Quinclidine derivatives as squalene synthase inhibitors

Details Quinclidine derivatives as squalene synthase inhibitors Quinclidine derivatives as squalene synthase inhibitors

1995-06-23

1997-11-25

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

546133, 546137, A61K 3146, C07D45302

Patent

active

056913494

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB93/01648, Aug. 4, 1993.


FIELD OF INVENTION

This invention concerns heterocyclic derivatives 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 derivatives in diseases and medical conditions where inhibition of squalene synthase is desirable, for example in treating diseases or medical conditions such as hypercholesterolemia and atherosclerosis.


BACKGROUND TO INVENTION

Several different classes of compounds have been reported to possess the capability of being able to lover 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 HMGCoA 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 heptatic LDL receptor and thus in a lowering of circulating blood cholesterol levels.
Squalene synthase 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 cardiovascular 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 have been reported in, for example, EP 458,214, U.S. Pat. No. 4,599,344, U.S. Pat. No. 3,725,410, GB 1,416,958, Khim, Farm, 12(11), (1978), 56-60; Khim. Farm, 7(8), (1973), 20-24, Heterocycles, 24, (1986), 971-7 Khim. Geterotsikl. Soedin, 3, (1983), 381-5, and 7, (1976), 776-780.
The present invention is based on the discovery that certain heterocyclic derivatives 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 the use of a compound of formula I (formula set out hereinafter together with the other chemical formulae referred to herein), 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 --, --CH.sub.2 S(O).sub.n --and --S(O).sub.n CH.sub.2 -- wherein n is 0, 1 or 2; and more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6

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