Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time, and they are not very palatable.
MEVACOR.RTM. (lovastatin), now commercially available, is one of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. In addition to the natural fermentation products, mevastatin and lovastatin, there are a variety of semi-synthetic and totally synthetic analogs thereof.
The naturally occurring compounds and their semi-synthetic analogs have the following general structural formulae: ##STR2## wherein: R.sup.1 is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and
R* is a polyhydronaphthyl moiety.
U.S. Pat. No. 4,517,373 discloses semi-synthetic hydroxy containing compounds represented by the above general formula wherein R* is ##STR3##
U.S. Pat. No. 4,537,859 and U.S. Pat. No. 4,448,979 also disclose semi-synthetic hydroxycontaining compounds represented by the above general formula wherein R* is ##STR4##
These compounds are prepared by the action of certain microorganisms on the corresponding non-hydroxylated substrates. One such organism described in U.S. Pat. No. 4,537,859 is of the genus Nocardia.
U.K. Patent 2,075,013 discloses semi-synthetic hydroxy containing compounds represented by the above general formula wherein R* is: ##STR5## wherein R.sup.1 is H or Me, and R.sup.2 is H or acyl.
U.S. Pat. No. 4,940,727 discloses 6-substituted compounds of the above general formula wherein R* is: ##STR6## wherein R is CH.sub.2 OH, ##STR7## CO.sub.2 R.sup.7 or ##STR8## and R.sup.1, R.sup.4, R.sup.7, R.sup.8 and R.sup.9 are broadly defined organic moieties.
U.S. Pat. Nos. 4,604,472 and 4,733,003 disclose compounds of the above formula wherein R* is: ##STR9## wherein X represents a hydrogen atom or a 2-methylbutyryl group, Y represents a hydrogen atom or a methyl group and R.sup.1 and R.sup.2 are the same or different and each represents an oxygen atom or a group of formula .dbd.N--OR.sup.3 where R.sup.3 is a hydrogen or alkyl moiety.
Copending U.S. patent application Ser. No. 213,010 filed June 29, 1988 discloses 5-oxygenated compounds of the above general formula wherein R* is ##STR10## R.sup.4 is H, alkyl or substituted alkyl and R.sup.5 and R.sup.6 are H, OH or OR.sup.7 where R.sup.7 represents a phosphoryl or acyl moiety.
U.S. Pat. No. 4,897,402 discloses 5-Oxa, Thia and Aza compounds of the above general formula where R* is: ##STR11## R.sup.1 is an alkyl or substituted alkyl group, R.sup.2 and R.sup.3 are H, alkyl or substituted alkyl and X is O, S(O).sub.n or NR.sup.4 where R.sup.4 is H, alkyl or substituted alkyl.
USPTO Backgrounds
USPTO Backgrounds