(11S,11aS)-4-(2-(1-((1-(allyloxy)-4-methyl-1,2-dioxopentan-3-yl)amino)-1-oxopropan-2-yl)hydrazinyl)benzyl 11-hydroxy-7-methoxy-2-methyl-5-oxo-8-((triisopropylsilyl)oxy)-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10( 5H)-carboxylate | 1430738-32-1

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

中文名称

——

中文别名

——

英文名称

(11S,11aS)-4-(2-(1-((1-(allyloxy)-4-methyl-1,2-dioxopentan-3-yl)amino)-1-oxopropan-2-yl)hydrazinyl)benzyl 11-hydroxy-7-methoxy-2-methyl-5-oxo-8-((triisopropylsilyl)oxy)-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10( 5H)-carboxylate

英文别名

(11S,11aS)-4-(2-(1-((1-(allyloxy)-4-methyl-1,2-dioxopentan-3-yl)amino)-1-oxopropan-2-yI)hydrazinyl)benzyl 11-hydroxy-7-methoxy-2-methyl-5-oxo-8-((triisopropylsilyl)oxy)-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylate；(11S,11aS)-4-(2-(1-((1-(allyloxy)-4-methyl-1,2-dioxopentan-3-yl)amino)-1-oxopropan-2-yl)hydrazinyl)benzyl 11-hydroxy-7-methoxy-2-methyl-5-oxo-8-((triisopropylsilyl)oxy)11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylate

(11S,11aS)-4-(2-(1-((1-(allyloxy)-4-methyl-1,2-dioxopentan-3-yl)amino)-1-oxopropan-2-yl)hydrazinyl)benzyl 11-hydroxy-7-methoxy-2-methyl-5-oxo-8-((triisopropylsilyl)oxy)-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10( 5H)-carboxylate化学式

CAS

1430738-32-1

化学式

C₄₃H₆₁N₅O₁₀Si

mdl

——

分子量

836.07

InChiKey

HYCHSEUJDUNWIH-VQXPXOEYSA-N

BEILSTEIN

——

EINECS

——

物化性质

沸点：

946.9±65.0 °C(Predicted)
密度：

1.22±0.1 g/cm3(Predicted)

计算性质

辛醇/水分配系数(LogP)：

7.22
重原子数：

59.0
可旋转键数：

16.0
环数：

4.0
sp3杂化的碳原子比例：

0.51
拓扑面积：

185.07
氢给体数：

4.0
氢受体数：

10.0

上下游信息

上游原料

中文名称	英文名称	CAS号	化学式	分子量
——	allyl 3-(2-(2-(4-((((2-((S)-2-(hydroxymethyl)-4-methyl-2,3-dihydro-1H-pyrrole-1-carbonyl)-4-methoxy-5-((triisopropylsilyl)oxy)phenyl)carbamoyl)oxy)methyl)phenyl)hydrazinyl)propanamido)-4-methyl-2-oxopentanoate	1430738-31-0	C₄₃H₆₃N₅O₁₀Si	838.086
——	allyl 3-(2-(2-(4-((((2-((S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-2,3-dihydro-1H-pyrrole-1-carbonyl)-4-methoxy-5-((triisopropylsilyl)oxy)phenyl)carbamoyl)oxy)methyl)phenyl)hydrazinyl)propanamido)-4-methyl-2-oxopentanoate	1430738-30-9	C₄₉H₇₇N₅O₁₀Si₂	952.349
——	prop-2-enyl (6S,6aS)-6-[tert-butyl(dimethyl)silyl]oxy-3-(5-iodopentoxy)-2-methoxy-11-oxo-8-[(E)-prop-1-enyl]-6a,7-dihydro-6H-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate	1430738-14-9	C₃₁H₄₅IN₂O₆Si	696.698
——	(S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-(5-methoxy-2-nitro-4-((triisopropylsilyl)oxy)benzoyl)-4,5-dihydro-1H-pyrrol-3-yl trifluoromethanesulfonate	1430738-06-9	C₂₉H₄₇F₃N₂O₉SSi₂	712.932
——	(S)-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-2,3-dihydro-1H-pyrrol-1-yl)(5-methoxy-2-nitro-4-((triisopropylsilyl)oxy)phenyl)methanone	1430738-22-9	C₂₉H₅₀N₂O₆Si₂	578.897
——	(S)-(2-amino-5-methoxy-4-((triisopropylsilyl)oxy)phenyl)(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-2,3-dihydro-1H-pyrrol-1-yl)methanone	1430738-23-0	C₂₉H₅₂N₂O₄Si₂	548.914
——	(S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-(5-methoxy-2-nitro-4-((triisopropylsilyl)oxy)benzoyl)pyrrolidin-3-one	1430738-05-8	C₂₈H₄₈N₂O₇Si₂	580.869
——	((2S,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxypyrrolidin-1-yl)(5-methoxy-2-nitro-4-((triisopropylsilyl)oxy)phenyl)methanone	1430738-04-7	C₂₈H₅₀N₂O₇Si₂	582.885

