Heterocycles as inhibitors of leukocyte adhesion and vla - 4 antagonists

 

The invention relates to heterocyclic compounds of the formula I, the values of the radicals see the claims. The compounds possess high inhibitory activity against VLA-4-dependent processes of adhesion and migration of leukocytes and can be used for the treatment and prevention of such diseases, which are caused undesirable degree of leukocyte adhesion and/or migration of leukocytes. A method for producing compounds according to the invention by condensation of its fragments, as well as pharmaceutical drug based on the active substance and the usual additives, which are able to inhibit VLA-4-dependent processes of adhesion and migration of leukocytes, 4 S. and 11 C.p. f-crystals.

Description text in facsimile form (see graphic part)

Claims

1. The heterocycles of the formula Iwhere W denotes the R1-A-C(R13); Y represents a carbonyl group; Z represents N(R0); And denotes a bivalent residue of phenylene, (C1-C6-alkylester; denotes a bivalent residue selected from (C1-C6)-alkylene; D is C(R2)(R3); E oboznachennyj, if necessary, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl;
R1represents-N(R28)-C(O)-N(R21)-R28, cyano - or nitro-group;
R2denotes hydrogen;
R3means CONHR4;
R4means (C1-C28)-alkyl, which if necessary can be replaced with residues selected from the range hydroxycarbonyl, R5and (C1-C8-alkoxycarbonyl;
R5means (C6-C14)-aryl;
R10denotes hydroxy, (C1-C8)-alkoxy;
R13means (C1-C6)-alkyl;
R21denotes hydrogen, (C1-C8)-alkyl, substituted if necessary (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl;
R28represents one of the residues R21;
b, C, d and f independently of one another denote 0 or 1, but not all at the same time can indicate 0;
e, g and h independently of one another denote 0, 1, 2, 3, 4, 5 or 6, in all their stereoisomeric forms and mixtures in all ratios, and their physiologically tolerated salts, but moreover, if W denotes 4-cyanophenyl-C(R13);
Y represents a carbonyl group;
Z represents NRoa;
In about the, the hen D cannot denote C(R2a)(R3a), and Roa, Raand R2aindependently of one another denote hydrogen, (C1-C8)-alkyl, substituted if necessary (C6-C14)-aryl, substituted in the aryl residue, if necessary, (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl; and
R3adenotes hydrogen, (C1-C8)alkyl, substituted if necessary (C6-C14)-aryl, substituted in the aryl residue, if necessary, (C6-C14)-aryl-(C1-C8)-alkyl, (C3-C8-cycloalkyl or 2-, 3-or 4-pyridyl.

2. The heterocycles of the formula I on p. 1, where W denotes the R1-A-C(R13); And denotes a bivalent residue of phenylene, methylindenyl; denotes a bivalent residue selected from methylene, ethylene, trimethylene or tetramethylene; F denotes R10CO; R is hydrogen; R0means (C1-C8)-alkyl, substituted if necessary (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl; R1represents-N(R28)-C(O)-N(R21)-R28, cyano - or nitro-group; R2denotes hydrogen; R3means CONHR4

3. The heterocycles of the formula I under item 1 or 2, where W denotes the R1-A-C(R13); Y represents a carbonyl group; Z represents N(R0); And denotes phenylene, methylindenyl; In denotes the methylene; D is C(R2)(R3); F denotes R10CO; R is hydrogen; R0means (C1-C8)-alkyl, substituted if necessary (C1-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl; R1represents-N(R28)-C(O)-N(R21)-R28, cyano - or nitro-group; R2denotes hydrogen; R3means CONHR4; R4denotes methyl, substituted hydroxycarbonyl, phenyl or benzyl, or methyl, substituted (C1-C8-alkoxycarbonyl, preferably (C1-C4-alkoxycarbonyl; R10denotes hydroxy or (C1-C8)-alkoxy, preferably (C1-C4)-alkoxy; R13means (C1-C6)-alkyl, preferably methyl; b, C, d represent 1; e, f and g denote 0; h denotes 1 or 2, preferably 1, in all their stereoisomeric forms and mixtures in all ratios, and their physiologically tolerated salts.

4. The heterocycles of the formula I under item 1 or 2, where methylindenyl; In denotes a bivalent residue selected from methylene, ethylene, trimethylene, tetramethylene; F denotes R10CO, R denotes hydrogen; R0means (C1-C8)-alkyl, substituted if necessary (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl; R1represents-N(R28)-C(O)-N(R21)-R28, cyano - or nitro-group; R2denotes hydrogen; R3means CONHR4; R4means (C1-C8)-alkyl, substituted (C6-C14)-aryl; b, C, d represent 1; e, f and g represent, independently of each other 0, 1, 2 or 3; h represents 1 or 2, preferably 1, in all their stereoisomeric forms and mixtures in all ratios, and their physiologically tolerated salts.

