WO2000004892A2 - Coadministration of acat and mmp inhibitors for the treatment of atherosclerotic lesions - Google Patents
Coadministration of acat and mmp inhibitors for the treatment of atherosclerotic lesions Download PDFInfo
- Publication number
- WO2000004892A2 WO2000004892A2 PCT/US1999/013948 US9913948W WO0004892A2 WO 2000004892 A2 WO2000004892 A2 WO 2000004892A2 US 9913948 W US9913948 W US 9913948W WO 0004892 A2 WO0004892 A2 WO 0004892A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- methyl
- phenyl
- biphenyl
- hydroxy
- Prior art date
Links
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
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Furan Compounds (AREA)
- Pyrane Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Indole Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Quinoline Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IL14098299A IL140982A0 (en) | 1998-07-21 | 1999-06-18 | Coadministration of acat and mmp inhibitors for the treatment of atherosclerotic lesions |
EP99930483A EP1098662A2 (en) | 1998-07-21 | 1999-06-18 | Coadministration of acat and mmp inhibitors for the treatment of atherosclerotic lesions |
PL99346011A PL346011A1 (en) | 1998-07-21 | 1999-06-18 | Coadministration of acat and mmp inhibitors for the treatment of atherosclerotic lesions |
CA002335062A CA2335062A1 (en) | 1998-07-21 | 1999-06-18 | Coadministration of acat and mmp inhibitors for the treatment of atherosclerotic lesions |
JP2000560885A JP2002521328A (ja) | 1998-07-21 | 1999-06-18 | アテローム性動脈硬化症病変の治療のためのacat阻害剤およびmmp阻害剤の併用投与 |
AU47017/99A AU4701799A (en) | 1998-07-21 | 1999-06-18 | Coadministration of ACAT and MMP inhibitors for the treatment of atherosclerotic lesions |
EA200100153A EA200100153A1 (ru) | 1998-07-21 | 1999-06-18 | Совместное назначение ингибиторов асат и ммр для лечения атеросклеротических поражений |
BR9912296-0A BR9912296A (pt) | 1998-07-21 | 1999-06-18 | Co-adminiostração de inibidores acat e mmp para o tratamento de lesões ateroscleróticas |
APAP/P/2001/002035A AP2001002035A0 (en) | 1998-07-21 | 1999-06-18 | Coadministration of ACAT and MMP inhibitors for the treatment of atherosclerotic lesions. |
EEP200100046A EE200100046A (et) | 1998-07-21 | 1999-06-18 | ACAT ja MMP inhibiitorite koosmanustamine aterosklerootiliste kahjustuste raviks |
KR1020017000930A KR20010083134A (ko) | 1998-07-21 | 1999-06-18 | 아테롬성 동맥경화증 병소의 치료를 위한 acat 및mmp 억제제의 병용 투여 |
SK50-2001A SK502001A3 (en) | 1998-07-21 | 1999-06-18 | Coadministration of acat and mmp inhibitors for the treatment of atherosclerotic lesions |
IS5809A IS5809A (is) | 1998-07-21 | 2001-01-12 | Samtíma inngjöf ACAT og MMP tálma til meðhöndlunar á skemmdum vegna fituhrörnunar |
BG105162A BG105162A (en) | 1998-07-21 | 2001-01-17 | Coadministration of acat and mmp inhibitors for the treatment of atherosclerotic lesions |
NO20010291A NO20010291L (no) | 1998-07-21 | 2001-01-18 | Coadministrasjon av ACAT og MMP inhibitorer for behandling av aterosklerotiske sår |
HR20010055A HRP20010055A2 (en) | 1998-07-21 | 2001-01-19 | Coadministration of acat and mmp inhibitors for the treatment of atherosclerotic lesions |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US9363998P | 1998-07-21 | 1998-07-21 | |
US60/093,639 | 1998-07-21 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2000004892A2 true WO2000004892A2 (en) | 2000-02-03 |
WO2000004892A3 WO2000004892A3 (en) | 2000-05-18 |
Family
ID=22239992
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/013948 WO2000004892A2 (en) | 1998-07-21 | 1999-06-18 | Coadministration of acat and mmp inhibitors for the treatment of atherosclerotic lesions |
Country Status (25)
Country | Link |
---|---|
EP (1) | EP1098662A2 (id) |
JP (1) | JP2002521328A (id) |
KR (1) | KR20010083134A (id) |
CN (1) | CN1310629A (id) |
AP (1) | AP2001002035A0 (id) |
AU (1) | AU4701799A (id) |
BG (1) | BG105162A (id) |