下游产品

中文名称	英文名称	CAS号	化学式	分子量
——	4-((S)-2-((S)-2-(((allyloxy)carbonyl)amino)-3-methylbutanamido)propanamido)benzyl (11S,11aS)-11-((tert-butyldimethylsilyl)oxy)-7-methoxy-2-methyl-5-oxo-8-((triisopropylsilyl)oxy)-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylate	1430738-33-2	C₄₉H₇₅N₅O₁₀Si₂	950.333

反应信息

作为反应物：

描述：

(11S,11aS)-4-(2-(1-((1-(allyloxy)-4-methyl-1,2-dioxopentan-3-yl)amino)-1-oxopropan-2-yl)hydrazinyl)benzyl 11-hydroxy-7-methoxy-2-methyl-5-oxo-8-((triisopropylsilyl)oxy)-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10( 5H)-carboxylate 在 2,6-二甲基吡啶、 lithium acetate dihydrate 作用下，以二氯甲烷、水、 N,N-二甲基甲酰胺为溶剂，反应 22.0h，生成 (11S,11aS)-4-(2-(1-((1-(allyloxy)-4-methyl-1,2-dioxopentan-3-yl)amino)-1-oxopropan-2-yl)hydrazinyl)benzyl 11-((tert-butyldimethylsilyl)oxy)-8-hydroxy-7-methoxy-2-methyl-5-oxo-11,11a-dihydro-1 H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylate

参考文献：

名称：

替硝林的按比例放大合成

摘要：

这项工作描述了能够合成合成的酪胺酸，一种吡咯并苯并二氮杂卓抗体-药物偶联物药物连接物。在四次合成运动过程中，开发了发现路线并扩大了规模，以提供可靠的制造过程。早期中间体以千克规模和高纯度生产，无需色谱。优化了中间阶段的反应，以最大程度地减少杂质的形成。使用少量关键的高压色谱步骤生产和纯化后期材料，最终在34个步骤后得到169 g批料。在撰写本文时，tesirine是多项临床试验中8种抗体-药物偶联物的药物连接物成分，其中4种是关键的。

DOI：

10.1021/acs.oprd.8b00205
作为产物：

描述：

prop-2-enyl (6S,6aS)-6-[tert-butyl(dimethyl)silyl]oxy-3-(5-iodopentoxy)-2-methoxy-11-oxo-8-[(E)-prop-1-enyl]-6a,7-dihydro-6H-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate 在草酰氯、碳酸氢钠、溶剂黄146 、二甲基亚砜、 2-乙氧基-1-乙氧碳酰基-1,2-二氢喹啉、三乙胺作用下，以四氢呋喃、二氯甲烷、水为溶剂，反应 151.25h，生成 (11S,11aS)-4-(2-(1-((1-(allyloxy)-4-methyl-1,2-dioxopentan-3-yl)amino)-1-oxopropan-2-yl)hydrazinyl)benzyl 11-hydroxy-7-methoxy-2-methyl-5-oxo-8-((triisopropylsilyl)oxy)-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10( 5H)-carboxylate

参考文献：

名称：

[EN] SYNTHESIS METHOD AND INTERMEDIATES USEFUL IN THE PREPARATION OF PYRROLOBENZODIAZEPINES
[FR] PROCÉDÉ DE SYNTHÈSE ET INTERMÉDIAIRES POUVANT SERVIR À PRÉPARER DES PYRROLOBENZODIAZÉPINES

摘要：

式I的化合物，其中：R7选自：ORA，其中RA选自C1-4饱和烷基，可选择地被苯基取代，该苯基可能带有氯取代基，吡啶基和呋喃基；氯；NH2；-CH2-O-C(=O)Me；R8为OProt°，其中Prot°是与Rc正交的基于硅的氧保护基团；R9选自H，甲基和甲氧基；Rs选自CF3，(CF2)3CF3，CH3和（式2）；Rc选自：(i)-C(=O)-ORC1，其中RC1是饱和的C1-4烷基基团；(ii)-CH2-O-C(=0)RC2，其中RC2是甲基或苯基；(iii)-CH2-O-Si-(RSi1)(RSi2)(RSi3)，其中RSi1，RSi2，RSi3分别选自C1-6饱和烷基和苯基；以及(iv)-C(-YRC3)(-YRC4)，其中每个Y独立地为O或S，且RC3和RC4独立地为饱和的C1-4烷基基团，或者一起形成C2-3亚烷基。

公开号：

WO2013053872A1

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文献信息

[EN] PYRROLOBENZODIAZEPINE-ANTIBODY CONJUGATES<br/>[FR] CONJUGUÉS ANTICORPS-PYRROLOBENZODIAZÉPINE

申请人：SPIROGEN SARL

公开号：WO2015052535A1

公开（公告）日：2015-04-16

Conjugates of specific PBD dimers with an antibody that binds to CD22, the antibody comprising a VH domain having the sequence according to SEQ ID NO. 1.

