DE69634900T2 - Proteintyrosine-kinaseinhibitoren zur behandlung der osteoarthritis - Google Patents

Proteintyrosine-kinaseinhibitoren zur behandlung der osteoarthritis Download PDF

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Publication number
DE69634900T2
DE69634900T2 DE69634900T DE69634900T DE69634900T2 DE 69634900 T2 DE69634900 T2 DE 69634900T2 DE 69634900 T DE69634900 T DE 69634900T DE 69634900 T DE69634900 T DE 69634900T DE 69634900 T2 DE69634900 T2 DE 69634900T2
Authority
DE
Germany
Prior art keywords
tyrosine kinase
protein tyrosine
kinase inhibitor
chondrocytes
tyrphostin
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.)
Expired - Fee Related
Application number
DE69634900T
Other languages
German (de)
English (en)
Other versions
DE69634900D1 (de
Inventor
R. Thomas SHARPE
W. George VASIOS
Nelson R. CAMPBELL
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.)
Osteoarthritis Sciences Inc Cambridge
OsteoArthritis Sciences Inc
Original Assignee
Osteoarthritis Sciences Inc Cambridge
OsteoArthritis Sciences Inc
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 Osteoarthritis Sciences Inc Cambridge, OsteoArthritis Sciences Inc filed Critical Osteoarthritis Sciences Inc Cambridge
Publication of DE69634900D1 publication Critical patent/DE69634900D1/de
Application granted granted Critical
Publication of DE69634900T2 publication Critical patent/DE69634900T2/de
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/472Non-condensed isoquinolines, e.g. papaverine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • A61K31/165Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/275Nitriles; Isonitriles
    • A61K31/277Nitriles; Isonitriles having a ring, e.g. verapamil
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic 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
    • A61K31/403Heterocyclic 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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035Isoindoles, e.g. phthalimide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/472Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
DE69634900T 1995-09-11 1996-09-11 Proteintyrosine-kinaseinhibitoren zur behandlung der osteoarthritis Expired - Fee Related DE69634900T2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US526290 1990-05-21
US52629095A 1995-09-11 1995-09-11
PCT/US1996/014491 WO1997011692A2 (en) 1995-09-11 1996-09-11 Protein tyrosine kinase inhibitors for treating osteoarthritis

Publications (2)

Publication Number Publication Date
DE69634900D1 DE69634900D1 (de) 2005-08-04
DE69634900T2 true DE69634900T2 (de) 2006-05-18

Family

ID=24096728

Family Applications (1)

Application Number Title Priority Date Filing Date
DE69634900T Expired - Fee Related DE69634900T2 (de) 1995-09-11 1996-09-11 Proteintyrosine-kinaseinhibitoren zur behandlung der osteoarthritis

Country Status (8)

Country Link
US (2) US6552066B1 (https=)
EP (1) EP0850055B1 (https=)
JP (1) JPH11512708A (https=)
AT (1) ATE298566T1 (https=)
AU (1) AU709191B2 (https=)
CA (1) CA2231509C (https=)
DE (1) DE69634900T2 (https=)
WO (1) WO1997011692A2 (https=)

