JP2013510122A - ブロモドメイン阻害剤としての縮合アゼピン誘導体 - Google Patents
ブロモドメイン阻害剤としての縮合アゼピン誘導体 Download PDFInfo
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- JP2013510122A JP2013510122A JP2012537380A JP2012537380A JP2013510122A JP 2013510122 A JP2013510122 A JP 2013510122A JP 2012537380 A JP2012537380 A JP 2012537380A JP 2012537380 A JP2012537380 A JP 2012537380A JP 2013510122 A JP2013510122 A JP 2013510122A
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- Prior art keywords
- phenyl
- methyl
- triazolo
- compound
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 102000001805 Bromodomains Human genes 0.000 title claims description 40
- 108050009021 Bromodomains Proteins 0.000 title claims description 39
- 239000003112 inhibitor Substances 0.000 title description 16
- 150000001538 azepines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 266
- 150000003839 salts Chemical class 0.000 claims abstract description 126
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 25
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 139
- -1 nitro, cyano, dimethylamino, benzoyl Chemical group 0.000 claims description 139
- 125000003545 alkoxy group Chemical group 0.000 claims description 60
- 238000000034 method Methods 0.000 claims description 50
- 125000000623 heterocyclic group Chemical group 0.000 claims description 46
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 44
- BOHXEHCCMXOJMM-UHFFFAOYSA-N n-(1-methyl-6-phenyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)naphthalene-2-carboxamide Chemical compound C12=CC=CC=C2N2C(C)=NN=C2C(NC(=O)C=2C=C3C=CC=CC3=CC=2)N=C1C1=CC=CC=C1 BOHXEHCCMXOJMM-UHFFFAOYSA-N 0.000 claims description 33
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 29
- 125000005843 halogen group Chemical group 0.000 claims description 29
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 150000002367 halogens Chemical group 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 201000010099 disease Diseases 0.000 claims description 26
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 21
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 21
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 125000004429 atom Chemical group 0.000 claims description 19
- 229940125763 bromodomain inhibitor Drugs 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 206010028980 Neoplasm Diseases 0.000 claims description 11
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 239000013543 active substance Substances 0.000 claims description 7
- 201000011510 cancer Diseases 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 230000004968 inflammatory condition Effects 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 230000001684 chronic effect Effects 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- YIIAEOSGRYXGSO-UHFFFAOYSA-N ethyl n-(1-methyl-6-phenyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)carbamate Chemical compound C12=CC=CC=C2N2C(C)=NN=C2C(NC(=O)OCC)N=C1C1=CC=CC=C1 YIIAEOSGRYXGSO-UHFFFAOYSA-N 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 230000001363 autoimmune Effects 0.000 claims description 5
- 150000001540 azides Chemical class 0.000 claims description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- HQXKNLNBUWKEHU-DTQAZKPQSA-N (e)-3-(4-fluorophenyl)-n-(1-methyl-6-phenyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)prop-2-enamide Chemical compound N1=C(C=2C=CC=CC=2)C2=CC=CC=C2N2C(C)=NN=C2C1NC(=O)\C=C\C1=CC=C(F)C=C1 HQXKNLNBUWKEHU-DTQAZKPQSA-N 0.000 claims description 4
- AHGSTKPQVCTIHA-UHFFFAOYSA-N 6-methoxy-n-(1-methyl-6-phenyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-1h-indole-2-carboxamide Chemical compound N1C2=CC(OC)=CC=C2C=C1C(=O)NC(C1=NN=C(C)N1C1=CC=CC=C11)N=C1C1=CC=CC=C1 AHGSTKPQVCTIHA-UHFFFAOYSA-N 0.000 claims description 4
- TUWDLUFFAHHNEF-UHFFFAOYSA-N benzyl n-(1-methyl-6-phenyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)carbamate Chemical compound N1=C(C=2C=CC=CC=2)C2=CC=CC=C2N2C(C)=NN=C2C1NC(=O)OCC1=CC=CC=C1 TUWDLUFFAHHNEF-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 229930192474 thiophene Natural products 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- NOXULISRIXJOPU-DTQAZKPQSA-N (e)-3-(4-chlorophenyl)-n-(1-methyl-6-phenyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)prop-2-enamide Chemical compound N1=C(C=2C=CC=CC=2)C2=CC=CC=C2N2C(C)=NN=C2C1NC(=O)\C=C\C1=CC=C(Cl)C=C1 NOXULISRIXJOPU-DTQAZKPQSA-N 0.000 claims description 2
- XOBMKWPZTPKYHP-SAPNQHFASA-N (e)-3-(4-methoxyphenyl)-n-(1-methyl-6-phenyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)prop-2-enamide Chemical compound C1=CC(OC)=CC=C1\C=C\C(=O)NC1C2=NN=C(C)N2C2=CC=CC=C2C(C=2C=CC=CC=2)=N1 XOBMKWPZTPKYHP-SAPNQHFASA-N 0.000 claims description 2
- AIBGAEDELSKJMK-UHFFFAOYSA-N 1-(1-methyl-6-phenyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-3-phenylurea Chemical compound N1=C(C=2C=CC=CC=2)C2=CC=CC=C2N2C(C)=NN=C2C1NC(=O)NC1=CC=CC=C1 AIBGAEDELSKJMK-UHFFFAOYSA-N 0.000 claims description 2
