US 5,767,115 AGranted

Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents

AssigneeSchering-Plough Corporation

InventorsStuart B. Rosenblum, Sundeep Dugar, Duane A. Burnett, John W. Clader, Brian A. McKittrick

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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.

Claims9

Dependent claims

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.

12 more elements

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.

22 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/617,751Filed 18 Mar 1996 · continuation in part
Priority: 21 Sep 1993
Granted: 16 Jun 1998
Term ends: Not estimatedThe source records don’t support an estimate.

Classification16 codes

C07D 205/08
Having one double bond between ring members or between a ring member and a non-ring member: with one oxygen atom directly attached in position 2,…
A61K 9/2018
Organic compounds, e.g. phospholipids, fats: sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
A61K 9/4858
Filling excipients; Inactive ingredients: organic compounds
A61K 31/21
Medicinal preparations containing organic active ingredients: esters, e.g. nitroglycerine, selenocyanates