Antagonists of peptide receptor fixed with calcitonin gene

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 ex

 

The text descriptions are given in facsimile form.

1. The compound of formula (I)

and its pharmaceutically acceptable salt or MES,

where V represents-N(R1)(R2or OR4;/p>

R4represents H, C1-6alkyl, C1-6halogenated or (C1-6alkylen)0-1R4'

R4' represents a C3-7cycloalkyl, phenyl, pyridyl, piperidinyl and R4' is optionally substituted by 1 or 2 identical or different substituents selected from the group consisting of C1-4of alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and

R1and R2each independently represents L1where L1selected from the group consisting of H, C1-6of alkyl, C2-6alkenyl,2-6the quinil-adamantyl, pyrrolidinyl, pyridyl, or

R1and R2together with the nitrogen atom to which they are attached form X,

where X represents pyrrolidinyl, piperazinil, piperidinyl, morpholino;

where X is optionally substituted by Y, where Y is DIOXOLANYL,1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, piperidinyl;

and where X and Y are not necessarily broken Z, where Z represents a-C1-3alkylene-, -C1-3alkylene-; and

Y is optionally and independently substituted by 1 Deputy selected from the group consisting of C1-4of alkyl, amino, C1-3alkylamino, -C1-6alkylamino(C1-3alkyl)2;

X and Y are not necessarily independent, what about contain 1 or 2 carbonyl, where the carbon atom of the indicated carbonyl is a member heterocycles containing X and Y;

provided that if X is replaced by Y, and

if X and Y are not torn Z, then

X and Y are not necessarily attached to a single carbon atom and together form spiritlessly balance;

Q is a Q' or Q";

where Q' is a (Sy)sR3and

Q" is NH(Sy)sR3, NHC(O)O(Sy)sR3, NHC(O)O(Sy)sR3or NHC(O)NH(Sy)sR3;

where Syrepresents a C1-3alkylene and s is 0 or 1;

U represents CH2or NH;

provided that if Q is a Q, then U represents CH2;

R3is an R3a,

where R3arepresents a

(i) a heterocycle having two condensed rings containing from 5 to 6 members in each of these rings, said heterocycle containing one to three identical or different heteroatoms selected from the group consisting of O, N and S, said heterocycle, optionally containing 1 carbonyl, where the carbon atom of the indicated carbonyl is a member of these condensed rings;

(ii) a 5-6 membered heterocycle containing from one of the three identical or different heteroatoms, selected from the group consisting of O, N and S, optionally containing 1 carbonyl, where the carbon atom of the indicated carbonyl is a member of the specified 5-6-membered heterocycle;

(iii)3-7cycloalkyl;

(iv) carbazolyl, phenyl, -O-phenyl, or naphthyl;

or

(v)1-8alkyl; and

where R3ais optionally substituted from 1 to 3 identical or different substituents selected from the group consisting of benzyl, phenyl, -O-phenyl, -O-C1-3alcelaphinae, -C1-3alkylene-OC(O)-phenyl, amino, nitro, halogen, C1-6of alkyl, C1-3mono-bi-tri-halogenoalkane, C1-3mono-bi-tri-halogenations, -OR, -C(O)R3', -C(O)O-R3' and-SO2R3';

R3' represents H or-C1-6alkyl;

provided that if R3' represents-C(O)R3' or-C(O)O-R3'then the specified-C(O)R3' or-C(O)O-R3' are unsubstituted;

D represents O;

And represents CH;

m and n independently have a value of 1;

E represents N or C;

p is 0 or 1;

if R is set to 1

then G, J and E together form Axor Andy;

Andxrepresents a condensed heterocycle having two fused rings containing from 5 to 6 members which each of these rings, specified heterocycle, containing from one to two identical or different heteroatoms selected from the group consisting of O, N; and

optional carbonyl containing 1, where the carbon atom of the indicated carbonyl is a member of the specified condensed heterocycle;

Andyis a 5-6-membered heterocycle containing one to three heteroatoms selected from the group consisting of O, N; and

optional carbonyl containing 1, where the carbon atom of the indicated carbonyl is a member of the specified 5-6-membered heterocycle;

where axand Ayare optionally substituted by phenyl; or when p is 0 such that C and J each is prisoedinim to a, then a is a C, and G, J and a together form spirocyclic ring system with the specified rings of said system containing a and where G, J and a together are GJA' or GJA";

where GJA' represents Andxor Ay; and

GJA represents Andxor Andyprovided that

Andxdoes not represent a 1,3-discontinously a heterocycle and

Aydoes not represent a 1,3-datagathering;

and, in addition, provided that

if Q is a Q, then R3is an R3a; and

the EU is and Q is a Q', then

R3is an R3a,

R has the value 0 and G, J and a together form GJA".

2. The compound according to claim 1, where Q is a Q'.

3. The compound according to claim 1, where Q is a Q', R3is an R3aand p is 0 provided that G, J and a together form GJA".

4. The compound according to claim 2 or 3, where Q is a Q' and U represents CH2.

5. The compound according to claim 2 or 3, where Q is a Q' and U represents NH.

6. The compound according to claim 1, where Q is a Q".

7. The connection according to claim 6, where Q" is NH(Sy)sR3.

8. The connection according to claim 6, where Q" is NHC(O)(Sy)sR3.

9. The connection according to claim 6, where Q" is NHC(O)O(Sy)sR3.

10. The connection according to claim 6, where Q" is NHC(O)NHC(Sy)sR3.

11. The compound according to claim 1, where V is a OR4.

12. The compound according to claim 1, where V represents-N(R1)(R2).

13. The compound according to claim 1, where R4represents H, C1-6alkyl or (C1-3alkylen)0-1R4' and R4' represents a C3-7cycloalkyl.

14. The compound according to claim 1, where V represents-N(R1)(R2and R1and R2each independently represents L1where L1selected from the group consisting the th of H, C1-6of alkyl, adamantyl, pyrrolidinyl, pyridyl; or

R1and R2together with the nitrogen atom to which they are attached form X,

where X represents pyrrolidinyl, piperazinil, piperidinyl, morpholino;

where X is replaced by Y, where Y is DIOXOLANYL,1-4alkyl, phenyl, pyrrolyl, pyridyl, piperidinyl;

and where X and Y are not necessarily attached to a single carbon atom and together form spiritlessly the rest.

