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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• This invention concerns a combination of a statin compound, which are known to cause a reduction in plasma levels of low-density lipoproteins (LDL) cholesterol, and an MMP inhibitor, which reduce the breakdown of connective tissues.
• the combination is useful for treating vascular disorders and preventing heart failure.
• statins which are compounds which inhibit the enzyme 3-hydroxy-3-methylglutaryl- coenzyme A (HMG-CoA) reductase, the enzyme responsible for catalyzing the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the cholesterol biosynthetic pathway.
• HMG-CoA 3-hydroxy-3-methylglutaryl- coenzyme A
• MMP native matrix metalloproteinases
• -2 are classes of naturally occurring enzymes found in most mammals. They are zinc proteases that hydrolyze collagens, proteoglycans, and glycoproteins.
• the classes include gelatinase A and B, stromelysin- 1 and -2, fibroblast collagenase, neutrophil collagenase, matrilysin, metalloelastase, and interstitial collagenase.
• This invention provides a method of treating and preventing heart failure and other vascular diseases in a mammal comprising administering an effective amount of a matrix metalloproteinase inhibitor together with a statin.
• the invention also provides a method for treating and preventing ventricular dilatation comprising administering an effective amount of a matrix metalloproteinase inhibitor together with a statin.
• the methods can be practiced by administering any statin in combination with any MMP inhibitor, e.g., any chemical compound that is effective in inhibiting the biological activity of a matrix metalloproteinase such as collagenase, stromelysin, gelatinase, or elastase.
• any MMP inhibitor e.g., any chemical compound that is effective in inhibiting the biological activity of a matrix metalloproteinase such as collagenase, stromelysin, gelatinase, or elastase.
• a matrix metalloproteinase such as collagenase, stromelysin, gelatinase, or elastase.
• Numerous compounds are known to be matrix metalloproteinase inhibitors, and any of such compounds can be utilized in the method of this invention.
• the matrix metalloproteinase inhibitor to be utilized is a substituted bicyclic compound of the formula
• A is phenyl or — Y N — where Y is CH or N;
• R! is a substituent such as alkyl, aryl, halo, amino, substituted and disubstituted amino, and alkoxy;
• R2 is carboxyalkyl ketone or oxime, or a carboxyalkyl sulfonamide such as
• R 3 is alkyl, substituted alkyl, amino, substituted and
• a particularly preferred embodiment is a method of treating and preventing heart failure and ventricular dilatation by administering a statin together with a biphenylsulfonamide (compounds of the above formula when A is phenyl) such as
• CHF and ventricular dilatation is treated or prevented by administering a statin together with a matrix metalloproteinase which is a substituted fused tricyclic compound of the formula
• R 3 is alkyl, halo, alkoxy, acyl, and aryl.
• a preferred method utilizes dibenzofurans and fluorenes of the above formula, for instance compounds such as
• R 2 is, for instance, NOH
• MMP inhibitors to be utilized are (S)-2- (dibenzofuran-3-sulfonylamino)-3-methyl-butyric acid and (S)-2-(dibenzofuran-3- sulfonylamino)-succinic acid.
• Typical statins to be employed in combination with the MMP inhibitor include atorvastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, lovastatin, dalvastatin, and fluindostatin.
• the statins can be employed as pharmaceutically acceptable salts.
• a particularly preferred composition of this invention utilizes a biphenylsulfonamide MMP inhibitor together with a statin selected from atorvastatin calcium, pravastatin sodium, simvastatin, lovastatin, and cerivastatin.
• the most preferred composition employs atorvastatin calcium together with the MMP inhibitor 2-(4'-bromobiphenyl-4-sulfonylamino)-3-methylbutyric acid.
• vascular diseases such as peripheral vascular disease, coronary heart disease, stroke, and restenosis.
• statin provides a surprisingly effective composition for treating and preventing vascular diseases.
• MMP inhibitors and statins are known in the art and are readily available.
• the compounds can be the free acid, a salt form, or the tetrazolyl or aldehyde analog.
