[3-(acridin-9-ylamino)-5-hydroxymethylphenyl]carbamic acidethyl ester | 237766-09-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: [3-(acridin-9-ylamino)-5-hydroxymethylphenyl]carbamic acidethyl ester
• 英文别名: ethyl N-[3-(acridin-9-yl)amino-5-hydroxymethyl]phenylcarbamate；ethyl N-[3-(acridin-9-ylamino)-5-(hydroxymethyl)phenyl]carbamate
• CAS: 237766-09-5
• 化学式: C₂₃H₂₁N₃O₃
• 分子量: 387.438
• InChiKey: HHFKXMNZFGOYPD-UHFFFAOYSA-N

物化性质

• 沸点：
  542.1±50.0 °C(Predicted)
• 密度：
  1.351±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  83.5
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  [3-(acridin-9-ylamino)-5-hydroxymethylphenyl]carbamic acidethyl ester 在 吡啶 、 4-二甲氨基吡啶 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 26.0h， 生成 4-[5-(2-Dimethylamino-ethylcarbamoyl)-1-methyl-1H-pyrrol-3-ylcarbamoyl]-butyric acid 3-(acridin-9-ylamino)-5-ethoxycarbonylamino-benzyl ester
  参考文献：
  名称：

  Antitumor AHMA Linked to DNA Minor Groove Binding Agents:  Synthesis and Biological Evaluation

  摘要：

  DNA minor groove binder hybrid molecules, netropsin derivatives such as N-[2-(dimethylamino)ethyl]-1-methyl-4-aminopyrrolo-2-carboxamide (MePy) or its derivatives containing two units of N-methylpyrrolecarboxamide (diMePy) and bisbenzimidazole (Ho33258), were linked to the NH2 function of AHMA or to the CH2OH group of AHMA-ethylcarbamate to form AHMA-N-netropsins (13-16) and AHMA-ethylcarbamate-O-netropsins (19-22), and AHMA-bis-benzimidazole (AHMA-Ho33258, 25), respectively. These conjugates' in vitro antitumor activity, inhibition of a variety of human tumor cell growth, revealed that AHMA-ethylcarbamate-O-netropsin derivatives were more cytotoxic than AHMA-N-netropsin compounds. In the same studies, all compounds bearing MePy were more potent than those compounds linked with diMePy. Moreover, AHMA-netropsin derivatives bearing a succinyl chain as the linking spacer were more potent than those compounds having a glutaryl bridge. Among these hybrid molecules, AHMA-ethylcarbamate-O-succinyl-MePy (19) was 2- to 6-fold more cytotoxic than the parent compound AHMA (5) in various cell lines, whereas compound 25 had very poor solubility and was inactive. Studies on the inhibitory effect against topoisomerase II (Topo II) and DNA interaction of these conjugates showed no correlation between the potency of DNA binding and inhibitory activity against Topo II.

  DOI：

  10.1021/jm0200714
• 作为产物：
  描述：

  氯甲酸乙酯 、 [3-(吖啶-9-基氨基)-5-氨基苯基]甲醇 在 吡啶 作用下， 以 N-甲基乙酰胺 为溶剂， 生成 [3-(acridin-9-ylamino)-5-hydroxymethylphenyl]carbamic acidethyl ester
  参考文献：
  名称：