15. The compound according to claim 1, where V represents-N(R1)(R2and R1and R2each independently represents L1where L1selected from the group consisting of H, C1-6the alkyl or

R1and R2together with the nitrogen atom to which they are attached form X, where X represents piperidinyl;

where X is replaced by Y, where Y is DIOXOLANYL,1-4alkyl or piperidinyl;

and where X and Y are not necessarily attached to a single carbon atom and together form spiritlessly the rest.

16. The compound according to claim 1, where V represents-N(R1)(R2and where R1and R2each independently represents L1where L1selected from the group consisting of H, C1-6the alkyl.

17. The compound according to claim 1, where V represents-N(R1)(R2and RG is R 1and R2together with the nitrogen atom to which they are attached form X, where X represents piperidinyl;

where X is replaced by Y, where Y is DIOXOLANYL,1-4alkyl or piperidinyl;

and where X and Y are not necessarily attached to a single carbon atom and together form spiritlessly the rest.

18. The compound according to claim 1, where V represents-N(R1)(R2and where R1and R2together with the nitrogen atom to which they are attached form X, where X represents piperidinyl;

where X is replaced by Y, where Y represents piperidinyl.

19. The compound according to claim 1, where V represents-N(R1)(R2and where R1and R2together with the nitrogen atom to which they are attached form X, where X represents morpholino;

where X is replaced by Y, where Y represents a C1-4alkyl.

20. The compound according to claim 1, where V represents-N(R1)(R2and where R1and R2together with the nitrogen atom to which they are attached form X, where X represents piperidinyl;

where X is replaced by Y, where Y represents a C1-4alkyl.

21. The compound according to claim 1, where V represents-N(R1)(R2and where

R1and R2together with the nitrogen atom to which they are attached, the image is t X,

where X represents piperidinyl;

where X is replaced by Y, where Y is DIOXOLANYL;

and where X and Y are attached to one carbon atom and together form spiritlessly the rest.

22. The compound according to claim 1, where R3is an R3aand R3arepresents a substituted or unsubstituted phenyl, hydroxyphenyl, naphthyl, C1-6alkyl, dihydroquinoline, hydroxynonenal, chinoline, dihydroisoquinoline, hydroisoquinoline, ethenolysis, dihydroquinazolines, hydrogenation, hintline, dihydroquinoxaline, hydroxyechinenone, honokalani, benzimidazolyl, indazoles, dihydrobenzofuranyl, hydroengineering, benzimidazolinyl, dihydrobenzofuranyl, hydrobiostation, benzothiazolyl, dihydroisoxazole, benzotriazolyl, dihydrobenzofuranyl, hydrosensation, benzothiazyl, dihydrobenzofuranyl, heroesofwarmone, benzofuranyl, benzodioxolyl, dihydroindolone, gerontology, indolyl, indolizinyl, isoindolyl, indolinyl, indazoles, pyrazolyl, pyrazolyl, pyrazolidine, furanyl, thienyl, pyrrolyl, pyrrolidyl, pyrrolidinyl, imidazolyl, imidazolyl, imidazolidinyl, pyridyl, purinol, carbazolyl, pyrimidinyl, piperidinyl, triazolopyrimidines, tetrahydropyrimidines, piperazinil or morphol the but.

23. The compound according to claim 1, where D represents O and m and n each is 1.

24. The compound according to claim 1, where R has a value of 1, and G, J and E together form Axor Andy.

25. The compound according to claim 1, where p is 0 such that G and J each is attached to a, then a is a C and G, J and a together form spirocyclic ring system with the specified rings of said system containing a and where G, J and a together are GJA' or GJA".

26. The compound according to claim 1, where p is 0 such that G and J each is attached to a, then a is a C and G, J and a together form spirocyclic ring system with the specified rings of said system containing a and where G, J and a together are GJA'.

27. The compound according to claim 1, where p is 0 such that G and J each is attached to a, then a is a C and G, J and a together form spirocyclic ring system with the specified rings of said system containing a and where G, J and a together are GJA".

28. The compound according to claim 1, where p is 0 such that G and J each is prisoedinim to a, then G, J and a together form spirocyclic ring system with the specified rings of said system containing a and where G, J and a together form a heterocycle selected from the group consisting of the z imidazolinone, imidazolidinone, dihydroquinoline, dihydroisoquinoline, dihydroquinazolines, dihydroquinoxaline, dihydroisoxazole, hydrobenzoin, dihydroisoquinolyl, dihydrobenzofuranyl, dehydrobenzperidol, dihydrobenzofuranyl, dihydroindolone, indolinyl, pyrazoline, pyrazolidine, pyrrolidine, pyrrolidine, imidazoline, imidazolidine, piperidine, piperazinil, morpholino.

29. A compound selected from the group consisting of

(±)-3-(1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-carbonyl]-amino}propionic acid;

(R)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[2-[1,4']bipyridinyl-1'-yl-1-(1H-indazol-5-ylmethyl)-2-oxoethyl]-amide;

(±)-4-(2-oxo-2,3-dihydrobenzoic-1-yl)-piperidine-1-carboxylic acid

[2-[1,4']bipyridinyl-1'-yl-1-(1H-indol-5-ylmethyl)-2-oxoethyl]-amide;

(±)-4-(2-oxo-2,3-dihydrobenzoic-1-yl)-piperidine-1-carboxylic acid

[2-[1,4']bipyridinyl-1'-yl-1-(1H-indazol-5-ylmethyl)-2-oxoethyl]-amide;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[2-[1,4']bipyridinyl-1'-yl-1-(1H-indol-5-ylmethyl)-2-oxoethyl]-amide;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[2-1,4']bipyridinyl-1'-yl-1-(1H-indazol-5-ylmethyl)-2-oxoethyl]-amide;

(±)-4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid

[1-(1H-indol-5-ylmethyl)-2-(4-isobutylpyrazine-1-yl)-2-oxoethyl]-amide;

(±)-4-(2-oxo-2,3-dihydrobenzoic-1-yl)-piperidine-1-carboxylic acid

[2-(1,4-dioxa-8-Aza-Spiro[4.5]Dec-8-yl)-1-(1H-indol-5-ylmethyl)-2-oxoethyl]-amide;

(±)-4-(2-oxo-2,3-dihydrobenzoic-1-yl)-piperidine-1-carboxylic acid

[1-(1H-indazol-5-ylmethyl)-2-(4-isobutylpyrazine-1-yl)-2-oxoethyl]-amide;

(±)-4-(2-oxo-2,3-dihydrobenzoic-1-yl)-piperidine-1-carboxylic acid

[2-(1,4-dioxa-8-Aza-Spiro[4.5]Dec-8-yl)-1-(1H-indazol-5-ylmethyl)-2-oxoethyl]-amide;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[2-(1,4-dioxa-8-Aza-Spiro[4.5]Dec-8-yl)-1-(1H-indazol-5-ylmethyl)-2-oxoethyl]-amide;

