Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1990-05-03
1992-12-08
Dees, Jose G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
549304, 549305, 549307, 549321, 549323, 549324, 558275, 558276, 560 41, 562444, C07C22934, C07C22932
Patent
active
051699761
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Variously substituted N-(biphen-2-ylmethyl)-3-hydroxyglutaramic acid and derivatives, as defined by the formula (I) below (alternatively named as 4-(biphen-2-ylmethylcarbamoyl)-3-hydroxybutyric acid derivatives) 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-dihydroxyomega-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 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;
X is F, Cl, Br, I, (C.sub.1 -C.sub.3)alkyl, CF.sub.3, benzyl, (C.sub.1 -C.sub.3)alkoxy, (C.sub.2 -C.sub.4)alkanoyloxy or (C.sub.2 -C.sub.4)alkoxycarbonyl; and
X.sup.1, X.sup.2 and X.sup.3 are each independently hydrogen, F, Cl, Br, I, (C.sub.1 -C.sub.3)alkyl, CF.sub.3, benzyl, (C.sub.1 -C.sub.3)alkoxy, (C.sub.2 -C.sub.4)alkanoyloxy or (C.sub.2 -C.sub.4)alkoxycarbonyl; and the pharmaceutically-acceptable cationic salts thereof when R is hydrogen.
The depiction of the substituents X, X.sup.1, X.sup.2 and X.sup.3 in the compound of the formula (I) is not intended to limit the substituents on each ring to two. Rather, while the substituent X is specifically substituted at the 3-position, it is intended that each of the remaining three substituents, if present, can be substituted at any open position on either phenyl ring. For example, all three of X.sup.1, X.sup.2 and X.sup.3 are optionally substituted on one or the other of the phenyl rings.
The preferred compound, because of its ease of preparation and level of hypocholesterolemic activity, has R as hydrogen, and X, X.sup.1 and X.sup.2 as 3,3',5-trimethyl and X.sup.4 as 4'-fluoro.
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 which comprises administering a blood cholesterol lowering effective amount of a compound of the formula (I) to said mammal.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is readily carried out. Thus, the hydroxy protected anhydride of 3-hydroxyglutaric anhydride (alternatively named 3-hydroxypentanedioic anhydride), e.g., 3-(t-butyldimethylsilyloxy)glutaric anhydride, is reacted with a diphen-2-ylamine of the formula ##STR3## wherein X, X.sup.1, X.sup.2 and X.sup.3 are as defined above, in the conventional manner long used to prepare half amides from amines and cyclic anhydrides. For example, see and Boyd, "Organic Chemistry",
REFERENCES:
patent: 3341528 (1967-09-01), Shavel et al.
patent: 4198425 (1980-04-01), Mitsui et al.
patent: 4375475 (1983-03-01), Willard et al.
patent: 4459422 (1984-07-01), Willard et al.
patent: 4603145 (1986-07-01), DeVries et al.
patent: 4678806 (1987-07-01), Baldwin et al.
patent: 4772626 (1988-09-01), Smith et al.
patent: 4855321 (1989-08-01), Smith et al.
Stokker et al., J. Med. Chem., vol. 28, pp. 347-358 (1985).
Dees Jos,e G.
Frazier B.
Lumb J. Trevor
McFarlin D. Stuart
Pfizer Inc.
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