US 5,326,783 AGranted

Cholesterol lowering compounds

AssigneeMerck & Co., Inc.

InventorsTesfaye Biftu, Chan-Hwa Kuo, Conrad Santini

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Abstract

This invention is directed to compounds of formula (I) which are novel C3- or C5-acyl sulfonamide, carboxamic acid or tetrazolyl analogs of the Zaragozic acids. These compounds inhibit the enzyme squalene synthase and are useful as cholesterol lowering agents. ##STR1##

Claims14

Dependent claims

A compound of structural formula (I) ##STR10## wherein A is --C(O)--, --NR.sup.3 --C(O)--, or --OC(O)--;

a is zero or 1;
R.sup.1 is selected from the group consisting of:
(1) C.sub.1-20 alkyl,
(2) substituted C.sub.1-20 alkyl in which one or more substituents is selected from a group herein termed X.sup.3 wherein the group X.sup.3 consists of:
(a) halogen,
(b) hydroxy,
(c) R.sup.3 R.sup.3 N--,
(d) R.sup.2 O--,
(e) R.sup.2 O--C(O)--,
(f) R.sup.3 --C(O)--O--,
(g) oxo,
(h) C.sub.3-10 cycloalkyl,
(i) aryl substituted with X and Y,
(j) heteroaryl substituted with X and Y,
(k) heterocycloalkyl,
(l) aryl S(O).sub.n, wherein aryl is substituted with X and Y,
(m) R.sup.3 --C(O)--NR.sup.3 --,
(n) R.sup.3 R.sup.3 N--C(O)--,
(o) --CO.sub.2 H,
(p) --vinylidene,
(q) R.sup.3 --C(O)--,
(r) R.sup.2 O--C(O)--O--,
(s) R.sup.3 R.sup.3 N--C(O)--O--, and
(t) R.sup.2 O--C(O)--NR.sup.3 --;
(3) C.sub.1-20 alkyl wherein one or more of the carbons is replaced by --NR.sup.3 --, --O--, or --S(O).sub.n --;
(4) substituted C.sub.1-20 alkyl wherein one or more of the carbons is replaced by --NR.sup.3 --, --O-- or --S(O).sub.n -- and wherein one or more carbon substituents is selected from the group X.sup.3, defined above;
(5) aryl substituted with X and Y;
(6) heteroaryl substituted with X and Y;
(7) C.sub.2-20 alkenyl wherein alkenyl contains one or more double bonds;
(8) substituted C.sub.2-20 alkenyl wherein alkenyl contains one or more double bonds and wherein one or more of the saturated carbons is substituted with a substituent selected from the group X.sup.3, defined above;
(9) C.sub.2-20 alkenyl wherein alkenyl contains one or more double bonds and one or more of the nonolefinic carbons is replaced by --NR.sup.3 --, --O-- or --S(O).sub.n --;
(10) substituted C.sub.2-20 alkenyl wherein alkenyl contains one or more double bonds and one or more of the nonolefinic carbons is replaced by --NR.sup.3 --, --O-- or --S(O).sub.n -- and wherein one or more of the saturated carbons is substituted with a substituent selected from the group X.sup.3, defined above;
(11) C.sub.3-10 cycloalkyl;
(12) substituted C.sub.3-10 cycloalkyl in which one or more of the substituents is selected from the group consisting of C.sub.1-10 alkyl--S(O).sub.n --, C.sub.1-10 alkyl, and the members of the group X.sup.3, defined above;
each R.sup.2 is independently selected from:
(1) C.sub.1-10 alkyl;
(2) aryl substituted with X and Y;
(3) arylC.sub.1-4 alkyl wherein aryl is substituted with X and Y;
(4) heteroaryl wherein heteroaryl is substituted with X and Y;
(5) heteroarylC.sub.1-4 alkyl-- wherein heteroaryl is substituted with X and Y;
(6) heterocycloalkylC.sub.1-4 alkyl--;
(7) C.sub.2-10 alkenyl;
(8) arylC.sub.2-10 alkenyl wherein aryl is substituted with X and Y;
and
(9) C.sub.3-10 alkynyl;
each R.sup.3 is independently selected from:
(1) C.sub.1-10 alkyl;
(2) aryl substituted with X and Y;
(3) arylC.sub.1-4 alkyl wherein aryl is substituted with X and Y;
(4) heteroaryl wherein heteroaryl is substituted with X and Y;
(5) heteroarylC.sub.1-4 alkyl-- wherein heteroaryl is substituted with X and Y;
(6) heterocycloalkylC.sub.1-4 alkyl--;
(7) C.sub.2-10 alkenyl;
(8) arylC.sub.2-10 alkenyl wherein aryl is substituted with X and Y;
(9) C.sub.3-10 alkynyl;
(10) hydrogen;
and
(11) C.sub.1-5 alkyl substituted with X.sup.1 ;
R.sup.4 is selected from the group consisting of:
(1) C.sub.1-20 alkyl;
(2) substituted C.sub.1-20 alkyl in which one or more substituents is selected from the group X.sup.3, defined above;
(3) C.sub.1-20 alkyl wherein one or more of the carbons is replaced by --NR.sub.3 --, --O--, or --S(O).sub.n --;
(4) substituted C.sub.1-20 alkyl wherein one or more of the carbons is replaced by --NR.sup.3 --, --O-- or --S(O).sub.n -- and wherein one or more carbon substituents is selected from the group X.sup.3, defined above;
(5) aryl substituted with X and Y;
(6) heteroaryl substituted with X and Y;
(7) C.sub.2-20 alkenyl wherein alkenyl contains one or more double bonds;
(8) substituted C.sub.2-20 alkenyl wherein alkenyl contains one or more double bonds and wherein one or more of the saturated carbons is substituted with a substituent selected from the group X.sup.3, defined above;
