Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents

Abstract

Hydroxy-substituted azetidinone hypocholesterolemic agents of the formula or a pharmaceutically acceptable salt thereof, wherein: Ar 1 and Ar 2 are aryl or R 4 -substituted aryl; Ar 3 is aryl or R 5 -substituted aryl; X, Y and Z are —CH 2 —, —CH(lower alkyl)— or —C(dilower alkyl)—; R and R 2 are —OR 6 , —O(CO)R 6 , —O(CO)OR 9 or —O(CO)NR 6 R 7 ; R 1 and R 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 4 is selected from lower alkyl, R 5 , —CF 3 , —CN, —NO 2 and halogen R 5 is selected from —OR 6 , —O(CO)R 6 , —O(CO)OR 9 , —O(CH 2 ) 1-5 OR 6 , —O(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 CON 6 R 7 , —(lower alkylene)COOR 6 and —CH═CH—COOR 6 ; R 6 , R 7 and R 8 are H, lower alkyl or aryl-substituted Ic R 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.

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  represented by the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 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  is R 5 -substituted phenyl, wherein R 5  is —OR 6 , wherein R6 R 6  is lower alkyl or hydrogen; 
 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 6  and R 7  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. 
 
     
     
       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; and 
 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(S)-(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  7 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  7. 
     
     
       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.