Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-02-07
1999-06-08
Robinson, Allen J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514221, 540546, 540552, 540595, C07D28110, C07D41704, C07D51304, A61K 3155
Patent
active
059104945
DESCRIPTION:
BRIEF SUMMARY
The present invention is concerned with new hypolipidemic 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 hyperlipidemic conditions, such as atherosclerosis.
Hyperlipidemic conditions are often associated with elevated plasma concentrations of low density lipoprotein (LDL) cholesterol and very low density lipoprotein (VLDL) cholesterol. Such concentrations can 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 hypolipidemic 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 hyperlipidemic 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)).
International Patent Application No. WO 93/16055 describes compounds of formula (O) ##STR2## wherein 1 is an integer of from 0 to 4; phenylalkoxy, wherein p is an integer of from 1 to 4 and groups are optionally substituted by one or more halogen atoms; salts, solvates and physiologically functional derivatives thereof, as being useful as hypolipidemic agents.
We have now discovered a group of compounds which have greater hypolipidemic activity in vivo than those specifically disclosed in International Patent Application No. WO 93/16055.
Accordingly the present invention provides compounds of the formula (I): ##STR3## wherein R.sup.1 is a straight chained C.sub.1-6 alkyl group; R.sup.2 is a straight chained C.sub.1-6 alkyl group; R.sup.3 is hydrogen or a group OR.sup.11 in which R.sup.11 is hydrogen, optionally substituted C.sub.1-6 alkyl or a C.sub.1-6 alkylcarbonyl group; R.sup.4 is pyridyl or optionally substituted phenyl; R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are the same or different and each is selected from hydrogen, halogen, cyano, R.sup.15 -acetylide, OR.sup.15, optionally substituted C.sub.1-6 alkyl, COR.sup.15, CH(OH)R.sup.15, S(O).sub.n R.sup.15, P(O)(OR.sup.15).sub.2, OCOR.sup.15, OCF.sub.3, OCN, SCN, NHCN, CH.sub.2 OR.sup.15, CHO, (CH.sub.2).sub.p CN, CONR.sup.12 R.sup.13, (CH.sub.2).sub.p CO.sub.2 R.sup.15, (CH.sub.2).sub.p NR.sup.12 R.sup.13, CO.sub.2 R.sup.15, NHCOCF.sub.3, NHSO.sub.2 R.sup.15, OCH.sub.2 OR.sup.15, OCH.dbd.CHR.sup.15, O(CH.sub.2 CH.sub.2 O).sub.n R.sup.15, O(CH.sub.2).sub.p SO.sub.3 R.sup.15, O(CH.sub.2).sub.p NR.sup.12 R.sup.13 and O(CH.sub.2).sub.p N.sup.+ R.sup.12 R.sup.13 R.sup.14 wherein p is an integer from 1-4, n is an integer from 0-3 and, R.sup.12, R.sup.13, R.sup.14 and R.sup.15 are independently selected from hydrogen and optionally substituted C.sub.1-6 alkyl; or R.sup.6 and R.sup.7 are linked to form a group ##STR4## wherein R.sup.12 and R.sup.13 are as hereinbefore defined and m is 1 or 2; and R.sup.9 and R.sup.10 are the same or different and each is hydrogen or C.sub.1-6 alkyl; and salts, solvates or a physiologically functional derivatives thereof, with the proviso that when R.sup.3 is hydrogen either R.sup.7 is not hydrogen or at least two of R.sup.5, R.sup.6, R.sup.7 and R
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Glaxo Wellcome Inc.
Hrubiec Robert T.
Morgan Lorie Ann
Qazi Sabiha N.
Robinson Allen J.
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