AU2006213814B2 - Proteasome inhibitors and methods of using the same - Google Patents
Proteasome inhibitors and methods of using the same Download PDFInfo
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- AU2006213814B2 AU2006213814B2 AU2006213814A AU2006213814A AU2006213814B2 AU 2006213814 B2 AU2006213814 B2 AU 2006213814B2 AU 2006213814 A AU2006213814 A AU 2006213814A AU 2006213814 A AU2006213814 A AU 2006213814A AU 2006213814 B2 AU2006213814 B2 AU 2006213814B2
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- methano
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- carbonyl
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Landscapes
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| ES2415756T3 (es) | 2005-11-09 | 2013-07-26 | Onyx Therapeutics, Inc. | Compuestos para la inhibición de enzimas |
| ES2415632T3 (es) | 2006-06-19 | 2013-07-26 | Onyx Therapeutics, Inc. | Epoxicetonas peptídicas para la inhibición del proteosoma |
| EP2044055A4 (en) * | 2006-07-21 | 2011-03-23 | Takeda Pharmaceutical | amide compounds |
| CN105837608B (zh) * | 2007-08-06 | 2018-06-08 | 米伦纽姆医药公司 | 蛋白酶体抑制剂及其组合物和用途 |
| WO2009026579A1 (en) * | 2007-08-23 | 2009-02-26 | Cornell Research Foundation, Inc. | Proteasome inhibitors and their use in treating pathogen infection and cancer |
| EP2207791B2 (en) | 2007-10-04 | 2019-08-07 | Onyx Therapeutics, Inc. | Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides |
| JP5600595B2 (ja) * | 2007-10-16 | 2014-10-01 | ミレニアム ファーマシューティカルズ， インコーポレイテッド | プロテアソーム阻害剤 |
| EP2088205A1 (en) | 2008-02-11 | 2009-08-12 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | PSMB10: A diagnosis marker and therapeutic target of chronic rejection. |
| AU2009260778B2 (en) | 2008-06-17 | 2014-08-28 | Takeda Pharmaceutical Company Limited | Boronate ester compounds and pharmaceutical compositions thereof |
| KR20110092266A (ko) * | 2008-08-04 | 2011-08-17 | 씨에이치디아이 파운데이션, 인코포레이티드 | 소정 키누레닌-3-모노옥시게나아제 억제제, 약학적 조성물, 및 그의 사용 방법 |
| AR075090A1 (es) | 2008-09-29 | 2011-03-09 | Millennium Pharm Inc | Derivados de acido 1-amino-2-ciclobutiletilboronico inhibidores de proteosoma,utiles como agentes anticancerigenos, y composiciones farmaceuticas que los comprenden. |
| EA024364B1 (ru) | 2008-10-21 | 2016-09-30 | Оникс Терапьютикс, Инк. | Способ лечения множественной миеломы |
| TWI504598B (zh) | 2009-03-20 | 2015-10-21 | Onyx Therapeutics Inc | 結晶性三肽環氧酮蛋白酶抑制劑 |
| EP2238973A1 (en) | 2009-04-07 | 2010-10-13 | Cephalon France | Lyophilized preparations of proteasome inhibitors |
| WO2011060179A1 (en) | 2009-11-13 | 2011-05-19 | Onyx Therapeutics, Inc | Use of peptide epoxyketones for metastasis suppression |
| CN102725300B (zh) | 2009-12-22 | 2015-03-11 | 赛福伦公司 | 蛋白酶体抑制剂及其制备、纯化、和应用的方法 |
| US8883785B2 (en) | 2010-01-25 | 2014-11-11 | Chdi Foundation, Inc. | Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
| EP2542238B1 (en) | 2010-03-01 | 2015-08-12 | Onyx Therapeutics, Inc. | Compounds for immunoproteasome inhibition |
| US9126997B1 (en) | 2010-09-07 | 2015-09-08 | Northwestern University | Synergistic effect of glucocorticoid receptor agonists in combination with proteosome inhibitors for treating leukemia and myeloma |
| WO2012048745A1 (en) * | 2010-10-14 | 2012-04-19 | Synthon Bv | Process for making bortezomib and intermediates for the process |
| MY166890A (en) | 2011-08-30 | 2018-07-24 | Chdi Foundation Inc | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
| US9428464B2 (en) | 2011-08-30 | 2016-08-30 | Chdi Foundation, Inc. | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
| UY34897A (es) | 2012-07-09 | 2014-01-31 | Onyx Therapeutics Inc | Profarmacos de inhibidores peptidicos de expoxi cetona proteasa |
