EA016445B1 - ИНГИБИТОРЫ p70 S6 КИНАЗЫ - Google Patents
ИНГИБИТОРЫ p70 S6 КИНАЗЫ Download PDFInfo
- Publication number
- EA016445B1 EA016445B1 EA200971051A EA200971051A EA016445B1 EA 016445 B1 EA016445 B1 EA 016445B1 EA 200971051 A EA200971051 A EA 200971051A EA 200971051 A EA200971051 A EA 200971051A EA 016445 B1 EA016445 B1 EA 016445B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- imidazol
- piperidine
- mmol
- compound
- fluoro
- Prior art date
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- 229940043355 kinase inhibitor Drugs 0.000 title abstract description 7
- 239000003757 phosphotransferase inhibitor Substances 0.000 title abstract description 7
- 108010013238 70-kDa Ribosomal Protein S6 Kinases Proteins 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 35
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims description 221
- -1 4-fluoro-3-trifluoromethylphenyl Chemical group 0.000 claims description 127
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 77
- 150000003839 salts Chemical class 0.000 claims description 68
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 61
- 125000001424 substituent group Chemical group 0.000 claims description 40
- 241000124008 Mammalia Species 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 18
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- 239000003085 diluting agent Substances 0.000 claims description 14
- 230000002401 inhibitory effect Effects 0.000 claims description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- 230000033115 angiogenesis Effects 0.000 claims description 13
- 239000003937 drug carrier Substances 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
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- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
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- 239000000243 solution Substances 0.000 description 60
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 40
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 32
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
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- 238000001914 filtration Methods 0.000 description 15
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
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- 210000004027 cell Anatomy 0.000 description 12
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 12
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- 238000004809 thin layer chromatography Methods 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 108091000080 Phosphotransferase Proteins 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
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- 206010028980 Neoplasm Diseases 0.000 description 8
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- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 8
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- 238000012360 testing method Methods 0.000 description 7
- ROLMZTIHUMKEAI-UHFFFAOYSA-N 4,5-difluoro-2-hydroxybenzonitrile Chemical compound OC1=CC(F)=C(F)C=C1C#N ROLMZTIHUMKEAI-UHFFFAOYSA-N 0.000 description 6
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61K31/4353—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
- A61K31/437—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 five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US91733107P | 2007-05-11 | 2007-05-11 | |
| PCT/US2008/062143 WO2008140947A1 (en) | 2007-05-11 | 2008-05-01 | P70 s6 kinase inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EA200971051A1 EA200971051A1 (ru) | 2010-06-30 |
| EA016445B1 true EA016445B1 (ru) | 2012-05-30 |
Family
