N¹,N¹-bis(2-chloroethyl)benzene-1,2-diamine | 13686-21-0

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: N¹,N¹-bis(2-chloroethyl)benzene-1,2-diamine
• 英文别名: N,N-bis(b-chloroethyl)-o-phenylenediamine；2-N,2-N-bis(2-chloroethyl)benzene-1,2-diamine
• CAS: 13686-21-0
• 化学式: C₁₀H₁₄Cl₂N₂
• 分子量: 233.141
• InChiKey: REUUVTULEYHTCC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  14
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  29.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  N¹,N¹-bis(2-chloroethyl)benzene-1,2-diamine 、 4-氯-6,7-二甲氧基喹唑啉 以 异丙醇 为溶剂， 反应 1.0h， 以76.5%的产率得到N¹,N¹-bis(2-chloroethyl)-N²-(6,7-dimethoxyquinazolin-4-yl)benzene-1,2-diamine hydrochloride
  参考文献：
  名称：

  新型喹唑啉氮芥菜衍生物的设计和合成作为潜在的癌症治疗剂

  摘要：

  设计，合成和评估了十三种新颖的喹唑啉氮芥子气衍生物在体外和体内的抗癌活性。在五种癌细胞系（HepG2，SH-SY5Y，DU145，MCF-7和A549）和一种正常人细胞系（GES-1）中进行了细胞毒性测定，其中化合物22b对HepG2的IC 50非常低（ IC 50值为3.06μM），低于索拉非尼。化合物22b可以抑制S和G 2 / M期的细胞周期并诱导细胞凋亡。在HepG2异种移植模型中，22b在体内具有显着的癌生长抑制作用，且宿主毒性低。

  DOI：

  10.1016/j.ejmech.2013.06.055
• 作为产物：
  描述：

  N,N-bis(2-hydroxyethyl)-2-nitroaniline 在 盐酸 、 氯化亚砜 、 tin(ll) chloride 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 1.17h， 生成 N¹,N¹-bis(2-chloroethyl)benzene-1,2-diamine
  参考文献：
  名称：

  Hypoxia-selective antitumor agents. 3. Relationships between structure and cytotoxicity against cultured tumor cells for substituted N,N-bis(2-chloroethyl)anilines

  摘要：

  A series of aniline mustards with a wide range of electron-donating and -withdrawing substituents in the 3- and 4-positions has been synthesized and evaluated for cytotoxicity in cell culture to examine the potential of using nitro group deactivated nitrogen mustards for the design of novel hypoxia-selective anticancer drugs (Denny, W. A.; Wilson, W. R. J. Med. Chem. 1986, 29, 879). Hydrolytic half-lives in tissue culture media, determined by bioassay against a cell line (UV4) defective in the repair of DNA interstrand cross-links showed the expected dependence on the Hammett electronic parameter, sigma, varying from 0.13 h for the 4-amino analogue to greater than 100 h for analogues with strongly electron-withdrawing substituents. Cytotoxic potencies in aerobic UV4 cultures showed a similar dependence on sigma. This dependence predicted that the 4-nitroaniline mustard would be 7200-fold less potent than its potential six-electron reduction product, the 4-amino compound, in growth inhibition assays using a 1-h drug exposure. The measured differential was much lower (225-fold) because of the instability of the latter compound, but a differential of 17,500-fold was observed in the initial rate of killing by using a clonogenic assay. The potential for formation of reactive mustards by reduction to the amine or hydroxylamine was demonstrated by the 4-nitroso compound, which had an aerobic toxicity similar to that of the amine. Although these features confirmed the original rationale, the 3-nitro- and 4-nitroaniline mustards had only minimal hypoxic selectivity against UV cells. Toxicity to hypoxic cells appears to be limited by the low reduction potentials of these compounds and consequent lack of enzymatic nitroreduction. However, this study has demonstrated that nitro groups can be used to latentiate aromatic nitrogen mustards and indicates that examples with higher reduction potentials could provide useful hypoxia-selective therapeutic agents.

  DOI：

  10.1021/jm00163a019

文献信息

• Nouvelles nitrosourées, leur procédé de préparation et leur application en thérapeutique
  申请人：CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE

  公开号：EP0117797A1

  公开（公告）日：1984-09-05

  La présente invention concerne de nouvelles nitrosourées, et leur préparation et leur application en thérapeutique. Il s'agit de composés de formule de séries L, D, DL, allo et thréo, dans lesquels: A représente le fragment d'un amino-acide de formule HN-(R)-A-COOH, où R représente un atome d'hydrogène, un radical organique en particulier un radical alkyle, ou bien forme avec l'atome d'azote et A un hétérocycle; Y représente un radical nitrosourée de formule et X représente un radical moutarde à l'azote de formule ou Application au traitement des tumeurs.

