Details for Patent: RE42461
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Title: | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
Abstract: | Hydroxy-substituted azetidinone hypocholesterolemic agents of the formula ##STR00001## or a pharmaceutically acceptable salt thereof, wherein: Ar.sup.1 and Ar.sup.2 are aryl or R.sup.4-substituted aryl; Ar.sup.3 is aryl or R.sup.5-substituted aryl; X, Y and Z are --CH.sub.2--, --CH(lower alkyl)-- or --C(dilower alkyl)--; R and R.sup.2 are --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9 or --O(CO)NR.sup.6R.sup.7; R.sup.1 and R.sup.3 are H or lower alkyl; q is 0 or 1; r is 0 or 1; m, n and p are 0-4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1-6; and provided that when p is O and r is 1, the sum of m, q and n is 1-5; R.sup.4 is selected from lower alkyl, R.sub.5, --CF.sub.3, --CN, --NO.sub.2 and halogen R.sup.5 is selected from --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9, --O(CH.sub.2).sub.1-5OR.sup.6, --O(CO)NR.sup.6R.sup.7, --NR.sub.6R.sup.7, --NR.sup.6(CO)R.sup.7, --NR.sup.6(CO)OR.sup.9, --NR.sup.6(CO)NR.sup.7R.sup.8, --NR.sup.6SO.sub.2R.sup.9, --COOR.sup.6, --CONR.sup.6R.sup.7, --COR.sup.6, --SO.sub.2NR.sup.6R.sup.7, S(O).sub.0-2R.sup.9, --O(CH.sub.2).sub.1-10--COOR.sup.6, --O(CH.sub.2).sub.1-10CON.sup.6R.sup.7, --(lower alkylene)COOR.sup.6 and --CH.dbd.CH--COOR.sup.6; R.sup.6, R.sup.7 and R.sup.8 are H, lower alkyl or aryl-substituted Ic R.sup.9 is lower alkyl, aryl or aryl-substituted lower alkyl; are disclosed, as well as a method of lowering serum cholesterol by administering said compounds, alone or in combination with a cholesterol biosynthesis inhibitor, pharmaceutical compositions containing them; and a process for preparing them. |
Inventor(s): | Rosenblum; Stuart B. (West Orange, NJ), Dugar; Sundeep (San Jose, CA), Burnett; Duane A. (Bernardsville, NJ), Clader; John W. (Milton, VT), McKittrick; Brian A. (New Vernon, NJ) |
Assignee: | Schering Corporation (Kenilworth, NJ) |
Filing Date: | Sep 14, 1994 |
Application Number: | 12/797,341 |
Claims: | 1. A compound represented by the formula ##STR00050## or a pharmaceutically acceptable salt thereof, wherein: Ar.sup.1 and Ar.sup.2 are independently selected from the group consisting of aryl and R.sup.4-substituted aryl; Ar.sup.3 is aryl or R.sup.5-substituted aryl; X, Y and Z are independently selected from the group consisting of --CH.sub.2--, --CH(lower alkyl)- and --C(dilower alkyl)-; R and R.sup.2 are independently selected from the group consisting of --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9 and --O(CO)NR.sup.6R.sup.7; R.sup.1 and R.sup.3 are independently selected from the group consisting of hydrogen, lower alkyl and aryl; q is 0 or 1; r is 0 or 1; m, n and p are independently 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5; R.sup.4 is 1-5 substituents independently selected from consisting of lower alkyl, --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9, --O(CH.sub.2).sub.1-5OR.sup.6, --(CO)NR.sup.6R.sup.7, --NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.7, --NR.sup.6(CO)OR.sup.9, --NR.sup.6(CO)NR.sup.7R.sup.8, --NR.sup.6SO.sub.2R.sup.9, --COOR.sup.6, --CONR.sup.6R.sup.7, -COR.sup.6, -SO.sub.2NR.sup.6R.sup.7, S(O).sub.0-2R.sup.9, --O(CH.sub.2).sub.1-10--COOR.sup.6, --O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, -(lower