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Details for Patent: 5,591,744

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Details for Patent: 5,591,744

Title: Benzoheterocyclic compounds
Abstract:Novel 4-oxoquinoline-3-carboxylic acid compounds of the formula: ##STR1## wherein R.sup.1 is cyclopropyl which may have 1 to 3 substituents of alkyl and halogen; phenyl which may be substituted by 1 to 3 substituents of alkoxy, halogen and OH; alkyl which may be substituted by halogen, alkanoyloxy or OH; alkenyl; or thienyl, R.sup.2 is 5- to 9-membered saturated or unsaturated heterocyclic ring which may be sustituted, R.sup.3 is alkyl or halogen, R.sup.4 is alkyl or halogen, R is H or alkyl, R.sup.1 and R.sup.3 may be taken together to form ##STR2## wherein R.sup.31 is H or alkyl, and X is halogen, provided that R.sup.3 and R.sup.4 are not simultaneously halogen, and salts thereof, said compounds having excellent antimicrobial activity and hence being useful as an antimicrobial agent, and a pharmaceutical composition containing said compound as an active ingredient.
Inventor(s): Ueda; Hiraki (Mishima, JP), Miyamoto; Hisashi (Tokushima, JP), Yamashita; Hiroshi (Tokushima, JP), Tone; Hitoshi (Itano, JP)
Assignee: Otsuka Pharmaceutical Company, Limited (Tokyo-to, JP)
Filing Date:Apr 08, 1988
Application Number:07/179,300
Claims:1. A compound of the formula: ##STR40## wherein R.sup.1 is a cyclopropyl which may be substituted by 1 to 3 of substituents selected from the group consisting of a C.sub.1 -C.sub.6 alkyl and a halogen atom; a phenyl which may be substituted by 1 to 3 of substituents selected from the group consisting of a C.sub.1 -C.sub.6 alkoxy, a halogen atom and hydroxy on phenyl ring; a C.sub.1 -C.sub.6 alkyl which may be substituted by a halogen atom, a C.sub.1 -C.sub.6 alkanoyloxy or hydroxy; a C.sub.2 -C.sub.6 alkenyl; or thienyl,

R.sup.2 is a 1-piperazinyl group which may have 1 to 3 substituents selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, and a 2-oxo-1,3-dioxolenemethyl group which may be substituted by phenyl group or a C.sub.1 -C.sub.6 alkyl group,

R.sup.3 is a C.sub.1 -C.sub.6 alkyl, or a halogen atom,

R.sup.4 is a C.sub.1 -C.sub.6 alkyl,

R is hydrogen atom or a C.sub.1 -C.sub.6 alkyl, and

X is a halogan atom, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R.sup.1 is a phenyl which may have 1 to 3 substituents selected from the group consisting of a C.sub.1 -C.sub.6 alkoxy group, a halogen atom and hydroxy group, or a C.sub.1 -C.sub.6 alkyl group which may by substituted by a halogen atom, a C.sub.2 -C.sub.6 alkanoyloxy group or hydroxy group, R is hydrogen atom, and X is fluorine atom, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein R.sup.1 is a C.sub.2 -C.sub.6 alkenyl group or thienyl group, R is hydrogen atom, and X is fluorine atom, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, wherein R.sup.1 is unsubstituted cyclopropyl, R is hydrogen atom, X is fluorine atom, R.sup.3 is a halogen atom, and R.sup.4 is a C.sub.1 -C.sub.6 alkyl group, or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein R.sup.1 is unsubstituted cyclopropyl, R is hydrogen atom, X is fluorine atom, R.sup.3 and R.sup.4 are each a C.sub.1 -C.sub.6 alkyl group, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 4, wherein R.sup.2 is a group of the formula: ##STR41## wherein R.sup.a is hydrogen atom or a C.sub.1 -C.sub.6 alkyl group, R.sup.b is hydrogen atom, a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 alkanoyl group, a phenyl(C.sub.1 -C.sub.6)alkyl group, or a 2-oxo-1,3-dioxolenemethyl group which is substituted by a C.sub.1 -C.sub.6 alkyl group, R.sup.c is hydrogen atom or a C.sub.1 -C.sub.6 alkyl group, or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6, wherein R.sup.a is hydrogen atom or a C.sub.1 -C.sub.6 alkyl group, R.sup.b is hydrogen atom or a C.sub.1 -C.sub.6 alkyl group, R.sup.c is hydrogen atom, R.sup.3 is fluorine or chlorine atom, and R.sup.4 is methyl group, or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 6, wherein R.sup.a is hydrogen atom or a C.sub.1 -C.sub.6 alkyl group, R.sup.b is hydrogen atom or a C.sub.1 -C.sub.6 alkyl group, R.sup.c is hydrogen atom, R.sup.3 is fluorine or chlorine atom, and R.sup.4 is ethyl group, or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 7, wherein R.sup.3 is fluorine atom, or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 8, wherein R.sup.3 is fluorine atom, or a pharmaceutically acceptable salt thereof.

