[go: up one dir, main page]

WO2012014114A1 - Inhibiteurs de métalloprotéinase de matrice - Google Patents

Inhibiteurs de métalloprotéinase de matrice Download PDF

Info

Publication number
WO2012014114A1
WO2012014114A1 PCT/IB2011/053155 IB2011053155W WO2012014114A1 WO 2012014114 A1 WO2012014114 A1 WO 2012014114A1 IB 2011053155 W IB2011053155 W IB 2011053155W WO 2012014114 A1 WO2012014114 A1 WO 2012014114A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
phenyl
oxo
hydroxy
methyl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2011/053155
Other languages
English (en)
Inventor
Manoj Kumar Khera
Jitendra Sattigeri
Viswajanani Sattigeri
Neeraj Kumar Yadav
Kewal Kumar
Abdul Rehman Abdul Rauf
Ian A. Cliffe
Pradip Kumar Bhatnagar
Abhijit Ray
Punit Srivastava
Sunanda Ghosh Dastidar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
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 Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Priority to CN2011800461515A priority Critical patent/CN103119030A/zh
Priority to AU2011284397A priority patent/AU2011284397A1/en
Priority to JP2013522322A priority patent/JP2013537533A/ja
Priority to EP11763767.8A priority patent/EP2598493A1/fr
Priority to PH1/2013/500198A priority patent/PH12013500198A1/en
Priority to BR112013002370A priority patent/BR112013002370A2/pt
Priority to KR1020137005055A priority patent/KR20130042590A/ko
Priority to MX2013001240A priority patent/MX2013001240A/es
Priority to CA2807097A priority patent/CA2807097A1/fr
Priority to SG2013007448A priority patent/SG187654A1/en
Publication of WO2012014114A1 publication Critical patent/WO2012014114A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/08—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 condensed with carbocyclic rings or ring systems
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to certain hydroxy propionic acid derivatives and the processes for the synthesis of the same.
  • This invention also relates to pharmacological compositions containing the compounds of the present invention, and methods of treating asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis, pulmonary inflammation, acute respiratory distress syndrome, perodontitis, multiple sclerosis, gingivitis, atherosclerosis, dry eye, neointimal
  • MMPs Metalloproteinases
  • Enzymes a naturally occurring superfamily of proteinases (enzymes) found in most mammals.
  • the superfamily is composed of at least 26 members of zinc-containing enzymes produced by many cell types and sharing structural and functional features. Based on structural and functional considerations, proteinases have been classified into different families and subfamilies (Vartak et al. , J. Drug Targeting, 15, p. 1-20 (2007); and Hopper, FEBS, 354, p.
  • MMP-1, -8 and -13 collagenases
  • MMP-2, and -9 gelatinases
  • MMP-12 metalloelastases
  • MMP-12 the MT-MMPs
  • MMP-14, -15, -16, -17, - 24 and 25 matrilysins
  • MMP-7 and -26 matrilysins
  • MMP- 3, -10 and -11 sheddases
  • TACE TNF-converting enzymes
  • MMPs are believed to be important in physiological and disease processes that involve remodeling, such as airway diseases, embryonic development, bone formation and uterine remodeling during menstruation.
  • One major biological function of MMPs is to catalyze the breakdown of connective tissues or extra-cellular matrix by their ability to hydrolyze various components of tissue or matrix.
  • MMPs are involved in the activation of zymogen (pro) forms of other MMPs thereby inducing MMP activation. They are also involved in the biosynthesis of TNF-alpha which is implicated in many pathological conditions.
  • MMP-9 which belongs to the gelatinase family, plays a major role in chronic inflammatory disorders like COPD, asthma and rheumatoid arthritis.
  • the concentration of MMP-9 has been reported to increase in diseases like asthma, interstitial pulmonary fibrosis (IPF), adult respiratory distress syndrome (ARDS), and in chronic obstructive pulmonary disease (COPD).
  • IPF interstitial pulmonary fibrosis
  • ARDS adult respiratory distress syndrome
  • COPD chronic obstructive pulmonary disease
  • MMP-9 Because of its proteolytic ability, MMP-9 has been implicated in tissue remodeling of the airways and lungs in chronic inflammatory diseases such as severe asthma and COPD.
  • MMP-9 is also likely to be physiologically important because of its ability to regulate the digestion of components of the extracellular matrix as well as the activity of other proteases and cytokines.
  • MMP-9 is secreted in neutrophils, macrophages, and osteoclasts, which are easily induced by cytokines and growth factors
  • MMP-12 also known as macrophage elastase or metalloelastase, is expressed in activated macrophages and has been shown to be secreted from alveolar macrophages from smokers, as well as in foam cells in atherosclerotic lesions. MMP-12 knockout mouse studies have shown the development of significant emphysema, thus supporting its role in COPD.
  • MMP-9 gelatinase B, 92 kDa Type IV collagenase
  • MMP-9 is one member of the MMP family that is released as a proenzyme and subsequently activated via a protease cascade in vivo.
  • TMP matrix metalloproteinase
  • Inhibition of the activity of one or more MMPs may be of benefit in treatment of various inflammatory, autoimmue and allergic diseases, such as, inflammation of the joint, inflammation of the GI tract, inflammation of the skin, collagen remodeling, wound healing disorders, etc.
  • MMP inhibitors The design and therapeutic application of MMP inhibitors has revealed that the requirement of a molecule to be an effective inhibitor of MMP class of enzymes is a functional group (e.g.. carboxylic acid, hydroxamic acid or sulphydryl) capable of chelating to the active site Zn 2+ ion (Whittaker et al, Chem. Rev., 99; p. 2735-76 (1999)).
  • a functional group e.g.. carboxylic acid, hydroxamic acid or sulphydryl
  • WO 2004/014310 discloses processes for the preparation of peripheral opioid antagonist compounds useful for gastrointestinal motility disorders.
  • WO 02/060888 discloses processes for preparing chromanylbenzoic acids.
  • WO 94/20455 discloses styryl derivatives as PDE-IV inhibitors useful in the prophylaxis and treatment of diseases such as asthma, where an unwanted inflammatory response or muscular spasm is present.
  • WO 2004/1 10974 discloses compounds and their physiologically functional derivatives described as inhibitors of matrix metalloproteinase enzymes.
  • WO 2004/1 13279 discloses inhibitors of matrix metalloproteinase.
  • WO 2005/026120 discloses compounds described as inhibitors of matrix metalloproteinase.
  • 2003/0139453 discloses diflourobutyric acid compounds useful for treating diseases associated with zinc metalloprotease activity.
  • WO 2006/090235 describes 5-phenyl-pentanoic acid derivatives described as matrix metalloproteinase inhibitors for the treatment of asthma and other diseases.
  • WO 2008/023336 discloses ⁇ -hydroxy and amino-substituted carboxylic acids, which act as matrix metalloproteinase inhibitors.
  • MMP inhibitors that are selective, e.g., for a few of the MMP subtypes.
  • An MMP inhibitor of improved selectivity would avoid potential side effects associated with inhibition of MMPs that are not involved in the pathogenesis of the disease being treated.
  • use of more selective MMP inhibitors would require administration of a lower amount of the inhibitor for treatment of disease than would otherwise be required and, after administration, partitioned in vivo among multiple MMPs. Still further, the administration of a lower amount of compound would improve the margin of safety between the dose of the inhibitor required for therapeutic activity and the dose of the inhibitor at which toxicity is observed.
