HRP20050247A2 - Pyrazole derivatives as transforming growth factor (tgf) inhibitors - Google Patents
Pyrazole derivatives as transforming growth factor (tgf) inhibitors Download PDFInfo
- Publication number
- HRP20050247A2 HRP20050247A2 HR20050247A HRP20050247A HRP20050247A2 HR P20050247 A2 HRP20050247 A2 HR P20050247A2 HR 20050247 A HR20050247 A HR 20050247A HR P20050247 A HRP20050247 A HR P20050247A HR P20050247 A2 HRP20050247 A2 HR P20050247A2
- Authority
- HR
- Croatia
- Prior art keywords
- alkyl
- phenyl
- cycloalkyl
- heteroaryl
- heterocycle
- Prior art date
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- 102000009618 Transforming Growth Factors Human genes 0.000 title description 16
- 108010009583 Transforming Growth Factors Proteins 0.000 title description 16
- 239000003112 inhibitor Substances 0.000 title description 8
- 150000003217 pyrazoles Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 166
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 106
- -1 hydroxy, oxo, mercapto Chemical class 0.000 claims description 55
- 238000000034 method Methods 0.000 claims description 35
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 26
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 25
- 125000001072 heteroaryl group Chemical group 0.000 claims description 24
- 239000000651 prodrug Substances 0.000 claims description 21
- 229940002612 prodrug Drugs 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
- 125000000623 heterocyclic group Chemical group 0.000 claims description 18
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 12
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 12
- 241001465754 Metazoa Species 0.000 claims description 11
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- 125000000172 C5-C10 aryl group Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 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 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000003368 amide group Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000003367 polycyclic group Chemical group 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 3
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 3
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 2
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- 125000006721 (C5-C10) heteroaryl (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 208000032544 Cicatrix Diseases 0.000 claims description 2
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 2
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 2
- 206010039710 Scleroderma Diseases 0.000 claims description 2
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 2
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- 150000002431 hydrogen Chemical class 0.000 claims 2
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 238000002360 preparation method Methods 0.000 description 60
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- 230000014759 maintenance of location Effects 0.000 description 21
- 239000002253 acid Substances 0.000 description 20
- 238000004128 high performance liquid chromatography Methods 0.000 description 20
- 239000002585 base Substances 0.000 description 19
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
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- 239000000543 intermediate Substances 0.000 description 9
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 9
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 8
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- 238000009472 formulation Methods 0.000 description 6
