3,5-difluoro-4-[bis(2-bromoethyl)-amino]benzoic acid

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3,5-difluoro-4-[bis(2-bromoethyl)-amino]benzoic acid
• 英文别名: 4-[Bis(2-bromoethyl)amino]-3,5-difluorobenzoic acid
• 化学式: C₁₁H₁₁Br₂F₂NO₂
• 分子量: 387.019
• InChiKey: ABYICUIYVQTPDK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  18
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  40.5
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  tert-butyl 3,4,5-trifluorobenzoate 在 4-二甲氨基吡啶 、 三乙胺 、 三氟乙酸 、 lithium bromide 作用下， 以 二氯甲烷 、 N,N-二甲基乙酰胺 、 丙酮 为溶剂， 反应 89.92h， 生成 3,5-difluoro-4-[bis(2-bromoethyl)-amino]benzoic acid
  参考文献：
  名称：

  Novel Fluorinated Prodrugs for Activation by Carboxypeptidase G2 Showing Good in Vivo Antitumor Activity in Gene-Directed Enzyme Prodrug Therapy

  摘要：

  Sixteen novel polyfluorinated benzoic acid mustards have been synthesized for use in gene-directed enzyme prodrug therapy (GDEPT). Eight of these were benzoic acid L-glutamate mustards for evaluation as prodrugs and the other eight were the active drugs formed by the action of the bacterial enzyme carboxypeptidase G2 (CPG2). All of the di- and trifluorinated prodrugs were efficiently cleaved by the enzyme. In contrast, the tetrafluorinated prodrugs were found to be competitive inhibitors of CPG2, the first such inhibitors to have been described. The di- and trifluorinated prodrugs were differentially cytotoxic to human breast carcinoma cells (MDA MB 361) expressing CPG2, compared to control cells that did not express the enzyme. The difluorinated prodrug {4-[bis(2-bromoethyl)amino]-3,5-difluorobenzoyl}-L-glutamic acid and its iodoethylamino analogue were effective substrates for the enzyme and showed excellent therapeutic activity in CPG2-expressing MDA MB 361 xenografts, either curing or greatly inhibiting tumor growth and extending the life of the animals.

  DOI：

  10.1021/jm0502182

文献信息

• [EN] NITROGEN MUSTARD COMPOUNDS AND PRODRUGS THEREFOR<br/>[FR] COMPOSES AZOTES DE MOUTARDE ET LEURS PROMEDICAMENTS
  申请人：CANCER RES CAMPAIGN TECH

  公开号：WO2000058271A1

  公开（公告）日：2000-10-05

  This invention pertains to nitrogen mustard compounds (Formula (II)) and prodrugs therefor (Formula (I)), methods for their preparation, pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, in therapy and treatment, for example, of cancer, wherein: R?1 and R2¿ are independently -Cl, -Br, -I, -OSO¿2?CH3, or -OSO2Ph; R?1a, R2a, R1b, and R2b¿ are independently -H, a C¿1-4?alkyl group, or a C1-4haloalkyl group; R?3¿ is -F, -Cl, -Br, -I, -OCHF¿2?, -C CH, -OCF3, -CH3, -CF3, -SF5, -SCF3, or -CF2CF3; R?4¿ is -H or as defined for R3; R5 is -H or -F; R7 is -H, -C(CH¿3?)3, or -CH2-CH=CH2; Z is -CH2-T-W; T is -CH2-, -O-, -S-, -(S=O)-, or -(SO2)-; W is one of: (1) -COOH; (2) -(C=O)OR?8¿; (3) -(C=O)NR9R9; (4) -SO¿2NHR?10; (5) -SO¿2OR?11; (6) -PO¿3R?11R11; (7) a tetrazol-5-yl group; (8) -CONH-SO¿2R?12; and, (9) -M-Het.

  本发明涉及氮芥类化合物（公式（II））及其前药（公式（I）），其制备方法，包括这些化合物的制药组合物，以及这些化合物和组合物在体内外治疗和治疗中的使用，例如癌症，其中：R?1和R2¿分别为-Cl，-Br，-I，-OSO¿2?CH3或-OSO2Ph; R?1a，R2a，R1b和R2b¿分别为-H，C¿1-4?烷基或C1-4卤代烷基; R?3¿为-F，-Cl，-Br，-I，-OCHF¿2？，-C CH，-OCF3，-CH3，-CF3，-SF5，-SCF3或-CF2CF3; R?4¿为-H或如R3所定义; R5为-H或-F; R7为-H，-C(CH¿3?)3或-CH2-CH=CH2; Z为-CH2-T-W; T为-CH2-，-O-，-S-，-(S=O)-或-(SO2)-; W为以下之一：（1）-COOH;（2）-(C=O)OR?8¿;（3）-(C=O)NR9R9;（4）-SO¿2NHR?10;（5）-SO¿2OR?11;（6）-PO¿3R?11R11;（7）噻唑-5-基团;（8）-CONH-SO¿2R?12;和（9）-M-Het。
• NITROGEN MUSTARD COMPOUNDS AND PRODRUGS THEREFOR
  申请人：CANCER RESEARCH TECHNOLOGY LIMITED

  公开号：EP1165493B1

  公开（公告）日：2005-01-19
• US6852755B1
  申请人：——

  公开号：US6852755B1

  公开（公告）日：2005-02-08
• Novel Fluorinated Prodrugs for Activation by Carboxypeptidase G2 Showing Good in Vivo Antitumor Activity in Gene-Directed Enzyme Prodrug Therapy
  作者：Lawrence C. Davies、Frank Friedlos、Douglas Hedley、Jan Martin、Lesley M. Ogilvie、Ian J. Scanlon、Caroline J. Springer

  DOI：10.1021/jm0502182

  日期：2005.8.1

  Sixteen novel polyfluorinated benzoic acid mustards have been synthesized for use in gene-directed enzyme prodrug therapy (GDEPT). Eight of these were benzoic acid L-glutamate mustards for evaluation as prodrugs and the other eight were the active drugs formed by the action of the bacterial enzyme carboxypeptidase G2 (CPG2). All of the di- and trifluorinated prodrugs were efficiently cleaved by the enzyme. In contrast, the tetrafluorinated prodrugs were found to be competitive inhibitors of CPG2, the first such inhibitors to have been described. The di- and trifluorinated prodrugs were differentially cytotoxic to human breast carcinoma cells (MDA MB 361) expressing CPG2, compared to control cells that did not express the enzyme. The difluorinated prodrug 4-[bis(2-bromoethyl)amino]-3,5-difluorobenzoyl}-L-glutamic acid and its iodoethylamino analogue were effective substrates for the enzyme and showed excellent therapeutic activity in CPG2-expressing MDA MB 361 xenografts, either curing or greatly inhibiting tumor growth and extending the life of the animals.