Glycylanilide derivatives, their preparation and their applicati

Details Glycylanilide derivatives, their preparation and their applicati Glycylanilide derivatives, their preparation and their applicati

1997-07-17

1998-06-02

Mosley, Terressa

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

564190, 564191, 564195, A01N 3718

Patent

active

057600872

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to new glycylanilide derivatives, to their preparation and to their application in human therapy. It also relates to the use of these derivatives for the manufacture of medicaments intended for the treatment of hypercholesterolemia or atherosclerosis.
Dietary cholesterol is absorbed in the form of free cholesterol by intestinal cells and esterified by the enzyme ACAT (acyl-CoA: cholesterol O-acyltransferase) in the serum. The inhibition of ACAT prevents the intestinal absorption and the accumulation of cholesterol in the arterial tissue. In addition, low density lipoproteins (LDL) are, after oxidation, taken up by the scavenger receptors and lead to the formation of the foam cell, the site of initiation of the atheromatous plaque (D. STEINBERG et al. England. J. Med. 320, 915-924, 1989).
The subject of the present invention is directed towards obtaining new hypocholesterolemic and antioxidant derivatives capable of acting both on the quality and the amount of the LDL, with the object of reducing their atherogenic potential and their long-term deleterious effect on the vascular wall.
The compounds of the present invention correspond to the general formula I. ##STR2## in which R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.7, which may be identical or different, represent, independently of one another, hydrogen or a linear or branched C.sub.1 -C.sub.4 alkyl radical. represent, independently of one another, hydrogen, a linear or branched C.sub.1 -C.sub.4 alkyl radical or an optionally substituted phenyl radical.
Since the compounds of general formula I can possess asymmetric centers, the present invention covers all the stereoisomers and mixtures thereof.
The compounds of general formula I may be prepared according to the following method (Scheme 1).
Step 1 chloroformate in dimethylformamide in the presence of triethylamine. acid in methanol. The compound II is thereby obtained.
Step 2a
Treatment of the compound II obtained in step 1 with an acid chloride III to obtain the compounds I in which A=CH.sub.2, or with an .alpha.-halogenated acid chloride, and then with a thiol R.sub.10 SH in a sodium/ethanol medium or in a medium comprising potassium tert-butylate in tert-butanol, to obtain the compounds I in which A=sulfur.
Treatment of the compound II with an acid chloride IV in ethyl acetat in the presence of triethylamine to obtain compounds of formula I in which A is a sulfur atom or a methylene group. ##STR3##
The compounds of general formula I can be used for the preparation of pharmaceutical compositions or medicaments intended for the treatment of diseases such as hypercholesterolemia or atherosclerosis.
A better understanding of the invention may be gained from the nonlimiting examples which follow, and which constitute advantageous embodiments of the process according to the invention.


EXAMPLE 1



N-(2-n-dodecylthio)propionamido-2',3',5'-trimethyl-4'-hydroxyglycylanilide
1. ##STR4## a) N-tert-butoxycarbonyl-2',3',5'-trimethyl-4'-hydroxyglycylanilide 1a
A solution of ethyl chloroformate (0.96 ml; 0.01 mol) in CH.sub.2 Cl.sub.2 (5 ml) is added dropwise to an ice-cold solution of boc-glycine (1.75 g; 0.01 mol) and N-methylmorpholine (2.19 mol; 0.02 mol) in methylene chloride (10 ml). After 20 minutes of contact at 0.degree. C., 2,3,6-trimethyl-4-aminophenol hydrochloride (1.88 g; 0.01 mol) in CH.sub.2 Cl.sub.2 (40 ml) is added under nitrogen. The reaction mixture is then stirred for 24 hours at room temperature and evaporated under vacuum. The residue is taken up with water and extracted with ethyl acetate. The organic phase is washed with N hydrochloric acid and with water, then dried (Na.sub.2 SO.sub.4) and concentrated under vacuum. The residue is purified by flash chromatography. 1.42 g of crystals 1a are obtained.
M.p.=208.degree. C.
TLC: Merck silica gel 60F254. Rf=0.54 (AcOEt)
12 ml of 6N hydrochloric acid are added to the compound 1a (3.08 g; 0.01 mol) in methanol (100 ml). The solution is stirred at 60.degree. C. for 5 hours and then concentrated under vacuum. The s

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