-methyl-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
5-fluoro-N-(4-{[(3R)-3-methylmorpholin-4-yl]sulfonyl}phenyl)-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
5-fluoro-N-{3-methyl-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
5-fluoro-N-(4-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]sulfonyl}phenyl)-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-yl}amino)-N,N-dimethylbenzenesulfonamide;
N-[4-(azetidin-1-ylsulphonyl)phenyl]-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
ethyl-4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-yl}amino)benzoate;
N-[4-(azetidin-1-ylcarbonyl)phenyl]-5-fluoro-4-[1-(tetrahydro-2H-Piran-4-yl)-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidine-2-amine;
N-{3-chloro-4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
5-fluoro-N-{3-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
5-fluoro-N-[4-(doing propylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
N-[4-(ethylsulfonyl)phenyl]-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
5-fluoro-N-{4-[(2-methoxyethyl)sulfonyl]phenyl}-4-[2-methyl-1-tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
N-(4-{[2-(diethylamino)ethyl]sulfonyl}phenyl)-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
2-{[4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-yl}amino)phenyl]sulfonyl}ethanol;
{5-fluoro-4-[3-(tetrahydro-Piran-4-yl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-amine;
5-{5-fluoro-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenylamino]-pyrimidine-4-yl}-1-(tetrahydro-Piran-4-yl)-1H-imidazol-2-carbonitrile; and
{5-fluoro-4-[2-methyl-3-(tetrahydro-Piran-4-yl)-3H-imidazol-4-yl]-pyrimidine-2-yl}-[4-(tetrahydro-Piran-2-elmersolver)-phenyl]-amine.

25. The compound according to claim 1 or 2, which is selected from:
the hydrochloride of N-[4-(azetidin-1-ylcarbonyl)phenyl]-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
the hydrochloride of N-{4-[(3,3-diversecity-1-yl)carbonyl]phenyl}-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
hydrochloride 5-fluoro-N-[3-methyl-4-(morpholine-4-ylmethyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
hydrochloride 5-fluoro-N-{4-[(4-foreperiod-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(tetrahydro-2H-feast of the-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
hydrochloride 4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]amino-N-(3-methoxypropyl)benzamide;
hydrochloride [4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]AMINOPHENYL]-(1,4-oxazepan-4-yl)methanone;
hydrochloride (4-ethylpiperazin-1-yl)-[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]AMINOPHENYL]-methanone;
hydrochloride (2,6-dimethylmorpholine-4-yl)-[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]AMINOPHENYL]-methanone;
hydrochloride [4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]AMINOPHENYL]-(3-ftorpirimidinu-1-yl)-methanone;
hydrochloride (3,3-debtorprovidian-1-yl)-[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]AMINOPHENYL]-methanone;
hydrochloride 4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]amino-N-tetrahydropyran-4-yl-benzamide;
hydrochloride [4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]AMINOPHENYL]-(3-hydroxypyrrolidine-1-yl)-methanone;
hydrochloride N-(2-cyanoethyl)-4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]amino-N-methyl-benzamide;
the hydrochloride of N-ethyl-4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]amino-N-(2-hydroxyethyl)benzamide;
hydrochloride 4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-and the)-pyrimidine-2-yl]amino-N-(2-hydroxyethyl)-N-methyl-benzamide;
hydrochloride 4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]amino-N-(2-hydroxyethyl)benzamide;
hydrochloride N-(2-dimethylaminoethyl)-4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]amino-benzamide;
hydrochloride (4-dimethylamino-1-piperidyl)-[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]AMINOPHENYL]-methanone;
hydrochloride [4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]AMINOPHENYL]-[4-(2-methoxyethyl)piperazine-1-yl]-methanone;
hydrochloride 4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]amino-N-[2-(1-piperidyl)ethyl]benzamide;
hydrochloride 4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]amino-N-isopropyl-benzamide;
the hydrochloride of N-[2-(3,3-debtorprovidian-1-yl)ethyl]-4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]amino-benzamide;
hydrochloride [4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]AMINOPHENYL]-(4-isopropylpiperazine-1-yl)-methanone;
hydrochloride [4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]AMINOPHENYL]-(4-methyl-1,4-diazepan-1-yl)-methanone;
hydrochloride 4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]amino-N-tetrahydrofuran-3-yl-benzamide;
hydrochloride 5-fluoro-N-[3-(methylsulphonyl)-4-(morpholine-4-ylmethyl)f the Nile]-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
hydrochloride 5-fluoro-N-[4-(methylsulphonyl)-3-(trifluoromethyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine;
hydrochloride 1,1-dioxide 6-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-yl}amino)-2,3-dihydro-4H-thiochroman-4-it;
hydrochloride 1,1-dioxide 6-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-yl}amino)thiochroman-4-ol.

