Anilide derivatives

Details Anilide derivatives Anilide derivatives

1994-06-20

1995-05-16

Bernhardt, Emily

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

544295, 544360, 544400, 544392, 544403, 560 16, 564214, C07D29515, C07D40104, C07D40304

Patent

active

054162122

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This application is a 371 of PCT/JP92/01661 filed Dec. 18, 1992.
This invention relates to an anilide derivative having a piperazine ring and a salt thereof, and more particularly to an anilide derivative having a piperazine ring and a salt thereof which have acyl-CoA cholesterol acyltransferase (hereinafter abbreviated as ACAT) inhibitory activity.


BACKGROUND OF THE INVENTION

An ACAT inhibitor is believed to act on the atherosclerotic lesions to inhibit accumulation of cholesterol esters thereby inhibiting onset and progress of atherosclerosis and also act on the mucosa of the small intestine to inhibit absorption of cholesterol.
It is also considered that an ACAT inhibitor suppresses formation of cholesterol esters in the liver, which leads to reduction in blood cholesterol level (see V. A. Kosykh. et al., Atherosclerosis, Vol. 68, pp. 67-76 (1987)).
Among known ACAT inhibitors, the compounds disclosed in U.S. Pat. No. 4,623,662, JP-A-60-41655, and JP-A-63-253060 (the term "JP-A" as used herein means an "unexamined published Japanese patent application") are structurally similar to the anilide derivatives of the present invention but their ACAT inhibitory action is not sufficient.
An object of the present invention is to provide a compound having a potent ACAT inhibitory activity.


DISCLOSURE OF THE INVENTION

As a result of extensive investigations for accomplishment of the above object, the inventors have found that certain anilide derivatives having a piperazine ring exhibit a potent ACAT inhibitory activity and completed the present invention.
The present invention provides an anilide derivative represented by formula (I): ##STR2## wherein R.sup.1 and R.sup.2, which may be the same or different, each represent an alkyl group having 1 to 4 carbon atoms; n represents 0, 1 or 2; A represents an alkylene group having 1 to 14 carbon atoms or a group represented by --CH.sub.2 CO--; and Ar represents a phenyl group, a phenyl group substituted with a halogen atom, a nitro group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkanoyl group having 2 to 5 carbon atoms or a trifluoromethyl group, a benzyl group, a pyridyl group, a pyridyl group substituted with a halogen atom or a trifluoromethyl group, or a pyrimidyl group, or a salt thereof.
The details of the present invention will hereinafter be described.
The alkyl group having 1 to 4 carbon atoms is a straight- or branched-chain alkyl group. The alkylene group having 1 to 14 carbon atoms is a straight-chain alkylene group. The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The alkoxy group having 1 to 4 carbon atoms is a straight- or branched-chain alkoxy group. The alkanoyl group having 2 to 5 carbon atoms is a straight- or branched-chain alkanoyl group. The salt of the compound of formula (I) includes a hydrochloride, a sulfate, an acetate, a maleate, a tartrate, a citrate, a succinate, a methanesulfonate, a p-toluenesulfonate, a malate, and a fumarate.
Of the compounds according to the present invention preferred are those in which R.sup.1 and R.sup.2 are each an isopropyl group; n is 0; A is an alkylene group having 1 to 14 carbon atoms; and Ar is a phenyl group. More preferred are those in which R.sup.1 and R.sup.2 are each an isopropyl group; n is 0; A is an alkylene group having 6 or 8 carbon atoms; and Ar is a phenyl group. The most preferred is the compound in which R.sup.1 and R.sup.2 are each an isopropyl group; n is 0; A is an alkylene group having 6 carbon atoms; and Ar is a phenyl group, i.e., N-( 2,6-diisopropylphenyl)-2-[6-(4-phenylpiperazinyl)hexylthio]acetamide.
The compound of formula (I) can be prepared by, for example, reacting an anilide derivative represented by formula ( II ): ##STR3## wherein R.sup.1, R.sup.2, n, and A are as defined above; and X represents a halogen atom, with a compound represented by formula: ##STR4## wherein Ar is as defined above, in the presence or absence of a base.
The compound of formula (II) is a novel co

REFERENCES:
patent: 3228949 (1966-01-01), Risse et al.
patent: 4623662 (1986-11-01), De Vries
patent: 4716175 (1987-12-01), Hoefle et al.

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