Families Citing this family (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11512708A (ja) * 1995-09-11 1999-11-02 オステオアルスリィティス サイエンシズ,インコーポレイテッド 変形性関節炎を治療するためのプロテインチロシンキナーゼインヒビター
IL119069A0 (en) 1996-08-14 1996-11-14 Mor Research Applic Ltd Pharmaceutical composition comprising tyrphostins
DE19845372A1 (de) * 1998-10-02 2000-04-20 Gruenenthal Gmbh Verwendung von Katecholderivaten als Proteinaseninhibitoren
US6153634A (en) 1998-12-17 2000-11-28 Hoffmann-La Roche Inc. 4,5-azolo-oxindoles
BR9916327A (pt) * 1998-12-17 2001-09-18 Hoffmann La Roche Oxindóis de 4-alquenila (e alquinila) como inibidores de cinases dependentes de ciclina, em particular, cdk2
CN1158283C (zh) 1998-12-17 2004-07-21 霍夫曼-拉罗奇有限公司 作为蛋白激酶抑制剂的4-和5-吡嗪基羟吲哚
EP1149093A1 (en) 1998-12-17 2001-10-31 F. Hoffmann-La Roche Ag 4-aryloxindoles as inhibitors of jnk protein kinases
JP4865129B2 (ja) 1999-01-13 2012-02-01 ザ・リサーチ・ファウンデーション・オブ・ステイト・ユニバーシティ・オブ・ニューヨーク タンパク質キナーゼ阻害剤を設計するための新規の方法
US7070936B1 (en) 1999-01-13 2006-07-04 The Research Foundation Of State University Of New York Method for designing protein kinase inhibitors
RU2271825C2 (ru) * 1999-07-21 2006-03-20 Омерос Корпорейшн Растворы и способы ингибирования боли, воспаления и разрушения хряща
US6313310B1 (en) 1999-12-15 2001-11-06 Hoffmann-La Roche Inc. 4-and 5-alkynyloxindoles and 4-and 5-alkenyloxindoles
EP1875900A3 (en) * 2000-01-24 2010-07-21 Genzyme Corporation JAK/STAT pathway inhibitors and the use thereof for the treatment of osteoarthritis
IL150763A0 (en) * 2000-01-24 2003-02-12 Genzyme Corp Jak/stat inhibitors and pharmaceutical compositions containing the same
EP1275398A4 (en) * 2000-04-06 2004-09-01 Kyowa Hakko Kogyo Kk DIAGNOSTIC AND MEDICINAL PRODUCTS FOR TREATING RHEUMATOID ARTHRITES
US7067550B2 (en) * 2000-11-03 2006-06-27 Massachusetts Institute Of Technology Treatments for neurotoxicity in Alzheimer's Disease
EP1341548A4 (en) * 2000-11-03 2006-06-14 Massachusetts Inst Technology METHOD FOR IDENTIFYING TREATMENTS AGAINST NEUROTOXICITY IN ALZHEIMER DISEASE CAUSED BY $ g (b) -AMYLOIDPEPTIDE
WO2003000188A2 (en) 2001-06-21 2003-01-03 Ariad Pharmaceuticals, Inc. Novel quinazolines and uses thereof
US7129225B2 (en) * 2001-10-22 2006-10-31 The Research Foundation Of State University Of New York Protection against and treatment of hearing loss
US7005445B2 (en) * 2001-10-22 2006-02-28 The Research Foundation Of State University Of New York Protein kinase and phosphatase inhibitors and methods for designing them
ATE361746T1 (de) * 2002-03-06 2007-06-15 Medical Res And Education Trus Botanischer extrakt mit antikrebs-aktivität enthaltend isoliquiritigenin
US6924285B2 (en) 2002-03-30 2005-08-02 Boehringer Ingelheim Pharma Gmbh & Co. Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
GB0309850D0 (en) 2003-04-30 2003-06-04 Astrazeneca Ab Quinazoline derivatives
WO2005003765A1 (en) * 2003-06-30 2005-01-13 Astrazeneca Ab Isothermal titration calorimetry assays
GB0326459D0 (en) 2003-11-13 2003-12-17 Astrazeneca Ab Quinazoline derivatives
WO2006007664A1 (en) * 2004-07-22 2006-01-26 Genomics Research Partners Pty Ltd Agents and methods for diagnosing osteoarthritis
US8697139B2 (en) 2004-09-21 2014-04-15 Frank M. Phillips Method of intervertebral disc treatment using articular chondrocyte cells
EP1838712B8 (en) 2004-12-14 2011-10-12 AstraZeneca AB Pyrazolopyrimidine compounds as antitumor agents
DE102005005274A1 (de) * 2005-02-04 2006-08-10 Peter Heger Verwendung von Hydroxystilben-haltigen Wirkstoffen zur Prävention und Behandlung chronisch-entzündlicher Erkrankungen
WO2007034144A1 (en) 2005-09-20 2007-03-29 Astrazeneca Ab 4- (ih-indazol-s-yl-amino)-quinazoline compounds as erbb receptor tyrosine kinase inhibitors for the treatment of cancer
ES2369739T3 (es) * 2006-03-20 2011-12-05 Seikagaku Corporation Agente terapéutico para la artritis reumatoide.
US7838542B2 (en) * 2006-06-29 2010-11-23 Kinex Pharmaceuticals, Llc Bicyclic compositions and methods for modulating a kinase cascade
EP1921070A1 (de) 2006-11-10 2008-05-14 Boehringer Ingelheim Pharma GmbH & Co. KG Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstelllung
EP2118075A1 (de) 2007-02-06 2009-11-18 Boehringer Ingelheim International GmbH Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung
WO2009026705A1 (en) * 2007-08-24 2009-03-05 The University Of Western Ontario Method of diagnosing and treating osteoarthritis
CA2711582A1 (en) 2008-02-07 2009-08-13 Boehringer Ingelheim International Gmbh Spirocyclic heterocycles, formulations containing said compounds, use thereof and processes for the preparation thereof
EP2303276B1 (en) 2008-05-13 2013-11-13 AstraZeneca AB Fumarate salt of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(n-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline
CN101396369B (zh) * 2008-08-07 2010-12-01 杜宁 槐角苷的制药应用
CA2733153C (en) 2008-08-08 2016-11-08 Boehringer Ingelheim International Gmbh Cyclohexyloxy substituted heterocycles, pharmaceutical compositions containing these compounds and processes for preparing them

