AU2003263431A1 - Novel isothiazole and isoxazole compounds as transforming growth factor (tgf) inhibitors - Google Patents
Novel isothiazole and isoxazole compounds as transforming growth factor (tgf) inhibitors Download PDFInfo
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- AU2003263431A1 AU2003263431A1 AU2003263431A AU2003263431A AU2003263431A1 AU 2003263431 A1 AU2003263431 A1 AU 2003263431A1 AU 2003263431 A AU2003263431 A AU 2003263431A AU 2003263431 A AU2003263431 A AU 2003263431A AU 2003263431 A1 AU2003263431 A1 AU 2003263431A1
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- Prior art keywords
- alkyl
- compound
- phenyl
- alkoxy
- cycloalkyl
- 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.)
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- 102000009618 Transforming Growth Factors Human genes 0.000 title description 18
- 108010009583 Transforming Growth Factors Proteins 0.000 title description 18
- 239000003112 inhibitor Substances 0.000 title description 10
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 title description 5
- 150000002545 isoxazoles Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 144
- 125000000217 alkyl group Chemical group 0.000 claims description 91
- -1 hydroxy, oxo, mercapto Chemical class 0.000 claims description 62
- 150000003839 salts Chemical class 0.000 claims description 36
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 201000010099 disease Diseases 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
- 239000000651 prodrug Substances 0.000 claims description 20
- 229940002612 prodrug Drugs 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 12
- 241001465754 Metazoa Species 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000003282 alkyl amino group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 8
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 5
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 5
- 125000003368 amide group Chemical group 0.000 claims description 5
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- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
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- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 3
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (5)
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| US41213102P | 2002-09-18 | 2002-09-18 | |
| US60/412,131 | 2002-09-18 | ||
| US48458003P | 2003-07-02 | 2003-07-02 | |
| US60/484,580 | 2003-07-02 | ||
| PCT/IB2003/004005 WO2004026865A1 (en) | 2002-09-18 | 2003-09-12 | Novel isothiazole and isoxazole compounds as transforming growth factor (tgf) inhibitors |
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| AU2003263431A1 true AU2003263431A1 (en) | 2004-04-08 |
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| AU (1) | AU2003263431A1 (enExample) |
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| CO (1) | CO5550458A2 (enExample) |
| EA (1) | EA200500286A1 (enExample) |
| EC (1) | ECSP055685A (enExample) |
| HR (1) | HRP20050246A2 (enExample) |
| IS (1) | IS7695A (enExample) |
| MA (1) | MA27444A1 (enExample) |
| MX (1) | MXPA05002378A (enExample) |
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| CA2498047C (en) * | 2002-09-18 | 2009-05-19 | Pfizer Products Inc. | Novel imidazole compounds as transforming growth factor (tgf) inhibitors |
| PL375975A1 (en) | 2002-09-18 | 2005-12-12 | Pfizer Products Inc. | Novel oxazole and thiazole compounds as transforming growth factor (tgf) inhibitors |
| EP1542684B1 (en) * | 2002-09-18 | 2009-12-02 | Pfizer Products Inc. | Novel pyrazole compounds as transforming growth factor (tgf) inhibitors |
| PA8595001A1 (es) * | 2003-03-04 | 2004-09-28 | Pfizer Prod Inc | Nuevos compuestos heteroaromaticos condensados que son inhibidores del factor de crecimiento transforante (tgf) |
| US7951805B2 (en) | 2004-09-20 | 2011-05-31 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase |
| US8071603B2 (en) | 2004-09-20 | 2011-12-06 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors |
| WO2006101521A2 (en) | 2004-09-20 | 2006-09-28 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors |
