Claims
- 1. A carbostyril derivative or a salt thereof of formula (1): ##STR22## wherein R.sup.1 is a hydrogen atom or a group --A--R.sup.1a, wherein A is a lower alkylene group, and R.sup.1a is selected from the group consisting of a hydrogen atom, an amino group, a phthalimido group, a thienylthio group, a lower alkanoylthio group, a mercapto group, a phenyl group which may possess one to three groups selected from the group consisting of a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group and a lower alkylenedioxy group as a substituent, a carboxy group, a lower alkoxycarbonyl group, a phenylthio group, and a lower alkylthio group;
- R.sup.2 is a hydrogen atom or a lower alkyl group;
- R.sup.3 is selected from the group consisting of a hydrogen atom, a hydroxy group, a lower alkoxy group, a lower alkoxy-lower alkoxy group, a lower alkoxy-lower alkoxy-lower alkoxy group, a lower alkoxy-lower alkoxy-lower alkoxy-lower alkoxy group, and a group --B--R.sup.3a wherein B is a lower alkylene group, a lower alkenylene group or a lower alkynylene group, and R.sup.3a is selected from the group consisting of a hydrogen atom, a hydroxy group, a lower alkoxy group, a lower alkyoxy-lower alkoxy group, a phenyl group which may possess one to three groups selected from the group consisting of a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a lower alkoxy group, a carboxy group and a lower alkoxycarbonyl group as a substituent, a thienyl group which may possess a halogen atom as substituent, a phthalimido group, a carboxy group, a lower alkoxycarbonyl group, a group --CO--N(R.sup.3b)--R.sup.3c wherein R.sup.3b is a hydrogen atom or a lower alkyl group, and R.sup.3c is a hydrogen atom, a lower alkyl group or a lower alkoxy group, and a group --N(R.sup.3b)--R.sup.3c wherein R.sup.3b and R.sup.3c are as defined above and may form a saturated heterocyclic ring with five or six members which may further possess one hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom;
- R.sup.4 is selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, and a lower alkylenedioxy group;
- R.sup.5 is selected from the group consisting of a hydrogen atom, a benzoyl group, a lower alkanoyl group, and a phenyl-lower alkyl group;
- R.sup.6 is an alkyl group with 1 to 12 carbon atoms, a lower alkoxy-lower alkyl group, or a phenyl-lower alkyl group which may possess a lower alkylenedioxy group as a substituent on the phenyl ring; and
- n is 1 or 2, or its salt].
- 2. A carbostyril derivative or its salt as claimed in claim 1, wherein R.sup.2 is a hydrogen atom and R.sup.5 is a hydrogen atom.
- 3. A carbostyril derivative or its salt as claimed in claim 1, wherein R.sup.5 is a benzoyl group, a lower alkanoyl group, or a phenyl-lower alkyl group.
- 4. A carbostyril derivative or its salt as claimed in claim 2, wherein R.sup.4 is selected from the group consisting of a hydrogen atom, a halogen atom, a lower alkoxy group, and a lower alkylenedioxy group; and
- R.sup.6 is an alkyl group with 1 to 12 carbon atoms.
- 5. A carbostyril derivative or its salt as claimed in claim 2, wherein R.sup.6 is a lower alkoxy-lower alkyl group, or a phenyl-lower alkyl group which may possess a lower alkylenedioxy group as a substituent on the phenyl ring.
- 6. A carbostyril derivative or its salt as claimed in claim 4, wherein R.sup.1 is a hydrogen atom or a group --A--R.sup.1a wherein A is a lower alkylene group; and R.sup.1a is selected from the group consisting of a hydrogen atom, a phthalimido group, a thienylthio group, a lower alkanoylthio group, and a phenyl group which may possess one to three groups selected from the group consisting of a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group and a lower alkylenedioxy group as a substituent.
- 7. A carbostyril derivative or its salt as claimed in claim 4, wherein R.sup.1 is a group --A--R.sup.1a wherein A is a lower alkylene group, and R.sup.1a is selected from the group consisting of an amino group, a mercapto group, a carboxy group, a lower alkoxycarbonyl group, a phenylthio group, and a lower alkylthio group.
- 8. A carbostyril derivative or its salt as claimed in claim 4, wherein R.sup.3 is a hydrogen atom, or a group --B--R.sup.3a wherein B is a lower alkylene group, a lower alkenylene group or a lower alkynylene group, and R.sup.3a is selected from the group consisting of a hydrogen atom, a lower alkoxy group, a lower alkoxy-lower alkoxy group, a carboxy group, and a group --CO--N(R.sup.3b)--R.sup.3c wherein R.sup.3b is a hydrogen atom or a lower alkyl group, and R.sup.3c is a hydrogen atom, a lower alkyl group or a lower alkoxy group.
- 9. A carbostyril derivative or its salt as claimed in claim 8, wherein R.sup.1 is a hydrogen atom or a group --A--R.sup.1a wherein A is a lower alkylene group, and R.sup.1a is selected from the group consisting of a hydrogen atom, a phthalimido group, a thienylthio group, a lower alkanoylthio group, and a phenyl group which may possess one to three groups selected from the group consisting of a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group and a lower alkylenedioxy group as a substituent.
