3,5-difluoro-4-[bis(2-hydroxyethyl)amino]benzoic acid | 298211-17-3

• 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-hydroxyethyl)amino]benzoic acid
• 英文别名: 4-(bis(2-hydroxyethyl)amino)-3,5-difluorobenzoic acid；3.5-Difluoro-4-[bis(2-hydroxyethyl)amino]benzoic acid；4-[bis(2-hydroxyethyl)amino]-3,5-difluorobenzoic acid
• CAS: 298211-17-3
• 化学式: C₁₁H₁₃F₂NO₄
• mdl: MFCD19458080
• 分子量: 261.225
• InChiKey: ZCMYFZNMBOYVNW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  18
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.363
• 拓扑面积：
  81
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3,5-difluoro-4-[bis(2-hydroxyethyl)amino]benzoic acid 在 4-二甲氨基吡啶 、 氰基磷酸二乙酯 、 三乙胺 、 lithium bromide 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 88.0h， 生成 di-tert-butyl {4-[bis(2-bromoethyl)amino]-3,5-difluorobenzoyl}-L-glutamate
  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
• 作为产物：
  描述：

  3,4,5-三氟苯腈 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 生成 3,5-difluoro-4-[bis(2-hydroxyethyl)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：Springer Caroline J.

  公开号：US06852755B1

  公开（公告）日：2005-02-08

  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 R 2 are independently —Cl, —Br, —I, —OSO 2 CH 3 , or —OSO 2 Ph; R 1a , R 2a , R 1b , and R 2b are independently —H, a C 1-4 alkyl group, or a C 1-4 haloalkyl group; R 3 is —F, —Cl, —Br, —I, —OCHF 2 , —C≡CH, —OCF 3 , —CH 3 , —CF 3 , —SF 5 , —SCF 3 , or —CF 2 CF 3 ; R 4 is —H or as defined for R 3− , R 5 is —H or —F; R 7 is —H, —C(CH 3 ) 3 , or —CH 2 —CH—CH 2 ; Z is —CH 2 —T—W; T is —CH 2 —, —O—, —S—, —(S═O)—, or —(SO 2 )—; W is one of: (1) —COOH; (2)—(C═O)OR 8 ; (3) —(C═O)NR 9 R 9 ; (4) —SO 2 NHR 10− , (5) SO 2 OR 11 ; (6)—PO 3 R 11 R 11 ; (7) a tetrazol-5-yl group; (8) —CONH—SO 2 R 12 ; and, (9)-M-Het.

  本发明涉及氮芥化合物(公式(II))及其前药(公式(I))，其制备方法，含有这种化合物的制药组合物，以及这种化合物和组合物在体内外治疗癌症等方面的应用，其中：R1和R2分别为—Cl、—Br、—I、—OSO2CH3或—OSO2Ph；R1a、R2a、R1b和R2b分别为—H、C1-4烷基或C1-4卤代烷基；R3为—F、—Cl、—Br、—I、—OCHF2、—C≡CH、—OCF3、—CH3、—CF3、—SF5、—SCF3或—CF2CF3；R4为—H或如R3所定义的；R5为—H或—F；R7为—H、—C(CH3)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)OR8；(3) —(C═O)NR9R9；(4) —SO2NHR10−，(5) SO2OR11；(6) —PO3R11R11；(7) 五元杂环基；(8) —CONH—SO2R12；以及(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
• Significant Differences in Biological Parameters between Prodrugs Cleavable by Carboxypeptidase G2 That Generate 3,5-Difluoro-phenol and -aniline Nitrogen Mustards in Gene-Directed Enzyme Prodrug Therapy Systems
  作者：I. Niculescu-Duvaz、I. Scanlon、D. Niculescu-Duvaz、F. Friedlos、J. Martin、R. Marais、C. J. Springer

  DOI：10.1021/jm030966w

  日期：2004.5.1

  Nine new nitrogen mustard compounds derived from 2,6-difluoro-4-hydroxy- (3a-e) and 2,6-difluoro-4-amino- (4a-d) aniline were synthesized as potential prodrugs. They were designed to be activated to their corresponding 3,5-difluorophenol and -aniline (4)-nitrogen mustards by the enzyme carboxypeptidase G2 (CPG2) in gene-directed enzyme prodrug therapy (GDEPT) models. The compounds were tested for cytotoxicity in the MDA MB-361 breast adenocarcinoma. The cell line was engineered to express stably either CPG2 tethered to the cell surface stCPG2(Q)3 or beta-galactosidase (beta-Gal) as control. The cytotoxicity differentials were calculated between CPG 2-expressing and -nonexpressing cells and yielded different results for the two series of prodrugs despite their structural similarities. While the phenol compounds are ineffective as prodrugs, their aniline counterparts exhibit outstanding activity in the tumor cell lines expressing CPG2. 3,5-Difluoro-4-[bis(2-chloroethyl)amino]phenyl}carbamoyl-L-glutamic acid gave a differential of >227 in MDA MB361 cells as compared with 19 exhibited by 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl-L-glutamic acid, 1a, which has been in clinical trials.
• US6852755B1
  申请人：——

  公开号：US6852755B1

  公开（公告）日：2005-02-08