N-(2-{[(8S)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-6H-thieno[3,2-e]indol-6-yl]carbonyl}-1H-indol-5-yl)-1H-indole-2-carboxamide | 960314-93-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: N-(2-{[(8S)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-6H-thieno[3,2-e]indol-6-yl]carbonyl}-1H-indol-5-yl)-1H-indole-2-carboxamide
• 英文别名: N-[2-[(8S)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydrothieno[3,2-e]indole-6-carbonyl]-1H-indol-5-yl]-1H-indole-2-carboxamide
• CAS: 960314-93-6
• 化学式: C₃₀H₂₃ClN₄O₃S
• 分子量: 555.057
• InChiKey: STVTZWBCUDXABZ-GOSISDBHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  39
• 可旋转键数：
  4
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  130
• 氢给体数：
  4
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(2-{[(8S)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-6H-thieno[3,2-e]indol-6-yl]carbonyl}-1H-indol-5-yl)-1H-indole-2-carboxamide 在 盐酸 、 4-二甲氨基吡啶 、 三乙胺 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 34.0h， 生成 (8S)-8-(chloromethyl)-6-({5-[(1H-indol-2-ylcarbonyl)amino]-1H-indol-2-yl}carbonyl)-1-methyl-7,8-dihydro-6H-thieno[3,2-e]indol-4-yl 4-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]piperazine-1-carboxylate
  参考文献：
  名称：

  [EN] FUNCTIONALIZED THIENO-INDOLE DERIVATIVES FOR THE TREATMENT OF CANCER
  [FR] DÉRIVÉS THIÉNO-INDOLES FONCTIONNALISÉS POUR LE TRAITEMENT DU CANCER

  摘要：

  本发明涉及具有细胞毒性活性的新型功能化噻吩吲衍生物（式（I）或（II）），并可用于治疗癌症和细胞增殖紊乱等疾病。本发明还涉及使用这些功能化噻吩吲衍生物制备共轭物。其中R1和R2共同形成一个基团（D）或（G）：其中R5为氢或C1-C4烷基；R3和R4独立地为氢、C1-C4烷基或C1-C4羟基烷基；n为0、1或2；每个X独立地为-O-、-S-或-NR4-；每个Y独立地为-CH=或-N=；R7和R8独立地为氢、卤素、羟基、C1-C4烷氧基、氰基、-NHCOOR3、-C（NH）NH2或-NR3R4；A为-O-、-NH-或-CO-；L为空或有条件可割离的基团；W为空或包含一个或多个自解离基团的自解离基团；Z为空或为肽、非肽或混合肽和非肽连接基团；RM为空或为反应性基团；R6为离去基团；A1为空或为A；L1为氢或L。

  公开号：

  WO2013149946A1
• 作为产物：
  描述：

  (8S)-8-(chloromethyl)-1-methyl-7,8-dihydro-6H-thieno[3,2-e]indol-4-ol 、 5-[((1H-indol-2-yl)carbonyl)amino]-1H-indole-2-carboxylic acid 在 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.33h， 以4.9 mg的产率得到N-(2-{[(8S)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-6H-thieno[3,2-e]indol-6-yl]carbonyl}-1H-indol-5-yl)-1H-indole-2-carboxamide
  参考文献：
  名称：

  CC-1065 和 Duocarmycins 关键类似物的合理设计、合成和评价

  摘要：

  设计、合成和评估 CC-1065 的可预测更有效的类似物，需要替换烷基化亚基中的单个骨架原子，并基于从化学物质之间的基本抛物线关系中出现的设计原则进行。反应性和细胞毒性。与预测一致，7-甲基-1,2,8,8a-四氢环丙[c]噻吩并[3,2-e]吲哚-4-酮（MeCTI）烷基化亚基及其异构体6-甲基-1,2，发现 8,8a-四氢环丙 [c] 噻吩并 [2,3-e]indol-4-one (iso-MeCTI) 比 CC-1065 中发现的 MeCPI 烷基化亚基稳定 5-6 倍，并且更稳定甚至比在 duocarmycin SA 中发现的 DSA 烷基化亚基还要好，使其处于此类抗肿瘤药物的最佳平衡稳定性和反应性点。它们与天然产物的关键类似物的结合提供了超过 MeCPI 衍生物效力的衍生物（3-10 倍），匹配或略微超过相应 DSA 衍生物的效力，与基于抛物线关系的预测一致. 其中值得注意的是，MeCTI-TMI

  DOI：

  10.1021/ja073989z

文献信息

• [EN] NEW ALKYLATING AGENTS<br/>[FR] NOUVEAUX AGENTS ALKYLANTS
  申请人：NERVIANO MEDICAL SCIENCES SRL

  公开号：WO2013149948A1

  公开（公告）日：2013-10-10

  The present invention relates to a novel class of alkylating agents comprising a thieno-indole moiety linked to a DNA-binding moiety, which have cytotoxic activity and are useful in treating diseases such as cancer, cellular proliferation disorders and viral infections. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising them and methods of treating diseases utilizing such compounds or the pharmaceutical composition containing them. The invention also relates to the use of this novel class of alkylating agents in the preparation of conjugates.