• statin where used in the specification and the appendant claims, is synonymous with the terms "3-hydroxy-3-methylglutaryl-Coenzyme A reductase inhibitor” and "HMG-CoA reductase inhibitor.” These three terms are used interchangeably throughout the specification and appendant claims. As the synonyms suggest, statins are inhibitors of 3-hydroxy-3-methylglutaryl- Coenzyme A reductase and, as such, are effective in lowering the level of blood plasma cholesterol. Statins and pharmaceutically acceptable salts thereof are particularly useful in lowering low-density lipoprotein cholesterol (LDL-C) levels in mammals and particularly in humans.
• LDL-C low-density lipoprotein cholesterol
• the HMG-CoA reductase inhibitors suitable for use herein include, but are not limited to, simvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, cerivastatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, or lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, cerivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, lovastatin, or pharmaceutically acceptable salts thereof.
• atorvastatin calcium is a particularly preferred statin to be employed in the present combination. See U.S. Patent 5,273,995 inco ⁇ orated herein by reference.
• statins disclosed herein are prepared by methods well-known to those skilled in the art. Specifically, simvastatin may be prepared according to the method disclosed in U.S. Patent 4,444,784, which is inco ⁇ orated herein by reference. Pravastatin may be prepared according to the method disclosed in U.S. Patent 4,346,227, which is inco ⁇ orated herein by reference. Cerivastatin may be prepared according to the method disclosed in U.S. Patent 5,502,199, which is inco ⁇ orated herein by reference. Cerivastatin may alternatively be prepared according to the method disclosed in European Patent Application Publication No. -6- EP617019. Mevastatin may be prepared according to the method disclosed in U.S.
• Velostatin may be prepared according to the methods disclosed in U.S. Patent 4,448,784 and U.S. Patent 4,450,171, both of which are inco ⁇ orated herein by reference.
• Fluvastatin may be prepared according to the method disclosed in U.S. Patent 4,739,073, which is inco ⁇ orated herein by reference.
• Compactin may be prepared according to the method disclosed in U.S. Patent 4,804,770, which is inco ⁇ orated herein by reference.
• Lovastatin may be prepared according to the method disclosed in U.S. Patent 4,231,938, which is inco ⁇ orated herein by reference.
• Dalvastatin maybe prepared according to the method disclosed in European Patent Application Publication No.
• Fluindostatin may be prepared according to the method disclosed in European Patent Application Publication No. 363934 Al .
• Dihydrocompactin may be prepared according to the method disclosed in U.S. Patent 4,450,171, which is inco ⁇ orated herein by reference.
• statins contain either a free carboxylic acid or a free amine group as part of the chemical structure.
• certain statins within the scope of this invention contain lactone moieties, which exist in equilibrium with the free carboxylic acid form. These lactones can be maintained as carboxylates by preparing pharmaceutically acceptable salts of the lactone.
• this invention includes pharmaceutically acceptable salts of those carboxylic acids or amine groups.
• pharmaceutically acceptable salts includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts.
• salts are intended to define but is not limited to such salts as the alkali metal salts, (e.g., sodium and potassium), alkaline earth metal salts (e.g., calcium and magnesium), aluminum salts, ammonium salts, and salts with organic amines such as benzathine (N,N'-dibenzylethylenediamine), choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benethamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2- hydroxymethyl-l,3-propanediol) and procaine.
• alkali metal salts e.g., sodium and potassium
• alkaline earth metal salts e.g., calcium and magnesium
• aluminum salts e.g., ammonium salts
• salts with organic amines such as benzathine (N,N'-dibenzyl
• pharmaceutically acceptable add addition salts is intended to define but is not limited to such salts as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, -7- hydrogen phosphate, dihydrogenphosphate, acetate, succinate, citrate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts.
• the pharmaceutically acceptable cationic salts of statins containing free carboxylic acids may be readily prepared by reacting the free acid form of the statin with an appropriate base, usually one equivalent, in a co-solvent.
• Typical bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, piperazine, and tromethamine.
• the salt is isolated by concentration to dryness or by addition of a non-solvent.
• salts are preferably prepared by mixing a solution of the acid with a solution of a different salt of the cation (sodium or potassium ethylhexanoate, magnesium oleate), employing a solvent (e.g., ethyl acetate) from which the desired cationic salt precipitates, or can be otherwise isolated by concentration and/or addition of a non-solvent.
