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US 5,491,170 AGranted
.beta.-carboxy sulfonamide ACAT inhibitors
AssigneeWarner-Lambert Company
InventorsHelen T. Lee, Joseph A. Picard, Drago R. Sliskovic
Life of this patent
Estimating the term…
Abstract
.beta.-Carboxy sulfonyl compounds of the formula ##STR1## wherein R.sub.1 is aryl, R.sub.3 is hydrogen or alkyl, R.sub.3 and R.sub.4 are hydrogen or alkyl, Y is --O--, --S--, or --NR.sub.2 --, and R.sub.5 is alkyl or aryl are potent inhibitors of the enzyme acyl CoA:cholesterol acyltransferase (ACAT) and are thus useful for treating hypercholesterolemia and atherosclerosis.
Claims40
A compound of Formula I ##STR21## wherein R.sub.1 is selected from (a) phenyl which is unsubstituted or is substituted with from 1 to 3 substituents selected from C.sub.1 -C.sub.4 alkyl,
- C.sub.1 -C.sub.4 alkoxy,
- C.sub.1 -C.sub.4 alkylthio,
- hydroxy,
- halo,
- nitro,
- cyano,
- trifluoromethyl,
- --COOH,
- --COOalkyl wherein alkyl has from 1 to 4 carbon atoms and which is straight or branched,
- --(CH.sub.2).sub.m NR.sub.x R.sub.y wherein m is 0 or 1, and each of R.sub.x and R.sub.y is independently hydrogen or C.sub.1 -C.sub.4 alkyl;
- (b) 1- or 2-naphthyl which is unsubstituted or substituted with from 1 to 3 substituents selected from
- C.sub.1 -C.sub.4 alkyl,
- C.sub.1 -C.sub.4 alkoxy,
- C.sub.1 -C.sub.4 alkylthio,
- hydroxy,
- halo,
- nitro,
- cyano,
- trifluoromethyl,
- --COOH,
- --COOalkyl wherein alkyl has from 1 to 4 carbon atoms and which is straight or branched,
- --(CH.sub.2).sub.m NR.sub.x R.sub.y wherein m is 0 or 1, and each of R.sub.x and R.sub.y is independently hydrogen or C.sub.1 -C.sub.4 alkyl;
- (c) a straight or branched hydrocarbon group having from 1 to 18 carbon atoms which is saturated or is unsaturated containing one double bond or two nonadjacent double bonds;
- or
- (d) a cycloalkyl group having from 3 to 10 carbon atoms;
- R.sub.2 is hydrogen or a group defined as for R.sub.1 ;
- R.sub.3 and R.sub.4 independently are C.sub.3 -C.sub.6 cycloalkyl, hydroxy-C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydrogen, C.sub.1 -C.sub.4 alkyl, 1- or 2-naphthyl, or naphthyl substituted with from 1 to 3 substituents selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, halo, nitro, cyano, trifluoromethyl, phenyl, or C.sub.3 -C.sub.8 cycloalkyl;
- or R.sub.3 and R.sub.4 taken together with the carbon to which they are attached complete a C.sub.3 -C.sub.8 carbocyclic ring;
- R.sub.5 is R.sub.6, C.sub.8 -C.sub.20 alkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.2 -C.sub.20 alkynyl and alkyl, alkenyl and alkenyl substituted with one or two groups defined by R.sub.6, where R.sub.6 is C.sub.3 -C.sub.6 cycloalkyl, phenyl, 1- or 2-naphthyl, and phenol and naphthyl substituted with from 1 to 3 substituents selected from:
- C.sub.1 -C.sub.4 alkyl,
- C.sub.1 -C.sub.4 alkoxy,
- C.sub.1 -C.sub.4 alkylthio,
- phenyl,
- hydroxy,
- halo,
- nitro,
- cyano,
- trifluoromethyl,
- --COOH,
- --COOalkyl wherein alkyl has from 1 to 4 carbon atoms and which is straight or branched,
- --(CH.sub.2).sub.m NR.sub.x R.sub.y wherein m is 0 or 1, and each of R.sub.x and R.sub.y is hydrogen or a straight chain alkyl group having 1 to 4 carbon atoms;
- and
- R.sub.6 is heteroaryl selected from a 5- or 6-membered monocyclic or fused bicyclic heterocyclic group containing at least 1 to 4 heteroatoms in at least one ring, said heteroatoms being nitrogen, oxygen, or sulfur and combinations thereof, said heterocyclic group being unsubstituted or substituted with amino, halo, nitro, hydroxy, cyano, trifluoromethyl, or an alkyl group having from 1 to 20 carbon atoms and the N-oxides thereof.
