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

• US 5,846,966 A
• Filed: 10/14/1997
• Issued: 12/08/1998
• Est. Priority Date: 09/21/1993
• Status: Expired due to Term

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Clader, John W., McKittrick, Brian A., Rosenblum, Stuart B., Burnett, Duane A., Dugar, Sundeep
• Primary Examiner(s): JORDAN, KIMBERLY R
• Application Number:
  US08/953,825
• Time in Patent Office: 420 Days
• Field of Search: 514/210, 514/423, 514/451, 514/460, 514/510, 514/824
• US Class Current: 514/210.02
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/21 Esters, e.g. nitroglycerine, selenocyanates
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 205/08 with one oxygen atom directly attached in position 2, e.g. beta-lactams
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Hydroxy-substituted azetidinone hypocholesterolemic agents of the formula ##STR1## or 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)NR⁶ R⁷ ;

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 0 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)_1-5 OR⁶, --O(CO)NR⁶ R⁷, --NR⁶ R⁷, --NR⁶ (CO)R⁷, --NR⁶ (CO)OR⁹, --NR⁶ (CO)NR⁷ R⁸, --NR⁶ SO₂ R⁹, --COOR⁶, --CONR⁶ R⁷, --COR⁶, --SO₂ NR⁶ R⁷, S(O)_0-2 R⁹, --O(CH₂)_1-10 --COOR⁶, --O(CH₂)_1-10 CONR⁶ R⁷, --(lower alkylene)COOR⁶ and --CH═CH--COOR⁶ ;

R⁶, R⁷ and R⁸ are H, lower alkyl, aryl or aryl-substituted lower alkyl;

R⁹ 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.

Claims

1. 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:

Ar¹ and Ar² are independently selected from the group consisting of aryl and R⁴ -substituted aryl;

Ar³ is aryl or R⁵ -substituted aryl;

X, Y and Z are independently selected from the group consisting of --CH₂ --, --CH(lower alkyl)-- and --C(dilower alkyl)--;

R and R² are independently selected from the group consisting of --OR⁶, --O(CO)R⁶, --O(CO)OR⁹ and --O(CO)NR⁶ R⁷ ;

R¹ and R³ 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;

R⁴ is 1-5 substituents independently selected from the group consisting of lower alkyl, --OR⁶, --O(CO)R⁶, --O(CO)OR⁹, --O(CH₂)_1-5 OR⁶, --O(CO)NR⁶ R⁷, --NR⁶ R⁷, --NR⁶ (CO)R⁷, --NR⁶ (CO)OR⁹, --NR⁶ (CO)NR⁷ R⁸, --NR⁶ SO₂ R⁹, --COOR⁶, --CONR⁶ R⁷, --COR⁶, --SO₂ NR⁶ R⁷, S(O)_0-2 R⁹, --O(CH₂)_1-10 --COOR⁶, --O(CH₂)_1-10 CONR⁶ R⁷, --(lower alkylene)COOR⁶, --CH═

CH--COOR⁶, --CF₃, --CN, --NO₂ and halogen;

R⁵ is 1-5 substituents independently selected from the group consisting of --OR⁶, --O(CO)R⁶, --O(CO)OR⁹, --O(CH₂)l 5OR⁶, --O(CO)N R⁶ R⁷, --NR⁶ R⁷, --NR⁶ (CO)R⁷, --NR⁶ (CO)OR⁹, --NR⁶ (CO)NR⁷ R⁸, --NR⁶ SO₂ R⁹, --COOR⁶, --CONR⁶ R⁷, --COR⁶, --SO₂ NR⁶ R⁷, S(O)_0-2 R⁹, --O(CH₂)_1-10 --COOR⁶, --O(CH₂)_1-10 CONR⁶ R⁷, --(lower alkylene)COOR⁶ and --CH═

CH--COOR⁶ ;

R⁶, R⁷ and R⁸ are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and

R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl;

in combination with an HMG CoA reductase inhibitor in a pharmaceutically acceptable carrier.

2. A pharmaceutical composition of claim 1 wherein, in the compound of formula I, Ar¹ is phenyl or R⁴ -substituted phenyl, wherein R⁴ is halogen;

Ar² is phenyl or R⁴ -substituted phenyl, wherein R⁴ is halogen or --OR⁶, wherein R⁶ is lower alkyl or hydrogen;

Ar³ is R⁵ -substituted phenyl, wherein R⁵ is --OR⁶, wherein R⁶ is lower alkyl or hydrogen;

X, Y, and Z are each --CH₂ --;

R¹ and R³ are each hydrogen;

R and R² are each --OR⁶, wherein R⁶ is hydrogen; and

the sum of m, n, p, q and r is 2, 3 or 4.

