Classifications

• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • 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

• Enzymes known as native matrix metalloproteinases 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. These enzymes are implicated in a number of diseases which result from breakdown of connective tissues, such as rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, and even tumor metastasis.
• MMP native matrix metalloproteinases
• Patent 5,756,545 covers MMP inhibitors especially 2-(4'-Bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid. This patent is hereby inco ⁇ orated by reference.
• Patent 5,441,975 teaches ACAT inhibitors, especially N-(2,6-Diisopropyl-phenyl)-2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl-acetamide.
• ACAT inhibitors especially N-(2,6-Diisopropyl-phenyl)-2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl-acetamide.
• This and other patents in the same patent family: 5,646,170; 5,693,657; and 5,366,987 are hereby inco ⁇ orated by reference.
• the instant invention is the coadministration of ACAT and MMP inhibitors for the reduction of both macrophage and smooth muscle cell components of atherosclerotic lesions in a mammal, particularly a human.
• the lesions are directly reduced, and so, the expansion of existing lesions and the development of new ones is impaired.
• Certain ACAT inhibitors and certain MMP inhibitors are disclosed as suitable for coadministration.
• compositions of the inhibitors are also included in the invention.
• ACAT inhibitors have been shown to reduce the accumulation of monocyte-macrophages within atherosclerotic lesions of rabbits.
• monocyte-macrophages have been reported to secrete such matrix metalloproteinases as MMP-7 and -9 while smooth muscle cells are noted to secrete MMP-1, -2, and -3.
• Inhibition of ACAT while directly reducing the accumulation of lipid-filled monocyte-macrophages will decrease the source of MMPs.
• MMP-7 Inhibition of MMPs will also limit the development of atherosclerotic lesions through reducing smooth muscle cell and monocyte migration into the development intima by limiting extracellular matrix remodeling.
• Coadministration of both agents will limit the development of new lesions by inhibiting cellular accumulation and stabilize the developed lesions by preventing both matrix remodeling and reducing the number of lipid-filled monocyte-macrophages, a source of MMP-7 and -9.
• the instant invention is a method for treating and/or preventing atherosclerotic lesions comprising coadministrating one or more MMP inhibitors and one or more ACAT inhibitors.
