CA2832763C - Tetrahydroquinoline derivatives useful as bromodomain inhibitors - Google Patents
Tetrahydroquinoline derivatives useful as bromodomain inhibitors Download PDFInfo
- Publication number
- CA2832763C CA2832763C CA2832763A CA2832763A CA2832763C CA 2832763 C CA2832763 C CA 2832763C CA 2832763 A CA2832763 A CA 2832763A CA 2832763 A CA2832763 A CA 2832763A CA 2832763 C CA2832763 C CA 2832763C
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- Prior art keywords
- compound
- methyl
- salt
- mmol
- amino
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- 102000001805 Bromodomains Human genes 0.000 title description 37
- 108050009021 Bromodomains Proteins 0.000 title description 35
- 239000003112 inhibitor Substances 0.000 title description 17
- 125000000147 tetrahydroquinolinyl group Chemical class N1(CCCC2=CC=CC=C12)* 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 165
- 150000003839 salts Chemical class 0.000 claims abstract description 100
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 29
- 238000011282 treatment Methods 0.000 claims abstract description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 26
- 201000010099 disease Diseases 0.000 claims abstract description 23
- 229940125763 bromodomain inhibitor Drugs 0.000 claims abstract description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 13
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- 125000001424 substituent group Chemical group 0.000 claims abstract description 6
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 5
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims abstract description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims abstract description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract 13
- -1 5-cyanopyridin-2-yl Chemical group 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 239000013543 active substance Substances 0.000 claims description 8
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- CUHOVDNLIFHFKG-WTYVLRPYSA-N 3-(dimethylamino)propyl 4-[(2s,4r)-1-acetyl-4-(4-chloroanilino)-2-methyl-3,4-dihydro-2h-quinolin-6-yl]benzoate Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=CC(=CC=1)C(=O)OCCCN(C)C)C(C)=O)C)C1=CC=C(Cl)C=C1 CUHOVDNLIFHFKG-WTYVLRPYSA-N 0.000 claims description 4
- PDTBUDVYUOJHEX-MHECFPHRSA-N 2-(dimethylamino)ethyl 4-[(2s,4r)-1-acetyl-2-methyl-4-(propan-2-yloxycarbonylamino)-3,4-dihydro-2h-quinolin-6-yl]benzoate Chemical compound CC(=O)N([C@@H](C)C[C@H](C1=C2)NC(=O)OC(C)C)C1=CC=C2C1=CC=C(C(=O)OCCN(C)C)C=C1 PDTBUDVYUOJHEX-MHECFPHRSA-N 0.000 claims description 3
- PLWKACLMXITMOG-IQGLISFBSA-N 2-(dimethylamino)ethyl 6-[(2r,4r)-1-acetyl-4-[(5-cyanopyridin-2-yl)amino]-2-methyl-3,4-dihydro-2h-quinolin-6-yl]pyridine-3-carboxylate Chemical compound N([C@@H]1C[C@H](N(C2=CC=C(C=C21)C=1N=CC(=CC=1)C(=O)OCCN(C)C)C(C)=O)C)C1=CC=C(C#N)C=N1 PLWKACLMXITMOG-IQGLISFBSA-N 0.000 claims description 3
- APULZVGKZDBBNA-WTYVLRPYSA-N 2-[4-[(2s,4r)-1-acetyl-4-(4-chloroanilino)-2-methyl-3,4-dihydro-2h-quinolin-6-yl]benzoyl]oxyethyl-trimethylazanium Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=CC(=CC=1)C(=O)OCC[N+](C)(C)C)C(C)=O)C)C1=CC=C(Cl)C=C1 APULZVGKZDBBNA-WTYVLRPYSA-N 0.000 claims description 3
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- QLJVEQQAHIBCEG-AFMDSPMNSA-N 3-(dimethylamino)propyl 6-[(2s,4r)-1-acetyl-4-[(5-cyanopyridin-2-yl)amino]-2-methyl-3,4-dihydro-2h-quinolin-6-yl]pyridine-3-carboxylate Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1N=CC(=CC=1)C(=O)OCCCN(C)C)C(C)=O)C)C1=CC=C(C#N)C=N1 QLJVEQQAHIBCEG-AFMDSPMNSA-N 0.000 claims description 3