(±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester;

3-(7-methyl-1H-indazol-5-yl)-2-[2',3'-dihydro-2'-oxaspiro(piperidine-4,4'-(1H)-hinzelin)carbylamine]-propionic acid methyl ester;

3-(7-methyl-1H-indazol-5-yl)-2-(1,2-dihydro-2-oxaspiro-4H-3,1-dihydroisoxazole-4',4-piperidine-carbylamine)-propionic acid methyl ester;

(±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hin the Zolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[2-[1,4']bipyridinyl-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxoethyl]-amide;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-2-piperidine-1-ileti]-amide;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[1-dimethylcarbamoyl-2-(7-methyl-1H-indazol-5-yl)-ethyl]-amide;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[1-(7-methyl-1H-indazol-5-ylmethyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl]-amide;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-2-pyrrolidin-1-ileti]-amide;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-2-(4-pyridin-4-reparation-1-yl)-ethyl]-amide;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-2-(4-pyridine-2-reparation-1-yl)-ethyl]-amide;

(±)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-[1,4-bipiperidine]-1-yl-2-oxoethyl]-2',3'-dihydro-2'-oxaspiro-[piperidine-4,4'-(1H)-hinzelin]-1-carboxamide;

(±)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-1-piperidinyl)-2-oxoethyl]-2',3'-dihydro-2'-oxaspiro-[piperidine-4,4'-(1H)-hinzelin]-1-carboxamide;

(±)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-[1,4-bipiperidine]-1-yl-2-oxoethyl]-1',2'-dihydro-2'-oxaspiro-[4H-3',1-benzoxazine-4,4'-piperidine]-1-carboxamide;

(±)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-(1-piperidinyl)-2-oxoethyl]-1',2'-dihydro-2'-oxaspiro-[4H-3',1-benzoxazine-4,4'-piperidine]-1-carboxamide;

(±)-[1-dimethylcarbamoyl-2-(7-methyl-1H-indazol-5-yl)-ethyl]-1',2'-dihydro-2'-oxaspiro-[4H-3',1-benzoxazine-4,4'-piperidine]-1-carboxamide;

(±)-[1-(2-adamantylidene)-2-(7-methyl-1H-indazol-5-yl)-ethyl]-1',2'-dihydro-2'-oxaspiro-[4H-3',1-benzoxazine-4,4'-piperidine]-1-carboxamide;

(±)-1',2'-dihydro-2'-oxaspiro-[4H-3',1-benzoxazine-4,4'-piperidine-1-carboxylic acid

[1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-2-(4-pyridin-4-reparation-1-yl)-ethyl]-amide;

(±)-1',2'-dihydro-2'-oxaspiro-[4H-3',1-benzoxazine-4,4'-piperidine-1-carboxylic acid

{2-(7-methyl-1H-indazol-5-yl)-1-[(pyridine-4-ylmethyl)-carbarnoyl]-ethyl}-amide;

(±)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-[1,4-piperidin]-1-yl-2-oxoethyl]-3',4'-dihydro-2'-oxaspiro[piperidine-4,4'-(1H)-quinoline]-1-carboxamide;

(±)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-[1-piperidinyl]-2-oxoethyl]-3',4'-dihydro-2'-oxaspiro[piperidine-4,4'-(1H)-quinoline]-1-carboxamide;

(±)-[1-dimethylcarbamoyl-2-(7-methyl-1H-indazol-5-yl)-ethyl]-1-3',4'-dihydro-2'-oxaspiro-[piperidine-4,4'-(1H)-quinoline]-1-carbox the amide;

(±)-4-oxo-2-phenyl-1,3,8-diazaspiro[4,5]Dec-1-ene-8-carboxylic acid

{1-(7-methyl-1H-indazol-5-ylmethyl)-2-[1,4]bipyridinyl-1'-yl-2-oxoethyl}-amide;

(±)-4-oxo-2-phenyl-1,3,8-diazaspiro[4,5]Dec-1-ene-8-carboxylic acid

{1-(7-methyl-1H-indazol-5-ylmethyl)-2-[1-piperidinyl]-2-oxoethyl}-amide;

(±)-4-oxo-2-phenyl-1,3,8-diazaspiro[4,5]Dec-1-ene-8-carboxylic acid

[1-dimethylcarbamoyl-2-(7-methyl-1H-indazol-5-yl)-ethyl]amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

{1-(1H-indazol-5-ylmethyl)-2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]-ethyl}-amide;

4-(3-(1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]-amino}propionyl)-piperazine-1-carboxylic acid benzyl ester;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[1-(1H-indazol-5-ylmethyl)-2-oxo-2-piperazine-1-ileti]-amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-carboxylic acid

{1-(1H-indazol-5-ylmethyl)-2-[4-(2-methyl-butyl)-piperazine-1-yl]-2-oxoethyl}amide;

3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-carbonyl]-amino}-propionic acid of cyclohexylurea ether;

(±)-3-(7-chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-Carbo is Il]-amino}-propionic acid methyl ester;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-carboxylic acid

[2-[1,4']bipyridinyl-1'-yl-1-(7-chloro-1H-indazol-5-ylmethyl)-2-oxoethyl]amide;

(±)-3-(7-ethyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]amino}propionic acid methyl ester;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[2-[1,4']bipyridinyl-1'-yl-1-(7-ethyl-1H-indazol-5-ylmethyl)-2-oxoethyl]amide;

(R)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-carboxylic acid

[2-[1,4']bipyridinyl-1'-yl-1-(2-methyl-1H-benzoimidazol-5-ylmethyl)-2-oxoethyl]amide;

(R)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-carboxylic acid

[2-[1,4']bipyridinyl-1'-yl-2-oxo-1-(2-oxo-2,3-dihydroisoxazole-6-ylmethyl)-ethyl]-amide;

(R)-3-(1H-benzotriazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-carbonyl]-amino}propionic acid methyl ester;

(R)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-carboxylic acid

[1-(1H-benzotriazol-5-ylmethyl)-2-[1,4']bipyridinyl-1'-yl-2-oxoethyl]-amide;

(R)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[2-[1,4']bipyridinyl-1'-yl-2-oxo-1-(2-oxo-2,3-dihydro-1H-indol-5-ylmethyl)-ethyl]amide;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-PIP is ridin-1-carboxylic acid