• the invention is further a method for preventing plaque rupture and for promoting lesion regression by administering a combination of an ACAT inhibitor and an MMP inhibitor.
• the method is practiced by administering a chemical compound 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.
• the numerous compounds known to be matrix metalloproteinase inhibitors are useful in the practice of this invention.
• the method is practiced by administering a chemical compound which inhibits the enzyme acyl-coenzyme A. holesterol acyltransferase.
• ACAT inhibitors are useful in the practice of this 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 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 United States Patent Application 339846 filed November 15, 1994, 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:
• [1,1 '-Biphenyl]-4-butanoic acid 4'-ethyl- ⁇ -(2-methylpropyl)- ⁇ -oxo-;
• [1,1 '-Biphenyl]-4-butanoic acid 2'-fluoro- -(2-methylpropyl)- ⁇ -oxo-;
• [1,1 '-Biphenyl]-4-butanoic acid 4 -methyl- ⁇ -(2-methylpropyl)- ⁇ -oxo-;
• [1,1 '-Biphenyl]-4-butanoic acid cx-(2-methyl-propyl)- ⁇ -oxo-4'-pentyl-;
• 2-Furancarboxylic acid 5-[4-(3-carboxy- 1 -oxo-6-phenylhexyl)phenyl]-; Benzenepentanoic acid, ⁇ - [2-oxo-2- [4-(3 -pyridinyl)phenyl] ethyl] -; Benzenepentanoic acid, ⁇ -[2-oxo-2-[4-[6-(pentyloxy)-3-pyridinyl]- phenyl] ethyl]-; [l,l'-Biphenyl]-4-butanoic acid, ⁇ -oxo-4'-(pentylthio)- ⁇ -(3- phenylpropyl) ;
• [1,1 '-Biphenyl]-4-butanoic acid 4'-methoxy- ⁇ -oxo- ⁇ -(3-phenylpropyl)-;
• [l,l'-Biphenyl]-4-butanoic acid 3'-chloro-4'-fluoro- ⁇ -oxo- ⁇ -(3- phenylpropyl)-;
• Benzenepentanoic acid ⁇ -[2-oxo-2-[4-(3-thienyl)phenyl]ethyl]-; [1,1 '-Biphenyl] -4-butanoic acid, 2',4'-dichloro- ⁇ -oxo- ⁇ -(3 -phenylpropyl)-; [1,1 '-Biphenyl] -4-butanoic acid, 4'-formyl- ⁇ -oxo- ⁇ -(3-phenylpropyl)-; [1,1 '-Biphenyl] -4-butanoic acid, ⁇ -oxo- ⁇ -(3-phenylpropyl)-3',5'- bis(trifluoromethyl)-;
• [1,1 '-Biphenyl] -4-butanoic acid 2'-formyl- ⁇ -oxo- ⁇ -(3-phenylpropyl)-;
• [1,1 '-Biphenyl]-4-butanoic acid 4-hydroxy- ⁇ -oxo- -(3-phenylpropyl)-;
• [1,1 '-Biphenyl] -4-butanoic acid ⁇ -oxo- ⁇ -(3-phenylpropyl)-4'-propoxy-
• [l ,l'-Biphenyl]-4-butanoic acid ⁇ -oxo-4'-(pentyloxy)- ⁇ -(3- phenylpropyl)-;
• [1,1 '-Biphenyl] -4-butanoic acid ⁇ -oxo-4'-(pentyloxy)- ⁇ -(3- phenylpropyl)-, (S)-;
• [l,l'-Biphenyl] -4-butanoic acid ⁇ -oxo-4'-(pentyloxy)- ⁇ -(3- phenylpropyl)-, (R)-;
• [1,1 '-Biphenyl] -4-butanoic acid 4'-(hexyloxy)- ⁇ -oxo- ⁇ -(3-phenylpropyl)-;
• [1,1 '-Biphenyl] -4-butanoic acid 4'-butoxy- ⁇ -oxo- ⁇ -(3-phenylpropyl)-;
• [1,1 '-Biphenyl]-4-butanoic acid 4'-chloro- ⁇ -[2-(3-iodophenyl)ethyl]- ⁇ -oxo-;
• [1,1 '-Biphenyl]-4-butanoic acid 4'-chloro- ⁇ -[2-(4-iodophenyl)ethyl]- ⁇ -oxo-;