3. A composition of claim 1 wherein the HMG CoA reductase inhibitor is selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin and atorvastatin.

4. A composition of claim 1 wherein the compound of formula I is 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;

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-methoxy-phenyl)-2-azetidinone;

3(R)- 3(S)-acetyloxy)-3-phenylpropyl!-1,4(S)-bis-(4-methoxy-phenyl)-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!-1l-(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(R)-(1(R)-hydroxy-3-phenylpropyl)-2-azetidinone.

5. A composition of claim 1 comprising a combination of 1-(4-fluorophenyl)-3(R)- 3(R)-(4-fluorophenyl)-3-hydroxypropyl)!-4(S)-(4-hydroxyphenyl)-2-azetidinone and lovastatin, pravastatin, fluvastatin, simvastatin or atorvastatin.

6. 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:

Ar¹ and Ar² are independently selected from the group consisting of aryl and R⁴ -substituted aryl;

Ar³ is aryl or R⁵ -substituted aryl;

X, Y and Z are independently selected from the group consisting of --CH₂ --, --CH(lower alkyl)-- and --C(dilower alkyl)--;

R and R² are independently selected from the group consisting of --OR⁶, --O(CO)R⁶, --O(CO)OR⁹ and --O(CO)NR⁶ R⁷ ;

R¹ and R³ 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;

R⁴ is 1-5 substituents independently selected from the group consisting of lower alkyl, --OR⁶, --O(CO)R⁶, --O(CO)OR⁹, --O(CH₂)_1-5 OR⁶, --O(CO)NR⁶ R⁷, --NR⁶ R⁷, --NR⁶ (CO) R⁷, --NR⁶ (CO)OR⁹, --NR⁶ (CO)NR⁷ R⁸, --NR⁶ SO₂ R⁹, --COOR⁶, --CONR⁶ R⁷, --COR⁶, --SO₂ NR⁶ R⁷, S(O)_0-2 R⁹, --O(CH₂)_1-10 --COOR⁶, --O(CH₂)_1-10 CONR⁶ R⁷, --(lower alkylene)COOR⁶, --CH═

CH--COOR⁶, --CF₃, --CN, --NO₂ and halogen;

R⁵ is 1-5 substituents independently selected from the group consisting of --OR⁶, --O(CO)R⁶, --O(CO)OR⁹, --O(CH₂)_1-5 OR⁶, --O(CO)NR⁶ R⁷, --NR⁶ R⁷, --NR⁶ (CO)R⁷, --NR⁶ (CO)OR⁹, --NR⁶ (CO)NR⁷ R⁸, --NR⁶ SO₂ R⁹, --COOR⁶, --CONR⁶ R⁷, --COR⁶, --SO₂ NR⁶ R⁷, S(O)_0-2 R⁹, --O(CH₂)_1-10 --COOR⁶, --O(CH₂)_1-10 CONR⁶ R⁷, --(lower alkylene)COOR⁶ and --CH═

CH--COOR⁶ ;

R⁶, R⁷ and R⁸ are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and

R⁹ 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.

7. A method of claim 6 wherein, in the compound of formula I, Ar¹ is phenyl or R⁴ -substituted phenyl, wherein R⁴ is halogen;

Ar² is phenyl or R⁴ -substituted phenyl, wherein R⁴ is halogen or --OR⁶, wherein R⁶ is lower alkyl or hydrogen;

Ar³ is R⁵ -substituted phenyl, wherein R⁵ is --OR⁶, wherein R⁶ is lower alkyl or hydrogen;

X, Y, and Z are each --CH₂ --;

R¹ and R³ are each hydrogen;

R and R² are each --OR⁶, wherein R⁶ is hydrogen; and

the sum of m, n, p, q and r is 2, 3 or 4.

8. A method of claim 6 wherein the HMG CoA reductase inhibitor is selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin and atorvastatin.

9. A method of claim 6 wherein the compound of formula I is 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;

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-methoxy-phenyl)-2-azetidinone;

3(R)- 3(S)-acetyloxy)-3-phenylpropyl!-1,4(S)-bis-(4-methoxy-phenyl)-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(R)-(1(R)-hydroxy-3-phenylpropyl)-2-azetidinone.

10. A method of claim 6 comprising administering a combination of 1-(4-fluorophenyl)-3(R)- 3(R)-(4-fluorophenyl)-3-hydroxypropyl)!-4(S)-(4-hydroxyphenyl)-2-azetidinone and lovastatin, pravastatin, fluvastatin, simvastatin or atorvastatin.