(S)-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)(3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone | 762245-27-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: (S)-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)(3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone
• 英文别名: [(3S)-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]-(5-methoxy-2-nitro-4-phenylmethoxyphenyl)methanone
• CAS: 762245-27-2
• 化学式: C₂₅H₂₄N₂O₆
• 分子量: 448.475
• InChiKey: RWTVVRYBJODJAZ-FQEVSTJZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  105
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (S)-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)(3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone 在 4-二甲氨基吡啶 、 lithium hydroxide monohydrate 、 1,4-环己二烯 、 palladium 10% on activated carbon 、 铁粉 、 potassium carbonate 、 氯化铵 、 戴斯-马丁氧化剂 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 4-[4-[[(6aS)-2-methoxy-14-oxo-7,12-dihydro-6aH-isoquinolino[3,2-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-1-methyl-N-[4-[1-methyl-5-[[2-methyl-2-(methyldisulfanyl)propyl]carbamoyl]pyrrol-3-yl]phenyl]imidazole-2-carboxamide
  参考文献：
  名称：

  Design, synthesis and evaluation of novel, potent DNA alkylating agents and their antibody-drug conjugates (ADCs)

  摘要：

  Antibody-drug conjugates (ADCs) incorporating potent indolinobenzodiazepine (IGN) DNA alkylators as the cytotoxic payload are currently undergoing clinical evaluation. The optimized design of these payloads consists of an unsymmetrical dimer possessing both an imine and an amine effectively eliminating DNA crosslinking and demonstrating improved tolerability in mice. Here we present an alternate approach to generating DNA alkylating ADCs by linking the IGN monomer with a biaryl system which has a high DNA binding affinity to potentially enhance tolerability. These BIA ADCs were found to be highly cytotoxic in vitro and demonstrated potent antitumor activity in vivo.

  DOI：

  10.1016/j.bmcl.2019.07.031
• 作为产物：
  描述：

  3,4-二氢一异喹啉-2,3-二甲酸-2-苄酯 在 锂硼氢 、 氯化亚砜 、 碘代三甲硅烷 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙腈 为溶剂， 反应 20.0h， 生成 (S)-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)(3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone
  参考文献：
  名称：

  具有DNA识别潜力的新型四氢异喹啉代[2,1-c] [1,4]苯并二氮杂ze环系统的合成。

  摘要：

  我们报道了具有DNA识别潜力的新型四氢异喹啉并[2,1-c] [1,4]苯并二氮杂ring环系统的第一个立体定向合成和反应性。

  DOI：

  10.1016/j.bmcl.2004.07.001

文献信息

• [EN] POLYCYCLIC AMIDES AS CYTOTOXIC AGENTS<br/>[FR] AMIDES POLYCYCLIQUES SERVANT D'AGENTS CYTOTOXIQUES
  申请人：FEMTOGENIX LTD

  公开号：WO2020049286A1

  公开（公告）日：2020-03-12

  The invention relates to a compound of formula (I): or pharmaceutically acceptable salts, solvates, tautomers, stereoisomers or mixtures thereof; wherein the fused ring moiety is a non-alkylating moiety; and wherein the compounds are useful as medicaments, in particular for use as a drug in an antibody-drug conjugate and in the treatment of a proliferative disease, a bacterial infection, a malarial infection and inflammation.

  该发明涉及公式(I)的化合物；或其药学上可接受的盐、溶剂合物、互变异构体、立体异构体或它们的混合物；其中融合环基团是非烷基化基团；这些化合物可用作药物，特别是用作抗体药物结合物中的药物，以及用于治疗增殖性疾病、细菌感染、疟疾感染和炎症。
• [EN] CYTOTOXIC AGENTS<br/>[FR] AGENTS CYTOTOXIQUES
  申请人：FEMTOGENIX LTD

  公开号：WO2019043417A1

  公开（公告）日：2019-03-07

  The invention relates to a compound of formula (I) or formula (II) or pharmaceutically acceptable salts, solvates, tautomers, stereoisomers or mixtures thereof; which are useful as medicaments, in particular as anti-proliferative agents and for use as a drug in an antibody-drug conjugate and in the treatment of proliferative diseases.

  该发明涉及公式（I）或公式（II）的化合物，或其药学上可接受的盐、溶剂合物、互变异构体、立体异构体或其混合物；这些化合物可用作药物，特别是作为抗增殖剂，并用作抗体-药物结合物中的药物，用于治疗增殖性疾病。
• [EN] BENZODIAZEPINE DERIVATIVES<br/>[FR] DÉRIVÉS DE BENZODIAZÉPINE
  申请人：IMMUNOGEN INC

  公开号：WO2019133652A1

  公开（公告）日：2019-07-04

  The invention relates to novel benzodiazepine derivatives with antiproliferative activity and more specifically to novel benzodiazepine compounds of formulae (I), (II) and (III). The invention also provides conjugates of the benzodiazepine compounds linked to a cell-binding agent. The invention further provides compositions and methods useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal using the compounds or conjugates of the invention.