• [1,1 '-Biphenyl]-4-butanoic acid 4'-bromo- ⁇ -oxo- ⁇ -(3-phenylpropyl)-; [l,l'-Biphenyl]-4-butanoic acid, - ⁇ -oxo- ⁇ -(3 -phenylpropyl)-; [1,1 '-Biphenyl]-4-butanoic acid, 4'-amino- ⁇ -oxo- ⁇ -(2-phenylethyl)-;
• [1,1 '-Biphenyl] -4-butanoic acid 4'-[[(l,l-dimethylethoxy)- carbonyl]amino]- ⁇ -oxo- ⁇ -(2-phenylethyl)-; [1,1 '-Biphenyl]-4-butanoic acid, 4'-(acetylamino) ⁇ -oxo- ⁇ -
• [1,1 '-Biphenyl] -4-butanoic acid ⁇ -[2-(2-carboxyphenyl)ethyl]-4'-chloro- ⁇ -oxo-;
• [1 ,1 '-Biphenyl] -4-butanoic acid 4'-chloro- ⁇ -[2-[2-[(diethylamino)- carbonyl]phenyl]ethyl]- ⁇ -oxo-;
• Cyclopentanecarboxylic acid 2-[(4'-chloro[ 1 , 1 '-biphenyl] -4-yl)carbonyl]- 5- [(phenylmethoxy)methyl] -, ( 1 ,2 ⁇ ,5 ⁇ )-;
• Cyclopentanecarboxylic acid 2-[(4'-chloro[ 1 , 1 '-biphenyl] -4-yl)carbonyl]- 5-(phenoxymethyl)-, (l ,2 ⁇ ,5 ⁇ )-; Cyclopentanecarboxylic acid, 2-[(benzoyloxy)-methyl]-5-[(4'-chloro[l,l'- bi ⁇ henyl]-4-yl)carbonyl]-, (1 ⁇ ,2 ⁇ ,5 ⁇ )-; 1 ,2-Benzenedicarboxylic acid, 1 -[[2-carboxy-3-[(4'-chloro[ 1 , 1 '-biphenyl]- 4-yl)carbonyl]cyclopentyl]-methyl]-2-methyl ester,( 1 ⁇ ,2 ⁇ ,3 ⁇ )-;
• Cyclopentanecarboxylic acid 2-[(4'-chloro[ 1 , 1 '-biphenyl] -4-yl)carbonyl]- 5-[(2-thienylthio)methyl]-, (l ⁇ ,2 ⁇ ,5 ⁇ )-; Cyclopentanecarboxylic acid, 2-[(benzoylamino)methyl]-5-[(4'- chloro[ 1 , 1 '-biphenyl]-4-yl)carbonyl]-, (1 ⁇ ,2 ⁇ ,5 ⁇ )-;
• Cyclopentanecarboxylic acid 2-[(4'-chloro[ 1 , 1 '-biphenyl]-4-yl)carbonyl]- 5 - [ [(2-methoxyethoxy)methoxy] methyl] -, (l ⁇ ,2 ⁇ ,5 ⁇ )-;
• Cyclopentanecarboxylic acid 2-[(4'-chloro[ 1 , 1 '-biphenyl]-4-yl)carbonyl]- 5-[[(phenylmethyl)thio]methyl]-, (l ⁇ ,2 ⁇ ,5 ⁇ )-;
• Cyclopentanecarboxylic acid 2-[(4'-chloro[ 1 , 1 '-biphenyl]-4-yl)carbonyl]- 5-[(phenylthio)methyl]-, (loc,2 ⁇ ,5 ⁇ )-;
• Cyclopentanecarboxylic acid 2-[(4'-chloro[l , l'-biphenyl]-4-yl)carbonyl]- 5-[(propylthio)methyl]-, (l ⁇ ,2 ⁇ ,5 ⁇ )-; Cyclopentanecarboxylic acid, 2-[(2-benzothiazolylthio)methyl]-5-[(4'- chloro[l,l'-biphenyl]-4-yl)carbonyl]-, (l ,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 ⁇ )-;
• Benzoic acid 3-methyl-, [2-carboxy-3-[(4'-chloro[l,l'-biphenyl]- 4-yl)carbonyl]cyclopentyl]rnethyl ester, (l ⁇ ,2 ⁇ ,3 ⁇ )-; Benzoic acid, 4-methyl-, [2-carboxy-3-[(4'-chloro[ 1 , 1 '-biphenyl]-
• Benzoic acid 3-methoxy-, [2-carboxy-3-[(4'-chloro [1,1 '-biphenyl] - 4-yl)carbonyl]cyclopentyl]methyl ester, (l ⁇ ,2 ⁇ ,3 ⁇ )-;
• 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]-
• Cyclopentanecarboxylic acid 2-[(4'-chloro[ 1 , 1 '-biphenyl]-4-yl)carbonyl]- 5-[(l,3-dihydro-5-nitro-l,3-dioxo-2H-isoindol-2-yl)methyl]-, (l ⁇ ,2 ⁇ ,5 ⁇ )-;
• [1,1 '-Biphenyl] -4-butanoic acid -(acetylamino)-4'-chloro- ⁇ -oxo-; 2/ -Isoindole-2-hexanoic acid, -[2-(4'-chloro[ 1 , 1 '-biphenyl] -4-yl)- 2 -oxoethyl] -1,3 -dihydro- 1 ,3 -dioxo- ;