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
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- C—CHEMISTRY; METALLURGY
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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US41214602P | 2002-09-18 | 2002-09-18 | |
US48454303P | 2003-07-02 | 2003-07-02 | |
PCT/IB2003/003933 WO2004026306A2 (en) | 2002-09-18 | 2003-09-08 | Pyrazole derivatives as transforming growth factor (tgf) inhibitors |
Publications (1)
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HRP20050247A2 true HRP20050247A2 (en) | 2005-10-31 |
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EP (2) | EP1542684B1 (es) |
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KR (1) | KR20050044807A (es) |
CN (1) | CN1681501A (es) |
AP (1) | AP2005003263A0 (es) |
AR (1) | AR041272A1 (es) |
AT (1) | ATE450258T1 (es) |
AU (1) | AU2003259475A1 (es) |
BR (1) | BR0314302A (es) |
CA (1) | CA2496295C (es) |
CO (1) | CO5550456A2 (es) |
DE (1) | DE60330362D1 (es) |
EA (1) | EA200500377A1 (es) |
EC (1) | ECSP055679A (es) |
ES (1) | ES2335099T3 (es) |
HR (1) | HRP20050247A2 (es) |
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MA (1) | MA27440A1 (es) |
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OA (1) | OA12929A (es) |
PA (1) | PA8583201A1 (es) |
PE (1) | PE20040988A1 (es) |
PL (1) | PL375979A1 (es) |
UY (1) | UY27985A1 (es) |
WO (1) | WO2004026306A2 (es) |
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PL375979A1 (en) * | 2002-09-18 | 2005-12-12 | Pfizer Products Inc. | Pyrazole derivatives as transforming growth factor (tgf) inhibitors |
ES2325687T3 (es) * | 2002-09-18 | 2009-09-14 | Pfizer Products Inc. | Compuestos de imidazol novedosos como inhibidores del factor de crecimiento transformante (tgf). |
MXPA05002332A (es) | 2002-09-18 | 2005-06-08 | Pfizer Prod Inc | Nuevos compuestos de oxazol y tiazol como inhibidores del factor de crecimiento transformador (tgf). |
CL2004000234A1 (es) * | 2003-02-12 | 2005-04-15 | Biogen Idec Inc | Compuestos derivados 3-(piridin-2-il)-4-heteroaril-pirazol sustituidos, antagonistas de aik5 y/o aik4; composicion farmaceutica y uso del compuesto en el tratamiento de desordenes fibroticos como esclerodermia, lupus nefritico, cicatrizacion de herid |
PA8595001A1 (es) | 2003-03-04 | 2004-09-28 | Pfizer Prod Inc | Nuevos compuestos heteroaromaticos condensados que son inhibidores del factor de crecimiento transforante (tgf) |
GB0313915D0 (en) * | 2003-06-16 | 2003-07-23 | Smithkline Beecham Corp | Compounds |
JP2008511630A (ja) * | 2004-08-31 | 2008-04-17 | バイオジェン・アイデック・エムエイ・インコーポレイテッド | TGF−βインヒビターとしてのピリミジニルピラゾール |
US20070275968A1 (en) * | 2004-09-07 | 2007-11-29 | Hitoshi Kurata | Substituted Biphenyl Derivative |
EP1804801A2 (en) * | 2004-10-15 | 2007-07-11 | Biogen Idec MA, Inc. | Methods of treating vascular injuries |
TW200639163A (en) | 2005-02-04 | 2006-11-16 | Genentech Inc | RAF inhibitor compounds and methods |
WO2007070866A2 (en) * | 2005-12-16 | 2007-06-21 | Alcon, Inc. | Control of intraocular pressure using alk5 modulation agents |
GEP20115239B (en) | 2006-10-31 | 2011-06-10 | Pfizer Prod Inc | Pyrazoline compounds as mineralocorticoid receptor antagonists |
CA2695114A1 (en) | 2007-08-01 | 2009-02-05 | Pfizer Inc. | Pyrazole compounds and their use as raf inhibitors |
ES2813875T3 (es) | 2014-01-01 | 2021-03-25 | Medivation Tech Llc | Compuestos y procedimientos de uso |
EP3277673B1 (en) | 2015-04-01 | 2022-05-04 | Rigel Pharmaceuticals, Inc. | Tgf-beta inhibitors |