• a solvent e.g., ethyl acetate
• the pharmaceutically acceptable acid addition salts of statins containing free amine groups may be readily prepared by reacting the free base form of the statin with the appropriate acid.
• the salt is of a monobasic acid (e.g., the hydrochloride, the hydrobromide, the p-toluenesulfonate, the acetate), the hydrogen form of a dibasic acid (e.g., the hydrogen sulfate, the succinate), or the dihydrogen form of a tribasic acid (e.g., the dihydrogen phosphate, the citrate), at least one molar equivalent and usually a molar excess of the acid is employed.
• a monobasic acid e.g., the hydrochloride, the hydrobromide, the p-toluenesulfonate, the acetate
• the hydrogen form of a dibasic acid e.g., the hydrogen sulfate, the succinate
• salts as the sulfate, the hemisuccinate, the hydrogen phosphate, or the phosphate
• the appropriate and exact chemical equivalents of acid will generally be used.
• the free base and the acid are usually combined in a co-solvent from which the desired salt precipitates, or can be otherwise isolated by concentration and/or addition of a non-solvent.
• MMP inhibitors and pharmaceutically acceptable acid addition salts thereof may occur as hydrates or solvates.
• statins of the instant invention and the pharmaceutically acceptable salts of the statins of the instant invention may also occur as hydrates or solvates. Said hydrates and solvates are also within the scope of the invention.
• a "matrix metalloproteinase inhibitor” as used herein is any chemical compound that inhibits by at least five percent the hydrolytic activity of at least -8- one matrix metalloproteinase enzyme that is naturally occurring in a mammal. Such compounds are also referred to as "MMP inhibitors". Numerous matrix metalloproteinase inhibitors are known, and all are useful in the method of this invention. For example, 4-biarylbutyric and 5-biarylpentanoic acid derivatives are described in WO 96/15096, which is inco ⁇ orated herein by reference. The compounds are defined generally as (T) X A-B-D-E-G. Over 400 specific compounds are named, and each is inco ⁇ orated herein and can be employed in this invention. Especially preferred compounds to be utilized include the following:
• Cyclopentanecarboxylic acid 2-[(4'-chloro[l,l '-biphenyl]-4-yl)carbonyl]- 5-[(phenylmethoxy)methyl]-, (l ⁇ ,2 ⁇ ,5 ⁇ )-;
• Cyclopentanecarboxylic acid 2-[(4'-chloro[l,l '-biphenyl]-4-yl)carbonyl]- 5-(phenoxymethyl)-, (l ⁇ ,2 ⁇ ,5 ⁇ )-;
• Cyclopentanecarboxylic acid 2-[(benzoyloxy)- methyl]-5-[(4'- chloro[l,l '-biphenyl]-4-yl)carbonyl]-, (l ⁇ ,2 ⁇ ,5 ⁇ )-;
• Cyclopentanecarboxylic acid 2-[(4'-chloro[l,l '-biphenyl]-4-yl)carbonyl]- 5-[(2-thienylthio)methyl]-, (l ⁇ ,2 ⁇ ,5 ⁇ )-;
• Cyclopentanecarboxylic acid 2-[(benzoylamino)methyl]-5-[(4'- chloro[l,l '-biphenyl]-4-yl)carbonyl]-, (l ⁇ ,2 ⁇ ,5 ⁇ )-;
