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 (78):
wherein R is methyl or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition, comprising a compound or pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier.
3. A method for inhibiting the adhesion of VCAM-1 to α4 integrin, which comprises administering an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 1 to a subject having a disease in which α4 integrin-dependent adhesion process participates in the pathology.
4. A compound of formula (36):
wherein R is hydrogen or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition, comprising a compound or pharmaceutically acceptable salt thereof according to claim 4 and a pharmaceutically acceptable carrier.
6. A method for inhibiting the adhesion of VCAM-1 to α4 integrin, which comprises administering an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 4 to a subject having a disease in which α4 integrin-dependent adhesion process participates in the pathology.
7. A compound of formula (80):
wherein R1 is amino, R2 is methyl, and R3 is hydrogen or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition, comprising a compound or pharmaceutically acceptable salt thereof according to claim 7 and a pharmaceutically acceptable carrier.
9. A method for inhibiting the adhesion of VCAM-1 to α4 integrin, which comprises administering an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 7 to a subject having a disease in which α4 integrin-dependent adhesion process participates in the pathology.
10. A pharmaceutical composition, comprising a compound of formula (37):
wherein R is dimethylamino or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
11. A method for inhibiting the adhesion of VCAM-1 to α4 integrin, which comprises administering an effective amount of a compound of formula (37):
wherein R is dimethylamino or a pharmaceutically acceptable salt thereof to a subject having a disease in which α4 integrin-dependent adhesion process participates in the pathology.
12. A pharmaceutical composition, comprising a compound of formula (80):
wherein R1 is dimethylamino, R2 is methyl, and R3 is H or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
13. A method for inhibiting the adhesion of VCAM-1 to α4 integrin, which comprises administering an effective amount of a compound of formula (80):
wherein R1 is dimethylamino, R2 is methyl, and R3 is H or a pharmaceutically acceptable salt thereof to a subject having a disease in which α4 integrin-dependent adhesion process participates in the pathology.
14. A pharmaceutical composition, comprising a compound of formula (80):
wherein R1 is methylamino, R2 is methyl, and R3 is H or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
15. A method for inhibiting the adhesion of VCAM-1 to α4 integrin, which comprises administering an effective amount of a compound of formula (80):
wherein R1 is methylamino, R2 is methyl, and R3 is H or a pharmaceutically acceptable salt thereof to a subject having a disease in which α4 integrin-dependent adhesion process participates in the pathology.
16. A method of making a compound of formula (9):
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 oxygen, sulfur, and nitrogen atoms;
R2, R3, and R4 may be the same or different from one another and each represent 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;
R1 represents a lower alkyl group;
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 represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkyloxy group or a nitro group;
or a pharmaceutically acceptable salt thereof,
said method comprising:
(i) reacting a compound of formula (8):
wherein:
Arm, R2, R3, R4, J, and J′ are as defined above;
P is the same as C as described above, a protected form of C, a substituent which can be converted into C, or a protected form of a substituent which can be converted into C;
Q has the structure D-T wherein D and T are described above, a protected form of D-T, a substituent which can be converted into D-T, or a protected form of a substituent which can be converted into D-T; and
Z is a solid phase carrier or a protecting group,
with (a) an alkyl halide or (b) an alcohol, to obtain said compound of formula (9) or pharmaceutically acceptable salt thereof;
(ii) if necessary, converting the group O-Z into the group B; and
(iii) if necessary, converting the group P into the group C, and converting the group Q into the group D-T.
17. The method of claim 16 , wherein said compound of formula (8) is prepared by a process comprising:
(i) reacting a compound of formula (7):
with a base, to obtain said compound of formula (8),
wherein said base is selected from the group consisting of a piperidine, tetramethylguanidine, and a mixture thereof.
18. The method of claim 17 , wherein said reacting of said compound of formula (7) with said base is carried out in a solvent which comprises dimethylformamide.
19. The method of claim 17 , wherein said compound of formula (7) is prepared by a process comprising:
(i) reacting a compound of formula (6):
with an isocyanate having a carboxylate ester group in the ortho position, to obtain said compound of formula (7).
20. The method of claim 16 , wherein said compound of formula (9) is the compound of formula (78):
wherein R is methyl or a pharmaceutically acceptable salt thereof.
21. The method of claim 16 , wherein said compound of formula (9) is the compound of formula (37):
wherein R is dimethylamino or a pharmaceutically acceptable salt thereof.
22. The method of claim 16 , wherein said compound of formula (9) is the compound of formula (80):
wherein R1 is dimethylamino, R2 is methyl, and R3 is H or a pharmaceutically acceptable salt thereof.
23. The method of claim 16 , which comprises, when Z is a solid phase carrier or a protecting group which is not a lower alkyl group, converting Z into a lower alkyl group.