- 10. A carbostyril derivative or its salt as claimed in claim 9, wherein R.sup.3 is a group --B--R.sup.3a wherein B is a lower alkylene group, and R.sup.3a is a lower alkoxy group or a lower alkoxy-lower alkoxy group.
- 11. A carbostyril derivative or its salt as claimed in claim 10, wherein R.sup.1 is a hydrogen atom or a group --A--R.sup.1a wherein A is a lower alkylene group, and R.sup.1a is a hydrogen atom.
- 12. A carbostyril derivative or its salt as claimed in claim 9, wherein R.sup.3 is a hydrogen atom, or a group --B--R.sup.3a wherein B is a lower alkylene group, and R.sup.3a is a hydrogen atom, a carboxy group, or a group --CO--N(R.sup.3b)--R.sup.3c wherein R.sup.3b is a hydrogen atom or a lower alkyl group, and R.sup.3c is a hydrogen atom, a lower alkyl group or a lower alkoxy group.
- 13. A carbostyril derivative or its salt as claimed in claim 12, wherein R.sup.1 is a hydrogen atom or a group --A--R.sup.1a wherein A is a lower alkylene group, and R.sup.1a is a hydrogen atom.
- 14. A carbostyril derivative or its salt as claimed in claim 9, wherein R.sup.3 is a group --B--R.sup.3a wherein B is a lower alkenylene group or a lower alkynylene group, and R.sup.3a is selected from the group consisting of a hydrogen atom, a lower alkoxy group, a lower alkoxy-lower alkoxy group, a carboxy group, and a group --CO--N(R.sup.3b)--R.sup.3c wherein R.sup.3b is a hydrogen atom or a lower alkyl group, and R.sup.3c is a hydrogen atom, a lower alkyl group or a lower alkoxy group.
- 15. A carbostyril derivative or its salt as claimed in claim 4, wherein R.sup.3 is selected from the group consisting of a hydroxy group, a lower alkoxy group, a lower alkoxy-lower alkoxy group, a lower alkoxy-lower alkoxy-lower alkoxy group, and a lower alkoxy-lower alkoxy-lower alkoxy-lower alkoxy group.
- 16. A carbostyril derivative or its salt as claimed in claim 15, wherein R.sup.1 is a hydrogen atom or a group --A--R.sup.1a wherein A is a lower alkylene group, and R.sup.1a is selected from the group consisting of a hydrogen atom, a phthalimido group, a thienylthio group, a lower alkanoylthio group, and a phenyl group which may possess one to three groups selected from the group consisting of a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group and a lower alkylenedioxy group as a substituent.
- 17. A carbostyril derivative or its salt as claimed in claim 16, wherein R.sup.1 is a hydrogen atom or a group --A--R.sup.1a wherein A is a lower alkylene group, and R.sup.1a is a hydrogen atom.
- 18. A carbostyril derivative or its salt as claimed in claim 17, wherein R.sup.3 is a lower alkoxy group.
- 19. A carbostyril derivative or its salt as claimed in claim 4, wherein R.sup.3 is a group --B--R.sup.3a wherein B is selected from the group consisting of a lower alkylene group, a lower alkenylene group and a lower alkynylene group, and R.sup.3a is selected from the group consisting of a hydroxy group, a phenyl group which may possess one to three groups selected from the group consisting of a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a lower alkoxy group, a carboxy group and a lower alkoxycarbonyl group as a substituent, a thienyl group which may possess a halogen atom as a substituent, a phthalimido group, a lower alkoxycarbonyl group and a group --CO--N(R.sup.3b)--R.sup.3c wherein a group --N(R.sup.3b)--R.sup.3c forms a saturated heterocyclic ring with five or six members which may further possess one hetero atom selected from the group consisting of a nitrogen atom, a oxygen atom and a sulfur atom.