alkylene)COOR.sup.6, --CH.dbd.CH--COOR.sup.6, --CF.sub.3, --CN, --NO.sub.2 and halogen; R.sup.5 is 1-5 substituents independently selected from the group consisting of --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9, --O(CH.sub.2).sub.1-5OR.sup.6, --(CO)NR.sup.6R.sup.7, --NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.7, --NR.sup.6(CO)OR.sup.9, --NR.sup.6(CO)NR.sup.7R.sup.8, --NR.sup.6SO.sub.2R.sup.9, --COOR.sup.6, --CONR.sup.6R.sup.7, --COR.sup.6, --SO.sub.2NR.sup.6R.sup.7, S(O).sub.0-2R.sup.9, --O(CH.sub.2).sub.1-10--COOR.sup.6, --O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, -(lower alkylene)COOR.sup.6 and --CH.dbd.CH--COOR.sup.6; R.sup.6, R.sup.7 and R.sup.8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and R.sup.9 is lower alkyl, aryl or aryl-substituted lower alkyl..]. .[.2. A compound of claim 1 wherein Ar.sup.1 is phenyl or R.sup.4-substituted phenyl, Ar.sup.2 is phenyl or R.sup.4-substituted phenyl and Ar.sup.3 is R.sup.5-substituted phenyl..]. 3. A compound .[.of claim 2.]. .Iadd.represented by the formula ##STR00051## or a pharmaceutically acceptable salt thereof, .Iaddend.wherein.Iadd.;.Iaddend. Ar.sup.1 is R.sup.4-substituted phenyl wherein R.sup.4 is halogen; Ar.sup.2 is R.sup.4-substituted phenyl) wherein R.sup.4 is halogen or --OR.sup.6, wherein R.sup.6 is lower alkyl or hydrogen; and Ar.sup.3 .Iadd.is .Iaddend.R.sup.5-substituted phenyl, wherein R.sup.5 is --OR.sup.6, wherein .[.R6.]. .Iadd.R.sup.6 .Iaddend.is lower alkyl or hydrogen.Iadd.; X, Y and Z are independently selected from the group consisting of --CH.sub.2--, --CH(lower alkyl)-- and --C(dilower alkyl)--; R and R.sup.2 are independently selected from the group consisting of --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9 and --O(CO)NR.sup.6R.sup.7; R.sup.1 and R.sup.3 are independently selected from the group consisting of hydrogen, lower alkyl and aryl; q is 0 or 1; r is 0 or 1; m, n and p are independently 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5; R.sup.6 and R.sup.7 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and R.sup.9 is lower alkyl, aryl or aryl-substituted lower alkyl.Iaddend.. .[.4. A compound of claim 1 wherein X, Y and Z are each --CH.sub.2--; R.sup.1 and R.sup.3 are each hydrogen; R and R.sup.2 are each --OR.sup.6, wherein R.sup.6 is hydrogen; and the sum of m, n, p, q and r is 2, 3 or 4..]. .[.5. A compound of claim 1 wherein m, n and r are each zero, q is 1 and p is 2..]. .[.6. A compound of claim 1 wherein p, q and n are each zero, r is 1 and m is 2 or 3..]. 7. A compound selected from the group consisting of .