Claims for Patent: 5,767,115

Summary for Patent: 5,767,115

Title:	Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
Abstract:	Hydroxy-substituted azetidinone hypocholesterolemic agents of the formula or a pharmaceutically acceptable salt thereof, wherein: Ar1 and Ar2 are aryl or R4-substituted aryl; Ar3 is aryl or R5-substituted aryl; X, Y and Z are -CH2-, -CH(lower alkyl)- or -C(dilower alkyl)-; R and R2 are -OR6, -O(CO)R6, -O(CO)OR9 or -O(CO)NR6R7; R1 and R3 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; R4 is selected from lower alkyl, R5, -CF3, -CN, -NO2 and halogen R5 is selected from -OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)1-5OR6, -O(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0-2R9, -O(CH2)1-10-COOR6, -O(CH2)1-10CONR6R7, -(lower alkylene)COOR6 and -CH=CH-COOR6; R6, R7 and R8 are H, lower alkyl, aryl or aryl-substituted Ic R9 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):	Stuart B. Rosenblum, Sundeep Dugar, Duane A. Burnett, John W. Clader, Brian A. McKittrick
Assignee:	Merck Sharp and Dohme LLC , Schering Plough Corp
Application Number:	US08/617,751
Patent Claims:	1. A compound represented by the formula ##STR56## or a pharmaceutically acceptable salt thereof, wherein: Ar1 and Ar2 are independently selected from the group consisting of aryl and R4 -substituted aryl;Ar3 is aryl or R5 -substituted aryl; X, Y and Z are independently selected from the group consisting of --CH2 --, --CH(lower alkyl)- and --C(dilower alkyl)-; R and R2 are independently selected from the group consisting of --OR6, --O(CO)R6, --O(CO)OR9 and --O(CO)NR6 R7 ; R1 and R3 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; R4 is 1-5 substituents independently selected from consisting of lower alkyl, --OR6, --O(CO)R6, --O(CO)OR9, --O(CH2)1-5 OR6, --O(CO)NR6 R7, --NR6 R7, --NR6 (CO)R7, --NR6 (CO)OR9, --NR6 (CO)NR7 R8, --NR6 SO2 R9, --COOR6, --CONR6 R7, -COR6, -SO2 NR6 R7, S(O)0-2 R9, --O(CH2)1-10 --COOR6, --O(CH2)1-10 CONR6 R7, -(lower alkylene)COOR6, --CH═CH--COOR6, --CF3, --CN, --NO2 and halogen; R5 is 1-5 substituents independently selected from the group consisting of --OR6, --O(CO)R6, --O(CO)OR9, --O(CH2)1-5 OR6, --O(CO)NR6 R7, --NR6 R7, --NR6 (CO)R7, --NR6 (CO)OR9, --NR6 (CO)NR7 R8, --NR6 SO2 R9, --COOR6, --CONR6 R7, --COR6, --SO2 NR6 R7, S(O)0-2 R9, --O(CH2)1-10 --COOR6, --O(CH2)1-10 CONR6 R7, -(lower alkylene)COOR6 and --CH═CH--COOR6 ; R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and R9 is lower alkyl, aryl or aryl-substituted lower alkyl. 2. A compound of claim 1 wherein Ar1 is phenyl or R4 -substituted phenyl, Ar2 is phenyl or R4 -substituted phenyl and Ar3 is R5 -substituted phenyl. 3. A compound of claim 2 wherein Ar1 is R4 -substituted phenyl wherein R4 is halogen; Ar2 is R4 -substituted phenyl wherein R4 is halogen or --OR6, wherein R6 is lower alkyl or hydrogen; and Ar3 R5 -substituted phenyl, wherein R5 is --OR6, wherein R6 is lower alkyl or hydrogen. 4. A compound of claim 1 wherein X, Y, and Z are each --CH2 --; R1 and R3 are each hydrogen; R and R2 are each --OR6, wherein R6 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 ofrel 3(R)-(2(R)-hydroxy-2-phenylethyl)-4(R)-(4-methoxyphenyl)-1-phenyl-2-azetidinone; rel 3(R)-(2(R)-hydroxy-2-phenylethyl)-4(S)-(4-methoxyphenyl)-1-phenyl-2-azetidinone; 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-azetidinone; 3(R)-(1(R)-hydroxy-3-phenylpropyl)-4(S)-(4-methoxyphenyl)-1-phenyl-2-azetidinone; rel-3(R)- (S)-hydroxy-(2-naphthalenyl)methyl!-4(3S)-(4-methoxyphenyl)-1-phenyl)-1 -phenyl-2-azetidinone; rel-3(R)- (R)-hydroxy-(2-naphthalenyl)methyl!-4(S)-(4-methoxyphenyl)-1-phenyl-2-azetidinone; 3(R)-(3(R)-hydroxy-3-phenylpropyl)-1,4(S)-bis-(4-methoxyphenyl)-2-azetidinone; 3(R)-(3(S)-hydroxy-3-phenylpropyl)-1,4(S)-bis-(4-methoxyphenyl)-2-azetidinone; 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-methoxyphenyl)-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-hydroxyphenyl)-2-azetidinone; 4(S)- 4-(acetyloxy)phenyl!-3(R)-(3(R)-hydroxy-3-phenylpropyl)-1-(4-methoxyphenyl)-2-azetidinone; 4(S)- 4-(acetyloxy)phenyl!-3(R)-(3(S)-hydroxy-3-phenylpropyl)-1(4-methoxyphenyl)-2-azetidinone; 1-(4 -fluorophenyl)-3(R)- 3(S)-(4-fluorophenyl)-3-hydroxypropyl)!-4(S)- 4-(phenylmethoxy)phenyl!-2-azetidinone; 3(R)- 3(R)-acetyloxy)-3-phenylpropyl!-1,4(S)-bis-(4-methoxyphenyl)-2-azetidinone; 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)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-phenylpropyl)-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.