  本发明涉及新的亚硝基脲及其制备和治疗应用，即系列 L、D、DL、allo 和 threo 的式化合物，其中：A 代表式 HN-(R)-A-COOH的氨基酸片段，其中 R 代表氢原子或有机基，特别是烷基，或者与氮原子和 A 形成杂环；Y 代表式中的亚硝基脲基，X 代表式中的氮芥基或应用于治疗肿瘤。
• Prodrugs for beta-lactamase and uses thereof
  申请人：Bristol-Myers Squibb Company

  公开号：EP0484870A2

  公开（公告）日：1992-05-13

  The instant invention relates to a novel method for the delivery of antitumor drugs to tumor cells by the administration of a tumor-selective antibody- β-lactamase conjugate that binds to tumor cells, and the additional administration of a cephalosporin prodrug that is converted at the tumor site, in the presence of the antibody-β-lactamase, to an active cytotoxic drug. According to the preferred embodiment of this invention, a cephalosporin mustard has been constructed which when cleaved by β-lactamase yields a cytotoxic nitrogen mustard. The methods, antibody-enzyme conjugate, prodrugs, pharmaceutical compositions, and combinations of this invention provide for enhanced selective killing of tumor cells and are thus useful in the treatment of cancers and other tumors.

  本发明涉及一种向肿瘤细胞递送抗肿瘤药物的新方法，该方法是通过给药与肿瘤细胞结合的肿瘤选择性抗体-β-内酰胺酶共轭物，以及额外给药头孢菌素原药，在抗体-β-内酰胺酶存在的情况下，该原药在肿瘤部位转化为活性细胞毒性药物。根据本发明的优选实施方案，已经构建了一种头孢菌素芥子气，当它被β-内酰胺酶裂解时，会产生一种具有细胞毒性的氮芥。本发明的方法、抗体-酶结合物、原药、药物组合物和组合物可增强对肿瘤细胞的选择性杀伤，因此可用于治疗癌症和其他肿瘤。
• [EN] POLYMERIC PRODRUGS OF AMINO- AND HYDROXYL-CONTAINING BIOACTIVE AGENTS<br/>[FR] PRODROGUES POLYMERIQUES D'AGENTS BIOACTIFS CONTENANT AMINE OU HYDROXY
  申请人：——

  公开号：WO1999030727A9

  公开（公告）日：1999-09-23

  [EN] The present invention is directed to double prodrugs containing polymeric-based transport forms. These polymeric prodrugs are preferably of formula (I) wherein: L1 is a bifunctional linking moiety; in formula (a) B is H, a leaving group, a residue of an amine-containing moiety, or a residue of a hydroxyl-containing moiety; Y1-4 are independently O, S, or NR12; R1, R4, R9, R10 and R12, are independently selected from the group consisting of hydrogen C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls; R2, R3, R5 and R6 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C1-6 alkoxy, phenoxy, C1-8 heteroalkyls, C1-8 heteroalkoxy, substituted C1-6 alkyls, C3-8 cycloalkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, halo-, nitro-, cyano-, carboxy-, C1-6 carboxyalkyls and C1-6 alkyl carbonyls; Ar is a moiety which when included in Formula (I) forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group; (m), (r), (s), (t), (u) and (v) are independently zero or one; (p) is zero or a positive integer; and R11 is a substantially non-antigenic polymer. The first prodrug is generated when the polymeric portion of the double prodrug is cleaved and the parent molecule is generated rapidly thereafter in vivo, preferably as a result of a 1,6 or 1,4 benzyl elimination-reaction. Methods of preparing the compounds and methods of treatment are also disclosed.
  [FR] L'invention concerne des prodrogues doubles contenant des formes de transport à base de polymères. Ces prodrogues polymériques présentent, de préférence, la formule (I) dans laquelle L1 est une fraction de liaison bifonctionnelle; dans la formule (a) B étant H, un groupe partant, un résidu d'une fraction contenant amine, ou un résidu d'une fraction contenant hydroxy; Y1-4 sont, indépendamment O, S ou NR12; R1, R4, R9, R10 et R12 sont, indépendamment, sélectionnés dans le groupe constitué par hydrogène, alkyles C1-6, alkyles ramifiés C3-12, cycloalkyles C3-8, alkyles substitués C1-6, cycloalkyles substitués C3-8, aryles, aryles substitués, aralkyles, hétéroalkyles C1-6, hétéroalkyles substitués C1-6; R2, R3, R5, et R6 sont, indépendamment, sélectionnés dans le groupe constitué par hydrogène, alkyles C1-6, alkcoxy C1-6, phénoxy, hétéroalkyles C1-8, hétéroalkcoxy C1-8, alkyles substitués C1-6, cycloalkyles C3-8, cycloalkyles substitués C3-8, aryles, aryles substitués, aralkyles, halo-, nitro-, cyano-, carboxy-, carboxyalkyles C1-6 et carbonylalkyles C1-6; Ar est une fraction qui, lorsqu'elle est comprise dans la formule (I), forme un hydrocarbure aromatique multisubstitué ou un groupe hétérocyclique multisubstitué; (m), (r), (s), (t), (u) et (v) sont indépendamment zéro ou 1; (p) est zéro ou un entier positif; et R11 est un polymère sensiblement non antigénique. La première prodrogue se libère après clivage de la partie polymérique de la prodrogue double, et la molécule parent est libère ensuite rapidement in vivo, de préférence après une réaction d'élimination du 1,6 ou 1,4 benzyle. On décrit des procédés de préparation des composés ainsi que des méthodes de traitement.
• Hypoxia-selective antitumor agents. 3. Relationships between structure and cytotoxicity against cultured tumor cells for substituted N,N-bis(2-chloroethyl)anilines
  作者：Brian D. Palmer、William R. Wilson、Susan M. Pullen、William A. Denny

