methyl 4-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carboxylate | 864076-04-0

• 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-aminophenyl)-1-methyl-1H-pyrrole-2-carboxylate
• 英文别名: methyl 4-(4-aminophenyl)-1-methylpyrrole-2-carboxylate
• CAS: 864076-04-0
• 化学式: C₁₃H₁₄N₂O₂
• 分子量: 230.266
• InChiKey: NPUTUVDECBQMOJ-UHFFFAOYSA-N

物化性质

• 沸点：
  411.9±40.0 °C(Predicted)
• 密度：
  1.18±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  57.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  methyl 4-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carboxylate 在 四氢吡咯 、 盐酸 、 4-二甲氨基吡啶 、 四(三苯基膦)钯 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三苯基膦 作用下， 以 1,4-二氧六环 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 10.0h， 生成 (S)-methyl 4-(4-(4-(4-(4-((7-methoxy-5-oxo-2,3,5,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl)oxy)butanamido)phenyl)-1-methyl-1H-pyrrole-2-carboxamido)phenyl)-1-methyl-1H-pyrrole-2-carboxylate
  参考文献：
  名称：

  GC-Targeted C8-Linked Pyrrolobenzodiazepine–Biaryl Conjugates with Femtomolar in Vitro Cytotoxicity and in Vivo Antitumor Activity in Mouse Models

  摘要：

  DNA binding 4-(1-methyl-1H-pyrrol-3-yl)-benzenamine (MPB) building blocks have been developed that span two DNA base pairs with a strong preference for GC-rich DNA. They have been conjugated to a pyrrolo[2,1-c][1,4]benzodiazepine (PBD) molecule to produce C8-linked PBD MPB hybrids that can stabilize GC-rich DNA by up to 13-fold compared to AT-rich DNA. Some have subpicomolar IC50 values in human tumor cell lines and in primary chronic lymphocytic leukemia cells, while being up to 6 orders less cytotoxic in the non-tumor cell line WI38, suggesting that key DNA sequences may be relevant targets in these ultrasensitive cancer cell lines. One conjugate, 7h (KMR-28-39), which has femtomolar activity in the breast cancer cell line MDA-MB-231, has significant dose-dependent antitumor activity in MDA-MB-231 (breast) and MIA PaCa-2 (pancreatic) human tumor xenograft mouse models with insignificant toxicity at therapeutic doses. Preliminary studies suggest that 7h may sterically inhibit interaction of the transcription factor NF-kappa B with its cognate DNA binding sequence.

  DOI：

  10.1021/jm301882a
• 作为产物：
  描述：

  1-(4-bromo-1-methyl-1H-pyrrol-2-yl)-2,2,2-trichloroethan-1-one 在 盐酸 、 四(三苯基膦)钯 、 硫酸 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 水 、 甲苯 为溶剂， 生成 methyl 4-(4-aminophenyl)-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。
• [EN] PIPERIDINOBENZODIAZEPINE COMPOUNDS WITH ANTI PROLIFERATIVE ACTIVITY<br/>[FR] COMPOSÉS DE PIPÉRIDINOBENZODIAZÉPINE AYANT UNE ACTIVITÉ ANTI-PROLIFÉRATIVE
  申请人：FEMTOGENIX LTD

  公开号：WO2017032983A1

  公开（公告）日：2017-03-02

  The invention relates to pyrridinobenzodiazepines (PDDs) comprising three fused 6-7-6-membered rings linked to aromatic groups, and pharmaceutically acceptable salts thereof, which are useful as medicaments, such as anti-proliferative agents. PDDs may be represented by formula (I): and salts and solvates thereof, wherein the dotted lines indicates the optional presence of a double bond between one or more of Ci and C2, C2and C3, and C3and C4; R1 and R2 are substituent groups; R3 is selected from H, C1-12 alkyl and CH2Ph; R4is selected from phenyl and C5-9heteroaryl groups optionally substituted, with the proviso that the optionally substituted C5-9heteroaryl is not indolyl; R19is selected from H and (CH2)t-NR20R21; Yiis N or CH; Y2 is N or CH; and wherein at least one of Y1and Y2 is CH; p is o or1; X1 is a connecting group; L is a linker group; X2 is a connecting group or is absent; q is selected from o,1, 2, 3,4,5and 6; A is selected from: for each Ai group one of Y3and Y4is selected from N-R17,S and O; and the other of Y3and Y4is CH; and Y5is selected from CH, N, S and COH; for each A2group one of Y6and Y7is independently selected from N and CH; and the other of Y6and Y7is CH; R13, R14, R17, R2oand R2iare independently selected from H and C1-6alkyl; and either: (i) R5and R6together form a double bond; (ii) R5is H and R6is OH; or (iii) R5is H and R6is OC1-6alkyl; with the proviso that when p is o and A is Ai, then: (a) for at least one Ai group one of Y3and Y4is selected from S and O; or (b) for at least one Ai group Y5is S; or (c) R4is not pyrrolyl, imidazolyl, optionally substituted pyrrolyl or optionally substituted imidazolyl.