BR (1) | BR9912296A (id) |
CA (1) | CA2335062A1 (id) |
CZ (1) | CZ2001126A3 (id) |
EA (1) | EA200100153A1 (id) |
EE (1) | EE200100046A (id) |
HR (1) | HRP20010055A2 (id) |
HU (1) | HUP0102880A3 (id) |
ID (1) | ID30030A (id) |
IL (1) | IL140982A0 (id) |
IS (1) | IS5809A (id) |
NO (1) | NO20010291L (id) |
OA (1) | OA11584A (id) |
PL (1) | PL346011A1 (id) |
SK (1) | SK502001A3 (id) |
TR (1) | TR200100205T2 (id) |
WO (1) | WO2000004892A2 (id) |
YU (1) | YU3501A (id) |
ZA (1) | ZA200100294B (id) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001034127A1 (en) * | 1999-11-05 | 2001-05-17 | Warner-Lambert Company | Prevention of plaque rupture by acat inhibitors |
WO2001044179A1 (en) * | 1999-12-17 | 2001-06-21 | Versicor, Inc. | Novel succinate compounds, compositions and methods of use and preparation |
US6544987B2 (en) | 1999-12-01 | 2003-04-08 | Pfizer Inc. | Compounds, compositions, and methods for stimulating neuronal growth and elongation |
EP1314423A1 (en) * | 2000-09-01 | 2003-05-28 | Sankyo Company, Limited | Medicinal compositions |
WO2004007444A3 (en) * | 2002-07-11 | 2004-09-10 | Vicuron Pharm Inc | N-hydroxyamide derivatives possessing antibacterial activity |
JP2005527556A (ja) * | 2002-04-03 | 2005-09-15 | トポターゲット ユーケー リミテッド | Hdac阻害剤としてのピペラジン結合を有するカルバミン酸化合物 |
WO2011092284A1 (en) * | 2010-01-29 | 2011-08-04 | Euroscreen S.A. | Novel amino acid derivatives and their use as gpr43 receptor modulators |
US8057814B2 (en) | 2001-01-11 | 2011-11-15 | Abbott Laboratories | Drug delivery from stents |
WO2016113713A1 (en) * | 2015-01-15 | 2016-07-21 | Biocant - Associação De Transferência De Tecnologia | Treatment of hutchinson-gilford progeria syndrome and diseases related to vascular ageing |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104211695B (zh) * | 2013-06-04 | 2017-04-12 | 中国医学科学院医药生物技术研究所 | 一组胺甲酰基苯磺酰类化合物的用途 |
CN106831697B (zh) * | 2017-03-15 | 2019-11-05 | 深圳市康道生物有限公司 | 川榛有效提取成分及其在防治动脉粥样硬化中的应用 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994019330A1 (en) * | 1993-02-18 | 1994-09-01 | Warner-Lambert Company | Heterocyclic-substituted alkyl amide acat inhibitors |
US5491172A (en) * | 1993-05-14 | 1996-02-13 | Warner-Lambert Company | N-acyl sulfamic acid esters (or thioesters), N-acyl sulfonamides, and N-sulfonyl carbamic acid esters (or thioesters) as hypercholesterolemic agents |
WO1997005868A1 (en) * | 1995-08-04 | 1997-02-20 | Warner-Lambert Company | Use of sulfamic acid derivatives, acyl sulfonamides or sulfonyl carbamates for the manufacture of a medicament for lowering lipoprotein levels |
WO1997044315A1 (en) * | 1996-05-17 | 1997-11-27 | Warner-Lambert Company | Biphenylsulfonamide matrix metalloproteinase inhibitors |
WO1998009934A1 (en) * | 1996-09-04 | 1998-03-12 | Warner-Lambert Company | Matrix metalloproteinase inhibitors and their therapeutic uses |
-
1999
- 1999-06-18 CN CN99808958A patent/CN1310629A/zh active Pending
- 1999-06-18 CZ CZ2001126A patent/CZ2001126A3/cs unknown
- 1999-06-18 SK SK50-2001A patent/SK502001A3/sk unknown
- 1999-06-18 EA EA200100153A patent/EA200100153A1/ru unknown
- 1999-06-18 WO PCT/US1999/013948 patent/WO2000004892A2/en not_active Application Discontinuation
- 1999-06-18 AU AU47017/99A patent/AU4701799A/en not_active Abandoned
- 1999-06-18 IL IL14098299A patent/IL140982A0/xx unknown
- 1999-06-18 EE EEP200100046A patent/EE200100046A/xx unknown
- 1999-06-18 PL PL99346011A patent/PL346011A1/xx unknown
- 1999-06-18 ID IDW20010333A patent/ID30030A/id unknown
- 1999-06-18 OA OA1200100022A patent/OA11584A/en unknown
- 1999-06-18 EP EP99930483A patent/EP1098662A2/en not_active Withdrawn
- 1999-06-18 TR TR2001/00205T patent/TR200100205T2/xx unknown
- 1999-06-18 KR KR1020017000930A patent/KR20010083134A/ko not_active Application Discontinuation
- 1999-06-18 AP APAP/P/2001/002035A patent/AP2001002035A0/en unknown