[1-(4-benzyloxy-2-oxo-2H-pyridine-1-ylmethyl)-2-[1,4']bipyridinyl-1'-yl-2-oxoethyl]amide;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[2-[1,4']bipyridinyl-1'-yl-1-(4-hydroxy-2-oxo-2H-pyridine-1-ylmethyl)-2-oxoethyl]-amide;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[2-[1,4']bipyridinyl-1'-yl-1-(4-hydroxypiperidine-1-ylmethyl)-2-oxoethyl]amide;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[2-[1,4']bipyridinyl-1'-yl-2-oxo-1-(1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-ylmethyl)-ethyl]amide;

(±)-3-(7,7-dimethyl-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]amino}propionic acid methyl ester;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[2-[1,4']bipyridinyl-1'-yl-1-(7,7-dimethyl-1,4,6,7-tetrahydropyrazolo

[4,3-C]pyridine-5-ylmethyl)-2-oxoethyl]amide;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[2-[1,4']bipyridinyl-1'-yl-1-(6-methoxypyridine-3-ylmethyl)-2-oxoethyl]amide;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[2-[1,4']bipyridinyl-1'-yl-1-(2-methoxypyridine-5-ylmethyl)-2-oxoethyl]amide;

< num="205"> (±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[1-(6-benzyloxypyridine-3-ylmethyl)-2-[1,4']bipyridinyl-1'-yl-2-oxoethyl]amide;

(±)-4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid

[2-[1,4']bipyridinyl-1'-yl-2-oxo-1-(6-oxo-1,6-dihydropyridines-3-ylmethyl)-ethyl]amide;

(R)-1-oxo-3,4-benzo-2,9-diazaspiro[5.5]undec-3-ene-9-carboxylic acid

(1-benzo[b]thiophene-3-ylmethyl-2-[1,4']bipyridinyl-1'-yl-2-oxoethyl)amide;

N-[(1R)-1-(benzo[b]Tien-3-ylmethyl)-2-[1,4-bipiperidine]-1-yl-2-oxoethyl]-3',4'-dihydro-2-oxaspiro-[piperidine-4,4'(1H)-quinoline]-1-carboxamide;

N-[(1R)-1-(benzo[b]Tien-3-ylmethyl)-2-[1,4-bipiperidine]-1-yl-2-oxoethyl]-2',3'-dihydro-1-oxaspiro-[piperidine-4,4'(1H)-isoquinoline]-1-carboxamide;

N-[(1R)-1-(benzo[b]Tien-3-ylmethyl)-2-[1,4'-bipiperidine]-1'-yl-2-oxoethyl]-1,2-dihydro-2-oxaspiro-[4H-3,1-benzoxazine-4,4'-piperidine]-1'-carboxamide;

1-[1,4']bipyridinyl-1'-yl-2-(3(8)-benzo[b]thiophene-3-ylmethyl)-4-[1',2'-dihydro-2'-oxaspiro-[4H-3',1-benzoxazine-4,4'-piperidinyl]-butane-1,4-dione;

(±)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[1',2'-dihydro-2'-oxaspiro-[4H-3',1-benzoxazine-4,4'-piperidinyl]-butyric acid methyl ester;

(±)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]-butyric acid methyl ester;

(&x000B1; )-1-[1,4']bipyridinyl-1'-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[1',2'-dihydro-2'-oxaspiro-[4H-3',1-benzoxazine-4,4'-piperidinyl]-butane-1,4-dione;

(±)-1-[1,4']bipyridinyl-1'-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]-butane-1,4-dione;

(±)-1-(1,4-dioxa-8-Aza-Spiro[4.5]Dec-8-yl)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]-butane-1,4-dione;

(±)-1-(1,4-dioxa-8-Aza-Spiro[4.5]Dec-8-yl)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[1',2'-dihydro-2'-oxaspiro-[4H-3',1-benzoxazine-4,4'-piperidinyl]-butane-1,4-dione;

(±)-N,N-dimethyl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]-butyramide;

(±)-1-(2,6-dimethylmorpholine-4-yl)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]-butane-1,4-dione;

(±)-2-(7-methyl-1H-indazol-5-ylmethyl)-1-(4-methylpiperidin-1-yl)-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]-butane-1,4-dione;

(±)-2-(7-methyl-1H-indazol-5-ylmethyl)-1-morpholine-4-yl-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]-butane-1,4-dione;

(±)-N,N-dimethyl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[1',2'-dihydro-2'-oxaspiro-[4H-3',1-benzoxazine-4,4'-piperidinyl]-butyramide;

(±)-2-(7-methyl-1H-indazol-5-ylmethyl)-1-(piperidine-1-yl)-4-[1',2'-dihydro-2'-oxaspiro-[4H-3',1-benzac asin-4,4'-piperidinyl]-butane-1,4-dione;

(±)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]-1-piperidine-1-ivatan-1,4-dione;

(±)-1-[1,4']bipyridinyl-1'-yl-2-(lH-indazol-5-ylmethyl)-4-[1',2'-dihydro-2'-oxaspiro-[4H-3',1-benzoxazine-4,4'-piperidinyl]butane-1,4-dione;

(±)-1-(1,4-dioxa-8-Aza-Spiro[4.5]Dec-8-yl)-2-(1H-indazol-5-ylmethyl)-4-[1',2'-dihydro-2'-oxaspiro-[4H-3',1-benzoxazine-4,4'-piperidinyl]butane-1,4-dione;

(±)-1-(1,4-dioxa-8-Aza-Spiro[4.5]Dec-8-yl)-2-(1H-indazol-5-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]butane-1,4-dione;

(±)-2-(1H-indazol-5-ylmethyl)-N,N-dimethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]butyramide;

(±)-5-{2-([1,4']bipyridinyl-1'-carbonyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]butyl}-indazol-1-carboxylic acid tert-butyl ether;

(±)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]-N-prop-2-inyl-butyramide;

(L)-{1-([1,4']bipyridinyl-1'-carbonyl)-3-oxo-3-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]-propyl}carbamino acid tert-butyl ether;

(L)-1-[1,4']bipyridinyl-1'-yl-2-(1H-indol-5-ylamino)-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-yl]butane-1,4-dione;

(L)-1-[1,4']bipyridinyl-1'-yl-2-(5-chloro-2-nitrophenylamino)-4-[4-(2-oxo-1,4-dihydro-2H-hin the Olin-3-yl)piperidine-1-yl]butane-1,4-dione;

