Patent EA-000966-B1 (EA)
Title: Penicillaminamide derivatives
Inventor: OSHIMA MASAHIORO
IPC: C07K5/06
Filed: 1996-07-19
Abstract: 1. A compound represented by the following general formula (I) or a salt thereof, or a hydrate thereof and a solvate thereof:   wherein: n represents 1 or 2; R<1> represents a C1-C10 alkyl group which may be substituted with a C3-C10 cycloalkyl group or carboxyl group, a C6-C10 aryl group which may be substituted , a C3-C10 cycloalkyl group which may be substituted, or a C7-C12 aralkyl group which may be substituted; R<2> represents hydrogen atom, a C1-C10 alkyl group, a C7-C12 aralkyl group which may be substituted, -COR<4> (wherein R<4> represents hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group, a C6-C10 aryl group which may be substituted, a C6-C10 aryloxy group which may be substituted, a C3-C10 cycloalkyl group which may be substituted, a C3-C10 cycloalkyloxy group which may be substituted, a C7-C12 aralkyl group which may be substituted, or a C7-C12 aralkyloxy group), or -SO2R<5> (wherein R<5> represents a C1-C10 alkyl group, a C6-C10 aryl group which may be substituted, a C3-C10 cycloalkyl group which may be substituted, or a C7-C12 aralkyl group which may be substituted), and  R<3> represents amino group or amidino group, provided that the following compounds: the compound wherein R<1> represents methyl group, R<2> represents ethoxycarbonyl group, R<3> represents amino group, and n represents 1; the compound wherein R<1> represents methyl group, R<2> represents methylsulfonyl group, R<3> represents amino group, and n represents 1; the compound wherein R<1> represents ethyl group, R<2> represents methylsulfonyl group, R<3> represents amino group, and n represents 1; and the compound wherein R<1> represents isopropyl group, R<2> represents ethoxycarbonyl group, R<3> represents amidino group, and n represents 1 are excluded. 2. The compound or the salt thereof, or the hydrate thereof or the solvate thereof according to claim 1, wherein a functional group which may substitute on the above-defined groups is selected from the group consisting of a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, hydroxyl group, carboxyl group, a C2-C7 carboxyalkyl group, a C2-C7 carboxyalkyloxy group, a C2-C7 acyl group, a C2-C7 acyloxy group, a C2-C7 alkoxycarbonyl group, a C2-C7 alkoxycarbonyloxy group, a C8-C10 aralkyloxycarbonyl group, a C7-C9 alkoxycarbonylalkoxy group, and a halogen atom. 3. The compound or the salt thereof, or the hydrate thereof or the solvate thereof according to claim 1, wherein R<1> represents a C4-C10 alkyl group, a C6-C10 aryl group which may be substituted, a C3-C10 cycloalkyl group which may be substituted, or a C7-C12 aralkyl group which may be substituted, and R<3> represents amidino group. 4. The compound or the salt thereof, or the hydrate thereof or the solvate thereof according to claim 1, wherein R<3> represents amino group. 5. The compound or the salt thereof, or the hydrate thereof or the solvate thereof according to claim 1, wherein R<2> represents hydrogen atom, a C1-C10 alkyl group, a C7-C12 aralkyl group which may be substituted, or -COR<4> wherein R<4> is the same as that defined above. 6. The compound or the salt thereof, or the hydrate thereof or the solvate thereof according to claim 1, wherein R<2> represents -COR<4> wherein R<4> represents a C1-C10 alkyl group, a C1-C10 alkoxy group, a C6-C10 aryl group which may be substituted, a C6-C10 aryloxy group which may be substituted, a C3-C10 cycloalkyl group which m ay be substituted, a C3-C10 cycloalkyloxy group which may be substituted, a C7-C12 aralkyl group which may be substituted, or a C7-C12 aralkyloxy group which may be substituted. 7. The compound accordingto claim 1, representing trans-4-amino-[(S)-N-[(S)-2-propoxycarbonylamino-3-isopropylthio-3-methyl-butanoyl]prolyl]aminomethylcyclohexane or a salt thereof, or a hydrate thereof or a solvate thereof. 8. The compound according to claim 1, representing trans-4-amino-[(S)-N-[(S)-2-ethoxycarbonylamino-3-isopropylthio-3-methyl-butanoyl]prolyl]aminomethylcyclohexane or a salt thereof, or a hydrate thereof or a solvate thereof. 9. A medicament comprising a substance selected from the group consisting of the compound and the salt thereof, and the hydrate thereof and the solvate thereof according to any one of claims 1 to 8. 10. The pharmaceutical composition according to claim 10 used as an anticoagulant. 11. Use of penicillaminamide derivative represented by the following general formula (I) or a salt thereof, or a hydrate thereof and a solvate thereof:   wherein: n represents 1 or 2; R<1> represents a C1-C10 alkyl group which may be substituted with a C3-C10 cycloalkyl group or carboxyl group, a C6-C10 aryl group which may be substituted , a C3-C10 cycloalkyl group which may be substituted, or a C7-C12 aralkyl group which may be substituted; R<2> represents hydrogen atom, a C1-C10 alkyl group, a C7-C12 aralkyl group which may be substituted, -COR<4> (wherein R<4> represents hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group, a C6-C10 aryl group which may be substituted, a C6-C10 aryloxy group which may be substituted, a C3-C10 cycloalkyl group which may be substituted, a C3-C10 cycloalkyloxy group which may be substituted, a C7-C12 aralkyl group which may be substituted, or a C7-C12 aralkyloxy group), or -SO2R<5> (wherein R<5> represents a C1-C10 alkyl group, a C6-C10 aryl group which may be substituted, a C3-C10 cycloalkyl group which may be substituted, or a C7-C12 aralkyl group which may be substituted), and  R<3> represents amino group or amidino group, provided that the following compounds: the compound wherein R<1> represents methyl group, R<2> represents ethoxycarbonyl group, R<3> represents amino group, and n represents 1; the compound wherein R<1> represents methyl group, R<2> represents methylsulfonyl group, R<3> represents amino group, and n represents 1; the compound wherein R<1> represents ethyl group, R<2> represents methylsulfonyl group, R<3> represents amino group, and n represents 1; and the compound wherein R<1> represents isopropyl group, R<2> represents ethoxycarbonyl group, R<3> represents amidino group, and n represents 1 are excluded as protease inhibitor. 12. The pharmaceutical composition according to claim 11 used as an anticoagulant. 13. Use according to claim 11 for thrombin inhibiting.