  DOI：10.1021/jm00163a019

  日期：1990.1

  A series of aniline mustards with a wide range of electron-donating and -withdrawing substituents in the 3- and 4-positions has been synthesized and evaluated for cytotoxicity in cell culture to examine the potential of using nitro group deactivated nitrogen mustards for the design of novel hypoxia-selective anticancer drugs (Denny, W. A.; Wilson, W. R. J. Med. Chem. 1986, 29, 879). Hydrolytic half-lives in tissue culture media, determined by bioassay against a cell line (UV4) defective in the repair of DNA interstrand cross-links showed the expected dependence on the Hammett electronic parameter, sigma, varying from 0.13 h for the 4-amino analogue to greater than 100 h for analogues with strongly electron-withdrawing substituents. Cytotoxic potencies in aerobic UV4 cultures showed a similar dependence on sigma. This dependence predicted that the 4-nitroaniline mustard would be 7200-fold less potent than its potential six-electron reduction product, the 4-amino compound, in growth inhibition assays using a 1-h drug exposure. The measured differential was much lower (225-fold) because of the instability of the latter compound, but a differential of 17,500-fold was observed in the initial rate of killing by using a clonogenic assay. The potential for formation of reactive mustards by reduction to the amine or hydroxylamine was demonstrated by the 4-nitroso compound, which had an aerobic toxicity similar to that of the amine. Although these features confirmed the original rationale, the 3-nitro- and 4-nitroaniline mustards had only minimal hypoxic selectivity against UV cells. Toxicity to hypoxic cells appears to be limited by the low reduction potentials of these compounds and consequent lack of enzymatic nitroreduction. However, this study has demonstrated that nitro groups can be used to latentiate aromatic nitrogen mustards and indicates that examples with higher reduction potentials could provide useful hypoxia-selective therapeutic agents.
• Design and synthesis of novel quinazoline nitrogen mustard derivatives as potential therapeutic agents for cancer
  作者：Shilei Li、Xiao Wang、Yong He、Mingxia Zhao、Yurong Chen、Jingli Xu、Man Feng、Jin Chang、Hongyu Ning、Chuanmin Qi

  DOI：10.1016/j.ejmech.2013.06.055

  日期：2013.9

  Thirteen novel quinazoline nitrogen mustard derivatives were designed, synthesized and evaluated for their anticancer activities in vitro and in vivo. Cytotoxicity assays were carried out in five cancer cell lines (HepG2, SH-SY5Y, DU145, MCF-7 and A549) and one normal human cell line (GES-1), in which compound 22b showed very low IC50 to HepG2 (the IC50 value is 3.06 μM), which was lower than Sorafenib

  设计，合成和评估了十三种新颖的喹唑啉氮芥子气衍生物在体外和体内的抗癌活性。在五种癌细胞系（HepG2，SH-SY5Y，DU145，MCF-7和A549）和一种正常人细胞系（GES-1）中进行了细胞毒性测定，其中化合物22b对HepG2的IC 50非常低（ IC 50值为3.06μM），低于索拉非尼。化合物22b可以抑制S和G 2 / M期的细胞周期并诱导细胞凋亡。在HepG2异种移植模型中，22b在体内具有显着的癌生长抑制作用，且宿主毒性低。