(L)-1-[1,4']bipyridinyl-1'-yl-2-(6-chloropyrimidine-4-ylamino)-4-[4-(2-oxo-1,4-dihydro-2-N-hinzelin-3-yl)piperidine-1-yl]butane-1,4-dione;

(L)-1-[1,4']bipyridinyl-1'-yl-2-(2-chloro-N-purine-6-ylamino)-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-yl]butane-1,4-dione;

(L)-2-(4-amino-6-methyl-5-nitropyrimidin-2-ylamino)-1-[1,4']bipyridinyl-1'-yl-4-[4-(2-oxo-1,4-dihydro-2H'-hinzelin-3-yl)piperidine-1-yl]butane-1,4-dione;

(L)-1-[1,4']bipyridinyl-1'-yl-2-(4,5-diamino-6-methylpyrimidin-2-ylamino)-4-[4-(2-oxo-1)4-dihydro-2H-hinzelin-3-yl)piperidine-1-yl]butane-1,4-dione;

(L)-1-[1,4']bipyridinyl-1'-yl-2-(7-methyl-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-ylamino)-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-yl]butane-1,4-dione;

(L)-1-[1,4']bipyridinyl-1'-yl-2-((2'-pyridyl)-methylamino)-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]butane-1,4-dione;

(L)-1-[1,4']bipyridinyl-1'-yl-2-((5'-indazole)-methylamino)-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-yl]-butane-1,4-dione;

(L)-1-[1,4']bipyridinyl-1'-yl-2-((3'-were 1)methylamino)-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]butane-1,4-dione;

(L)-1-[1,4']bipyridinyl-1'-yl-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]-2-(pyrimidine-4-ylamino)-butane-1,4-dione;

(L)-1-[1,4']bipyridinyl-1'-yl-2-(4-hydroxycyclohexyl)-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]-b is tan-1,4-dione;

(L)-1-[1,4']bipyridinyl-1'-yl-2-[(1H-indazol-4-ylmethyl)-amino]-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]-butane-1,4-dione;

(L)-N-{1-([1,4']bipyridinyl-1'-carbonyl)-3-oxo-3-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]-propyl}-4-methoxybenzamide;

(L)-N-{1-([1,4']bipyridinyl-1'-carbonyl)-3-oxo-3-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]-propyl}-4-hydroxybenzamide;

(L)-1H-pyrazole-3-carboxylic acid{1-([1,4']bipyridinyl-1'-carbonyl)-3-oxo-3-[4-(2-oxo-1H-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]-propyl}amide; and

(±)-1-[1,4']bipyridinyl-1'-yl-2-(1H-indazol-5-ylamino)-4-[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-yl]butane-1,4-dione;

and its pharmaceutically acceptable salt and solvate.

30. A compound selected from the group consisting of

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipyridinyl-1'-yl-1-(7-bromo-1H-indazol-5-ylmethyl)-2-oxoethyl]amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid [2-oxo-1-(2-oxo-2,3-dihydroisoxazole-6-ylmethyl)-2-(4-pyridin-4-reparation-1-yl)ethyl]amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-carboxylic acid [2-oxo-1-(2-oxo-2,3-dihydroisoxazole-6-ylmethyl)-2-piperidine-1-ileti]-amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid 2-(4-methylpiperazin-1-yl)-2-oxo-1-(2-oxo-2,3-dihydroisoxazole-6-ylmethyl)-ethyl]-amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipyridinyl-1'-yl-1-(4-methyl-2-oxo-2,3-dihydroisoxazole-6-ylmethyl)-2-oxoethyl]amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipyridinyl-1'-yl-1-(4-chloro-2-oxo-2,3-dihydroisoxazole-6-ylmethyl)-2-oxoethyl]amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid [1-(4-methyl-2-oxo-2,3-dihydroisoxazole-6-ylmethyl)-2-oxo-2-piperidine-1-ileti]amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid [1-(4-chloro-2-oxo-2,3-dihydroisoxazole-6-ylmethyl)-2-oxo-2-piperidine-1-ileti]amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid [1-dimethylcarbamoyl-2-(4-methyl-2-oxo-2,3-dihydroisoxazole-6-yl)ethyl]amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid [2-(4-chloro-2-oxo-2,3-dihydroisoxazole-6-yl)-1-dimethylcarbamoyl]amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid[1-(4-methyl-2-oxo-2,3-dihydroisoxazole-6-ylmethyl)-2-oxo-2-(4-pyridin-4-yl-piperazine-1-yl)ethyl]amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid [1-(4-chloro-2-oxo-2,3-dihydroisoxazole-6-ylmethyl)-2-oxo-2-(4-pyridin-4-reparation-1-yl)ethyl]amide;

4-(2-oxo-1,4-dihydro-2H-hee who azolin-3-yl)-piperidine-1-carboxylic acid[2-[1,4]bipyridinyl-1'-yl-1-(4-ethyl-2-oxo-2,3-dihydroisoxazole-6-ylmethyl)-2-oxoethyl]amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-carboxylic acid[2-[1,4']bipyridinyl-1'-yl-2-oxo-1-(2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl)ethyl]amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-carboxylic acid [2-[1,4']bipyridinyl-1'-yl-1-(7-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl)-2-oxoethyl]amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid[2-[1,4']bipyridinyl-1'-yl-1-(7-chloro-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl)-2-oxoethyl]-amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid[2-[1,4']bipyridinyl-1'-yl-1-(7-ethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl)-2-oxoethyl]-amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid[2-[1,4']bipyridinyl-1'-yl-1-(3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl)-2-oxoethyl]-amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid[2-[1,4']bipyridinyl-1'-yl-1-(3,7-dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl)-2-oxoethyl] amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carboxylic acid[2-[1,4']bipyridinyl-1'-yl-1-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl)-2-oxoethyl]amide;

4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-carboxylic acid[2-[1,4']bipyridinyl-1'-yl-1-(7-ethyl-3-methyl-2-oxo-2,3-dihydro-1 is-benzoimidazol-5-ylmethyl)-2-oxoethyl]amide;

3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]amino}propionic acid isopropyl ester;

3-(7-chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]-amino}propionic acid isopropyl ester;

3-(7-ethyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]-amino}propionic acid isopropyl ester;

3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]-amino}propionic acid tert-butyl ether;

3-(7-chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid tert-butyl ether;

3-(7-ethyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-carbonyl]amino}propionic acid tert-butyl ether;

3-(7-chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-carbonyl]-amino}propionic acid of cyclohexylurea ether;

3-(7-ethyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]amino}propionic acid of cyclohexylurea ether;

3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]-amino}propionic acid 1-methylpiperidin-4-silt ether;

