Carbamate derivatives, process for producing the same and use thereof
View Patent ↗Novel carbamate derivatives which are useful as drugs because of inhibiting activated blood coagulation factor X and thus exerting an anticoagulant effect. Compounds represented by the formula: wherein R 1 represents a group represented by the formula: (wherein Y 1 represents CH═CH, etc.), which may be substituted, etc.; the ring A represents an oxo-substituted nitrogen-containing heterocyclic ring which may be further substituted; R 2 represents a hydrogen atom, optionally substituted C 1-4 alkyl, etc.; R 3 represents optionally substituted C 1-4 alkyl, etc.; and Z represents an optionally substituted nitrogen containing heterocyclic group, etc., or salts thereof.
1. A compound represented by the formula:
wherein R 1 denotes a group represented by the formula:
(wherein Y 1 denotes O, NH, S, CH 2 CH 2 , CH═CH, N═CH, OCH 2 , SCH 2 or two hydrogen atoms), or a group represented by the formula:
(wherein Y 2 denotes O, S, N═C or CH═CH), each of which may be substituted,
ring A is a ring represented by:
wherein n denotes 1 or 2, and m denotes 2 or 3 and may be further substituted,
R 2 denotes a hydrogen atom, an optionally substituted C 1-4 alkyl group, an optionally esterified carboxyl group or a cyano group, R 3 denotes a C 1-4 alkyl group or a C 2-4 alkenyl group, each of which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an optionally substituted alkoxy group, an optionally substituted amino group and an optionally esterified carboxyl group, and Z denotes (1) an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group, or a salt thereof.
2. The compound according to claim 1 , wherein R 1 is an optionally substituted naphthyl group.
3. The compound according to claim 1 , wherein R 1 is 6-halogeno-2-naphthyl group.
4. The compound according to claim 1 , wherein R 1 is an optionally substituted benzopyranyl group.
5. The compound according to claim 1 , wherein R 1 is 7-halogeno-2H-3-benzopyranyl group.
6. The compound according to claim 1 , wherein R 1 is an optionally substituted phenyl group.
7. The compound according to claim 1 , wherein R 1 is 4-C 2-4 alkenyl-phenyl group.
8. The compound according to claim 1 , wherein ring A is an optionally substituted oxopiperazine ring.
9. The compound according to claim 1 , wherein R 2 is a hydrogen atom.
10. The compound according to claim 1 , wherein R 3 is a C 1-4 alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an optionally substituted alkoxy group, an optionally substituted amino group and an optionally esterified carboxyl group.
11. The compound according to claim 1 , wherein R 3 is methyl, ethyl, or propyl.
12. The compound according to claim 1 , wherein Z is an optionally substituted imidoyl group.
13. The compound according to claim 1 , wherein Z is an optionally substituted C 1-4 imidoyl group.
14. The compound according to claim 1 , wherein Z is an optionally substituted amidino group.
15. The compound according to claim 1 , wherein Z is an optionally substituted nitrogen-containing heterocyclic group.
16. The compound according to claim 1 , wherein Z is a nitrogen-containing heterocyclic group which may be substituted with a substituent selected from a C 1-4 alkyl group and an optionally substituted amino group.
17. The compound according to claim 1 , wherein Z is an optionally substituted pyrimidyl group.
18. The compound according to claim 1 , wherein Z is an optionally substituted pyridyl group.
19. The compound according to claim 1 , which is a compound selected form the group consisting of 4-(6-chloronaphthalene-2-sulfonyl)-1-[4-methoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone, 4-(6-chloronaphthalene-2-sulfonyl)-1-[4-ethoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone, 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[4-methoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone, 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[4-ethoxycarbonylamino-1-(4pyridyl)piperidin-4ylmethyl]-2-piperazinone, 1-[4-methoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone, 1-[4-ethoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone, 1-[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone, 1-[4-propoxycarbonylamino-1-(4-pyridyl)piperidin-4-ylmethyl]-4-(4-vinylbenzenesulfonyl)-2-piperazinone, 1-[4-ethoxycarbonylamino-1-(4-pyridyl)piperidin-4ylmethyl]-4-(4-bromobenzensulfonyl)-2piperazinone and 1-[4ethoxycarbonylamino-1-(2-methyl-4-pyridyl)piperidin-4-ylmethyl]-4-(4-bromobenzenesulfonyl)-2-piperazinone or a salt thereof.
20. A prodrug of a compound represented by the formula:
wherein R 1 denotes a group represented by the formula:
(wherein Y 1 denotes O, NH, S, CH 2 CH 2 , CH═CH, N═CH, OCH 2 , SCH 2 or two hydrogen atoms), or a group represented by the formula:
(wherein Y 2 denotes O, S, N═C or CH═CH), each of which may be substituted,
ring A is a ring represented by:
wherein n denotes 1 or 2, and m denotes 2 or 3 and may be further substituted,
R 2 denotes a hydrogen atom, an optionally substituted C 1-4 alkyl group, an optionally esterified carboxyl group or a cyano group, R 3 denotes a C 1-4 alkyl group or a C 2-4 alkenyl group, each of which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an optionally substituted alkoxy group, an optionally substituted amino group and an optionally esterified carboxyl group, and Z denotes an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group, or a salt thereof.
21. A pharmaceutical composition, which comprises an effective amount of a compound represented by the formula:
wherein R 1 denotes a group represented by the formula:
(wherein Y 1 denotes O, NH, S, CH 2 CH 2 , CH═CH, N═CH, OCH 2 , SCH 2 or two hydrogen atoms), or a group represented by the formula:
(wherein Y 2 denotes O, S, N═C or CH═CH), each of which may be substituted,
ring A is a ring represented by:
wherein n denotes 1 or 2, and m denotes 2 or 3 and may be further substituted,
R 2 denotes a hydrogen atom, an optionally substituted C 1-4 alkyl group, an optionally esterified carboxyl group or a cyano group, R 3 denotes a C 1-4 alkyl group or a C 2-4 alkenyl group, each of which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an optionally substituted alkoxy group, an optionally substituted amino group and an optionally esterified carboxyl group, and Z denotes an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group, or a salt thereof, or a prodrug thereof and a pharmaceutically acceptable carrier.
22. A process for preparing a compound represented by the formula:
wherein each symbol is as defined hereinafter, or a salt thereof, which comprises (1) reacting a compound represented by the formula:
R 1 SO 2 Q
wherein Q denotes a leaving group, and the other symbol is as defined in claim 1 , or a salt thereof, with a compound represented by the formula:
wherein the symbols are as defined in claim 1 , or a salt thereof,
(2) reacting a compound represented by the formula:
wherein symbols are as defined in claim 1 , or a salt thereof, with a compound represented by the formula:
L 1 -Z
wherein L 1 denotes a leaving group, and the other symbol is as defined in claim 1 , or a salt thereof, or
(3) reacting a compound represented by the formula;
wherein the symbols are as defined in claim 1 , or a salt thereof, with a compound represented by the formula:
L 2 -COOR 3
wherein L 2 denotes a leaving group, and the other symbol is as defined in claim 1 , or a salt thereof.
23. A method for inhibiting blood coagulation in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof, or a prodrug thereof to the mammal.
24. A method for inhibiting activated blood coagulation factor X in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof, or a prodrug thereof to the mammal.
25. A method for preventing and/or treating cardiac infarction, cerebral thrombosis, deep vein thrombosis, pulmonary thrombotic embolus or thrombotic embolus during or after operation in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof, or a prodrug thereof to the mammal.