Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1990-03-27
1992-09-29
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560 56, 560183, 562465, 562467, 562469, 562472, 562470, 562586, 562587, C07C 6976
Patent
active
051515458
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Variously substituted 3,5-dihydroxy-6,8-nonadienoic acids and derivatives, as defined by the formula (I) below, possess hypocholesterolemic (blood cholesterol lowering) activity and so are useful in the prevention and treatment of certain cardiovascular diseases such as atherosclerosis.
Previously reported as hypocholesterolemic compounds have been variously substituted 6-phenyl-, 6-(2-phenethyl)-, 6-(3-phenylpropyl)- and 6-(2-styryl) -4-hydroxy-6-hexanolides including, in particular, ##STR1## and the corresponding ring opened 3,5-dihydroxy -omega-substituted- (hexan-, heptan-, octan- and 6-hepten-)oic acids [Willard et al., U.S. Pat. Nos. 4,375,475 and 4,459,422; see also Mitsui et al., U.S. Pat. No. 4,198,425; Stokker et al., J. Med. Chem., vol. 28, pp. 347-358 (1985)].
SUMMARY OF THE INVENTION
The present invention is directed to hypocholesterolemic compounds having the relative stereochemical formula ##STR2## wherein R is hydrogen, (C.sub.1 -C.sub.3)alkyl, phenyl, benzyl or a conventional radical forming an ester group which is hydrolyzable under physiological conditions; independently hydrogen, (C.sub.1 -C.sub.3)alkyl, benzyl, naphthyl, phenyl or phenyl mono or disubstituted with the same or different substituents selected from the group consisting of F, Cl, Br, I, (C.sub.1 -C.sub.3)alkyl, CF.sub.3, (C.sub.1 -C.sub.3)alkoxy, benzyl and phenyl; with the proviso that at least one of R.sup.1 and R.sup.2 is other than hydrogen or (C.sub.1 -C.sub.3)alkyl; and bonded carbon atom which they are attached to form a diradical ylidene group of the formula ##STR3## wherein n is 0 or 1 and Y is oxygen, OCH.sub.2, sulfur, SCH.sub.2, methylene (CH.sub.2) or ethylene (CH.sub.2 CH.sub.2); and the pharmaceutically acceptable cationic salts thereof when R is hydrogen.
Exemplary of such ylidene groups are ##STR4## all named according to the "IUPAC Nomenclature of Organic Chemistry", 1979 Edition Pergammon Press, New York, N.Y., 1979, pp. 17, 21, 23, 27, 30, 57 and 62. It is understood that formula (I) represents relative stereochemistry and that the compounds of the present invention are racemic, comprised of equal portions of enantiomers (i.e., compounds which are mirror images, equally rotating plane polarized light, but in opposite directions). It is to be expected that the pharmacological activity resides primarily in one of these two enantiomers. It is also to be understood that the geometry about the C6-C7 double bond is that shown in the formula (I); i.e., the trans or E geometric isomer.
Preferred compounds, because of their ease of preparation and level of hypocholesterolemic activity, have R as methyl or hydrogen and R.sup.3 as hydrogen. Within those classes, preferred compounds have R.sup.1 and R.sup.2 as each phenyl, 4-chlorophenyl or 4-fluorophenyl, or taken together with the double bonded carbon to which they are attached to form a 9-xanthenylidene group or an 8,9-dihydro-6H-benzocyclohepten-5(7H)-ylidene group.
Pharmaceutically-acceptable cationic salts include, but are not limited to, those of sodium, potassium, calcium, N,N'-dibenzylethylenediamine, N-methylglucamine (meglumine) and diethanolamine. The preferred cationic salts are those of potassium and sodium.
The reference to esters which are hydrolyzable under physiological conditions refers to those esters frequently referred to as "pro-drugs". Such esters are now as well-known and common in the medicinal art as pharmaceutically-acceptable salts. Such esters are generally used to enhance oral absorption, but in any event are readily hydrolyzed in vivo to the parent acid. The more preferred ester forming radicals are those wherein R is: -C.sub.6)alkyl. The most preferred radicals are pivaloyloxymethyl and 1-(ethoxycarbonyloxy)ethyl.
The present invention also encompasses pharmaceutical compositions for the treatment or prevention of atherosclerosis in a mammal which comprises a blood cholesterol lowering effective amount of a compound of the formula (I); and method of treating or preventing atherosclerosis in a mammal w
REFERENCES:
patent: 4198425 (1980-04-01), Mitsui et al.
patent: 4255444 (1981-03-01), Oka et al.
patent: 4294846 (1981-10-01), Albers-Schonberg et al.
patent: 4351844 (1982-09-01), Patchett et al.
patent: 4375475 (1983-03-01), Willard et al.
patent: 4459422 (1984-07-01), Willard et al.
patent: 4654363 (1987-03-01), Prugh
Stokker, J. Med. Chem., vol. 28, pp. 347-358 (1985).
McCarthy Peter A.
Walker Frederick J.
Killos Paul J.
Lumb J. Trevor
McFarlin D. Stuart
Pfizer Inc.
Richardson Peter C.
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