26. The compound according to claim 1 or 2, representing 4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]amino-N-methyl-benzamide.

27. The compound according to claim 1 or 2, a represents 5-fluoro-N-[4-(methylsulphonyl)phenyl]-4-[1-(tetrahydro-2H-Piran-4-yl)-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidine-2-amine.

28. The compound according to claim 1 or 2, representing 4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidine-2-yl]amino-N-(2-morpholinoethyl)benzamide.

29. The compound according to claim 1 or 2, representing [4-[5-fluoro-4-[3-tetrahydropyran-4-yl-2-(trifluoromethyl)imidazol-4-yl]-pyrimidine-2-yl]AMINOPHENYL]-(4-methylpiperazin-1-yl)-methanon.

30. The compound according to claim 1 or 2, a represents 5-fluoro-N-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-amine.

31. The compound according to claim 1 or 2, a represents 5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]-N-[4-(morpholine-4-ylmethyl)phenyl]pyrim the DIN-2-amine.

32. The compound according to claim 1 or 2, a represents N,N-diethyl-4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-Piran-4-yl)-1H-imidazol-5-yl]pyrimidine-2-yl}amino)benzamide.

33. The compound according to any one of claims 1 to 32 possessing inhibitory activity against the kinase-3 glikogensintetazy (GSK3).

34. The use of compounds according to any one of claims 1 to 32 in the manufacture of a medicinal product for the prevention and/or treatment of Alzheimer's disease and Parkinson's disease.

35. The application 34, where the disease is a disease of Alzheimer's.

36. The use of compounds according to any one of claims 1 to 32 in the manufacture of a medicinal product for the prevention and/or treatment predimensioned States, moderate cognitive failure and type II diabetes.

37. The use of compounds according to any one of claims 1 to 32 in the manufacture of a medicine for preventing and/or treating a chronic neurodegenerative diseases, bipolar disorder, schizophrenia and cognitive disorders.

38. The application of clause 37, where the disorder is a bipolar disorder.

39. The use of compounds according to any one of claims 1 to 32 in the manufacture of a medicinal product for the prevention and/or treatment of disorders related to bones.

40. Pharmaceutical composition having inhibitory activity against the kinase-3 glikogensintetazy (GSK3), the content is Asa as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 32, together with pharmaceutically acceptable excipients, carriers or diluents.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (11) given below and pharmaceutically acceptable salts thereof: chemical formula 1

in which: each of G1, G2, G3 and G8 independently denotes -N=, -CR1= or -C(-G9-X)=; one of G1, G2, G3 and G8 is-C(-G9-X)=; X is C1-6 alkyl (where C1-6 can be optionally substituted with a group selected from a halogen atom, hydroxy, cyano and -NR56R57), aryl, heterocycle (where the heterocycle denotes a 5-9-member saturated or unsaturated cyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulphur atoms, and can be a monocycle or condensed ring, and can be optionally substituted with a halogen atom, C1-6 alkyl; C1-6 alkoxy, R33R34NCS-, R3R4NCO-); G9 denotes a single bond, an oxygen atom, a sulphur atom, ring G6 denotes a divalent aryl group or divalent pyridyl group (where the divalent pyridyl group can be optionally substituted with a halogen atom); A is a group of formula (2) given below, or a group of formula (3) given below. Chemical formula 2

