Phenylalanine derivatives
Specified phenylalanine derivatives and analogues thereof have an antagonistic activity to α4 integrin. They are used as therapeutic agents for various diseases concerning α4 integrin.
1. A compound of formula (1):
wherein:
A represents a group of formula (3):
wherein Arm represents a cyclic alkyl group or an aromatic ring containing 0, 1, 2, 3, or 4 hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom;
X represents C(═O), S(═O) 2 , C(—R5)(—R6), C(═C(R5)(R6)), C(═S), S(═O), P(═O)(—OH), or P(—H)(═O);
R2, R3, R4, R5, and R6 may be the same or different from one another and each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkenyl group, a substituted lower alkenyl group, a lower alkynyl group, a substituted lower alkynyl group, 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 alkylthio group, a lower alkoxyl group and lower alkylthio group substituted with a cycloalkyl group(s) which may contain a hetero atom(s) in the ring thereof, a lower alkoxyl group and lower alkylthio group substituted with an aryl group(s), a lower alkoxyl group and lower alkylthio 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 hydroxyalkoxyl group, a lower halogenoalkyl group, a lower halogenoalkoxyl group, a lower halogenoalkylthio 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 alkylsulfonyl group, a substituted or unsubstituted sulfamoyl group or an ammonium group, R5 and R6 may be bonded together to form a ring which may contain one or two oxygen, nitrogen or sulfur atoms
B represents hydroxyl group, a lower alkoxyl group or hydroxylamino group;
C represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl 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) or a lower alkyl group substituted with a heteroaryl group(s);
D represents a lower alkyl group, a lower alkenyl group, a lower alkynyl group, 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 hydroxyalkoxyl 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 or a substituted or unsubstituted sulfamoyl group;
C and D may be bonded together to form a ring which may contain one or two oxygen, nitrogen, or sulfur atoms;
T represents an interatomic bond, C(═O), C(═S), S(═O), S(═O) 2 , N(H)—C(═O), or N(H)—C(═S);
J and J′ may be the same or different from each other and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkyloxy group or a nitro group;
or a pharmaceutically acceptable salt thereof.
2. A compound or pharmaceutically acceptable salt according to claim 1 , wherein Arm represents a benzene ring.
3. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R2, R3, and R4 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkoxyl group, a halogen lower alkyl group, substituted or unsubstituted amino group, or an ammonium group.
4. A compound or pharmaceutically acceptable salt according to claim 1 , wherein B represents hydroxyl group or a lower alkoxyl group.
5. A compound or pharmaceutically acceptable salt according to claim 1 , wherein C represents a hydrogen atom or a lower alkyl group.
6. A compound or pharmaceutically acceptable salt according to claim 1 , wherein D represents a cycloalkyl group(s) which may contain a hetero atom(s) in the ring thereof, an aryl group, or a heteroaryl group.
7. A compound or pharmaceutically acceptable salt according to claim 1 , wherein J and J′ each represent a hydrogen atom.
8. A compound or pharmaceutically acceptable salt according to claim 1 , wherein T represents C(═O).
9. A compound or pharmaceutically acceptable salt according to claim 1 , wherein X represents C(═O) or C(═S).
10. A compound or pharmaceutically acceptable salt according to claim 1 , wherein X is C(═O).
11. A compound or pharmaceutically acceptable salt according to claim 1 , wherein:
Arm represents a benzene ring;
R2, R3, and R4 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkoxyl group, a halogen lower alkyl group, substituted or unsubstituted amino group, or an ammonium group;
B represents hydroxyl group or a lower alkoxyl group;
C represents a hydrogen atom or a lower alkyl group;
D represents a cycloalkyl group(s) which may contain a hetero atom(s) in the ring thereof, an aryl group, or a heteroaryl group;
J and J′ each represent a hydrogen atom;
T represents C(═O); and
X represents C(═O) or C(═S).
12. A compound or pharmaceutically acceptable salt according to claim 11 , wherein X is C(═O).