5. The heterocycles of the formula I on PP. 1, 2, or 4, where W denotes the R1-A-C(R13); Y represents a carbonyl group; Z represents N(R0); And denotes phenylene, methylindenyl; In denotes the methylene; D is C(R2)(R3); F denotes R10CO; R is hydrogen; R0means (C1-C8)-alkyl, substituted if necessary (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl; R1represents-N(R; R4means (C1-C6)-alkyl, substituted (C6-C10)-aryl; R10denotes hydroxy or (C1-C8)-alkoxy, preferably (C1-C4)-alkoxy; R13means (C1-C6)-alkyl, preferably methyl; b, C, d represent 1; e, f and g denote 0; h denotes 1 or 2, preferably 1, in all their stereoisomeric forms and mixtures in all ratios, and their physiologically tolerated salts.

6. The heterocycles of the formula I under item 1 or 2, where In denotes methylene, in all their stereoisomeric forms and mixtures in all ratios, and their physiologically tolerated salts.

7. The heterocycles of the formula I on PP. 1-6, where R1represents-N(R28)-C(O)-N(R21)-R28or cyano, in all their stereoisomeric forms and mixtures in all ratios, and their physiologically tolerated salts.

8. The method of obtaining compounds of the formula I according to one or more of the paragraphs. 1-7, characterized in that carry out the condensation of the fragments of the compounds of formula II

with the compound of the formula III

moreover, W, Y, Z, B, D, E and R and b, d, e, f, g and h are defined as indicated in paras. 1-7 and G denotes hydroxycarbonyl, (C1-CWNYE esters or mixed anhydrides or isocyanato.

9. The heterocycles of formula Ib

where W denotes the R1-A-C(R13);
Y represents a carbonyl group;
Z represents N(R0);
And denotes the divalent residue of phenylene, (C1-C6-alkylester;
In denotes a bivalent residue selected from (C1-C6)-alkylene;
D represents C(R2)(R3);
E denotes R10CO;
R denotes hydrogen;
R0means (C1-C8)-alkyl, substituted if necessary (C1-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl;
R1represents-N(R28)-C(O)-N(R21)-R28cyano - or nitro-group;
R2denotes hydrogen;
R3means CONHR4;
R4means (C1-C28)-alkyl, which if necessary can be replaced with residues selected from the range hydroxycarbonyl, R5and (C1-C8-alkoxycarbonyl;
R5means (C6-C14)-aryl;
R10denotes hydroxy, (C1-C8)-alkoxy;
R13means (C1-C6)-alkyl;
R21denotes hydrogen, (C1-C8)-alkyl, substituted if necessary (C6-C14)>b, C, d and f independently of one another denote 0 or 1, but not all at the same time can indicate 0;
e, g and h independently of one another denote 0, 1, 2, 3, 4, 5 or 6, and their physiologically tolerated salts for use as pharmaceuticals.

10. The heterocycles of formula Ib under item 9 and/or their physiologically tolerated salts as tools for inhibition of inflammation.

11. The heterocycles of formula Ib under item 9 and/or their physiologically tolerated salts for the manufacture of medicines for the treatment or prevention of diseases in which leukocyte adhesion and/or migration of leukocytes has an undesirable degree, or diseases in which play the role of VLA-4-dependent adhesion processes.

12. The heterocycles of formula Ib under item 9 and/or their physiologically tolerated salts for the manufacture of medicines for the treatment or prevention of rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, inflammatory diseases of the Central nervous system, asthma, allergies, cardiovascular diseases, arteriosclerosis, residual Anosov, diabetes, to prevent damage to transplants of organs, for inhibition of tumor growth or metastasis of opuholei tolerated salts for the treatment or prevention of diseases, in which leukocyte adhesion and/or migration of leukocytes has an undesirable degree, or diseases in which play the role of VLA-4-dependent adhesion processes.

14. The heterocycles of formula Ib under item 9 and/or their physiologically tolerated salts for the treatment or prevention of rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, inflammatory diseases of the Central nervous system, asthma, allergies, cardiovascular diseases, arteriosclerosis, residual Anosov, diabetes, to prevent damage to transplants of organs, for inhibition of tumor growth or metastasis of a tumor, for the treatment of malaria or for inhibition of inflammation.

15. Pharmaceutical drug-based active agents and conventional additives, which are able to inhibit VLA-4-dependent processes of adhesion and migration of leukocytes, characterized in that the active substance it contains one or more compounds of the formula Ib under item 9 and/or their physiologically tolerated salt in an effective amount together with a pharmaceutically impeccable substances-carriers and/or additives.

 

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