| EP2316458A1 (en) | 2004-09-20 | 2011-05-04 | Xenon Pharmaceuticals Inc. | Pyridazine derivatives for inhibiting human stearoyl-coa-desaturase |
| AU2005286647A1 (en) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors |
| AR051026A1 (es) | 2004-09-20 | 2006-12-13 | Xenon Pharmaceuticals Inc | Derivados heterociclicos y su uso como inhibidores de la estearoil-coa desaturasa |
| AU2005286846A1 (en) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as therapeutic agents |
| EP1919882A2 (en) | 2005-02-17 | 2008-05-14 | Synta Pharmaceuticals Corporation | Isoxazole combretastatin derivatives for the treatment of proliferative disorders |
| JP2009513563A (ja) | 2005-06-03 | 2009-04-02 | ゼノン・ファーマシューティカルズ・インコーポレイテッド | ヒトのステアロイル−ＣｏＡデサチュラーゼ阻害剤としてのアミノチアゾール誘導体 |
| BRPI0619966A2 (pt) * | 2005-12-16 | 2011-10-25 | Alcon Inc | controle de pressão intra-ocular usando agentes de modulação de alk5 |
| TWI453207B (zh) | 2008-09-08 | 2014-09-21 | Signal Pharm Llc | 胺基三唑并吡啶，其組合物及使用其之治療方法 |
| BR112015023261A2 (pt) | 2013-03-14 | 2017-07-18 | Massachusetts Inst Technology | composições e métodos para expansão e cultura de células-tronco epiteliais |
| LT3089971T (lt) | 2014-01-01 | 2020-10-12 | Medivation Technologies Llc | Junginiai ir panaudojimo būdai |
| KR102493376B1 (ko) | 2014-09-03 | 2023-01-27 | 더 브리검 앤드 우먼즈 하스피털, 인크. | 청력 손실의 치료를 위해 내이 털세포를 생성하기 위한 조성물, 시스템, 및 방법 |
| EP3313420B1 (en) | 2015-06-25 | 2024-03-13 | The Children's Medical Center Corporation | Methods and compositions relating to hematopoietic stem cell expansion, enrichment, and maintenance |
| JP2019506153A (ja) | 2016-01-08 | 2019-03-07 | マサチューセッツ インスティテュート オブ テクノロジー | 分化した腸内分泌細胞およびインスリン産生細胞の作製 |
| US10213511B2 (en) | 2016-03-02 | 2019-02-26 | Frequency Therapeutics, Inc. | Thermoreversible compositions for administration of therapeutic agents |
| US11260130B2 (en) | 2016-03-02 | 2022-03-01 | Frequency Therapeutics, Inc. | Solubilized compositions for controlled proliferation of stem cells / generating inner ear hair cells using a GSK3 inhibitor: IV |
| US10201540B2 (en) | 2016-03-02 | 2019-02-12 | Frequency Therapeutics, Inc. | Solubilized compositions for controlled proliferation of stem cells / generating inner ear hair cells using GSK3 inhibitors: I |
| AU2017235461B2 (en) | 2016-03-15 | 2023-02-23 | Children's Medical Center Corporation | Methods and compositions relating to hematopoietic stem cell expansion |
| CA3048220A1 (en) | 2016-12-30 | 2018-07-05 | Frequency Therapeutics, Inc. | 1h-pyrrole-2,5-dione compounds and methods of using them to induce self-renewal of stem/progenitor supporting cells |
| AU2019240065A1 (en) | 2018-03-20 | 2020-09-24 | Icahn School Of Medicine At Mount Sinai | Kinase inhibitor compounds and compositions and methods of use |
| US20210254006A1 (en) | 2018-06-06 | 2021-08-19 | Ideaya Biosciences, Inc. | Methods of culturing and/or expanding stem cells and/or lineage committed progenitor cells using lactam compounds |
| EP3837351A1 (en) | 2018-08-17 | 2021-06-23 | Frequency Therapeutics, Inc. | Compositions and methods for generating hair cells by downregulating foxo |
| CA3109647A1 (en) | 2018-08-17 | 2020-02-20 | Frequency Therapeutics, Inc. | Compositions and methods for generating hair cells by upregulating jag-1 |
| CA3124700A1 (en) | 2018-12-31 | 2020-07-09 | Icahn School Of Medicine At Mount Sinai | Kinase inhibitor compounds and compositions and methods of use |
Family Cites Families (18)
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| JPS5095272A (enExample) * | 1973-12-24 | 1975-07-29 | ||
| US6514977B1 (en) | 1997-05-22 | 2003-02-04 | G.D. Searle & Company | Substituted pyrazoles as p38 kinase inhibitors |
| PL336990A1 (en) | 1997-05-22 | 2000-07-31 | Searle & Co | 3(5)-heteroaryl group substituted pyrazoles as inhibitors of kinase p 38 |
| CA2288787A1 (en) | 1997-05-22 | 1998-11-26 | G.D. Searle And Co. | Pyrazole derivatives as p38 kinase inhibitors |
| ES2187473T3 (es) | 1999-04-09 | 2003-06-16 | Smithkline Beecham Corp | Triarylimidazoles. |
| AR029803A1 (es) | 2000-02-21 | 2003-07-16 | Smithkline Beecham Plc | Imidazoles sustituidos con piridilo y composiciones farmaceuticas que las comprenden |
