Replaced-alanine

 

The invention relates to compounds of General formula (I)where R1is hydrogen or lower alkyl; X1X2and X6independently represent CR2; one of X3X4and X5is CR3and others independently represent CR2where R2is hydrogen, lower alkyl or lower alkoxy; and R3represents a group-L1-(CH2)n-C(=O)-NR4-CH2-CH2-Y, in which R4is aryl or heteroaryl, or R4is alkyl or alkenyl, each optionally substituted by one or more groups selected from halogen, oxo, R5or NH-C(=O)R7or R4is cycloalkyl or heterocyclization, each optionally substituted by one or more groups selected from oxo, R6or-L-R6; R5is carboxy, aryl, cycloalkyl, heteroaryl, heterocyclization, -ZR7or-NY1Y2; R6is aryl or heterocyclization; R7is alkyl or aryl; L2is alkylene; Y1and Y2independently are hydrogen, alkyl or aryl; or a group-NY1Y2may form a 5-7-membered ring is oxo or alkyl; and (ii) may also contain About as an additional heteroatom; Z is O and L1is R9-R10- bond, in which R9is a straight or branched C1-6alkalinous chain, R10is-C(=Z)-NR11-; R11represents hydrogen or R4; Y represents carboxypropyl, n is an integer from 1 to 6; and their prodrugs, and pharmaceutically acceptable salts, solvate of such compounds and their prodrugs; compounds of formula Ia, where one of X4or X5group C-R9-CON(R11)-CH2-CON(R4)-CH2-CH2-Y X1and X2- CR2; X3and X6= SN; another group of X4or X5= SN; a pharmaceutical composition having the ability to regulate the interaction of VCAM-1 and fibronectin with integrin VLA-4 (11); and methods for treating humans or animals suffering from or susceptible to diseases that can be treated by introducing an inhibitor of cell adhesion. 5 C. and 25 C.p. f-crystals, 16 PL.

Description text in facsimile form (see graphic material)

Claims

1. Connection total sup> X2and X6independently represent CR2;

one of X3X4and X5is CR3and others independently represent CR2where R2is hydrogen, lower alkyl or lower alkoxy;

R3represents a group of

-Ll-(CH2)n-C(=O)-NR4-CH2-CH2-Y,

in which R4is aryl or heteroaryl or R4is alkyl or alkenyl, each optionally substituted by one or more groups selected from halogen, oxo, R5or NH-C(=O)R7or R4is cycloalkyl or heterocyclization, each optionally substituted by one or more groups selected from oxo, R6or-L2-R6;

R5is carboxy, aryl, cycloalkyl, heteroaryl, heterocyclization, -ZR7or-NY1Y2;

R6is aryl or heterocyclization;

R7is alkyl or aryl;

L2is alkylene;

Y1and Y2independently are hydrogen, alkyl or aryl, or the group-NY1Y2may form a 5-7 membered cyclic amine which (i) may be optionally substituted by one or more substituents selected from the

L1is-R9-R10-bond, in which R9is a straight or branched C1-6alkalinous chain;

R10is-C(=Z)-NR11-;

R11represents hydrogen or R4;

Y represents carboxypropyl,

n is an integer from 1 to 6;

and its prodrugs, and pharmaceutically acceptable salt and solvate of such compounds and their prodrugs.

2. Connection on p. 1, in which R1represents hydrogen.

3. Connection under item 1 or 2, wherein X1is CR2where R2is1-4the alkyl or C1-4alkoxy.

4. Connection on p. 3 in which R2is stands.

5. Connection to one of the preceding paragraphs, in which X2is CR2where R2is1-4the alkyl or C1-4alkoxy.

6. Connection on p. 5, in which R2is methoxy.

7. Connection to one of the preceding paragraphs, in which X3is SN.

8. Connection to one of the preceding paragraphs, in which X6is SN.

9. Connection to one of the preceding paragraphs, in which one of X4and X5is CR3and the other is CH.

10. The connection p is made by a straight or branched C1-6alkylenes chain, and R10represents-C(=O)-NR11where R11choose from one of the following groups:

(i) hydrogen;

(ii)1-6of alkyl;

(iii) C1-6of alkyl, substituted R5where R5is aryl;

(iv) C1-6of alkyl, substituted R5where R5is heteroaryl;

(v) C1-6of alkyl, substituted R5where R5is cycloalkyl;

(vi) C1-6of alkyl, substituted R5where R5is carboxy, or

(vii) C1-6of alkyl, substituted R5where R5is NY1Y2.

11. Connection to one of the preceding paragraphs, in which the group R3n is 1.

12. The compounds of formula (Ia)

in which R4, R9, R11and Y are as defined in paragraph 1;

X1and X2each independently represents CR2(where each group R2is as defined in one of the paragraphs.1, 3, 4, 5 or 6) and R9-CON(R11)-CH2-CON(R4)-CH2-CH2-Y is attached to the ring at the 3 - or 4-th position,

and their prodrugs and pharmaceutically acceptable salt and solvate (e.g., hydrates) of compounds of formula (Ia) and their prodrugs.

