JP5524343B2 - ベンゾジアゼピンブロモドメイン阻害剤 - Google Patents
ベンゾジアゼピンブロモドメイン阻害剤 Download PDFInfo
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- JP5524343B2 JP5524343B2 JP2012537329A JP2012537329A JP5524343B2 JP 5524343 B2 JP5524343 B2 JP 5524343B2 JP 2012537329 A JP2012537329 A JP 2012537329A JP 2012537329 A JP2012537329 A JP 2012537329A JP 5524343 B2 JP5524343 B2 JP 5524343B2
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- 0 COc(cc1)cc(C(c(cc2)ccc2Cl)=N[C@]2CC(O*)=O)c1NC2=O Chemical compound COc(cc1)cc(C(c(cc2)ccc2Cl)=N[C@]2CC(O*)=O)c1NC2=O 0.000 description 3
- WMJPNHZLHUIRSV-ZJFPTPTDSA-N CC([C@H](CC(OC)=O)N=C(c(cc1)ccc1Cl)c1c2)Nc1ccc2OC Chemical compound CC([C@H](CC(OC)=O)N=C(c(cc1)ccc1Cl)c1c2)Nc1ccc2OC WMJPNHZLHUIRSV-ZJFPTPTDSA-N 0.000 description 1
- JINCKLGZGZPISY-PKHIMPSTSA-N CCNC(C[C@@H]1N=C(C(C=C2)=CCC2Cl)c(cc(cc2)OC)c2-[n]2c1nnc2C)=O Chemical compound CCNC(C[C@@H]1N=C(C(C=C2)=CCC2Cl)c(cc(cc2)OC)c2-[n]2c1nnc2C)=O JINCKLGZGZPISY-PKHIMPSTSA-N 0.000 description 1
- CVRWSADMYVWLRM-QFIPXVFZSA-N CCc(nc1C)c2[n]1-c(ccc(OC)c1)c1C(c1ccc(C)cc1)=N[C@H]2CC(NCC)=O Chemical compound CCc(nc1C)c2[n]1-c(ccc(OC)c1)c1C(c1ccc(C)cc1)=N[C@H]2CC(NCC)=O CVRWSADMYVWLRM-QFIPXVFZSA-N 0.000 description 1
- MIQUXYBYLZSOIJ-UHFFFAOYSA-N COc(cc1C(c(cc2)ccc2Cl)=O)ccc1N Chemical compound COc(cc1C(c(cc2)ccc2Cl)=O)ccc1N MIQUXYBYLZSOIJ-UHFFFAOYSA-N 0.000 description 1
- VHZXZZWPVBGOFL-VMSUTVGLSA-N Cc1nnc2[n]1-c(ccc(OC)c1)c1C(c(cc1)ccc1Cl)=N[C@H]2/C=C/C(O)=O Chemical compound Cc1nnc2[n]1-c(ccc(OC)c1)c1C(c(cc1)ccc1Cl)=N[C@H]2/C=C/C(O)=O VHZXZZWPVBGOFL-VMSUTVGLSA-N 0.000 description 1
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
- A61K31/55—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
-
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
-
- 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
-
- 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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Description
全ての温度は℃で表す。
TLC 薄層クロマトグラフィー
AcOH 酢酸
AcCl 塩化アセチル
PPTS p−トルエンスルホン酸ピリジニウム
DCM ジクロロメタン
1,2−DCE 1,2−ジクロロエタン
DIC ジイソプロピルカルボジイミド
DIEA N,N−ジイソプロピルエチルアミン
DMF N,N−ジメチルホルムアミド
DMAP 4−ジメチルアミノピリジン
Fmoc 9H−フルオレン−9−イルメチル)オキシ]カルボニル
HATU O−(7−アザベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムヘキサフルオロホスフェート
HBTU O−(ベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムヘキサフルオロホスフェート
