Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-01-18
1996-07-30
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546157, 546158, A61K 3147, C07D40112
Patent
active
055411983
DESCRIPTION:
BRIEF SUMMARY
This application is the National phase of PCT/JP94/00760 filed on May 11, 1994.
INDUSTRIAL FIELD OF UTILIZATION
The present invention relates to novel carbostyril derivatives.
DISCLOSURE OF THE INVENTION
The carbostyril derivatives of the present invention are represented by the following general formula (1): ##STR4## [wherein, R.sup.1 is a hydrogen atom, a fluorine atom or a methyl group; R is a group of the formula ##STR5## (R.sup.2 is a methyl group, a trifluoromethyl group or a nitro group), or a group of the formula ##STR6## (R.sup.3 is a fluorine atom and p is an integer of 2 or 3); and n is an integer of 2 or 3].
The carbostyril derivatives of the present invention have a strong activity for inhibiting the adhesion of platelets and show low adverse effects to the cardiovascular system, etc., and are useful agent for treatment and prevention of arteriosclerotic diseases and thrombotic diseases.
PRIOR ART
Japanese Patent Application Kokai (Laid-Open) No. 45220/1988 (corresponding to EP-A-0240015 and U.S. Pat. No. 5,008,274) discloses the carbostyril compounds represented by the following general formula: ##STR7## (wherein, R is an unsaturated heterocyclic residual group having 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; said unsaturated heterocyclic residual group may have, on the heterocyclic residual ring, 1 to 3 substituents selected from the group consisting of an oxo group; a thio group; a phenyl group; a phenyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group, a halo-lower alkyl group, a halogen atom, a hydroxyl group, an amino group, a lower alkylamino group, a carboxyl group and a lower alkoxy group; a cycloalkyl group; a phenylthio group; a lower alkyl group; a lower alkyl group having 1 to 2 substituents selected from the group consisting of an amino group, a lower alkylamino group and a carboxyl group; an amino group; a hydroxyl group; a cyano group; a carboxyl group; a lower alkoxycarbonyl group; a phenyl-lower alkyl group which may have hydroxyl groups as the substituents on the phenyl ring; a phenylsulfonyl group which may have lower alkyl groups as the substituents on the phenyl ring; a lower alkoxy-substituted phenyl-lower alkyl group; a lower alkylthio group; a lower alkenyl group; a lower alkoxy group and a pyridyl group;
R.sup.1 is a hydrogen atom, a lower alkyl group or a phenyl-lower alkyl group;
R.sup.2 is a hydrogen atom, a halogen atom, a lower alkylsulfonyloxy group, a lower alkoxy group or a hydroxyl group;
Z is an oxygen atom, a sulfur atom, a group of the formula ##STR8## a group of the formula ##STR9## a group of the formula ##STR10## (wherein R.sup.3 is a hydrogen atom or a lower alkyl group) or a group of the formula --NH--; group of the formula --SO.sub.2 --;
the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton is a single or double bond).
Since said carbostyril derivatives and salt thereof possess activities for inhibition of thrombotic adhesion, they can be used not only for the treatment and prevention of arteriosclerosis, ischemic heart disease, chronic arterial obstruction, and acute or chronic nephritis, but also in the treatment of artificial dialysis and implantation of artificial organs, etc.
Some of the carbostyril derivatives of the present invention represented by the above general formula (1) are similar, in chemical structure, to the above-mentioned carbostyril compounds disclosed in prior art literatures, but none of the present carbostyril derivatives is disclosed therein. Further, as shown in the pharmacological test results given later, the present carbostyril derivatives have a very strong activity for inhibiting the adhesion of platelets, even when compared with the prior art compounds having chemical structures most similar to those of the present carbostyril derivatives.
DETAILED DESCRIPTION OF THE INVENTION
Ateriosclerosis is an arterial lesion associated with the hypertrophy,
REFERENCES:
patent: 5008274 (1991-04-01), Nishi et al.
"3,4-Dihydroquinolin-2(1H)-one as Combined Inhibitors of Thromboxane A.sub.2 Synthase and cAMP Phosphodiesterase.sup.1 ", G. Martinez et al., J. Med. Chem, 35:4(620-628) 1992.
"A Platelet-Dependent Serum Factor That Stimulates the Proliferation of Arterial Smooth Muscle Cells In Vitro", R. Ross et al, Proc. Nat. Acad. Sci USA, 71:4(1207-1210) 1974.
"The Pathogenesis of Atherosclerosis--An Update", R. Ross, The New England Journal of Medicine, 314:8(488-500) 1986.
Nishi Takao
Okada Minoru
Shu Yoshio
Tamura Katsumi
Uno Tetsuyuki
Huang Evelyn
Ivy C. Warren
Otsuka Pharmaceutical Co. Ltd.
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