# US 5,744,467 A · Sulfur-substituted azetidinone compounds useful as hypocholesterolemic agents

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 5,744,467 A
- Document ID: US5744467A
- Status: Granted
- Kind: A
- Application number: 08/813,585
- Filed: 1997-01-08
- Granted: 1998-04-28
- Earliest claimed: 1994-11-18
- Assignees: Schering Corporation
- Inventors: Brian A. McKittrick; Sundeep Dugar; Duane A. Burnett
- Web page: https://patentgrep.com/patent/US5744467A

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61P 3/06: Antihyperlipidemics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C07D 205/08: with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Sulfur-substituted azetidinone hypocholesterolemic agents of the formula ##STR1## or a pharmaceutically acceptable salt thereof are disclosed, as well as pharmaceutical compositions containing them, and a method of lowering serum cholesterol by administering said compounds, alone or in combination with a cholesterol biosynthesis inhibitor.

## Claims

### Claim 1

A pharmaceutical composition for the treatment or prevention of atherosclerosis, or for the reduction of plasma cholesterol levels, comprising a compound represented by the structural formula ##STR45## or a pharmaceutically acceptable salt thereof, wherein: Ar.sup.1 is aryl, R.sup.10 -substituted aryl or heteroaryl;
Ar.sup.2 is aryl or R.sup.4 -substituted aryl;
Ar.sup.3 is aryl or R.sup.5 -substituted aryl;
X and Y are independently selected from the group consisting of --CH.sub.2 --, --CH(lower alkyl)- and --C(dilower alkyl)-;
R is --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 is hydrogen, lower alkyl or aryl; or R and R.sup.1 together are .dbd.O;
q is 0 or 1;
r is 0, 1 or 2;
m and n are independently 0, 1, 2, 3 or 4; provided that the sum of m, n and q is 2, 3 or 4;
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 and --CH.dbd.CH--COOR.sup.6 ;
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, --CF.sub.3, --CN, --NO.sub.2, halogen, -(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;
R.sup.9 is lower alkyl, aryl or aryl-substituted lower alkyl; and
R.sup.10 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, --CF.sub.3, --CN, --NO.sub.2 and halogen; a cholesterol biosynthesis inhibitor and a pharmaceutically acceptable carrier.

### Claim 2 (depends on 1)

A pharmaceutical composition of claim 1 wherein the cholesterol biosynthesis inhibitor is selected from the group consisting of HMG CoA reductase inhibitors.

### Claim 3 (depends on 2)

A pharmaceutical composition of claim 2 wherein the cholesterol biosynthesis inhibitor is selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin and atorvastastin.

### Claim 4

A method of treating or preventing atherosclerosis or reducing plasma cholesterol levels comprising simultaneously or sequentially administering to a mammal in need of such treatment an effective amount of a cholesterol biosynthesis inhibitor and a compound represented by the structural formula ##STR46## or a pharmaceutically acceptable salt thereof, wherein: Ar.sup.1 is aryl, R.sup.10 -substituted aryl or heteroaryl;
Ar.sup.2 is aryl or R.sup.4 -substituted aryl;
Ar.sup.3 is aryl or R.sup.5 -substituted aryl;
X and Y are independently selected from the group consisting of --CH.sub.2 --, --CH(lower alkyl)- and --C(dilower alkyl)-;
R is --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 is hydrogen, lower alkyl or aryl; or R and R.sup.1 together are .dbd.O;
q is 0 or 1;
r is 0, 1 or 2;
m and n are independently 0, 1, 2, 3 or 4; provided that the sum of m, n and q is 2, 3 or 4;
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 and --CH.dbd.CH--COOR.sup.6 ;
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, --CF.sub.3, --CN, --NO.sub.2, halogen, -(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;
R.sup.9 is lower alkyl, aryl or aryl-substituted lower alkyl; and
R.sup.10 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, --CF.sub.3, --CN, --NO.sub.2 and halogen.

### Claim 5 (depends on 4)

A method as claimed in claim 4, wherein the cholesterol biosynthesis inhibitor is selected from the group consisting of HMG CoA reductase inhibitors.

### Claim 6 (depends on 5)

A method as claimed in claim 5, wherein the cholesterol biosynthesis inhibitor is selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin and atorvastatin.

### Claim 7 (depends on 3)

A composition of claim 3 comprising a compound of formula I wherein q is 0; Ar.sup.1 is phenyl, R.sup.10 -substituted phenyl or thienyl; Ar.sup.2 is R.sup.4 -substituted phenyl; Ar.sup.3 is phenyl or R.sup.5 -substituted phenyl; X and Y are each --CH.sub.2 --; and the sum of m and n is 2, 3 or 4.

