Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-08-15
1998-10-06
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540552, C07D 2810, A61K 3155
Patent
active
058176527
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/GB94/00299, filed Feb. 15, 1994.
The present invention is concerned with new hypolipidaemic compounds, with processes and novel intermediates for their preparation, with pharmaceutical compositions containing them and with their use in medicine, particularly in the prophylaxis and treatment of hypolipidaemic conditions, such as atherosclerosis.
Hypolipidamic conditions are often associated with elevated plasma concentrations of low density lipoprotein (LDL) cholesterol and very low density lipoprotein (VLDL) cholesterol. Such concentrations may be reduced by decreasing the absorption of bile acids from the intestine. One method by which this may be achieved is to inhibit the bile acid active uptake system in the terminal ileum. Such inhibition stimulates the conversion of cholesterol to bile acid by the liver and the resulting increase in demand for cholesterol produces a corresponding increase in the rate of clearance of LDL and VLDL cholesterol from the blood plasma or serum.
There has now been identified a novel class of heterocyclic compounds which reduce the plasma or serum concentrations of LDL and VLDL cholesterol and in consequence are particularly useful as hypolipidaemic agents. By decreasing the concentrations of cholesterol and cholesterol ester in the plasma, the compounds of the present invention retard the build-up of atherosclerotic lesions and reduce the incidence of coronary heart disease-related events. The latter are defined as cardiac events associated with increased concentrations of cholesterol and cholesterol ester in the plasma or serum.
For the purposes of this specification, a hyperlipidaemic condition is defined as any condition wherein the total cholesterol concentration (LDL+VLDL) in the plasma or serum is greater than 240 mg/dL (6.21 mmol/L) (J. Amer. Med. Assn. 256, 20, 2849-2858(1986)). U.S. Pat. No. 3,362,962 describes a genus of benzothiazepines outside the scope of the present invention which have muscle-relaxant and anticonvulsant activity; there is no disclosure in the patent specification that the compounds described therein may be useful as hypolipidaemic agents.
According to the present invention, there is provided a compound of formula (I) ##STR2## l is an integer of from 0 to 4; n is an integer of from 0 to 2; aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl, alkaryl, --O(CH.sub.2).sub.p SO.sub.3 R.sup.11, --O(CH.sub.2).sub.p NR.sup.11 R.sup.12, --O(CH.sub.2).sub.p N.sup.+ R.sup.11 R.sup.12 R.sup.14, --COR.sup.11, --CO.sub.2 R.sup.11, --CONR.sup.11 R.sup.12, --CH.sub.2 OR.sup.11, --NR.sup.11 R.sup.12, --NHCOR.sup.11, --NHSO.sub.2 R.sup.11, --SR.sup.11, --SO.sub.2 R.sup.11, --SO.sub.2 NR.sup.11 R.sup.12, --SO.sub.3 R.sup.11 wherein p is an integer of from 1 to 4, R.sup.11 and R.sup.12 are independently selected from hydrogen, C.sub.1-6 alkyl and phenyl, and R.sup.14 is hydrogen or C.sub.1-6 alkyl or R is a group --OCH.sub.2 O-- which forms a further ring attached to X, wherein said alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralyl and alkaryl groups are optionally substituted by one or more atoms or groups selected from halogen, nitro, nitrile, alkyl, alkoxy, --COR.sup.11, --CO.sub.2 R.sup.11, --SO.sub.3 R.sup.11 wherein R.sup.11 is as hereinbefore defined and --NR.sup.14 R.sup.15 wherein R.sup.14 is as hereinbefore defined and R.sup.15 is hydrogen or C.sub.1-6 alkyl; (including cycloalkyl and cycloalkylalkyl), C.sub.1-4 alkoxy, pyrryl, thienyl, pyridyl, 1,3-benzodioxolo, phenyl and naphthyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, cyano, nitro, carboxyl, phenyl, phenoxy, benzyloxy, --COR.sup.11, --CO.sub.2 R.sup.11, --CONR.sup.11 R.sup.12, --CH.sub.2 OR.sup.11, --NR.sup.11 R.sup.12, --NHCOR.sup.11, --NHSO.sub.2 R.sup.11, --SR.sup.11, --SO.sub.2 R.sup.11, --SO.sub.3 R.sup.11 (wherein R.sup.11 and R.sup.12 are as hereinbefore defined) --O(CH.sub.2).sub.p NR.sup.11 R.sup.12, --O(CH.sub.2).sub.p N.sup.+ R.sup.11 R.sup.12 R.sup.13 and --O(CH.sub.2).sub.p SO.sub.3 R.sup.11
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Brieaddy Lawrence Edward
Hodgson, Jr. Gordon Lewis
Ford John M.
Glaxo Wellcome Inc.
Hrubiec Robert T.
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