N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N⁵-carbamoyl-N-[4-({[{2-[({[(8S)-8-(chloromethyl)-1-methyl-6-({5-[({5-[2-(pyrrolidin-1-yl)ethoxy]-1H-indol-2-yl}carbonyl)amino]-1H-indol-2-yl}carbonyl)-7,8-dihydro-6H-thieno[3,2-e]indol-4-yl]oxy}carbonyl)(methyl)amino]ethyl}(methyl)carbamoyl]oxy}methyl)phenyl]-L-ornithinamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N⁵-carbamoyl-N-[4-({[{2-[({[(8S)-8-(chloromethyl)-1-methyl-6-({5-[({5-[2-(pyrrolidin-1-yl)ethoxy]-1H-indol-2-yl}carbonyl)amino]-1H-indol-2-yl}carbonyl)-7,8-dihydro-6H-thieno[3,2-e]indol-4-yl]oxy}carbonyl)(methyl)amino]ethyl}(methyl)carbamoyl]oxy}methyl)phenyl]-L-ornithinamide
• 英文别名: N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N5-carbamoyl-N-[4-({[{2-[({[(8S)-8-(chloromethyl)-1-methyl-6-({5-[({5-[2-(pyrrolidin-1-yl)ethoxy]-1H-indol-2-yl}carbonyl)amino]-1H-indol-2-yl}carbonyl)-7,8-dihydro-6H-thieno[3,2-e]indol-4-yl]oxy}carbonyl)(methyl)amino]ethyl}(methyl)carbamoyl]oxy}methyl)phenyl]-L-ornithinamide；[(8S)-8-(chloromethyl)-1-methyl-6-[5-[[5-(2-pyrrolidin-1-ylethoxy)-1H-indole-2-carbonyl]amino]-1H-indole-2-carbonyl]-7,8-dihydrothieno[3,2-e]indol-4-yl] N-[2-[[4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrol-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methoxycarbonyl-methylamino]ethyl]-N-methylcarbamate
• 化学式: C₇₀H₈₂ClN₁₃O₁₃S
• 分子量: 1381.02
• InChiKey: MUFPNILWOMRQMW-SCPFROOHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.1
• 重原子数：
  98
• 可旋转键数：
  32
• 环数：
  10.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  361
• 氢给体数：
  8
• 氢受体数：
  15

反应信息

• 作为产物：
  描述：

  6-(马来酰亚胺基)己酸琥珀酰亚胺酯 、 L-valyl-N⁵-carbamoyl-N-[4-({[{2-[({[(8S)-8-(chloromethyl)-1-methyl-6-({5-[({5-[2-(pyrrolidin-1-yl)ethoxy]-1H-indol-2-yl}carbonyl)amino]-1H-indol-2-yl}carbonyl)-7,8-dihydro-6H-thieno[3,2-e]indol-4-yl]oxy}carbonyl)(methyl)amino]ethyl}(methyl)carbamoyl]oxy}methyl)phenyl]-L-ornithinamide 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以41%的产率得到N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N⁵-carbamoyl-N-[4-({[{2-[({[(8S)-8-(chloromethyl)-1-methyl-6-({5-[({5-[2-(pyrrolidin-1-yl)ethoxy]-1H-indol-2-yl}carbonyl)amino]-1H-indol-2-yl}carbonyl)-7,8-dihydro-6H-thieno[3,2-e]indol-4-yl]oxy}carbonyl)(methyl)amino]ethyl}(methyl)carbamoyl]oxy}methyl)phenyl]-L-ornithinamide
  参考文献：
  名称：

  [EN] NEW ALKYLATING AGENTS
  [FR] NOUVEAUX AGENTS ALKYLANTS

  摘要：

  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。

  公开号：

  WO2013149948A1

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。
• [EN] ASYMMETRIC PROCESS FOR THE PREPARATION OF THIENO-INDOLES DERIVATIVES<br/>[FR] PROCÉDÉ ASYMÉTRIQUE POUR LA PRÉPARATION DE DÉRIVÉS DE THIÉNO-INDOLES
  申请人：NERVIANO MEDICAL SCIENCES SRL