  该发明涉及含有与芳香族基团连接的三个融合的6-7-6环的吡啶苯二氮䓬（PDDs）及其药学上可接受的盐，这些化合物可用作药物，如抗增殖剂。 PDDs可以用公式（I）表示：及其盐和溶剂化合物，其中虚线表示Ci和C2，C2和C3以及C3和C4中的一个或多个之间的双键的可选存在；R1和R2是取代基；R3从H，C1-12烷基和CH2Ph中选择；R4从苯基和C5-9杂环基团中选择，可选择地取代，但有条件的是可选择地取代的C5-9杂环基团不是吲哚基；R19从H和（CH2）t-NR20R21中选择；Yi是N或CH；Y2是N或CH；其中Y1和Y2中至少一个是CH；p是o或1；X1是连接基团；L是连接基团；X2是连接基团或不存在；q从o，1，2，3，4，5和6中选择；A从以下中选择：对于每个Ai基团，Y3和Y4中的一个从N-R17，S和O中选择；另一个从CH中选择；Y5从CH，N，S和COH中选择；对于每个A2基团，Y6和Y7中的一个独立地从N和CH中选择；另一个是CH；R13，R14，R17，R2o和R2i独立地从H和C1-6烷基中选择；并且：（i）R5和R6一起形成双键；（ii）R5是H，R6是OH；或（iii）R5是H，R6是OC1-6烷基；但有条件的是当p是o且A是Ai时，那么：（a）对于至少一个Ai基团，Y3和Y4中的一个从S和O中选择；或（b）对于至少一个Ai基团，Y5是S；或（c）R4不是吡咯基，咪唑基，可选择地取代的吡咯基或可选择地取代的咪唑基。
• ANTIPROLIFERATIVE COMPOUNDS AND CONJUGATES MADE THEREFROM
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：US20180110873A1

  公开（公告）日：2018-04-26

  A compound capable of inhibiting cell proliferation, having a structure according to formula (I) wherein the variables in formula (I) are as defined in the specification. Such compounds are useful as anti-cancer agents, especially in antibody-drug conjugates.

  一种能够抑制细胞增殖的化合物，其结构符合以下公式（I） 其中公式（I）中的变量如规范中所定义。这些化合物可用作抗癌药物，特别是在抗体药物结合物中。
• [EN] PYRROLOBENZODIAZEPINE COMPOUNDS<br/>[FR] COMPOSÉS PYRROLOBENZODIAZÉPINE
  申请人：FEMTOGENIX LTD

  公开号：WO2015166289A1

  公开（公告）日：2015-11-05

  The invention relates to pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) of formula (I) and in particular to PBD dimers linked through the C1 position, and PBD monomers linked through the C1 position to aromatic groups, and pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular as anti-proliferative agents. (I) and salts or solvates thereof, wherein: the dotted lines indicates the optional presence of a double bond between C1 and C2 or C2 and C3; R2-R7 are independently selected substituent groups; and either: (i) R8 and R9 together form a double bond; (ii) R8 is H and R9 is OH; or (iii) R8 is H and R9 is ORA and RA is C1-6 alkyl; where R1 has the formula: -X-L-X'-D -X-L-X'- is a linker group and D has the formula (II) or (III): or where the compound is a dimer with each monomer being the same or different and being of formula (I) where the R1 of the first monomer and R'1 or R'6 of the second monomer, or R6 of the first monomer and R'1 of the second monomer, form together a bridge having the formula -X-L-X'- linking the monomers.