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Family Applications (1)
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Families Citing this family (37)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UA99284C2 (ru) * | 2007-05-11 | 2012-08-10 | Елі Ліллі Енд Компані | ИНГИБИТОРЫ р70 S6-КИНАЗЫ |
| US8252791B2 (en) * | 2008-08-13 | 2012-08-28 | Jenrin Discovery, Inc. | Purine compounds as cannabinoid receptor blockers |
| AR074072A1 (es) | 2008-11-11 | 2010-12-22 | Lilly Co Eli | Compuesto de imidazol -piperidin -pirrol-pirimidin-6-ona, composicion farmaceutica que lo comprende y su uso para preparar un medicamento util para tratar el glioblastoma multiforme |
| BRPI0921840A2 (pt) * | 2008-11-11 | 2018-10-09 | Lilly Co Eli | produto compreendendo o composto inibidor de p70 s6 quinase e inibidor de mtor, composto inibidor de p70 s6 quinase e uso do mesmo |
| EP2355821A1 (en) * | 2008-11-11 | 2011-08-17 | Eli Lilly and Company | P70 s6 kinase inhibitor and egfr inhibitor combination therapy |
| SI2396307T1 (sl) | 2009-02-11 | 2015-02-27 | Merck Patent Gmbh | Novi amino azaheterockliäśni karboksamidi |
| JP5763636B2 (ja) | 2009-08-07 | 2015-08-12 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ | 新規なアザ複素環化合物 |
| EA020151B1 (ru) * | 2009-10-23 | 2014-09-30 | Эли Лилли Энд Компани | Ингибиторы akt и фармацевтические составы, их содержащие |
| CA2788678C (en) | 2010-02-03 | 2019-02-26 | Signal Pharmaceuticals, Llc | Identification of lkb1 mutation as a predictive biomarker for sensitivity to tor kinase inhibitors |
| UA110113C2 (xx) | 2010-07-29 | 2015-11-25 | Біциклічні азагетероциклічні карбоксаміди | |
| AU2011282684B2 (en) | 2010-07-29 | 2015-05-21 | Merck Patent Gmbh | Cyclic amine azaheterocyclic carboxamides |
| LT2643313T (lt) | 2010-11-24 | 2016-10-25 | Merck Patent Gmbh | Chinazolino karboksamido azetidinai |
| US9321760B2 (en) | 2011-09-12 | 2016-04-26 | Merck Patent Gmbh | Aminopyrimidine derivatives for use as modulators of kinase activity |
| PT2755965T (pt) | 2011-09-12 | 2017-11-02 | Merck Patent Gmbh | Novas imidazol aminas como moduladores da atividade quinase |
| EP2892534B8 (en) * | 2012-09-06 | 2021-09-15 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
| AU2013203714B2 (en) | 2012-10-18 | 2015-12-03 | Signal Pharmaceuticals, Llc | Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for TOR kinase inhibitory activity |
| US9580443B2 (en) | 2012-11-16 | 2017-02-28 | Merck Patent Gmbh | Heterocyclic derivatives as modulators of kinase activity |
| EP2920154B1 (en) | 2012-11-16 | 2017-10-11 | Merck Patent GmbH | Novel imidazol-piperidinyl derivatives as modulators of kinase activity |
| NZ706418A (en) | 2012-11-29 | 2019-09-27 | Merck Patent Gmbh | Azaquinazoline carboxamide derivatives |
| AR095202A1 (es) * | 2013-03-11 | 2015-09-30 | Merck Patent Gmbh | Heterociclos como moduladores de la actividad quinasa |
| CA2909579A1 (en) | 2013-04-17 | 2014-10-23 | Signal Pharmaceuticals, Llc | Combination therapy comprising a tor kinase inhibitor and n-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide for treating cancer |
| US9505764B2 (en) | 2013-04-17 | 2016-11-29 | Signal Pharmaceuticals, Llc | Treatment of cancer with dihydropyrazino-pyrazines |
| CA2909629C (en) | 2013-04-17 | 2022-12-13 | Signal Pharmaceuticals, Llc | Pharmaceutical formulations, processes, solid forms and methods of use relating to 1-ethyl-7-(2-methyl-6-(1h-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1h)-one |
| US9630966B2 (en) | 2013-04-17 | 2017-04-25 | Signal Pharmaceuticals, Llc | Treatment of cancer with dihydropyrazino-pyrazines |