  该发明涉及具有抗增殖活性的新型苯二氮卓衍生物，更具体地涉及具有公式（I）、（II）和（III）的新型苯二氮卓化合物。该发明还提供了与细胞结合剂连接的苯二氮卓化合物的结合物。此外，该发明还提供了使用该发明的化合物或结合物抑制异常细胞生长或治疗哺乳动物增殖性疾病的有效组合物和方法。
• [EN] ASYMMETRIC CONJUGATE COMPOUNDS<br/>[FR] COMPOSÉS CONJUGUÉS ASYMÉTRIQUES
  申请人：FEMTOGENIX LTD

  公开号：WO2017194960A1

  公开（公告）日：2017-11-16

  The invention relates to compound of formula (I): A-X1-L-X2-B and salts, solvates and tautomers thereof, which are useful as medicaments, in particular as anti-proliferative agents and for use as a drug in an antibody-drug conjugate; wherein A is a group selected from (A1), (A2), (A3), (A4) and (A5); X1 and X2 are independently selected from O, S, NR28, CR28R29, CR28R29O, C(=O), C(=O)NR28, NR28C(=O), C(O)-RA-C(O)-NH, C(O)-RA-NH-C(O), C(O) -NH-RA-C(O), NH-C(O)-RA-C(O), NH-C(O)-RA-C(O)-NH, NH-C(O)-RA-NH-C(O), C(O)-NH-RA-NH-C(O), C(O)-NH-RA-C(O)-NH, O-C(O) and C(O)-O or is absent; L is selected from an amino acid, a peptide chain having from 2 to 12 amino acids, a paraformaldehyde chain –(OCH2)1-24-, a polyethylene glycol chain -(OCH2CH2)1-12- and –(CH2)m-Y6-(CH2)n- wherein Y6 is selected from –(CH2)z- and a group (L1) a group (L1) that is selected from arylene, monocyclic heteroarylene, monocyclic cycloalkylene, monocyclic cycloalkenylene and monocyclic heterocyclylene groups optionally substituted with up to three optional substituent groups; and B is a polycyclic group selected from (B1), (B2) and (B3).

  该发明涉及化合物的公式(I)：A-X1-L-X2-B及其盐、溶剂合物和互变异构体，其作为药物具有实用性，特别是作为抗增殖剂并用作抗体药物结合物中的药物；其中A是从(A1)、(A2)、(A3)、(A4)和(A5)中选择的基团；X1和X2分别选择自O、S、NR28、CR28R29、CR28R29O、C(=O)、C(=O)NR28、NR28C(=O)、C(O)-RA-C(O)-NH、C(O)-RA-NH-C(O)、C(O)-NH-RA-C(O)、NH-C(O)-RA-C(O)、NH-C(O)-RA-C(O)-NH、NH-C(O)-RA-NH-C(O)、C(O)-NH-RA-NH-C(O)、C(O)-NH-RA-C(O)-NH、O-C(O)和C(O)-O或者不存在；L选择自氨基酸、具有2至12个氨基酸的肽链、对甲醛链-(O )1-24-、聚乙二醇链-(O )1-12-和-(CH2)m-Y6-( )n-，其中Y6选择自-( )z-和一个基团(L1)，该基团(L1)选择自芳基、单环杂芳基、单环环烷基、单环环烯烃基和单环杂环烷基，可选地取代高达三个可选取代基团；B是从(B1)、(B2)和(B3)中选择的多环基团。
• [EN] CYTOTOXIC BENZODIAZEPINE DERIVATIVES AND CONJUGATES THEREOF<br/>[FR] DÉRIVÉS DE BENZODIAZÉPINE CYTOTOXIQUES ET LEURS CONJUGUÉS
  申请人：IMMUNOGEN INC

  公开号：WO2018195243A1

  公开（公告）日：2018-10-25

  The invention relates to novel benzodiazepine derivatives with antiproliferative activity and more specifically to novel benzodiazepine compounds of formulae (I) and (II). The invention also provides conjugates of the benzodiazepine compounds linked to a cell-binding agent. The invention further provides compositions and methods useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal using the compounds or conjugates of the invention.

  该发明涉及具有抗增殖活性的新型苯二氮䓬啶衍生物，更具体地涉及具有化学式(I)和(II)的新型苯二氮䓬啶化合物。该发明还提供了将苯二氮䓬啶化合物与细胞结合剂结合的共轭物。该发明还提供了使用该发明的化合物或共轭物抑制异常细胞生长或治疗哺乳动物增殖性疾病的组合物和方法。