  公开号：WO2017012924A1

  公开（公告）日：2017-01-26

  The present invention relates to a new process for the preparation of thieno-indole derivatives of formula (Ia) or (Ib), exploiting an asymmetric synthesis for the preparation of key (8S) or (8R) 8-(halomethyl)-1-alkyl-7,8-dihydro- 6H-thieno[3,2-e]indol-4-ol intermediates, and to useful intermediate compounds of such process. Thieno-indole derivatives are described and claimed in GB2344818, WO2013/149948 and WO2013/149946, which also disclose processes for their preparation. Thieno-indole enantiopure derivatives can now be advantageously prepared through a new asymmetric synthesis of the key 8-(halomethyl)-7,8-dihydro-6H-thieno[3,2-e]indol intermediates, which, avoiding the chiral resolution step, provides benefits in terms of reducing time and costs of the whole process for their preparation. The synthesis starts from the N-alkylation of 5-amino-4-halo-3-alkyl-1-benzothiophene-7-ol derivatives with enantiopure glycidyl 3-nosylate, followed by intramolecular 6-endo-tet cyclization using alkyl Grignard reagents; Mitsunobu activation of the secondary alcohol promotes internal spirocyclization, affording the 4,4a,5,6-tetrahydro- 8H-cyclopropa[c]thieno[3,2-e]indol-8-one derivatives; finally, stereo-electronically controlled regioselective cyclopropane opening yields the key enantiopure 8-(halomethyl)-1-alkyl-7,8-dihydro-6H-thieno[3,2-e]indol-4-ol intermediates, which can be further derivatized following teachings disclosed in WO2013/149948 or WO2013/149946, to prepare the final thieno-indole derivatives of formula (Ia) or (Ib). Such compounds are disclosed to be alkylating compounds with cytotoxic activity, therefore useful as such in the treatment of a variety of cancers and in cell proliferative disorders, or, conjugated with different types of nucleophiles, in the preparation of Antiboby Drug Conjugated derivatives.

  本发明涉及一种新的制备式(Ia)或(Ib)的噻吩吲衍生物的过程，利用不对称合成制备关键的(8S)或(8R) 8-(卤代甲基)-1-烷基-7,8-二氢-6H-噻吩[3,2-e]吲-4-醇中间体，并涉及该过程的有用中间体化合物。噻吩吲衍生物已在GB2344818，WO2013/149948和WO2013/149946中进行了描述和声明，这些文献还披露了它们的制备过程。现在可以通过新的不对称合成制备具有对映体纯度的噻吩吲衍生物的关键8-(卤代甲基)-7,8-二氢-6H-噻吩[3,2-e]吲醇中间体，避免手性分离步骤，从而在减少整个制备过程的时间和成本方面提供了好处。合成从5-氨基-4-卤代-3-烷基-1-苯并噻吩-7-醇衍生物与对映纯的环氧丙烷基3-磺酰酸酯进行N-烷基化开始，随后使用烷基格氏试剂进行分子内6-内环四元环化反应；次级醇的Mitsunobu活化促进内部螺环化反应，得到4,4a,5,6-四氢-8H-环丙基[c]噻吩[3,2-e]吲酮衍生物；最后，立体电子控制的区域选择性环丙烷开放反应产生关键的对映纯8-(卤代甲基)-1-烷基-7,8-二氢-6H-噻吩[3,2-e]吲-4-醇中间体，可以根据WO2013/149948或WO2013/149946中披露的教导进一步衍生化，制备最终的式(Ia)或(Ib)的噻吩吲衍生物。这些化合物被披露为具有细胞毒活性的烷基化合物，因此在治疗各种癌症和细胞增殖性疾病方面非常有用，或者与不同类型的亲核试剂结合，制备抗体药物结合衍生物。
• Thieno-indole moieties and methods of treating using the same
  申请人：NERVIANO MEDICAL SCIENCES S.R.L.

  公开号：US10071074B2

  公开（公告）日：2018-09-11

  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. The present invention also relates to methods of treating ovarian cancer by administration of compounds of formula (II):

  本发明涉及一类新型烷化剂，该类烷化剂包含一个与 DNA 结合基相连的噻吩-吲哚分子，具有细胞毒性活性，可用于治疗癌症、细胞增殖障碍和病毒感染等疾病。本发明还提供了制备这些化合物的方法、含有这些化合物的药物组合物以及利用这些化合物或含有这些化合物的药物组合物治疗疾病的方法。本发明还涉及这类新型烷化剂在制备共轭物中的用途。本发明还涉及通过施用式（II）化合物治疗卵巢癌的方法：
• Asymmetric process for the preparation of thieno-indoles derivatives
  申请人：NERVIANO MEDICAL SCIENCES S.R.L.

