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WO1999047138A1 - Associations statine-inhibiteur de metalloprotease matricielle - Google Patents

Associations statine-inhibiteur de metalloprotease matricielle Download PDF

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Publication number
WO1999047138A1
WO1999047138A1 PCT/US1998/024681 US9824681W WO9947138A1 WO 1999047138 A1 WO1999047138 A1 WO 1999047138A1 US 9824681 W US9824681 W US 9824681W WO 9947138 A1 WO9947138 A1 WO 9947138A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
methyl
phenyl
ethyl
oxo
Prior art date
Application number
PCT/US1998/024681
Other languages
English (en)
Inventor
Roger Schofield Newton
Bruce David Roth
Original Assignee
Warner-Lambert Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warner-Lambert Company filed Critical Warner-Lambert Company
Priority to JP2000536378A priority Critical patent/JP2002506818A/ja
Priority to EP98960279A priority patent/EP1063991A1/fr
Priority to NZ505994A priority patent/NZ505994A/xx
Priority to CA002309588A priority patent/CA2309588A1/fr
Priority to AU15916/99A priority patent/AU1591699A/en
Priority to KR1020007010223A priority patent/KR20010041916A/ko
Priority to BR9815745-0A priority patent/BR9815745A/pt
Publication of WO1999047138A1 publication Critical patent/WO1999047138A1/fr

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
    • A61K31/40—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

  • 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.
  • 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
  • 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
  • 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
  • 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.
  • 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[ 1 , 1 '-biphenyl]-4-yl)carbonyl]- 5-[[[(phenylmethoxy)carbonyl]-amino]methyl]-, (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 ⁇ )-;
  • 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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  • Health & Medical Sciences (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)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une composition pharmaceutique comprenant un inhibiteur de métalloprotéase matricielle et une statine, ladite composition servant à traiter des maladies vasculaires.
PCT/US1998/024681 1998-03-17 1998-11-20 Associations statine-inhibiteur de metalloprotease matricielle WO1999047138A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
JP2000536378A JP2002506818A (ja) 1998-03-17 1998-11-20 スタチン−マトリックスメタロプロテイナーゼ阻害剤組み合わせ物
EP98960279A EP1063991A1 (fr) 1998-03-17 1998-11-20 Associations statine-inhibiteur de metalloprotease matricielle
NZ505994A NZ505994A (en) 1998-03-17 1998-11-20 Statin-matrix metalloproteinase inhibitor combinations useful fro treating vascular diseases
CA002309588A CA2309588A1 (fr) 1998-03-17 1998-11-20 Associations statine-inhibiteur de metalloprotease matricielle
AU15916/99A AU1591699A (en) 1998-03-17 1998-11-20 Statin-matrix metalloproteinase inhibitor combinations
KR1020007010223A KR20010041916A (ko) 1998-03-17 1998-11-20 스타틴-매트릭스 메탈로프로테이나제 저해제 복합제제
BR9815745-0A BR9815745A (pt) 1998-03-17 1998-11-20 Combinações de inibidor de metaloproteinase de matriz estatina

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7826598P 1998-03-17 1998-03-17
US60/078,265 1998-03-17

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US09297592 A-371-Of-International 1999-05-03
US09/977,162 Continuation US20020049237A1 (en) 1998-03-17 2001-10-12 Statin-MMP inhibitor combinations

Publications (1)

Publication Number Publication Date
WO1999047138A1 true WO1999047138A1 (fr) 1999-09-23

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PCT/US1998/024681 WO1999047138A1 (fr) 1998-03-17 1998-11-20 Associations statine-inhibiteur de metalloprotease matricielle

Country Status (18)

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EP (1) EP1063991A1 (fr)
JP (1) JP2002506818A (fr)
KR (1) KR20010041916A (fr)
AR (1) AR018113A1 (fr)
AU (1) AU1591699A (fr)
BR (1) BR9815745A (fr)
CA (1) CA2309588A1 (fr)
CO (1) CO5070670A1 (fr)
GT (1) GT199900039A (fr)
HN (1) HN1999000029A (fr)
MY (1) MY140504A (fr)
NZ (1) NZ505994A (fr)
PA (1) PA8469001A1 (fr)
PE (1) PE20000348A1 (fr)
SV (1) SV1999000026A (fr)
UY (1) UY25436A1 (fr)
WO (1) WO1999047138A1 (fr)
ZA (1) ZA992106B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007054789A1 (fr) * 2005-11-08 2007-05-18 Ranbaxy Laboratories Limited Combinaison pharmaceutique
WO2010005389A1 (fr) * 2008-07-11 2010-01-14 Forskarpatent I Syd Ab Protéines conjuguées ou fusionnées à un anticorps spécifique des protéines ldl oxydées
US7816347B2 (en) 2004-12-15 2010-10-19 Solvay Pharmaceuticals Gmbh Pharmaceutical compositions comprising NEP-inhibitors, inhibitors of the endogenous endothelin producing system and HMG CoA reductase inhibitors
US8057814B2 (en) 2001-01-11 2011-11-15 Abbott Laboratories Drug delivery from stents