, chemical formula 3 , G4 is an oxygen atom or sulphur atom; G5 is an oxygen atom or sulphur atom; G7 is an oxygen atom, -CR42R43-, -CONR44-, -NR44CO, -NR45-, CR42R43NR45-, -S-, -NR44S(=O)2-; R1 is a hydrogen atom, a halogen atom, cyano, C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a halogen atom), carbamoyl or C2-7 alkynyl (where C2-7 alkynyl can be optionally substituted with C1-4 acyl); when G2 or G3 denotes -CR1=, then G8 is -C(-G9-X)=, and X is R3R4NCO-, R33R34NCS-; when G8 is -CR1=, then G3 denotes -C(-G9-X)=, and X is R3R4NCO, or R33R34NCS-; when G1 or G8 denotes -CR4 then G2 is -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; or when G2 is -CR1=, then G1 denotes -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; R1 can form a single bond or -CH2- with R4 or R34; R2 denotes hydroxy or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from a halogen atom, hydroxy, C1-6 alkoxy, formyl and -CO2R50); R3, R4, R9 and R10 each independently denotes a hydrogen atom, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, a halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R6 and R7 each independently denotes a hydrogen atom, C1-6 alkoxy, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R33 and R34 each independently denotes a hydrogen atom, C1-6 alkyl, the combination of R3 and R4 together with a nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom or C1-6 alkyl; the combination of R6 and R7 together with the nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom, C1-6 alkyl or an oxo group; R45 is a hydrogen atom, R13 and R14 each independently denotes a hydrogen atom, C1-6 alkyl or COR32; R56 and R57 each independently denotes a hydrogen atom or C1-6 alkyl, and R5, R8, R28, R29, R32, R42, R43, R44, and R50 each independently denotes a hydrogen atom or C1-6 alkyl. The invention also relates to a pharmaceutical composition, as well as to a medicinal agent for treating cell proliferative disorder.

EFFECT: obtaining novel biologically active compounds having inhibitory effect on cell proliferation.

15 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 5-nitrofuran derivatives of formula I: where R=piperidino, pyrrolidineo, diethylamino, morpholino.

EFFECT: presented preparation of new biologically active compounds which exhibit antimicrobial activity.

1 cl, 4 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of general formula ii-d and to their pharmaceutically acceptable salts. In formula ii-d: , R2 represents C1-3-alkyl or cyclopropyl; R5 represents CH2CH3, CH2CF3, CH2CH2CF3, or Ry represents or Jl represents hydrogen atom or CH3J2 represents C1-4-alkyl; and Cy represents C3-5-cycloalkyl.

EFFECT: production of new compounds of general formula ii-d and their pharmaceutically acceptable salts which exhibit properties of an Aurora-protein kinase activity inhibitor and can be used in treating proliferative disorders.

12 cl, 8 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 3-(1,3-oxazol-4-yl)pyridin-2(1H)-one derivatives of general formula 1, , where 1a R=Br, R'=CH2OCH3, R"=CH3; 1b R=H, R'=CH2, R"=CH3; 1c R=H, R1=CH2OCH3, R"=Ph; 1d R=H, R'=CH3, R"=Ph; 1e R=Br, R=CH3, R" - fur-2-yl, which can be used as potential biologically active substances and intermediate products for synthesis of novel heterocyclic systems. The method of producing 3 -(2-substituted-1,3 -oxazol-4-yl)pyridin-2( 1 H)-ones of general formula I involves formation of a heterocyclic system of 3-(1,3-oxazol-4-yl)pyridin-2(1H)-one as a result of base-catalysed regrouping of 3-acylamino-2-furfurylfuro[2,3-b]pyridines while boiling said compounds in ethanol for 4-20 hours with addition of 6-7 mmol of potassium hydroxide per 1 mol of the initial 3-acylamino-2-furfurylfuro[2,3-b]pyridine.

EFFECT: high yield.

1 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A is a monocyclic or polycyclic aryl or heteroaryl group, where the heteroaryl radical denotes a 5-10-member cyclic system containing at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N; optionally substituted with one or more substitutes independently selected from a group comprising halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, C1-4alkoxy and a hydroxyl group; B is a monocyclic nitrogen-containing heteroaryl group, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from S and N; optionally substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, aryl and C1-8alkylthio; either a) R1 is a group of formula: -L-(CR'R")n-G, where L is a binding group selected from a group consisting of a direct bond, -(CO)-, -(CO)NR'- and -SO2-; R' and R" is independently selected from hydrogen atoms; n assumes values from 0 to 1; and G is selected from a group consisting of a hydrogen atom and C1-4alkyl, aryl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O, S and N; C3-8cycloalkyl and saturated heterocyclic groups, where heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one or two carbon atoms are substituted with a N heteroatom; where alkyl, C3-8cycloalkyl, aryl or heteroaryl groups are unsubstituted or substituted with one or more substitutes selected from halogen atoms; and R2 is a group selected from hydrogen atoms, halogen atoms and C1-4alkyl, C2-5alkynyl, C1-4alkoxy, -NH2 and cyano groups, where alkyl and alkynyl groups may be unsubstituted or substituted with one aryl group; or b) R2, R1 and -NH- group to which R1 is bonded form a group selected from groups of formulae and , where: Ra is selected from a hydrogen atom or groups selected from C1-4alkyl, C3-8cycloalkyl, aryl, aryl-C1-4alkyl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O and N; saturated heterocyclic rings, where the heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one carbon atom is substituted with a heteroatom selected from O and N; and C1-4alkylthio; where the aryl or heteroaryl groups are unsubstituted or substituted with one or more groups selected from halogen atoms, cyano group, trifluoromethoxy and carbamoyl; Rb denotes hydrogen; and pharmaceutically acceptable salts thereof and N-oxides; provided that the compound is not selected from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]formamide. The invention also relates to a pharmaceutical composition, use of compounds in any of claims 1-20, a method of treating a subject, as well as a composite product.