3-(7-chloro-1H-indazol-5-yl)-2-{[-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid 1-methylpiperidin-4-silt ether;

3-(7-ethyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid 1-methylpiperidin-4-silt ether;

3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid 1-methylcyclohexanol ether;

3-(7-chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]amino}propionic acid 1-methylcyclohexanol ether;

3-(7-ethyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-carbonyl]amino}propionic acid 1-methylcyclohexanol ether;

3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]amino}propionic acid

4-phenylcyclohexylamine ether;

3-(7-chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid 4-phenylcyclohexylamine ether;

3-(7-ethyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]amino}propionic acid 4-phenylcyclohexylamine ether;

3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]amino}propionic acid 1-benzylpiperidine-4-silt ether;

3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)piperidine-1-carbonyl]amino}propiona the second acid 1-pyridine-4-Eletropaulo ether; and

3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-hinzelin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid 1-pyridine-3-jatiluwih ether,

or its pharmaceutically acceptable salt and solvate.

31. Nonterminal in vivo methods of identifying compounds against migraine, comprising introducing the compound according to claims 1-30 mammal in a quantity that may cause the increase of blood flow, followed by the introduction of the test compound in a quantity able to reverse the specified CGRP-induced increase in blood flow, where the specified mammal is a transgenic mammal with human RAMP1 having Thr, or downregulation of endogenous RAMP1 mammal having Thr.

32. Nonterminal in vivo methods of identifying compounds against migraine, comprising the administration to a mammal test the connection before releasing compounds according to claims 1 to 30, where the specified test compound is administered in a quantity that may cause the increase of blood flow, and where the specified specified test the connection, enter in the quantity, is able to suppress the specified CGRP-induced increase in blood flow, where the specified mammal is a transgenic mammal with human RAMP1 having Thr, or downregulation of endogenous RAMP1 mammal having Thr.

33. Netterminal is hydrated in vivo methods of identifying compounds against migraine, includes introduction to the mammal the compound according to claims 1 to 30 in number, can cause an increase in the diameter of the peripheral artery, with subsequent introduction of the test compound in a quantity able to reverse the specified CGRJP-induced increase in the diameter of the peripheral artery, where the specified mammal is a transgenic mammal with human RAMP1 having Thr, or downregulation of endogenous RAMP1 mammal having Thr.

34. Nonterminal in vivo methods of identifying compounds against migraine, comprising the administration to a mammal test the connection before releasing compounds according to claims 1 to 30, where the specified connection according to claims 1-30 enter in the quantity that may cause an increase in the diameter of the peripheral artery, and where the specified test the connection, enter in the quantity, is able to suppress the specified CGRP-induced increase in the diameter of the peripheral artery, where the specified mammal is a transgenic mammal with human RAMP1 having Thr, or downregulation of endogenous RAMP1 mammal having Thr.



 

Same patents:

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to new compounds with formula I, their pharmaceutical salts and to complex esters. The invented compounds have inhibiting propertied towards catepsin K and can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved, for example, inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis and tumorous diseases. In general formula I R represents H, R13 represents (inferior)alkyl, C3-C10cylcloalkyl or C3-C10cycloalkyl(inferior)alkyl, each of which is independently optionally substituted with a halogen atom, hydroxyl, CN, NO2 or optionally mono- or di(inferior)alkyl substituted amino group; and R14 represents H or optionally substituted phenyl, phenyl-W-, phenyl(inferior)alkyl-W-, C3-C10cycloalkyl, C3-C10cycloalkyl-W-, N-heterocyclyl, N-heterocyclyl -W-. Substitutes of the indicated values of radicals are shown in the formula of invention. The invention also relates to methods of obtaining the compounds.

EFFECT: obtaining pyrrolopyrimidines with inhibiting properties towards catepsin K, which can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved.

4 cl, 59 tbl, 10 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes novel spiroazacyclic compounds of the general formula: wherein X means -CH2, -CH2O, -OCH2 or oxygen atom (O); Y represents O; Z means -CH or nitrogen atom (N); R1 means (C1-C6)-alkyl optionally substituted with morpholinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 2-oxoimidazolidinyl, imidazolidinyl, 2-oxooxazolidinyl, oxazalidinyl or (C3-C6)-cycloalkyl, (C2-C8)-alkyl ester or benzyl ester; m is chosen from group comprising 0 or 1; R4 means hydrogen atom or benzyl optionally substituted with halogen atom or (C1-C4)-alkyl; R5 means hydrogen atom or benzyl optionally substituted with halogen atom, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; R6 means hydrogen atom or benzyl optionally substituted with (C1-C4)-alkoxy-, cycloalkyl-(C1-C4-alkoxy)- or halogen-(C1-C4-alkoxy)-group; R2 and R3 mean hydrogen atom and at least two radicals among R4, R5 and R6 mean optionally substituted benzyl. Also, invention relates to a method for inhibition of activity of serotonin 5-HT2A receptors, a method for treatment of state mediated by serotonin 5-HT2A receptors, and using spiroazacyclic compounds proposed.

EFFECT: improved method of treatment, valuable medicinal properties of compounds.

35 cl, 3 tbl, 2 dwg, 45 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to substituted derivatives of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I in form of racemates, pure stereoisomers, particularly enantiomers or diastereomers in any ratio in mixture, in form of acids, or bases, or salts thereof, preferably physiologically acceptable salts, more preferably in form of hydrochlorides or solvates, in particular hydrates, wherein R1 and R2 are independently H, C3-C10-cycloalkyl, optionally substituted with O-alkylaryl, (C1-C12-alkyl)aryl, with the proviso, that at least one R1 and R2 is not H; R3 is H, SOR12 or COR13; R12 and R13 are independently C1-C10-alkyl, monocyclic 5-membered heterocyclic group having at least one heteroatom selected from sulfur atoms, optionally substituted with halogen; OR20, wherein R20 represents H, C1-C10-alkyl. Invention also relates to method for production of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I including a) compound of formula II interaction with methylenation agent, preferably with Ph3PCH3Br in presence of potassium tert-butylate in tetrahydrofuran (THF) to produce compound of formula III; d) compound of formula III interaction with ethylchloroximidoacetate of formula IV in presence of base, preferably of sodium hydrocarbonate or lithium hydroxide, preferably in organic solvent such as methanol, dichloromethane or TGF to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula V; c) compound of formula V interaction, directly or after previous saponification of functional group presenting in formula V (namely carboxylic acid ethyl ester) and optionally after activation of formed functional group (namely carboxylic acid) with amine of formula HNR1R2 wherein R1 and R2 are as defined above, to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula VI; d) protective group removing from compound of formula VI to produce compound of formula I, wherein R3 is H; and optionally e) converting of compound of formula I, wherein R3 is H, by treatment with acid chloride of formula R12SO2Cl to compound of formula I, wherein R3 is SO2R12 or converting by treatment with carboxylic acid chloride of formula R13COCl to compound of formula I, wherein R3 is COR13. Moreover disclosed is drug having analgesic action and containing at least one substituted 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula I.

