Phenylalanine derivatives
Specific 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 pharmaceutical composition comprising a phenylalanine compound of formula (2) or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier thereof, wherein
R21 represents a hydroxyl group, an alkoxyl group having 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with one or more methyl groups or one or more methoxy groups,
R22 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,
R24 represents a methyl group or an ethyl group,
R 2 ′ represents a hydrogen atom, a fluorine atom or a chlorine atom,
X 2 represents —CH(R2a)-, —CH 2 CH 2 — or —N(R2a)CH 2 CH 2 —, wherein R2a represents a hydrogen atom or a methyl group, and
Y 21 and Y 22 represent either one of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).
2. A pharmaceutical composition comprising a phenylalanine compound of formula (3) or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier thereof, wherein
R31 represents a hydroxyl group, an alkoxyl group having 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with one or more methyl groups or one or more methoxy groups,
R 34 represents a methyl group or an ethyl group,
R3′ represents a hydrogen atom or a fluorine atom,
the formula (3-1) represents 4-morpholinyl group, 4-thiomorpholinyl group, 3-tetrahydrothiazolyl group, 1-piperazinyl group of which the fourth position may be substituted with an alkyl group having 1 to 3 carbon atoms, or 1-imidazolyl group which may be substituted with a methyl group, an ethyl group or an amino group,
wherein X3 represents an oxygen atom, a nitrogen atom which may be substituted with an alkyl group having 1 to 3 carbon atoms, or a sulfur atom, and
Y 31 and Y 32 represent either one of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).
3. A pharmaceutical composition comprising a phenylalanine compound of formula (4) or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier thereof, wherein
R 41 represents a hydroxyl group, an alkoxyl group having 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with one or more methyl groups or one or more methoxy groups,
Ring represents a benzene ring, a pyridine ring, a thiophene ring, a piperidine ring of which the first position may be substituted with an alkyl group having 1 to 3 carbon atoms, a piperazine ring of which the first and/or fourth position may be substituted with an alkyl group having 1 to 3 carbon atoms, or a pyrrolidine ring of which the first position may be substituted with an alkyl group having 1 to 3 carbon atoms,
R 44 represents a methyl group or an ethyl group, and
Y 41 and Y 42 represent either one of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).
4. A pharmaceutical composition comprising a phenylalanine compound of formula (8) or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier thereof, wherein
R 81 represents a hydroxyl group, an alkoxyl group having 1 to 6 carbon atoms, a morpholinoethyloxy group, a benzyloxy group which may be substituted with one or more methyl groups or one or more methoxy groups, or hydroxyethyl group,
R 82 represents a methyl group or an ethyl group,
R 84 represents a methyl group or an ethyl group,
n 8 represents an integer from 0 to 2, and
Y 81 and Y 82 represent either one of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).
5. A pharmaceutical composition comprising a phenylalanine compound of formula (9) or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier thereof, wherein
R 91 represents a hydroxyl group, an alkoxyl group having 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with one or more methyl groups or one or more methoxy groups,
R 92 represents a hydroxyl group, an alkoxyl group having 1 to 6 carbon atoms, an amino group or a benzyloxy group which may be substituted with one or more methyl groups or one or more methoxy groups,
R 94 represents a methyl group or an ethyl group,
X 9 represents an atomic bond, —CH 2 —, —CH 2 CH 2 — or —CH═CH—, and
Y 91 and Y 92 represent either one of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).
6. A pharmaceutical composition comprising a phenylalanine compound of formula (11) or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier thereof, wherein
R 111 represents an alkoxyl group having 1 to 6 carbon atoms or a morpholinoethyloxy group,
R 114 represents a methyl group or an ethyl group, and
Y 111 and Y 112 represent either one of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).
7. A pharmaceutical composition comprising a phenylalanine compound of formula (13) or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier thereof, wherein
R131 represents a hydroxyl group, an alkoxyl group having 1 to 6 carbon atoms, a morpholinoethyloxy group or a benzyloxy group which may be substituted with one or more methyl groups or one or more methoxy groups, R13a and R13b each independently represent an alkyl group having 1 to 3 carbon atoms, or N(R13a)R13b represents 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group, 4-thiomorpholinyl group, 3-tetrahydrothiazolyl group or 1-piperazinyl group of which the fourth position may be substituted with an alkyl group having 1 to 3 carbon atoms, and
Y 131 and Y 132 represent either one of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).
8. A pharmaceutical composition comprising a phenylalanine compound of formula (14) or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier thereof, wherein
R141 represents a hydroxyl group, an alkoxyl group having 1 to 6 carbon atoms or a morpholinoethyloxy group,
R144 represents a methyl group or an ethyl group,
a hydroxyl group on a quinazolinedione ring is located on the sixth or seventh position of the ring, and
Y 141 and Y 142 represent either one of the combinations, (Cl, Cl), (Cl, Me), (Cl, F), (F, F) and (F, Me).