Anilide derivative

Details Anilide derivative Anilide derivative

1993-05-25

1995-12-12

Raymond, Richard L.

Organic compounds -- part of the class 532-570 series

Organic compounds

Esters having the thiocarboxylate group, -cx-, wherein the...

564162, 564200, 564218, C07C32734, C07C32325, C07C32341, A61K 31265

Patent

active

054751306

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to a compound having an activity to inhibit ACAT (acyl-coenzyme A cholesterol acyltransferase).


BACKGROUND ART

It is known that ACAT is an enzyme which catalyzes synthesis of cholesterol esters from fatty acid acyl-coenzyme A and cholesterol, and esterification of cholesterol in the living body is effected mostly by the function of ACAT (A. A. Spector et al., Prog. Lipid Res., vol.18, pp.31-53 (1979)).
In addition, since increase in the ACAT activity has been found in experimentally prepared atherosclerotic lesions, a relationship between the accumulation of cholesterol esters and the ACAT activity in atherosclerotic lesions has been indicated (St. Clair et al., Circ. Res., vol.27, pp.213-225 (1970); St. Clair et al., Prog. Cardiovasc. Dis., vol.26, pp.109-132 (1983); P. M. Kinnuen et al., Biochemistry, vol.27, pp.7344-7350 (1988)).
On the other hand, with regard to the absorption of dietary cholesterol, it is known that free cholesterol in the intestinal tract is esterificated in the small intestine mucous membrane and then secreted as chylomicron into the lymphatic duct, and ACAT located in the small intestine mucous membrane is greatly concerned in the esterification of cholesterol (K. E. Sucklinget et al., J. Lipid Res., vol.26, pp.647-671 (1985); J. G. Heider et al., J. Lipid Res., vol.34, pp.176-183 (1983)).
Thus, it seems that an ACAT inhibitor can inhibit formation and progress of atherosclerosis by inhibiting accumulation of cholesterol esters in atherosclerotic lesions and also can inhibit absorption of cholesterol in the small intestine mucous membrane.
Examples of prior art ACAT inhibitors include substituted urea derivatives disclosed in U.S. Pat. No. 4,623,662 and anilide derivatives disclosed in JP-A-60-41655 and JP-A-63-253060, though their functions are not sufficient enough.
Though compounds similar to the compound of the present invention have been disclosed in JP-A-54-39028 and U.S. Pat. No. 3,878,248, they have no strong ACAT inhibiting activities.
A primary object of the present invention is to provide a compound having a potent ACAT inhibiting activity.


DISCLOSURE OF THE INVENTION

The present invention relates to an anilide derivative represented by the following formula (I): ##STR2## wherein X is an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms; Y is a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms; Z is an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms; A is an alkylene group having 1 to 4 carbon atoms; R is an alkyl group having 6 to 20 carbon atoms, an alkanoyl group having 2 to 20 carbon atoms or a benzyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms; and n is 0, 1 or 2.
The alkyl group according to the present invention is a straight- or branched-chain alkyl group, and the alkyl groups represented by X and Z include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and the like groups, and those represented by R include octyl, decyl, dodecyl, tetradecyl, pentadecyl, eicosanyl and the like groups. Preferably, the alkyl group represented by X is an isopropyl group, and the alkyl group represented by R is an alkyl group having 8 to 16 carbon atoms. The alkoxy group disclosed herein is a straight- or branched-chain alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy or the like group. The alkylene group is a straight- or branched-chain alkylene group such as methylene, ethylene, trimethylene, dimethylmethylene, tetramethylene or the like group.
The compound of formula I can be produced, for example, by the following process. That is, the thioester portion of an anilide derivative represented by the following formula (II): ##STR3## (in formula (II), X, Y, Z and A are the same as defined above) is converted into a thiol form by hydrolysis according to an ordinary ester hydrolysis technique (for example, its reaction with potassium hydroxide in water-containing e

REFERENCES:
patent: 3878248 (1975-04-01), Phillips
patent: 4329363 (1982-05-01), Dorn et al.
patent: 4623662 (1986-11-01), De Vries

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