  公开号：US10174048B2

  公开（公告）日：2019-01-08

  The present invention relates to a new process for the preparation of thieno-indole derivatives of formula (Ia) or (Ib), exploiting an asymmetric synthesis for the preparation of key (8S) or (8R) 8-(halomethyl)-1-alkyl-7,8-dihydro-6H-thieno[3,2-e]indol-4-ol intermediates, and to useful intermediate compounds of such process. Thieno-indole derivatives are described and claimed in GB2344818, WO2013/149948 and WO2013/149946, which also disclose processes for their preparation. Thieno-indole enantiopure derivatives can now be advantageously prepared through a new asymmetric synthesis of the key 8-(halomethyl)-7,8-dihydro-6H-thieno[3,2-e]indol intermediates, which, avoiding the chiral resolution step, provides benefits in terms of reducing time and costs of the whole process for their preparation. The synthesis starts from the N-alkylation of 5-amino-4-halo-3-alkyl-1-benzothiophene-7-ol derivatives with enantiopure glycidyl 3-nosylate, followed by intramolecular 6-endo-tet cyclization using alkyl Grignard reagents; Mitsunobu activation of the secondary alcohol promotes internal spirocyclization, affording the 4,4a,5,6-tetrahydro-8H-cyclopropa[c]thieno[3,2-e]indol-8-one derivatives; finally, stereo-electronically controlled regioselective cyclopropane opening yields the key enantiopure 8-(halomethyl)-1-alkyl-7,8-dihydro-6H-thieno[3,2-e]indol-4-ol intermediates, which can be further derivatized following teachings disclosed in WO2013/149948 or WO2013/149946, to prepare the final thieno-indole derivatives of formula (Ia) or (Ib). Such compounds are disclosed to be alkylating compounds with cytotoxic activity, therefore useful as such in the treatment of a variety of cancers and in cell proliferative disorders, or, conjugated with different types of nucleophiles, in the preparation of Antibody Drug Conjugated derivatives.

  本发明涉及一种制备式(Ia)或(Ib)噻吩-吲哚衍生物的新工艺，利用不对称合成制备关键的(8S)或(8R)8-(卤甲基)-1-烷基-7,8-二氢-6H-噻吩并[3,2-e]吲哚-4-醇中间体，以及该工艺的有用中间体化合物。噻吩-吲哚衍生物在 GB2344818、WO2013/149948 和 WO2013/149946 中均有描述和权利要求，其中还公开了其制备工艺。现在，通过对关键的 8-（卤甲基）-7,8-二氢-6H-噻吩并[3,2-e]吲哚中间体进行新的不对称合成，就可以制备出噻吩并吲哚对映体纯衍生物，该方法避免了手性解析步骤，在减少整个制备过程的时间和成本方面具有优势。该合成首先用 3-对映体缩水甘油酸酯对 5-氨基-4-卤-3-烷基-1-苯并噻吩-7-醇衍生物进行 N-烷基化，然后用烷基格氏试剂进行分子内 6-内向四环化；仲醇的 Mitsunobu 活化促进了内部螺环化，从而得到 4,4a,5,6-四氢-8H-环丙[c]噻吩并[3,2-e]吲哚-8-酮衍生物；最后，立体电子控制的区域选择性环丙烷开环产生关键的不对映纯的 8-（卤甲基）-1-烷基-7,8-二氢-6H-噻吩并[3,2-e]吲哚-4-醇中间体，这些中间体可以按照 WO2013/149948 或 WO2013/149946 中公开的方法进一步衍生，制备最终的式 (Ia) 或 (Ib) 的噻吩-吲哚衍生物。此类化合物被公开为具有细胞毒性活性的烷基化化合物，因此可用于治疗各种癌症和细胞增殖性疾病，或与不同类型的亲核物共轭，制备抗体药物共轭衍生物。
• NEW ALKYLATING AGENTS
  申请人：Nerviano Medical Sciences S.r.l.

  公开号：EP2836494B1

  公开（公告）日：2019-08-21