  本发明涉及一种新型的烷基化剂类别，包括与DNA结合基团连接的噻吩-吲哚基团，具有细胞毒活性，并可用于治疗癌症、细胞增殖紊乱和病毒感染等疾病。本发明还提供了制备这些化合物的方法、包含它们的药物组合物以及利用这些化合物或含有它们的药物组合物治疗疾病的方法。该发明还涉及将这种新型烷基化剂类别用于制备共轭物的用途。
• ALKYLATING AGENTS
  申请人：NERVIANO MEDICAL SCIENCES S.R.L.

  公开号：US20150051154A1

  公开（公告）日：2015-02-19

  The present invention relates to a novel class of alkylating agents comprising a thieno-indole moiety linked to a DNA-binding moiety, which have cytotoxic activity and are useful in treating diseases such as cancer, cellular proliferation disorders and viral infections. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising them and methods of treating diseases utilizing such compounds or the pharmaceutical composition containing them. The invention also relates to the use of this novel class of alkylating agents in the preparation of conjugates.

  本发明涉及一种新型的烷基化剂类别，包括与DNA结合基团相连的噻吩-吲哚基团，具有细胞毒活性，并可用于治疗癌症、细胞增殖紊乱和病毒感染等疾病。本发明还提供了制备这些化合物的方法、包含它们的药物组合物以及利用这些化合物或含有它们的药物组合物治疗疾病的方法。该发明还涉及将这种新型烷基化剂类别用于制备共轭物的用途。
• FUNCTIONALIZED THIENO-INDOLE DERIVATIVES FOR THE TREATMENT OF CANCER
  申请人：NERVIANO MEDICAL SCIENCES S.R.L

  公开号：US20150080316A1

  公开（公告）日：2015-03-19

  The invention relates to new functionalized thieno-indole derivatives of formula (I) or (II) which have cytotoxic activity and are useful in treating diseases such as cancer and cellular proliferation disorders. The invention also relates to the use of these functionalized thieno-indole derivatives in the preparation of conjugates. Formula (I) or (II) wherein R 1 and R 2 taken together form a group (D) or (G): wherein R 5 is hydrogen or C 1 -C 4 alkyl; R 3 and R 4 are independently hydrogen, C 1 -C 4 alkyl or C 1 -C 4 hydroxyalkyl; n is 0, 1 or 2; each of X is independently —O—, —S— or —NR 4 —; each of Y is independently —CH═ or —N═; R 7 and R 8 are independently hydrogen, halogen, hydroxy, C 1 -C 4 alkoxy, cyano, —NHCOOR 3 , —C(NH)NH 2 or —NR 3 R 4 ; A is —O—, —NH— or —CO—; L is null or a conditionally-cleavable moiety; W is null or a self-immolative moiety comprising one or more self-immolative groups; Z is null or a peptidic, non peptidic or hybrid peptidic and non peptidic linker; RM is null or a reactive moiety; R 6 is a leaving group; A 1 is null or A; L 1 is hydrogen or L.

  本发明涉及公式（I）或（II）的新型功能化噻吩吲衍生物，具有细胞毒性活性，并可用于治疗癌症和细胞增殖障碍等疾病。本发明还涉及使用这些功能化噻吩吲衍生物制备共轭物。公式（I）或（II）中，R1和R2共同形成一个基团（D）或（G）：其中R5为氢或C1-C4烷基；R3和R4分别为氢、C1-C4烷基或C1-C4羟基烷基；n为0、1或2；X各自独立地为—O—、—S—或—NR4—；Y各自独立地为—CH═或—N═；R7和R8各自独立地为氢、卤素、羟基、C1-C4烷氧基、氰基、—NHCOOR3、—C（NH）NH2或—NR3R4；A为—O—、—NH—或—CO—；L为空或一个有条件可剪切的基团；W为空或一个自我解离基团，包括一个或多个自我解离基团；Z为空或一个肽、非肽或杂交肽非肽连接基；RM为空或一个反应性基团；R6为一个离去基团；A1为空或A；L1为氢或L。
• NEW ALKYLATING AGENTS
  申请人：Nerviano Medical Sciences S.r.l.

  公开号：EP2836494B1

  公开（公告）日：2019-08-21
• THIENO-INDOLE MOIETIES AND METHODS OF TREATING USING THE SAME
  申请人：NERVIANO MEDICAL SCIENCES S.R.L.

  公开号：US20170071907A1

  公开（公告）日：2017-03-16

  The present invention relates to a novel class of alkylating agents comprising a thieno-indole moiety linked to a DNA-binding moiety, which have cytotoxic activity and are useful in treating diseases such as cancer, cellular proliferation disorders and viral infections. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising them and methods of treating diseases utilizing such compounds or the pharmaceutical composition containing them. The invention also relates to the use of this novel class of alkylating agents in the preparation of conjugates.