- 1999-06-18 JP JP2000560885A patent/JP2002521328A/ja active Pending
- 1999-06-18 CA CA002335062A patent/CA2335062A1/en not_active Abandoned
- 1999-06-18 BR BR9912296-0A patent/BR9912296A/pt not_active IP Right Cessation
- 1999-06-18 YU YU3501A patent/YU3501A/sh unknown
- 1999-06-18 HU HU0102880A patent/HUP0102880A3/hu unknown
-
2001
- 2001-01-10 ZA ZA200100294A patent/ZA200100294B/en unknown
- 2001-01-12 IS IS5809A patent/IS5809A/is unknown
- 2001-01-17 BG BG105162A patent/BG105162A/xx unknown
- 2001-01-18 NO NO20010291A patent/NO20010291L/no not_active Application Discontinuation
- 2001-01-19 HR HR20010055A patent/HRP20010055A2/hr not_active Application Discontinuation
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994019330A1 (en) * | 1993-02-18 | 1994-09-01 | Warner-Lambert Company | Heterocyclic-substituted alkyl amide acat inhibitors |
US5491172A (en) * | 1993-05-14 | 1996-02-13 | Warner-Lambert Company | N-acyl sulfamic acid esters (or thioesters), N-acyl sulfonamides, and N-sulfonyl carbamic acid esters (or thioesters) as hypercholesterolemic agents |
WO1997005868A1 (en) * | 1995-08-04 | 1997-02-20 | Warner-Lambert Company | Use of sulfamic acid derivatives, acyl sulfonamides or sulfonyl carbamates for the manufacture of a medicament for lowering lipoprotein levels |
WO1997044315A1 (en) * | 1996-05-17 | 1997-11-27 | Warner-Lambert Company | Biphenylsulfonamide matrix metalloproteinase inhibitors |
WO1998009934A1 (en) * | 1996-09-04 | 1998-03-12 | Warner-Lambert Company | Matrix metalloproteinase inhibitors and their therapeutic uses |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001034127A1 (en) * | 1999-11-05 | 2001-05-17 | Warner-Lambert Company | Prevention of plaque rupture by acat inhibitors |
US6544987B2 (en) | 1999-12-01 | 2003-04-08 | Pfizer Inc. | Compounds, compositions, and methods for stimulating neuronal growth and elongation |
WO2001044179A1 (en) * | 1999-12-17 | 2001-06-21 | Versicor, Inc. | Novel succinate compounds, compositions and methods of use and preparation |
EP1314423A1 (en) * | 2000-09-01 | 2003-05-28 | Sankyo Company, Limited | Medicinal compositions |
EP1314423A4 (en) * | 2000-09-01 | 2004-05-19 | Sankyo Co | MEDICAL CONNECTIONS |
US8057814B2 (en) | 2001-01-11 | 2011-11-15 | Abbott Laboratories | Drug delivery from stents |
JP2005527556A (ja) * | 2002-04-03 | 2005-09-15 | トポターゲット ユーケー リミテッド | Hdac阻害剤としてのピペラジン結合を有するカルバミン酸化合物 |
WO2004007444A3 (en) * | 2002-07-11 | 2004-09-10 | Vicuron Pharm Inc | N-hydroxyamide derivatives possessing antibacterial activity |
AU2003267991B2 (en) * | 2002-07-11 | 2009-10-08 | Vicuron Pharmaceuticals, Inc. | N-hydroxyamide derivatives possessing antibacterial activity |
WO2011092284A1 (en) * | 2010-01-29 | 2011-08-04 | Euroscreen S.A. | Novel amino acid derivatives and their use as gpr43 receptor modulators |
WO2016113713A1 (en) * | 2015-01-15 | 2016-07-21 | Biocant - Associação De Transferência De Tecnologia | Treatment of hutchinson-gilford progeria syndrome and diseases related to vascular ageing |
Also Published As
Publication number | Publication date |
---|---|
ID30030A (id) | 2001-11-01 |
TR200100205T2 (tr) | 2001-05-21 |
HUP0102880A2 (en) | 2002-06-29 |
HUP0102880A3 (en) | 2002-11-28 |
CA2335062A1 (en) | 2000-02-03 |
IL140982A0 (en) | 2002-02-10 |
JP2002521328A (ja) | 2002-07-16 |
NO20010291D0 (no) | 2001-01-18 |
IS5809A (is) | 2001-01-12 |
PL346011A1 (en) | 2002-01-14 |
KR20010083134A (ko) | 2001-08-31 |
NO20010291L (no) | 2001-01-18 |
EE200100046A (et) | 2002-06-17 |
AU4701799A (en) | 2000-02-14 |
HRP20010055A2 (en) | 2002-04-30 |
WO2000004892A3 (en) | 2000-05-18 |
BG105162A (en) | 2001-12-29 |
AP2001002035A0 (en) | 2001-03-31 |
CN1310629A (zh) | 2001-08-29 |
CZ2001126A3 (cs) | 2002-01-16 |
EP1098662A2 (en) | 2001-05-16 |
EA200100153A1 (ru) | 2001-08-27 |
YU3501A (sh) | 2005-06-10 |
ZA200100294B (en) | 2002-01-10 |
OA11584A (en) | 2004-07-20 |