### Claim 8 (depends on 3)

A composition of claim 3 comprising a compound of formula I wherein q is 1; Ar.sup.1 is phenyl, R.sup.10 -substituted phenyl or thienyl; Ar.sup.2 is R.sup.4 -substituted phenyl; Ar.sup.3 is phenyl or R.sup.5 -substituted phenyl; X and Y are each --CH.sub.2 --; the sum of m and n is 1, 2 or 3; and R.sup.1 is hydrogen and R is --OR.sup.6, wherein R.sup.6 is hydrogen, or wherein R and R.sup.1 together form a .dbd.O group.

### Claim 9 (depends on 3)

A composition of claim 3 wherein the compound of formula I is selected from the group consisting of
trans-1-(4-fluorophenyl)-4-(4-hydroxyphenyl)-3-›(2-phenylethyl)-thio!-2-aze tidinone;
trans-4-(4-methoxyphenyl)-1-phenyl-3-›(2-phenylethyl)thio!-2-azetidinone;
cis-4-(4-methoxyphenyl)-1-phenyl-3-›(2-phenylethyl)thio!-2-azetidinone;
trans-1-(4-fluorophenyl)-4-(4-hydroxyphenyl)-3-›(2-phenylethyl)-sulfinyl!-2 -azetidinone;
cis-1-(4-fluorophenyl)-4-(4-hydroxyphenyl)-3-›(2-phenylethyl)-sulfinyl!-2-a zetidinone;
trans-4-(4-methoxyphenyl)-1-phenyl-3-›(2-phenylethyl)sulfinyl!-2-azetidinon e;
cis-4-(4-methoxyphenyl)-1-phenyl-3-›(2-phenylethyl)sulfinyl!-2-azetidinone;
trans-4-›1-(4-fluorophenyl)-4-oxo-3-›(2-phenylethyl)sulfinyl!-2-azetidinyl! -phenyl acetate;
cis-4-›1-(4-fluorophenyl)-4-oxo-3-›(2-phenylethyl)sulfinyl!-2-azetidinyl!-p henyl acetate; and
(+/-)-trans-4-(4-methoxyphenyl)- 1-phenyl-3-›(2-phenylethyl)-sulfonyl!-2-azetidinone;
trans-1-(4-fluorophenyl)-3-››2-(4-fluorophenyl)-2-oxoethyl!thio!-4-( 4-hydroxyphenyl)-2-azetidinone;
trans-1-(4-fluorophenyl)-3-››2-(4-fluorophenyl)-2-hydroxyethyl!thio!-4-( 4-hydroxyphenyl)-2-azetidinone;
(3R,4R) 1-(4-fluorophenyl)-3-››2-(4-fluorophenyl)-2-oxoethyl!-sulfinyl!-4-(4-hydro xyphenyl)-2-azetidinone;
1-(4-fluorophenyl)-3(R)-››2-(4-fluorophenyl)-2(R)-hydroxyethyl !-sulfinyl!-4(R)-(4-hydroxyphenyl)-2-azetidinone;
1-(4-fluorophenyl)-3(R)-››2-(4-fluorophenyl)-2(S)-hydroxyethyl!-sulfinyl!-4 (R)-(4-hydroxyphenyl)-2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-››2-(2-thienyl)-2-oxoethyl!thio!-4-(4-hydroxyph enyl)-2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-››2-(3-thienyl)-2-oxoethyl!thio!-4-(4-hydroxyph enyl)-2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-››2-(3-pyridinyl)-2-oxoethyl!thio!-4-(4-hydroxy phenyl)-2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-››2-(4-pyridinyl)-2-oxoethyl!thio!-4-(4-hydroxy phenyl)-2-azetidinone;
(3R,4R) trans- 1 -(4-fluorophenyl)-3-››2-(2-pyridinyl)-2-oxoethyl!thio!-4-(4-hydroxyphenyl) -2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-››2-hydroxy-2-(3-thienyl)ethyl!-thio!-4-(4-hydr oxyphenyl)-2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-››2-hydroxy-2-(4-pyridinyl)ethyl!-thio!-4-(4-hy droxyphenyl)-2-azetidinone;
(3S,4R) cis-1-(4-fluorophenyl)-3-››2-(4-fluorophenyl)-2-oxoethyl!thio!-4-(4-hydrox yphenyl)-2-azetidinone; and
(3S,4R) cis-1-(4-fluorophenyl)-3-››2-(4-fluorophenyl)-2-hydroxyethyl!thio!-4-(4-hy droxyphenyl)-2-azetidinone.

