ES2564318T3 - Inhibidor de bromodominio de benzodiazepina - Google Patents
Inhibidor de bromodominio de benzodiazepina Download PDFInfo
- Publication number
- ES2564318T3 ES2564318T3 ES10773325.5T ES10773325T ES2564318T3 ES 2564318 T3 ES2564318 T3 ES 2564318T3 ES 10773325 T ES10773325 T ES 10773325T ES 2564318 T3 ES2564318 T3 ES 2564318T3
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- Spain
- Prior art keywords
- alkyl
- methyl
- compound
- methyloxy
- triazolo
- 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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- 229940125763 bromodomain inhibitor Drugs 0.000 title description 16
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 title description 2
- 229940049706 benzodiazepine Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 230
- 150000003839 salts Chemical class 0.000 claims abstract description 97
- 238000011282 treatment Methods 0.000 claims abstract description 47
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 45
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 26
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims abstract description 25
- 125000004452 carbocyclyl group Chemical group 0.000 claims abstract description 23
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 23
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 23
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 22
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 21
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims abstract description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 18
- 201000011510 cancer Diseases 0.000 claims abstract description 17
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 17
- 150000002367 halogens Chemical class 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 14
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims abstract description 13
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 11
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 11
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 11
- 125000005843 halogen group Chemical group 0.000 claims abstract description 10
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 8
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 6
- 125000004429 atom Chemical group 0.000 claims abstract description 5
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract 5
- 238000002360 preparation method Methods 0.000 claims description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 239000003085 diluting agent Substances 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000005884 carbocyclylalkyl group Chemical group 0.000 claims description 5
- 210000000481 breast Anatomy 0.000 claims description 4
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 4
- 230000002440 hepatic effect Effects 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 208000037828 epithelial carcinoma Diseases 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 230000002489 hematologic effect Effects 0.000 claims description 2
- 210000004072 lung Anatomy 0.000 claims description 2
- 201000005296 lung carcinoma Diseases 0.000 claims description 2
- 230000000926 neurological effect Effects 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 138
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 117
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 98
- 235000002639 sodium chloride Nutrition 0.000 description 95
- 238000001819 mass spectrum Methods 0.000 description 85
- -1 azido, amino, hydroxyl Chemical group 0.000 description 82
- 239000000543 intermediate Substances 0.000 description 82
- 239000000203 mixture Substances 0.000 description 81
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- 239000000243 solution Substances 0.000 description 57
- 238000000034 method Methods 0.000 description 51
- 239000007787 solid Substances 0.000 description 51
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 39
- 239000002904 solvent Substances 0.000 description 39
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 34
- 102000001805 Bromodomains Human genes 0.000 description 34
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- 108050009021 Bromodomains Proteins 0.000 description 33
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 230000002829 reductive effect Effects 0.000 description 30
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- 238000006243 chemical reaction Methods 0.000 description 25
- 229910052938 sodium sulfate Inorganic materials 0.000 description 25
- 235000011152 sodium sulphate Nutrition 0.000 description 25
- 239000007832 Na2SO4 Substances 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 23
- 125000001309 chloro group Chemical group Cl* 0.000 description 22
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
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- 239000008346 aqueous phase Substances 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 15
- 239000003112 inhibitor Substances 0.000 description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
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- 150000001412 amines Chemical class 0.000 description 13
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- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 229910052739 hydrogen Inorganic materials 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- 239000007821 HATU Substances 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
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Classifications
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- C—CHEMISTRY; METALLURGY
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- 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
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- 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
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
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- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
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- A61P37/02—Immunomodulators
