Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-07-31
2001-11-06
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252180, C514S340000, C514S341000, C544S295000, C544S360000, C546S268100, C546S274100
Reexamination Certificate
active
06313127
ABSTRACT:
This invention concerns heterocyclic compounds 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 compounds 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 compounds in diseases and medical conditions such as hypercholesterolemia and atherosclerosis.
There is clinical evidence that raised serum cholesterol levels increase the risk of 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 have been obtained by controlling the dietry 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 being able 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 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 promotes replacement of bile acids by synthesis in the liver from cholesterol, which 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 via LDL receptor upregulation.
The present invention is based on the discovery that certain heterocyclic compounds 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, or a pharmaceutically acceptable salt thereof, wherein
According to the present invention there is provided a compound of formula I,
wherein
G
1
is CH or N;
G
2
is CH or N;
n is 1 or 2;
R is hydrogen, halogeno, trifluoromethyl, trifluoromethoxy, cyano, amino, hydroxy, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di(1-4C)alkylarnino or phenyl(1-4C)alkyl;
A is methylene or ethylene; B is ethylene; and wherein A and B may independently optionally bear a substituent selected from (1-6C)alkyl, (1-6C)alkoxy, phenyl(1-4C)alkyl, halogeno and (1-6C)alkoxycarbonyl;
T is CH or N;
when T is CH, X
1
is selected from CR
1
R
2
, SO
2
, SO, CO, CR
3
R
4
O, a bond, O, S and NR
5
; and when T is N, X
1
is selected from CR
1
R
2
, SO
2
, SO, CO, CR
3
R
4
O and a bond; wherein R
1
, R
2
, R
3
, R
4
and R
5
are independently selected from hydrogen and (1-4C)alkyl;
Y
1
represents CR
6
R
7
or a bond, wherein R
6
and R
7
are independently selected from hydrogen and (1-4C)alkyl;
Ar
1
is a phenylene, naphthylene, a 5- or 6-membered monocyclic heteroaryl ring containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulphur, or a 9- or 10-membered bicyclic heteroaryl ring containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulphur;
Q is selected from hydrogen and a group of formula L
1
X
2
L
2
Z in which L
1
is a bond, (1-4C)alkylene or (2-4C)alkenylene, L
2
is a bond or (1-4C)alkylene, X
2
is a bond, O, S, SO, SO
2
, CR
8
R
9
, CO, OSO
2
, OCR
8
R
9
, OCO, SO
2
O, CR
8
(R
9
)O, COO, NR
10
SO
2
, SO
2
NR
11
, NR
12
CO, CONR
12
, NR
13
CONR
14
and NR
14
in which R
8
and R
9
are independently selected from hydrogen, hydroxy and (1-4C)alkyl; and R
10
, R
11
, R
12
, R
13
and R
14
are independently selected from hydrogen and (1-4C)alkyl;
Z is hydrogen, (1-4C)alkyl, phenyl, naphthyl, phenyl(2-4C)alkenyl, phenyl(2-4C)alkynyl or a heterocyclic moiety containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulphur;
and wherein the phenyl, naphthyl or heteroaryl moiety in Ar
1
and the alkyl, phenyl, naphthyl, or heterocyclic moiety in Z may optionally bear one or more substituents selected from halogeno, hydroxy, oxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, hydroxy(1-6C)alkyl, (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, halogeno(1-6C) alkylthio, halogeno(1-6C)alkoxy, (1-6C)alkanoyl, tetrazoyl, phenyl, phenoxy, phenylsulphonyl, piperidinocarbonyl, morpholinocarbonyl, hydroxy(1-6C)alkyl and amino(1-6C)alkyl; wherein any phenyl containing substituents may optionally bear one or more substituents selected from halogeno, trifluoromethyl, trifluoromethoxy, cyano, amino, hydroxy, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino and di(1-4C)alkylamino;
provided that the compound is not N-[4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]phenyl]-(E)-4-chlorostyrenesulphonamide or N-[4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]phenyl]4′-bromio-4-biplhenylesulphonamide;
and pharmaceutically acceptable salts thereof.
The chemical formulae referred to herein by Roman numerals are, for convenience, set out on a separate sheet following the Examples.
It will be understood that when formula I compounds 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 also 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 possess the property of inhibiting oxido-squalene cyclase.
It is also to be understood that generic terms such as “alkyl” include both the straight chain an
Brown George Robert
Cumming John Graham
Newcombe Nicholas John
Stokes Elaine Sophie Elizabeth
Waterson David
Pillsbury & Winthrop LLP
Raymond Richard L.
Zeneca Limited
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