  • chirality can have an influence on drug absorption, distribution, metabolism and elimination. Pure single isomers may also offer advantages in terms of these pharmacokinetic parameters thus enabling better developability of such molecules as drug candidates. It is also known that chirality has a significant effect of the physicochemical properties and crystallinity of a chiral molecule which in turn have profound effects on the pharmacokinetics and developability of the molecule. Besides those mentioned above, regulatory principles guide one to preferably develop single isomers as drug candidates in order to avoid any pharmacological, pharmacokinetic and toxicological problems that may arise due to interactions of an unwanted isomer with undesirable molecular targets.
  • the present invention is directed to overcoming problems encountered in the art. Summary of the Invention
  • the present invention provides some hydroxy propionic acid derivatives, which act as matrix metalloprotease inhibitors, corresponding processes for the synthesis of and pharmaceutical compositions containing the compounds of the present invention.
  • the present invention relates to matrix metalloproteinase inhibitors useful as effective therapeutic or prophylactic agents in treatment of various inflammatory, autoimmune, and allergic diseases and other inflammatory disorders characterized by the over-expression and over- activation of a matrix metalloproteinase using the compounds.
  • the present invention discloses a novel class of compounds that are dual MMP- 9/12 inhibitors and have desirable activity profiles.
  • the compounds of this invention have beneficial potency and/or selectivity.
  • compositions containing such compounds are provided together with the pharmaceutically acceptable carriers or diluents, which can be used for the treatment or prevention of inflammatory or autoimmune diseases.
  • These pharmaceutical compositions may be administered or coadministered by a wide variety of routes including, for example, oral, topical, rectal, intranasal or by parenteral route.
  • the composition may also be administered or co-administered in slow release dosage forms.
  • specific enantiomers have been shown by way of examples, the racemates, diastereomers, pharmaceutically acceptable salts, and pharmaceutically acceptable solvates, having the same type of activity, are also provided.
  • Pharmaceutical compositions comprising such compounds, with optionally included excipients are also provided.
  • Therapeutically effective amounts of one or more compounds of the present invention can be used in combination with one or more other therapeutic agents, for example, other anti-inflammatory agents, beta agonists, antihypertensive agents, immunosuppressive agents and anti-infective agents.
  • other therapeutic agents for example, other anti-inflammatory agents, beta agonists, antihypertensive agents, immunosuppressive agents and anti-infective agents.
  • R f and R q are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as defined earlier and m is an integer 0-2 ⁇ ; can be selected from heteroaryl or heterocyclyl.
  • G_ can be selected from phenyl, fluorophenyl, heteroaryl or heterocyclyl;
  • R f and R q are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and
  • alkylheterocyclyl n is as defined earlier and m is an integer 0-2 ⁇ ; can be selected from heteroaryl or heterocyclyl.
  • the current invention provides a compound of Formula lb:
  • Ra can be hydrogen or fluorine
  • L ⁇ nd _ are as defined earlier.
  • the current invention provides a compound of Formula Ic:
  • L la is selected from S(0) n , NHCO(CH 2 ) consult and NHCO(O); are as defined earlier.
  • the enantiomers, diastereomers, rotational isomers, TV-oxides, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates of these compounds, prodrugs and metabolites having the same type of activity are also provided, as well as pharmaceutical compositions comprising the compounds, their metabolites, enantiomers, diastereomers, conformational isomers, TV-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable carrier and optionally included excipients.
  • the invention encompasses compounds of Formula (I), which may include, but are not limited to the following, for example
  • compositions comprising therapeutically effective amounts of one or more compounds described herein together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • compounds according to Formula I/Ia/Ib/Ic for use in treating or preventing various inflammatory and allergic diseases comprising administering to a mammal in need thereof.
  • inflammatory and allergic diseases are asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis, pulmonary inflammation, acute respiratory distress syndrome, perodontitis, multiple sclerosis, gingivitis, atherosclerosis, dry eye, neointimal proliferation associated with restenosis and ischemic heart failure, stroke, renal disease or tumour metastasis.
  • the present invention relates to the therapeutically effective dose of a compound of Formula I/Ia/Ib/Ic in combination with one or more of other therapeutic agents used for treating various inflammatory and allergic diseases.
  • therapeutic agents include, but are not limited to: ) Anti-inflammatory agents, experimental or commercial (i) such as nonsteroidal anti-inflammatory agents piroxicam, diclofenac, propionic acids, fenamates, pyrazolones, salicylates, phosphodiesterase inhibitors including PDE-4 inhibitors, p38 MAP Kinase/Cathepsin inhibitors, CCR-3 antagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists, cell adhesion inhibitors (specially ICAM), adenosine 2a agonists, (ii) leukotrienes LTC4/LTD4/LTE4/LTB4-Inhibitors, 5 -lipoxygenase inhibitors
  • dexbudesonide diflorasone, difluprednate, fluticasone, flunisolide
  • halometasone haloperedone, hydrocortisone, methylprednisolone,
  • Preferred corticosteroids include, for example, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, and dexamethasone;
  • Beta-agonists experimental or commercial
  • suitable p2-agonists include, for example, one or more of albuterol, salbutamol, biltolterol, pirbuterol, levosalbutamol, tulobuterol, terbutaline, bambuterol, metaproterenol, fenoterol, salmeterol, carmoterol, arformoterol, formoterol, and their pharmaceutically acceptable salts or solvates thereof one or more ⁇ 2- agonists may be chosen from those in the art or subsequently discovered,
  • the p2-agonists may include one or more compounds described in, for example, U.S. Patent Nos.
  • antihypertensive agents e.g., ACE inhibitors, e.g., enalapril, lisinopril, valsartan, telmisartan and quinapril, (ii) angiotensin II receptor antagonists and agonists, e.g., losartan, candesartan, irbesartan, valsartan, and eprosartan, (iii) ⁇ - blockers, and (iv) calcium channel blockers; 4) immunosuppressive agents, for example, cyclosporine, azathioprine and methotrexate, anti-inflammatory corticosteroids; and
  • anti-infective agents e.g. , antibiotics, antivirals.
  • alkyl refers to a straight or branched fully saturated hydrocarbon chain which is optionally substituted by one or more halo atom, and which has 1 to 20 carbon atoms unless otherwise specified. This term is exemplified by groups such as methyl, ethyl, ⁇ -propyl, so-propyl, «-butyl, so-butyl, t-butyl, «-hexyl, «-decyl, «-tetradecyl, trifluoromethyl, chloroethyl, and the like.
  • alkenyl refers to a branched or unbranched unsaturated hydrocarbon group containing at least one double bond with cis or trans geometry and preferably having 2 to 20 carbon atoms. Examples of alkenyl group include ethenyl, 2-propenyl and isopropenyl.
  • cycloalkyl refers to a non aromatic cyclic group having 3 to 20 ring carbon atoms and form one to three rings and may optionally contain one or more olefinic bonds. Polycyclic ring systems may be a spiro, fused or bridged arrangement.