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997016184A1 (fr) * 1995-11-02 1997-05-09 Warner-Lambert Company Procede et composition pharmaceutique visant a reguler la concentration lipidique
WO1997044315A1 (fr) * 1996-05-17 1997-11-27 Warner-Lambert Company Inhibiteurs de metalloproteinase matricielle de biphenylsulfonamide
WO1998025597A2 (fr) * 1996-12-09 1998-06-18 Warner-Lambert Company Procede destine a traiter et a prevenir l'insuffisance cardiaque et la dilatation ventriculaire
WO1998033780A1 (fr) * 1997-01-30 1998-08-06 Bristol-Myers Squibb Company Antagonistes de l'endotheline: n-[[2'-[[4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-n,3,3-trimethylbutanamide et n-(4,5-dimethyl-3-isoxazolyl)-2'-[3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide et leurs sels
WO1999011260A1 (fr) * 1997-08-29 1999-03-11 Pfizer Inc. Therapie combinee utilisant de l'atorvastatine et un antihypertenseur

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997016184A1 (fr) * 1995-11-02 1997-05-09 Warner-Lambert Company Procede et composition pharmaceutique visant a reguler la concentration lipidique
WO1997044315A1 (fr) * 1996-05-17 1997-11-27 Warner-Lambert Company Inhibiteurs de metalloproteinase matricielle de biphenylsulfonamide
WO1998025597A2 (fr) * 1996-12-09 1998-06-18 Warner-Lambert Company Procede destine a traiter et a prevenir l'insuffisance cardiaque et la dilatation ventriculaire
WO1998033780A1 (fr) * 1997-01-30 1998-08-06 Bristol-Myers Squibb Company Antagonistes de l'endotheline: n-[[2'-[[4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-n,3,3-trimethylbutanamide et n-(4,5-dimethyl-3-isoxazolyl)-2'-[3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide et leurs sels
WO1999011260A1 (fr) * 1997-08-29 1999-03-11 Pfizer Inc. Therapie combinee utilisant de l'atorvastatine et un antihypertenseur

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Landmark study reveals aggressive cholesterol lowering with lipitor resulted in significant cardiovascular benefit", WWW.WARNER-LAMBERT.COM/INFO/PRESS_NOV_11_98.HTML, November 1998 (1998-11-01), pages 1 - 3, XP002102057 *
"LIPITOR (R). Atorvastatin Calcium", WWW.PARKE-DAVIS.COM/LIPITOR.HTM, 1998 - 1999, pages 1 - 13, XP002102056 *
PORTER KE ET AL: "Marimastat inhibits neointimal thickening in a model of human vein graft stenosis", BR J SURG, OCT 1998, 85 (10) P1373-7, ENGLAND, XP002102054 *
ZEMPO N ET AL: "Regulation of vascular smooth muscle cell migration and proliferation in vitro and in injured rat arteries by a synthetic matrix metalloproteinase inhibitor.", ARTERIOSCLER THROMB VASC BIOL, JAN 1996, 16 (1) P28-33, UNITED STATES, XP002102055 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8057814B2 (en) 2001-01-11 2011-11-15 Abbott Laboratories Drug delivery from stents
US8465758B2 (en) 2001-01-11 2013-06-18 Abbott Laboratories Drug delivery from stents
US7816347B2 (en) 2004-12-15 2010-10-19 Solvay Pharmaceuticals Gmbh Pharmaceutical compositions comprising NEP-inhibitors, inhibitors of the endogenous endothelin producing system and HMG CoA reductase inhibitors
WO2007054789A1 (fr) * 2005-11-08 2007-05-18 Ranbaxy Laboratories Limited Combinaison pharmaceutique
WO2010005389A1 (fr) * 2008-07-11 2010-01-14 Forskarpatent I Syd Ab Protéines conjuguées ou fusionnées à un anticorps spécifique des protéines ldl oxydées

Also Published As

Publication number Publication date
UY25436A1 (es) 2001-10-25
ZA992106B (en) 1999-09-30
PA8469001A1 (es) 2002-09-17
AU1591699A (en) 1999-10-11
MY140504A (en) 2009-12-31
CA2309588A1 (fr) 1999-09-23
GT199900039A (es) 2000-09-06
EP1063991A1 (fr) 2001-01-03
CO5070670A1 (es) 2001-08-28
SV1999000026A (es) 2000-01-18
NZ505994A (en) 2003-10-31
KR20010041916A (ko) 2001-05-25
JP2002506818A (ja) 2002-03-05
PE20000348A1 (es) 2000-05-22
BR9815745A (pt) 2000-11-14
AR018113A1 (es) 2001-10-31
HN1999000029A (es) 1999-09-29

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