| WO2014072985A1 (en) * | 2012-11-06 | 2014-05-15 | Natco Pharma Limited | Novel boronic acid derivatives as anti cancer agents |
| US9493439B1 (en) | 2014-04-07 | 2016-11-15 | University Of Kentucky Research Foundation | Proteasome inhibitors |
| CN106458957B (zh) * | 2014-04-08 | 2020-08-18 | 爱博利瓦有限公司 | 新型细胞可渗透琥珀酸化合物 |
| TWI746422B (zh) | 2014-05-20 | 2021-11-21 | 美商千禧製藥公司 | 用於癌症治療的方法 |
| JP2017520610A (ja) | 2014-07-17 | 2017-07-27 | シーエイチディーアイ ファウンデーション，インコーポレーテッド | Ｈｉｖ関連障害を治療するための方法及び組成物 |
| ES2928298T3 (es) * | 2017-02-28 | 2022-11-16 | Chia Tai Tianqing Pharmaceutical Group Co Ltd | Derivado de azetidina |
| GB201808149D0 (en) | 2018-05-18 | 2018-07-11 | Univ Court Univ Of Glasgow | Protected amino acids |
| CN112513052B (zh) * | 2018-08-02 | 2022-12-16 | 正大天晴药业集团股份有限公司 | 氮杂环丁烷衍生物的硼酸酯 |
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| DE3301354A1 (de) | 1983-01-18 | 1984-07-19 | Matth. Hohner Ag, 7218 Trossingen | Elektronisches musikinstrument |
| US4499082A (en) * | 1983-12-05 | 1985-02-12 | E. I. Du Pont De Nemours And Company | α-Aminoboronic acid peptides |
| US4537773A (en) * | 1983-12-05 | 1985-08-27 | E. I. Du Pont De Nemours And Company | α-Aminoboronic acid derivatives |
| US5187157A (en) | 1987-06-05 | 1993-02-16 | Du Pont Merck Pharmaceutical Company | Peptide boronic acid inhibitors of trypsin-like proteases |
| US5250720A (en) * | 1987-06-05 | 1993-10-05 | The Dupont Merck Pharmaceutical Company | Intermediates for preparing peptide boronic acid inhibitors of trypsin-like proteases |
| US5242904A (en) * | 1987-06-05 | 1993-09-07 | The Dupont Merck Pharmaceutical Company | Peptide boronic acid inhibitors of trypsin-like proteases |
| EP0315574A3 (de) * | 1987-11-05 | 1990-08-22 | Hoechst Aktiengesellschaft | Renin-Inhibitoren |
| WO1989009225A1 (en) | 1988-03-28 | 1989-10-05 | The Regents Of The University Of California | Nerve growth factor peptides |
| US5023236A (en) * | 1988-04-07 | 1991-06-11 | Corvas, Inc. | Factor VII/VIIA active site inhibitors |
| US4963655A (en) * | 1988-05-27 | 1990-10-16 | Mayo Foundation For Medical Education And Research | Boron analogs of amino acid/peptide protease inhibitors |
| US5159060A (en) * | 1988-05-27 | 1992-10-27 | Mayo Foundation For Medical Education And Research | Cytotoxic boronic acid peptide analogs |
| US5106948A (en) * | 1988-05-27 | 1992-04-21 | Mao Foundation For Medical Education And Research | Cytotoxic boronic acid peptide analogs |
| DE3827340A1 (de) | 1988-08-12 | 1990-02-15 | Hoechst Ag | Verwendung von (alpha)-aminoboronsaeure-derivaten zur prophylaxe und behandlung von viruserkrankungen |
| IL97428A0 (en) | 1990-03-05 | 1992-06-21 | Cephalon Inc | Chymotrypsin-like proteases and their inhibitors |
| EP0583536B1 (en) | 1992-08-14 | 1997-03-05 | The Procter & Gamble Company | Liquid detergents containing an alpha-amino boronic acid |
| EP0684829A4 (en) | 1993-02-10 | 1997-05-21 | Harvard College | THE ROLE OF ATP-UBIQUITIN-DEPENDENT PROTEOLYSIS IN MHC-1 DEPENDENT ANTIGENT PRESENTATION AND RELATED INHIBITORS. |
| IL109319A0 (en) | 1993-04-27 | 1994-07-31 | Du Pont Merck Pharma | Amidino and guanidino substituted boronic acid compounds |
| US5658885A (en) * | 1993-04-27 | 1997-08-19 | The Dupont Merck Pharmaceutical Company | Amidino and guanidino substituted boronic acid inhibitors of trypsin-like enzymes |
| ES2184763T3 (es) | 1993-04-30 | 2003-04-16 | Merck & Co Inc | Inhibidores de trombina. |
| US5672582A (en) | 1993-04-30 | 1997-09-30 | Merck & Co., Inc. | Thrombin inhibitors |
| FR2707085B1 (fr) | 1993-06-30 | 1995-08-18 | Adir | Nouveaux dérivés d'alpha amino acides, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent. |