[.rel 3(R)-(2(R)-hydroxy-2-phenylethyl)-4(R)-(4-methoxyphenyl)-1-phenyl-2-azeti- dinone; rel 3(R)-(2(R)-hydroxy-2-phenylethyl)-4(S)-(4-methoxyphenyl)-1-phenyl-2-azeti- dinone; 3(S)-(1(S)-hydroxy-3-phenylpropyl)-4(S)-(4-methoxyphenyl)-1-phenyl- -2-azetidinone; 3(S)-(1(R)-hydroxy-3-phenylpropyl)-4(S)-(4-methoxyphenyl)-1-phenyl-2-azet- idinone; 3(R)-(1(R)-hydroxy-3-phenylpropyl)-4(S)-(4-methoxyphenyl)-1-pheny- l-2-azetidinone; rel-3(R)-[(S)-hydroxy-(2-naphthalenyl)methyl]-4(S)-(4-methoxyphenyl)-1-ph- enyl)-1-phenyl-2-azetidinone; rel-3(R)-[(R)-hydroxy-(2-naphthalenyl)methyl]-4(S)-(4-methoxyphenyl)-1-ph- enyl-2-azetidinone; 3(R)-(3(R)-hydroxy-3-phenylpropyl)-1,4(S)-bis-(4-methoxyphenyl-2-azetidin- one; 3(R)-(3(S)-hydroxy-3-phenylpropyl)-1,4(S)-bis-(4-methoxyphenyl-2-azet- idinone; 4(S)-(4-hydroxyphenyl)-3(R)-(3(R)-hydroxy-3-phenylpropyl-1-(4-met- hoxyphenyl)-2-azetidinone; 4(S)-(4-hydroxyphenyl)-3(R)-(3(S)-hydroxy-3-phenylpropyl-1-(4-methoxyphen- yl)-2-azetidinone; rel 3(R)-[3(RS)-hydroxy-3-[4-methoxymethoxy)-phenyl]propyl]-1,4(S)-bis-(4-met- hoxyphenyl)-2-azetidinone;.]. 1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-- hydroxyphenyl)-2-azetidinone; .Iadd.and.Iaddend. 1-(4-fluorophenyl)-3(R)-[3(R)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-- hydroxyphenyl)-2-azetidinone.[.; 4(S)-[4-(acetyloxy)phenyl]-3(R)-(3(R)-hydroxy-3-phenylpropyl)-1-(4-methox- yphenyl)-2-azetidinone; 4(S)-[4-(acetyloxy)phenyl]-3(R)-(3(S)-hydroxy-3-phenylpropyl)-1-(4-methox- yphenyl)-2-azetidinone; 1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-[4(- S)-(phenylmethoxy)phenyl]-2-azetidinone; 3(R)-[3(R)-acetyloxy)-3-phenylpropyl]-1,4(S)-bis-(4-methoxyphenyl)-2-azet- idinone; 3(R)-[3(S)-acetyloxy)-3-phenylpropyl]-1,4(S)-bis-(4-methoxyphenyl- )-2-azetidinone; 3(R)-[3(R)-(acetyloxy)-3-(4-fluorophenyl)propyl]-4(S)-[4-(acetyloxy)pheny- l]-1-(4-fluorophenyl)-2-azetidinone; 3(R)-[3(S)-(acetyloxy)-3-(4-fluorophenyl)propyl]-4(S)-[4-(acetyloxy)pheny- l]-1-(4-fluorophenyl)-2-azetidinone; 3(R)-[3(R)-(acetyloxy)-3-(4-chlorophenyl)propyl]-4(S)-[4-(acetyloxy)pheny- l]-1-(4-chlorophenyl)-2-azetidinone; 3(R)-[3(S)-(acetyloxy)-3-(4-chlorophenyl)propyl]-4(S)-[4-(acetyloxy)pheny- l]-1-(4-chlorophenyl)-2-azetidinone; and rel 1-(4-fluorophenyl)-4(S)-(4-hydroxyphenyl)-3(1R)-(1(R)-hydroxy-3-phenylpro- pyl)-2-azetidinone.].. 8. A pharmaceutical composition for the treatment or prevention of .[.athersclerosis.]., .Iadd.atherosclerosis .Iaddend.or for the reduction of plasma cholesterol levels, comprising an effective amount of a compound of claim .[.1.]. .Iadd.7 .Iaddend.in a pharmaceutically acceptable carrier. 9. A method of treating or preventing atherosclerosis or reducing plasma cholesterol levels comprising administering to a mammal in need of such treatment an effective amount of a compound of claim .[.1.]. .Iadd.7.Iaddend.. .Iadd.10. A compound comprising 1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-4-(- hydroxyphenyl)-2-azetidinone or a pharmaceutically acceptable salt thereof..Iaddend. .Iadd.11. A compound represented by the formula: ##STR00052## .Iaddend. .Iadd.12. A pharmaceutical composition for the treatment or prevention of atherosclerosis, or for the reduction of plasma cholesterol levels, comprising an effective amount of a compound according to claims 10 or 11 in a pharmaceutically acceptable carrier..Iaddend. .Iadd.13. A method of treating or preventing atherosclerosis or reducing plasma cholesterol levels comprising administering to a mammal in need of such treatment an effective amount of a compound according to claims 10 or 11..Iaddend. |