  • Cycloalkyl groups include, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, adamantyl, bicyclo[2.2./]heptanyl, bicyclo[2.2.2]octane, tricycle[3JJ.i]decane, and the like.
  • aryl refers to an aromatic system having from 6 to 14 carbon atoms and up to three rings which may be fused or directly joined.
  • Representative examples of such aryl group include, but are not limited to, phenyl, biphenyl, naphthyl, phenanthrene, anthracenyl, azulenyl, and indanyl.
  • Aryl group may also comprise one or more rings which are not fully aromatic and examples of such system are indane, indene, 2, 3 dihydrobenzofuran and 1 ,2,3,4-tetrahydronaphthalene
  • heteroaryF refers to an aromatic system having from 5 to 14 membered carbon atoms and up to three rings, which may be fused or directly joined, and containing from one to eight heteroatoms selected from N, O and S.
  • heteroaryl groups are pyridinyl, quinolinyl, oxazolyl, imidazolyl, pyrrolyl, thiophenyl, 1,2,3-triazolyl, 1 ,2,4- triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, and the like.
  • heterocyclyl refers to a non-aromatic monocyclic or polycyclic ring system, which may be fused spiro or bridged, having 3 to 12 ring atoms and up to eight heteroatoms selected from N, O and S.
  • heterocyclyl ring systems include piperidine, morpholine, piperazine, isoquinoline, oxazolidine, tetrahydrofuran, dihydrofuran, dihydropyridine, dihydroisoxazole, dihydrobenzofuran, azabicyclohexane, dihydroindole, tetrahydroquinoline, pyrrolidine, azepine, azetidine, aziridine,
  • cycloalkylalkyl refers respectively, to cycloalkyl, aryl, heteroaryl or heterocyclyl group linked to the remainder of the molecule via an alkyl group.
  • amino refers to -NH 2 .
  • alkoxy denotes the group O-alkyl, wherein alkyl is the same as defined above.
  • halogen or halo refers to fluorine, chlorine, bromine or iodine.
  • halogeno-Ci-C 6 alkyF refers to Ci-C 6 alkyl of which one or more hydrogen(s) is/are replaced by halogen.
  • halogeno Ci-C ⁇ alkoxy refers to as halogen atom bonded to C C 6 alkoxy group. Examples of such groups include trifluoromethoxy, trichloromethoxy, difluoromethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2-bromoethoxy etc.
  • hydroxyl or "hydroxy” refers to -OH.
  • thiol refers to the group -SH.
  • alkylthiol refers to a thiol group when hydrogen is replaced by alkyl, for example, methylthio, ethylthio, propylthio, t-butylthio, cyclopropylthio, and the like.
  • cyano refers to as C ⁇ N.
  • the term “leaving group” refers to groups that exhibit or potentially exhibit the properties of being labile under the synthetic conditions and also of being readily separated from synthetic products under defined conditions. Examples of leaving groups include, but are not limited to, halogen (e.g., F, CI, Br, I), triflates, tosylate, mesylates, alkoxy, thioalkoxy, or hydroxy radicals, and the like.
  • protecting groups refers to moieties that prevent chemical reaction at a location of a molecule intended to be left unaffected during chemical modification of such molecule. Unless otherwise specified, protecting groups may be used on groups, such as hydroxy, amino, or carboxy. Examples of protecting groups are found in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2 nd Ed., John Wiley and Sons, New York, N.Y. The species of the carboxylic protecting groups, amino protecting groups or hydroxy protecting groups employed are not critical, as long as the derivatised moieties/moiety are/is stable to conditions of subsequent reactions and can be removed without disrupting the remainder of the molecule.
  • Each stereogenic carbon may be of the R or S configuration. Although the specific compounds exemplified in this application may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are envisioned.
  • salts of carboxylic acid moiety which may be prepared by reacting the compound with appropriate base to provide corresponding base addition salts.
  • bases are alkali metal hydroxide including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide.
  • salts of organic bases such as lysine, arginine, guanidine, ethanolamine, choline and the like; inorganic bases e.g., ammonium or substituted ammonium salts are also included.
  • compounds of the present invention may also form the acid addition salts by treating the said compounds with pharmaceutically acceptable organic and inorganic acids, e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide; other mineral acids and their corresponding salts such as sulphate, nitrate, phosphate, etc.; and alkyl and mono-arylsulphonates, such as ethane sulphonate, toluene sulphonate and benzene sulphonate; and other organic acids and their corresponding salts such as acetate, tartarate, maleate, succinate, citrate, etc.
  • the salt forms differ from the compound described herein in certain physical properties such as solubility, but the salts are otherwise equivalent for the purpose of this invention.
  • solvates refers to solvates with water ⁇ i.e., hydrates) or pharmaceutically acceptable solvents, for example, solvates with ethanol, and the like. Such solvates are also encompassed within the scope of the disclosure.
  • polymorphs includes all crystalline forms as well as amorphous forms for compounds described herein and as such are included in the present invention.
  • pharmaceutically acceptable carriers is intended to include non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • pharmaceutically acceptable means approved by the regulatory agency of the federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • inflammatory conditions and autoimmune disorders in which the compounds of the invention have potentially beneficial effects in treatment methods may include, but are not limited to diseases of the respiratory tract such as asthma (including allergen-induced asthmatic reactions), cystic fibrosis, bronchitis (including chronic bronchitis), chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), chronic pulmonary inflammation, rhinitis and upper respiratory tract inflammatory disorders (URID), ventilator induced lung injury, silicosis, pulmonary sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, arthritis, e.g., rheumatoid arthritis, osteoarthritis, infectious arthritis, psoriatic arthritis, traumatic arthritis, rubella arthritis, Reiter's syndrome, gouty arthritis and prosthetic joint failure, gout, acute synovitis, spondylitis and non-articular inflammatory conditions, e.g.
  • diseases of the respiratory tract such as asthma (including aller
  • herniated/ruptured/prolapsed intervertebral disk syndrome bursitis, tendonitis, tenosynovitic, fibromyalgic syndrome and other inflammatory conditions associated with ligamentous sprain and regional musculoskeletal strain, inflammatory disorders of the gastrointestinal tract, e.g.
  • ulcerative colitis ulcerative colitis
  • diverticulitis Crohn's disease
  • inflammatory bowel diseases irritable bowel syndrome and gastritis
  • multiple sclerosis systemic lupus erythematosus, scleroderma, autoimmune exocrinopathy, autoimmune encephalomyelitis, diabetes, tumor angiogenesis and metastasis, cancer including carcinoma of the breast, colon, rectum, lung, kidney, ovary, stomach, uterus, pancreas, liver, oral, laryngeal and prostate, melanoma, acute and chronic leukemia, periodontal disease, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, epilepsy, muscle degeneration, inguinal hernia, retinal degeneration, diabetic retinopathy, macular degeneration, inguinal hernia, ocular inflammation, bone resorption diseases, osteoporosis, osteopetrosis, graft vs.
  • the compound of Formula II (wherein _ is as defined earlier, X is O or S and R k is H, halo, alkyl, alkoxy, cyano, halogeno-Ci-C 6 alkyl or halogeno-Ci-C6 alkoxy and z is 0-4) can react with a compound of Formula III to give a compound of