| CN105377299B (zh) | 2013-04-17 | 2018-06-12 | 西格诺药品有限公司 | 用于治疗前列腺癌的包含二氢吡嗪并-吡嗪化合物和雄激素受体拮抗剂的组合疗法 |
| WO2014172436A1 (en) | 2013-04-17 | 2014-10-23 | Signal Pharmaceuticals, Llc | Combination therapy comprising a tor kinase inhibitor and a 5-substituted quinazolinone compound for treating cancer |
| CA2908742C (en) | 2013-04-17 | 2021-06-01 | Signal Pharmaceuticals, Llc | Combination therapy comprising a tor kinase inhibitor and a cytidine analog for treating cancer |
| NZ629486A (en) | 2013-05-29 | 2017-11-24 | Signal Pharm Llc | Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1h)-one, a solid form thereof and methods of their use |
| US9771369B2 (en) | 2014-03-04 | 2017-09-26 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
| EP3125935B1 (en) | 2014-04-03 | 2019-10-23 | Merck Patent GmbH | Combinations of cancer therapeutics |
| NZ714742A (en) | 2014-04-16 | 2017-04-28 | Signal Pharm Llc | Solid forms of 1-ethyl-7-(2-methyl-6-(1h-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1h)-one, compositions thereof and methods of their use |
| US9512129B2 (en) | 2014-04-16 | 2016-12-06 | Signal Pharmaceuticals, Llc | Solid forms comprising 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one and a coformer |
| WO2016040078A1 (en) * | 2014-09-10 | 2016-03-17 | Eli Lilly And Company | Substituted phenyl imidazolyl piperidyl compounds as p70s6k1 inhibitors |
| WO2016164641A1 (en) | 2015-04-08 | 2016-10-13 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
| CN106187899B (zh) * | 2016-06-28 | 2019-07-16 | 绍兴文理学院 | 一种氟代氮杂芳烃的合成方法 |
| TWI787284B (zh) | 2017-06-22 | 2022-12-21 | 美商西建公司 | 以b型肝炎病毒感染表徵之肝細胞癌之治療 |
| WO2022101459A1 (en) | 2020-11-16 | 2022-05-19 | Merck Patent Gmbh | Kinase inhibitor combinations for cancer treatment |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005117909A2 (en) * | 2004-04-23 | 2005-12-15 | Exelixis, Inc. | Kinase modulators and methods of use |
| WO2008075109A1 (en) * | 2006-12-21 | 2008-06-26 | Astex Therapeutics Limited | Substituted piperidines having protein kinase inhibiting activity |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL1004346C2 (nl) | 1996-10-23 | 1998-04-24 | Dsm Nv | Werkwijze voor het scheiden van een mengsel van enantiomeren in een geschikt oplosmiddel. |
| PA8474101A1 (es) | 1998-06-19 | 2000-09-29 | Pfizer Prod Inc | Compuestos de pirrolo [2,3-d] pirimidina |
| MY179032A (en) | 2004-10-25 | 2020-10-26 | Cancer Research Tech Ltd | Ortho-condensed pyridine and pyrimidine derivatives (e.g.purines) as protein kinase inhibitors |
| JP5274842B2 (ja) | 2004-12-28 | 2013-08-28 | エグゼリクシス， インコーポレイテッド | 免疫疾患、炎症疾患および増殖疾患の処置のためのセリン−スレオニンキナーゼモジュレーター（ｐ７０Ｓ６Ｋ、Ａｋｔ−１およびＡｋｔ−２）としての［１Ｈ−ピペラゾ［３，４−ｄ］ピリミジン−４−イル］−ピペラジンまたは［１Ｈ−ピペラゾ［３，４−ｄ］ピリミジン−４−イル］−ピペラジン化合物 |
| US20090325924A1 (en) | 2005-06-30 | 2009-12-31 | Stuart Edward | GPCR Agonists |
| EP2037931A2 (en) | 2006-04-25 | 2009-03-25 | Astex Therapeutics Limited | Pharmaceutical combinations of pk inhibitors and other active agents |
| DK3421471T3 (da) | 2006-04-25 | 2021-06-14 | Astex Therapeutics Ltd | Purin- og deazapurinderivater som farmaceutiske forbindelser |
| WO2008012635A2 (en) | 2006-07-26 | 2008-01-31 | Pfizer Products Inc. | Amine derivatives useful as anticancer agents |
| UA99284C2 (ru) * | 2007-05-11 | 2012-08-10 | Елі Ліллі Енд Компані | ИНГИБИТОРЫ р70 S6-КИНАЗЫ |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005117909A2 (en) * | 2004-04-23 | 2005-12-15 | Exelixis, Inc. | Kinase modulators and methods of use |
| WO2008075109A1 (en) * | 2006-12-21 | 2008-06-26 | Astex Therapeutics Limited | Substituted piperidines having protein kinase inhibiting activity |
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