US 5,846,966 AGranted

Combinations of hydroxy-substituted azetidinone compounds and HMG CoA Reductase Inhibitors

AssigneeSchering 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 0 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.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 H, lower alkyl, aryl or aryl-substituted lower alkyl; 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.

Claims10

Dependent claims

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 represented by the formula I ##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 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 1, 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 the group 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)l 5OR.sup.6, --O(CO)N R.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;
in combination with an HMG CoA reductase inhibitor in a pharmaceutically acceptable carrier.

13 more elements

A method of treating or preventing atherosclerosis or reducing plasma cholesterol levels comprising administering to a mammal in need thereof an effective amount of a compound represented by the formula I ##STR57## 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 1, 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 the group 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;
in combination with an effective amount of a cholesterol biosynthesis inhibitor selected from the group consisting of HMG CoA reductase inhibitors.

13 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/953,825Filed 14 Oct 1997 · continuation in part
Priority: 21 Sep 1993
Granted: 8 Dec 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

Family

Serial102,440Parent of this continuation-in-part · filed 21 Sep 1993
Serial257,593Parent of this continuation-in-part · filed 9 Jun 1994
Serial617,751Parent of this continuation-in-part · filed 18 Mar 1996
US 5,767,115 AParent of this continuation-in-part
US 5,631,365 AParent of this continuation-in-part
US 5,846,966 AThis patent

From the US filing history. Foreign family members aren’t listed.