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Landscapes
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- Physical Education & Sports Medicine (AREA)
- Transplantation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0919433 | 2009-11-05 | ||
| GB0919433A GB0919433D0 (en) | 2009-11-05 | 2009-11-05 | Novel compounds |
| GBGB1010509.6A GB201010509D0 (en) | 2010-06-22 | 2010-06-22 | Novel compounds |
| GB201010509 | 2010-06-22 | ||
| PCT/EP2010/061518 WO2011054553A1 (en) | 2009-11-05 | 2010-08-06 | Benzodiazepine bromodomain inhibitor |
| WOPCT/EP2010/061518 | 2010-08-06 | ||
| GB201014231 | 2010-08-25 | ||
| GBGB1014231.3A GB201014231D0 (en) | 2010-08-25 | 2010-08-25 | Novel compounds |
| PCT/EP2010/066697 WO2011054845A1 (en) | 2009-11-05 | 2010-11-03 | Benzodiazepine bromodomain inhibitor |
Publications (1)
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| ES2564318T3 true ES2564318T3 (es) | 2016-03-21 |
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| ES10773325.5T Active ES2564318T3 (es) | 2009-11-05 | 2010-11-03 | Inhibidor de bromodominio de benzodiazepina |
| ES16152464.0T Active ES2654423T3 (es) | 2009-11-05 | 2010-11-03 | Inhibidor de bromodominio de benzodiacepina |
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| Application Number | Title | Priority Date | Filing Date |
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| ES16152464.0T Active ES2654423T3 (es) | 2009-11-05 | 2010-11-03 | Inhibidor de bromodominio de benzodiacepina |
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| EP (2) | EP3050885B1 (enExample) |
| JP (3) | JP5702396B2 (enExample) |
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| CN (1) | CN102781943B (enExample) |
| AU (1) | AU2010317096B2 (enExample) |
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| IL (2) | IL219253A (enExample) |
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| SI (1) | SI2496582T1 (enExample) |
| SM (1) | SMT201600104B (enExample) |
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| BRPI0714886B8 (pt) | 2006-07-10 | 2021-05-25 | Paion Uk Ltd | sais de benzodiazepina, seus usos e seus processos de preparação, e composição farmacêutica |
| AU2010317096B2 (en) * | 2009-11-05 | 2015-03-26 | Glaxosmithkline Llc | Benzodiazepine bromodomain inhibitor |
| CN103154246B (zh) | 2010-05-14 | 2015-11-25 | 达那-法伯癌症研究所 | 用于治疗白血病的组合物和方法 |
| ES2606958T3 (es) | 2010-05-14 | 2017-03-28 | Dana-Farber Cancer Institute, Inc. | Compuestos de tienotriazolodiazepina para tratar una neoplasia |
| JP5715241B2 (ja) * | 2010-05-14 | 2015-05-07 | ダナ−ファーバー キャンサー インスティテュート， インコーポレイテッド | 新生物、炎症性疾患、およびその他の障害を治療するための組成物および方法 |
| CN103180318B (zh) | 2010-05-14 | 2017-05-10 | 达那-法伯癌症研究所 | 雄性避孕组合物以及使用方法 |
| EP2450039A1 (en) | 2010-11-08 | 2012-05-09 | PAION UK Ltd. | Dosing regimen for sedation with CNS 7056 (Remimazolam) |
| 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 |
| WO2012151512A2 (en) | 2011-05-04 | 2012-11-08 | Constellation Pharmaceuticals, Inc. | Bromodomain inhibitors and uses thereof |
| WO2012174487A2 (en) | 2011-06-17 | 2012-12-20 | Constellation Pharmaceuticals, Inc. | Bromodomain inhibitors and uses thereof |
| GB201114103D0 (en) * | 2011-08-17 | 2011-09-28 | Glaxosmithkline Llc | Novel compounds |
| WO2013027168A1 (en) | 2011-08-22 | 2013-02-28 | Pfizer Inc. | Novel heterocyclic compounds as bromodomain inhibitors |
| WO2013033268A2 (en) * | 2011-08-29 | 2013-03-07 | Coferon, Inc. | Bivalent bromodomain ligands, 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 |
| WO2013155695A1 (en) | 2012-04-20 | 2013-10-24 | Abbott Laboratories | Isoindolone derivatives |
| GEAP201813666A (en) * | 2012-05-22 | 2018-01-25 | Paion Uk Ltd | Compositions comprising short-acting benzodiazepines |
| TWI602820B (zh) | 2012-06-06 | 2017-10-21 | 星宿藥物公司 | 溴域抑制劑及其用途 |
| WO2013184878A1 (en) | 2012-06-06 | 2013-12-12 | Constellation Pharmaceuticals, Inc. | Benzo [b] isoxazoloazepine bromodomain inhibitors and uses thereof |
| HK1208681A1 (en) | 2012-06-12 | 2016-03-11 | Abbvie Inc. | Pyridinone and pyridazinone derivatives |
| JP6333251B2 (ja) | 2012-08-16 | 2018-05-30 | バイエル ファーマ アクチエンゲゼルシャフト | ２，３−ベンゾジアゼピン類 |
| BR112015002824A2 (pt) * | 2012-08-16 | 2017-08-08 | Glaxosmithkline Llc | composto, uso de um composto, composição farmacêutica, e, produto farmacêutico de combinação. |
| WO2014048945A1 (de) * | 2012-09-28 | 2014-04-03 | Bayer Pharma Aktiengesellschaft | Bet-proteininhibitorische 5-aryl-triazolo-azepine |
| JP2016507496A (ja) | 2012-12-21 | 2016-03-10 | ゼニス・エピジェネティクス・コーポレイションＺｅｎｉｔｈ Ｅｐｉｇｅｎｅｔｉｃｓ Ｃｏｒｐ． | ブロモドメイン阻害剤としての新規複素環式化合物 |
| AR094963A1 (es) | 2013-03-04 | 2015-09-09 | Ono Pharmaceutical Co | Reacción de oxidación excelente en el índice de conversión |
| EP2970312B1 (en) | 2013-03-11 | 2017-11-15 | The Regents of The University of Michigan | Bet bromodomain inhibitors and therapeutic methods using the same |
| EP2970285B1 (en) * | 2013-03-11 | 2019-04-17 | AbbVie Inc. | Fused tetracyclic bromodomain inhibitors |
| BR112015022391B1 (pt) * | 2013-03-12 | 2021-12-21 | Abbvie Inc | Compostos inibidores do domínio bromo tetracíclico, composição farmacêutica que compreende os referidos compostos e usos terapêuticos dos mesmos |
| WO2014159392A1 (en) | 2013-03-14 | 2014-10-02 | Dana-Farber Cancer Institute, Inc. | Bromodomain binding reagents and uses thereof |
| EA201591746A1 (ru) | 2013-03-14 | 2016-08-31 | КОНВЕРДЖЕН ЭлЭлСи | Способы и композиции для ингибирования бромодомен-содержащих белков |
| EA035469B1 (ru) | 2013-03-15 | 2020-06-22 | Инсайт Холдингс Корпорейшн | Трициклические гетероциклы как ингибиторы белков бэт |
| EA027139B1 (ru) | 2013-04-26 | 2017-06-30 | Бейджин, Лтд. | Замещенные 5-(3,5-диметилизоксазол-4-ил)индолин-2-оны |
| CN104146970A (zh) * | 2013-05-05 | 2014-11-19 | 王元青 | 治疗精神疾病的冻干粉针剂 |
| CN103202815B (zh) * | 2013-05-05 | 2014-09-24 | 李友香 | 治疗精神疾病的注射剂 |
| KR102307566B1 (ko) | 2013-06-21 | 2021-10-05 | 제니쓰 에피제네틱스 리미티드 | 신규한 바이사이클릭 브로모도메인 억제제 |
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