  • Path A (When X is S): The compound of Formula VI undergoes hydrolysis to give a compound of Formula VII, which then further undergoes oxidation to give a compound of Formula VIII.
  • Path B (When X is O): The compound of Formula VI undergoes hydrolysis to give a compound of Formula IX.
  • the reaction of a compound of Formula II with a compound of Formula III to give a compound of Formula IV can be carried out in the presence of a base, for example, potassium carbonate, cesium carbonate, sodium acetate or potassium acetate in a solvent, for example, dimethylformamide, acetonitrile, toluene, tetrahydrofuran, acetone, dioxane, or mixture(s) thereof.
  • a base for example, potassium carbonate, cesium carbonate, sodium acetate or potassium acetate
  • a solvent for example, dimethylformamide, acetonitrile, toluene, tetrahydrofuran, acetone, dioxane, or mixture(s) thereof.
  • asymmetric aldol addition of a compound of Formula IV with a compound of Formula V to give a compound of Formula VI can be carried out by generating the enolates with titanium tetrachloride, dibutyl boron triflate, dialkyl boron chloride or tin(II) triflate, in the presence of a base, for example, tetramethylethylenediamine,
  • Hydrolysis of a compound of Formula VI (Path A, when X is S) to give a compound of Formula VII can be carried out with hydrogen peroxide and lithium hydroxide, in the presence of a solvent, for example, tetrahydrofuran, water, or mixture(s) thereof.
  • a solvent for example, tetrahydrofuran, water, or mixture(s) thereof.
  • Oxidation of a compound of Formula VII to give a compound of Formula VIII can be carried out with an oxidizing agent, for example, meta chloro perbenzoic acid, oxone or hydrogen peroxide, in a solvent, for example, chloroform, dichoromethane, methanol, water, tetrachloromethane, or mixture(s) thereof.
  • an oxidizing agent for example, meta chloro perbenzoic acid, oxone or hydrogen peroxide
  • a solvent for example, chloroform, dichoromethane, methanol, water, tetrachloromethane, or mixture(s) thereof.
  • the compound of Formula V undergoes aldol addition with a compound of Formula X (wherein G can be nitro or C(O)O-benzyl) to give a compound of Formula XI, which then can be reduced to give a compound of Formula XII (wherein G 1 can be amino or COOH).
  • Aldol addition of a compound of Formula X to a compound of Formula V to give a compound of Formula XI can be carried out in a similar way as the aldol addition of a compound of Formula IV with a compound of Formula V to give a compound of Formula VI.
  • Reduction of a compound of Formula XI to give a compound of Formula XII can be carried out with one or more reducing agents, for example, palladium-carbon/hydrogen, Raney nickel/hydrogen, platinum/hydrogen or mixture thereof in a solvent, for example, tetrahydrofuran, methanol, ethanol, propanol, isopropanol, or mixtures thereof.
  • one or more reducing agents for example, palladium-carbon/hydrogen, Raney nickel/hydrogen, platinum/hydrogen or mixture thereof in a solvent, for example, tetrahydrofuran, methanol, ethanol, propanol, isopropanol, or mixtures thereof.
  • the compound of Formula XII (when G] is amino) can react through two pathways.
  • Path C Compound of Formula XII couples with a compound of Formula XIII (wherein Rk and z are as defined earlier) to give a compound of Formula XIV, which then undergoes hydrolysis to give a compound of Formula XV.
  • Path D Compound of Formula XII couples with a compound of Formula XVI (wherein X is a leaving group for example halogen and R j is -(CH 2 ) 0-1 -CO-, -C(0)O, -S0 2- , and R k is as defined earlier) to give a compound of Formula XVII, which then undergo hydrolysis to give a compound of Formula XVIII.
  • X is a leaving group for example halogen and R j is -(CH 2 ) 0-1 -CO-, -C(0)O, -S0 2- , and R k is as defined earlier
  • a suitable base for example, potassium carbonate ⁇ sodium carbonate, triethylamine, diisopropylethyl amine, etc. in the presence of solvents like acetonitrile, dimethylformamide, toluene,
  • a base for example, triethylamine (TEA), N-methyl-morpholine (NMM), N,N-dimethylaminopyridine
  • the compound of Formula XII (when Gi is COOH) can couple with a compound of Formula XIX to give a compound of Formula XX, which then undergoes hydrolysis to give a compound of Formula XXI.
  • the coupling of compound of Formula XII with a compound of Formula XIX to give a compound of Formula XX can be carried out in the presence of a coupling agent 1- ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) or N ⁇ V-dicyclohexylcarbodiimide (DCC) and optionally activating catalyst HOBT and an organic base
  • a coupling agent 1- ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) or N ⁇ V-dicyclohexylcarbodiimide (DCC) optionally activating catalyst HOBT and an organic base
  • XII can also be activated by converting to the corresponding acid chloride (using thionyl chloride, oxalyl chloride, etc.) or the anhydride (pivaloyl chloride, etc.) and coupled with the corresponding anilines.
  • Hydrolysis of compound of Formula XX to give a compound of Formula XXI can be carried out in a similar way as the hydrolysis of compound of Formula VI to give a compound of Formula VII.
  • Table 1 lists the type of compounds synthesized by using the synthetic procedure as demonstrated in Schemes I-IV.
  • compositions disclosed herein comprise pharmaceutically effective amounts of compounds described herein formulated together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • Solid form preparations for oral administration include capsules, tablets, pills, powder, granules, lozenges, troches, and cachets.
  • active compounds can be mixed with one or more inert, pharmaceutically acceptable excipients or carriers, for example, sodium citrate, dicalcium phosphate and/or fillers or extenders (for example, starches, lactose, sucrose, glucose, mannitol, silicic acid, or mixtures thereof); binders, for example, carboxymethylcellulose, alginates, gelatins, polyvinylpyrrolidinone, sucrose, acacia or mixtures thereof; disintegrating agents, for example, agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates, sodium carbonate, or mixtures thereof; absorption acceletors, for example, quaternary ammonium compounds; wetting agents, for example, cetyl alcohol, glycerol mono stearate or mixtures thereof; adsorbants, for example, sodium
  • Capsules, tablets or pills may also comprise buffering agents.
  • Tablets, capsules, pills or granules can be prepared using one or more coatings or shells to modulate the release of active ingredients, for example, enteric coatings or other coatings known to one of ordinary skill in the art.
  • Liquid form preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • active compounds can be mixed with water or one or more non-toxic solvents, solubilizing agents or emulsifiers, for example, water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, for example, cottonseed, groundnut, corn, germ, olive, castor and sesame oil, glycerol, fatty acid esters of sorbitan or mixtures thereof.
  • solubilizing agents or emulsifiers for example, water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,
  • Oral compositions can also include one or more adjuvants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, or mixtures thereof.
  • adjuvants for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, or mixtures thereof.
  • injectable preparations for example, sterile injections, and aqueous suspensions may be formulated according to methods known to one of ordinary skill in the art, and in particular, using one or more suitable dispersing or wetting and suspending agents.