40 more elements
The compound of claim 4 which is 2,4,6-triisopropylphenyl-(2,6-diisopropylphenylsulfamoyl)acetate;
- 2,6,-diisoproplphenyl(2,6-diisopropylphenylsulfamoyl)acetate;
- (2,6-diisopropylphenylsulfamoyl)-acetic acid 2,4,6-trimethoxyphenyl ester;
- and
- (2,4,6-triisopropylphenylsulfamoyl)-acetic acid, 2,6-diisopropyl ester.
1 more element
A compound of Formula II ##STR22## wherein R.sub.1 is selected from (a) phenyl which is unsubstituted or is substituted with from 1 to 3 substituents selected from C.sub.1 -C.sub.4 alkyl,
- C.sub.1 -C.sub.4 alkoxy,
- C.sub.1 -C.sub.4 alkylthio,
- hydroxy,
- halo,
- nitro,
- cyano,
- trifluoromethyl,
- --COOH,
- --COOalkyl wherein alkyl has from 1 to 4 carbon atoms and which is straight or branched,
- --(CH.sub.2).sub.m NR.sub.x R.sub.y wherein m is 0 or 1, and each of R.sub.x and R.sub.y is independently hydrogen or C.sub.1 -C.sub.4 alkyl;
- (b) 1- or 2-naphthyl which is unsubstituted or substituted with from 1 to 3 substituents selected from
- C.sub.1 -C.sub.4 alkyl,
- C.sub.1 -C.sub.4 alkoxy,
- C.sub.1 -C.sub.4 alkylthio,
- hydroxy,
- halo,
- nitro,
- cyano,
- trifluoromethyl,
- --COOH,
- --COOalkyl wherein alkyl has from 1 to 4 carbon atoms and which is straight or branched,
- --(CH.sub.2).sub.m NR.sub.x R.sub.y wherein m is 0 or 1, and each of R.sub.x and R.sub.y is independently hydrogen or C.sub.1 -C.sub.4 alkyl;
- (c) a straight or branched hydrocarbon group having from 1 to 18 carbon atoms which is saturated or is unsaturated containing one double bond or two nonadjacent double bonds;
- or
- (d) a cycloalkyl group having from 3 to 10 carbon atoms;
- R.sub.2 is hydrogen or a group defined as for R.sub.1 ;
- R.sub.3 and R.sub.4 independently are C.sub.3 -C.sub.6 cycloalkyl, hydroxy-C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydrogen, C.sub.1 -C.sub.4 alkyl, phenyl, 1- or 2-naphthyl, or phenyl or naphthyl substituted with from 1 to 3 substituents selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, halo, nitro, cyano, trifluoromethyl, phenyl, or C.sub.3 -C.sub.8 cycloalkyl;
- or R.sub.3 and R.sub.4 taken together with the carbon to which they are attached complete a C.sub.3 -C.sub.8 carbocyclic ring;
- R.sub.5 is R.sub.6, C.sub.1 -C.sub.20 alkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.2 -C.sub.20 alkynyl and alkyl, alkenyl and alkenyl substituted with one or two groups defined by R.sub.6, where R.sub.6 is hydrogen, C.sub.3 -C.sub.6 cycloalkyl, phenyl, 1- or 2-naphthyl, and phenyl and naphthyl substituted with from 1 to 3 substituents selected from:
- C.sub.1 -C.sub.4 alkyl,
- C.sub.1 -C.sub.4 alkoxy,
- C.sub.1 -C.sub.4 alkylthio,
- phenyl,
- hydroxy,
- halo,
- nitro,
- cyano,
- trifluoromethyl,
- --COOalkyl wherein alkyl has from 1 to 4 carbon atoms and which is straight or branched,
- --(CH.sub.2).sub.m NR.sub.x R.sub.y wherein m is 0 or 1, and each of R.sub.x and R.sub.y is hydrogen or a straight chain alkyl group having 1 to 4 carbon atoms;
- and
- R.sub.6 is heteroaryl selected from a 5- or 6-membered monocyclic or fused bicyclic heterocyclic group containing at least 1 to 4 heteroatoms in at least one ring, said heteroatoms being nitrogen, oxygen, or sulfur and combinations thereof, said heterocyclic group being unsubstituted or substituted with amino, halo, nitro, hydroxy, cyano, trifluoromethyl, or an alkyl group having from 1 to 20 carbon atoms and the N-oxides thereof.