• [1,1 '-Biphenyl]-4-butanoic acid 4'-chloro- ⁇ -[2-[3-[(diethylamino)- carbonyl]phenyl] ethyl] - ⁇ -oxo- ;
• [1,1 '-Biphenyl] -4-butanoic acid ⁇ -[2-[3-[(butylamino)carbonyl]- phenyl]ethyl]-4'-chloro- ⁇ -oxo-;
• [1,1 '-Biphenyl]-4-butanoic acid 4'-methoxy- ⁇ -oxo- ⁇ -(2-phenyl ethyl)-; [1,1 '-Biphenyl]-4-butanoic acid, 4'-hydroxy- ⁇ -oxo- ⁇ -(2-phenylethyl)-; [1,1 '-Biphenyl]-4-butanoic acid, 4'-ethoxy- ⁇ -oxo- ⁇ -(2-phenylethyl)-;
• [1,1 '-Biphenyl] -4-butanoic acid ⁇ -oxo- ⁇ -(2-phenylethyl)-4'-propoxy-; [1,1 '-Biphenyl] -4-butanoic acid, ⁇ -oxo-4'-(pentyloxy)- ⁇ -(2-phenylethyl)-; [1,1 '-Biphenyl]-4-butanoic acid, 4'-(hexyloxy)- ⁇ -oxo- ⁇ -(2-phenylethyl)-; [1,1 '-Biphenyl]-4-butanoic acid, 4'-butoxy- ⁇ -oxo- -(2-phenylethyl)-; [1,1 '-Biphenyl] -4-butanoic acid, ⁇ -oxo- ⁇ -(2-phenylethyl)-4'-
• [1,1 '-Biphenyl] -4-butanoic acid -[2-(3-iodophenyl)ethyl]- ⁇ -oxo-4'- (phenylmethoxy)-;
• [1,1 '-Biphenyl] -4-butanoic acid ⁇ -[2-(3-[(diethylamino)carbonyl]- phenyl]ethyl]- ⁇ -oxo-4'-(pentyloxy)-;
• [1,1 '-Biphenyl] -4-butanoic acid 4'-chloro- ⁇ -heptyl- ⁇ -oxo-; [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro- -decyl - ⁇ -oxo-; [1,1 '-Biphenyl]-4-butanoic acid, 4'-nitro- ⁇ -oxo- -(2-phenyl ethyl)-; [1,1 '-Biphenyl] -4-butanoic acid, 4'-cyano- ⁇ -oxo- ⁇ -(2-phenylethyl)-; [1,1 '-Biphenyl] -4-butanoic acid, 4'-chloro- ⁇ -[2-(2-iodophenyl)ethyl]- ⁇ - oxo-;
• [l,l'-Biphenyl]-4-butanoic acid 4'-chloro- ⁇ -oxo- -phenyl-; [1,1 '-Biphenyl]-4-butanoic acid, 4'-chloro- ⁇ -oxo- ⁇ -(phenylmethyl)-; [1,1 '-Biphenyl] -4-butanoic acid, 4'-chloro- ⁇ -oxo- ⁇ -(2-phenylethyl)-;
• [1,1 '-Biphenyl]-4-butanoic acid 4'-bromo- ⁇ -oxo- ⁇ -(3-phenylpropyl)-; [1,1 '-Biphenyl] -4-butanoic acid, ⁇ -oxo- ⁇ -(3-phenylpropyl)-; [1,1 '-Biphenyl]-4-butanoic acid, 4'-amino- ⁇ -oxo- ⁇ -(2-phenylethyl)-;
• [1 ,1 '-Biphenyl] -4-butanoic acid 4'-[[(l,l-dimethylethoxy)- carbonyl]amino]- ⁇ -oxo- ⁇ -(2-phenylethyl)-; [1,1 '-Biphenyl] -4-butanoic acid, 4'-(acetylamino)- ⁇ -oxo- ⁇ -
• [1,1 '-Biphenyl]-4-butanoic acid ⁇ -[2-(2-carboxyphenyl)ethyl]-4'-chloro- ⁇ -oxo-;
• [1,1 '-Biphenyl]-4-butanoic acid 4'-chloro- ⁇ -[2-[2-[(diethylamino)- carbonyl)phenyl] ethyl] - ⁇ -oxo- ;
• 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 96/1 1209, 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: N- [2 ,3 -bis- Acetylmercaptopropanoyl] -L-leucyl-L-pheny lalanine N-methylamide;
• N-(Acetylmercaptoacyl)-L-leucyl-L-tryptophan methylamide (RS)-2-Mercaptopentanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-Mercaptopropanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-Mercapto-3-methylbutanoyl-L-leucyl-L-phenylalanine N-methylamide;