• Cyclopentanecarboxylic acid 2-[(4'-chloro[l,l'-biphenyl]-4-yl)carbonyl]- 5-[[(2-methoxyethoxy)methoxy]methyl]-, (l ⁇ ,2 ⁇ ,5 ⁇ )-;
• Cyclopentanecarboxylic acid 2-[(4'-chloro[l,l'-biphenyl]-4-yl)carbonyl]- 5-[[(phenylmethyl)thio]methyl]-, (l ⁇ ,2 ⁇ ,5 ⁇ )-;
• Cyclopentanecarboxylic acid 2-[(4'-chloro[l,l '-biphenyl]-4-yl)carbonyl]- 5-[(phenylthio)methyl]-, (l ⁇ ,2 ⁇ ,5 ⁇ )-;
• Cyclopentanecarboxylic acid 2-[(4'-chloro[l ,l '-biphenyl]-4-yl)carbonyl]- 5 - [(propylthio)methy 1] -, ( 1 ⁇ ,2 ⁇ ,5 ⁇ )- ;
• Benzoic acid 2-[[[2-carboxy-3-[(4'-chloro[l,l'-biphenyl]-4-yl)- carbonyl]cyclopentyl]methyl]thio]-, 1 -methyl ester, (l ⁇ ,2 ⁇ ,3 ⁇ )-;
• Cyclopentanecarboxylic acid 2-[(4'-chloro[ 1 , 1 '-biphenyl]-4-yl)carbonyl]- 5-[[[(phenylmethoxy)carbonyl]-amino]methyl]-, (l ⁇ ,2 ⁇ ,5 ⁇ )-;
• Cyclopentanecarboxylic acid 2-[(2-benzoxazolylthio)methyl]-5-[(4'- chloro[l,l '-biphenyl]-4-yl)carbonyl]-, (l ⁇ ,2 ⁇ ,5 ⁇ )-;
• Cyclopentanecarboxylic acid 2- [(4 ' -chloro [1,1 ' -biphenyl] -4-yl )carbonyl] - 5-[(l,3-dihydro-4-nitro-l,3-dioxo-2H-isoindol-2-yl)methyl]-, (l ⁇ ,2 ⁇ ,5 ⁇ )-;
• Cyclopentanecarboxylic acid 2-[(4'-chloro[l,l '-biphenyl]-4-yl)carbonyl]- 5-[(l,3-dihydro-5-nitro-l,3-dioxo-2H-isoindol-2-yl)methyl]-, (l ⁇ ,2 ⁇ ,5 ⁇ )-;
• Cyclopentanecarboxylic acid 2-[(4'-chloro[ 1 , 1 '-biphenyl]-4-yl)carbonyl]- 5-[(phenylmethyl)thio]-, (l ⁇ ,2 ⁇ ,5 ⁇ )-;
• Cyclopentanecarboxylic acid 2-[(4'-chloro[l,l '-biphenyl-4-yl)carbonyl]- 5-[(phenylmethyl)thio]-, (l ⁇ ,2 ⁇ ,5 ⁇ )-;
• [l,l '-Biphenyl]-4-butanoic acid 4'-nitro- ⁇ -oxo- ⁇ -(2-phenylethyl)-;
• [l,l '-Biphenyl]-4-butanoic acid 4'-cyano- ⁇ -oxo- ⁇ -(2-phenylethyl)-;
• [1,1 '-Biphenyl] -4-butanoic acid 4'-chloro- ⁇ -[2-(2-iodophenyl)ethyl]- ⁇ - oxo-;
• Fenbufen and compounds related to fenbufen can be utilized. Such compounds are described in United States Patent Number 3,784,701 and by Child, et al.. J. Pharm. Sci., 1977;66:466-476, and Arzneim-Forsch, 1980;30(4A):695- 702, all of which are inco ⁇ orated herein by reference. Preferred compounds from the fenbufen series to be utilized in this invention have the formula o O "R, where R is
• peptides are known matrix metalloproteinase inhibitors. Typical of such peptides are those described in United States Patent Number 5,300,501; 5,530,128; 5,455,258; 5,552,419; WO 95/13289; and WO 96/11209, all of which are inco ⁇ orated herein by reference. Such compounds are illustrated by the formula
• variable groups can include hydrogen alkyl, aryl, heteroaryl, alkenyl, alkynyl, carboxy, and the like.
• Preferred compounds from within this class which can be utilized in the method of this invention include the following:
• MMP matrix metalloproteinase
• Pal is 3-pyridylalanine
• N 2 "[(R or S)-[[(R)-(Amino)[(5-bromo-2,3-dihydro-6-hydroxy- 1 ,3-dioxo- lH-benz[d,e]isoquinol-2-yl)methyl](hydroxy)phosphinyl]methyl]-4- methylvaleryl]-N3 , 1 -dimethyl-L-valinamide hydrobromide;

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