US 5,179,117 A · Antihypercholesterolemic 2-substituted imidazoles

Abstract

The compounds of the described invention are potent ACAT inhibitors and are useful in pharmaceutical compositions for the treatment of atherosclerosis and have the formulas: ##STR1## when Q is a double bond wherein: R.sup.1 and R.sup.2 are each H, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.4 -C.sub.10 -C.sub.10 cyloalkylalkyl, C.sub.7 -C.sub.14 aralkyl, 2-,3- or 4-pyridinyl, 2-thienyl, 2-furanyl, phenyl optionally substituted by F, Cl, Br, OH, CN, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.8 alkyl, CH.sub.3 S(O).sub.r, NO.sub.2, CF.sub.3 NR.sup.7 R.sup.8 or NR.sup.7 C(O)R.sup.8 ; R.sup.3 is N.C.sub.1 -C.sub.6 alkyl, allyl or benzyl or phenyl both optionally substituted F, Cl, CH.sub.3, CH.sub.3), or CF.sub.3 ; C.sub.1 -C.sub.4 carboalkyl; R.sup.4 is H, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.1 -C.sub.3 perfluoroalkyl or, benzyl or phenyl both optionally substituted by C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.4 -alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carbalkoxy, NR.sup.7 R.sup.8 or ##STR2## 2-,3-, or 4-pyridinyl, pyrimidinyl or biphenyl; R.sup.5 is H, C.sub.1 -C.sub.6 alkyl or benzyl; R.sub.6 is H, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl or benzyl or phenyl each optionally substituted by C.sub.1 -.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3,NO.sub.2, C.sub.1 -C.sub.3 carbarbalkoxy, NR.sup.7 R.sup.8, NR.sup.7 C(O).sup.8 ; pentafluorophenyl; R.sup.7 and R.sup.8 are each H, C.sub.1 -C.sub.4 alkyl, benzyl or phenyl; X is S(O).sub.r, O, NR.sup.5, bond; Y is O, S, H.sub.2, NR.sup.7 ; Z is NHR.sup.4, OR.sup.4 or R.sup.4 ; provided that when Y is NR.sup.7, Z cannot be OR.sup.4 or R.sup.4 ; m,n are 1-6; r is 0-2; Q is a single bond, double bond, --C(O)N(R.sup.7); --N(R.sup.7)C(O)--, --C(O)O--, --OC(O)--; E is a single bond, O, NR.sup.7, S, --C(O)N(R.sup.7)--, --N(R.sup.7)C(O)--, --N(R.sup.7)C(O)N(R.sup.8)--, --N(R.sup.7)C(O)O--, --OC(O)N(R.sup.7)--, --N(R.sup.7) C(NH)N(.sup.8), --C(O)O--, --OC(O)--; or a pharmaceutically acceptable salt thereof.

Claims24

Dependent claims

A compound of the Formula (I) or Formula (1a) when Q is a double bond:

##STR25## when Q is a double bond the stereoisomers or pharmaceutically acceptable salts thereof, wherein:
R.sup.1 and R.sup.2 are independently selected from H, C.sub.1 -C.sub.8 branched alkyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 arylalkyl, 2-, 3-, or 4-pyridinyl, 2-thienyl, 2-furanyl, phenyl or phenyl substituted with 1 to 3 substituents each of which is independently selected from F, Cl, Br, OH, CN, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, CH.sub.3 S(O).sub.r, NO.sub.2, CF.sub.3, NR.sup.7 R.sup.8 or NR.sup.7 C(O)R.sup.8 ;
R.sup.3 is, C.sub.1 -C.sub.6 alkyl, allyl, or benzyl or phenyl or benzyl or phenyl substituted with F, Cl, CH.sub.3, CH.sub.3 O, or CF.sub.3 ;
or C.sub.1 -C.sub.4 carboalkyl;
R.sup.4 is H, straight chain C.sub.1 -C.sub.8, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.1 -C.sub.3 perfluoroalkyl, or benzyl or phenyl or benzyl or phenyl substituted with 1 to 3 substituents each of which is independently selected from C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.1 -C.sub.4 alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8 or NR.sup.7 C(O)R.sup.8 ;
2-, 3-, or 4-pyridinyl, pyrimidinyl or biphenyl;
R.sup.5 is H, C.sub.1 -C.sub.6 alkyl or benzyl;
R.sup.6 is H, 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 cycloalkylalkyl, or, benzyl or phenyl or benzyl or phenyl substituted with 1 to 3 substituents each of which is independently selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.3 carboalkoxy, NR.sup.7 R.sup.8, or NR.sup.7 C(O)R.sup.8 ;
or pentafluorophenyl;
R.sup.7 and R.sup.8 are independently selected from H, or C.sub.1 -C.sub.4 alkyl, benzyl or phenyl;
X is S(O).sub.r, O, NR.sup.5, or a single bond;
Y is O, S, H.sub.2, or NR.sup.7 ;
Z is NHR.sup.4, OR.sup.4 or R.sup.4 ;
provided that when Y--NR.sup.7, Z cannot be OR.sup.4 or R.sup.4 ;
m and n are 1-6;
r is 0-2;
Q is selected from a double bond, --C(O)N(R7)--, --N(R7)C(O)--, --C(O)O--, or --OC(O)--
E is selected from O, NR.sup.7, S, --C(O)N(R.sup.7)--, --N(R.sup.7)C(O)--, --N(R.sup.7)C(O)N(R.sup.8)--, --N(R.sup.7)C(O)O--, --OC(O)N(R.sup.7)--, --N(R.sup.7)C(NH)N(R.sup.8)--, --C(O)0--, or --OC(O)--.