• N-phenylamide N-[l(R)-Carboxy-ethyl]- ⁇ -(S)-(2-phenyl-ethyl)glycine-(L)-phenylalanine, N-phenylamide;
• N-phenylamide (2-((Hydroxy(methyl)phosphinyl)methyl)-4-phenylbutanoyl)-L-leucine, N-phenylamide;
• 1,5-pentanedioic acid 1 -(L-leucine, N-phenylamide)amide
• 1,5-pentanedioic acid 1 -(L-leucine, N-phenylamide)amide
• inhibitors of matrix metalloproteinases are known.
• a large number of inhibitors are characterized as hydroxamic acid-based and/or carboxylic acid-based compounds. Typical of such compounds are those described in the following references, all of which are inco ⁇ orated herein by reference, since all of the disclosed compounds can be used in the method of this invention.
• aryl sulfonamides of the formula where Ar is carbocyclic or heterocyclic aryl, and R, Rl, and R 2 include hydrogen, alkyl, aryl, heteroaryl, amino, substituted and disubstituted amino. These compounds are disclosed in European Patent Number 0606046, inco ⁇ orated herein by reference. Specific compounds to be employed in the present method include:
• Rl, R 2 , R- , and R 4 can be hydrogen or alkyl and X is OR ⁇ or NHR5 where R ⁇ includes hydrogen, alkyl and aryl, A includes alkyl, and n is
• Typical compounds to be employed in the instant method include the following:
• tricyclic butyric acid derivatives which are inhibitors of matrix metalloprotienases are employed in the instant invention.
• a preferred group of tricyclic butyric acid derivatives are defined by the formula:
• n is zero or an integer of 1 to 5, alkyl, or -(CH 2 ) n -cycloalkyl wherein n is as defined above, or N-N-R ⁇ wherein R6 and R ⁇ a are each the same or different and
• R6a each is as defined above for R ⁇ ; R and R a are each the same or different and each is hydrogen,
• n is as defined above
• n is as defined above
• R 7 is O or S and p or q is each zero or an integer of 1 to 5 and the sum of p + q equals an integer of 5, -(CH 2 )p-R ⁇ "(CH 2 )q-heteroaryl wherein p, q, and R 7 are as defined above, alkyl, -(CH ) n -cycloalkyl wherein n is as defined above, or
• r is an integer of 1 to 9; a is zero or an integer of 1 to 3; R 5 is OH,
• R 6a the same or different and are as defined above for R ⁇ , or
• R3 and R 4 are each the same or different and each is hydrogen, alkyl,
• R ⁇ and R ⁇ are each the same or
• R 6a different and are as defined above for R ⁇ , or -(CH 2 ) n -N-R 6 wherein R 6 and ROa are each the same or
• R 6a different and are as defined above for R ⁇ ;
• W, Wl, Z, and Z ⁇ are each the same or different and each is CR- wherein R 3 is as defined above, or

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