(9) C.sub.2-20 alkenyl wherein alkenyl contains one or more double bonds and one or more of the nonolefinic carbons is replaced by --NR.sup.3 --, --O-- or --S(O).sub.n --;
(10) substituted C.sub.2-20 alkenyl wherein alkenyl contains one or more double bonds and one or more of the nonolefinic carbons is replaced by --NR.sup.3 --, --O-- or --S(O).sub.n -- and wherein one or more of the saturated carbons is substituted with a substituent selected from the group X.sup.3, defined above;
(11) C.sub.3-10 cycloalkyl;
(12) substituted C.sub.3-10 cycloalkyl in which one or more of the substituents is selected from the group X.sup.3, defined above;
and
(13) hydrogen;
R.sup.5 is selected from the group consisting of:
(1) hydrogen;
(2) C.sub.1-10 alkyl;
(3) aryl substituted with X and Y;
(4) arylC.sub.1-4 alkyl, wherein aryl is substituted with X and Y;
(5) R.sup.2 O--C(O)--;
(6) C.sub.3-10 cycloalkyl;
(7) R.sup.3 --C(O)--;
and
(8) R.sup.3 R.sup.3 N--C(O)--;
n is zero, 1 or 2;
Z.sup.1 is selected from:
(1) --CONHOH,
(2) --CONHSO.sub.2 R, and
(3) tetrazolyl;
Z.sup.2 is --CO.sub.2 R.sup.6 ;
Z.sup.3 is
R is selected from:
(1) C.sub.1-10 alkyl,
(2) phenyl substituted with X and Y,
(3) C.sub.1-10 alkyl substituted with phenyl, wherein the phenyl is substituted with X and Y, and
(4) heteroaryl substituted with X and Y;
R.sup.6 is independently selected at each occurrence from the group consisting of:
(1) C.sub.1-20 alkyl;
(2) substituted C.sub.1-20 alkyl in which one or more substituents is selected from the group X.sup.3, defined above,
(3) C.sub.1-20 alkyl wherein one or more of the carbons is replaced by --NR.sup.3 --, --O--, or --S(O).sub.n --;
(4) substituted C.sub.1-20 alkyl wherein one or more of the carbons is replaced by --NR.sup.3 --, --O--, or --S(O).sub.n -- and wherein one or more carbon substituents is selected from the group X.sup.3, defined above;
(5) C.sub.2-20 alkenyl wherein alkenyl contains one or more double bonds;
(6) substituted C.sub.2-20 alkenyl wherein alkenyl contains one or more double bonds and wherein one or more of the saturated carbons is substituted with a substituent selected from the group X.sup.3, defined above;
(7) C.sub.2-20 alkenyl wherein alkenyl contains one or more double bonds and one or more of the nonolefinic carbons is replaced by --NR.sup.3 --, --O--, or --S(O).sub.n --;
(8) substituted C.sub.2-20 alkenyl wherein alkenyl contains one or more double bonds and one or more of the nonolefinic carbons is replaced by --NR.sup.3 --, --O--, or --S(O).sub.n -- and wherein one or more of the saturated carbons is substituted with a substituent selected from the group X.sup.3, defined above;
(9) C.sub.2-20 alkynyl wherein alkynyl contains one or more triple bonds;
(10) substituted C.sub.2-20 alkynyl wherein alkynyl contains one or more triple bonds and wherein one or more of the saturated carbons is substituted with a substituent selected from the group X.sup.3, defined above;
(11) C.sub.2-20 alkynyl wherein alkynyl contains one or more triple bonds and one or more of the saturated carbons is replaced by --NR.sup.3 --, --O--, or --S(O).sub.n --;
(12) substituted C.sub.2-20 alkynyl wherein alkynyl contains one or more --triple bonds-- and one or more of the saturated carbons is replaced by --NR.sup.3 --, --O--, or --S(O).sub.n -- and wherein one or more of the saturated carbons is substituted with a substituent selected from the group X.sup.3, defined above;
(13) aryl substituted with X and Y;
(14) heteroaryl substituted with X and Y;
(15) C.sub.3-5 cycloalkyl;
(16) substituted C.sub.3-5 cycloakyl in which one or more of the substituents is selected from:
(a) R.sup.3 O--, and
(b) R.sup.3 R.sup.3 N--;
and
(17) hydrogen;
aryl including X, Y substitution is:
##STR11## heteroaryl including X, Y substitution is selected from ##STR12## wherein:
Q is --NR.sup.3, --O-- or --S--;
heterocycloalkyl is selected from:
##STR13## wherein:
M is --NR.sup.3, --O--, --S-- or --CH.sub.2 --;
X and Y are each independently selected from:
(1) hydrogen;
(2) hydroxy;
(3) halogen;
(4) trifluoromethyl;
(5) C.sub.1-10 alkyl;
(6) aryl substituted with X.sup.1 and Y.sup.1 ;
(7) R.sup.2 O--;
(8) arylcarbonyloxy--, wherein aryl is substituted with X.sup.1 and Y.sup.1 ;
(9) R.sup.3 --C(O)--O--;
(10) --CO.sub.2 R.sup.2 ;
(11) --CO.sub.2 H;
and
(12) nitro;
and
X.sup.1 and Y.sup.1 are each independently selected from:
(1) hydrogen;
(2) hydroxy;
(3) halogen;
(4) trifluoromethyl;
(5) C.sub.1-4 alkyl;
(6) R.sup.2 O--;
(7) R.sup.3 --C(O)--O--;
(8) --CO.sub.2 R.sup.2 ;
(9) --CO.sub.2 H;
and
(10 ) nitro;
or the pharmaceutically acceptable salt thereof.

147 more elements

Dependencies are inferred from the claim text.

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