Et2O ジエチルエーテル
EtOAc 酢酸エチル
i−Pr2O ジ−イソプロピルエーテル
Config. 絶対配置
ローソン試薬 2,4−ビス(4−メトキシフェニル)−1,3−ジチア−2,4−ジホスフェタン−2,4−ジスルフィド
MeCN アセトニトリル
MeOH メタノール
Rt 保持時間
THF テトラヒドロフラン
RT 室温
Pd/C パラジウム炭素
LC/MSは、2種類の装置で実施した分析用HPLCによる分析を指す:
a)Supelcosil LCABZ+PLUSカラム(3μm、3.3cm×4.6mm ID)では、0.1%HCO2Hおよび0.01M酢酸アンモニウム水溶液(溶媒A)、ならびに95%アセトニトリルおよび0.05%HCO2H水溶液(溶媒B)で、3mL/分の流速で以下の溶出勾配0〜0.7分 0%B、0.7〜4.2分 0→100%B、4.2〜5.3分 100%B、5.3〜5.5分 100→0%Bを用いて溶出する。質量スペクトル(MS)を、エレクトロスプレー陽イオン化[([M+H]+および[M+NH4]+分子イオンを得るためにES+ve]またはエレクトロスプレー陰イオン化[([M−H]−分子イオンを得るためにES−ve]モードを用いてFisons VG Platform質量分析計で記録した。この装置からの分析データを以下のフォーマット:[M+H]+または[M−H]−で与える。
本明細書において参照されるLC−MS法AおよびBの実験詳細は以下の通りである:
LC/MS(方法A)は、Supelcosil LCABZ+PLUSカラム(3μm、3.3cm×4.6mm ID)で、0.1% HCO2Hおよび0.01M酢酸アンモニウム水溶液(溶媒A)、ならびに95%アセトニトリルおよび0.05%HCO2H水溶液(溶媒B)を用いて、3mL/分の流速で以下の溶出勾配0〜0.7分 0%B、0.7〜4.2分 0→100%B、4.2〜5.3分 100%B、5.3〜5.5分 100→0%Bを用いて溶出する実施した。質量スペクトル(MS)を、エレクトロスプレー陽イオン化[([M+H]+および[M+NH4]+分子イオンを得るためにES+ve]またはエレクトロスプレー陰イオン化[([M−H]−分子イオンを得るためにES−ve]モードを用いてFisons VG Platform質量分析計で記録した。この装置からの分析データは以下のフォーマット:[M+H]+または[M−H]−で与える。
蛍光異方性結合アッセイ
ブロモドメイン2、3および4に対する式(I)の化合物の結合を、蛍光異方性結合アッセイを用いて評価した。
y=a+((b−a)/(1+(10∧×/10∧c)∧d)
式中、「a」は最小値であり、「b」はヒル勾配(Hill slope)であり、「c」はpIC50であり、「d」は最大値である。
細菌性リポ多糖(LPS)などのtoll様受容体のアゴニストによる単球細胞の活性化により、TNFαを含む重要な炎症性メディエータの生成が生じる。そのような経路は、様々な自己免疫および炎症性疾患の病態生理学に重要であると広く認められている。
動物に投与した高用量のエンドトキシン(細菌性リポ多糖)は、強力な炎症反応、心臓血管機能の異常調節、臓器不全および最終的に死亡を含む深刻なショック症候群を生じる。このパターンの反応は、ヒトの敗血症および敗血性ショックと非常に類似しており、顕著な細菌感染に対する身体の反応は同様に生命を脅かす危険性がある。
ビヒクル 4/66(6%)
実施例1 24/56(52%)
これらのデータは、上記のモデルにおいて試験した実施例1が、静脈内投与後に顕著な動物の生存効果を生じたことを実証している。これは、式(I)の化合物がヒトにおける炎症反応に対して十分な効果についての可能性を有することを示唆している。
Claims (14)
- 請求項2に記載の式(I)の化合物またはその医薬的に許容可能な塩と、1種以上の医薬的に許容可能な担体、希釈剤または賦形剤とを含んでなる、医薬組成物。
- 請求項3に記載の式(I)の化合物と、1種以上の医薬的に許容可能な担体、希釈剤または賦形剤とを含んでなる、医薬組成物。
- 1種以上の他の治療活性剤と共に請求項2に記載の式(I)の化合物もしくはその医薬的に許容可能な塩、または請求項3に記載の式(I)の化合物を含んでなる、組合せ医薬品。
- 治療に使用するための請求項2に記載の式(I)の化合物またはその医薬的に許容可能な塩。
- 治療に使用するための請求項3に記載の式(I)の化合物。
- 慢性自己免疫病態および/または炎症性病態の治療における使用のための、請求項2に記載の式(I)の化合物もしくはその医薬的に許容可能な塩、または請求項3に記載の式(I)の化合物。
- 癌の治療における使用のための、請求項2に記載の式(I)の化合物もしくはその医薬的に許容可能な塩、または請求項3に記載の式(I)の化合物。
- 癌が血液癌、肺癌、乳癌、結腸癌を含む上皮癌、正中線癌、間葉癌、肝臓腫瘍、腎腫瘍および神経学的腫瘍から選択される、請求項10に記載の使用のための式(I)の化合物またはその医薬的に許容可能な塩。
- 血液癌が白血病である、請求項11に記載の使用のための式(I)の化合物またはその医薬的に許容可能な塩。
