Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-08-13
2002-08-27
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S357000
Reexamination Certificate
active
06440972
ABSTRACT:
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 ischaemic 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 in cholesterol levels in blood plasma have been obtained. Consequently, there is a need for therapeutic approaches to reducing cholesterol levels.
Several different classes of compounds have been reported to possess the ability to lower cholesterol levels in blood plasma. For example agents which inhibit the enzyme 3-hydroxy-3-methyl glutaryl CoA (HMGCoA) reductase, which is essential for the production of cholesterol, have been reported to reduce levels of cholesterol in blood plasma (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. Such agents act by sequestering bile acids within the intestinal tract resulting in a lowering of the levels of bile acid circulating in the enterohepatic system. This in turn promotes replacement of bile acids, which are synthesised in the liver from cholesterol. This results in an upregulation of the hepatic LDL cholesterol receptor and in a consequential 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 interupt 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 in a separate sheet following the Examples), or a pharmaceutically-acceptable acceptable salt thereof, wherein:
R is selected from halogeno, cyano, nitro, carboxy, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkanoyl, (1-6C)alkoxycarbonyl and halogeno(1-6C)alkyl;
R
1
is selected from hydrogen, amino, halogeno, cyano, nitro, carboxy, (1-6C) alkyl, (1-6C)alkoxy, (1-6C)alkanoyl, (1-6C)alkoxycarbonyl, halogeno(1-6C)alkyl, N-(1-6C)alkylamino, N,N-di-[(1-6C)alkyl]amino, (1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl;
m is 1 or 2;
A is selected from a direct bond and (1-4C)alkylene;
T
1
is selected from N and CR
2
, wherein R
2
may be hydrogen, (1-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl (preferably R
2
is hydrogen);
T
2
is selected from N and CH;
T
3
is selected from N and CR
2
, wherein R
2
is as defined above; provided that when T
2
is CH then T
3
is not CR
2
and when T
1
is CR
2
then T
3
is not CR
2
;
wherein the heterocyclic ring containing T
1
and the heterocyclic ring containing T
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(1-6C)alkyl, phenyl(2-6C)alkenyl and a heteroaryl moiety containing up to 3 heteroatoms selected from nitrogen, oxygen and sulphur;
and wherein Q may be unsubstituted or may bear one or more substituents selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, (1-4C)alkylenedioxy, (1-6C)alkylamino, N,N-di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, di-N[(1-6C)alkyl]carbamoyl, (1-6C)alkanoylamino, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (1-6C)alkanoyl and a heteroaryl group comprising a 5- or 6-membered monocyclic heteroaryl ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur.
The compounds of the present invention are oxido-squalene cyclase inhibitors and hence possess the property of inhibiting cholesterol biosynthesis. There is provided as a feature of the invention a compound of formula I (as hereinbefore defined), or a pharmaceutically-acceptable salt thereof, for use in medical therapy. Also provided is the use of a compound of formula I (as hereinbefore defined), or a pharmaceutically-acceptable acceptable salt thereof, for the manufacture of a medicament for treating diseases or medical conditions in which inhibition of oxido-squalene cyclase is desirable. There is also provided the use of a compound of formula I (as hereinbefore defined), or a pharmaceutically-acceptable acceptable salt thereof, for the manufacture of a medicament for inhibiting cholesterol biosynthesis. The compounds of the present invention will be useful in treating diseases or medical conditions in which an inhibition of oxido-squalene cyclase is desirable, for example those in which a lowering of the level of cholesterol in blood plasma is desirable. In particular, the compounds of the present invention will be useful in treating hypercholesterolemia and/or ischaemic diseases associated with atheromatous vascular degeneration such as atherosclerosis.
Thus the present invention also provides the use of a compound of formula I (as hereinbefore defined), or a pharmaceutically-acceptable salt thereof, for the manufacture of a medicament for treating diseases or medical conditions in which a lowering of the level of cholesterol in blood plasma is desirable (such as hypercholesterolemia and atherosclerosis).
Thus according to a further feature of the present invention there is provided a method of inhibiting oxido-squalene cyclase in a warm-blooded animal (such as man) requiring such treatment, which method comprises administering to said animal an effective amount of a compound of formula I (as hereinbefore defined), or a pharmaceutically-acceptable salt thereof. In particular, the present invention provides a method of inhibiting cholesterol biosynthesis, and more particularly to a method of treating hypercholesterolemia and atheromatous vascular degneration (such as atherosclerosis).
In particular, the compounds of the present invention are potentially useful in inhibiting cholesterol biosynthesis in man and hence in treating the above-mentioned medical conditions in man.
It will be understood that when a compound of formula I contains a chiral centre, it may exist in, and be isolated in, an optically active or racemic form. The invention includes any optically active or racemic form of a compound of for
McKenzie Thomas
Shah Mukund J.
Zeneca Limited
LandOfFree
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