15 more elements

A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of a compound of the formula (I):

##STR26## when Q is a double bond the stereoisomers or pharmaceutically acceptable salts thereof, wherein:
R.sup.1 and R.sup.2 are independently selected from H, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 arylalkyl, 2-, 3-, or 4- pyridinyl, 2-thienyl, 2-furanyl, phenyl or phenyl substituted with 1 to 3 substituents each of which is independently selected from F, Cl, Br, OH, CN, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, CH.sub.3 S(O).sub.r, NO.sub.2, CF.sub.3, NR.sup.7 R.sup.8 or NR.sup.7 C(O)R.sup.8 ;
R.sup.3 is H, C.sub.1 -C.sub.6 alkyl, allyl, or benzyl or phenyl or benzyl or phenyl substituted with F, Cl, CH.sub.3, CH.sub.3 O, or CF.sub.3 ;
or C.sub.1 -C.sub.4 carboalkyl;
R.sup.4 is H, straight chain C.sub.1 -C.sub.8, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.1 -C.sub.3 perfluoroalkyl or, benzyl or phenyl or benzyl or phenyl substituted with 1 to 3 substituents each of which is independently selected from C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.1 -C.sub.4 alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8 or NR.sup.7 C(O)R.sup.8 ;
2-, 3-, or 4- pyridinyl, pyrimidinyl or biphenyl;
R.sup.5 is H, C.sub.1 -C.sub.8 alkyl or benzyl;
R.sup.6 is H, 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 cycloalkyl, or, benzyl or phenyl or benzyl or phenyl substituted with 1 to 3 substituents each of which is independently selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.3 carboalkoxy, NR.sup.7 R.sup.8, or NR.sup.7 C(O)R.sup.8 ;
or pentafluoro-phenyl;
R.sup.7 and R.sup.8 are independently selected from H, or C.sub.1 -C.sub.4 alkyl, benzyl or phenyl;
X is S(O).sub.r, O, NR.sup.5, or a single bond;
Y is O, S, H.sub.2, or NR.sup.7 ;
Z is NHR.sup.4, OR.sup.4 or R.sup.4 ;
provided that when Y=NR.sup.7, Z cannot be OR.sup.4 or R.sup.4 ;
m and n are 1-6;
r is 0-2;
Q is selected from a double bond, --C(O)N(R7)--, --N(R7)C(O)--, --C(O)O--, or --OC(O)--;
E is selected from O, NR.sup.7, S, --C(O)N(R.sup.7)--, --N(R.sup.7)C(O)--, --N(R.sup.7)C(O)N(R.sup.8)--, --N(R.sup.7)C(O))--, --OC(O)N(R.sup.7)--, --N(R.sup.7)C(NH)N(R.sup.8)--, --C(O)O--, or --OC(O)--.

15 more elements

A method of treating hypercholesterolemia or atherosclerosis in a mammal, said method comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the formula (I):

##STR27## when Q is a double bond the stereoisomers or pharmaceutically acceptable salts thereof, wherein:
R.sup.1 and R.sup.2 are independently selected from H, C.sub.1 -C.sub.8 branched alkyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 arylalkyl, 2-, 3-, or 4-pyridinyl, 2-thienyl, 2-furanyl, phenyl or phenyl substituted with 1 to 3 substituents each of which is independently selected from F, Cl, Br, OH, CN, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, CH.sub.3 S(O).sub.r, NO.sub.2, CF.sub.3, NR.sup.7 R.sup.8 or NR.sup.7 C(O)R.sup.8 ;
R.sup.3 is, C.sub.1 -C.sub.6 alkyl, allyl, or benzyl or phenyl or benzyl or phenyl substituted with F, Cl, CH.sub.3, CH.sub.3 O, or CF.sub.3 ;
or C.sub.1 -C.sub.4 carboalkyl;
R.sup.4 is H, straight chain C.sub.1 -C.sub.8, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.1 -C.sub.3 perfluoroalkyl, or benzyl or phenyl or benzyl or phenyl substituted with 1 to 3 substituents each of which is independently selected from C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.1 -C.sub.4 alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8 or NR.sup.7 C(O)R.sup.8 ;
2-, 3-, or 4-pyridinyl, pyrimidinyl or biphenyl;
R.sup.5 is H, C.sub.1 -C.sub.6 alkyl or benzyl;
R.sup.6 is H, 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 cycloalkylalkyl, or, benzyl or phenyl or benzyl or phenyl substituted with 1 to 3 substituents each of which is independently selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.3 carboalkoxy, NR.sup.7 R.sup.8, or NR.sup.7 C(O)R.sup.8 ;
or pentafluorophenyl;
R.sup.7 and R.sup.8 are independently selected from H, or C.sub.1 -C.sub.4 alkyl, benzyl or phenyl;
X is S(O).sub.r, O, NR.sup.5, or a single bond;
Y is O, S, H.sub.2, or NR.sup.7 ;
Z is NHR.sup.4, OR.sup.4 or R.sup.4 ;
provided that when Y--NR.sup.7, Z cannot be OR.sup.4 or R.sup.4 ;
m and n are 1-6;
r is 0-2;
Q is selected from a double bond, --C(O)N(R7)--, --N(R7)C(O)--, --C(O)O--, or --OC(O)--;
E is selected from O, NR.sup.7, S, --C(O)N(R7)--, --N(R.sup.7)C(O)--, --N(R.sup.7)C(O)N(R.sup.8)--, --N(R.sup.7)C(O)O--, --OC(O)N(R.sup.7)--, --N(R.sup.7)C(NH)N(R.sup.8)--, --C(O)O--, or --OC(O)--.

15 more elements

Dependencies are inferred from the claim text.

Antihypercholesterolemic 2-substituted imidazoles

Life of this patent

Antihypercholesterolemic 2-substituted imidazoles

Life of this patent

Abstract

Claims24