| WO1995009838A1 (en) | 1993-10-01 | 1995-04-13 | Merrell Pharmaceuticals Inc. | INHIBITORS OF β-AMYLOID PROTEIN PRODUCTION |
| IL111175A0 (en) | 1993-10-07 | 1994-12-29 | Du Pont Merck Pharma | Electrophilic peptide analogs as inhibitors of trypsin-like serine proteases and pharmaceutical compositions containing them |
| GB9401483D0 (en) | 1994-01-26 | 1994-03-23 | Sandoz Ltd | Organic compounds |
| US5693617A (en) * | 1994-03-15 | 1997-12-02 | Proscript, Inc. | Inhibitors of the 26s proteolytic complex and the 20s proteasome contained therein |
| US6660268B1 (en) | 1994-03-18 | 2003-12-09 | The President And Fellows Of Harvard College | Proteasome regulation of NF-KB activity |
| US6083903A (en) * | 1994-10-28 | 2000-07-04 | Leukosite, Inc. | Boronic ester and acid compounds, synthesis and uses |
| US5614649A (en) * | 1994-11-14 | 1997-03-25 | Cephalon, Inc. | Multicatalytic protease inhibitors |
| US5550262A (en) * | 1994-11-14 | 1996-08-27 | Cephalon, Inc. | Multicatalytic protease inhibitors |
| US5834487A (en) * | 1996-09-24 | 1998-11-10 | Cv Therapeutics | Inhibition of 26S and 20S proteasome by indanones |
| CN1133649C (zh) | 1996-10-18 | 2004-01-07 | 沃泰克斯药物股份有限公司 | 丝氨酸蛋白酶、特别是丙型肝炎病毒ns3蛋白酶的抑制剂 |
| GB9623908D0 (en) | 1996-11-18 | 1997-01-08 | Hoffmann La Roche | Amino acid derivatives |
| US6096778A (en) * | 1997-10-07 | 2000-08-01 | Cephalon, Inc. | α-ketoamide multicatalytic protease inhibitors |
| AU735685B2 (en) | 1997-12-16 | 2001-07-12 | Cephalon, Inc. | Multicatalytic protease inhibitors for use as anti-tumor agents |
| US6075150A (en) * | 1998-01-26 | 2000-06-13 | Cv Therapeutics, Inc. | α-ketoamide inhibitors of 20S proteasome |
| GB9806815D0 (en) * | 1998-03-30 | 1998-05-27 | Hoffmann La Roche | Amino acid derivatives |
| US6462019B1 (en) | 1998-07-10 | 2002-10-08 | Osteoscreen, Inc. | Inhibitors of proteasomal activity and production for stimulating bone growth |
| EP0995757A3 (en) | 1998-08-26 | 2002-05-22 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Bivalent inhibitors of the proteasome |
| HK1040533A1 (zh) | 1998-10-20 | 2002-06-14 | Millennium Pharmaceuticals, Inc. | 监察蛋白脢体抑制剂药物活动的方法 |
| EP1053750A1 (en) | 1999-04-22 | 2000-11-22 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Use of proteasome-inhibitor for the induction of programmed cell death (apoptosis) |
| JP2002543058A (ja) | 1999-04-27 | 2002-12-17 | ノバルティス アクチエンゲゼルシャフト | プロテアソーム・インヒビターとしての２，４−ジアミノ−３−ヒドロキシカルボン酸誘導体の使用 |
| SE9901573D0 (sv) | 1999-05-03 | 1999-05-03 | Astra Ab | New compounds |
| AU5788800A (en) | 1999-07-07 | 2001-01-22 | Du Pont Pharmaceuticals Company | Peptide boronic acid inhibitors of hepatitis c virus protease |
| US7122627B2 (en) | 1999-07-26 | 2006-10-17 | Bristol-Myers Squibb Company | Lactam inhibitors of Hepatitis C virus NS3 protease |
| WO2001020995A1 (en) | 1999-09-23 | 2001-03-29 | Washington University | Compounds directed against pilus biogenesis and activity in pathogenic bacteria; methods and compositions for synthesis thereof |
| JP2003528039A (ja) | 1999-10-20 | 2003-09-24 | オステオスクリーン，インコーポレイテッド | 骨および毛成長を刺激するためのプロテアソーム活性のインヒビター |
| CZ2003195A3 (cs) | 2000-07-21 | 2003-04-16 | Schering Corporation | Peptidové inhibitory serinové proteázy NS3 a farmaceutický prostředek |
| EP1430903A1 (de) | 2000-10-12 | 2004-06-23 | Viromics Gmbh | Verwendung von Proteasome Hemmern zur Behandlung von Virus-Infektionen |
| DE60239384D1 (de) | 2001-01-25 | 2011-04-21 | Us Of America Represented By The Secretary Dept Of Health And Human Services | Formulierungen von borsäure-verbindungen |
| EP1412757A2 (en) | 2001-04-09 | 2004-04-28 | Allan Christian Shaw | Method for identification of proteins from intracellular bacteria |
