Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-02-02
1995-11-21
Chan, Nicky
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549363, A61K 3135, C07D31904
Patent
active
054687713
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
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 (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.
Squalene synthetase is the enzyme involved in the first committed step of the de novo cholesterol biosynthetic pathway. This enzyme catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene. The inhibition of this committed step to cholesterol should leave unhindered biosynthetic pathways to ubiquinone, dolichol and isopentenyl t-RNA.
Previous efforts at inhibiting squalene synthetase have employed pyrophosphate or pyrophosphate analogs containing compounds such as those described in P. Oritz de Montellano et al., J. Med Chem. 20, 243 (1977) and E. J. Corey and R. Volante, J, Am. Chem. Soc., 98, 1291 (1976). S. Billet (U.S. Pat. No. 4,871,721) described isoprenoid (phosphinylmethyl)phosphonates as inhibitors of squalene synthetase.
Recently certain nonphosphorus containing inhibitors of squalene synthetase have been isolated as natural products. These natural product inhibitors are described in U.S. Pat. Nos. 5,132,320 issued Jul. 21, 1992, 5,096,923 issued Mar. 17, 1992 and 5,102,907 issued Apr. 7, 1992. A need still remains for a more effective squalene synthetase inhibitor, i.e. one that provides a greater antihypercholesterolemic effect and exhibits a good safety profile.
The present invention is directed to a biotransormed analog of the above-noted natural products.
DETAILED DESCRIPTION OF THE INVENTION
This invention is concerned with a compound of structural formula (I) which is useful as a cholesterol lowering agent: ##STR3## or a pharmaceutically acceptable salt thereof. Chemically this compound is known as (1S,3S,4S,5S,6R,7R)-1-[(4S)-acetoxy-3-methylene-5-methyl-6-phenyl]hexyl-4, 6,7-trihydroxy-6-0-(4,6-dimethyl-7-hydroxy-2-octenoyl)-2,8-dioxabicyclo [3.2.1]octane-3,4,5-tricarboxylic acid.
The compound of structural formula I is prepared by biotransformation of the compound of structural formula II: ##STR4## by incubation of a Streptomyces sp., in a nutrient medium in the presence of the compound of structural formula II.
The preferred strain of the Streptomyces sp. is believed to be Streptomyces cyanus and is deposited in the culture collection of Merck & Co. Inc., Rahway, N.J. as HA 6962. A sample of this was deposited Jul. 24, 1991 under the Budapest Treaty with the American Type Culture Collection at 1230, Parklawn Drive, Rockville Md. 20852 and has been assigned accession number ATCC 55214.
The following is a general description of Streptomyces sp., strain HA6962, ATCC 55214.
Observations of growth, general cultural characteristics and carbon source utilization were made in accordance with the methods of Shitling and Gottleib (Internat. J. System. Bacteriol. 16: 313-340). Chemical composition of the cells was determined using the methods of Lechevalier and Lechevalier (in Actinomycete Taxonomy, A. Dietz and D. W. Thayer, Ed. Society for Industrial Microbiology, 1980). Coloration of the culture was determined by comparison with color standards contained in the Inter-Society Color Council-National Bureau of Standards Centroid Color Charts (U.S. Dept. of Commerce National Bureau of Standards supplement to NBS Circular 553, 1985).
Source
This culture was isolated from a soil sample collected in Somerset, NJ.
Analysis of Cell Wall Composition:
Peptidoglycan contains LL-diaminopimelic acid.
General Growth Characteristics:
Good growth on yeast malt extract agar (YME), glycerol asparagine agar, inorganic salt starch agar, oatmeal, trypticase soy agar, Czapek's agar, and peptone iron
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patent: 5256689 (1993-10-01), Chiang et al.
patent: 5258401 (1993-11-01), Berger et al.
patent: 5270332 (1993-12-01), Chen et al.
patent: 5284758 (1994-02-01), Bills et al.
Arison Byron H.
Chen Shieh-Shung T.
Gagliardi Magda M.
Garrity George M.
Huang Leeyuan
Chan Nicky
Merck & Co. , Inc.
Quagliato Carol S.
Winokur Melvin
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