Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-24
2002-01-01
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S295000, C546S187000, C514S316000
Reexamination Certificate
active
06335341
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 treating or preventing diseases and medical conditions such as hypercholesterolemia, atherosclerosis and other medical conditions associated with elevated cholesterol levels.
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 is possible to obtain some reduction by means of diet, only modest reductions are 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 which are able to lower cholesterol levels in blood plasma. For example agents which inhibit the enzyme HMGCoA reductase, an enzyme 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 these agents lower cholesterol levels indirectly by sequestering bile acids within the intestinal tract resulting in lower levels of bile acid circulating in the enteroheptatic system. Replacement of bile acids, which is synthesised in the liver from cholesterol, is promoted. This in turn results in an upregultion 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 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 on a seperate sheet following the examples together with the other formulae referred to herein), or a pharmaceutically acceptable salt thereof, wherein:
G is selected from CH or N;
R1 is selected from hydrogen, halogeno, (1-6C)alkyl, halogeno(1-6C)alkyl, cyano, nitro, (1-6C)alkoxycarbonyl, and NR
3
R
4
wherein R
3
and R
4
are independently selected from hydrogen and (1-6C)alkyl, and wherein upto 3 R1 groups may be present:
T
1
is selected from CH or N;
T
2
and T
3
are independently selected from N and CR, wherein R is selected from hydrogen, hydroxyl and (C1-4)alkyl and wherein either ring containing T
2
or T
3
is optionally substituted with an oxo group;
R2 is selected from hydrogen or (1-4C)alkyl;
Q is selected from SO
2
, CO and CH
2
;
Ar is selected from a five or six membered heterocycle containing up to 3 heteroatoms selected from nitrogen, oxygen and sulphur, phenyl, phenyl (2-6C)alkenyl and naphthyl in which any Ar group is optionally substituted by one or more substituents selected from (1-6C)alkyl, halogeno, halogeno (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, cyano, (1-6C)alkylamido, nitro, NR
3
R
4
wherein R
3
and R
4
are independently selected from hydrogen and (1-4C)alkyl; provided that both T
2
and T
3
are not N and that when T
2
is CR then T
1
is not CH.
The compounds of the present invention are oxido-squalene cyclase inhibitors and hence possess the property of inhibiting cholesterol biosynthesis. Provided as a further feature of the invention is compounds of formula (I), or a pharmaceutically acceptable salt, for use in medical therapy. 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 treating diseases or medical conditions in which inhibition of oxidosqualene cyclase is desirable. 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 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).
The compounds of the present invention are useful in treating diseases or medical conditions in which 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 are 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, 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, the compounds of the invention may exist in, and be isolated in, optically active or racemic form. The invention includes any optically active or racemic form of a compound of formula I which possesses the beneficial pharmacological effect of inhibiting oxido-squalene cyclase. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by, resolution of a racemic form, by synthesis from optically active starting materials or by asymmetric synthesis. It will be appreciated that certain compounds of formula I may exist as geometrical isomers. The invention includes any geometrical isomer of a compound of formula I which possesses the beneficial pharmacological effect of inhibiting oxido-squalene cyclase.
It will also be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It is to be understood that the present invention encompasses all such solvated forms which
Johnson Michael Clyde
Newcombe Nicholas John
Liu Hong
Zeneca Limited
LandOfFree
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