SK502001A3 (en) | 2002-06-04 |
BR9912296A (pt) | 2001-04-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5948780A (en) | Method for treating and preventing heart failure and ventricular dilatation | |
EP1047450B1 (en) | Ace inhibitor-mmp inhibitor combinations | |
AU737117B2 (en) | Use of matrix metalloproteinase inhibitors for treating neurological disorders and promoting wound healing | |
WO2000004892A2 (en) | Coadministration of acat and mmp inhibitors for the treatment of atherosclerotic lesions | |
US20020049237A1 (en) | Statin-MMP inhibitor combinations | |
KR20010041916A (ko) | 스타틴-매트릭스 메탈로프로테이나제 저해제 복합제제 | |
US20050020607A1 (en) | Statin-MMP inhibitor combinations | |
MXPA01000780A (en) | Coadministration of acat and mmp inhibitors for the treatment of atherosclerotic lesions | |
EP1366765A1 (en) | Use of matrix metalloproteinase inhibitors for treating neurological disorders and promoting wound healing | |
MXPA00003736A (en) | Ace inhibitor-mmp inhibitor combinations | |
MXPA99002254A (en) | Use of matrix metalloproteinase inhibitors for treating neurological disorders and promoting wound healing | |
AU2003248291A1 (en) | Statin-matrix metalloproteinase inhibitor combinations |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: P-35/01 Country of ref document: YU Ref document number: 99808958.3 Country of ref document: CN |
|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AL AU BA BB BG BR CA CN CU CZ EE GD GE HR HU ID IL IN IS JP KP KR LC LK LR LT LV MG MK MN MX NO NZ PL RO SG SI SK SL TR TT UA US UZ VN YU ZA |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
AK | Designated states |
Kind code of ref document: A3 Designated state(s): AE AL AU BA BB BG BR CA CN CU CZ EE GD GE HR HU ID IL IN IS JP KP KR LC LK LR LT LV MG MK MN MX NO NZ PL RO SG SI SK SL TR TT UA US UZ VN YU ZA |
|
AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
ENP | Entry into the national phase |
Ref document number: 2335062 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: IN/PCT/2001/00019/MU Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 47017/99 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1200100030 Country of ref document: VN |
|
WWE | Wipo information: entry into national phase |
Ref document number: PV2001-126 Country of ref document: CZ Ref document number: 2001/00294 Country of ref document: ZA Ref document number: 200100294 Country of ref document: ZA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 502001 Country of ref document: SK Ref document number: 1999930483 Country of ref document: EP Ref document number: 509358 Country of ref document: NZ |
|
ENP | Entry into the national phase |
Ref document number: 1999 105162 Country of ref document: BG Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 140982 Country of ref document: IL Ref document number: 2001/00205 Country of ref document: TR |
|
ENP | Entry into the national phase |
Ref document number: 2000 560885 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: P20010055A Country of ref document: HR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020017000930 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2001/000780 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 200100153 Country of ref document: EA |
|
ENP | Entry into the national phase |
Ref document number: 20010138 Country of ref document: UZ Kind code of ref document: A |
|
WWP | Wipo information: published in national office |
Ref document number: 1999930483 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1020017000930 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 09744185 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: PV2001-126 Country of ref document: CZ |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1999930483 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1020017000930 Country of ref document: KR |