  • Acceptable vehicles and solvents include one or more of water, Ringer's solution, isotonic sodium chloride, or mixtures thereof.
  • Suppositories for rectal administration of the compound of this invention can be prepared by mixing the drug with suitable nonirritating excipients, such as cocoa butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at body temperature and which therefore melt in the rectum and release the drug.
  • suitable nonirritating excipients such as cocoa butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at body temperature and which therefore melt in the rectum and release the drug.
  • Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • Active compounds can be admixed under sterile condition with one or more pharmaceutically acceptable carriers and optionally any preservatives or buffers as may be required.
  • Ophthalmic formulations, eardrops, eye ointments, powders and solutions are also encompassed within the scope of this invention.
  • compositions may be in unit dosage form.
  • the preparations can be subdivided into unit doses containing appropriate quantities of active components.
  • Unit dosage forms can be packed preparations containing discrete capsules, powders, in vials or ampoules, ointments, capsules, sachets, tablets, gels, creams or any combination and number of such packed forms.
  • Step 1 Synthesis of 4-[(4-chlorophenyl)sulfanyl]benzaldehyde To a solution of 4-chlorothiophenol (1.0 g, 0.0069 mol) in dimethylformamide
  • Step 2 Synthesis of 3- ⁇ (3S)-4-[(4S)-4-benzyl-2-oxo-l,3-thiazolidin-3-yl]-3-[(S)- ⁇ 4-[(4- chlorophenyl)sulfanyl]phenyl ⁇ (hydroxy)methyl]-4-oxobutyl ⁇ -l,2,3-benzotriazin- 4(3H)-one
  • Step 4 Synthesis of (2S)-2-[(S)- ⁇ 4-[(4-chlorophenyl)sulfonyl]phenyl ⁇ (hydroxy) methyI]-4-(4-oxo-l,2,3-benzotriazin-3(4/f)-yl)butanoic acid (Compound No. 2)
  • Step 2 Synthesis of 3-[(3S)-4-[(4S)-4-benzyl-2-oxo-l,3-thiazolidin-3-yl]-3- ⁇ (S)- hydroxy[4-(4-methoxyphenoxy)phenyl]methyl ⁇ -4-oxobutyl]-l,2,3-benzotriazin-4(3H - one
  • Step 3 Synthesis of (2S)-2- ⁇ (S)-hydroxy[4-(4-methoxyphenoxy)phenyI]methyI ⁇ -4-(4- oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 56)
  • Example III Synthesis of 3-rf35.4 ⁇ 4-AmmophenylV3-(r(4S)-4-benzyl-2-oxo-1.3- thiazolidin-3 -yl] carbonyl ⁇ -4-hydroxybutyl] - 1 ,2,3 -benzotriazin-4(3H)-one
  • Step 1 Synthesis of 3- ⁇ (3S)-4-[(4S)-4-benzyl-2-oxo-l, 3-thiazolidin-3-yl]-3-[(S)- hydroxy(4-nitrophenyl)methyl]-4-oxobutyl ⁇ -l,2,3-benzotriazin-4(3H)-one
  • Step 1 Synthesis of V- ⁇ 4-[(15,2S)-2- ⁇ [(4S)-4-benzyl-2-oxo-l,3-thiazolidin-3- yl]carbonyl ⁇ -l-hydroxy-4-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)butyl]phenyl ⁇ -2-fluoro-
  • Step 2 Synthesis of (2S)-2-[(S)-[4-( ⁇ [2-fIuoro-4-(trifIuoromethyl)phenyl]carbonyl ⁇ amino)phenyl](hydroxy)methyl]-4-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 46)
  • Example V Synthesis of (25 f )-2-[( ' S)-(4- ⁇ [(4-ethylphenyl carbonyllamino ⁇ phenyl (hvdroxy)methyl1-4-(4-oxo- l ,2.3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 10) Step 1: Synthesis of 3- ⁇ (3S)-4-[(4S)-4-benzyl-2-oxo-l,3-thiazolidin-3-yl]-3-[(S)- hydroxy(4-nitrophenyl)methyl]-4-oxobutyl ⁇ -l,2,3-benzotriazin-4(3H)-one
  • Step 3 Synthesis of N- ⁇ 4-[(15,2S)-2- ⁇ [(4S)-4-benzyl-2-oxo-l,3-thiazolidin-3- yl]carbonyl ⁇ -l-hydroxy-4-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)butyl]phenyl ⁇ -4- ethylbenzamide
  • MMPs Matrix Metalloproteinases
  • New chemical entities of the present invention and corresponding standards used in the present invention were prepared (stock 10 mM) in 100% DMSO and subsequent dilutions were made in MMP assay buffer [50 mM HEPES, 10 mM CaCl 2, 150 nM NaCl, 1 ⁇ Zinc Acetate, 600 ⁇ CHAPS (pH 7.4)].
  • Assays used human MMPs expressed either as full length or catalytic domain.
  • the Collagenase (MMP-1), Gelatinase (MMP-9), Elastase (MMP- 12) and membrane type-1 (MMP- 14) were cleaved and activated using reagent APMA (4-amino phenyl mercuric acetate) to obtain active catalytic domains.
  • reagent APMA 4-amino phenyl mercuric acetate
  • IC 5 o values were calculated using least square regression analysis method by Graph-Pad prism version 4.2 software; using a 5-6 point dose response curve in presence of inhibitor. IC 50 values were averaged for duplicate assay data and values tabulated.
  • the present invention relates to compounds that act as dual MMP-9/12 inhibitors, which have desirable activity profiles.
  • MMP-9 activities of the compounds disclosed in the invention provided IC 50 values from about 10 micromolar to about 1 nM, or from about 1 micromolar to about 1 nM, or from about 650 nM to about 1 nM, or from about 300 nM to about 1 nM, or from about 100 nM to about 1 nM, or from about 50 nM to about 1 nM, or from about 30 nM to about 1 nM, or from about 20 nM to about 1 nM, or from about 12 nM to about 1 nM, as compared to about 1.4 nM to 3.2 nM for marimastat.
  • MMP-12 activities of the compounds disclosed in the invention provided IC 50 values from about 10 micromolar to about 1 nM, or from about 1 micromolar to about 1 nM, or from about 300 nM to about 1 nM, or from about 100 nM to about 1 nM, or from about 50 nM to about 1 nM, or from about 30 nM to about 1 nM, or from about 20 nM to about 1 nM, or from about 15 nM to about 1 nM, or from about 7 nM to about 1 nM as compared to 0.2 nM to 0.9 nM for marimastat.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Rheumatology (AREA)
  • Oncology (AREA)
  • Neurology (AREA)
  • Otolaryngology (AREA)
  • Communicable Diseases (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biomedical Technology (AREA)
  • Hospice & Palliative Care (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Transplantation (AREA)
  • Vascular Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne certains dérivés d'acide hydroxypropionique et les procédés pour les synthétiser. Cette invention concerne également des compositions pharmacologiques contenant les composés de la présente invention, et des procédés de traitement de l'asthme, de la polyarthrite rhumatoïde, de la BPCO, de la rhinite, de l'ostéoarthrite, du rhumatisme psoriasique, du psoriasis, de la fibrose pulmonaire, de l'inflammation pulmonaire, du syndrome de détresse respiratoire aigu, de la parodontite, de la sclérose en plaques, de la gingivite, de l'athérosclérose, du syndrome de l'œil sec, de la prolifération néo-intimale qui conduit à la resténose et à l'insuffisance cardiaque ischémique, de l'accident vasculaire cérébral, de maladies rénales, de métastases de tumeurs et d'autres troubles inflammatoires caractérisés par une sur-expression et une sur-activation d'une métalloprotéinase de matrice, au moyen des composés.
PCT/IB2011/053155 2010-07-30 2011-07-14 Inhibiteurs de métalloprotéinase de matrice Ceased WO2012014114A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
CN2011800461515A CN103119030A (zh) 2010-07-30 2011-07-14 基质金属蛋白酶抑制剂
AU2011284397A AU2011284397A1 (en) 2010-07-30 2011-07-14 Matrix metalloproteinase inhibitors
JP2013522322A JP2013537533A (ja) 2010-07-30 2011-07-14 マトリックスメタロプロテイナーゼ阻害剤
EP11763767.8A EP2598493A1 (fr) 2010-07-30 2011-07-14 Inhibiteurs de métalloprotéinase de matrice
PH1/2013/500198A PH12013500198A1 (en) 2010-07-30 2011-07-14 Matrix metalloproteinase inhibitors
BR112013002370A BR112013002370A2 (pt) 2010-07-30 2011-07-14 composto, composição farmacêutica e processo de preparação de um composto
KR1020137005055A KR20130042590A (ko) 2010-07-30 2011-07-14 기질 메탈로프로테나제 저해제
MX2013001240A MX2013001240A (es) 2010-07-30 2011-07-14 Inhibidores de metaloproteinas de matriz.
CA2807097A CA2807097A1 (fr) 2010-07-30 2011-07-14 Inhibiteurs de metalloproteinase de matrice
SG2013007448A SG187654A1 (en) 2010-07-30 2011-07-14 Matrix metalloproteinase inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1810DE2010 2010-07-30
IN1810/DEL/2010 2010-07-30

