Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1998-05-27
1999-11-23
Kumar, Shailendra
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514618, 514629, 514824, 564162, 564215, 564223, A61K 3116, C07C23305
Patent
active
059901730
DESCRIPTION:
BRIEF SUMMARY
The subject-matter of the present invention is novel anilide derivatives, their preparation and their application in human therapeutics.
It also relates to the use of these derivatives in the manufacture of medicaments intended for the treatment of hypercholesterolemia or of atherosclerosis.
Dietary cholesterol is absorbed in the form of free cholesterol by intestinal cells and then esterified by the enzyme ACAT (acyl-CoA: cholesterol O-acyltransferase) in the serum. Inhibition of ACAT prevents the intestinal absorption and the accumulation of cholesterol in arterial tissue. In addition, low density lipoproteins (LDL) are, after oxidation, captured by scavenger receptors and result in 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 object of the present invention is targeted at obtaining novel hypocholesterolemic and antioxidant derivatives which can act both on the amount and the quality of the LDL, with the aim of reducing their atherogenic potential and their long-term deleterious effects on the vascular wall.
The compounds of the present invention correspond to the general formula I ##STR2## in which:
R.sub.1 and R.sub.2, which are identical or different, represent, independently of one another: substituted by one or more C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxyl or halo groups phenyl group optionally substituted by one or more C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxyl or halo groups
As it is possible for the compounds of general formula I to possess asymmetric centers, the present invention covers the various stereoisomers or enantiomers and their mixtures.
The compounds of general formula I can be used in the preparation of pharmaceutical compositions or of medicaments intended for the treatment of diseases such as hypercholesterolemia or atherosclerosis.
Finally, the synthetic processes which make it possible to access the compounds of general formula I also form part of the present invention.
The compounds of general formula I can be obtained according to one of the following methods (Scheme I): .alpha.-haloacyl halide II, in which Hal and Hal' represent bromine or chlorine and R.sub.1 and R.sub.2 have the same meaning as above, in the presence of a base, such as triethylamine, in order to access the compound III. and A have the same meaning as above, in a sodium/methanol or potassium tert-butoxide/tert-butanol medium, in order to give the compound I. .alpha.-halo acid V, in which Hal, R.sub.1 and R.sub.2 have the same meaning as above, in the presence of an activator, such as dicyclohexylcarbodiimide or 2-chloro-1-methylpyridinium iodide, and of a base, such as triethylamine, in order to access the compound III, subsequently treated in a way identical to that described in Method A-b. derivative IV, in which R.sub.1, R.sub.2, R.sub.3 and A have the same meaning as above, in the presence of an activator, such as dicyclohexylcarbodiimide or 2-chloro-1-methylpyridinium iodide, and of triethylamine, in order to give the compound I. ##STR3##
The invention can be better understood using the following non-limiting examples which constitute advantageous embodiments according to the invention.
EXAMPLE 1
2',3',5'-Trimethyl-4'-hydroxy-.alpha.-(dodecylthio)propionanilide 1. ##STR4## a--2',3',5'-Trimethyl-4'-hydroxy-.alpha.-bromopropionanilide 1a.
Triethylamine (3.48 ml; 0.25 mol) is added to a solution of 2,3,6-trimethyl-4-aminophenol hydrochloride (1.87 g; 0.01 mol) in dimethylformamide placed under nitrogen. .alpha.-Bromopropionyl chloride (1.32 ml; 0.0125 mol) is subsequently added dropwise and the reaction mixture is stirred for one hour at room temperature.
After diluting with water, extraction is carried out with ethyl acetate. The organic phase is washed with N hydrochloric acid and with water and then dried (MgSO.sub.4) and concentrated to dryness under vacuum. The residue is taken up in hexane, filtered off and dried to give the compound 1a (2.10 g).
M.p.=186.degree. C.
REFERENCES:
patent: 5254590 (1993-10-01), Malen et al.
M Sato et al, Patent Abstracts of Japan 18(262) May 19, 1994.
Autin Jean-Marie
Delhon Andre
Junquero Didier
Oms Philippe
Patoiseau Jean-Fran.cedilla.ois
Kumar Shailendra
Pierre Fabre Medicament
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