ES2756748T3 - Uso de derivados de piridilo bicíclicos de anillo fusionado como inhibidores de fgfr4 - Google Patents
Uso de derivados de piridilo bicíclicos de anillo fusionado como inhibidores de fgfr4 Download PDFInfo
- Publication number
- ES2756748T3 ES2756748T3 ES15781518T ES15781518T ES2756748T3 ES 2756748 T3 ES2756748 T3 ES 2756748T3 ES 15781518 T ES15781518 T ES 15781518T ES 15781518 T ES15781518 T ES 15781518T ES 2756748 T3 ES2756748 T3 ES 2756748T3
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- Prior art keywords
- alkyl
- fgfr4
- ring
- dihydro
- carboxamide
- Prior art date
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- 101150082429 FGFR4 gene Proteins 0.000 title 1
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- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 42
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- 150000001860 citric acid derivatives Chemical class 0.000 claims description 3
- HXNZAVZZAPTZBP-UHFFFAOYSA-N N-(5-cyanopyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide Chemical compound OCc1cc2CCCN(C(=O)Nc3ccc(cn3)C#N)c2nc1C=O HXNZAVZZAPTZBP-UHFFFAOYSA-N 0.000 claims 1
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- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical group [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 claims 1
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 abstract description 5
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- BGVAIBDDJMMAML-UHFFFAOYSA-N phenyl n-(5-cyanopyridin-2-yl)carbamate Chemical compound C=1C=CC=CC=1OC(=O)NC1=CC=C(C#N)C=N1 BGVAIBDDJMMAML-UHFFFAOYSA-N 0.000 description 1
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
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Classifications
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- 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
- A61K31/435—Heterocyclic 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
- A61K31/4353—Heterocyclic 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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic 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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- 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
- A61K31/435—Heterocyclic 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A—HUMAN NECESSITIES
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- 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
- A61K31/495—Heterocyclic 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
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- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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| PCT/US2015/053677 WO2016054483A1 (en) | 2014-10-03 | 2015-10-02 | Use of ring-fused bicyclic pyridyl derivatives as fgfr4 inhibitors |
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| CN114364798A (zh) | 2019-03-21 | 2022-04-15 | 欧恩科斯欧公司 | 用于治疗癌症的Dbait分子与激酶抑制剂的组合 |
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Family Cites Families (65)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5424186A (en) | 1989-06-07 | 1995-06-13 | Affymax Technologies N.V. | Very large scale immobilized polymer synthesis |
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| GB9420999D0 (en) | 1994-10-18 | 1994-12-07 | Smithkline Beecham Plc | Novel compounds |
| CA2261633A1 (en) | 1996-07-29 | 1998-02-05 | Banyu Pharmaceutical Co., Ltd. | Chemokine receptor antagonists |
| US6048861A (en) | 1997-12-17 | 2000-04-11 | Merck & Co., Inc. | Integrin receptor antagonists |
| CO4980854A1 (es) | 1998-02-10 | 2000-11-27 | Novartis Ag | Inhibidores de celulas b particularmente amidas, proceso par su produccion y composiciones farmaceuticas que los contiene |
| CA2386474A1 (en) | 1999-09-20 | 2001-03-29 | Takeda Chemical Industries, Ltd. | Melanin concentrating hormone antagonist |
| WO2001034602A2 (en) * | 1999-11-08 | 2001-05-17 | Merck & Co., Inc. | Process and intermediates for the preparation of imidazolidinone alpha v integrin antagonists |
