Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-06-30
1998-08-11
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546133, A61K 4340, C07D45300
Patent
active
057927774
DESCRIPTION:
BRIEF SUMMARY
The present application is a 371 of PCT/GB92/01968, filed Oct. 27, 1992.
FIELD OF INVENTION
This invention concerns heterocyclic compounds which are useful in inhibiting squalene synthetase, processes for their preparation and pharmaceutical compositions containing them. The present invention is also concerned with methods of using such heterocyclic compounds in diseases and medical conditions where inhibition of squalene synthetase is desirable, for example in treating diseases or medical conditions such as hypercholesterolemia and atherosclerosis.
BACKGROUND
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 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 synthesis results, inter alia, in a lowering of circulating blood cholesterol levels.
Squalene synthetase (also referred to as squalene synthase in the art) 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 are known to be one of the main risk factors for ischaemic cardiovacsular disease. Thus, an agent which inhibits squalene synthetase 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 synthetase 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 synthetase inhibitors is reported in published European Patent Application No. 409,181; and the preparation of isoprenoid (phosphinylmethyl)phosphonates as inhibitors of squalene synthetase is reported by Biller et al, J. Med. Chem., 1988, 31, 1869.
Certain quinuclidine derivatives have been reported in EP 412,797 to stimulate central muscarinic acetlycholine receptors. Qunicluidine derivatives which inhibit choline uptake are reported by G H Sterling et al. in J Pharm Sci, (1991), 80(8), 785-789.
SUMMARY OF INVENTION
The present invention is based on the discovery that certain heterocyclic compounds are inhibitors of squalene synthetase, and are hence useful in treating diseases and medical conditions in which inhibition of squalene synthetase is desirable.
According to the present invention there is provided the use of a biphenylylquinuclidine compound of formula I (formula set out hereinafter together with the other chemical formulae referred to herein), or a pharmaceutically-acceptable salt thereof, wherein: R.sup.1 is hydrogen or hydroxy; R.sup.2 is hydrogen; or R.sup.1 and R.sup.2 are joined together so that CR.sup.1 -CR.sup.2 is a double bond; and one or both ring A and ring B may be optionally unsubstituted or independently substituted by one or more substituents selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alk
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Brown George Robert
Harrison, deceased Peter John
Mallion Keith Blakeney
Raymond Richard L.
Zeneca Limited
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