Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1986-09-17
1989-04-11
Hollrah, Glennon H.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
2604109N, C07C 6702
Patent
active
048208655
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND TO THE DISCLOSURE
The present invention relates to a series of new derivatives of the known compound MB-530B, to processes for their preparation and to pharmaceutical compositions containing them.
MB-530B has been disclosed in United Kingdom Patent Specifications No. 2,046,737 and No. 2,049,664, in both of which it is designated "Monacolin K", but it has also been assigned the designation "MB-530B", by which it is referred to herein. MB-530B can exist in the form of a lactone, termed "MB-530B lactone", which has the structural formula: ##STR4## or in the form of a corresponding free hydroxy-carboxylic acid, termed "MB-530B carboxylic acid", which has the structural formula: ##STR5##
These MB-530B compounds have been isolated and purified from the metabolic products of various microorganisms, including microorganisms of the genus Monascus, especially Monascus ruber, a species of mould. They have been shown to inhibit the biosynthesis of cholesterol in enzyme systems and in systems comprising cultured cells separated from experimental animals by competing with the rate-limiting enzyme active in the biosynthesis of cholesterol, that is to say 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and, as a result, they significantly reduce serum cholesterol levels in animals.
Salts and esters of MB-530B carboxylic acid, which share the activity of the parent compound, have been disclosed in United Kingdom Patent Specification No. 2,055,100.
There is also known a series of compounds which bear structural similarities to the MB-530B compounds--this series comprises the compounds known as ML-236B and derivatives thereof. ML-236B lactone, which is disclosed in U.S. Pat. No. 3,983,140, has the structural formula: ##STR6## and this, of course, also forms a corresponding free hydroxycarboxylic acid. Like the MB-530B compounds, ML-236B lactone and its corresponding carboxylic acid have the ability to inhibit the biosynthesis of cholesterol.
A number of compounds structurally related to ML-236B have also been discovered and some have been found to share this ability to inhibit the biosynthesis of cholesterol. Of the ML-236B derivatives which have been discovered, the most relevant form the subject of co-pending U.S. patent application Ser. No. 270,846, filed June 5th 1981. In the lactone form, these compounds may be represented by the structural formula: ##STR7## and have been named "IsoM-4 lactone" or "IsoM-4' lactone", depending upon the particular configuration of the various asymmetric carbon atoms present in the molecule. The corresponding IsoM-4 carboxylic acid and IsoM-4' carboxylic acid are also disclosed and these compounds were all found to have the ability to inhibit the biosynthesis of cholesterol.
We have now discovered a new series of compounds, which are derivatives of MB-530B, and which, whilst having an ability to inhibit the biosynthesis of cholesterol which is generally at least comparable with that of the known compounds, are metabolised with much greater difficulty after administration than are MB-530B and ML-236B. The compounds of the invention are thus less readily deactivated in vivo and hence have more persistent activity, with attendant advantages well recognised in the art.
BRIEF SUMMARY OF INVENTION
The compounds of the present invention are the lactones of formula (I): ##STR8## in which R.sup.1 represents a group of formula ##STR9## (wherein R.sup.2 represents a C.sub.1 -C.sub.10 alkyl group) and the corresponding free hydroxy-carboxylic acids, which may be represented by the structural formula (II): ##STR10## (in which R.sup.1 is as defined above) and salts and esters of said acids.
The compounds of the present invention may be prepared by the enzymatic hydroxylation of MB-530B lactone, MB-530B carboxylic acid or a salt or ester of said carboxylic acid or a corresponding compound in which the 2-methylbutyryloxy group at the 1-position has been replaced by another acyloxy group. (these compounds are hereinafter collectively referred to as "MB-530B compounds"). The MB-530B compound
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Tanaka Minoru
Terahara Akira
Hollrah Glennon H.
Russell Mark W.
Sankyo Company Limited
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