Peripheral vasodilators

Details Peripheral vasodilators Peripheral vasodilators

1994-10-14

1997-01-07

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

546156, A61K 3147, C07D215227, C07D21548

Patent

active

055917518

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The present invention relates to peripheral vasodilators each comprising a carbostyril derivative as an active ingredient, as well as to novel carbostyril derivatives having an excellent peripheral vasodilating activity.
There have been made a number of studies on various carbostyril derivatives and their pharmacological activities. For example, Japanese Patent Application Kokai (Laid-Open) No. 3182/1989 describe that the carbostyril derivatives represented by the following general formula: ##STR2## [wherein, R is a group of the formula: ##STR3## or a group of the formula: ##STR4## (R.sup.1' is a group of the formula: --NR.sup.4' R.sup.5' or the like; R.sup.2' is a hydrogen atom or a lower alkyl group; and R.sup.3' is a hydrogen atom, a lower alkyl group or the like)] have a myocardial contraction increasing activity, a coronary blood flow increasing activity, a hypotensive activity, a norepinephrin vasocontraction inhibitory effect and an anti-inflammatory effect and are useful as a cardiotonic for treating various heart diseases, an anti-hypertensive agent and an anti-inflammatory agent. It is not known, however, that such carbostyril derivatives have a peripheral vasodilating activity.
In addition to the above, various carbostyril derivatives, each of which having chemical structural formula similar to that of the carbostyril derivative represented by the below-mentioned general formula (1), have been known in some prior art references, for example Japanese Patent Kokai (Laid-open) No. Sho 57-171974 (1982) [Japanese Patent Publication No. Sho 64-9313 (1989)]; Japanese Patent Kokai (Laid-open) No. Sho 57-154129 (1982) [Japanese Patent Publication No. Sho 64-53248 (1989)]; Japanese Patent Kokai (Laid-open) No. Sho 59-29668 (1984) [Japanese Patent Publication No. Hei 2-22751 (1990)]; Japanese Patent Kokai (Laid-open) Nos. Sho 54-16478 (1979); Sho 55-85520 (1980); Sho 51-65770 (1976); Sho 51-68574 (1976); Sho 51-118771 (1976); Sho 52-282 (1977); Sho 52-283 (1977); Sho 51-118474 (1977); Sho 52-83380 (1977); Sho 63-35562 (1988) as well as U.S. Pat. Nos. 4,487,772; 4,454,130; 4,468,402; 4,886,809; 5,071,856 (EP-A-0255134); U.S. Pat. No. 4,845,100 (EP-A-0202760); U.S. Pat. Nos. 4,514,401; 4,455,422; 4,567,187; 4,460,593; 4,619,932 and 5,008,274 (EP-A-0240015).
The carbostyril derivatives disclosed in the above-mentioned prior art references indeed possess certain pharmacological activities, for example myocardial contraction increasing activity (positive inotropic activity), coronary blood flow increasing activity, hypotensive activity and antiinflammatory activity, etc. However, such known carbostyril derivatives do not possess any peripheral vasodilating activities at all.
Hence, development of novel carbostyril derivatives having a peripheral vasodilating activity has been desired.


SUMMARY OF THE INVENTION

The present inventors synthesized a number of carbostyril derivatives and examined their pharmacological activities. As a result, the present inventors found that each of the carbostyril derivatives represented by the following general formula (1) and their salts ##STR5## (wherein, R.sup.1 represents a hydrogen atom or a lower alkyl group; R.sup.2 and R.sup.3, which may be the same or different, each represent a hydrogen atom, a lower alkyl group, a phenylthio-lower alkyl group, a phenoxy-lower alkyl group which may have, on the phenyl ring, 1-3 substituents selected from the group consisting of halogen atoms and lower alkoxy groups, or a phenyl-lower alkyl group; R.sup.4 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group or a phenyl-lower alkylamino group; and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton represents a single bond or a double bond) have peripheral vasodilating activity and are useful as peripheral vasodilators.
The present inventors further found that, among the carbostyril derivatives represented by the above general formula (1) and their salts, the carbostyril derivatives rep

REFERENCES:
patent: 4454130 (1984-06-01), Tominaga
patent: 4468402 (1984-08-01), Tominaga
patent: 4487772 (1984-12-01), Tominaga
patent: 5306719 (1994-04-01), Tamada
Copy of International Search Report dated Jun. 15, 1994 for International Application No. PCT/JP94/00157.

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