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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- ZZBWJSLHFRIKGH-UHFFFAOYSA-N phenyl 7-(dimethoxymethyl)-3,4-dihydro-2H-1,8-naphthyridine-1-carboxylate Chemical compound COC(OC)c1ccc2CCCN(C(=O)Oc3ccccc3)c2n1 ZZBWJSLHFRIKGH-UHFFFAOYSA-N 0.000 description 1
- FNAPZFAKBBOCSZ-UHFFFAOYSA-N phenyl 7-(dimethoxymethyl)-6-iodo-3,4-dihydro-2H-1,8-naphthyridine-1-carboxylate Chemical compound COC(OC)c1nc2N(CCCc2cc1I)C(=O)Oc1ccccc1 FNAPZFAKBBOCSZ-UHFFFAOYSA-N 0.000 description 1
- 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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Classifications
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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
- A61K31/435—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
- 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
- A61K31/495—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
-
- 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
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- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (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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| CN113105454B (zh) * | 2016-05-20 | 2022-10-11 | 江苏豪森药业集团有限公司 | Fgfr4抑制剂、其制备方法和应用 |
| WO2018055503A1 (en) | 2016-09-20 | 2018-03-29 | Novartis Ag | Combination comprising a pd-1 antagonist and an fgfr4 inhibitor |
| SG11201903911UA (en) | 2016-11-02 | 2019-05-30 | Novartis Ag | Combinations of fgfr4 inhibitors and bile acid sequestrants |
| TWI723480B (zh) * | 2018-07-27 | 2021-04-01 | 大陸商北京加科思新藥研發有限公司 | 用作fgfr4抑制劑的稠環衍生物 |
| EA202192575A1 (ru) | 2019-03-21 | 2022-01-14 | Онксео | Соединения dbait в сочетании с ингибиторами киназ для лечения рака |
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Family Cites Families (65)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5143854A (en) | 1989-06-07 | 1992-09-01 | Affymax Technologies N.V. | Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof |
| US5424186A (en) | 1989-06-07 | 1995-06-13 | Affymax Technologies N.V. | Very large scale immobilized polymer synthesis |
| GB9420999D0 (en) | 1994-10-18 | 1994-12-07 | Smithkline Beecham Plc | Novel compounds |
| EP0916668A4 (en) | 1996-07-29 | 2000-08-16 | Banyu Pharma Co Ltd | CHEMOKIN RECEPTOR ANTAGONISTS |
| US6048861A (en) | 1997-12-17 | 2000-04-11 | Merck & Co., Inc. | Integrin receptor antagonists |
| AR015514A1 (es) | 1998-02-10 | 2001-05-02 | Novartis Ag | Compuesto de amida, proceso para su preparacion y composicion farmaceutica que lo contiene |
| EP1218336A2 (en) | 1999-09-20 | 2002-07-03 | Takeda Chemical Industries, Ltd. | Melanin concentrating hormone antagonist |
| PL355011A1 (en) * | 1999-11-08 | 2004-03-22 | 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 |
| TW200305423A (en) | 2002-02-14 | 2003-11-01 | Ono Pharmaceutical Co | N-carbamoyl nitrogen-containing condensed ring compound and medicament containing same as active ingredient |
| AU2003252478A1 (en) | 2002-07-10 | 2004-02-02 | Ono Pharmaceutical Co., Ltd. | Ccr4 antagonist and medicinal use thereof |
| US20060004029A1 (en) * | 2002-08-30 | 2006-01-05 | Akihiko Tsuruoka | Nitrogen-containing aromatic derivatives |
| CA2510851A1 (en) | 2002-12-20 | 2004-07-08 | Warner-Lambert Company Llc | Benzoxazines and derivatives thereof as inhibitors of pi3ks |
| US7098332B2 (en) | 2002-12-20 | 2006-08-29 | Hoffmann-La Roche Inc. | 5,8-Dihydro-6H-pyrido[2,3-d]pyrimidin-7-ones |
| 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 |
| RU2366655C2 (ru) | 2003-03-14 | 2009-09-10 | Оно Фармасьютикал Ко., Лтд. | Азотсодержащие гетероциклические производные и лекарственные средства, содержащие их в качестве активного ингредиента |
| JP2006522814A (ja) | 2003-04-11 | 2006-10-05 | タイゲン・バイオテクノロジー | アミノキノリン化合物 |
| WO2005023761A2 (en) | 2003-09-11 | 2005-03-17 | Kemia, Inc. | Cytokine inhibitors |
| WO2007009883A1 (en) | 2005-07-15 | 2007-01-25 | F. Hoffmann-La Roche Ag | Novel heteroaryl fused cyclic amines |
| WO2007067537A1 (en) * | 2005-12-07 | 2007-06-14 | Osi Pharmaceuticals, Inc. | Pyrrolopyridine kinase inhibiting compounds |
| GEP20105074B (en) * | 2005-12-21 | 2010-09-10 | Novartis Ag | Pyrimidinyl aryl urea derivatives being fgf inhibitors |
| CA2635845A1 (en) | 2005-12-29 | 2007-07-12 | Janssen Pharmaceutica N.V. | Prokineticin 2 receptor antagonists |
| ES2582652T3 (es) | 2006-02-10 | 2016-09-14 | Genentech, Inc. | Anticuerpos anti-FGF19 y métodos de uso de los mismos |
| CA2644368A1 (en) | 2006-03-10 | 2007-09-20 | Ono Pharmaceutical Co., Ltd. | Nitrogenated heterocyclic derivative, and pharmaceutical agent comprising the derivative as active ingredient |
