Heterocyclic derivative glycyl-beta-alanine as antagonists of vitronectin

 

The invention relates to a group of new compounds - heterocyclic derivatives of glycyl-beta-alanine General formula Ior pharmaceutically acceptable salt of this compound, whereis a 5-8-membered monocyclic heterocyclic, optionally unsaturated ring containing from 1 to 4 heteroatoms selected from the group comprising N and S, and1selected from the group comprising SN, SN2, N, NH, O and S, provided thatis not pyrrolidinium when V represents NH; a represents a group of the formulawhere Y1selected from the group comprising N-R2and R2means hydrogen; R2means hydrogen, R7when not with R2and R8mean hydrogen, alkyl, substituted alkoxy group, or R2together with R7form a 4 to 12-membered ring containing 2 nitrogen atom a heterocycle, optionally substituted by one or more substituents selected from the group comprising hydroxy, C1-C10alkyl, halogen, sporadically; And refers to a group

where R2together with R7form a 5-8-clan alseny alkoxygroup; or denotes A group

where R2together with R7form a 5-8-membered ring containing 2 nitrogen atom a heterocycle, optionally substituted hydroxy-group; R8- alkyl, substituted alkoxygroup; V means-N(R6)-; R6is hydrogen; Y and Z denote hydrogen, t = 0, n and R = 1, 2; R means X-R3where X is-O-; R3is hydrogen, alkyl; R1selected from the group including aryl, alkyl, optionally substituted one or more times by halogen, alkyl, HE; monocyclic heterocycle; haloalkyl; R11means hydrogen, or a pharmaceutically acceptable salt of the compounds; pharmaceutical compositions having properties antagonistV3-integrin, as well as to a method of treating diseases mediatedV3-integrin in a mammal. 3 S. and 19 C.p. f-crystals, 1 table.

Description text in facsimile form (see graphic part).


Claims

1. The compound of the formula I

where

is a 5-8-membered monocycle is h groups, including N and S, and1selected from the group comprising SN, SN2, N, NH and S, provided that

is not pyrrolidinium when V represents NH;
A represents a group of the formula

where Y1means N-R2and R2means hydrogen;
R2means hydrogen, R7when not with R2and R8means hydrogen, alkyl, substituted alkoxygroup or R2together with R7form 4-12 heterocycle containing 2 nitrogen atom, optionally substituted by one or more substituents selected from the group comprising hydroxy, C1-C10alkyl, halogen, sporadically;
or a represents a group of the formula

where R2together with R7form a 5-8-membered ring containing two nitrogen atom a heterocycle;
R5means hydrogen;
R8means alkyl, optionally substituted by alkoxygroup;
or a represents a group of the formula

where R2together with R7form a 5-8-membered ring containing 2 nitrogen atom a heterocycle, optionally substituted hydroxy-group;
R8means of ALD;
t = 0,
n = 1, 2;
p = 1, 2;
R means X-R3where X is-O-; R3means hydrogen, alkyl;
R1selected from the group including aryl, alkyl, optionally substituted one or more times by halogen, alkyl, HE; monocyclic heterocycle; haloalkyl;
R11means hydrogen,
or pharmaceutically acceptable salt of this compound.

2. Connection on p. 1 formula

where

does


where R32denotes H, alkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, and an alkyl group optionally substituted by one or more substituents selected from the group comprising hydroxy, alkoxy, amino, alkylamino, dialkylamino, Arielle alkylsulfonyl, carboxy and carboxyprimaquine.

3. Connection on p. 2, selected from the group consisting of compounds







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4. Connection on p. 1 formula

where

does

5. Connection on p. 4, selected from the group consisting of compounds






















6. Connection on p. 1 32D/img_data/66/666435.gif">
7. Connection under item 6, selected from the group consisting of compounds






8. Connection on p. 1 formula

where

does


9. Connection on p. 8 formula


10. Connection on p. 1 formula

where

does

11. Connection on p. 10 formulas

12. Pharmaceutical composition having properties antagonistV3-integrin containing a therapeutically effective amount of the compounds according to paragraphs. 1-10 or 11 and a pharmaceutically acceptable carrier.

13. The method of treatment of diseases mediatedV3-integrin in a mammal, najdawi the p> 14. The method according to p. 13, characterized in that it is used for treatment of tumor metastasis.

15. The method according to p. 13, characterized in that it is used for treatment of solid tumor growth.

16. The method according to p. 13, characterized in that it is used to treat angiogenesis.

17. The method according to p. 13, characterized in that it is used for the treatment of osteoporosis.

18. The method according to p. 13, characterized in that it is used for the treatment of malignant humoral hypercalcemia.

19. The method according to p. 13, characterized in that it is used to treat migration of smooth muscle cells.

20. The method according to p. 13, characterized in that it is used to inhibit restenosis.

21. The method according to p. 13, characterized in that it is used to treat rheumatoid arthritis.

22. The method according to p. 13, characterized in that it is used to treat macular degeneration.

 

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