13. With the 4alkylen.

14. Connection on p. 13, in which R9represents methylene.

15. Connection to one of the preceding paragraphs, in which R11represents hydrogen, straight or branched C1-4alkyl, straight or branched C1-3alkyl, substituted aryl, heteroaryl,3-8CEC-lalqila or carboxy, or straight or branched C2-3alkyl, substituted-NY1Y2.

16. Connection to one of the preceding paragraphs, in which R11represents hydrogen.

17. Connection to one of the preceding paragraphs, in which R4represents a straight or branched C1-6alkyl, substituted R5where R5is aryl.

18. Connection on p. 17, in which R4is 3,4-dis1-3alkoxybenzyl.

19. Connection at one PM.12-18, in which the group R9-C(=O)-N(R11)-C(=O)-NR4-CH2-CH2-Y is attached to the 4-th position of the ring.

20. Connection on p. 12, in which R4is1-10alkyl, C1-6alkyl, substituted aryl, heteroaryl, cycloalkyl, heterocyclization,1-6alkoxy, halogen or-NY1Y2or R4is1-4alkenyl; R11is bodoro the R11is2-3alkyl, substituted-NY1Y2; R9is1-4alkylene; X1is CR2where R2is C1-4by alkyl; X2is CR2where R2is1-4alkoxy; Y is carboxy; and the group-R-C(=O)-N(R4)-CH2-C(=O)-NR4-CH2-CH2-Y is attached to the 4-th position of the ring; and their prodrugs, and pharmaceutically acceptable salt and solvate (e.g., hydrates) of such compounds and their prodrugs.

21. Connection on p. 1, selected from the following:

3-{[({[3-methoxy-4-(3-o-tolylurea)phenyl]acetyl}-N-methylamino)acetyl]-[3-(2-oxo-pyrrolidin-1-yl)-prop-1-yl]amino}-propionic acid (compound A);

3-{(3,4-dimethoxybenzyl)-[({[3-methoxy-4-(3-o-tolylurea)phenyl]-acetyl-N-methylamino)acetyl]amino}propionic acid (compound C);

3-{[({[3-methoxy-4-(3-o-tolylurea)phenyl]acetyl}amino)acetyl]-[3-(2-oxopyrrolidin-1-yl)-prop-1-yl]amino}propionic acid (compound D);

3-[(2,3-dimethoxybenzyl)-([2-[3-methoxy-4-(3-o-tolylurea)phenyl]-acetylamino}acetyl)amino]propionic acid (compound AO);

3-[N-(3,4-dimethoxybenzyl)-2-{2-[3-methoxy-4-(3-o-tolylurea)-phenyl]acetylamino}acetamido]propionic acid (compound BD) the slots (connection KW);

3-{(3-ethoxy-4-methoxybenzyl)-[({[3-methoxy-4-(3-o-tolylurea)phenyl]acetyl}amino)acetyl]amino}propionic acid (compound LE);

3-{(3,4-diethoxybenzoic)-[({[3-methoxy-4-(3-o-tolylurea)phenyl]-acetyl}amino)acetyl]amino}propionic acid (compound LF),

and their prodrugs, and pharmaceutically acceptable salts and solvate of such compounds and their prodrugs.

22. 3-[N-(3,4-dimethoxybenzyl)-2-{2-[3-methoxy-4-(3-o-tolylurea)-phenyl]acetylamino}acetamido]propionic acid (compound BD) and its pharmaceutically acceptable salt and solvate.

23. Pharmaceutical composition having the ability to regulate the interaction of VCAM-I and fibronectin with integrin VLA-4 (11containing an effective amount of the compounds under item 1 or a pharmaceutically acceptable salt or MES of such compounds in combination with a pharmaceutically acceptable carrier or excipient.

24. Connection on p. 1 or a corresponding prodrug, or pharmaceutically acceptable salt, or MES of such compounds, or prodrugs for use in the treatment of a patient suffering from or prone to diseases that can be treated by the introduction of inhibitor glue the/p>25. The composition according to p. 23 for use in the treatment of a patient suffering from or prone to diseases that can be treated by introducing an inhibitor of cell adhesion, carried out with the participation41.

26. Connection under item 1 for use in the treatment of inflammatory diseases.

27. Connection under item 1 for use in the treatment of asthma.

28. Connection on p. 1, or a corresponding prodrug, or pharmaceutically acceptable salt, or MES of such a compound, or its prodrug used in the manufacture of a medicinal product for the treatment of a patient suffering from or prone to diseases that can be treated by introducing an inhibitor of cell adhesion, carried out with the participation41.

29. Connection on p. 1, or a corresponding prodrug, or pharmaceutically acceptable salt, or MES of such a compound, or its prodrug used in the manufacture of a medicinal product for the treatment of asthma.

30. A method of treating human or animal suffering from or predisposed to the disease that can be treated by the introduction of Inga1involving the introduction of a specified patient an effective amount of the compounds under item 1, or a corresponding prodrug, or pharmaceutically acceptable salt, or MES of such compounds, or prodrugs.

 

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