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0446120A (ja) 1990-06-11 1992-02-17 Kyowa Hakko Kogyo Co Ltd 血管新生抑制剤
CA2086425C (en) * 1990-07-06 2006-01-17 Craig A. Dionne Fibroblast growth factor receptors
US5262565A (en) * 1990-11-16 1993-11-16 Eisai Co., Ltd. Naphthalene derivatives
JPH06506202A (ja) 1991-03-22 1994-07-14 ゼノバ リミテッド 医薬用キサントン誘導体
JP3176619B2 (ja) 1991-09-05 2001-06-18 ファルノ−ヴェトロファルム ゲゼルシャフト ミット ベシュレンクテル ハフツング 芳香族スルホンアミド化合物、阻害剤及びそれを含有する医薬組成物
GB2262524A (en) 1991-12-18 1993-06-23 Sandoz Ltd Pharmaceutically active 2-hydroxy-benzylamines
CZ285937B6 (cs) 1992-01-16 1999-12-15 Hoechst Aktiengesellschaft Arylcykloalkylové deriváty, způsob přípravy těchto derivátů a jejich použití
US5565448A (en) 1992-02-24 1996-10-15 Smithkline Beecham Corporation Medicament
WO1993018173A2 (en) 1992-03-11 1993-09-16 Xenova Limited Cd4 binding agents and inhibitors of collagenase and protein kinase c
JPH0725761A (ja) * 1993-07-09 1995-01-27 Kureha Chem Ind Co Ltd 軟骨保護剤
AU691820B2 (en) * 1993-07-15 1998-05-28 Cancer Research Campaign Technology Limited Prodrugs of protein tyrosine kinase inhibitors
WO1995005824A1 (en) 1993-08-24 1995-03-02 Smithkline Beecham Corporation Aaptamines and method of use thereof
ATE202571T1 (de) 1993-09-14 2001-07-15 Merck & Co Inc Humane protein-tyrosinphosphatase decodierende cdna
IL107736A (en) * 1993-11-24 2001-01-11 Yissum Res Dev Co Pharmaceutical composition for the prevention of septic shock and for the treatment of chronic inflammatory diseases
US5591740A (en) 1995-06-07 1997-01-07 Osteoarthritis Sciences, Incorporated Use of debromohymenialdisine for treating osteoarthritis
JPH11512708A (ja) * 1995-09-11 1999-11-02 オステオアルスリィティス サイエンシズ,インコーポレイテッド 変形性関節炎を治療するためのプロテインチロシンキナーゼインヒビター
FR2753969B1 (fr) * 1996-09-27 1998-10-30 Adir Nouveaux derives de flavones, leur procede de preparation et les compositions pharmaceutiques qui les contiennent

Also Published As

Publication number Publication date
AU7107496A (en) 1997-04-17
ATE298566T1 (de) 2005-07-15
DE69634900D1 (de) 2005-08-04
CA2231509C (en) 2008-07-08
EP0850055A2 (en) 1998-07-01
WO1997011692A3 (en) 1997-07-03
US6552066B1 (en) 2003-04-22
EP0850055B1 (en) 2005-06-29
JPH11512708A (ja) 1999-11-02
US20030060515A1 (en) 2003-03-27
CA2231509A1 (en) 1997-04-03
WO1997011692A2 (en) 1997-04-03
AU709191B2 (en) 1999-08-26

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