methyl 4-(4-((tert-butoxycarbonyl)amino)phenyl)-1-methyl-1H-pyrrole-2-carboxylate | 864076-02-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: methyl 4-(4-((tert-butoxycarbonyl)amino)phenyl)-1-methyl-1H-pyrrole-2-carboxylate
• 英文别名: Methyl 4-(4-(tert-butoxycarbonylamino)phenyl)-1-methyl-1H-pyrrole-2-carboxylate；methyl 1-methyl-4-[4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]pyrrole-2-carboxylate
• CAS: 864076-02-8
• 化学式: C₁₈H₂₂N₂O₄
• 分子量: 330.384
• InChiKey: CAIJLZGQTNHYPU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  69.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 4-(4-((tert-butoxycarbonyl)amino)phenyl)-1-methyl-1H-pyrrole-2-carboxylate 在 盐酸 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 反应 2.0h， 生成 methyl 4-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carboxylate
  参考文献：
  名称：

  新型的广谱抗生素，含有吡咯并苯二氮杂卓环，具有抗多药耐药革兰氏阴性菌的活性。

  摘要：

  迫切需要找到对多药耐药（MDR）革兰氏阴性病原体具有活性的新抗生素类别，因为抗生素的生产线基本上是空的。具有C8连接的脂族杂环的改性吡咯并苯并二氮杂卓可提供一类新型的广谱抗菌剂，其对包括世界卫生组织优先病原体在内的MDR革兰氏阴性细菌具有活性。构效关系确定第三环对于革兰氏阴性活性特别重要。除铜绿假单胞菌外，对于MDR革兰氏阴性，先导化合物的最低抑菌浓度范围为0.125至2 mg / L，对于MDR革兰氏阳性菌种，最低抑菌浓度为0.03至1 mg / L。铅化合物可快速杀菌，可在4小时内将活菌数减少> 5 log鲍曼不动杆菌和肺炎克雷伯菌。铅化合物在基于凝胶的测定中抑制DNA促旋酶，IC 50为3.16±1.36 mg / L。这项研究为开发新型广谱抗生素提供了一种新的化学支架，可以帮助补充抗生素。

  DOI：

  10.1021/acs.jmedchem.0c00328
• 作为产物：
  描述：

  1-(4-bromo-1-methyl-1H-pyrrol-2-yl)-2,2,2-trichloroethan-1-one 在 四(三苯基膦)钯 、 硫酸 、 potassium carbonate 作用下， 以 甲醇 、 乙醇 、 水 、 甲苯 为溶剂， 生成 methyl 4-(4-((tert-butoxycarbonyl)amino)phenyl)-1-methyl-1H-pyrrole-2-carboxylate
  参考文献：
  名称：

  Mechanistic insight into the repair of C8-linked pyrrolobenzodiazepine monomer-mediated DNA damage

  摘要：

  我们对吡咯并苯并二氮杂环（PBD）单体的作用方式的理解仍不完整。这项研究揭示了PBD单体在细菌中引起DNA损伤的潜力，并确定了修复这些PBD加合物所涉及的机制。

  DOI：

  10.1039/d2md00194b

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。
• DNA-Model-Based Design and Execution of Some Fused Benzodiazepine Hybrid Payloads for Antibody–Drug Conjugate Modality
  作者：Prasanna Sivaprakasam、Ivar McDonald、Christiana Iwuagwu、Naidu S. Chowdari、Kevin M. Peese、David R. Langley、Heng Cheng、Michael R. Luzung、Michael A. Schmidt、Bin Zheng、Yichen Tan、Patricia Cho、Souvik Rakshit、Thirumalai Lakshminarasimhan、Sivakrishna Guturi、Kishorekumar Kanagavel、Umamaheswararao Kanusu、Ankita G. Niyogi、Somprabha Sidhar、Rajappa Vaidyanathan、Martin D. Eastgate、Srikanth Kotapati、Madhura Deshpande、Chin Pan、Pina M. Cardarelli、Chunshan Xie、Chetana Rao、Patrick Holder、Ganapathy Sarma、Gregory Vite、Sanjeev Gangwar

