US 5,478,830 AGranted

Fused-ring heterocycles for the treatment of atherosclerosis

AssigneeThe Du Pont Merck Pharmaceutical Company

InventorsC. Anne Higley, Ruth R. Wexler, Richard G. Wilde

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Abstract

This invention relates to pyrazolo pyrimidines for the treatment of atherosclerosis as inhibitors of acyl--CoA, cholesterol acyetransferase (ACAT), and their use as antihypercholesterolemic agents, pharmaceutical compositions and preparation, and having the formula (I): ##STR1## wherein: A and Q are selected independently from CH or N with no more than two nitrogens per ring: D, E, and G are selected independently from CR.sup.1 or N with no more than two nitrogens per ring; X is S(O).sub.r, O, NR.sup.4 or CH.sup.2 ; J is C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 branched alkyl, C.sub.3 -C.sub.10 alkenyl or C.sub.3 -C.sub.10 alkynyl; Y is O, S, H.sub.2 or NH: Z is NHR.sup.3, OR.sup.3 or R.sup.3 : R.sup.1 is selected independently from H, NO.sub.2, Br, Cl, F, CF.sub.3, CN, CH.sub.3 S(O).sub.r, C.sub.1 -C.sub.8 alkyl or alloxy, C.sub.3 -C.sub.8, branched alkyl, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.5 R.sup.6 or NR.sup.5 COR.sup.6 ; R.sup.2 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.8 alkenyl or alkynyl, C.sub.7 -C.sub.14 araalkyl where the aryl group is optionally substituted; phenyl optionally substituted benzyl optionally substituted 2-, 3-, or 4- pyridinyl, pyrimidinyl: or biphenyl: R.sup.3 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloallylalkyl, C.sub.3 -C.sub.6 alkenyl or alkynyl, C.sub.1 -C.sub.3 perfluoroalkyl, C.sub.7 -C.sub.14 araalkyl where the aryl group is optionally substituted phenyl optionally substituted benzyl optionally substituted 2-, 3-, or 4- pyridinyl, pyrimidinyl; or biphenyl: R.sup.4 is H, C.sub.1 -C.sub.6 alkyl or benzyl; R.sup.5 and R.sup.6 are selected independently from H or C.sub.1 -C.sub.4 alkyl; r is 0 to 2: or a pharmaceutically acceptable salt thereof.

A compound of the formula (I):

##STR54## wherein:
X is S(O).sub.r, O, NR.sup.4 or CH.sub.2 ;
J is C.sub.2 -C.sub.10 alkylene, C.sub.3 -C.sub.10 alkenylene or C.sub.3 -C.sub.10 alkynylene;
Y is O, S, or NH;
Z is NHR.sup.3, OR.sup.3 or R.sup.3 ;
R.sup.1 is selected independently from H, NO.sub.2, Br, Cl, F, CF.sub.3, CN, CH.sub.3 S(O).sub.r, C.sub.1 -C.sub.8 alkyl or alkoxy, C.sub.1 -C.sub.4 carboalkoxy, NR.sub.5 R.sub.6 or NR.sub.5 COR.sub.6 ;
R.sup.2 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.8 alkenyl or alkynyl, C.sub.7 -C.sub.14 araalkyl where the aryl group is optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, OH, CN, CO.sub.2 H, CF.sub.3, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.5 R.sup.6, or NR.sup.5 COR.sup.6 ;
phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, OH, CN, CO.sub.2 H, CF.sub.3, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.5 R.sup.6 or NR.sup.5 COR.sup.6 ;
benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, OH, CN, CO.sub.2 H, CF.sub.3, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.5 R.sup.6, or NR.sup.5 COR.sup.6 ;
2-, 3-, or 4- pyridinyl, pyrimidinyl;
or biphenyl;
R.sup.3 is C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.3 -C.sub.6 alkenyl or alkynyl, C.sub.1 -C.sub.3 perfluoroalkyl, C.sub.7 -C.sub.14 araalkyl where the aryl group is optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, OH, CN, CO.sub.2 H, CF.sub.3, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.5 R.sup.6, or NR.sup.5 COR.sup.6 ;
phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, C.sub.3 -C.sub.8 branched alkyl, F, Br, Cl, OH, CN, CO.sub.2 H, CF.sub.3, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.5 R.sup.6, or NR.sup.5 COR.sup.6 ;
benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, OH, CN, CO.sub.2 H, CF.sub.3, C.sub.1 -C.sub.4 carboalkoxy, NR.sup. 5 R.sup.6, or NR.sup.5 COR.sup.6 ;
2-, 3-, or 4- pyridinyl, pyrimidinyl;
or biphenyl;
R.sup.4 is H, C.sub.1 -C.sub.6 alkyl or benzyl;
R.sup.5 and R.sup.6 are selected independently from H or C.sub.1 -C.sub.4 alkyl;
r is 0 to 2;
or a pharmaceutically acceptable salt thereof.

17 more elements

Abstract

Claims12