24. A method of making a compound of formula (8):
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 oxygen, sulfur, and nitrogen atoms;
R1 is hydrogen;
R2, R3, and R4 may be the same or different from one another and each represent 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;
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 represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkyloxy group or a nitro group;
or a pharmaceutically acceptable salt thereof,
said method comprising:
(i) cyclizing a compound of formula (11) with a cylclizing agent selected from the group consisting of carbonyldiimidazole, triphosgene, p-nitrophenylchloroformate, and a mixture thereof:
wherein:
Arm, R2, R3, R4, J, and J′ are as defined above;
P is the same as C as described above, a protected form of C, a substituent which can be converted into C, or a protected form of a substituent which can be converted into C;
Q has the structure D-T wherein D and T are described above, a protected for of D-T, a substituent which can be converted into D-T, or a protected form of a substituent which can be converted into D-T; and
Z is a solid phase carrier or a protecting group,
with a cyclizing agent, to obtain said compound of formula (9) or pharmaceutically acceptable salt thereof;
(ii) if necessary, converting the group O-Z into the group B; and
(iii) if necessary, converting the group P into the group C, and converting the group Q into the group D-T.
25. The method of clam 24 , wherein said compound of formula (11) is prepared by a process comprising:
(i) reducing a compound of formula (10):
to obtain said compound of formula (11).
26. The method of claim 25 , wherein said reducing is carried out with a reducing agent which is at least one member selected from the group consisting of SnCl 2 , a hydrate thereof, and mixtures thereof.
27. The method of claim 25 , wherein said compound of formula (10) is prepared by a process comprising:
(i) reacting a compound of formula (6):
with an acylchloride having a nitro group in the ortho position, to obtain said compound of formula (10).
28. The method of claim 27 , wherein said reacting is carried out in the presence of 2,6-lutidine.
29. The method of claim 25 , wherein said compound of formula (10) is prepared by a process comprising:
(i) reacting a compound of formula (6):
with an activated carboxylic acid having a nitro group in the ortho position, to obtain said compound of formula (10).
30. The method of claim 24 , which comprises, when Z is a solid phase carrier or a protecting group which is not a lower alkyl group, converting Z into a lower alkyl group.
31. A method of making a compound of formula (9):
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 oxygen, sulfur, and nitrogen atoms;
R1, R2, R3, and R4 may be the same or different from one another and each represent 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;
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 represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkyloxy group or a nitro group;
or a pharmaceutically acceptable salt thereof,
said method comprising:
(i) cyclizing a compound of formula (43) with a cylclizing agent selected from the group consisting of carbonyldiimidazole, triphosgene, p-nitrophenylchloroformate, and a mixture thereof:
wherein:
Arm, R1, R2, R3, R4, J, and J′ are as defined above;
P is the same as C as described above, a protected form of C, a substituent which can be converted into C, or a protected form of a substituent which can be converted into C;
Q has the structure D-T wherein D and T are described above, a protected for of D-T, a substituent which can be converted into D-T, or a protected form of a substituent which can be converted into D-T; and
Z is a solid phase carrier or a protecting group,
with cyclizing agent which is at least one member selected from the group consisting of carbonyldiimidazole, triphosgene, p-nitrophenylchloroformate, and mixtures thereof, to obtain said compound of formula (9) or pharmaceutically acceptable salt thereof;
(ii) if necessary, converting the group O-Z into the group B; and
(iii) if necessary, converting the group P into the group C, and converting the group Q into the group D-T.
32. The method of claim 31 , wherein said compound of formula (43) is prepared by a process comprising:
(i) converting the F in a compound of formula (42):
to an amino group, to obtain said compound of formula (43).
33. The method of claim 32 , wherein said compound of formula (42) is prepared by a process comprising:
(i) reacting a compound of formula (6):
with a carboxylic acid having a fluoro group in the ortho position, to obtain said compound of formula (7).
34. The method of claim 31 , wherein said compound of formula (9) is the compound of formula (78):
wherein R is methyl or a pharmaceutically acceptable salt thereof.
35. The method of claim 31 , wherein said compound of formula (9) is the compound of formula (37):
wherein R is dimethylamino or a pharmaceutically acceptable salt thereof.
36. The method of claim 31 , wherein said compound of formula (9) is the compound of formula (80):
wherein R1 is dimethylamino, R2 is methyl, and R3 is H or a pharmaceutically acceptable salt thereof.
37. The method of claim 31 , which comprises, when Z is a solid phase carrier or a protecting group which is not a lower alkyl group, converting Z into a lower alkyl group.
38. A method for inhibiting the adhesion of VCAM-1 to α4 integrin, which comprises administering an effective amount of a compound of formula (1):
wherein:
A represents one of the following general formulae (2), (3), or (3-2):
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 oxygen, sulfur and nitrogen atoms;
the composite line of a solid line and a dotted line in the formula (3-2) represents a single bond or a double bond;
U, V, and X represent C(═O), S(═O) 2 , C(—R5)(—R6), C(═C(R5)(R6)), C(═S), S(═O), P(═O)(—OH) or P(—H)(═O);
W represents C(—R7) or a nitrogen atom;
R1, R2, R3, R4 R5, R6 and R7 may be the same or different from one another and each represent 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 represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkyloxy group or a nitro group;
provided that the phenylalanine derivatives of the general formula (1) do not include compounds having the following formula (A-1) or (A-2) when A represents the formula (3-2).
or a pharmaceutically acceptable salt thereof, to a subject having a disease in which α4 integrin-dependent adhesion process participates in the pathology.