Publications (1)

Publication Number Publication Date
WO2012014114A1 true WO2012014114A1 (fr) 2012-02-02

Family

ID=44720049

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2011/053155 Ceased WO2012014114A1 (fr) 2010-07-30 2011-07-14 Inhibiteurs de métalloprotéinase de matrice

Country Status (12)

Country Link
EP (1) EP2598493A1 (fr)
JP (1) JP2013537533A (fr)
KR (1) KR20130042590A (fr)
CN (1) CN103119030A (fr)
AU (1) AU2011284397A1 (fr)
BR (1) BR112013002370A2 (fr)
CA (1) CA2807097A1 (fr)
CO (1) CO6680674A2 (fr)
MX (1) MX2013001240A (fr)
PH (1) PH12013500198A1 (fr)
SG (1) SG187654A1 (fr)
WO (1) WO2012014114A1 (fr)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9056057B2 (en) 2012-05-03 2015-06-16 Kala Pharmaceuticals, Inc. Nanocrystals, compositions, and methods that aid particle transport in mucus
WO2015150363A1 (fr) 2014-04-03 2015-10-08 Bayer Pharma Aktiengesellschaft Acides cyclopentanecarboxyliques à disubstitution 2,5 et leur utilisation
WO2015150362A2 (fr) 2014-04-03 2015-10-08 Bayer Pharma Aktiengesellschaft Dérivés chiraux d'acide cyclopentanecarboxylique à disubstitution 2,5 et leur utilisation
WO2015150366A1 (fr) * 2014-04-03 2015-10-08 Bayer Pharma Aktiengesellschaft Dérivés d'éthers phénoliques à substitutions cycliques et leur utilisation
WO2015150364A1 (fr) * 2014-04-03 2015-10-08 Bayer Pharma Aktiengesellschaft Acides benzotriazinonebutyriques substitués et leur utilisation
WO2015150350A1 (fr) 2014-04-03 2015-10-08 Bayer Pharma Aktiengesellschaft Acides cyclopentanecarboxyliques à disubstitution 2,5 pour traiter des maladies des voies respiratoires
WO2015189117A1 (fr) * 2014-06-12 2015-12-17 Bayer Pharma Aktiengesellschaft Dérivés de l'acide 4-oxobutanoïque hétérobicycliques substitués et utilisation desdits dérivés
US9353122B2 (en) 2013-02-15 2016-05-31 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9353123B2 (en) 2013-02-20 2016-05-31 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9688688B2 (en) 2013-02-20 2017-06-27 Kala Pharmaceuticals, Inc. Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof
US9790232B2 (en) 2013-11-01 2017-10-17 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US9827191B2 (en) 2012-05-03 2017-11-28 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US9890173B2 (en) 2013-11-01 2018-02-13 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10253036B2 (en) 2016-09-08 2019-04-09 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10328053B2 (en) 2016-08-26 2019-06-25 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10336767B2 (en) 2016-09-08 2019-07-02 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10688041B2 (en) 2012-05-03 2020-06-23 Kala Pharmaceuticals, Inc. Compositions and methods utilizing poly(vinyl alcohol) and/or other polymers that aid particle transport in mucus
US10766907B2 (en) 2016-09-08 2020-09-08 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US11219596B2 (en) 2012-05-03 2022-01-11 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103254290B (zh) * 2013-05-30 2014-09-03 南通广泰生化制品有限公司 基质金属蛋白酶-2多肽抑制剂及其应用
CN103304634B (zh) * 2013-05-30 2015-04-29 温州芳植生物科技有限公司 基质金属蛋白酶-2多肽抑制剂及其应用
CN121001714A (zh) * 2023-09-12 2025-11-21 株式会社Lg化学 具有抗炎活性的化妆品组合物

Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3642896A (en) 1966-09-23 1972-02-15 Allen & Hanburys Ltd Process for the preparation of alpha**1-tertiary butylaminomethyl - 4 - hydroxy-m-xylene-alpha**1 alpha**3-diol
US3700681A (en) 1971-02-16 1972-10-24 Pfizer 2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-aminoethyl)pyridines
US3937838A (en) 1966-10-19 1976-02-10 Aktiebolaget Draco Orally active bronchospasmolytic compounds and their preparation
US3994974A (en) 1972-02-05 1976-11-30 Yamanouchi Pharmaceutical Co., Ltd. α-Aminomethylbenzyl alcohol derivatives
US4011258A (en) 1973-06-21 1977-03-08 Aktiebolaget Draco Orally active bronchospasmolytic compounds
US4419364A (en) 1980-07-09 1983-12-06 Aktiebolaget Draco Bronchospasmolytic carbamate derivatives
US4579985A (en) 1983-11-15 1986-04-01 Shell Oil Company Process for the preparation of hydrocarbons
US4992474A (en) 1983-04-18 1991-02-12 Glaxo Group Ltd. Phenethanolamine derivatives
WO1994020455A1 (fr) 1993-03-10 1994-09-15 Celltech Therapeutics Limited Derives du styrene, leur preparation et leur utilisation comme inhibiteurs de la phosphodiesterase iv
WO2002060888A1 (fr) 2001-01-30 2002-08-08 Pfizer Products Inc. Procedes de preparation d'acides chromanylbenzoiques
US20030139453A1 (en) 2000-03-21 2003-07-24 The Procter & Gamble Company Difluorobutyric acid metalloprotease inhibitors
WO2004014310A2 (fr) 2002-08-08 2004-02-19 Adolor Corporation Nouveaux procedes de preparation de composes antagonistes opioides peripheriques et de leurs intermediaires
WO2004110974A1 (fr) 2003-06-03 2004-12-23 Glaxo Group Limited Composes presentant une efficacite therapeutique
WO2004113279A1 (fr) 2003-06-20 2004-12-29 Glaxo Group Limited Inhibiteurs de la metalloproteinase de la matrice
WO2005026120A1 (fr) 2003-09-13 2005-03-24 Glaxo Group Limited Inhibiteurs de metalloproteinases matricielles
WO2006090235A1 (fr) 2005-02-22 2006-08-31 Ranbaxy Laboratories Limited Derives d'acide 5-phenyl-pentanoique en tant qu'inhibiteurs de metalloproteinase matricielle dans le traitement de l'asthme et d'autres maladies
WO2008023336A2 (fr) 2006-08-22 2008-02-28 Ranbaxy Laboratories Limited Inhibiteurs de la métalloprotéinase matricielle

Patent Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3642896A (en) 1966-09-23 1972-02-15 Allen & Hanburys Ltd Process for the preparation of alpha**1-tertiary butylaminomethyl - 4 - hydroxy-m-xylene-alpha**1 alpha**3-diol
US3644353A (en) 1966-09-23 1972-02-22 Allen & Hanburys Ltd 4 hydroxy-alpha'aminomethyl-m-xylene-alpha' alpha**3-diols
US3705233A (en) 1966-09-23 1972-12-05 Allen & Hanburys Ltd Phenylaminoethanol derivatives
US3937838A (en) 1966-10-19 1976-02-10 Aktiebolaget Draco Orally active bronchospasmolytic compounds and their preparation
US3700681A (en) 1971-02-16 1972-10-24 Pfizer 2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-aminoethyl)pyridines
US3994974A (en) 1972-02-05 1976-11-30 Yamanouchi Pharmaceutical Co., Ltd. α-Aminomethylbenzyl alcohol derivatives
US4011258A (en) 1973-06-21 1977-03-08 Aktiebolaget Draco Orally active bronchospasmolytic compounds
US4419364A (en) 1980-07-09 1983-12-06 Aktiebolaget Draco Bronchospasmolytic carbamate derivatives
US5126375A (en) 1983-04-18 1992-06-30 Glaxo Group Ltd. Phenethanolamine derivatives
US4992474A (en) 1983-04-18 1991-02-12 Glaxo Group Ltd. Phenethanolamine derivatives
US5243076A (en) 1983-04-18 1993-09-07 Glaxo Group Ltd. Phenethanolamine derivatives
US4579985A (en) 1983-11-15 1986-04-01 Shell Oil Company Process for the preparation of hydrocarbons
WO1994020455A1 (fr) 1993-03-10 1994-09-15 Celltech Therapeutics Limited Derives du styrene, leur preparation et leur utilisation comme inhibiteurs de la phosphodiesterase iv
US20030139453A1 (en) 2000-03-21 2003-07-24 The Procter & Gamble Company Difluorobutyric acid metalloprotease inhibitors
WO2002060888A1 (fr) 2001-01-30 2002-08-08 Pfizer Products Inc. Procedes de preparation d'acides chromanylbenzoiques
WO2004014310A2 (fr) 2002-08-08 2004-02-19 Adolor Corporation Nouveaux procedes de preparation de composes antagonistes opioides peripheriques et de leurs intermediaires
WO2004110974A1 (fr) 2003-06-03 2004-12-23 Glaxo Group Limited Composes presentant une efficacite therapeutique
WO2004113279A1 (fr) 2003-06-20 2004-12-29 Glaxo Group Limited Inhibiteurs de la metalloproteinase de la matrice
WO2005026120A1 (fr) 2003-09-13 2005-03-24 Glaxo Group Limited Inhibiteurs de metalloproteinases matricielles
WO2006090235A1 (fr) 2005-02-22 2006-08-31 Ranbaxy Laboratories Limited Derives d'acide 5-phenyl-pentanoique en tant qu'inhibiteurs de metalloproteinase matricielle dans le traitement de l'asthme et d'autres maladies
WO2008023336A2 (fr) 2006-08-22 2008-02-28 Ranbaxy Laboratories Limited Inhibiteurs de la métalloprotéinase matricielle

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
HOPPER, FEBS, vol. 354, 1994, pages 1 - 6
T.W. GREENE, P.G.M. WUTS: "Protective Groups in Organic Synthesis", JOHN WILEY AND SONS
VARTAK ET AL., J. DRUG TARGETING, vol. 15, 2007, pages 1 - 20
WHITTAKER ET AL., CHEM. REV., vol. 99, 1999, pages 2735 - 76