| JP2009539815A (ja) * | 2006-06-09 | 2009-11-19 | アストラゼネカ アクチボラグ | 固形腫瘍の治療用のａ５ｂ１アンタゴニストとしてのＮ−（ベンゾイル）−Ｏ−［２−（ピリジン−２−イルアミノ）エチル］−Ｌ−チロシン誘導体と関連化合物 |
| 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 |
| CA2679268A1 (en) | 2007-03-09 | 2008-09-18 | Novartis Ag | Treatment of melanoma |
| CL2008000947A1 (es) | 2007-04-02 | 2008-10-10 | Genentech Inc | Uso de un antagonista de la proteina beta-klotho (klb) para tratar trastornos asociados a la expresion o actividad de klb. |
| WO2009079008A1 (en) | 2007-12-19 | 2009-06-25 | Yangbo Feng | Benzopyrans and analogs as rho kinase inhibitors |
| FR2933702A1 (fr) | 2008-07-08 | 2010-01-15 | Sanofi Aventis | Antagonistes specifiques du recepteur fgf-r4 |
| WO2010026291A1 (en) | 2008-09-03 | 2010-03-11 | Licentia Ltd. | Materials and methods for inhibiting cancer cell invasion related to fgfr4 |
| US20110172217A1 (en) | 2008-09-05 | 2011-07-14 | Shionogi & Co., Ltd. | Ring-fused morpholine derivative having pi3k-inhibiting activity |
| NZ593536A (en) | 2008-12-19 | 2013-07-26 | Genentech Inc | Quinoline derivatives 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 |
| CA2761009A1 (en) | 2009-05-04 | 2010-11-11 | 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. |
| EP2493864B1 (en) | 2009-10-30 | 2014-10-01 | Novartis AG | N-oxide of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea |
| KR20120130104A (ko) | 2010-02-01 | 2012-11-28 | 닛뽕 케미파 가부시키가이샤 | Ｇｐｒ119 작동약 |
| 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 |
| PE20130774A1 (es) | 2010-07-29 | 2013-06-26 | Rigel Pharmaceuticals Inc | Compuestos heterociclicos activadores de ampk y metodos para emplearlos |
| 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 |
| SG193331A1 (en) | 2011-03-18 | 2013-10-30 | Lupin Ltd | Benzo [b] [1, 4] oxazin derivatives as calcium sensing receptor modulators |
| CA2828890A1 (en) | 2011-04-07 | 2012-10-11 | Genentech, Inc. | Anti-fgfr4 antibodies and methods of use |
| GB201118656D0 (en) | 2011-10-28 | 2011-12-07 | Astex Therapeutics Ltd | New compounds |
| SG11201500125QA (en) | 2012-07-11 | 2015-02-27 | Blueprint Medicines Corp | Inhibitors of the fibroblast growth factor receptor |
| EP2906552B1 (en) | 2012-10-12 | 2017-11-22 | Bristol-Myers Squibb Company | Guanidine substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
| US9403774B2 (en) | 2012-10-12 | 2016-08-02 | Bristol-Myers Squibb Company | Guanidine and amine substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
| EP2922572A1 (en) | 2012-11-23 | 2015-09-30 | 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 |
| US9321786B2 (en) | 2013-03-15 | 2016-04-26 | Celgene Avilomics Research, Inc. | Heteroaryl compounds and uses thereof |
| CN105307657B (zh) | 2013-03-15 | 2020-07-10 | 西建卡尔有限责任公司 | 杂芳基化合物和其用途 |
| PH12015502383B1 (en) | 2013-04-19 | 2023-02-03 | 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 |
| PH12016500676B1 (en) | 2013-10-18 | 2022-07-20 | Eisai R&D Man Co Ltd | Pyrimidine fgfr4 inhibitors |
| TN2016000115A1 (en) * | 2013-10-25 | 2017-07-05 | Novartis Ag | Ring-fused bicyclic pyridyl derivatives as fgfr4 inhibitors. |
| RS63405B1 (sr) | 2013-10-25 | 2022-08-31 | Blueprint Medicines Corp | Inhibitori receptora faktora rasta fibroblasta |
| AU2015277438B2 (en) | 2014-06-16 | 2020-02-27 | 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 |
| 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 |
| WO2016151501A1 (en) * | 2015-03-25 | 2016-09-29 | Novartis Ag | Pharmaceutical combinations |
| SG11201903911UA (en) | 2016-11-02 | 2019-05-30 | Novartis Ag | Combinations of fgfr4 inhibitors and bile acid sequestrants |
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2015
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- 2015-10-02 WO PCT/US2015/053677 patent/WO2016054483A1/en not_active Ceased
- 2015-10-02 ES ES15781518T patent/ES2756748T3/es active Active
- 2015-10-02 EP EP15781518.4A patent/EP3200786B1/en active Active
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2018
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2019
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| JP6794514B2 (ja) | 2020-12-02 |
| US10463653B2 (en) | 2019-11-05 |
| US20190231760A1 (en) | 2019-08-01 |
| EP3200786A1 (en) | 2017-08-09 |
| JP2017530154A (ja) | 2017-10-12 |
| US20190076412A1 (en) | 2019-03-14 |
| JP6585167B2 (ja) | 2019-10-02 |
| EP3200786B1 (en) | 2019-08-28 |
| US20180185341A1 (en) | 2018-07-05 |
| US10507201B2 (en) | 2019-12-17 |
| JP2019218398A (ja) | 2019-12-26 |
| WO2016054483A1 (en) | 2016-04-07 |
| PL3200786T3 (pl) | 2020-03-31 |
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