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Last Updated: March 28, 2024

Details for Patent: 5,767,115


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Title: Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
Abstract:Hydroxy-substituted azetidinone hypocholesterolemic agents of the formula ##STR1## 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.6 R.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.sup.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.1-5 OR.sup.6, --O(CO)NR.sup.6 R.sup.7, --NR.sub.6 R.sup.7, --NR.sup.6 (CO)R.sup.7, --NR.sup.6 (CO)OR.sup.9, --NR.sup.6 (CO)NR.sup.7 R.sup.8, --NR.sup.6 SO.sub.2 R.sup.9, --COOR.sup.6, --CONR.sup.6 R.sup.7, --COR.sup.6, --SO.sub.2 NR.sup.6 R.sup.7, S(O).sub.0-2 R.sup.9, --O(CH.sub.2).sub.1-10 --COOR.sup.6, --O(CH.sub.2).sub.1-10 CONR.sup.6 R.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, aryl 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 (Bridgewater, NJ), Burnett; Duane A. (Fanwood, NJ), Clader; John W. (Cranford, NJ), McKittrick; Brian A. (Bloomfield, NJ)
Assignee: Schering-Plough Corporation (Kenilworth, NJ)
Filing Date:Mar 18, 1996
Application Number:08/617,751
Claims:1. A compound represented by the formula ##STR56## 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.6 R.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.1-5 OR.sup.6, --O(CO)NR.sup.6 R.sup.7, --NR.sup.6 R.sup.7, --NR.sup.6 (CO)R.sup.7, --NR.sup.6 (CO)OR.sup.9, --NR.sup.6 (CO)NR.sup.7 R.sup.8, --NR.sup.6 SO.sub.2 R.sup.9, --COOR.sup.6, --CONR.sup.6 R.sup.7, -COR.sup.6, -SO.sub.2 NR.sup.6 R.sup.7, S(O).sub.0-2 R.sup.9, --O(CH.sub.2).sub.1-10 --COOR.sup.6, --O(CH.sub.2).sub.1-10 CONR.sup.6 R.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.1-5 OR.sup.6, --O(CO)NR.sup.6 R.sup.7, --NR.sup.6 R.sup.7, --NR.sup.6 (CO)R.sup.7, --NR.sup.6 (CO)OR.sup.9, --NR.sup.6 (CO)NR.sup.7 R.sup.8, --NR.sup.6 SO.sub.2 R.sup.9, --COOR.sup.6, --CONR.sup.6 R.sup.7, --COR.sup.6, --SO.sub.2 NR.sup.6 R.sup.7, S(O).sub.0-2 R.sup.9, --O(CH.sub.2).sub.1-10 --COOR.sup.6, --O(CH.sub.2).sub.1-10 CONR.sup.6 R.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 wherein 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 R.sup.5 -substituted phenyl, wherein R.sup.5 is --OR.sup.6, wherein R6 is lower alkyl or hydrogen.

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-azetid inone;

rel 3(R)-(2(R)-hydroxy-2-phenylethyl)-4(S)-(4-methoxyphenyl)-1-phenyl-2-azetid inone;

3(S)-(1(S)-hydroxy-3-phenylpropyl)-4(S)-(4-methoxyphenyl)-1-phenyl-2-azetid inone;

3(S)-(1(R)-hydroxy-3-phenylpropyl)-4(S)-(4-methoxyphenyl)-1-phenyl-2-azetid inone;

3(R)-(1(R)-hydroxy-3-phenylpropyl)-4(S)-(4-methoxyphenyl)-1-phenyl-2-azetid inone;

rel-3(R)-[(S)-hydroxy-(2-naphthalenyl)methyl]-4(3S)-(4-methoxyphenyl)-1-phe nyl)-1 -phenyl-2-azetidinone;

rel-3(R)-[(R)-hydroxy-(2-naphthalenyl)methyl]-4(S)-(4-methoxyphenyl)-1-phen yl-2-azetidinone;

3(R)-(3(R)-hydroxy-3-phenylpropyl)-1,4(S)-bis-(4-methoxyphenyl)-2-azetidino ne;

3(R)-(3(S)-hydroxy-3-phenylpropyl)-1,4(S)-bis-(4-methoxyphenyl)-2-azetidino ne;

4(S)-(4-hydroxyphenyl)-3(R)-(3(R)-hydroxy-3-phenylpropyl-1-(4-methoxyphenyl )-2-azetidinone;

4(S)-(4-hydroxyphenyl)-3(R)-(3(S)-hydroxy-3-phenylpropyl-1-(4-methoxyphenyl )-2-azetidinone;

rel 3(R)-[3(RS)-hydroxy-3-[4-(methoxymethoxy)-phenyl]-1,4(S)-bis-(4-methoxyphe nyl)-2-azetidinone;

1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(.sup .4 -hydroxyphenyl)-2-azetidinone;

1-(4-fluorophenyl)-3(R)-[3(R)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hy droxyphenyl)-2-azetidinone;

4(S)-[4-(acetyloxy)phenyl]-3(R)-(3(R)-hydroxy-3-phenylpropyl)-1-(4-methoxyp henyl)-2-azetidinone;

4(S)-[4-(acetyloxy)phenyl]-3(R)-(3(S)-hydroxy-3-phenylpropyl)-1(4-methoxyph enyl)-2-azetidinone;

1-(.sup.4 -fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-[4-(phen ylmethoxy)phenyl]-2-azetidinone;

3(R)-[3(R)-acetyloxy)-3-phenylpropyl]-1,4(S)-bis-(4-methoxyphenyl)-2-azetid inone;

3(R)-[3(S)-acetyloxy)-3-phenylpropyl]-1,4(S)-bis-(4-methoxyphenyl)-2-azetid inone;

3(R)-[3(R)-(acetyloxy)-3-(4-fluorophenyl)propyl]-4(S)-[4-(acetyloxy)phenyl] -1-(4-fluorophenyl)-2-azetidinone;

3(R)-[3(S)-(acetyloxy)-3-(4-fluorophenyl)propyl]-4(S)-[4-(acetyloxy)phenyl] -1-(4-fluorophenyl)-2-azetidinone;

3(R)-[3(R)-(acetyloxy)-3-(4-chlorophenyl)propyl]-4(S)-[4-(acetyloxy)phenyl] -1-(4-chlorophenyl)-2-azetidinone;

3(R)-[3(S)-(acetyloxy)-3-(4-chlorophenyl)propyl]-4(S)-[4-(acetyloxy)phenyl] -1-(4-chlorophenyl)-2-azetidinone; and

rel 1-(4-fluorophenyl)-4(S)-(4-hydroxyphenyl)-3(1R)-(1(R)-hydroxy-3-phenylprop yl)-2-azetidinone.

8. A pharmaceutical composition for the treatment prevention of athersclerosis, or for the reduction of plasma cholesterol levels, comprising an effective amount of a compound of claim 1 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.

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