Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-06-05
1998-03-24
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514241, 514255, 514256, 544180, 544238, 546133, 546134, 546137, A01N 4390, C07D45302
Patent
active
057313237
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB93/02617, Dec. 21, 1993.
This invention concerns heterocyclic-compounds which are useful in inhibiting squalene synthase, processes for their preparation and pharmaceutical compositions containing them. The present invention is also concerned with methods of using such heterocyclic compounds in treating diseases and medical conditions where inhibition of squalene synthase is desirable, for example in treating diseases or medical conditions such as hypercholesterolemia and atherosclerosis.
Several different classes of compounds have been reported to possess the capability of being able to lower cholesterol levels in blood plasma. For example agents which inhibit the enzyme HMG CoA reductase, which is essential for the production of cholesterol, have been reported to reduce levels of serum cholesterol. Illustrative of this class of compounds is the HMG CoA reductase inhibitor known as lovastatin which is disclosed in U.S. Pat. No. 4,231,938. Other agents which are reported to lower serum cholesterol include those which act by complexing with bile acids in the intestinal system and which are hence termed "bile acid sequestrants". It is believed that many of such agents act by sequestering bile acids within the intestinal tract. This results in a lowering of the levels of bile acid circulating in the enteroheptatic system and promoting replacement of bile acids by synthesis in the liver from cholesterol which results in an upregulation of the hepatic LDL receptor and hence in a lowering of circulating blood cholesterol levels.
Squalene synthase (also referred to in the art as squalene synthetase) is a microsomal enzyme which catalyses the first committed step of cholesterol biosynthesis. Two molecules of farnesyl pyrophosphate (FPP) are condensed in the presence of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) to form squalene. The inhibition of this committed step to cholesterol should leave unhindered biosynthetic pathways to ubiquinone, dolichol and isopentenyl t-RNA. Elevated cholesterol levels bare known to be one of the main risk factors for ischaemic cardiovacsular disease. Thus, an agent which inhibits squalene synthase should be useful in treating diseases and medical conditions in which a reduction in the levels of cholesterol is desirable, for example hypercholesterolemia and atherosclerosis.
Thus far, the design of squalene synthase inhibitors has concentrated on the preparation of analogues of the substrate farnesyl pyrophosphate (FPP), and hence on compounds which contain phosphorus groups. For example, the preparation of phosphorous-containing squalene synthase inhibitors is reported in published European Patent Application No. 409,181; and the preparation of isoprenoid (phosphinylmethyl)phosphonates as inhibitors of squalene synthase is reported by Biller et al, J. Med. Chem., 1988, 31, 1869. Quinuclidine derivatives are reported in, for example, EP 458,214 to be muscarinic agonists. Recently, certain quinuclidine derivatives have been reported (WO 92/15579 and U.S. Pat. No. 5,135,935) to inhibit squalene synthase.
The present invention is based on the discovery that certain heterocyclic compounds are inhibitors of squalene synthase, and are hence useful in treating diseases and medical conditions in which inhibition of squalene synthase is desirable.
According to the present invention there is provided a compound of formula I (formula set out hereinafter together with the other chemical formulae referred to herein in Roman numerals), or a pharmaceutically acceptable salt thereof, wherein: double bond; --CH.sub.2 O--, --OCH.sub.2 --, --CH.sub.2 NH--, --NHCH.sub.2 --, --CH.sub.2 CO--, --COCH.sub.2 --, --N.dbd.CH--, --CH.dbd.N--, --CH.sub.2 S-- and --SCH.sub.2 -- (wherein the sulphur atom in the latter two groups may optionally bear one or two oxygen atoms); independently selected from nitrogen, oxygen and sulphur; and wherein Ar may optionally be unsubstituted or may bear one or more substituents independently selected from halogeno, h
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Dahlen Garth M.
Ivy C. Warren
Zeneca Limited
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