| US6407241B1 (en) | 1999-11-08 | 2002-06-18 | Merck & Co., Inc. | Process and intermediates for the preparation of imidazolidinone αv integrin antagonists |
| JPWO2003068753A1 (ja) | 2002-02-14 | 2005-06-02 | 小野薬品工業株式会社 | Ｎ−カルバモイル窒素含有縮合環化合物およびその化合物を有効成分として含有する薬剤 |
| JPWO2004007472A1 (ja) | 2002-07-10 | 2005-11-17 | 小野薬品工業株式会社 | Ｃｃｒ４アンタゴニストおよびその医薬用途 |
| BR0313871A (pt) * | 2002-08-30 | 2005-07-19 | Eisai Co Ltd | Derivados aromáticos contendo nitrogênio |
| US7098332B2 (en) * | 2002-12-20 | 2006-08-29 | Hoffmann-La Roche Inc. | 5,8-Dihydro-6H-pyrido[2,3-d]pyrimidin-7-ones |
| MXPA05006742A (es) | 2002-12-20 | 2005-09-08 | Warner Lambert Co | Benzoxazinas y derivados de las mismas como inhibidores de fosfoinositido-3-quinasas. |
| JP2007524596A (ja) | 2003-02-28 | 2007-08-30 | トランスフォーム・ファーマシューティカルズ・インコーポレイテッド | 共結晶医薬組成物 |
| TW201018661A (en) | 2003-03-14 | 2010-05-16 | Ono Pharmaceutical Co | Heterocyclic rinf having nitrogen atom derivatives and medicament containing the derivatives as active ingredient |
| AU2004229404B2 (en) | 2003-04-11 | 2008-01-10 | Taigen Biotechnology | Aminoquinoline compounds |
| JP4895811B2 (ja) | 2003-09-11 | 2012-03-14 | ケミア，インコーポレイテッド | サイトカイン阻害剤 |
| BRPI0613045A2 (pt) | 2005-07-15 | 2010-12-14 | Hoffmann La Roche | aminas cÍclicas fundidas a heteroarila |
| EP1963320A1 (en) * | 2005-12-07 | 2008-09-03 | OSI Pharmaceuticals, Inc. | Pyrrolopyridine kinase inhibiting compounds |
| CN101336237B (zh) | 2005-12-21 | 2015-09-30 | 诺华股份有限公司 | 作为fgf抑制剂的嘧啶基芳基脲衍生物 |
| CN101405002A (zh) | 2005-12-29 | 2009-04-08 | 詹森药业有限公司 | 激肽原2受体拮抗剂 |
| AU2007254005B2 (en) | 2006-02-10 | 2012-11-29 | Genentech, Inc. | Anti-FGF19 antibodies and methods using same |
| JPWO2007105637A1 (ja) | 2006-03-10 | 2009-07-30 | 小野薬品工業株式会社 | 含窒素複素環誘導体およびそれらを有効成分とする薬剤 |
| EP2049490A1 (en) * | 2006-06-09 | 2009-04-22 | Astra Zeneca AB | N-(benzoyl)-o- [2- (pyridin- 2 -ylamino) ethyl]-l-tyrosine derivatives and related compounds as a5b1 antagonists for the treatment of solid tumors |
| WO2007146230A2 (en) | 2006-06-14 | 2007-12-21 | Merck & Co., Inc. | Non-nucleoside reverse transcriptase inhibitors |
| EP1918376A1 (en) | 2006-11-03 | 2008-05-07 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | FGFR4 promotes cancer cell resistance in response to chemotherapeutic drugs |
| WO2008112509A1 (en) | 2007-03-09 | 2008-09-18 | Novartis Ag | Treatment of melanoma |
| NO2550972T3 (cg-RX-API-DMAC7.html) | 2007-04-02 | 2018-07-21 | ||
| JP2011507848A (ja) | 2007-12-21 | 2011-03-10 | ザ スクリプス リサーチ インスティチュート | Ｒｈｏキナーゼインヒビターとしてのベンゾピランおよびアナログ |
| FR2933702A1 (fr) | 2008-07-08 | 2010-01-15 | Sanofi Aventis | Antagonistes specifiques du recepteur fgf-r4 |
| CN102224170A (zh) | 2008-09-03 | 2011-10-19 | 利琴蒂亚有限公司 | 抑制与fgfr4相关的癌细胞侵袭的材料和方法 |
| EP2341052A4 (en) | 2008-09-05 | 2011-10-12 | Shionogi & Co | RING-CONDENSED MORPHOLINE DERIVATIVITY WITH PI3K-INHIBITING EFFECT |
| WO2010080478A1 (en) | 2008-12-19 | 2010-07-15 | Genentech, Inc. | Compounds and methods of use |
| GB0906472D0 (en) | 2009-04-15 | 2009-05-20 | Astex Therapeutics Ltd | New compounds |
| GB0906470D0 (en) * | 2009-04-15 | 2009-05-20 | Astex Therapeutics Ltd | New compounds |
| SG175877A1 (en) | 2009-05-04 | 2011-12-29 | Plexxikon Inc | Compounds and methods for inhibition of renin, and indications therefor |
| MX2012004995A (es) | 2009-10-29 | 2012-10-03 | Sirtris Pharmaceuticals Inc | Piridinas biciclicas y analogos como moduladores de sirtuina. |
| CN102596916B (zh) | 2009-10-30 | 2015-06-17 | 诺瓦提斯公司 | 3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-脲的n-氧化物 |
| JPWO2011093501A1 (ja) | 2010-02-01 | 2013-06-06 | 日本ケミファ株式会社 | Ｇｐｒ１１９作動薬 |
| WO2011111880A1 (ko) | 2010-03-08 | 2011-09-15 | 주식회사 메디젠텍 | 세포핵에서 세포질로의 ｇｓｋ３의 이동을 억제하는 화합물을 함유하는 세포핵에서 세포질로의 gsk3 이동에 의해 발생되는 질환의 치료 또는 예방용 약학적 조성물 |
| ES2823350T3 (es) | 2010-07-29 | 2021-05-06 | Rigel Pharmaceuticals Inc | Compuestos heterocíclicos que activan AMPK y métodos de uso de los mismos |