EFFECT: new drug with analgesic action.

11 cl, 6 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.

EFFECT: improved preparing method, valuable biochemical and medicinal properties.

10 cl, 6 tbl, 337 ex

The invention relates to new derivatives of oxazolidinones General formula (I) listed in the description, as well as their salt

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with the general formula (I) in the racemic, enantiomeric form or in any combination of these forms and in which: A represents -CH2-, -C(O)-, -C(O)-C(Ra)(Rb)-; X represents -CH-; Ra and Rb independently represent the hydrogen atom or a radical (C1-C6)alkyl; Rj represents the atom of hydrogen; a radical (C1-C8)alkyl, not necessarily substituted hydroxyl or by one or more identical or different radicals of halogens; (C2-C6)alkenyl; or a radical of the formula -(CH2)n-X1; R2 represents a radical (C1-C8)alkyl not necessarily substituted hydroxyl or by one or more identical or different radicals of halogens; (C2-C6)alkenyl; or a radical of the formula -(CH2)n-X1; each X1 independently represents (C1-C6)alkoxy, (C3-C7)cycloalkyl or heteroaryl, and radicals (C3-C7)cycloalkyl, aryl and heteroaryl are not necessarily replaced by one or more either identical or various assistants chosen from: -(CH2)n'-V1-Y1, halogen and; V1 represents -O-, -S- or a covalent bond; Y1 represents a radical (C1-C6)alkyl, not necessarily substituted hydroxyl or by one or more identical or different radicals of halogens; n represents an integer from 0 up to 6 and n ' - an integer from 0 up to 2 that if n is equal 0 then X1 does not represent a radical alkoxy); or R1 and R2 form together with the atom of nitrogen to which they are attached, heterobicycloalkyl or heterocycloalkyl, are not necessarily replaced by one or more either identical or various substitutes chosen from: hydroxy, (C1-C6)alkyl, not necessarily substituted by hydroxy, (C1-C6)alkoxycarbonyl, heterocycloalkyl and-C(O)NV1'Y1', in which V1' and Y1' independently represent the atom of hydrogen or (C1-C6)alkyl; or R1 and R2 together form a radical of the formula: R3 represents-Z3, -C(RZ3)(R'Z3)-Z3, -C(RZ3)(R'Z3)-(CH2)p-Z3 or -C(O)Z'3; RZ3 and R'Z3 independently represent atom of hydrogen or a radical (C1-C6)alkyl; Z3 represents Z3b, Z3c, Z3d or Z3e; Z3b represents (C1-C6)alkoxy, (C1-C6)alkythio, (C1-C6)alkylamino, or a radical di((C1-C6)alkyl) amino; Z3c represents aryl or a radical heteroaryl; Z3d represents C1-C6)alkoxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, di((C1-C6)alkyl) aminocarbonyl, (C1-C6)alkyl-C(O)NH-, (C3-C7) cycloalkyl, heterocycloalkyl; and radicals (C3-C7) cycloalkyl and heterocycloalkyl are not necessarily replaced by one or more either identical or various substitutes chosen from: (C1-C6)alkoxy, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl and oxy, radicals aryl and heteroaryl are not necessarily replaced by one or more either identical or various substitutes chosen from: halogen, cyanogen, nitro, azide, oxy, (C1-C6)alkylcarbonyl-(C1-C6)alkenyl, (C1-C6)alkylaminocarbonyl-(C1-C6)alkenyl, -SO2-NR31R32, heterocycloalkyl, heteroaryl or -(CH2)P'-V3-Y3; R31 and R32 form together with atom of nitrogen to which they are attached, heterocycloalkyl, V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -O-C(O)-, -SO2-, -SO2NH-, -NR'3-SO2-, -NR'3-, -NR'3-C(O)-, -C(O)-NR'3-, -NH-C(O)-NR'3- or covalent bonds; Y3 represents the atom of hydrogen; radical (C1-C6)alkyl, not necessarily replaced by one or more either identical or different radicals of halogens; radical aryl or a radical aryl-(C1-C6)alkyl; Z3e represents a radical of the formula

, Z'3 represents a radical aryl, not necessarily replaced by one or more oreither identical or various substitutes chosen from: halogen, nitro and -(CH2)P"-V'3-Y'3; V'3 represents -O-, -C(O)-, -C(O)-O, -C(O)-NR'3-,-NH-C(O)-NR'3- or covalent bonds; Y'3 represents the atom of hydrogen or a radical (C1-C6)alkyl, not necessarily replaced by one or more either identical or different radicals of halogens; R'3 represents the atom of hydrogen (C1-C6)alkyl or a radical (C1-C6)alkoxy; p represents an integer from 1 up to 4; p' and p" independently represent an integer from 0 up to 4; R4 represents a radical of the formula -(CH2)S-R'4; R'4 represents a radical guanidine; heterocycloalkyl containing, at least, one atom of nitrogen and not necessarily substituted (C1-C6)alkyl or aralkyl; heteroaryl containing, at least, one atom of nitrogen and not necessarily substituted (C1-C6)alkyl or a radical of the formula -NW4W'4; W4 represents an atom of hydrogen or (C1-C8) alkyl; W'4 represents a radical of the formula -(CH2)S-Z4; Z4 represents an atom of hydrogen (C1-C8) alkyl, (C3-C7)cycloalkyl, heteroaryl and aryl; s and s' independently represent an integer from 0 up to 6; and i) if R3 represents -C(O)-Z'3 and R4 represents a radical of the formula -(CH2)S-NW4W'4, and W4 and W'4 independently represent an atom of hydrogen or a radical C1-C6)alkyl, then -(CH2)s represents neither radical ethylene nor radical -(CH2)-CH((C1-C4)alkyl) and ii), if R3 represents -Z3c and Z3c represents phenyl or naphthyl, then phenyl and naphthyl are not substituted by cyanogen; also note that if R3 represents -Z3d, then Z3d, represents only one (C3-C7)cycloalkyl or heterocycloalkyl; or to their pharmaceutically acceptable salts. The invention also relates to the method of obtaining the compounds of the formula (I), to a pharmaceutical composition, and to the application of compounds of the formula (I) and (I ').

