N-[(2,4-diaminopteridin-6-yl)methyl]dibenz[b,f]azepine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯氮卓类
• 英文名称: N-[(2,4-diaminopteridin-6-yl)methyl]dibenz[b,f]azepine
• 英文别名: [N-(2,4-Diaminopteridin-6-YL)-methyl]-dibenz[B,F]azepine；6-(benzo[b][1]benzazepin-11-ylmethyl)pteridine-2,4-diamine
• 化学式: C₂₁H₁₇N₇
• 分子量: 367.413
• InChiKey: NXCCIJQEAKMFGW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  28
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  107
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  亚氨基芪 、 6-溴乙基-喋啶-2,4-二胺 在 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 反应 12.17h， 以78%的产率得到N-[(2,4-diaminopteridin-6-yl)methyl]dibenz[b,f]azepine
  参考文献：
  名称：

  二氢叶酸还原酶选择性抑制剂的基于结构的设计：具有桥联的二芳基胺侧链的2，4-二氨基蝶啶类似物的合成和抗寄生虫活性。

  摘要：

  N-[（2,4-diaminopteridin-6-yl）methyl] dibenz是寻找来自艾滋病和其他免疫系统疾病患者的机会病原体的有效的和选择性抑制剂二氢叶酸还原酶（DHFR）的一部分， [b，f] azepine（4a）和相应的二氢二苯并[b，f] azepine，二氢ac啶，吩恶嗪，吩噻嗪，咔唑和二苯胺类似物是由2，4-二氨基-6-（溴甲基）哌啶在50-75中合成的在室温下，通过与胺的钠盐在干燥的四氢呋喃中反应，得到5％的收率。测试了产品抑制卡氏肺孢子虫（pcDHFR），弓形虫（tgDHFR），鸟分枝杆菌（maDHFR）和大鼠肝脏（rlDHFR）的DHFR的能力。该系列中效价和物种选择性最佳组合的成员是4a，IC（50）值分别针对四种酶，分别为0. 21、0.043、0.012和4.4 microM。二氢ac啶，吩噻嗪和咔唑类似物也是有效的，但非选择性。在测试的化合物中，4a是

  DOI：

  10.1021/jm990331q

文献信息

• Dicyclic and Tricyclic Diaminopyrimidine Derivatives as Potent Inhibitors of <i>Cryptosporidium parvum</i> Dihydrofolate Reductase: Structure-Activity and Structure-Selectivity Correlations
  作者：Richard G. Nelson、Andre Rosowsky

  DOI：10.1128/aac.45.12.3293-3303.2001

  日期：2001.12

  A structurally diverse library of 93 lipophilic di- and tricyclic diaminopyrimidine derivatives was tested for the ability to inhibit recombinant dihydrofolate reductase (DHFR) cloned from human and bovine isolates of Cryptosporidium parvum (J. R. Vásquez et al., Mol. Biochem. Parasitol. 79:153–165, 1996). In parallel, the library was also tested against human DHFR and, for comparison, the enzyme from Escherichia coli . Fifty percent inhibitory concentrations (IC ₅₀ s) were determined by means of a standard spectrophotometric assay of DHFR activity with dihydrofolate and NADPH as the cosubstrates. Of the compounds tested, 25 had IC ₅₀ s in the 1 to 10 μM range against one or both C. parvum enzymes and thus were not substantially different from trimethoprim (IC ₅₀ s, ca. 4 μM). Another 25 compounds had IC ₅₀ s of <1.0 μM, and 9 of these had IC ₅₀ s of <0.1 μM and thus were at least 40 times more potent than trimethoprim. The remaining 42 compounds were weak inhibitors (IC ₅₀ s, >10 μM) and thus were not considered to be of interest as drugs useful against this organism. A good correlation was generally obtained between the results of the spectrophotometric enzyme inhibition assays and those obtained recently in a yeast complementation assay (V. H. Brophy et al., Antimicrob. Agents Chemother. 44:1019–1028, 2000; H. Lau et al., Antimicrob. Agents Chemother. 45:187–195, 2001). Although many of the compounds in the library were more potent than trimethoprim, none had the degree of selectivity of trimethoprim for C. parvum versus human DHFR. Collectively, the results of these assays comprise the largest available database of lipophilic antifolates as potential anticryptosporidial agents. The compounds in the library were also tested as inhibitors of the proliferation of intracellular C. parvum oocysts in canine kidney epithelial cells cultured in folate-free medium containing thymidine (10 μM) and hypoxanthine (100 μM). After 72 h of drug exposure, the number of parasites inside the cells was quantitated by indirect immunofluorescence microscopy. Sixteen compounds had IC ₅₀ s of <3 μM, and five of these had IC ₅₀ s of <0.3 μM and thus were comparable in potency to trimetrexate. The finding that submicromolar concentrations of several of the compounds in the library could inhibit in vitro growth of C. parvum in host cells in the presence of thymidine (dThd) and hypoxanthine (Hx) suggests that lipophilic DHFR inhibitors, in combination with leucovorin, may find use in the treatment of intractable C. parvum infections.