11. 7-(1-piperazinyl)-1-cyclopropyl-6, 8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

12. 7-(3-Methyl-1-piperazinyl)-1-cyclopropyl-6, 8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

13. An antimicrobial composition which comprises as an essential active ingredient an effective amount of a compound as set forth in claim 1 in admixture with a pharmaceutically acceptable carrier or diluent.

14. The composition according to claim 13, wherein the active compound is 7-(1-piperazinyl)-1-cyclopropyl-6, 8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

15. The composition according to claim 13, wherein the active compound is 7-(3-methyl-1-piperazinyl)-1-cyclopropyl-6, 8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

16. A compound of the formula: ##STR42## wherein R.sup.1 is cyclopropyl which may be substituted by 1 to 3 substituents selected from the group consisting of lower alkyl and a halogen atom; phenyl which may be substituted by 1 to 3 substituents selected from the group consisting of lower alkoxy, a halogen atom and hydroxy; lower alkyl which may be substituted by a halogen atom, lower alkanoyloxy or hydroxy; lower alkenyl; or thienyl; R.sup.2 is a 5-to 9-membered saturated or unsaturated heterocyclic ring which may be substituted,

R.sup.3 is lower alkyl or a halogen atom, R.sup.4 is lower alkyl, R is a hydrogen atm or lower alkyl,

X is a halogen atom, or a pharmaceutically acceptable salt thereof.

17. A compound of the formula: ##STR43## wherein R.sup.1 is a cyclopropyl which may be substituted by 1 to 3 substituents selected from the group consisting of lower alkyl and a halogen atom; R.sup.2 is a 5- to 9-membered saturated or unsaturated heterocyclic ring which may be substituted,

R.sup.3 is lower alkyl or a halogen atom, R.sup.4 is lower alkyl, R is a hydrogen atom or lower alkyl,

X is a halogen atom, or a pharmaceutically acceptable salt thereof.

18. 7-(3-Amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-5-methyl- 1, 4-dihydro-4-oxoquinoline-3-carboxylic acid.

19. A compound of the formula: ##STR44## wherein R is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group; R.sup.1A is a cyclopropyl which may be substituted by 1 to 3 of substituents selected from the group consisting of a C.sub.1 -C.sub.6 alkyl and a halogen atom; a phenyl which may be substituted by 1 to 3 of substituents selected from the group consisting of a C.sub.1 -C.sub.6 alkoxy, a halogen atom and hydroxy on the phenyl ring; a C.sub.1 -C.sub.6 alkyl which may be substituted by a halogen atom, a C.sub.1 -C.sub.6 alkanoyloxy or hydroxy; a C.sub.2 -C.sub.6 alkenyl; or thienyl;

R.sup.2 is a 1-pynolidinyl group which may have 1 to 3 substituents selected from the group consisting of an amino group which may have 1 to 2 substituents selected from a C.sub.1 -C.sub.6 alkyl group and a (C.sub.1 -D.sub.6)alkoxy-carbonyl group, an amino(C.sub.1 -C.sub.6)alkyl group which may have 1 to 2 substituents selected from a C.sub.1 -C.sub.6 alkyl group and a (C.sub.1 C.sub.6)alkoxy-carbonyl group on the amino moiety, and a C.sub.1 -C.sub.6 alkyl group; or a morpholino group which may have 1 to 3 substituents of C.sub.1 -C.sub.6 alkyl groups; or a 1-piperidinyl group which may have 1 to 3 substituents selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, hydroxy, a halogen atom, and oxo group; or 1,4-diazabicyclo[4.3.0]nonan-4-yl group;

R.sup.3A is a C.sub.1 -C.sub.6 alkyl group, or a halogen atom;

R.sup.4 is a C.sub.1 -C.sub.6 alkyl group; and

X is a halogen atom,

or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 19, wherein R.sup.1A is a C.sub.2 -C.sub.6 alkenyl group or a thienyl group, R is a hydrogen atom, and X is a fluorine atom, or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 19, wherein R.sup.1A is unsubstituted cyclopropyl, R is a hydrogen atom, X is a fluorine atom, R.sup.3A is a halogen atom, and R.sup.4 is a C.sub.1 -C.sub.6 alkyl group, or a pharmaceutically acceptable salt thereof.

22. The compound according to claim 19, wherein R.sup.1A is a phenyl which may be substituted by 1 to 3 of substituents selected from the group consisting of a C.sub.1 -C.sub.6 alkoxy, a halogen atom and hydroxy on the phenyl ring, or R.sup.1A is a C.sub.1 -C.sub.6 alkyl group which may be substituted by a halogen atom, a C.sub.2 -C.sub.6 alkanoyloxy or hydroxy; R is a hydrogen atom; and X is a fluorine atom, or a pharmaceutically acceptable salt thereof.