- 20. A method of preparing a carbostyril derivative of formula (1): ##STR23## wherein R.sup.1 is a hydrogen atom or a group --A--R.sup.1a wherein A is a lower alkylene group, and R.sup.1a is selected from the group consisting of a hydrogen atom, an amino group, a phthalimido group, a thienylthio group, a lower alkanoylthio group, a mercapto group, a phenyl group which may possess one to three groups selected from the group consisting of a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group and a lower alkylenedioxy group as a substituent, a carboxy group, a lower alkoxycarbonyl group, a phenylthio group, and a lower alkylthio group;
- R.sup.2 is a hydrogen atom or a lower alkyl group;
- R.sup.3 is selected from the group consisting of a hydrogen atom, a hydroxy group., a lower alkoxy group, a lower alkoxy-lower alkoxy group, a lower alkoxy-lower alkoxy-lower alkoxy group, a lower alkoxy-lower alkoxy-lower a alkoxy-lower alkoxy group, and a group --B--R.sup.3a wherein B is a lower alkylene group, a lower alkenylene group or a lower alkynylene group, and R.sup.3a is selected from the group consisting of a hydrogen atom, a hydroxy group, a lower alkoxy group, a lower alkyoxy-lower alkoxy group, a phenyl group which may possess one to three groups selected from the group consisting of a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a lower alkoxy group, a carboxy group and a lower alkoxycarbonyl group as a substituent, a thienyl group which may possess a halogen atom as substituent, a phthalimido group, a carboxy group, a lower alkoxycarbonyl group, a group --CO--N(R.sup.3b)--R.sup.3c wherein R.sup.3b is a hydrogen atom or a lower alkyl group, and R.sup.3c is a hydrogen atom, a lower alkyl group or a lower alkoxy group, and a group --N(R.sup.3b)--R.sup.3c wherein R.sup.3b and R.sup.3c are as defined above and may form a saturated heterocyclic ring with five or six members which may further possess one hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom;
- R.sup.4 is selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, and a lower alkylenedioxy group;
- R.sup.5 is selected from the group consisting of a hydrogen atom, a benzoyl group, a lower alkanoyl group, and a phenyl-lower alkyl group;
- R.sup.6 is an alkyl group with 1 to 12 carbon atoms, a lower alkoxy-lower alkyl group, or a phenyl-lower alkyl group which may possess a lower alkylenedioxy group as a substituent on the phenyl ring; and
- n is 1 or 2,
- which comprises the step of reducing or saponifying a compound of the formula (1-A): ##STR24## to provide a compound of the formula (1-B): ##STR25## wherein in the above formulas, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6 and n are the same meanings as defined above in formula (1), and R.sup.5' is a benzoyl group, a lower alkanoyl group or a phenyl-lower alkyl group.
- 21. An extracellular matrix metalloproteinases inhibitor composition comprising a pharmacologically effective amount of a carbostyril derivative defined in claim 1 or its salt and a pharmacologically-acceptable carrier.
- 22. A carbostyril derivative or its salt as claimed in claim 2, wherein R.sup.4 is a lower alkylenedioxy group and n is 1.
- 23. A carbostyril derivative or its salt as claimed in claim 22, wherein R.sup.1 is a hydrogen atom, R.sup.3 is a lower alkyl group and R.sup.6 is an alkyl group with 1 to 12 carbon atoms.
- 24. A carbostyril derivative or its salt as claimed in claim 23, wherein R.sup.3 is a methyl group or an ethyl group, and R.sup.6 is a lower alkyl group.
- 25. A carbostyril derivative or its salt which is selected from the group consisting of:
- 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methyl-6,7-methylenedioxy-3,4-dihydrocarbostyril;
- 1-ethyl-3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-6,7-methylenedioxy-3,4-dihydrocarbostyril;
- 1-ethyl-3S-[4-(N-hydroxyamino)-2R-pentylsuccinyl]amino-6,7-methylenedioxy-3,4-dihydrocarbostyril;
- 3S-[4-(N-hydroxyamino)-2R-pentylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril; and
- 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxymethoxy-3,4-dihydrocarbostyril.
- 26. A carbostyril derivative that is 1-ethyl-3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-6,7-methylenedioxy-3,4-dihydrocarbostyril or its salt.
- 27. A carbostyril derivative or a salt thereof selected from the group consisting of 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril,
- 3S-[4-(N-hydroxyamino)-2R-isobutyl-3S-acetylthiomethylsuccinyl]amino-3,4-dihydrocarbostyril,
- 3S-[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril,
- 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxymethyl-3,4-dihydrocarbostyril,
- 1-carboxymethyl-3S-[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-3,4-dihydrocarbostyril,
- 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxyethoxymethyl-3,4-dihydrocarbostyril,
- 3S-[4-(N-hydroxyamino)-2R-heptylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril,
- 7-chloro-3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxymethyl-3,4-dihydrocarbostyril,
- 3S-[4-(N-hydroxyamino-2R-isobutylsuccinyl]amino-1-methoxyethyl-3,4-dihydrocarbostyril,
- 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxyethyl-6,7-methylenedioxy-3,4-dihydrocarbostyril, and
- 3R-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxyethyl-6,7-methylenedioxy-3,4-dihydrocarbostyril.
Priority Claims (3)
| Number |
Date |
Country |
Kind |
| 5-58264 |
Mar 1993 |
JPX |
|
| 5-256873 |
Oct 1993 |
JPX |
|
| 6-216890 |
Sep 1994 |
JPX |
|
CROSS REFERENCE TO RELATED APPLICATION
This application is a Continuation-in-part of Ser. No. 08/338,600 filed Nov. 18, 1994, now abandoned which is a 371 of PCT/JP94/00434, filed Mar. 17, 1994.
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Non-Patent Literature Citations (1)
| Entry |
| Chemical Abstracts, 122:230797, 1994. |
Continuation in Parts (1)
|
Number |
Date |
Country |
| Parent |
338600 |
Nov 1994 |
|
Patent Grant
5594006