  DOI：10.1021/acsmedchemlett.0c00578

  日期：2021.3.11

  a panel of various cancer cell lines. One of the payloads was appended with a lysosome-cleavable peptide linker and conjugated with an anti-mesothelin antibody via a site-specific conjugation method mediated by the enzyme bacterial transglutaminase (BTGase). Antibody–drug conjugate (ADC) 50 demonstrated good plasma stability and lysosomal cleavage. A single intravenous dose of ADC 50 (5 or 10 nmol/kg)

  设计并执行了一个新系列，其中四氢异喹啉稠合苯二氮卓 (TBD) 环系统与 (1-甲基-1 H-吡咯-3-基) 苯 (“MPB”) 有效负载的替代物相结合，用于与单克隆抗体偶联用于抗癌治疗。DNA 模型有助于合理识别“MPB”结合成分的修饰和引导结构-活性关系的生成。当针对一组不同的癌细胞系进行测试时，这种混合系列的有效载荷表现出出色的体外活性。其中一个有效载荷附加了一个可溶酶体切割的肽接头，并通过由酶细菌转谷氨酰胺酶 (BTGase) 介导的位点特异性结合方法与抗间皮素抗体结合。抗体-药物偶联物 (ADC)50展示了良好的血浆稳定性和溶酶体裂解。在 N87 胃癌异种移植模型中，单次静脉注射 ADC 50 （5 或 10 nmol/kg）显示出强大的疗效。
• [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] PYRROLOBENZODIAZEPINES<br/>[FR] PYRROLOBENZODIAZÉPINES
  申请人：UCL BUSINESS PLC

  公开号：WO2013164592A1

  公开（公告）日：2013-11-07

  A compound of formula (I) or a salt or solvate thereof, wherein the dotted double bond indicates the presence of a single or double bond between C2 and C3; R2 is selected from -H, -OH, =O, =CH2, -CN, -R, OR, halo, dihalo, =CHR, =CHRR', -O- SO2-R, CO2R and COR; R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn and halo; where R and R' are independently selected from optionally substituted C1-7 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R10 and R11 either together form a double bond, or are selected from H and QRQ respectively, where Q is selected from O, S and NH and RQ is H or C1-7 alkyl or H and SOxM, where x is 2 or 3, and M is a monovalent pharmaceutically acceptable cation; A is selected from (A1), (A2), (A3), (A4) or (A5) where X1 and Y1 are selected from: CH and NH; CH and NMe; N and NMe; CH and S; N and S; N and O; and CH and O, respectively; X2 and Y2 are selected from: CH and NH; CH and NMe; N and NMe; CH and S; N and S; N and O; and CH and O, respectively; Z1 is selected from O and S; Z2 is selected from CH and N; F is selected from a single bond and –(E-F1)m-; each E is independently selected from a single bond, and –C(=O)-NH-; each F1 is independently a C3-20 heteroarylene group; m is 1, 2 or 3; G is selected from hydrogen, C1-4alkyl, -C(=O)-O-C1-4alkyl, -(CH2)n-C3-20 heterocycloalkyl, and –O-(CH2)n-C3-20 heterocycloalkyl group; each n is 0-4; provided that A2 is not A2', where X1 and Y1 of A2' are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; and provided that A3 is not A3', where X2 and Y2 of A3' are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; B is either a single bond or (B1), where X and Y of B1 are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; and R1 is C1-4 alkyl.