- YKHPDEJRXBTLOU-UHFFFAOYSA-N 1-[(4-methoxyphenyl)methyl]-3-(1-methyl-6-phenyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)urea Chemical compound C1=CC(OC)=CC=C1CNC(=O)NC1C2=NN=C(C)N2C2=CC=CC=C2C(C=2C=CC=CC=2)=N1 YKHPDEJRXBTLOU-UHFFFAOYSA-N 0.000 claims description 2
- RATMGGWUORWQNG-UHFFFAOYSA-N 1-benzyl-3-(1-methyl-6-phenyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)urea Chemical compound N1=C(C=2C=CC=CC=2)C2=CC=CC=C2N2C(C)=NN=C2C1NC(=O)NCC1=CC=CC=C1 RATMGGWUORWQNG-UHFFFAOYSA-N 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- NOIUHLVGASAAKC-UHFFFAOYSA-N 3-bromo-n-(1-methyl-6-phenyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)benzamide Chemical compound N1=C(C=2C=CC=CC=2)C2=CC=CC=C2N2C(C)=NN=C2C1NC(=O)C1=CC=CC(Br)=C1 NOIUHLVGASAAKC-UHFFFAOYSA-N 0.000 claims description 2
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- BOVHWQDJYASZCX-UHFFFAOYSA-N 5-methyl-n-(1-methyl-6-phenyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-1h-indole-2-carboxamide Chemical compound C12=CC=CC=C2N2C(C)=NN=C2C(NC(=O)C=2NC3=CC=C(C)C=C3C=2)N=C1C1=CC=CC=C1 BOVHWQDJYASZCX-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 3
- RKQFBOPLNMCUMU-UHFFFAOYSA-N 1-methyl-6-phenyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine Chemical class C12=CC=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 RKQFBOPLNMCUMU-UHFFFAOYSA-N 0.000 claims 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical group CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims 1
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 abstract description 2
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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
- 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
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- 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
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Transplantation (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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| GBGB0919426.7A GB0919426D0 (en) | 2009-11-05 | 2009-11-05 | Novel compounds |
| GB0919426.7 | 2009-11-05 | ||
| PCT/EP2010/066696 WO2011054844A1 (en) | 2009-11-05 | 2010-11-03 | Condensed azepine derivatives as bromodomain inhibitors |
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| US (1) | US20120202799A1 (enExample) |
| EP (1) | EP2496581A1 (enExample) |
| JP (1) | JP2013510122A (enExample) |
| GB (1) | GB0919426D0 (enExample) |
| WO (1) | WO2011054844A1 (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2017510605A (ja) * | 2014-04-09 | 2017-04-13 | カイノス・メディスン・インコーポレイテッドＫａｉｎｏｓ Ｍｅｄｉｃｉｎｅ， Ｉｎｃ． | がんを予防または治療するための、ブロモドメイン阻害化合物およびそれを含む医薬組成物 |
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| MX354217B (es) | 2010-05-14 | 2018-02-19 | Dana Farber Cancer Inst Inc | Composiciones y metodos para el tratamiento de leucemia. |
| CA2799381A1 (en) | 2010-05-14 | 2011-11-17 | Dana-Farber Cancer Institute, Inc. | Male contraceptive compositions and methods of use |
| MX362384B (es) | 2010-05-14 | 2019-01-15 | Dana Farber Cancer Inst Inc | Composiciones y metodos para tratar neoplasias, enfermedades inflamatorias y otros trastornos. |
| AR084070A1 (es) | 2010-12-02 | 2013-04-17 | Constellation Pharmaceuticals Inc | Inhibidores del bromodominio y usos de los mismos |
| WO2012075456A1 (en) | 2010-12-02 | 2012-06-07 | Constellation Pharmaceuticals | Bromodomain inhibitors and uses thereof |
| EP2705039B1 (en) | 2011-05-04 | 2017-07-26 | Constellation Pharmaceuticals, Inc. | Bromodomain inhibitors and uses thereof |
| WO2012174487A2 (en) | 2011-06-17 | 2012-12-20 | Constellation Pharmaceuticals, Inc. | Bromodomain inhibitors and uses thereof |
| WO2013027168A1 (en) | 2011-08-22 | 2013-02-28 | Pfizer Inc. | Novel heterocyclic compounds as bromodomain inhibitors |
| WO2013033270A2 (en) * | 2011-08-29 | 2013-03-07 | Coferon, Inc. | Bromodomain ligands capable of dimerizing in an aqueous solution, and methods of using same |
| WO2013033269A1 (en) * | 2011-08-29 | 2013-03-07 | Coferon, Inc. | Bioorthogonal monomers capable of dimerizing and targeting bromodomains and methods of using same |
| DE102011082013A1 (de) | 2011-09-01 | 2013-03-07 | Bayer Pharma AG | 6H-Thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine |
| WO2013097052A1 (en) | 2011-12-30 | 2013-07-04 | Abbott Laboratories | Bromodomain inhibitors |
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- 2010-11-03 WO PCT/EP2010/066696 patent/WO2011054844A1/en not_active Ceased
- 2010-11-03 US US13/501,557 patent/US20120202799A1/en not_active Abandoned
- 2010-11-03 EP EP10773086A patent/EP2496581A1/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017510605A (ja) * | 2014-04-09 | 2017-04-13 | カイノス・メディスン・インコーポレイテッドＫａｉｎｏｓ Ｍｅｄｉｃｉｎｅ， Ｉｎｃ． | がんを予防または治療するための、ブロモドメイン阻害化合物およびそれを含む医薬組成物 |
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| GB0919426D0 (en) | 2009-12-23 |
| US20120202799A1 (en) | 2012-08-09 |
| WO2011054844A1 (en) | 2011-05-12 |
| EP2496581A1 (en) | 2012-09-12 |
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