(11S,11aS)-10-(tert-butyloxycarbonyl)-8,11-dihydroxy-7-methoxy-2-oxo-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 英文名称: (11S,11aS)-10-(tert-butyloxycarbonyl)-8,11-dihydroxy-7-methoxy-2-oxo-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one
• 英文别名: tert-butyl (6S,6aS)-3,6-dihydroxy-2-methoxy-8,11-dioxo-6,6a,7,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate
• 化学式: C₁₈H₂₂N₂O₇
• 分子量: 378.382
• InChiKey: AFBQRGAEARPZNB-LRDDRELGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  117
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (11S,11aS)-10-(tert-butyloxycarbonyl)-8,11-dihydroxy-7-methoxy-2-oxo-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one 在 potassium tert-butylate 、 对甲苯磺酸 、 溶剂黄146 作用下， 以 四氢呋喃 、 水 、 乙酸乙酯 为溶剂， 反应 22.17h， 生成 tert-butyl (11S,11aS)-8-hydroxy-7-methoxy-2-methylene-5-oxo-11-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylate
  参考文献：
  名称：

  Pyrrolobenzodiazepine Dimer Antibody–Drug Conjugates: Synthesis and Evaluation of Noncleavable Drug-Linkers

  摘要：

  Three rationally designed pyrrolobenzodiazepine (PBD) drug-linkers have been synthesized via intermediate 19 for use in antibody drug conjugates (ADCs). They lack a cleavable trigger in the linker and consist of a maleimide for cysteine antibody conjugation, a hydrophilic spacer, and either an alkyne (6), triazole (7), or piperazine (8) link to the PBD. In vitro IC50 values were 11-48 ng/mL in HER2 3+ SK-BR-3 and KPL-4 (7 inactive) for the anti-HER2 ADCs (HER2 0 MCF7, all inactive) and 0.10-1.73 mu g/mL (7 inactive) in CD22 3+ BJAB and WSU-DLCL2 for anti-CD22 ADCs (CD22 0 Jurkat, all inactive at low doses). In-vivo antitumor efficacy for the anti-HER2 ADCs in Founder 5 was observed with tumor stasis at 0.5-1 mg/kg, 1 mg/kg, and 3-6 mg/kg for 6, 8, and 7, respectively. Tumor stasis at 2 mg/kg was observed for anti-CD22 6 in WSU-DLCL2. In summary, noncleavable PBD-ADCs exhibit potent activity, particularly in HER2 models.

  DOI：

  10.1021/acs.jmedchem.7b00736
• 作为产物：
  描述：

  5-甲氧基-2-硝基-4-苯基甲氧基苯甲酰氯 在 甲醇 、 锂硼氢 、 2,2,6,6-四甲基哌啶氧化物 、 tin(II) chloride dihdyrate 、 碘苯二乙酸 、 palladium 10% on activated carbon 、 氢气 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 为溶剂， -20.0~20.0 ℃ 、206.85 kPa 条件下， 反应 59.5h， 生成 (11S,11aS)-10-(tert-butyloxycarbonyl)-8,11-dihydroxy-7-methoxy-2-oxo-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one
  参考文献：
  名称：

  Pyrrolobenzodiazepine Dimer Antibody–Drug Conjugates: Synthesis and Evaluation of Noncleavable Drug-Linkers

  摘要：

  Three rationally designed pyrrolobenzodiazepine (PBD) drug-linkers have been synthesized via intermediate 19 for use in antibody drug conjugates (ADCs). They lack a cleavable trigger in the linker and consist of a maleimide for cysteine antibody conjugation, a hydrophilic spacer, and either an alkyne (6), triazole (7), or piperazine (8) link to the PBD. In vitro IC50 values were 11-48 ng/mL in HER2 3+ SK-BR-3 and KPL-4 (7 inactive) for the anti-HER2 ADCs (HER2 0 MCF7, all inactive) and 0.10-1.73 mu g/mL (7 inactive) in CD22 3+ BJAB and WSU-DLCL2 for anti-CD22 ADCs (CD22 0 Jurkat, all inactive at low doses). In-vivo antitumor efficacy for the anti-HER2 ADCs in Founder 5 was observed with tumor stasis at 0.5-1 mg/kg, 1 mg/kg, and 3-6 mg/kg for 6, 8, and 7, respectively. Tumor stasis at 2 mg/kg was observed for anti-CD22 6 in WSU-DLCL2. In summary, noncleavable PBD-ADCs exhibit potent activity, particularly in HER2 models.