EFFECT: obtaining new biologically active compounds on their basis, possessing activity with respect to receptors MC4.

41 cl, 535 ex

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

FIELD: chemistry.

SUBSTANCE: as photosensibilizers emulsions of alkylthiosubstituted phalocyanides of general formula , where R1=R4=Cl, R2=R3=n-C10H21S, M=Zn or R1=t-C4H9S, R2=R3=R4=H, M=HH or R1=t-C4H9S, R2=R4=H, R3=t-C4H9, M=HH or R1=R3=t-C4H9S, R2=R4=H, M=HH or R1=R2=R3=R4=t-C4H9S, M=HH or R1=R4=Cl, R2=R3=t-C4H9S, M=Zn, in water solution of Proxanol 268 are suggested.

EFFECT: elaboration of highly selective and efficient photosensibilizers for application in photodynamic therapy of tumours.

3 cl, 18 ex, 4 tbl, 9 dwg

FIELD: medicine; pharmacology.

SUBSTANCE: way of obtaining of new derivatives of a chlorophyll with two N, N-dimethylaminomethyl groups is described. The method lies in treatment of chlorine e6 derivative by bis-N, N-dimethylaminomethane in an admixture of butylene oxide with acetic acid at temperature of boiling of a reactionary admixture with the subsequent allocation of target product with column chromatography.

EFFECT: high output of a product and simplicity of technology.

3 ex

FIELD: chemistry.

SUBSTANCE: method is performed by the following way: unfiltered culture liquid is acidated to pH 2-2.5, sorb on cationite KU-23/100 in pulsing fluidisated mode with subsequent desorption using elution systems with pH 6.0±0.1, containing sodium citrate 1.5% and carbamide 0.5%. Coproporphyrin III is precipitaled on produced eluate, reducing pH to 3.5±0.1. Produced precipitate is extracted with hydrochloric acid solution, thereafter chromatographic cleaning of extract on molecular sorbent follows. End product is precipitaled on eluate. Then extraction and chromatographic cleaning are repeated, whereupon end product is precipitaled on eluate and transformed into potassium salt.

EFFECT: technology allows for production of water-soluble preparation based unfiltered culture liquid.

3 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to pharmacology, namely to production of biologically active compounds, specifically to improved method of chlorine e6 production applied for production of photosensitisers for photodynamic cancer therapy. Method is performed by processing sulphuric acid concentrated spirulina methanolic suspensions followed by filtration, dilution with water, alkali neutralisation by, filtration of settled deposition through celite layer followed with washing in hot water and petroleum-ether, elution with acetone celite, silica gel based chromatography, recrystallisation of mixed chloride methylene- methanol, release of produced alkylpheophorbide and its dilution with acetone, alkali processing, hydrochloric acid neutralisation, a filtration through celite layer, washing in water, aqueous ammonia, lyophilisation, dilution with aqueous alkali, filtration through sephadex layer, neutralisation, centrifugation and lyophilisation.

EFFECT: production of pure product with reagents taken in small amounts.

1 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention concerns a new compound, zinc meso-trans-dihexadecyltetrabenzoporphyrinate .

EFFECT: compound can be applied as a fat-soluble green colorant for solution dyeing of paraffin and polyethylene.

1 cl, 2 ex, 2 dwg

Compound // 2323940

FIELD: chemistry.

SUBSTANCE: photosensitising agents obtained by reducing a double bond in porphyrinic macrocycle of sulphonated mesotetraphenylporphyrine, preferably disulphonated mesotetraphenylporphyrine, such as TPPS2a. Resulting sulphonated mesotetraphenylchlorines are compounds of formula (I) , (where X stands for -SO3Н; each of n, p, q and r independently stands for 0 or 1; and sum of n, p, q and r is an integer from 1 to 4, preferably at least 2, in particular, 2 or 4), isomers or isomeric mixture. Compounds in accordance with the said invention and pharmaceutically suitable salts thereof have a high extinction coefficient in the region of 630 to 680 nm.

EFFECT: compounds are widely used as photosensitising agents for photochemical internalisation of molecules and photodynamic therapy.

25 cl, 8 ex, 8 dwg

FIELD: chemistry of coordination compounds, chemical technology, medicine.

SUBSTANCE: invention relates to an improved method for synthesis of metallic complexes of chlorophyll (A) derivatives with transient metal ions (Ni2+, Zn2+, Co2+, Cu2+). Method involves boiling the parent ligand with transient metal salt followed by isolation of the end product. Method involves using methylpyropheophorbid (a) or chlorin e6 13-N-methylamide-15,17-dimethylester or 13(2)-hydroxymethlpheiphorbid (a) as a ligand, and acetyl acetonate of the corresponding metal is used as transient metal salt, and boiling is carried out in equimolar amount of reagents for 2-3 h. By alternative variant the method involves boiling the parent ligand with transient metal salt followed by isolation of the end product wherein methylpyropheophorbid (a) or chlorin e6 13-N-methylamide-15,17-dimethyl ester, or 13(2)-hydroxymethylpheophorbid (a) is used as a ligand. Acetyl acetonate of the corresponding metal is used as transient metal salt in 10-fold excess. Acetyl acetonate is added to the reaction mixture by two equal portions followed by boiling for 1-2 min after each addition. Method provides high yield and without using large excess of metal salts. Invention can be used in synthesis of antitumor and antiviral preparations used in medicine.

EFFECT: improved method of synthesis, valuable medicinal properties of complexes.

3 cl, 1 dwg, 8 ex

FIELD: medicine, radiation therapy.

SUBSTANCE: the present innovation refers to radiosensitizers that contain as an active component halogenated derivatives of borated porphyrines that contain a great number of carboranic cells which are selectively accumulated in neoplasms' tissues in the irradiated volume and could be applied in such type of cancer therapy that include but are not restricted with boron-neutron-capturing therapy and photodynamic therapy. The present innovation , also, deals with applying these radiosensitizers for visualization of the tumor and treating the cancer.

EFFECT: higher efficiency.

35 cl, 2 dwg, 8 ex, 7 tbl

FIELD: organic chemistry.

SUBSTANCE: claimed method includes interaction of 1,3-diaminopropane with paraformaldehyde at room temperature for 10-20 min under stirring and recrystallization of condensation product from ethanol or heptane.

EFFECT: method of high yield.

1 dwg, 2 ex

Up!