Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents

Abstract

Hydroxy-substituted azetidinone hypocholesterolemic agents of the formulaor 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 or aryl-substituted IcR9 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.

We claim:  
     
       1. A compound represented by the formula                    
       or a pharmaceutically acceptable salt thereof, wherein: 
       Ar 1  and Ar 2  are independently selected from the group consisting of aryl and R 4 -substituted aryl;  
       Ar 3  is aryl or R 5 -substituted aryl;  
       X, Y and Z are independently selected from the group consisting of —CH 2 —, —CH(lower alkyl)- and —C(dilower alkyl)-;  
       R and R 2  are independently selected from the group consisting of —OR 6 , —O(CO)R 6 , —O(CO)OR 9  and —O(CO)NR 6 R 7 ;  
       R 1  and R 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 4  is 1-5 substituents independently selected from consisting of lower alkyl, —OR 6 , —O(CO)R 6 , —O(CO) OR 9 , —O(CH 2 ) 1-5 OR 6 , —(CO)NR 6 R 7 , —NR 6 R 7 , —NR 6 (CO)R 7 , —NR 6 (CO)OR 9 , —NR 6 (CO)NR 7 R 8 , —NR 6 SO 2 R 9 , —COOR 6 , —CONR 6 R 7 , -COR 6 , -SO 2 NR 6 R 7 , S(O) 0-2 R 9 , —O(CH 2 ) 1-10 —COOR 6 , —O(CH 2 ) 1-10 CONR 6 R 7 , -(lower alkylene)COOR 6 , —CH═CH—COOR 6 , —CF 3 , —CN, —NO 2  and halogen;  
       R 5  is 1-5 substituents independently selected from the group consisting of —OR 6 , —O(CO)R 6 , —O(CO) OR 9 , —O(CH 2 ) 1-5 OR 6 , —(CO)NR 6 R 7 , —NR 6 R 7 , —NR 6 (CO)R 7 , —NR 6 (CO)OR 9 , —NR 6 (CO)NR 7 R 8 , —NR 6 SO 2 R 9 , —COOR 6 , —CONR 6 R 7 , —COR 6 , —SO 2 NR 6 R 7 , S(O) 0-2 R 9 , —O(CH 2 ) 1-10 —COOR 6 , —O(CH 2 ) 1-10 CONR 6 R 7 , -(lower alkylene)COOR 6  and —CH═CH—COOR 6 ;  
       R 6 , R 7  and R 8  are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and  
       R 9  is lower alkyl, aryl or aryl-substituted lower alkyl.  
     
     
       2. A compound of  claim 1  wherein Ar 1  is phenyl or R 4 -substituted phenyl, Ar 2  is phenyl or R 4 -substituted phenyl and Ar 3  is R 5 -substituted phenyl. 
     
     
       3. A compound of  claim 2  wherein Ar 1  is R 4 -substituted phenyl wherein R 4  is halogen; Ar 2  is R 4 -substituted phenyl wherein R 4  is halogen or —OR 6 , wherein R 6  is lower alkyl or hydrogen; and Ar 3  R 5 -substituted phenyl, wherein R 5  is —OR 6 , wherein R6 is lower alkyl or hydrogen. 
     
     
       4. A compound of  claim 1  wherein X, Y, and Z are each —CH 2 —; R 1  and R 3  are each hydrogen; R and R 2  are each —OR 6 , wherein R 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-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(S)-(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]propyl]-1,4(S)-bis-(4-methoxyphenyl)-2-azetidinone;  
       1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(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 or prevention of athersclerosis , atherosclerosis 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 . 
     
     
       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.   
     
     
       11. A compound represented by the formula:                    
         
     
     
       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. 
     
     
       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 .