  Alkyl N-\x9b3-(acridin-9-yl)amino-5-hydroxymethyl! phenylcarbamates

  摘要：

  该发明提供了以下式的化合物：其中R.sup.1是C.sub.1-6烷基；或苯基；R.sup.2是氢；具有式--COR.sup.a的酰基，其中R.sup.a是C.sub.1-6烷基或苯基；或具有式--CO(CH.sub.2).sub.n COCH.sub.3的乙酰烷基羰基，其中n=1-3；R.sup.3和R.sup.4是取代物，位于吖啶环的不同位置（即C-1'-C-8'），R.sup.3和R.sup.4可以相同也可以不同，并且独立地表示：氢；C.sub.1-6烷基；C.sub.1-6烷氧基；硝基；具有式--NR.sup.b R.sup.c的氨基，其中R.sup.b和R.sup.c可以相同也可以不同，独立地表示氢或C.sub.1-6烷基；具有式--NH(CH.sub.2).sub.n NR.sup.d R.sup.e的氨基烷基氨基，其中R.sup.d和R.sup.e可以相同也可以不同，独立地表示氢，C.sub.1-6烷基，具有式--(CH.sub.2).sub.n OH的羟基烷基，其中n=1-3，或C.sub.1-6卤代烷基；具有式--CONHR.sup.f的烷基氨基羰基，其中R.sup.f是C.sub.1-6烷基；具有式--CONH(CH.sub.2).sub.n NR.sup.g R.sup.h的烷基氨基烷基氨基羰基，其中n=1-5，R.sup.g和R.sup.h可以相同也可以不同，独立地表示氢，C.sub.1-6烷基，或硝基；卤素基；具有式--CH.sub.2).sub.n OH的羟基烷基；具有式--CH.sub.2 CONHR.sup.f的氨基甲酸酯基，其中R.sup.f如上所定义；具有式--CH.sub.2 OCOR.sup.f的烷基羰氧甲基基团，其中R.sup.f如上所定义；磺酸烷基，其式为--SO.sub.3 R.sup.f，R.sup.f如上所定义；和磺酰基，其式为--SO.sub.2 R.sup.f，其中R.sup.f如上所定义；但是当R.sup.2，R.sup.3和R.sup.4为氢时，R.sup.1不是叔丁基；以及其药学上可接受的盐。本发明还涉及合成上述化合物的方法，由此产生的中间化合物，包含上述化合物的药物组合物，以及用于治疗疾病的用途和方法。

  公开号：

  US05939428A1

文献信息

• Aniline or phenol mustards linked to DNA-affinic molecules or water-soluble aromatic rings and their use as cancer therapeutic agents
  申请人：Su Tsann-Long

  公开号：US20080171765A1

  公开（公告）日：2008-07-17

  New aniline or phenol N-mustards linked to DNA-affinity carriers (such as 9-anilinoacridines, acridines and quinolines), aminobenzamides or aminophenol ethers by a urea, carbamic acid, carbanic acid ester, hydrazineurea, hydrazinecarbamic acid ester, phenoxyurea, phenoxycarbamic acid ester linkage with improved chemical stability and anti-tumor therapeutic efficacy are provided.

  提供了与DNA亲和载体（如9-苯胺基吖啶、吖啶和喹啉）、氨基苯甲酰胺或氨基酚醚通过脲、碳酸酯、碳酸酯、叠氮脲、叠氮碳酸酯、苯氧基脲、苯氧基碳酸酯链接的新苯胺或酚N-芥子素，具有改善的化学稳定性和抗肿瘤治疗效果。
• New analogues of AHMA as potential antitumor agents: synthesis and biological activity
  作者：Jang-Yang Chang、Chyun-Feng Lin、Wen-Yu Pan、Valeriy Bacherikov、Ting-Chao Chou、Ching-Huang Chen、Huajin Dong、Shu-Yun Cheng、Tsong-Jen Tasi、Yi-Wen Lin、Kuo-Tung Chen、Li-Tzong Chen、Tsann-Long Su

  DOI：10.1016/j.bmc.2003.09.001

  日期：2003.11

  A series of new analogues of 3-(9-acridinylamino)-5-hydroxymethylaniline (AHMA, 1) and AHMA-ethylcarbamate (2) were synthesized by introducing an O-alkylcarboxylic acid esters to the CH2OH function, displacing the CH2OH function with a dimethylaminocarboxamido group or with a methyl function introduced at the meta-, para- or ortho-position to the NH2 group to form 5-(9-acridinylamino)-m-toluidines (AMTs), 5-(9-acridinylamino)-p-toluidines (APTs) or 5-(9-acridinylamino)-o-toluidines (AOTs), respectively. The inhibitions of a variety of human tumor cell growth, interactions with DNA as well as inhibitory effect against topoisomerase 11 (Topo 11) of these new agents were studied. Among AMT, APT and AOT derivatives with dimethylaminoethylcarboxamido and Me at C4 and C5 of acridine moiety (i.e., 21c, 23c and 26c) were more cytotoxic than AHMA (1) and AHMA-ethylcarbamate (2), depending upon the tumor cell line tested. Detailed structure-activity relationships of the new analogues were studied. (C) 2003 Elsevier Ltd. All rights reserved.
• Novel DNA-directed alkylating agents: Design, synthesis and potent antitumor effect of phenyl N-mustard-9-anilinoacridine conjugates via a carbamate or carbonate linker
  作者：Naval Kapuriya、Kalpana Kapuriya、Huajin Dong、Xiuguo Zhang、Ting-Chao Chou、Yu-Ting Chen、Te-Chang Lee、Wen-Chuan Lee、Tung-Hu Tsai、Yogesh Naliapara、Tsann-Long Su