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Immunology (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Quinoline Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1106743.6 | 2011-04-21 | ||
| GB201106743A GB201106743D0 (en) | 2011-04-21 | 2011-04-21 | Novel compounds |
| PCT/EP2012/057111 WO2012143413A1 (en) | 2011-04-21 | 2012-04-19 | Tetrahydroquinoline derivatives useful as bromodomain inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2832763A1 CA2832763A1 (en) | 2012-10-26 |
| CA2832763C true CA2832763C (en) | 2019-09-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2832763A Expired - Fee Related CA2832763C (en) | 2011-04-21 | 2012-04-19 | Tetrahydroquinoline derivatives useful as bromodomain inhibitors |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US9029395B2 (https=) |
| EP (1) | EP2699550B1 (https=) |
| JP (1) | JP5840763B2 (https=) |
| KR (1) | KR101896599B1 (https=) |
| CN (1) | CN103619820B (https=) |
| AU (1) | AU2012244759B2 (https=) |
| BR (1) | BR112013026834A2 (https=) |
| CA (1) | CA2832763C (https=) |
| EA (1) | EA022341B1 (https=) |
| ES (1) | ES2544302T3 (https=) |
| GB (1) | GB201106743D0 (https=) |
| IL (1) | IL228707A (https=) |
| MX (1) | MX338515B (https=) |
| SG (1) | SG194469A1 (https=) |
| WO (1) | WO2012143413A1 (https=) |
| ZA (1) | ZA201307645B (https=) |
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| GB201107325D0 (en) | 2011-05-04 | 2011-06-15 | Glaxosmithkline Llc | Novel compounds |
| US9073878B2 (en) | 2012-11-21 | 2015-07-07 | Zenith Epigenetics Corp. | Cyclic amines as bromodomain inhibitors |
| US9765039B2 (en) | 2012-11-21 | 2017-09-19 | Zenith Epigenetics Ltd. | Biaryl derivatives as bromodomain inhibitors |
| AU2013365926B9 (en) | 2012-12-21 | 2019-01-17 | Zenith Epigenetics Ltd. | Novel heterocyclic compounds as bromodomain inhibitors |
| NZ710765A (en) * | 2013-03-14 | 2020-05-29 | Glaxosmithkline Ip No 2 Ltd | 2,3-disubstituted 1 -acyl-4-amino-1,2,3,4-tetrahydroquinoline derivatives and their use as bromodomain inhibitors |
| MX366703B (es) | 2013-03-15 | 2019-07-22 | Incyte Holdings Corp | Heterociclos tricíclicos como inhibidores de la proteína bet. |
| CA2915838C (en) | 2013-06-21 | 2023-04-18 | Zenith Epigenetics Corp. | Bicyclic bromodomain inhibitors |
| EP3010918B1 (en) | 2013-06-21 | 2018-08-15 | Zenith Epigenetics Ltd. | Novel substituted bicyclic compounds as bromodomain inhibitors |
| AR096837A1 (es) | 2013-07-08 | 2016-02-03 | Incyte Corp | Heterociclos tricíclicos como inhibidores de proteínas bet |
| JP6542212B2 (ja) | 2013-07-31 | 2019-07-10 | ゼニス・エピジェネティクス・リミテッドＺｅｎｉｔｈ Ｅｐｉｇｅｎｅｔｉｃｓ Ｌｔｄ． | ブロモドメイン阻害剤としての新規キナゾリノン |
| WO2015081189A1 (en) | 2013-11-26 | 2015-06-04 | Incyte Corporation | Bicyclic heterocycles as bet protein inhibitors |
| US9399640B2 (en) | 2013-11-26 | 2016-07-26 | Incyte Corporation | Substituted pyrrolo[2,3-c]pyridines and pyrazolo[3,4-c]pyridines as BET protein inhibitors |
| WO2015095492A1 (en) | 2013-12-19 | 2015-06-25 | Incyte Corporation | Tricyclic heterocycles as bet protein inhibitors |
| EP3105232B1 (en) * | 2014-02-10 | 2019-08-28 | Concert Pharmaceuticals Inc. | Substituted triazolobenzodiazepines |
| EA034972B1 (ru) | 2014-04-23 | 2020-04-13 | Инсайт Корпорейшн | 1h-пирроло[2,3-c]пиридин-7(6h)-оны в качестве ингибиторов белков bet |
| RU2743074C2 (ru) | 2014-08-01 | 2021-02-15 | Нуэволюшон А/С | Соединения, активные по отношению к бромодоменам |
| SG11201701043UA (en) | 2014-09-12 | 2017-03-30 | Glaxosmithkline Ip No 2 Ltd | Tetrahydroquinoline derivatives as bromodomain inhibitors |