  DOI：

  10.1021/acs.jmedchem.7b00736

文献信息

• Pyrrolobenzodiazepines as key intermediates in the synthesis of dimeric cytotoxic pyrrolobenzodiazepines
  申请人：Howard Wilson Philip

  公开号：US20070191309A1

  公开（公告）日：2007-08-16

  Compounds and a method of synthesis of compounds of formula (Ia) or (Ib): and salts, solvates, and chemically protected forms thereof, wherein the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3; R 2 and R 3 are independently selected from —H, ═O, ═CH 2 , —CN, —R, OR, halo, ═CH—R, O—SO 2 —R, CO 2 R and COR; R 10 is a carbamate-based nitrogen protecting group; and R 11 is an oxygen protecting group.

  化合物及其合成方法公式（Ia）或（Ib）的化合物：以及其盐、溶剂化物和化学保护形式，其中点线表示C1和C2或C2和C3之间存在双键的可选存在；R2和R3独立地选择自—H，═O，═CH2，—CN，—R，OR，卤素，═CH—R，O—SO2—R，CO2R和COR；R10是基于碳酸酯的氮保护基；R11是氧保护基。
• [EN] PYRROLOBENZODIAZEPINES AS KEY INTERMEDIATES IN THE SYNTHESIS OF DIMERIC CYTOTOXIC PYRROLOBENZODIAZEPINES<br/>[FR] PYRROLOBENZODIAZEPINES
  申请人：SPIROGEN LTD

  公开号：WO2005085259A3

  公开（公告）日：2006-01-05
• US7557099B2
  申请人：——

  公开号：US7557099B2

  公开（公告）日：2009-07-07
• Pyrrolobenzodiazepine Dimer Antibody–Drug Conjugates: Synthesis and Evaluation of Noncleavable Drug-Linkers
  作者：Stephen J. Gregson、Luke A. Masterson、Binqing Wei、Thomas H. Pillow、Susan D. Spencer、Gyoung-Dong Kang、Shang-Fan Yu、Helga Raab、Jeffrey Lau、Guangmin Li、Gail D. Lewis Phillips、Janet Gunzner-Toste、Brian S. Safina、Rachana Ohri、Martine Darwish、Katherine R. Kozak、Josefa dela Cruz-Chuh、Andrew Polson、John A. Flygare、Philip W. Howard

  DOI：10.1021/acs.jmedchem.7b00736

  日期：2017.12.14

  Three rationally designed pyrrolobenzodiazepine (PBD) drug-linkers have been synthesized via intermediate 19 for use in antibody drug conjugates (ADCs). They lack a cleavable trigger in the linker and consist of a maleimide for cysteine antibody conjugation, a hydrophilic spacer, and either an alkyne (6), triazole (7), or piperazine (8) link to the PBD. In vitro IC50 values were 11-48 ng/mL in HER2 3+ SK-BR-3 and KPL-4 (7 inactive) for the anti-HER2 ADCs (HER2 0 MCF7, all inactive) and 0.10-1.73 mu g/mL (7 inactive) in CD22 3+ BJAB and WSU-DLCL2 for anti-CD22 ADCs (CD22 0 Jurkat, all inactive at low doses). In-vivo antitumor efficacy for the anti-HER2 ADCs in Founder 5 was observed with tumor stasis at 0.5-1 mg/kg, 1 mg/kg, and 3-6 mg/kg for 6, 8, and 7, respectively. Tumor stasis at 2 mg/kg was observed for anti-CD22 6 in WSU-DLCL2. In summary, noncleavable PBD-ADCs exhibit potent activity, particularly in HER2 models.