US10669528B2 (en) | 2015-06-25 | 2020-06-02 | Children's Medical Center Corporation | Methods and compositions relating to hematopoietic stem cell expansion, enrichment, and maintenance |
US20190119642A1 (en) | 2016-03-15 | 2019-04-25 | Children's Medical Center Corporation | Methods and compositions relating to hematopoietic stem cell expansion |
JP6954932B2 (ja) * | 2016-06-13 | 2021-10-27 | ジェンフリート セラピューティクス(シャンハイ)インコーポレイテッド | TGF−βRI阻害剤としてのベンゾトリアゾール由来のα、β−不飽和アミド系化合物 |
JP2019531753A (ja) * | 2016-10-26 | 2019-11-07 | アイカーン スクール オブ メディシン アット マウント サイナイ | 膵β細胞における細胞増殖を増加させるための方法、治療方法、及び組成物 |
MX2019004822A (es) | 2016-11-14 | 2019-09-11 | Jiangsu Hengrui Medicine Co | Derivado del pirazol 3,4-bipiridilo y metodo de preparacion del mismo y aplicacion medica del mismo. |
JP2021503486A (ja) | 2017-11-20 | 2021-02-12 | アイカーン スクール オブ メディシン アット マウント サイナイ | キナーゼ阻害剤化合物ならびに組成物および使用法 |
US11236112B2 (en) | 2017-12-13 | 2022-02-01 | Genfleet Therapeutics (Shanghai) Inc. | Crystal form and salt form of TGF-βRI inhibitor and preparation method therefor |
US11788064B2 (en) | 2018-01-05 | 2023-10-17 | Icahn School Of Medicine At Mount Sinai | Method of increasing proliferation of pancreatic beta cells, treatment method, and composition |
US11866427B2 (en) | 2018-03-20 | 2024-01-09 | Icahn School Of Medicine At Mount Sinai | Kinase inhibitor compounds and compositions and methods of use |
TW202012390A (zh) * | 2018-06-29 | 2020-04-01 | 日商日本歐愛特農業科技股份有限公司 | 新穎之經取代吡唑衍生物 |
EP3886854A4 (en) | 2018-11-30 | 2022-07-06 | Nuvation Bio Inc. | PYRROLE AND PYRAZOLE COMPOUNDS AND METHODS OF USE THERE |
BR112021011224A2 (pt) | 2018-12-11 | 2021-08-24 | Theravance Biopharma R&D Ip, Llc | Inibidores de alk5 |
CN110467601B (zh) * | 2019-08-29 | 2021-07-02 | 杭州市西溪医院 | 一种吡唑联吡啶酮类化合物、中间体及其制备方法及应用 |
CA3160307A1 (en) | 2019-11-22 | 2021-05-27 | Theravance Biopharma R&D Ip, Llc | Substituted 1,5-naphthyridines or quinolines as alk5 inhibitors |
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US4060598A (en) | 1967-06-28 | 1977-11-29 | Boehringer Mannheim G.M.B.H. | Tablets coated with aqueous resin dispersions |
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JP3734180B2 (ja) * | 1994-12-28 | 2006-01-11 | エーザイ株式会社 | 新規ピラゾール誘導体 |
US6087381A (en) | 1997-05-22 | 2000-07-11 | G. D. Searle & Company | Pyrazole derivatives as p38 kinase inhibitors |
RU2249591C2 (ru) | 1997-05-22 | 2005-04-10 | Дж.Д. Серл Энд Ко. | 3(5)-гетероарилзамещенные пиразолы в качестве ингибиторов киназы p38 |
US6514977B1 (en) | 1997-05-22 | 2003-02-04 | G.D. Searle & Company | Substituted pyrazoles as p38 kinase inhibitors |
DE60001229T2 (de) | 1999-04-09 | 2003-10-30 | Smithkline Beecham Corp., Philadelphia | Triarylimidazole |
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 |
WO2002040468A1 (en) | 2000-11-16 | 2002-05-23 | Smithkline Beecham Corporation | Compounds |
GB0027987D0 (en) | 2000-11-16 | 2001-01-03 | Smithkline Beecham Plc | Compounds |
GB0100762D0 (en) | 2001-01-11 | 2001-02-21 | Smithkline Beecham Plc | Novel use |
EP1355903B1 (en) * | 2001-02-02 | 2005-03-16 | SmithKline Beecham Corporation | Pyrazole derivatives against tgf overexpression |
GB0102672D0 (en) * | 2001-02-02 | 2001-03-21 | Glaxo Group Ltd | Compounds |
US20040097502A1 (en) * | 2001-02-02 | 2004-05-20 | Gellibert Francoise Jeanne | Pyrazoles as tgf inhibitors |
AP2002002460A0 (en) | 2001-03-09 | 2002-06-30 | Pfizer Prod Inc | Novel benzimidazole anti-inflammatory compounds. |
