Organic compounds -- part of the class 532-570 series – Organic compounds – Fatty compounds having an acid moiety which contains the...
Patent
1993-09-13
1996-03-12
Dees, Jose G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Fatty compounds having an acid moiety which contains the...
554 42, 554 68, 554 69, 554101, 554150, 554154, 554225, 554229, 544180, 544235, 544242, 544253, 546244, C07C23100
Patent
active
054987865
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to novel processes for synthesizing intermediates in the preparation of N-aryl and N-heteroarylamide inhibitors of the enzyme acyl coenzyme A: cholesterol acyltransferase (ACAT), and to novel intermediates used in such processes.
The foregoing ACAT inhibitors having synthetic intermediates which may be prepared by the processes of this invention are described and claimed in PCT Patent Application PCT/US 89/04033, entitled "New N-Aryl and N-Heteroarylamide and Urea Derivatives as Inhibitors of Acyl Coenzyme A: Cholesterol Acyl Transferase" and filed Sep. 15, 1989. They are also described and claimed in the United States continuation-in-part application 648677 claiming priority from such PCT application and filed on Mar. 21, 1991. The present application claims priority as a continuation-in-part of United States parent application 648243 filed on Jan. 31, 1991. These ACAT inhibitors are useful in the prevention of atherosclerosis, myocardial infarction and stroke.
Cholesterol that is consumed in the diet (dietary cholesterol) is absorbed as free cholesterol by the mucosal cells of the small intestine. It is then esterified by the enzyme ACAT, packaged into particles known as chylomicrons, and released into the bloodstream. Chylomicrons are particles into which dietary cholesterol is packaged and transported in the bloodstream. By inhibiting the action of ACAT, the ACAT inhibitors referred to above prevent intestinal absorption of dietary cholesterol and thus lower serum cholesterol levels. They are therefore useful in preventing atherosclerosis, heart attacks and strokes.
Also, by inhibiting the action of ACAT, the ACAT inhibitors referred to above enable cholesterol to be removed from the walls of blood vessels. This activity renders such compounds useful in slowing or reversing the development of atherosclerosis as well as in preventing heart attacks and strokes.
SUMMARY OF THE INVENTION
This invention relates to a process for preparing a compound of the formula ##STR1## wherein R.sup.1 is selected from the group consisting of hydroxy, (C.sub.1 -C.sub.6) alkoxy, benzyloxy wherein the benzyl moiety may optionally be substituted with from one to three substituents independently selected from the group consisting of (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6) alkoxy, (C.sub.1 -C.sub.6)alkylthio, halo (e.g., chloro, fluoro, bromo or iodo), nitro and trifluoromethyl, or R.sup.1 is NHR.sup.5 wherein R.sup.5 is ##STR2## wherein B, D, E and G are independently carbon or nitrogen, with the proviso that at least one of B, D and E is nitrogen, and R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)alkylthio, (C.sub.5 -C.sub.7)cycloalkylthio and NR.sup.10 R.sup.11, wherein R.sup.10 and R.sup.11 are independently selected from hydrogen and (C.sub.1 -C.sub.6)alkyl, and wherein R.sup.6, R.sup.7, R.sup.8 and R.sup.9, when attached to a bicyclic system of formula A, may be attached to either ring of such system, with the proviso that no more than 3 non-hydrogen substituents may be attached to any one ring of such system; R.sup.2 is a hydrocarbon containing 6 to 12 carbons; R.sup.4 is selected from the group consisting of (C.sub.4 -C.sub.12) straight or branched alkyl, (C.sub.4 -C.sub.12) cycloalkyl-(C.sub.1 -C.sub.6)alkyl, phenyl, substituted phenyl, (C.sub.1 14 C.sub.6)alkyl-phenyl or (C.sub.1 -C.sub.6)alkyl-(substituted phenyl), wherein there may be from 1 to 3 substituents on the substituted phenyl moieties and wherein such substituents are independently selected from the group consisting of (C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)alkylthio, (C.sub.1 -C.sub.6)alkyl, halo (e.g. fluoro, chloro, bromo or iodo) and trifluoromethyl;
comprising reacting, respectively, a compound of the formula ##STR3## wherein R.sup.1 and R.sup.2 are defined as above and X is a leaving group (e.g., chloro, fluoro, bromo, iodo and ##STR4## wherein R.sup.3 is se
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Chang George
Kelly Sarah E.
Butterfield Garth
Carr Deborah D.
Dees Jos,e G.
Ginsburg Paul H.
Pfizer Inc.
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