  DOI：10.1016/j.bmc.2008.12.022

  日期：2009.2

  A series of phenyl N-mustard-9-anilinoacridine conjugates via a carbamate or carbonate linker was synthesized for antitumor evaluation. The carbamate or carbonate linker is able to lower the reactivity of the phenyl N-mustard pharmacophore and thus, these conjugates are rather chemically stable. The in vitro studies revealed that these derivatives possessed significant cytotoxicity with IC50 in sub-micromolar range in inhibiting human lymphoblastic leukemia (CCRF-CEM), breast carcinoma (MX-1), colon carcinoma (HCT-116) and human non-small cell lung cancer (H1299) cell growth in vitro. Compounds 10a, 10b, 10e, 10i, and 15a were selected for evaluating their antitumor activity in nude mice bearing MX1 and HCT-116 xenografts. Remarkably, total tumor remission was achieved by these agents with only one cycle of treatment. Interestingly, no tumor relapse was found in mice treated with 10a over 129 days. This agent is capable of inducing DNA interstrand cross-linking in human non-small lung cancer H1299 cells in a dose dependent manner by modified comet assay and has a long half-life in rat plasma. (c) 2008 Elsevier Ltd. All rights reserved.
• Antitumor AHMA Linked to DNA Minor Groove Binding Agents:  Synthesis and Biological Evaluation
  作者：Kamesh Rastogi、Jang-Yang Chang、Wen-Yu Pan、Ching-Huang Chen、Ting-Chao Chou、Li-Tzong Chen、Tsann-Long Su

  DOI：10.1021/jm0200714

  日期：2002.9.1

  DNA minor groove binder hybrid molecules, netropsin derivatives such as N-[2-(dimethylamino)ethyl]-1-methyl-4-aminopyrrolo-2-carboxamide (MePy) or its derivatives containing two units of N-methylpyrrolecarboxamide (diMePy) and bisbenzimidazole (Ho33258), were linked to the NH2 function of AHMA or to the CH2OH group of AHMA-ethylcarbamate to form AHMA-N-netropsins (13-16) and AHMA-ethylcarbamate-O-netropsins (19-22), and AHMA-bis-benzimidazole (AHMA-Ho33258, 25), respectively. These conjugates' in vitro antitumor activity, inhibition of a variety of human tumor cell growth, revealed that AHMA-ethylcarbamate-O-netropsin derivatives were more cytotoxic than AHMA-N-netropsin compounds. In the same studies, all compounds bearing MePy were more potent than those compounds linked with diMePy. Moreover, AHMA-netropsin derivatives bearing a succinyl chain as the linking spacer were more potent than those compounds having a glutaryl bridge. Among these hybrid molecules, AHMA-ethylcarbamate-O-succinyl-MePy (19) was 2- to 6-fold more cytotoxic than the parent compound AHMA (5) in various cell lines, whereas compound 25 had very poor solubility and was inactive. Studies on the inhibitory effect against topoisomerase II (Topo II) and DNA interaction of these conjugates showed no correlation between the potency of DNA binding and inhibitory activity against Topo II.
• Alkyl N-\x9b3-(acridin-9-yl)amino-5-hydroxymethyl! phenylcarbamates
  申请人：National Health Research Institutes