| US9527864B2 (en) | 2014-09-15 | 2016-12-27 | Incyte Corporation | Tricyclic heterocycles as BET protein inhibitors |
| AU2015326910B2 (en) * | 2014-10-02 | 2018-03-01 | Glaxosmithkline Intellectual Property (No.2) Limited | Compound |
| EP3227281A4 (en) | 2014-12-01 | 2018-05-30 | Zenith Epigenetics Ltd. | Substituted pyridinones as bromodomain inhibitors |
| HK1246273B (en) | 2014-12-01 | 2019-12-06 | 恒翼生物医药(上海)股份有限公司 | Substituted pyridines as bromodomain inhibitors |
| EP3230277B1 (en) | 2014-12-11 | 2019-09-18 | Zenith Epigenetics Ltd. | Substituted heterocycles as bromodomain inhibitors |
| HK1245247A1 (zh) | 2014-12-17 | 2018-08-24 | 恒翼生物医药科技(上海)有限公司 | 溴结构域的抑制剂 |
| GB201504694D0 (en) | 2015-03-19 | 2015-05-06 | Glaxosmithkline Ip Dev Ltd | Covalent conjugates |
| WO2016203335A1 (en) | 2015-06-18 | 2016-12-22 | Pfizer Inc. | Novel pyrido[2,3-b]pyrazinones as bet-family bromodomain inhibitors |
| TW201722966A (zh) | 2015-10-29 | 2017-07-01 | 英塞特公司 | Bet蛋白質抑制劑之非晶固體形式 |
| KR102643344B1 (ko) | 2016-06-20 | 2024-03-07 | 인사이트 코포레이션 | Bet 저해제의 결정질 고체 형태 |
| US10918647B2 (en) | 2016-07-26 | 2021-02-16 | University Of Southern California | Selective bromodomain inhibition of fungal Bdf1 |
| WO2018111805A1 (en) * | 2016-12-13 | 2018-06-21 | St. Jude Children's Research Hospital | Tetrahydroquinoline-based bromodomain inhibitors |
| US11833155B2 (en) | 2020-06-03 | 2023-12-05 | Incyte Corporation | Combination therapy for treatment of myeloproliferative neoplasms |
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| ES2388434T3 (es) | 2003-11-03 | 2012-10-15 | Glaxo Group Limited | Dispositivo de administración de fluido |
| JP2008156311A (ja) | 2006-12-26 | 2008-07-10 | Institute Of Physical & Chemical Research | Ｂｒｄ２ブロモドメイン結合剤 |
| WO2009084693A1 (ja) | 2007-12-28 | 2009-07-09 | Mitsubishi Tanabe Pharma Corporation | 抗癌剤 |
| JP5572154B2 (ja) * | 2009-03-31 | 2014-08-13 | 興和株式会社 | テトラヒドロキノリン化合物を有効成分とする貧血の予防及び／又は治療剤 |
| GB0919431D0 (en) * | 2009-11-05 | 2009-12-23 | Glaxosmithkline Llc | Novel compounds |
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| WO2011054851A1 (en) | 2009-11-05 | 2011-05-12 | Glaxosmithkline Llc | Novel process |
| GB0919432D0 (en) * | 2009-11-05 | 2009-12-23 | Glaxosmithkline Llc | Use |
| GB201106750D0 (en) * | 2011-04-21 | 2011-06-01 | Glaxosmithkline Llc | Novel compounds |
| GB201107325D0 (en) * | 2011-05-04 | 2011-06-15 | Glaxosmithkline Llc | Novel compounds |
| WO2013033270A2 (en) * | 2011-08-29 | 2013-03-07 | Coferon, Inc. | Bromodomain ligands capable of dimerizing in an aqueous solution, and methods of using same |
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| GB201106743D0 (en) | 2011-06-01 |
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| EP2699550B1 (en) | 2015-06-10 |
| KR101896599B1 (ko) | 2018-09-07 |
| CA2832763A1 (en) | 2012-10-26 |
| JP2014511891A (ja) | 2014-05-19 |
| KR20140025484A (ko) | 2014-03-04 |
| CN103619820B (zh) | 2015-08-19 |
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| EA022341B1 (ru) | 2015-12-30 |
| ES2544302T3 (es) | 2015-08-28 |
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| IL228707A (en) | 2016-09-29 |
| MX338515B (es) | 2016-04-20 |
| EA201391285A1 (ru) | 2014-04-30 |
| CN103619820A (zh) | 2014-03-05 |
| MX2013012190A (es) | 2014-01-31 |
| AU2012244759B2 (en) | 2016-03-03 |
| US20140039006A1 (en) | 2014-02-06 |
| US9029395B2 (en) | 2015-05-12 |
| ZA201307645B (en) | 2015-04-29 |
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