| WO2002094857A1 (en) | 2001-05-23 | 2002-11-28 | The Curators Of The University Of Missouri | Inverse solid phase synthesis of peptides |
| BR0210112A (pt) | 2001-05-30 | 2004-06-08 | Novartis Ag | Derivados do ácido 2-{[n-(2-amino-3-(heteroarila ou arila)propionil)-aminoacil]-amino}-alquilborÈnico |
| KR100399359B1 (ko) * | 2001-07-07 | 2003-09-26 | 삼성전자주식회사 | 전하 펌프 회로 |
| WO2003015706A2 (en) | 2001-08-16 | 2003-02-27 | Washington State University Research Foundation | Borinic acid protease inhibitors |
| WO2003033507A1 (en) | 2001-10-12 | 2003-04-24 | Kyorin Pharmaceutical Co., Ltd. | Benzylmalonic acid derivatives and proteasome inhibitors contaiing the same |
| JP4412586B2 (ja) * | 2002-01-08 | 2010-02-10 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | エポネマイシンおよびエポキソマイシン類似物およびそれらの用途 |
| US20060237868A1 (en) | 2003-08-13 | 2006-10-26 | Seiko Precision Inc. | Method and device for manufacturing card |
| EP2527347A1 (en) | 2007-08-06 | 2012-11-28 | Millennium Pharmaceuticals, Inc. | Proteasome inhibitors |
-
2006
- 2006-02-09 US US11/351,193 patent/US7468383B2/en not_active Expired - Fee Related
- 2006-02-10 JP JP2007555228A patent/JP2008530108A/ja active Pending
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- 2006-02-10 CA CA2597273A patent/CA2597273C/en not_active Expired - Fee Related
- 2006-02-10 EP EP06734698A patent/EP1846424B1/en not_active Not-in-force
- 2006-02-10 AT AT06734698T patent/ATE456571T1/de active
- 2006-02-10 TW TW095104473A patent/TWI367886B/zh not_active IP Right Cessation
- 2006-02-10 DK DK06734698.1T patent/DK1846424T3/da active
- 2006-02-10 MX MX2007009664A patent/MX2007009664A/es active IP Right Grant
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- 2006-02-10 SI SI200630615T patent/SI1846424T1/sl unknown
- 2006-02-10 AU AU2006213814A patent/AU2006213814B2/en not_active Ceased
- 2006-02-10 WO PCT/US2006/004664 patent/WO2006086600A1/en not_active Ceased
- 2006-02-10 DE DE602006012013T patent/DE602006012013D1/de active Active
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- 2006-02-10 NZ NZ560607A patent/NZ560607A/en not_active IP Right Cessation
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- 2007-07-17 IL IL184678A patent/IL184678A/en not_active IP Right Cessation
-
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- 2008-11-06 US US12/265,998 patent/US8283367B2/en not_active Expired - Fee Related
-
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- 2010-04-27 CY CY20101100375T patent/CY1109985T1/el unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005021558A2 (en) * | 2003-08-14 | 2005-03-10 | Cephalon, Inc. | Proteasome inhibitors and methods of using the same |
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| US20090075936A1 (en) | 2009-03-19 |
| PL1846424T3 (pl) | 2010-06-30 |
| CA2597273A1 (en) | 2006-08-17 |
| EP1846424B1 (en) | 2010-01-27 |
| IL184678A0 (en) | 2007-12-03 |
| EP1846424A1 (en) | 2007-10-24 |
| CY1109985T1 (el) | 2014-09-10 |
| NZ560607A (en) | 2009-11-27 |
| HK1106534A1 (en) | 2008-03-14 |
| DE602006012013D1 (de) | 2010-03-18 |
| MX2007009664A (es) | 2007-09-26 |
| SI1846424T1 (sl) | 2010-05-31 |
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| AU2006213814A1 (en) | 2006-08-17 |
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| US8283367B2 (en) | 2012-10-09 |
| IL184678A (en) | 2012-05-31 |
| US7468383B2 (en) | 2008-12-23 |
| MY147921A (en) | 2013-02-15 |
| CA2597273C (en) | 2013-12-17 |
| JP2008530108A (ja) | 2008-08-07 |
| ATE456571T1 (de) | 2010-02-15 |
| ES2339698T3 (es) | 2010-05-24 |
| US20060189806A1 (en) | 2006-08-24 |
| PT1846424E (pt) | 2010-04-15 |
| DK1846424T3 (da) | 2010-05-17 |
| WO2006086600A1 (en) | 2006-08-17 |
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