Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-08-13
2002-05-21
Shah, Mukund J. (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S295000, C544S333000, C544S335000, C544S360000
Reexamination Certificate
active
06391880
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 sonic 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 ability to lower cholesterol levels in blood plasma. For example agents which inhibit the enzyme HMGCoA reductase, which is essential for the production of cholesterol, have been reported to reduce levels of serum cholesterol. Illustrative of this class of compounds in 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. This results in a lowering of the levels of bile acid circulating in the enteroheptatic system and promotes replacement of bile acids by synthesis in the liver from cholesterol. In turn this results in an upregulation of the hepatic LDL cholesterol receptor and in 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 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 arc 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 compounds 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 salt thereof, wherein:
G is selected from CH and N;
T
1
is selected from N and CR, wherein R may be hydrogen, (1-4C)alkyl, (2-4C)alkenyl and (2-4C)alkynyl, (preferably R is hydrogen);
R
1
is hydrogen, amino, halogeno, cyano, nitro, carboxy, (1-6C)alkanoyl, (1-6C)alkyl, (1-6C)alkoxy, 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 (1-4C)alkylene, carbonyl or (1-4C)alkylcarbonyl, (preferably A is (1-4C)alkylcarbonyl or carbonyl);
T
2
is selected from CH and N;
T
3
is selected from N and CR, wherein R is as defined above, (preferably R is hydrogen);
provided that when T
2
is CII then T
3
is not CR and when T
1
is CR then T
3
is not CR;
a and b are independently selected from 2 and 3;
c and d are independently selected from 1 and 2;
wherein the ring containing T
1
and the 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;
X is selected from oxy, thio, sulphinyl, sulphonyl, carbonyl, carbonylamino, N-(1-6C)alkylcarbonylamino, sulphonylamino, methylene, (1-4C)alkymethylene and di-(1-6C)alkylmethylene, and when T
2
is CH, X may also be selected from aminosulphonyl and oxycarbonyl;
Q is selected from (5-7C)cycloalkyl, a heterocyclic moiety containing up to 4 heteroatoms selected from nitrogen oxygen and sulphur phenyl, naphthyl, phenyl(1-4C)alkyl and phenyl(2-6C)alkenyl, and wherein the last three groups may optionally bear a phenyl substituent;
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, 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, tetrazolyl and a heteroaryl group comprising a 5- or 6-membered monocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur.
The compounds of the present invention arc 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, or a pharmaceutically-acceptable salt thereof, for use as a medicament. Accordingly, there is also provided the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting cholesterol biosynthesis. Thus 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. As inhibitors of cholesterol biosynthesis, the compounds of the present invention will also be useful in treating fungal infections.
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 adminstering to said animal an effective amount of a compound of formula I, 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 degeneration (such as atherosclerosis).
Thus the present invention also provides the use of a compound of formula I 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).
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 compounds of formula I contain a chiral centre, they may exist in, and be isolated in, optically active or racernic form. The invention includes any optically active or racemic form of a compound of formula I which possesses the beneficial pharmacological effect of inhibitin
Brown George Robert
Foubister Alan John
Newcombe Nicholas John
Shah Mukund J.
Truong Tamthom N.
Zeneca Limited
LandOfFree
Heterocyclic compounds useful as oxido-squalene cyclase... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Heterocyclic compounds useful as oxido-squalene cyclase..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Heterocyclic compounds useful as oxido-squalene cyclase... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2863315