- 慢性自己免疫病態および/または炎症性病態を治療するための薬剤の製造における、請求項2に記載の式(I)の化合物もしくはその医薬的に許容可能な塩、または請求項3に記載の式(I)の化合物の使用。
- 癌を治療するための薬剤の製造における、請求項2に記載の式(I)の化合物もしくはその医薬的に許容可能な塩、または請求項3に記載の式(I)の化合物の使用。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0919433.3 | 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 |
GB1010509.6 | 2010-06-22 | ||
PCT/EP2010/061518 WO2011054553A1 (en) | 2009-11-05 | 2010-08-06 | Benzodiazepine bromodomain inhibitor |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2013510107A JP2013510107A (ja) | 2013-03-21 |
JP5524343B2 true JP5524343B2 (ja) | 2014-06-18 |
Family
ID=42667965
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2012537329A Active JP5524343B2 (ja) | 2009-11-05 | 2010-08-06 | ベンゾジアゼピンブロモドメイン阻害剤 |
Country Status (32)
Country | Link |
---|---|
US (3) | US9023842B2 (ja) |
EP (3) | EP2722334B1 (ja) |
JP (1) | JP5524343B2 (ja) |
KR (1) | KR101424989B1 (ja) |
CN (1) | CN102762569B (ja) |
AU (1) | AU2010314395B2 (ja) |
BR (1) | BR112012010706A2 (ja) |
CA (1) | CA2779355C (ja) |
CL (1) | CL2012001178A1 (ja) |
CO (1) | CO6540003A2 (ja) |
CR (1) | CR20120283A (ja) |
CY (2) | CY1114988T1 (ja) |
DK (2) | DK2722334T3 (ja) |
DO (1) | DOP2012000114A (ja) |
EA (1) | EA020390B1 (ja) |
ES (3) | ES2446647T3 (ja) |
HK (3) | HK1191012A1 (ja) |
HR (2) | HRP20140107T1 (ja) |
HU (1) | HUE026421T2 (ja) |
IL (2) | IL219090A0 (ja) |
MA (1) | MA33803B1 (ja) |
ME (1) | ME02360B (ja) |
MX (1) | MX2012005295A (ja) |
MY (1) | MY160456A (ja) |
NZ (1) | NZ599258A (ja) |
PE (1) | PE20121181A1 (ja) |
PL (2) | PL2722334T3 (ja) |
PT (2) | PT2496580E (ja) |
RS (2) | RS53179B (ja) |
SI (2) | SI2496580T1 (ja) |
SM (2) | SMT201400024B (ja) |
WO (1) | WO2011054553A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013510123A (ja) * | 2009-11-05 | 2013-03-21 | グラクソスミスクライン エルエルシー | ベンゾジアゼピンブロモドメイン阻害剤 |
JP2013510121A (ja) * | 2009-11-05 | 2013-03-21 | グラクソスミスクライン エルエルシー | 自己免疫性及び炎症性疾患を治療するためのブロモドメイン阻害剤 |
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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 |
BR122014024883A2 (pt) | 2010-05-14 | 2019-08-20 | Dana-Farber Cancer Institute, Inc. | Compostos no tratamento de neoplasia |
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 |
AR084070A1 (es) | 2010-12-02 | 2013-04-17 | Constellation Pharmaceuticals Inc | Inhibidores del bromodominio y usos de los mismos |