将特定PBD二聚体与结合到CD22的抗体结合，该抗体包括具有根据SEQ ID NO. 1序列的VH结构域。
[EN] ANTIBODIES AND ANTIBODY-DRUG CONJUGATES<br/>[FR] ANTICORPS ET CONJUGUÉS ANTICORPS-MÉDICAMENT

申请人：MEDIMMUNE LTD

公开号：WO2015155345A1

公开（公告）日：2015-10-15

This application provides antibodies and antigen binding fragments thereof which are capable of specifically binding the 5T4 cell surface antigen, antibody-drug conjugates, and antibody-imaging agent conjugates, as well as means and methods for producing and using them.

该应用程序提供了能够特异性结合5T4细胞表面抗原、抗体药物偶联物以及抗体成像剂偶联物的抗体及其抗原结合片段，以及生产和使用它们的方法和手段。
[EN] AXL ANTIBODY-DRUG CONJUGATE AND ITS USE FOR THE TREATMENT OF CANCER<br/>[FR] CONJUGUÉ ANTICORPS ANTI-AXL-MÉDICAMENT ET SON UTILISATION POUR LE TRAITEMENT DU CANCER

申请人：PF MEDICAMENT

公开号：WO2014174111A1

公开（公告）日：2014-10-30

The present invention relates to an antibody-drug conjugate capable of binding to the protein Axl. From one aspect, the invention relates to an antibody-drug conjugate comprising an antibody capable of binding to Axl, said antibody being conjugated to at least one drug which is a pyrrolobenzodiazepme dimer (PBD dimer) drug. The invention also comprises method of treatment and the use of said antibody-drug conjugate for the treatment of cancer.

本发明涉及一种能够结合蛋白质Axl的抗体药物结合物。从一个方面来看，该发明涉及一种包括能够结合Axl的抗体的抗体药物结合物，所述抗体与至少一种药物结合，该药物是吡咯苯并二氮杂环二聚体（PBD二聚体）药物。该发明还包括治疗方法以及利用所述抗体药物结合物治疗癌症的用途。
[EN] PYRROLOBENZODIAZEPINES AND CONJUGATES THEREOF<br/>[FR] PYRROLOBENZODIAZÉPINES ET LEURS CONJUGUÉS

申请人：SPIROGEN SARL

公开号：WO2015052322A1

公开（公告）日：2015-04-16

RJW/FP7067259 150 ABSTRACT A compound which is selected from A: A O OO O O O I O NH O O O O O O O O N H N H N H OO OH H O N N OO H N N B: 5 B O OO O O O Br O NH O O O O O O O O N H N H N H OO OH H O N N OO H N N; and C C O O N H N H O N H OO OO O O N O OO O O O O NH O O O O O O O O N H N H N H OO OH H O N N OO OH H N N; and salts and solvates thereof.

RJW/FP7067259 150 摘要一种从A中选择的化合物：A O OO O O O I O NH O O O O O O O O N H N H N H OO OH H O N N OO H N N B：5 B O OO O O O Br O NH O O O O O O O O N H N H N H OO OH H O N N OO H N N；以及C C O O N H N H O N H OO OO O O N O OO O O O O NH O O O O O O O O N H N H N H OO OH H O N N OO OH H N N；以及其盐和溶剂化合物。
Design and Synthesis of Tesirine, a Clinical Antibody–Drug Conjugate Pyrrolobenzodiazepine Dimer Payload

作者：Arnaud C. Tiberghien、Jean-Noel Levy、Luke A. Masterson、Neki V. Patel、Lauren R. Adams、Simon Corbett、David G. Williams、John A. Hartley、Philip W. Howard

DOI：10.1021/acsmedchemlett.6b00062

日期：2016.11.10

Pyrrolobenzodiazepine dimers are an emerging class of warhead in the field of antibody drug conjugates (ADCs). Tesirine (SG3249) was designed to combine potent antitumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics. One of the reactive imines was capped with a cathepsin B-cleavable valine-alanine linker. A robust synthetic route was developed to allow the production of tesirine on clinical scale, employing a flexible, convergent strategy. Tesirine was evaluated in vitro both in stochastic and engineered ADC constructs and was confirmed as a potent and versatile payload. The conjugation of tesirine to anti-DLL3 rovalpituzumab has resulted in rovalpituzumab-tesirine (Rova-T), currently under evaluation for the treatment of small cell lung cancer.