Phenylalanine derivatives
Specific phenylalanine derivatives or pharmaceutically acceptable salts thereof have an antagonistic effect on the α 4 integrins and, therefore, are usable as therapeutic agents or preventive agents for diseases in which α 4 integrin-depending adhesion process participates in the pathology, such as inflammatory diseases, rheumatoid arthritis, inflammatory bowel diseases, systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, asthma, psoriasis, allergy, diabetes, cardiovascular diseases, arterial sclerosis, restenosis, tumor proliferation, tumor metastasis and transplantation rejection.
1. A phenylalanine compound of formula (1) or a pharmaceutically acceptable salt thereof:
wherein A represents one of formula 24, 25-1, 25-3, 25-4, or 26-1
E represents a hydrogen atom;
T represents a C═(O) group;
D represents an aryl group;
B represents a hydroxyl group or lower alkoxyl group;
J and J′ may be the same or different from each other and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkyloxy group or nitro group
wherein in formula 24
Ra represents a hydrogen atom, a fluorine atom, a chloro atom, a bromo atom, a nitro group, an alkyl group having 1 to 3 carbon atoms or an alkoxyl group having 1 to 3 carbon atoms,
Rb represents a hydrogen atom, a fluorine atom, a chloro atom, a bromo atom, a nitro group, an alkyl group having 1 to 3 carbon atoms, an amino group, an amino group substituted by one or two alkyl groups having 1 to 3 carbon atoms, a carbamoyl group or a carbamoyl group substituted by one or two alkyl groups having 1 to 3 carbon atoms; and
in formula 26-1
Ra to Rd may be the same or different from each other, and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group which may contain a hetero atom(s) in the chain thereof, a lower alkenyl group which may contain a hetero atom(s) in the chain thereof, a lower alkynyl group which may contain a hetero atom(s) in the chain thereof, a cycloalkyl group which may contain a hetero atom(s) in the ring thereof, an aryl group, a heteroaryl group, a lower alkyl group substituted with a cycloalkyl group(s) which may contain a hetero atom(s) in the ring thereof, a lower alkyl group substituted with an aryl group(s), a lower alkyl group substituted with a heteroaryl group(s), a lower alkoxyl group, a lower alkoxyl group substituted with a cycloalkyl group(s) which may contain a hetero atom(s) in the ring thereof, a lower alkoxyl group substituted with an aryl group(s), a lower alkoxyl group substituted with a heteroaryl group(s), a cycloalkyloxy group which may contain a hetero atom(s) in the ring thereof, an aryloxy group, a heteroaryloxy group, a lower hydroxyalkyl group, a lower hydroxyalkenyl group, a lower hydroxylalkoxyl group, a lower halogenoalkyl group, a lower halogenoalkoxyl group, a lower halogenoalkenyl group, nitro group, cyano group, a substituted or unsubstituted amino group, carboxyl group, a lower alkyloxycarbonyl group, a substituted or unsubstituted carbamoyl group, a lower alkanoyl group, an aroyl group, a lower alkylthio group, a lower alkylsulfonyl group, a substituted or unsubstituted sulfonylamino group or a substituted or unsubstituted sulfamoyl group, and Ra, Rb, Rc and Rd may form a ring between them.
2. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein A represents the formula (24):
and
J and J′ represent a hydrogen atom.
3. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 2 , wherein D represents 2,6-dichlorophenyl group, 2,6-dichloro-4-tetrazolyl-phenyl group, 2,6-dichloro-4-lower-alkylsulfonylamino-phenyl group or 3,5-dichloropyridine-4-yl group.
4. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein A represents formula (25-1), (25-3) or (25-4):
and
J and J′ represent a hydrogen atom.
5. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 4 , wherein D represents 2,6-dichlorophenyl group, 2,6-dichloro-4-tetrazolyl-phenyl group, 2,6-dichloro-4-lower-alkylsulfonylamino-phenyl group or 3,5-dichloropyridine-4-yl group.
6. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein A represents formula (26-1):
and
J and J′ represent a hydrogen atom.
7. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 6 , wherein D represents 2,6-dichlorophenyl group, 2,6-dichloro-4-tetrazolyl-phenyl group, 2,6-dichloro-4-lower-alkylsulfonylamino-phenyl group or 3,5-dichloropyridine-4-yl group.
8. The phenylalanine compound or pharmaceutically acceptable salt thereof according to claim 1 , represented by:
9. A method of treating inflammatory diseases in which an α 4 integrin-depending adhesion process participates in the pathology, which comprises administering a therapeutically effective amount of a phenylalanine compound or a pharmaceutically acceptable salt thereof according to claim 1 to a subject in need thereof.
10. A method of treating rheumatoid arthritis, inflammatory bowel diseases, systemic lupus erythematosus, multiple sclerosis, Sjägren's syndrome, asthma, psoriasis, allergy, arterial sclerosis, and restenosis, which comprises administering a therapeutically effective amount of a phenylalanine compound or a pharmaceutically acceptable salt thereof according to claim 1 to a subject in need thereof.
11. A composition comprising a phenylalanine compound or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier.
12. The composition according to claim 11 , wherein A represents formula 24, and D represents an aryl group.
13. The composition according to claim 11 , wherein A represents formula 24.
14. The composition according to claim 11 , wherein A represents formula 25-1, and D represents an aryl group.
15. The composition according to claim 11 , wherein A represents formula 25-1.
16. The composition according to claim 11 , wherein A represents formula 25-3, and D represents an aryl group.
17. The composition according to claim 11 , wherein A represents formula 25-3.
18. The composition according to claim 11 , wherein A represents formula 25-4, and D represents an aryl group.
19. The composition according to claim 11 , wherein A represents formula 25-4.
20. The composition according to claim 11 , wherein A represents formula 26-1, and D represents an aryl group.
21. The composition according to claim 11 , wherein A represents formula 26-1.
22. The compound according to claim 1 , wherein A represents formula 24.
23. The compound according to claim 1 , wherein A represents formula 25-1.
24. The compound according to claim 1 , wherein A represents formula 25-3.
25. The compound according to claim 1 , wherein A represents formula 25-4.
26. The compound according to claim 1 , wherein A represents formula 26-1.