US9249161B2 (en) | 2010-12-02 | 2016-02-02 | Constellation Pharmaceuticals, Inc. | Bromodomain inhibitors and uses thereof |
US9422292B2 (en) | 2011-05-04 | 2016-08-23 | 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 |
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 |
EP2838881B1 (en) | 2012-04-20 | 2018-08-08 | AbbVie Inc. | Isoindolone derivatives |
TWI602820B (zh) | 2012-06-06 | 2017-10-21 | 星宿藥物公司 | 溴域抑制劑及其用途 |
US9624244B2 (en) | 2012-06-06 | 2017-04-18 | Constellation Pharmaceuticals, Inc. | Benzo [B] isoxazoloazepine bromodomain inhibitors and uses thereof |
AU2012382373A1 (en) | 2012-06-12 | 2014-12-11 | Abbvie Inc. | Pyridinone and pyridazinone derivatives |
KR20150042231A (ko) | 2012-08-16 | 2015-04-20 | 글락소스미스클라인 엘엘씨 | 소세포폐암을 치료하기 위한 벤조디아제핀 |
WO2014026997A1 (de) | 2012-08-16 | 2014-02-20 | Bayer Pharma Aktiengesellschaft | 2,3-benzodiazepine |
EP2900672B1 (de) | 2012-09-28 | 2017-02-22 | Bayer Pharma Aktiengesellschaft | Bet-proteininhibitorische 5-aryl-triazolo-azepine |
US9422290B2 (en) | 2012-11-13 | 2016-08-23 | Boehringer Ingelheim International Gmbh | Triazolopyridazine |
US9266891B2 (en) | 2012-11-16 | 2016-02-23 | Boehringer Ingelheim International Gmbh | Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors |
WO2014080291A2 (en) | 2012-11-21 | 2014-05-30 | Rvx Therapeutics Inc. | Biaryl derivatives as bromodomain inhibitors |
US9073878B2 (en) | 2012-11-21 | 2015-07-07 | Zenith Epigenetics Corp. | Cyclic amines as bromodomain inhibitors |
US9271978B2 (en) | 2012-12-21 | 2016-03-01 | Zenith Epigenetics Corp. | Heterocyclic compounds as bromodomain inhibitors |
US9492460B2 (en) * | 2013-02-27 | 2016-11-15 | Bristol-Myers Squibb Company | Carbazole compounds useful as bromodomain inhibitors |
WO2014134583A2 (en) * | 2013-02-28 | 2014-09-04 | Washington University | Methods of treatment of human cytomegalovirus infection and diseases with bromodomain inhibitors |
BR112015022861A8 (pt) | 2013-03-11 | 2019-11-26 | Abbvie Inc | inibidores de bromodomínio |
MX2015012158A (es) | 2013-03-11 | 2015-12-01 | Abbvie Inc | Inhibidores de bomodominio tetraciclicos fusionados. |
KR20150135359A (ko) | 2013-03-14 | 2015-12-02 | 컨버진 엘엘씨 | 브로모도메인-함유 단백질의 억제를 위한 방법 및 조성물 |
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