Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-05-01
1999-12-07
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540491, 540552, C07D28110, A61K 3155
Patent
active
059984007
DESCRIPTION:
BRIEF SUMMARY
This application is filed pursuant to 35 U.S.C. .sctn.371 as a United States National Phase Application of International Application No. PCT/GB95/02700 filed Nov. 16, 1995 which claims priority from GB9423172.7 filed Nov. 17, 1994.
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 and associated conditions such as atherosclerosis.
Hyperlipidemic conditions are often associated with elevated plasma concentrations of low density lipoprotein (LDL) 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 cholesterol from the blood plasma or serum.
A novel class of heterocyclic compounds has been identified which reduce the plasma or serum concentrations of LDL 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.
International Patent Application No. WO 93/16055 describes 1,4-benzothiazepine compounds which have hypolipidemic activity. A group of novel substituted 1,5-benzothiazepine compounds has now been discovered which also have hypolipidemic activity.
Accordingly, the present invention provides compounds of the formula (I) ##STR2## wherein R.sup.1 and R.sup.2 are the same or different and each is optionally substituted C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, or R.sup.1 and R.sup.2 together with the carbon atom to which they are attached form an optionally substituted C.sub.3-6 spiro-cycloalkyl group; optionally substituted with one to eight substituents which are the same or different and are each selected from halogen, hydroxy, nitro, phenyl-C.sub.1-6 alkoxy, C.sub.1-6 alkoxy, optionally substituted C.sub.1-6 alkyl, S(O).sub.n R.sup.8, SO.sub.2 NR.sup.8 R.sup.9, CO.sub.2 R.sup.8, O(CH.sub.2 CH.sub.2 O).sub.n R.sup.8, OSO.sub.7 R.sup.8, O(CH.sub.2).sub.p SO.sub.3 R.sup.8, O(CH.sub.2).sub.p NR.sup.9 R.sup.10 and O(CH.sub.2).sub.p N.sup.+ R.sup.9 R.sup.10 R.sup.11 wherein R.sup.8 to R.sup.11 are the same or different and are independently selected from hydrogen or optionally substituted C.sub.1-6 alkyl, and wherein p is an integer from 1-4 and n is an integer from 0-3; which are the same or different and each is hydrogen. halogen, cyano, R.sup.8 -acetylide, OR.sup.8, optionally substituted C.sub.1-6 alkyl. COR.sup.8, CH(OH)R.sup.8, S(O).sub.n R.sup.8, SO.sub.2 NR.sup.8 R.sup.9, P(O)(OR.sup.8).sub.2, OCOR.sup.8, OCF.sub.3, OCN, SCN, NHCN, CH.sub.2 OR.sup.8, CHO, (CH.sub.2).sub.p CN, CONR.sup.9 R.sup.10, (CH.sub.2).sub.p COR.sup.8, (CH.sub.2).sub.p NR.sup.9 R.sup.10, CO.sub.2 R.sup.8, NHCOCF.sub.3, NHSO.sub.2 R.sup.8, OCH.sub.2 OR.sup.8, OCH.dbd.CHR.sup.8, O(CH.sub.2 CH.sub.2 O).sub.n R.sup.8, OSO.sub.2 R.sup.8, O(CH.sub.2).sub.p SO.sub.3 R.sup.8, O(CH.sub.2).sub.p NR.sup.9 R.sup.10 and O(CH.sub.2).sub.p N.sup.+ R.sup.9 R.sup.10 R.sup.11 wherein R.sup.8 to R.sup.11, n, and p are as hereinbefore defined; or R.sup.5a and R.sup.5b, R.sup.5b and R.sup.5c, or R.sup.5c and R.sup.5d together with the ring to which they are attached form a cyclic group --O(CR.sup.9 R.sup.10).sub.m O-- wherein R.sup.9 and R.sup.10 are as hereinbefore defined and m is 1 or 2; optionally substituted C .sub.1-6 alkyl, C.sub.3-6 cycloalkyl, or R.s
REFERENCES:
patent: 5610153 (1997-03-01), Buhlmayer et al.
patent: 5817653 (1998-10-01), Elliot et al.
Ried et al., Liebigs Ann. Chem. (1980), (8), 1252-1258.
Ried et al., Liebigs Ann. Chem. (1980), (11), 1913-1916.
Brieaddy Lawrence Edward
Handlon Anthony Louis
Hodgson, Jr. Gordon Lewis
Glaxo Wellcome Inc.
Kifle Bruck
Morgan Lorie Ann
Raymond Richard L.
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