  公开号：US05939428A1

  公开（公告）日：1999-08-17

  The invention provides a compound of the following formula: ##STR1## wherein R.sup.1 is C.sub.1-6 alkyl; or phenyl; R.sup.2 is hydrogen; an acyl group of the formula --COR.sup.a wherein R.sup.a is C.sub.1-6 alkyl or phenyl; or an acetylalkylcarbonyl group of the formula --CO(CH.sub.2).sub.n COCH.sub.3 wherein n=1-3; and R.sup.3 and R.sup.4 are substituents at different position(s) of the acridine ring (i.e. C-1'-C-8'), and R.sup.3 and R.sup.4 may be the same or different and independently represent: hydrogen; C.sub.1-6 alkyl; C.sub.1-6 alkyloxy; a nitro group; an amino group of the formula --NR.sup.b R.sup.c wherein R.sup.b and R.sup.c may be the same or different and independently represent hydrogen or C.sub.1-6 alkyl; an aminoalkylamino group of the formula --NH(CH.sub.2).sub.n NR.sup.d R.sup.e wherein R.sup.d and R.sup.e may be the same or different and independently represent hydrogen, C.sub.1-6 alkyl, a hydroxyalkyl group of the formula --(CH.sub.2).sub.n OH wherein n=1-3, or C.sub.1-6 haloalkyl; an alkylaminocarbonyl group of the formula --CONHR.sup.f wherein R.sup.f is C.sub.1-6 alkyl; an alkylaminoalkylaminocarbonyl group of the formula --CONH(CH.sub.2).sub.n NR.sup.g R.sup.h wherein n=1-5, and R.sup.g and R.sup.h may be the same or different and independently represent hydrogen, C.sub.1-6 alkyl, or a nitro group; a halogen group; a hydroxyalkyl group of the formula --CH.sub.2).sub.n OH wherein n=1-3; a carbamate group of the formula --CH.sub.2 CONHR.sup.f wherein R.sup.f is as defined above; an alkylcarbonyloxymethyl group of the formula --CH.sub.2 OCOR.sup.f wherein R.sup.f is as defined above; alkyl sufonate of the formula --SO.sub.3 R.sup.f is as defined above; and an alkylsulfonyl group of the formula --SO.sub.2 R.sup.f wherein R.sup.f is as defined above; with the proviso that when R.sup.2, R.sup.3 and R.sup.4 are hydrogen, R.sup.1 is not t-butyl; and the pharmaceutically acceptable salts thereof. The present invention also relates to a process for synthesizing the above-identified compound, intermediate compounds produced thereby, pharmaceutical compositions comprising the above compounds, and uses and method thereof for treating diseases.

  该发明提供了以下式的化合物：其中R.sup.1是C.sub.1-6烷基；或苯基；R.sup.2是氢；具有式--COR.sup.a的酰基，其中R.sup.a是C.sub.1-6烷基或苯基；或具有式--CO(CH.sub.2).sub.n COCH.sub.3的乙酰烷基羰基，其中n=1-3；R.sup.3和R.sup.4是取代物，位于吖啶环的不同位置（即C-1'-C-8'），R.sup.3和R.sup.4可以相同也可以不同，并且独立地表示：氢；C.sub.1-6烷基；C.sub.1-6烷氧基；硝基；具有式--NR.sup.b R.sup.c的氨基，其中R.sup.b和R.sup.c可以相同也可以不同，独立地表示氢或C.sub.1-6烷基；具有式--NH(CH.sub.2).sub.n NR.sup.d R.sup.e的氨基烷基氨基，其中R.sup.d和R.sup.e可以相同也可以不同，独立地表示氢，C.sub.1-6烷基，具有式--(CH.sub.2).sub.n OH的羟基烷基，其中n=1-3，或C.sub.1-6卤代烷基；具有式--CONHR.sup.f的烷基氨基羰基，其中R.sup.f是C.sub.1-6烷基；具有式--CONH(CH.sub.2).sub.n NR.sup.g R.sup.h的烷基氨基烷基氨基羰基，其中n=1-5，R.sup.g和R.sup.h可以相同也可以不同，独立地表示氢，C.sub.1-6烷基，或硝基；卤素基；具有式--CH.sub.2).sub.n OH的羟基烷基；具有式--CH.sub.2 CONHR.sup.f的氨基甲酸酯基，其中R.sup.f如上所定义；具有式--CH.sub.2 OCOR.sup.f的烷基羰氧甲基基团，其中R.sup.f如上所定义；磺酸烷基，其式为--SO.sub.3 R.sup.f，R.sup.f如上所定义；和磺酰基，其式为--SO.sub.2 R.sup.f，其中R.sup.f如上所定义；但是当R.sup.2，R.sup.3和R.sup.4为氢时，R.sup.1不是叔丁基；以及其药学上可接受的盐。本发明还涉及合成上述化合物的方法，由此产生的中间化合物，包含上述化合物的药物组合物，以及用于治疗疾病的用途和方法。