EFFECT: obtaining novel biologically active compounds having adenosine A2B receptor antagonist activity.

27 cl, 160 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-quinolyloxazoles of formula (I) or pharmaceutically acceptable salts thereof, having PDE4 inhibiting properties, a pharmaceutical composition based on said compounds and use thereof to prepare a medicinal agent which inhibits inflammatory cell recruitment in respiratory tracts. , where is , X is O, R1 is alkyl, R3 and R4 are independently selected from H, R5 and R6 are independently selected from a group comprising H, alkyl, hydroxyalkyl, t equals 1 or 2. Values of substitutes R7-R11, R13 are given in the formula of invention.

EFFECT: high efficiency of using the composition.

24 cl, 1 dwg, 64 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates or tautomers thereof, where substitute M is selected from groups D1 and D2, having structural formulae given below, and R1, E, A and X are as described in the formula of invention. Disclosed also are pharmaceutical compositions which contain these compounds, methods for synthesis of these compounds, intermediate compounds and synthesis methods thereof, as well as use of compounds of formula (I) in preventing or treating diseases mediated by CDK kinases, GSK-3 kinases or Aurora kinases.

EFFECT: high effectiveness of the compounds.

40 cl, 8 dwg, 18 tbl, 84 ex

Aromatic compound // 2416608

FIELD: chemistry.

SUBSTANCE: invention describes a novel compound of general formula (1), where radicals R1, R2, X1, Y and A are as described in claim 1 of the invention. The invention also describes a method of obtaining compounds of formula (1), as well as a pharmaceutical composition based on said compounds, for treating fibrosis.

EFFECT: novel compounds with excellent collagen formation suppression, cause fewer side-effects and which are safer are obtained.

62 cl, 2717 ex, 432 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds described by formula in which radical and symbol values are specified in the patent claim, and their pharmaceutically acceptable salts. These compounds inhibit tompomyosine-related kinases (Trk), and can find application in treating a malignant growth, such as breast cancer, rectal cancer and prostate cancer. Also, the invention relates to a method for producing these compounds, a based pharmaceutical composition and to methods of application thereof.

EFFECT: preparation of the pharmaceutical composition which can find application in treating a malignant growth.

18 cl, 134 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described 3,4-substituted piperidines applicable in diagnostics and drug therapy of a warm-blooded animal, preferentially for therapy of a disease which depends on renin activity; application of a compound of such kind for preparing a pharmaceutical composition for therapy of the disease which depends on renin activity; application of the compound of such kind for therapy of the disease which depends on renin activity; the pharmaceutical compositions containing 3,4-substituted piperidine, and/or a therapeutic mode involving administration of 3,4-substituted piperidine, a method for producing 3,4-substituted piperidine. The preferential compound (which also can be presented in the form of salts) are described by formula I' wherein R1, R2, T, R3 and R4 are such as described by the patent claim.

EFFECT: production of the compounds for therapy of the disease which depends on renin activity.

28 cl, 1 tbl, 375 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to medication, possessing antioxidant, cardioprotective, antidiabetic, anti-inflammatory, hepatoprotective, antitumoral and antiviral action. Medication, which has antioxidant, cardioprotective, antidiabetic, anti-inflammatory, hepatoprotective, antitumoral and antiviral action, representing luteolin 7,3'-disulphate, is obtained from water-ethanol extract of sea grass of family Zosteraceae.

EFFECT: medication has efficient antioxidant, cardioprotective, antidiabetic, anti-inflammatory, hepatoprotective, antitumoral and antiviral action.