Cited By (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9532955B2 (en) 2012-05-03 2017-01-03 Kala Pharmaceuticals, Inc. Nanocrystals, compositions, and methods that aid particle transport in mucus
US10688041B2 (en) 2012-05-03 2020-06-23 Kala Pharmaceuticals, Inc. Compositions and methods utilizing poly(vinyl alcohol) and/or other polymers that aid particle transport in mucus
US12115246B2 (en) 2012-05-03 2024-10-15 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US11878072B2 (en) 2012-05-03 2024-01-23 Alcon Inc. Compositions and methods utilizing poly(vinyl alcohol) and/or other polymers that aid particle transport in mucus
US11872318B2 (en) 2012-05-03 2024-01-16 The Johns Hopkins University Nanocrystals, compositions, and methods that aid particle transport in mucus
US11642317B2 (en) 2012-05-03 2023-05-09 The Johns Hopkins University Nanocrystals, compositions, and methods that aid particle transport in mucus
US11318088B2 (en) 2012-05-03 2022-05-03 Kala Pharmaceuticals, Inc. Compositions and methods utilizing poly(vinyl alcohol) and/or other polymers that aid particle transport in mucus
US11219597B2 (en) 2012-05-03 2022-01-11 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US10646436B2 (en) 2012-05-03 2020-05-12 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US11219596B2 (en) 2012-05-03 2022-01-11 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US9393212B2 (en) 2012-05-03 2016-07-19 Kala Pharmaceuticals, Inc. Nanocrystals, compositions, and methods that aid particle transport in mucus
US9737491B2 (en) 2012-05-03 2017-08-22 The Johns Hopkins University Nanocrystals, compositions, and methods that aid particle transport in mucus
US12178920B2 (en) 2012-05-03 2024-12-31 The Johns Hopkins University Nanocrystals, compositions, and methods that aid particle transport in mucus
US10646437B2 (en) 2012-05-03 2020-05-12 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US9393213B2 (en) 2012-05-03 2016-07-19 Kala Pharmaceuticals, Inc. Nanocrystals, compositions, and methods that aid particle transport in mucus
US10993908B2 (en) 2012-05-03 2021-05-04 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US9827191B2 (en) 2012-05-03 2017-11-28 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US9056057B2 (en) 2012-05-03 2015-06-16 Kala Pharmaceuticals, Inc. Nanocrystals, compositions, and methods that aid particle transport in mucus
US10688045B2 (en) 2012-05-03 2020-06-23 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US10945948B2 (en) 2012-05-03 2021-03-16 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US10736854B2 (en) 2012-05-03 2020-08-11 The Johns Hopkins University Nanocrystals, compositions, and methods that aid particle transport in mucus
US10857096B2 (en) 2012-05-03 2020-12-08 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US9877970B2 (en) 2013-02-15 2018-01-30 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US10966987B2 (en) 2013-02-15 2021-04-06 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9827248B2 (en) 2013-02-15 2017-11-28 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US10398703B2 (en) 2013-02-15 2019-09-03 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9353122B2 (en) 2013-02-15 2016-05-31 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9688688B2 (en) 2013-02-20 2017-06-27 Kala Pharmaceuticals, Inc. Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof
US11369611B2 (en) 2013-02-20 2022-06-28 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9353123B2 (en) 2013-02-20 2016-05-31 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9833453B2 (en) 2013-02-20 2017-12-05 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9861634B2 (en) 2013-02-20 2018-01-09 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US10285991B2 (en) 2013-02-20 2019-05-14 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US10758539B2 (en) 2013-02-20 2020-09-01 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9790232B2 (en) 2013-11-01 2017-10-17 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US9890173B2 (en) 2013-11-01 2018-02-13 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10160765B2 (en) 2013-11-01 2018-12-25 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US11713323B2 (en) 2013-11-01 2023-08-01 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10975090B2 (en) 2013-11-01 2021-04-13 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10618906B2 (en) 2013-11-01 2020-04-14 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
WO2015150363A1 (fr) 2014-04-03 2015-10-08 Bayer Pharma Aktiengesellschaft Acides cyclopentanecarboxyliques à disubstitution 2,5 et leur utilisation
WO2015150362A2 (fr) 2014-04-03 2015-10-08 Bayer Pharma Aktiengesellschaft Dérivés chiraux d'acide cyclopentanecarboxylique à disubstitution 2,5 et leur utilisation
WO2015150366A1 (fr) * 2014-04-03 2015-10-08 Bayer Pharma Aktiengesellschaft Dérivés d'éthers phénoliques à substitutions cycliques et leur utilisation
WO2015150364A1 (fr) * 2014-04-03 2015-10-08 Bayer Pharma Aktiengesellschaft Acides benzotriazinonebutyriques substitués et leur utilisation
WO2015150350A1 (fr) 2014-04-03 2015-10-08 Bayer Pharma Aktiengesellschaft Acides cyclopentanecarboxyliques à disubstitution 2,5 pour traiter des maladies des voies respiratoires
WO2015150362A3 (fr) * 2014-04-03 2015-12-10 Bayer Pharma Aktiengesellschaft Dérivés chiraux d'acide cyclopentanecarboxylique à disubstitution 2,5 et leur utilisation
WO2015189117A1 (fr) * 2014-06-12 2015-12-17 Bayer Pharma Aktiengesellschaft Dérivés de l'acide 4-oxobutanoïque hétérobicycliques substitués et utilisation desdits dérivés
US10328053B2 (en) 2016-08-26 2019-06-25 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10874640B2 (en) 2016-08-26 2020-12-29 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US12161625B2 (en) 2016-08-26 2024-12-10 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10626121B2 (en) 2016-09-08 2020-04-21 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US11104685B2 (en) 2016-09-08 2021-08-31 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US11021487B2 (en) 2016-09-08 2021-06-01 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10336767B2 (en) 2016-09-08 2019-07-02 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10766907B2 (en) 2016-09-08 2020-09-08 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10253036B2 (en) 2016-09-08 2019-04-09 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US11420974B2 (en) 2018-02-26 2022-08-23 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof

Also Published As

Publication number Publication date
MX2013001240A (es) 2013-08-27
CO6680674A2 (es) 2013-05-31
AU2011284397A1 (en) 2013-02-21
BR112013002370A2 (pt) 2017-06-20
EP2598493A1 (fr) 2013-06-05
JP2013537533A (ja) 2013-10-03
SG187654A1 (en) 2013-03-28
CN103119030A (zh) 2013-05-22
PH12013500198A1 (en) 2013-03-11
CA2807097A1 (fr) 2012-02-02
KR20130042590A (ko) 2013-04-26

Similar Documents

Publication Publication Date Title
EP2598493A1 (fr) Inhibiteurs de métalloprotéinase de matrice
WO2012038942A1 (fr) Inhibiteurs de métalloprotéinase matricielle
AU2015208932B2 (en) (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase I inhibitors
CZ173398A3 (cs) Inhibitory metaloproteinasy, farmaceutické prostředky je obsahující a jejich farmaceutické použití, způsob a meziprodukty pro jejich výrobu
CA2812362A1 (fr) Inhibiteurs de metalloproteinase matricielle
CA2812361A1 (fr) Inhibiteurs des metalloproteinases matricielles
JP7338711B2 (ja) Ｄｐアンタゴニスト
EP1856063B1 (fr) Derives d'acide-phenyl-pentanoique en tant qu'inhibiteurs de metalloproteinase matricielle dans le traitement de l'asthme et d'autres maladies
US9193699B2 (en) Apoptosis inducing compounds
RAUF et al. International Bureau
HK1115379B (en) 5-phenyl-pentanoic acid derivatives as matrix metalloproteinase inhibitors for the treatment of asthma and other diseases

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201180046151.5

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11763767

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2807097

Country of ref document: CA

Ref document number: 2013522322

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 224513

Country of ref document: IL

Ref document number: 12013500198

Country of ref document: PH

Ref document number: MX/A/2013/001240

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2011763767

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2011284397

Country of ref document: AU

Date of ref document: 20110714

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20137005055

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: DZP2013000127

Country of ref document: DZ

WWE Wipo information: entry into national phase

Ref document number: 13040146

Country of ref document: CO

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112013002370

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112013002370

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20130130