ATE402164T1 (de) * | 2001-04-26 | 2008-08-15 | Eisai R&D Man Co Ltd | Stickstoffhaltige verbindung mit kondensiertem ring und pyrazolylgruppe als substituent und medizinische zusammensetzung davon |
AR039241A1 (es) | 2002-04-04 | 2005-02-16 | Biogen Inc | Heteroarilos trisustituidos y metodos para su produccion y uso de los mismos |
AR040726A1 (es) | 2002-07-31 | 2005-04-20 | Smithkline Beecham Corp | Compuesto de 2- fenilpiridin-4-il-heterociclico, composicion farmaceutica que lo comprende y su uso para la fabricacion de un medicamento |
PL375979A1 (en) | 2002-09-18 | 2005-12-12 | Pfizer Products Inc. | Pyrazole derivatives as transforming growth factor (tgf) inhibitors |
BR0314577A (pt) | 2002-09-18 | 2005-08-09 | Pfizer Prod Inc | Derivados de triazol como inibidores do fator de crescimento de transformação (tgf) |
AP2005003262A0 (en) | 2002-09-18 | 2005-03-31 | Pfizer Prod Inc | Novel isothiazole and isoxazole compounds as tranforming growth factor (TGF) inhibitors. |
MXPA05002332A (es) | 2002-09-18 | 2005-06-08 | Pfizer Prod Inc | Nuevos compuestos de oxazol y tiazol como inhibidores del factor de crecimiento transformador (tgf). |
ES2325687T3 (es) | 2002-09-18 | 2009-09-14 | Pfizer Products Inc. | Compuestos de imidazol novedosos como inhibidores del factor de crecimiento transformante (tgf). |
PA8595001A1 (es) | 2003-03-04 | 2004-09-28 | Pfizer Prod Inc | Nuevos compuestos heteroaromaticos condensados que son inhibidores del factor de crecimiento transforante (tgf) |
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2003
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- 2003-09-08 AU AU2003259475A patent/AU2003259475A1/en not_active Abandoned
- 2003-09-08 EP EP03797443A patent/EP1542684B1/en not_active Expired - Lifetime
- 2003-09-08 DE DE60330362T patent/DE60330362D1/de not_active Expired - Lifetime
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- 2003-09-08 OA OA1200500078A patent/OA12929A/en unknown
- 2003-09-08 EA EA200500377A patent/EA200500377A1/ru unknown
- 2003-09-08 KR KR1020057004598A patent/KR20050044807A/ko not_active Application Discontinuation
- 2003-09-08 CA CA2496295A patent/CA2496295C/en not_active Expired - Fee Related
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- 2003-09-08 JP JP2004568904A patent/JP4519657B2/ja not_active Expired - Fee Related
- 2003-09-08 CN CNA038222655A patent/CN1681501A/zh active Pending
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- 2003-09-08 ES ES03797443T patent/ES2335099T3/es not_active Expired - Lifetime
- 2003-09-08 BR BR0314302-3A patent/BR0314302A/pt not_active IP Right Cessation
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- 2003-09-16 AR ARP030103356A patent/AR041272A1/es unknown
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- 2003-09-17 US US10/667,189 patent/US6958354B2/en not_active Expired - Fee Related
- 2003-09-17 PA PA20038583201A patent/PA8583201A1/es unknown
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2005
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- 2005-02-17 IS IS7698A patent/IS7698A/is unknown
- 2005-03-16 CO CO05024529A patent/CO5550456A2/es not_active Application Discontinuation
- 2005-03-16 EC EC2005005679A patent/ECSP055679A/es unknown
- 2005-03-16 HR HR20050247A patent/HRP20050247A2/hr not_active Application Discontinuation
- 2005-03-18 MA MA28154A patent/MA27440A1/fr unknown
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2006
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- 2009-11-12 US US12/617,027 patent/US20100056571A1/en not_active Abandoned
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