| WO2012061337A1 (en) * | 2010-11-02 | 2012-05-10 | Exelixis, Inc. | Fgfr2 modulators |
| JP5620417B2 (ja) * | 2011-02-07 | 2014-11-05 | 中外製薬株式会社 | アミノピラゾール誘導体を含む医薬 |
| KR20140051846A (ko) | 2011-03-18 | 2014-05-02 | 루핀 리미티드 | 칼슘 감지 수용체 조절자로서의 벤조[ｂ][1,4]옥사진 유도체 |
| EP2694551A1 (en) | 2011-04-07 | 2014-02-12 | Genentech, Inc. | Anti-fgfr4 antibodies and methods of use |
| GB201118656D0 (en) * | 2011-10-28 | 2011-12-07 | Astex Therapeutics Ltd | New compounds |
| BR112015000653A2 (pt) | 2012-07-11 | 2019-11-05 | Blueprint Medicines Corp | compostos inibidores do receptor de fator de crescimento de fibroblasto, sua composição farmacêutica e seus usos |
| US9403774B2 (en) | 2012-10-12 | 2016-08-02 | Bristol-Myers Squibb Company | Guanidine and amine substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
| WO2014059202A1 (en) | 2012-10-12 | 2014-04-17 | Bristol-Myers Squibb Company | Guanidine substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
| WO2014079709A1 (en) | 2012-11-23 | 2014-05-30 | Ab Science | Use of small molecule inhibitors/activators in combination with (deoxy)nucleoside or (deoxy)nucleotide analogs for treatment of cancer and hematological malignancies or viral infections |
| EA036160B1 (ru) | 2013-03-15 | 2020-10-08 | Селджен Кар Ллс | Гетероарильные соединения и их применение |
| AR095464A1 (es) | 2013-03-15 | 2015-10-21 | Celgene Avilomics Res Inc | Compuestos de heteroarilo y usos de los mismos |
| DK2986610T5 (en) | 2013-04-19 | 2018-12-10 | Incyte Holdings Corp | BICYCLIC HETEROCYCLES AS FGFR INHIBITORS |
| GB201307577D0 (en) | 2013-04-26 | 2013-06-12 | Astex Therapeutics Ltd | New compounds |
| US9783504B2 (en) | 2013-07-09 | 2017-10-10 | Dana-Farber Cancer Institute, Inc. | Kinase inhibitors for the treatment of disease |
| AR097455A1 (es) | 2013-08-28 | 2016-03-16 | Astellas Pharma Inc | Composición farmacéutica que contiene compuesto de pirimidina como un ingrediente activo |
| SG11201602069WA (en) | 2013-10-18 | 2016-04-28 | Eisai R&D Man Co Ltd | Pyrimidine fgfr4 inhibitors |
| PH12016500739B1 (en) | 2013-10-25 | 2022-04-29 | Blueprint Medicines Corp | Inhibitors of the fibrolast growth factor receptor |
| CN105683188B (zh) | 2013-10-25 | 2018-02-09 | 诺华股份有限公司 | 作为fgfr4抑制剂的稠环二环吡啶基衍生物 |
| WO2015195509A2 (en) | 2014-06-16 | 2015-12-23 | Ngm Biopharmaceuticals, Inc. | Methods and uses for modulating bile acid homeostasis and treatment of bile acid disorders and diseases |
| JP6585167B2 (ja) * | 2014-10-03 | 2019-10-02 | ノバルティス アーゲー | Ｆｇｆｒ４阻害剤としての縮環二環式ピリジル誘導体の使用 |
| JP2018509448A (ja) * | 2015-03-25 | 2018-04-05 | ノバルティス アーゲー | 組合せ医薬 |
| US9802917B2 (en) * | 2015-03-25 | 2017-10-31 | Novartis Ag | Particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide |
| ES2934341T3 (es) | 2016-11-02 | 2023-02-21 | Novartis Ag | Combinaciones de inhibidores de FGFR4 y secuestrantes de ácidos biliares |
-
2015
- 2015-10-02 JP JP2017517705A patent/JP6585167B2/ja active Active
- 2015-10-02 PL PL15781518T patent/PL3200786T3/pl unknown
- 2015-10-02 ES ES15781518T patent/ES2756748T3/es active Active
- 2015-10-02 WO PCT/US2015/053677 patent/WO2016054483A1/en not_active Ceased
- 2015-10-02 US US15/516,443 patent/US20180185341A1/en not_active Abandoned
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2018
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2019
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- 2019-09-04 JP JP2019161051A patent/JP6794514B2/ja active Active
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| JP6794514B2 (ja) | 2020-12-02 |
| US20190231760A1 (en) | 2019-08-01 |
| WO2016054483A1 (en) | 2016-04-07 |
| PL3200786T3 (pl) | 2020-03-31 |
| US10507201B2 (en) | 2019-12-17 |
| US20180185341A1 (en) | 2018-07-05 |
| US10463653B2 (en) | 2019-11-05 |
| US20190076412A1 (en) | 2019-03-14 |
| JP6585167B2 (ja) | 2019-10-02 |
| EP3200786A1 (en) | 2017-08-09 |
| JP2019218398A (ja) | 2019-12-26 |
| JP2017530154A (ja) | 2017-10-12 |
| EP3200786B1 (en) | 2019-08-28 |
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