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HMG-CoA reductase inhibitors

a reductase inhibitor and coa technology, applied in the field of hmgcoa reductase inhibitors, can solve problems such as unpalatable, and achieve the effect of being used as anti-hypercholesterolemic agents

Inactive Publication Date: 2000-01-18
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This invention relates to novel compounds which are HMG-CoA reductase inhibitors and are useful as antihypercholesterolemic agents. Specifically, the compounds of this invention are analogs of mevinolin and related compounds which possess a hydroxyalkyl group, acyloxyalkyl or carbamoyloxyalkyl group of the structure ##STR9## a carboxy group, an alkoxycarbonyl group, a carbamoyl group of structure ##STR10## or a ketone group of the stru

Problems solved by technology

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.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

The following media are utilized in the bioconversion reactions described below:

______________________________________ Grams per liter distilled water ______________________________________ Medium A Yeast extract 4.0 Malt extract 10.0 Nutrient broth 4.0 Dextrose 4.0 pH 7.4 Medium sterilized for 20 min. at 121.degree. C. Medium B Dextroxe 10.0 Polypeptone 2.0 Meat extract 1.0 Corn steep liquor 3.0 pH 7.0 Medium sterilized for 20 min. at 121.degree. C. ______________________________________

I. Culture Conditions and Bioconversion

A lyophilized tube of Nocardia autotrophica subsp. canberrica ATCC 35204 (MA-6180) was used to inoculate 18.times.175 agar slants (Medium A) which were incubated at 27.degree. C. for 7 days. The slant culture was washed with 5 ml of sterile medium B and transferred to a 250 ml flask containing 50 ml of sterile medium B.

This first stage seed was grown at 27.degree. C. on a 220 rpm shaker and, after 24 hours, 2 ml was transferred to another flask of sterile mediu...

example 2

Preparation of 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(S)-hydroxymethyl-1,2, 3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-one

(a) 6(R)-[2-[8(S)-Nitrosyloxy-2(S),6(S)-dimethyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-d ecahydronaphthyl-1(S)]ethyl]-4(R)-(tert-butyldimethylsilyloxy)-3,4,5,6-tetr ahydro-2H-pyran-2-one (2a)

A stream of nitrosyl chloride gas was passed into a stirred solution of 6(R)-[2-[8(S)-hydroxy-2(S), 6(S)-dimethyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S)]ethyl]-4( R)-(tert-butyldimethylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one (800 mg, 1.82 mmol) in pyridine (14 ml) at 0.degree. C. until the solution was saturated (brownish fumes filled the reaction flask). The resulting mixture was stirred at 0.degree. C. for another 10 minutes, poured into cold water and extracted with diethyl ether. The extract was washed successively with dilute HCl, water and 5% NaHCO.sub.3, dried (MgSO.sub.4), filtered and concentr...

example 3

Preparation of 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(S)-(1-hydroxyethyl)-1 ,2,3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5 ,6-tetrahydro-2H-pyran-2-one

(a) 6(R)-[2-[8(S)-Nitrosyloxy-2(S),6(S)-dimethyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-d ecahydronaphthyl-1(S)]ethyl]-4(R)-(tert-butyldimethylsilyloxy)-3,4,5,6-tetr ahydro-2H-pyran-2-one (3a)

A stream of nitrosyl chloride gas was passed into a stirred solution of 6(R)-[2-[8(S)-hydroxy-2(S), 6(S)-dimethyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S)]ethyl]-4( R)-(tert-butyldimethylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one (800 mg, 1.82 mmol) in pyridine (14 ml) at 0.degree. C. until the solution was saturated (brownish fumes filled the reaction flask). The resulting mixture was stirred at 0.degree. C. for another 10 minutes, poured into cold water and extracted with diethyl ether. The extract was washed successively with dilute HCl, water and 5% NaHCO.sub.3, dried (MgSO.sub.4), filtered and conce...

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PUM

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Abstract

Novel 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are useful as antihypercholesterolemic agents and are represented by the following general structural formula (II):

Description

BACKGROUND OF THE INVENTIONHypercholesterolemia 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 functions 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 semisynthetic analogs have the following general structural formulae: ##STR2## wherein: Z 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 ace...

Claims

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Application Information

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IPC IPC(8): C07C69/732C07D309/30C07D309/00C07C69/00C12P7/62C12P17/06
CPCC07C69/732C07D309/30C12P7/62C12P17/06C12R1/365C12N1/205C12R2001/365
Inventor SMITH, ROBERT L.HALCZENKO, WASYLHARTMAN, GEORGE D.STOKKER, GERALD E.INAMINE, EDWARD S.HENSENS, OTTO D.HOUCK, DAVID R.LEE, TA JYH
Owner MERCK & CO INC
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