4 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to hematology and cardiology, and can be used for reduction of spontaneous erythrocyte aggregation in case of arterial hypertension with abdominal obesity. For this purpose at the background of hypocaloric diet, dosed static and dynamic physical exercise and daily swimming for not less than 30 minutes per day in the middle of the day lisinopril and metformin are introduced. Physical exercise includes morning hygienic gymnastics, therapeutic and preventive gymnastics, dosed physical exercised throughout the day. Lisinopril is introduced in dose 10 mg 1 time per day in the morning. Metformin is introduced in dose 500 mg 2 times per day. Treatment is carried out for 2 months.

EFFECT: method makes it possible to normalise spontaneous erythrocyte aggregation during 2 months, bringing it to the level close to that of healthy people, thus favouring prevention of vascular complications in patients with arterial hypertension with abdominal obesity.

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to bis[3-(4-chlorophenyl)-1-(4-methylphenyl)carboxamido-1,3-propanedionato]oxovanadium of formula: . The compound has hypoglycemic and antihypoxic activity.

EFFECT: obtaining a compound having high hypoglycaemic and antihypoxic activity and low toxicity.

1 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology and endocrinology, and can be used for decreasing spontaneous erythrocyte aggregation in impaired glucose tolerance. That is ensured by introduction of metformin with underlying graduated static and dynamic physical exercises and daily swimming for at least 40 minutes a day in the middle of day. Physical exercises include morning hygienic gymnastics, therapeutic exercises, graduated physical exercises during the day. Metformin 500 mg is introduced 2 times a day. The therapy is carries out for 1.5 months.

EFFECT: method allows normalising spontaneous erythrocyte aggregation for 1,5 months, approaching a level close to such in healthy people, thereby promoting prevention of vascular complications in patients with impaired glucose tolerance.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an ester presented by formula [2] where R1' represents 1) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, or 2) -CO-C1-C6 alkoxy; R2' represents 1) hydrogen or 2) C1-C6 alkyl, R3', R4' and R5' are identical or different, and each represents 1) hydrogen, 2) halogen, 3) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, 4) C1-C6 alkoxy, 5) -COR13' where R13' represents (a) hydroxy, (b) C1-C6 alkyl, (c) C1-C6 alkoxy which is optionally substituted by one or more identical or different substitutes selected from (1) hydroxy, (2) C1-C6 alkoxy which is optionally substituted by phenyl, (3) -NR11'CO-C1-C6 alkyl where R11' represents hydrogen, (4) -CONR8'R9' where R8' and R9' are identical or different, and each represents C1-C6 alkyl, (5) -CO- C1-C6 alkoxy optionally substituted by phenyl, (6) phenyl optionally substituted by one or more identical or different substitutes selected from halogen, C1-C6 alkoxy and -CO-C1-C6 alkoxy, and (7) a heterocycle selected from pyridyl, thienyl and which all can be substituted by one or more identical or different C1-C6 alkyl groups, or (d) -OR19' where R19' represents a group or a group or piperidyl which is optionally substituted by -CO-C1-C6alkyl, 6) a heterocycle selected from oxadiazolyl and tetrazolyl, and said heterocycle is optionally substituted by C1-C6 alkyl optionally substituted by one or more identical or different substitutes selected from -CONR8'R9' (R8' and R9' have the same values as defined above) and -CO-aralkyloxy, or 7) nitrile; R6' and R7' are identical or different, and each represents 1) C1-C6 alkyl or 2) a nitrogen-containing 5 or 6-members saturated heterocycle containing a monocycle formed when R6', R7' and a neighbouring nitrogen atom are taken together, and optionally including oxygen as a heteroatom; Y1, Y2, Y3 are identical or different, and represent, 1) all carbon atoms, or 2) one of Y1, Y2, Y3 represent a nitrogen atom, and the others are carbon atoms; Y4 represent a carbon or nitrogen atom ;-X- represents 1) -(CH2)1 where 1 represents an integer 1 to 3, 2) -CH2-NR18'-CH2- where R18' represents C1-C6 alkyl, or 3) or to its pharmaceutically acceptable salt.

EFFECT: compounds presented by formula are effective as agents for treatment or prevention hyperlipidemia, arteriosclerosis, coronary artery disease, obesity, diabetes and hypertension or similar diseases since they are withdrawn very quickly and exhibit excellent MTP inhibitory activity.

23 cl, 32 tbl, 137 ex

FIELD: medicine.