23. The compound according to claim 19, wherein R.sup.1A is unsubstituted cyclopropyl, R is a hydrogen atom, X is a fluorine atom, R.sup.3A and R.sup.4 are each a C.sub.1 -C.sub.6 alkyl group, or a pharmaceutically acceptable salt thereof.

24. The compound according to claim 19, wherein R.sup.1A is unsubstituted cyclopropyl, R is a hydrogen atom, X is a fluorine atom, R.sup.3A is a halogen atom, and R.sup.4 is a C.sub.1 -C.sub.6 alkyl group, and R.sub.2 is a 1-pyrrolidinyl group which may have 1 to 3 substituents selected from the group consisting of an amino group which may have 1 to 2 substituents selected from a C.sub.1 -C.sub.6 alkyl group and a (C.sub.1 -C.sub.6)alkoxy-carbonyl group, an amino-(C.sub.1 -C.sub.6)alkyl group which may have 1 to 2 substituents selected from a C.sub.1 -C.sub.6 alkyl group and a (C.sub.1 -C.sub.6)alkoxy-carbonyl group on the amino moiety, and a C.sub.1 -C.sub.6 alkyl group, or a pharmaceutically acceptable salt thereof.

25. The compound according to claim 24, wherein R.sup.2 is a group of the ##STR45## wherein R.sup.f is an amino which may have 1 to 2 substituents selected from a C.sub.1 -C.sub.6 alkyl group and a (C.sub.1 -C.sub.6)alkoxy-carbonyl group, or an amino (C.sub.1 -C.sub.6)alkyl group which may have 1 to 2 substituents selected from a C.sub.1 -C.sub.6 alkyl group and a (C.sub.1 -C.sub.6)alkoxy-carbonyl group on the amino moiety, R.sup.g is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group; R.sup.3A is a fluorine or chlorine atom; and R.sup.4 is a methyl or ethyl group; or a pharmaceutically acceptable salt thereof.

26. The compound according to claim 25, wherein R.sup.3A is a fluorine atom, and R.sup.4 is a methyl group, or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 19, wherein R.sup.1A is unsubstituted cyclopropyl, R is a hydrogen atom, X is a fluorine atom, R.sup.3A is a halogen atom, and R.sup.4 is a C.sub.1 -C.sub.6 alkyl group, and R.sup.2 is a morpholino group which may have 1 to 3 substituents of C.sub.1 -C.sub.6 alkyl groups, or a pharmaceutically acceptable salt thereof.

28. The compound according to claim 27, wherein R.sup.2 is a group of the formula: ##STR46## wherein R.sup.d is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group, R.sup.e is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group, R.sup.3A is a fluorine or chlorine atom; R.sup.4 is a methyl or ethyl group, or a pharmaceutically acceptable salt thereof.

29. The compound according to claim 28, wherein R.sup.3A is a fluorine atom, and R.sup.4 is a methyl group, or a pharmaceutically acceptable salt thereof.

30. The compound according to claim 19, wherein R.sup.1A is unsubstituted cyclopropyl, R is a hydrogen atom, X is a fluorine atom, R.sup.3A is a halogen atom, and R.sup.4 is a C.sub.1 -C.sub.6 alkyl group, and R.sup.2 is a 1-piperidinyl group which may have 1 to 3 substituents selected from the group consisting of a C.sub.1 -C.sub.6 alkyl group, hydroxy, a halogen atom, and oxo group, or a pharmaceutically acceptable salt thereof.

31. The compound according to claim 30, wherein R.sup.2 is a group of the formula: ##STR47## wherein R.sup.h is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group, R.sup.i is a hydrogen atom, hydroxy, a halogen atom or oxo group, R.sup.j is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group; R.sup.3A is a fluorine or chlorine atom; R.sup.4 is a methyl or ethyl group; or a pharmaceutically acceptable salt thereof.

32. The compound according to claim 31, wherein R.sup.3A is a fluorine atom and R.sup.4 is a methyl group, or a pharmaceutically acceptable salt thereof.

33. The compound according to claim 19, wherein R.sup.1A is unsubstituted cyclopropyl, R is a hydrogen atom, X is a fluorine atom, R.sup.3A is a halogen atom, and R.sup.4 is a C.sub.1 -C.sub.6 alkyl group, and R.sup.2 is 1,4-diazomcyclo[4.3.0]nonan-4-yl 4-yl group, or pharmaceutically acceptable salt thereof.

34. The compound according to claim 33, wherein R.sup.3A is a fluorine or chlorine atom and R.sup.4 is a methyl or ethyl group, or a pharmaceutically acceptable salt thereof.

35. The compound according to claim 34, wherein R.sup.3A is a fluorine atom and R.sup.4 is a methyl group, or a pharmaceutically acceptable salt thereof.

36. An antimicrobial composition which comprises as an active ingredient an effective amount of a compound as set forth in claim 18 in admixture with a pharmaceutically acceptable carrier or diluent.

37. An antimicrobial composition which comprises as an active ingredient an effective amount of a compound as set forth in claim 19 in admixture with a pharmaceutically acceptable carrier or diluent.
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