39 more elements
A compound of Formula III ##STR23## wherein R.sub.1 is selected from (a) phenyl which is unsubstituted or is substituted with from 1 to 3 substituents selected from C.sub.1 -C.sub.4 alkyl,
- C.sub.1 -C.sub.4 alkoxy,
- C.sub.1 -C.sub.4 alkylthio,
- hydroxy,
- halo,
- nitro,
- cyano,
- trifluoromethyl,
- --COOH,
- --COOalkyl wherein alkyl has from 1 to 4 carbon atoms and which is straight or branched,
- --(CH.sub.2).sub.m NR.sub.x R.sub.y wherein m is 0 or 1, and each of R.sub.x and R.sub.y is independently hydrogen or C.sub.1 -C.sub.4 alkyl;
- (b) 1- or 2-naphthyl which is unsubstituted or substituted with from 1 to 3 substituents selected from
- C.sub.1 -C.sub.4 alkyl,
- C.sub.1 -C.sub.4 alkoxy,
- C.sub.1 -C.sub.4 alkylthio,
- hydroxy,
- halo,
- nitro,
- cyano,
- trifluoromethyl,
- --COOH,
- --COOalkyl wherein alkyl has from 1 to 4 carbon atoms and which is straight or branched,
- --(CH.sub.2).sub.m NR.sub.x R.sub.y wherein m is 0 or 1, and each of R.sub.x and R.sub.y is independently hydrogen or C.sub.1 -C.sub.4 alkyl;
- (c) a straight or branched hydrocarbon group having from 8 to 18 carbon atoms which is saturated or is unsaturated containing one double bond or two nonadjacent double bonds;
- or
- (d) a cycloalkyl group having from 3 to 10 carbon atoms;
- R.sub.2 is hydrogen or a group defined as for R.sub.1 ;
- R.sub.3 and R.sub.4 independently are C.sub.3 -C.sub.6 cycloalkyl, hydroxy-C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydrogen, C.sub.1 -C.sub.4 alkyl, 1- or 2-naphthyl, or naphthyl substituted with from 1 to 3 substituents selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, halo, nitro, cyano, trifluoromethyl, phenyl, or C.sub.3 -C.sub.8 cycloalkyl;
- or R.sub.3 and R.sub.4 taken together with the carbon to which they are attached complete a C.sub.3 -C.sub.8 carbocyclic ring;
- R.sub.2 ' is R.sub.2 as defined above;
- R.sub.5 is R.sub.6, C.sub.1 -C.sub.20 alkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.2 -C.sub.20 alkynyl and alkyl, alkenyl and alkenyl substituted with one or two groups defined by R.sub.6, where R.sub.6 is C.sub.3 -C.sub.6 cycloalkyl, 1- or 2-naphthyl, and phenyl and naphthyl substituted with from 1 to 3 substituents selected from:
- C.sub.1 -C.sub.4 alkyl,
- C.sub.1 -C.sub.4 alkoxy,
- C.sub.1 -C.sub.4 alkylthio,
- phenyl,
- hydroxy,
- halo,
- nitro,
- cyano,
- trifluoromethyl,
- --COOH,
- --COOalkyl wherein alkyl has from 1 to 4 carbon atoms and which is straight or branched,
- --(CH.sub.2).sub.m NR.sub.x R.sub.y wherein m is 0 or 1, and each of R.sub.x and R.sub.y is hydrogen or a straight chain alkyl group having 1 to 4 carbon atoms;
- and
- R.sub.6 is heteroaryl selected from a 5- or 6-membered monocyclic or fused bicyclic heterocyclic group containing at least 1 to 4 heteroatoms in at least one ring, said heteroatoms being nitrogen, oxygen, or sulfur and combinations thereof, said heterocyclic group being unsubstituted or substituted with amino, halo, nitro, hydroxy, cyano, trifluoromethyl, or an alkyl group having from 1 to 20 carbon atoms and the N-oxides thereof.
41 more elements
Dependencies are inferred from the claim text.