  该发明涉及式(I)的吡咯并[2,1-c][1,4]苯二氮杂环己烯（PBDs），特别是通过C1位置连接的PBD二聚体，以及通过C1位置连接到芳基的PBD单体，以及其药用可接受的盐，这些化合物可用作药物，特别是作为抗增殖剂。其中：虚线表示C1和C2或C2和C3之间的双键的可选存在；R2-R7是独立选择的取代基团；且：（i）R8和R9一起形成一个双键；（ii）R8为H且R9为OH；或者（iii）R8为H且R9为ORA，RA为C1-6烷基；其中R1具有以下结构式：-X-L-X'-D -X-L-X'-为一个连接基团，D具有结构式（II）或（III）；或者该化合物是一个二聚体，每个单体相同或不同，具有式（I），其中第一个单体的R1和第二个单体的R'1或R'6，或第一个单体的R6和第二个单体的R'1，共同形成一个具有结构式-X-L-X'-的桥连接单体的桥。
• [EN] PDD AND BPD COMPOUNDS<br/>[FR] COMPOSÉS DDP ET BPD
  申请人：FEMTOGENIX LTD

  公开号：WO2016198869A1

  公开（公告）日：2016-12-15

  The invention relates to pyrridinobenzodiazepines (PDDs) comprising three fused 6-7- 6–membered rings and to benzopyrridodiazecines (BPDs) comprising three fused 6-8- 6–membered rings and, in particular, to PDD or BPD dimers linked together or PDD and BPD monomers linked to aromatic groups, and pharmaceutically acceptable salts thereof, which are useful as medicaments, such as anti-proliferative agents. PDDs and BPDs may be represented by formula (I): and salts or solvates thereof, wherein R2, R4-R6 and R8 are independently selected substituent groups; and either: (i) R9 and R10 together form a double bond; (ii) R9 is H and R10 is OH; or (iii) R9 is H and R10 is ORA and RA is C1-6 alkyl; wherein each of m, n, u and w may be 0 or 1; where (a) the compound is a dimer with each monomer being the same or different and being of formula (I) where one of R1, R2, R3 and R7 of the first monomer and one of R'1, R'2, R3 and R'7 of the second monomer form together a bridge having the formula –X-L-X'- linking the monomers and m + n + u + w = 1; or (b) a dimer and one of R1, R2 and R3 of the first monomer and one of R'1, R'2 and R3 of the second monomer form together a bridge having the formula –X-L-X'- linking the monomers and m = n = u = w = o; or (c) one of R1, R2, R3 and R7 has the formula: –X- L-X'-D or -(CH2)f-O-R14 and m + n + u + w = o or 1; or (d) R7 has the formula: –X-L-X'- D or -(CH2)g-O -15 and m + n + u + w = 1; and X-L-X'- is a linker group and D has the formula (II) or (III):

  该发明涉及到包含三个融合的6-7-6环的吡啶苯二氮杂环己烷（PDDs）以及包含三个融合的6-8-6环的苯基吡啶二氮杂环己烷（BPDs），特别是涉及到连接在一起的PDD或BPD二聚体或连接到芳香基团的PDD和BPD单体，以及其药用可接受盐，这些化合物可用作药物，如抗增殖剂。PDDs和BPDs可以用以下公式（I）表示：以及其盐或溶剂化合物，其中R2、R4-R6和R8是独立选择的取代基团；并且：（i）R9和R10共同形成双键；（ii）R9为H且R10为OH；或（iii）R9为H且R10为ORA，RA为C1-6烷基；其中m、n、u和w中的每个可能为0或1；其中（a）该化合物是一个二聚体，每个单体相同或不同且为公式（I）的其中一个，其中第一个单体的R1、R2、R3和R7中的一个和第二个单体的R'1、R'2、R3和R'7中的一个共同形成具有公式-X-L-X'-的桥连接单体，且m + n + u + w = 1；或（b）一个二聚体，第一个单体的R1、R2和R3中的一个和第二个单体的R'1、R'2和R3中的一个共同形成具有公式-X-L-X'-的桥连接单体，且m = n = u = w = o；或（c）R1、R2、R3和R7中的一个具有以下公式：-X-L-X'-D或-(CH2)f-O-R14，且m + n + u + w = o或1；或（d）R7具有以下公式：-X-L-X'-D或-(CH2)g-O-15，且m + n + u + w = 1；而X-L-X'-是一个连接基团，D具有以下公式（II）或（III）。