Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-02-12
2000-07-25
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514252, 514256, 514269, 514274, 514275, 544238, 544295, 544296, 544298, 544311, 544317, 544319, 544320, 544321, 544323, 544326, 544327, 544329, A01N 4354, A01N 4358, A01N 4340, C07D40300, C07D23902
Patent
active
060937181
DESCRIPTION:
BRIEF SUMMARY
This invention concerns heterocyclic derivatives which are useful in inhibiting oxido-squalene cyclase. processes for their preparation and pharmaceutical compositions containing them. The present invention is also concerned with heterocyclic derivatives capable of inhibiting cholesterol biosynthesis and hence in lowering cholesterol levels in blood plasma. The present invention also relates to methods of using such heterocyclic derivatives in diseases and medical conditions such as hypercholesterolemia and atherosclerosis.
There is evidence that high serum cholesterol levels are an important risk factor in coronary heart disease and associated diseases such as atherosclerosis and ischemic heart disease. As a result there has been a great deal of interest in finding ways of lowering cholesterol levels in blood plasma. Although it has been possible to obtain some reduction by means of diet, only modest reductions have been obtained by controlling the dietary intake of cholesterol. Consequently, there is a need for therapeutic approaches to reducing cholesterol levels.
Several different classes of compounds have been reported to possess the capability of lowering cholesterol levels in blood plasma. For example agents which inhibit the enzyme HMGCoA reduces, 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 work by complexing with bile acids in the intestinal system, called "bile acid sequestrants". By lowering the levels of bile acid circulating in the enterohepatic system replacement of bile acids by synthesis in the liver from cholesterol is promoted. This results in an upregulation of the hepatic LDL cholesterol receptor and as a consequence a lowering of circulating blood cholesterol levels.
The biosynthesis of cholesterol is a complex process which will be considered here as three principal stages, namely 1) the conversion of acetic acid to mevalonic acid 2) the conversion of mevalonic acid to squalene and 3) the conversion of squalene to cholesterol. In the last stage, squalene is first converted into 2,3-oxido-squalene and then to lanosterol. Lanosterol is then converted to cholesterol through a number of enzymatic steps.
The conversion of 2,3-oxido-squalene to lanosterol is a key step in the biosynthesis of cholesterol. This conversion is catalysed by the enzyme oxido-squalene cyclase. It follows that inhibition of this enzyme decreases the amount of lanosterol available for conversion to cholesterol. Consequently, inhibition of oxido-squalene cyclase should interrupt cholesterol biosynthesis and give rise to a lowering of cholesterol levels in blood plasma.
The present invention is based on the discovery that certain heterocyclic derivatives are inhibitors of oxido-squalene cyclase and are hence useful in treating diseases and medical conditions in which inhibition of oxido-squalene cyclase is desirable.
According to the present invention there is provided a compound of formula I (set out hereinafter together with the other formulae referred to herein on a separate sheet following the examples), or a pharmaceutically acceptable salt thereof, wherein: (2-4C)alkenyl, (2-4C)alkynyl; (1-6C)dialkylamino or (1-6C)alkoxy; that when T.sup.2 is CH then T.sup.3 is not CR and when T.sup.1 is CR then T.sup.3 is not CR; containing T.sup.2 may, independently, be optionally substituted by one or more substituents selected from (1-6C)alkyl, (1-6C)alkoxy, phenyl(1-4C)alkyl, halogeno and (1-6C)alkoxycarbonyl;
Q is selected from phenyl, naphthyl, phenyl(2-6C)alkenyl and a heteroaryl moiety which comprises a 5- or 6-membered monocyclic heteroaryl ring containing up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur and wherein Q may be unsubstituted or may bear one or more substituents selected from halogeno.
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Brown George Robert
Newcombe Nicholas John
Stokes Elaine Sophie Elizabeth
Waterson David
Schroeder Ben
Shah Mukund J.
Zeneca Limited
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