SUBSTANCE: present invention refers to medicine, namely to therapy and endocrinology, and can be used for glucose level correction by gluconeogenesis optimisation in a body. That is ensured by introduction of a daily dietary intake with a carbohydrate quota reduced to 150-100 g and the content of glucogenic amino acids increased to 20000-40000 mg 2-3 times a week. Said dietary intake is prescribed after intensive physical exercises allowing to lose 2000-3000 kcal/day. Such loads are carried out in the form accessible to a specific person as jogging, swimming, football, volleyball or work in the garden.

EFFECT: method provides a protein-glucogenic diet stimulating gluconeogenesis enzyme development by a liver.

3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention aims at improving pharmacological activity of an antidiabetic composition. Said technical effect is ensured by the fact that there is offered a polypharmaceutical herbal tea which contains herbs comprising vitamins and digestible sugars and metabolism-regulation plants. The tea contains: goat's rue (Galega) herb, European walnut leaf, knotgrass herb, dense mullein blossom, dandelion root, tillet blossom, white mulberry leaf, horseheal root, cowberry leaf, bean valves, common periwinkle leaf, common argimony herb in various proportions. The offered composition can be presented in the form of phyto tea in filter bags 2.0 g.

EFFECT: administration of said preparation allows reducing doses of antidiabetic preparations.

2 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology and angiologia, and can be used for optimising vascular wall activity in patients with degree I-II arterial hypertension (AH) associating metabolic syndrome (MS) suffered eye vessel thrombosis. That is ensured by introduction of the preparations pioglitazone and amlodipine with underlying an individually prescribed hypocaloric diet and graduated physical exercises. The hypocaloric diet is calculated in kcal by formula: for women of 18-30 years old - (0.0621 × body weight, kg + 2.0357) × 240, of 31-60 years old - (0.342 × body weight, kg + 3.5377) × 240, over 60 years old - (0.0377 × body weight, kg + 2.7545) × 240, for men of 18-30 years old - (0.0630 × body weight, kg + 2.8957) × 240, of 31-60 years old - (0.0484 × body weight, kg + 3.6534) × 240; over 60 years old - (0.0491 × body weight, kg + 2.4587) × 240. The graduated physical exercises represent morning hygienic gymnastics, therapeutic exercises and graduated physical exercises throughout a day. The preparations pioglitazone 30 mg and amlodipine 10 mg are introduced once a day in the same time. The therapy is performed for 4 months.

EFFECT: method provides correction of reduced vascular wall function in the patients with degree I-II AH associating MS suffered eye vessel thrombosis for 4 months and allows avoiding vascular complications in such patients.

1 dwg, 1 tbl, 2 ex

FIELD: veterinary science.

SUBSTANCE: invention refers to a composition including alginate containing high concentration of mannuronic acid and a polycation of a polydispersity index less than 1.5. The composition is especially suitable for manufacturing of biologically compatible microcapsules containing live cells for allo- or xenografting.

EFFECT: microcapsules are more durable and can keep their structural and functional integrity for a long period of time as compared with common alginate microcapsules.

57 cl, 2 ex, 6 tbl

FIELD: medicine.

SUBSTANCE: invention relates to complex immunomodelling treatment of patients with chronic heart failure (CHF). For this purpose to patients with CHF of II-IV functional classes according to NYHA and LV ejection fraction less than 45% at the background of conventional complex therapy, which includes application of diuretics, vasodilatators, cardiac glycosides, inhibitors of angiotensin-converting enzyme, additionally introduced is carvedilol in dose 12.5-50 mg/day. Introduction is performed in two intakes in equal parts for 12 months.

EFFECT: reduction of cytokine activity and syndrome correction of secondary immunodeficiency, which reduces severity of tissue affection and improves microcirculation and central hemodynamics, reduction of CHF severity and prevention of heart remodeling in said group of patients.

2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: what is offered is a monoclonal antibody which binds with Aβ Globulomer containing CDRs of a heavy and light chain. There are described: composition for diagnosing Alzheimer's disease, and also a composition and an antibody-based vaccine for preventing or treating Alzheimer's disease. What is disclosed is application of the antibody for preparing a drug for the intended application stated above. There are described: versions of a diagnostic technique for Alzheimer's disease, an antibody-based diagnostic kit for Alzheimer's disease.

EFFECT: use of the invention provides new Aβ Globulomer antibodies which are detected more selectively than common antibodies.

16 cl, 10 dwg, 5 tbl, 6 ex

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