  摘要 对 93 种亲脂性二环和三环二氨基嘧啶衍生物的结构多样性文库进行了测试，以检测其抑制从人和牛分离的副隐孢子虫中克隆的重组二氢叶酸还原酶（DHFR）的能力。 副猪隐孢子虫 (J. R. Vásquez et al., Mol. Biochem. Parasitol. 79:153-165, 1996)。与此同时，该文库还针对人类 DHFR 进行了测试，并与来自 大肠杆菌 .五成抑制浓度（IC 50 s）是通过以二氢叶酸和 NADPH 为共底物的 DHFR 活性标准分光光度法测定的。在测试的化合物中，25 个化合物的 IC 50 在 1 至 10 μM 范围内，对一种或两种 C. parvum 因此与三甲氧苄啶（IC 50 s，约为 4 μM）没有本质区别。另外 25 种化合物的 IC 50 s 为 1.0 μM，其中 9 种化合物的 IC 50 为 0.1 μM，因此药效至少是三甲氧苄啶的 40 倍。其余 42 种化合物为弱抑制剂（IC 50 s，>10 μM），因此不被认为是对这种生物有用的药物。分光光度法酶抑制测定的结果与最近在酵母互补测定中获得的结果之间通常具有良好的相关性（V. H. Brophy 等人，Antimicrob.Agents Chemother.44:1019-1028, 2000; H. Lau et al.Agents Chemother.45:187-195, 2001).虽然文库中的许多化合物都比三甲氧苄氨嘧啶更有效，但没有一种化合物具有三甲氧苄氨嘧啶对副猪嗜血杆菌的选择性。 副猪嗜血杆菌 对人类 DHFR 的选择性。总之，这些检测结果构成了目前最大的亲脂性抗酚化合物潜在抗隐孢子虫药物数据库。该化合物库中的化合物还作为细胞内副猪嗜血杆菌增殖抑制剂进行了测试。 副猪嗜血杆菌 卵囊在含有胸苷（10 μM）和次黄嘌呤（100 μM）的无叶酸培养基中培养的犬肾上皮细胞中的增殖抑制剂。药物暴露 72 小时后，通过间接免疫荧光显微镜对细胞内的寄生虫数量进行量化。16种化合物的IC 50 为 <3 μM，其中五个化合物的 IC 50 s 为 <0.3 μM，因此其效力与三甲曲沙相当。研究发现，库中几种亚摩尔浓度的化合物可抑制副嗜血杆菌的体外生长。 副猪嗜血杆菌 在胸苷（dThd）和次黄嘌呤（Hx）存在的宿主细胞中的体外生长。 C. parvum 感染。
• Dibenz[B,F]azepine compounds, pharmaceutical compositions comprising same and methods of use thereof
  申请人：Dana-Farber Cancer Institute

  公开号：US07056911B1

  公开（公告）日：2006-06-06

  The invention relates to pharmaceutically active compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention and particularly useful for the treatment or prophylaxis of diseases associated with parasitic infection such as pneumocystis pneumonia, toxoplasmosis, cryptosporidiosis, leischmaniasis and malaria.

  该发明涉及具有药用活性的化合物，以及利用或包含一种或多种这样的化合物的治疗方法和制药组合物。该发明的化合物特别适用于治疗或预防与寄生虫感染相关的疾病，如肺孢子虫肺炎、弓形虫病、隐孢子虫病、利什曼病和疟疾。
• US7056911B1
  申请人：——

  公开号：US7056911B1

  公开（公告）日：2006-06-06
• Structure-Based Design of Selective Inhibitors of Dihydrofolate Reductase:  Synthesis and Antiparasitic Activity of 2,4-Diaminopteridine Analogues with a Bridged Diarylamine Side Chain
  作者：Andre Rosowsky、Vivian Cody、Nikolai Galitsky、Hongning Fu、Andrew T. Papoulis、Sherry F. Queener

  DOI：10.1021/jm990331q

  日期：1999.11.1

  selective inhibitors of dihydrofolate reductase (DHFR) enzymes from opportunistic pathogens found in patients with AIDS and other immune disorders, N-[(2,4-diaminopteridin-6-yl)methyl]dibenz[b,f]azepine (4a) and the corresponding dihydrodibenz[b,f]azepine, dihydroacridine, phenoxazine, phenothiazine, carbazole, and diphenylamine analogues were synthesized from 2, 4-diamino-6-(bromomethyl)pteridine in

  N-[（2,4-diaminopteridin-6-yl）methyl] dibenz是寻找来自艾滋病和其他免疫系统疾病患者的机会病原体的有效的和选择性抑制剂二氢叶酸还原酶（DHFR）的一部分， [b，f] azepine（4a）和相应的二氢二苯并[b，f] azepine，二氢ac啶，吩恶嗪，吩噻嗪，咔唑和二苯胺类似物是由2，4-二氨基-6-（溴甲基）哌啶在50-75中合成的在室温下，通过与胺的钠盐在干燥的四氢呋喃中反应，得到5％的收率。测试了产品抑制卡氏肺孢子虫（pcDHFR），弓形虫（tgDHFR），鸟分枝杆菌（maDHFR）和大鼠肝脏（rlDHFR）的DHFR的能力。该系列中效价和物种选择性最佳组合的成员是4a，IC（50）值分别针对四种酶，分别为0. 21、0.043、0.012和4.4 microM。二氢ac啶，吩噻嗪和咔唑类似物也是有效的，但非选择性。在测试的化合物中，4a是