Oxazolidine derivatives and pharmaceutically acceptable salts th

Details Oxazolidine derivatives and pharmaceutically acceptable salts th Oxazolidine derivatives and pharmaceutically acceptable salts th

1993-12-21

1996-01-02

Daus, Donald G.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514340, 546275, 548229, C07D26324, A61K 3142

Patent

active

054808995

DESCRIPTION:

BRIEF SUMMARY
This is a 371 of PCT/JP93/00559 filed Apr. 28, 1993.


TECHNICAL FIELD

The present invention relates to novel oxazolidine derivatives and pharmaceutically acceptable salts thereof which have an activity to decrease triglyceride and cholesterol in the blood and which is useful as an anti-hyperlipidemic agent.


BACKGROUND ART

According to epidemiological investigation in Helsinki, it is considered that triglyceride and cholesterol in the blood are closely associated with the onset of hyperlipidemia (Circulation, 1992; vol. 85: 37-45). Therefore, for more effective and proper suppression of hyperlipidemia, it is desired to inhibit both the synthesis of triglyceride and cholesterol in the blood. Now there is a strong demand for the development of drugs capable of potently inhibiting their syntheses in the blood. However, while the phenylcarboxylic acid derivatives and the like disclosed in Japanese Unexamined Patent Publications Nos. 56452/1990 corresponding to U.S. Pat. No. 4,999,378, and 275666/1991 corresponding to U.S. Pat. No. 5,145,865 are known as compounds capable of lowering blood triglyceride and cholesterol, a compound which can satisfactorily produce the effect of lowering both of them has not yet been developed.


DISCLOSURE OF THE INVENTION

The present inventors conducted extensive research in view of the problems in the prior art and found that novel oxazolidine derivatives represented by the following formula (I) and pharmaceutically acceptable salts thereof have an excellent activity to inhibit the synthesis of triglyceride and activity to inhibit the synthesis of cholesterol and are useful as a medicament. The present invention has been accomplished based on this finding.
The present invention provides an oxazolidine derivative represented by the formula (I) ##STR2## wherein R.sup.1, R.sup.2 and R.sup.3 are the same or different, and each represents a hydrogen atom, a lower alkyl group optionally having one or more halogen atoms, a lower alkoxy group optionally having one or more halogen atoms, a hydroxyl group, a halogen atom, a nitro group, an amino group optionally having one or more acetyl or lower alkyl groups, a carboxyl group, a lower alkoxycarbonyl group, a cyano group, a lower alkanoyl group or a 2-oxazolyl group, or R.sup.1 and R.sup.2 may be combined with each other to represent an alkylene chain --(CH.sub.2).sub.p -- or an alkylenedioxy chain --O(CH.sub.2).sub.q O-- wherein p is 3, 4 or 5, q is 1, 2 or 3, thus forming a cyclic structure, m and n are each 0 or 1, R.sup.4 and R.sup.5 are the same or different and each represents a hydrogen atom or a lower alkyl group, X is a carbon atom or a nitrogen atom, Y is a hydroxymethyl group, an aldehyde group or a group represented by COOR.sup.6 (R.sup.6 is a lower alkyl group, a benzyl group or a hydrogen atom), A is a lower alkylene group, a carbonyl group or a sulfonyl group, B is a lower alkylene group, E is a lower alkylene group which may be substituted with a halogen atom or is a lower alkenylene group, Z is an oxygen atom or a sulfur atom, with the proviso that when n is 0, a compound wherein m is 1 and Y is a hydroxymethyl group is excluded and that when n is 0, a compound wherein Y is a group represented by COOR.sup.6 (R.sup.6 is a lower alkyl group) is excluded; or a pharmaceutically acceptable salt thereof.
With the oxazolidine derivative of the formula (I), optical isomers and geometrical isomers exist. The present invention includes these isomers and mixtures thereof.
The compounds of the formula (I) and pharmaceutically acceptable salts thereof according to the present invention have an activity to decrease blood triglyceride and cholesterol. These compounds have the features of being highly absorbable in the living body, having a long-sustained efficacy, and being excellent in the safety, the absorption and the excretion and less toxic. Thus the compounds are useful as drugs such as an anti-hyperlipidemic agent, an agent for preventing and treating arteriosclerosis, an anti-obesity agent and the like.
Thus the present in

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