| GB0007405D0 (en) | 2000-03-27 | 2000-05-17 | Smithkline Beecham Corp | Compounds |
| PE20020506A1 (es) | 2000-08-22 | 2002-07-09 | Glaxo Group Ltd | Derivados de pirazol fusionados como inhibidores de la proteina cinasa |
| GB0027987D0 (en) * | 2000-11-16 | 2001-01-03 | Smithkline Beecham Plc | Compounds |
| WO2002040468A1 (en) | 2000-11-16 | 2002-05-23 | Smithkline Beecham Corporation | Compounds |
| GB0100762D0 (en) | 2001-01-11 | 2001-02-21 | Smithkline Beecham Plc | Novel use |
| JP2004521915A (ja) * | 2001-02-02 | 2004-07-22 | グラクソ グループ リミテッド | Ｔｇｆ過剰発現に対するピラゾール誘導体 |
| GB0102672D0 (en) * | 2001-02-02 | 2001-03-21 | Glaxo Group Ltd | Compounds |
| WO2002062787A1 (en) * | 2001-02-02 | 2002-08-15 | Glaxo Group Limited | Pyrazoles as tgf inhibitors |
| GB0102668D0 (en) * | 2001-02-02 | 2001-03-21 | Glaxo Group Ltd | Compounds |
| US6673818B2 (en) * | 2001-04-20 | 2004-01-06 | Pharmacia Corporation | Fluoro-substituted benzenesulfonyl compounds for the treatment of inflammation |
| AR039241A1 (es) | 2002-04-04 | 2005-02-16 | Biogen Inc | Heteroarilos trisustituidos y metodos para su produccion y uso de los mismos |
| JP2005539000A (ja) | 2002-07-31 | 2005-12-22 | スミスクライン・ビーチャム・コーポレイション | Ａｌｋ５阻害剤としての２−フェニルピリジン−４−イル誘導体 |
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2003
- 2003-09-12 MX MXPA05002378A patent/MXPA05002378A/es active IP Right Grant
- 2003-09-12 CA CA002499332A patent/CA2499332A1/en not_active Abandoned
- 2003-09-12 AU AU2003263431A patent/AU2003263431A1/en not_active Abandoned
- 2003-09-12 CN CNA038222043A patent/CN1681809A/zh active Pending
- 2003-09-12 HR HR20050246A patent/HRP20050246A2/hr not_active Application Discontinuation
- 2003-09-12 EP EP03797466A patent/EP1542995A1/en not_active Withdrawn
- 2003-09-12 JP JP2004568905A patent/JP2006506443A/ja not_active Withdrawn
- 2003-09-12 WO PCT/IB2003/004005 patent/WO2004026865A1/en not_active Ceased
- 2003-09-12 AP AP2005003262A patent/AP2005003262A0/xx unknown
- 2003-09-12 EA EA200500286A patent/EA200500286A1/ru unknown
- 2003-09-12 PL PL03375973A patent/PL375973A1/xx not_active Application Discontinuation
- 2003-09-12 OA OA1200500074A patent/OA12925A/en unknown
- 2003-09-12 KR KR1020057004662A patent/KR20050057441A/ko not_active Ceased
- 2003-09-12 BR BR0314286-8A patent/BR0314286A/pt not_active IP Right Cessation
- 2003-09-15 TW TW092125380A patent/TW200410954A/zh unknown
- 2003-09-16 UY UY27983A patent/UY27983A1/es not_active Application Discontinuation
- 2003-09-16 AR ARP030103359A patent/AR041275A1/es unknown
- 2003-09-17 PE PE2003000951A patent/PE20050076A1/es not_active Application Discontinuation
- 2003-09-17 PA PA20038583101A patent/PA8583101A1/es unknown
- 2003-09-17 US US10/667,167 patent/US7030125B2/en not_active Expired - Fee Related
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2005
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- 2005-03-17 EC EC2005005685A patent/ECSP055685A/es unknown
- 2005-03-18 CO CO05025189A patent/CO5550458A2/es not_active Application Discontinuation
- 2005-03-18 MA MA28158A patent/MA27444A1/fr unknown
- 2005-04-15 NO NO20051852A patent/NO20051852L/no unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BR0314286A (pt) | 2005-08-02 |
| ECSP055685A (es) | 2005-05-30 |
| NO20051852L (no) | 2005-06-16 |
| CA2499332A1 (en) | 2004-04-01 |
| AR041275A1 (es) | 2005-05-11 |
| AP2005003262A0 (en) | 2005-03-31 |
| TW200410954A (en) | 2004-07-01 |
| UY27983A1 (es) | 2004-04-30 |
| IS7695A (is) | 2005-02-14 |
| KR20050057441A (ko) | 2005-06-16 |
| HRP20050246A2 (en) | 2005-10-31 |
| WO2004026865A1 (en) | 2004-04-01 |
| US7030125B2 (en) | 2006-04-18 |
| MXPA05002378A (es) | 2005-05-23 |
| OA12925A (en) | 2006-10-13 |
| PA8583101A1 (es) | 2004-04-23 |
| US20040116473A1 (en) | 2004-06-17 |
| PL375973A1 (en) | 2005-12-12 |
| EP1542995A1 (en) | 2005-06-22 |
| EA200500286A1 (ru) | 2005-08-25 |
| PE20050076A1 (es) | 2005-03-26 |
| MA27444A1 (fr) | 2005-07-01 |
| JP2006506443A (ja) | 2006-02-23 |
| CO5550458A2 (es) | 2005-08-31 |
| CN1681809A (zh) | 2005-10-12 |
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