### Claim 10 (depends on 6)

A method of claim 6 comprising a compound of formula I wherein q is 0; Ar.sup.1 is phenyl, R.sup.10 -substituted phenyl or thienyl; Ar.sup.2 is R.sup.4 -substituted phenyl; Ar.sup.3 is phenyl or R.sup.5 -substituted phenyl; X and Y are each --CH.sub.2 --; and the sum of m and n is 2, 3 or 4.

### Claim 11 (depends on 6)

A method of claim 6 comprising a compound of formula I wherein q is 1; Ar.sup.1 is phenyl, R.sup.10 -substituted phenyl or thienyl; Ar.sup.2 is R.sup.4 -substituted phenyl; Ar.sup.3 is phenyl or R.sup.5 -substituted phenyl; X and Y are each --CH.sub.2 --; the sum of m and n is 1, 2 or 3; and R.sup.1 is hydrogen and R is --OR.sup.6, wherein R.sup.6 is hydrogen, or wherein R and R.sup.1 together form a .dbd.O group.

### Claim 12 (depends on 6)

A method of claim 6 wherein the compound of formula I is selected from the group consisting of
trans-1-(4-fluorophenyl)-4-(4-hydroxyphenyl)-3-›(2-phenylethyl)-thio!-2-aze tidinone;
trans-4-(4-methoxyphenyl)-1-phenyl-3-›(2-phenylethyl)thio!-2-azetidinone;
cis-4-(4-methoxyphenyl)-1-phenyl-3-›(2-phenylethyl)thio!-2-azetidinone;
trans-1-(4-fluorophenyl)-4-(4-hydroxyphenyl)-3-›(2-phenylethyl)-sulfinyl!-2 -azetidinone;
cis-1-(4-fluorophenyl)-4-(4-hydroxyphenyl)-3-›(2-phenylethyl)-sulfinyl!-2-a zetidinone;
trans-4-(4-methoxyphenyl)-1-phenyl-3-›(2-phenylethyl)sulfinyl!-2-azetidinon e;
cis-4-(4-methoxyphenyl)-1-phenyl-3-›(2-phenylethyl)sulfinyl!-2-azetidinone;
trans-4-›1-(4-fluorophenyl)-4-oxo-3-›(2-phenylethyl)sulfinyl!-2-azetidinyl! -phenyl acetate;
cis-4-›1-(4-fluorophenyl)-4-oxo-3-›(2-phenylethyl)sulfinyl!-2-azetidinyl!-p henyl acetate; and
(+/-)-trans-4-(4-methoxyphenyl)-1-phenyl-3-›(2-phenylethyl)-sulfonyl!-2-aze tidinone;
trans-1-(4-fluorophenyl)-3-››2-(4-fluorophenyl)-2-oxoethyl!thio!-4-(4-hydro xyphenyl)-2-azetidinone;
trans-1-(4-fluorophenyl)-3-››2-(4-fluorophenyl)-2-hydroxyethyl!thio!-4-(4-h ydroxyphenyl)-2-azetidinone;
(3R,4R) 1-(4-fluorophenyl)-3-››2-(4-fluorophenyl)-2-oxoethyl!-sulfinyl!-4-(4-hydro xyphenyl)-2-azetidinone;
1-(4-fluorophenyl)-3(R)-››2-(4-fluorophenyl)-2(R)-hydroxyethyl !-sulfinyl!-4(R)-(4-hydroxyphenyl)-2-azetidinone;
1-(4-fluorophenyl)-3(R)-››2-(4-fluorophenyl)-2(S)-hydroxyethyl!-sulfinyl!-4 (R)-(4-hydroxyphenyl)-2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-››2-(2-thienyl)-2-oxoethyl!thio!-4-(4-hydroxyph enyl)-2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-››2-(3-thienyl)-2-oxoethyl!thio!-4-(4-hydroxyph enyl)-2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-››2o(3-pyridinyl)-2-oxoethyl!thio!-4-(4-hydroxy phenyl)-2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-››2-(4-pyridinyl)-2-oxoethyl!thio!-4-(4-hydroxy phenyl)-2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-››2-(2-pyridinyl)-2-oxoethyl!thio!-4-(4-hydroxy phenyl)-2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-››2-hydroxy-2-(3-thienyl)ethyl!-thio!-4-(4-hydr oxyphenyl)-2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-››2-hydroxy-2-(4-pyridinyl)ethyl!-thio!-4-(4-hy droxyphenyl)-2-azetidinone;
(3S,4R) cis-1-(4-fluorophenyl)-3-››2-(4-fluorophenyl)-2-oxoethyl!thio!-4-(4-hydrox yphenyl)-2-azetidinone; and
(3S,4R) cis-1-(4-fluorophenyl)-3-››2-(4-fluorophenyl)-2-hydroxyethyl!thio!-4-(4-hy droxyphenyl)-2-azetidinone.