Combination of a cholesterol biosynthesis inhibitor and a .beta.-lactam cholesterol absorption inhibitor

• US 5,661,145 A
• Filed: 06/20/1995
• Issued: 08/26/1997
• Est. Priority Date: 12/23/1992
• Status: Expired due to Term

• Current Assignee: Schering Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Davis, Harry R.
• Primary Examiner(s): JORDAN, KIMBERLY R
• Application Number:
  US08/454,348
• Time in Patent Office: 798 Days
• Field of Search: 514/210, 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 31/365 Lactones
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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

Abstract

Methods of reducing plasma cholesterol levels and treating or preventing atherosclerosis comprising administering an effective amount of a combination of a cholesterol biosynthesis inhibitor and a β-lactam cholesterol absorption inhibitor, as well as pharmaceutical compositions and kits useful in those methods, are disclosed.

Claims

1. 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 or prevention an effective amount of a cholesterol biosynthesis inhibitor selected from the group consisting of HMG CoA reductase inhibitors and a β

-lactam cholesterol absorption inhibitor represented by the structural formula ##STR9## or a pharmaceutically acceptable salt thereof, wherein D is B'"'"'--(CH₂)_q --, wherein B'"'"' is phenyl and q is 3 or 4;

B'"'"'--O--(CH₂)₂ --, wherein B'"'"' is p-fluoro-phenyl or p-methoxyphenyl;

3-phenyl-1-propenyl or

B'"'"'--(CH₂)--V--, wherein B'"'"' is phenyl and V is cyclopropylene;

A is --(CH₂)_p --X--B wherein p is zero, X is a bond and B is ##STR10## R₁, R₂ and R₃ are selected from the group consisting of H, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonyl-alkoxy, lower alkyl lower alkanedioyl, allyloxy, phenoxy, OH, m-halogeno and --C(O)R₁₂ ;

R₄ is (R₇)_n -substituted phenyl, wherein n is 1 and R₇ is lower alkyl, lower alkoxy, halogeno, OH or --OCF₃ ; and

R₁₂ is alkoxy.

2. The method as claimed in claim 1, wherein the β

-lactam cholesterol absorption inhibitor is (3R-4S)-1,4-bis-(4-methoxy-phenyl)-3-(3-phenylpropyl)-2-azetidinone.

3. A method of claim 1 wherein the cholesterol biosynthesis inhibitor is selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin and atorvastatin.

4. A pharmaceutical composition for the treatment or prevention of athersclerosis, or for the reduction of plasma cholesterol levels, comprising a β

-lactam cholesterol absorption inhibitor represented by the structural formula ##STR11## or a pharmaceutically acceptable salt thereof, wherein D is B'"'"'--(CH₂)_q --, wherein B'"'"' is phenyl and q is 3 or 4;

B'"'"'--O--(CH₂)₂ --, wherein B'"'"' is p-fluoro-phenyl or p-methoxyphenyl;

3-phenyl-1-propenyl;

or

B'"'"'--(CH₂)--V--, wherein B'"'"' is phenyl and V is cyclopropylene;

A is --(CH₂)_p --X--B wherein p is zero, X is a bond and B is ##STR12## R₁, R₂ and R₃ are selected from the group consisting of H, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonyl-alkoxy, lower alkyl lower alkanedioyl, allyloxy, phenoxy, OH, m-halogeno and --C(O)R₁₂ ;

R₄ is (R₇)_n -substituted phenyl, wherein n is 1 and R₇ is lower alkyl, lower alkoxy, halogeno, OH or --OCF₃ ; and

R₁₂ is alkoxy, a cholesterol biosynthesis inhibitor selected from the group consisting of HMG CoA reductase inhibitors and a pharmaceutically acceptable carrier.

5. A pharmaceutical composition of claim 4 wherein the cholesterol biosynthesis inhibitor is selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin and atorvastatin.

6. A pharmaceutical composition of claim 4 wherein the β

-lactam cholesterol absorption inhibitor is (3R-4S)-1,4-bis-(4-methoxy-phenyl)-3-(3-phenylpropyl)-2-azetidinone and the cholesterol biosynthesis inhibitor is selected from the group consisting of lovastatin, fluvastatin, atorvastatin, pravastatin and simvastatin.

7. A kit comprising in separate containers in a single package pharmaceutical compositions wherein said pharmaceutical compositions are combined to treat or prevent athersclerosis or to reduce plasma cholesterol levels which comprises in one container an effective amount of a cholesterol biosynthesis inhibitor selected from the group consisting of HMG CoA reductase inhibitors in a pharmaceutically acceptable carrier, and in a second container, an effective amount of a β

-lactam cholesterol absorption inhibitor represented by the structural formula ##STR13## or a pharmaceutically acceptable salt thereof, wherein D is B'"'"'--(CH₂)_q --, wherein B'"'"' is phenyl and q is 3 or 4;

B'"'"'--O--(CH₂)₂ --, wherein B'"'"' is p-fluoro-phenyl or p-methoxyphenyl;

3-phenyl-1-propenyl;

or

B'"'"'--(CH₂)--V--, wherein B'"'"' is phenyl and V is cyclopropylene;

A is --(CH₂)_p --X--B wherein p is zero, X is a bond and B is ##STR14## R₁, R₂ and R₃ are selected from the group consisting of H, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonyl-alkoxy, lower alkyl lower alkanedioyl, aliyloxy, phenoxy, OH, m-halogeno and --C(O)R₁₂ ;

R₄ is (R₇)_n -substituted phenyl, wherein n is 1 and R₇ is lower alkyl, lower alkoxy, halogeno, OH or --OCF₃ ; and

R₁₂ is alkoxy in a pharmaceutically acceptable carrier.