  化合物的化学式(I)或其盐或溶剂化合物，其中点虚线表示C2和C3之间存在单键或双键；R2选自-H、-OH、=O、=CH2、-CN、-R、OR、卤素、二卤素、=CHR、=CHRR'、-O-SO2-R、CO2R和COR；R7选自H、R、OH、OR、SH、SR、NH2、NHR、NRR'、硝基、Me3Sn和卤素；其中R和R'分别独立选自可选择的取代C1-7烷基、C3-20杂环烷基和C5-20芳基；R10和R11要么一起形成双键，要么分别选自H和QRQ，其中Q选自O、S和NH，RQ为H或C1-7烷基或H和SOxM，其中x为2或3，M为一价的药用可接受阳离子；A选自(A1)、(A2)、(A3)、(A4)或(A5)，其中X1和Y1选自：CH和NH；CH和NMe；N和NMe；CH和S；N和S；N和O；以及CH和O，依此类推；X2和Y2选自：CH和NH；CH和NMe；N和NMe；CH和S；N和S；N和O；以及CH和O，依此类推；Z1选自O和S；Z2选自CH和N；F选自单键和-(E-F1)m-；每个E独立选自单键和-C(=O)-NH-；每个F1独立为C3-20杂芳基；m为1、2或3；G选自氢、C1-4烷基、-C(=O)-O-C1-4烷基、-( )n-C3-20杂环烷基和-O-( )n-C3-20杂环烷基；每个n为0-4；条件是A2不是A2'，其中A2'的X1和Y1选自：CH和NMe；COH和NMe；CH和S；N和NMe；N和S，依此类推；条件是A3不是A3'，其中A3'的X2和Y2选自：CH和NMe；COH和NMe；CH和S；N和NMe；N和S，依此类推；B要么是单键，要么是(B1)，其中B1的X和Y选自：CH和NMe；COH和NMe；CH和S；N和NMe；N和S，依此类推；R1为C1-4烷基。
• [EN] PBD ANTIBACTERIAL AGENTS<br/>[FR] AGENTS ANTIBACTÉRIENS DE TYPE PBD
  申请人：KING'S COLLEGE LONDON

  公开号：WO2017098257A1

  公开（公告）日：2017-06-15

  The invention relates to pyrrolobenzodiazepines compounds (PBDs) and to pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular, to treat bacterial infections. The PBDs are compounds of formula (I): and salts and solvates thereof; wherein: dotted lines indicates the optional presence of a double bond; X, X1, X2, X3 and X4 are connecting functional groups; L is C1-12 alkylene; R4, R5 and R6 are independently selected from phenylene, cyclopentanylene, cyclohexanylene, 5 - to 9 -membered heteroarylene and 5 - to 6-membered hetereocyclylene groups, and these groups are optionally substituted with up to three optional substituent groups; R7 is selected from N(C1-6 alkyl)(C1-6alkyl), 5 - to 6-membered nitrogen-containing hetereocyclyl groups, a monosaccharide moiety and an amino monosaccharide moiety wherein these groups are optionally substituted; and R8 and R9 either together form a double bond, or are selected from H and OR14, or R8 is a prodrug moiety and R9 is OR14; m is 0 or 1; with the proviso that when X4 is C(O)NH then the up to three optional substituents of R7 are not selected from (CH2)k -CO2R12; with the proviso that when X4 is (CH2)tO then R4 is not phenylene, m is 1 and R6 is not a 5 - to 9 -membered heteroarylene; and with the proviso that when X4 is C(O)NH or NHC(O) that R4 and/or R6 is not 5 - to 9 -membered heteroarylene.

  该发明涉及吡咯苯二氮杂环烷化合物（PBD）及其药用可接受盐，其作为药物具有治疗细菌感染的功效。PBD是具有以下结构式（I）的化合物：及其盐和溶剂化物；其中：虚线表示双键的可选存在；X、X1、X2、X3和X4是连接的功能基团；L为C1-12烷基；R4、R5和R6分别选自苯环、环戊烷基、环己烷基、5-至9-成员杂芳烃基和5-至6-成员杂环烷基，这些基团可选地被高达三个可选取代基团取代；R7选自N（C1-6烷基）（C1-6烷基）、5-至6-成员含氮杂环基团、单糖基团和氨基单糖基团，其中这些基团可选地被取代；R8和R9要么一起形成双键，要么选自H和OR14，或者R8是前药基团且R9是OR14；m为0或1；但是当X4为C（O）NH时，R7的高达三个可选取代基团不选自（CH2）k-CO2R12；但是当X4为（ ）tO时，R4不是苯环，m为1且R6不是5-至9-成员杂芳烃基；但是当X4为C（O）NH或NHC（O）时，R4和/或R6不是5-至9-成员杂芳烃基。