2,4-diamino-6-<(3',4'-dichloro-N-methylanilino)methyl>pyrido<3,2-d>pyrimidine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 英文名称: 2,4-diamino-6-<(3',4'-dichloro-N-methylanilino)methyl>pyrido<3,2-d>pyrimidine
• 英文别名: 6-(((3,4-Dichlorophenyl)(methyl)amino)methyl)pyrido[3,2-d]pyrimidine-2,4-diamine；6-[(3,4-dichloro-N-methylanilino)methyl]pyrido[3,2-d]pyrimidine-2,4-diamine
• 化学式: C₁₅H₁₄Cl₂N₆
• 分子量: 349.222
• InChiKey: DIJUWZJIGDFPAA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  94
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  N-(3,4-二氯-苯基)-甲酰胺 在 lithium aluminium tetrahydride 、 碳酸氢钠 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 144.0h， 生成 2,4-diamino-6-<(3',4'-dichloro-N-methylanilino)methyl>pyrido<3,2-d>pyrimidine
  参考文献：
  名称：

  来自卡氏肺孢子虫和弓形虫的二氢叶酸还原酶的2，4-二氨基吡啶并[3，2-d]嘧啶抑制剂。

  摘要：

  由以下化合物合成了六个先前未知的2,4-二氨基-6-（苯胺基甲基）-和2,4-二氨基-6-[（N-甲基苯胺基）-甲基]吡啶基[3,2-d]嘧啶（5-10）通过在室温下在存在或不存在NaHCO3的条件下，用适当的苯胺或N-甲基苯胺在二甲基甲酰胺中处理，来制备2,4-二氨基-6-（溴甲基）-吡啶并[3,2-d]嘧啶氢溴酸盐（11.HBr）。测试了化合物5-10作为卡氏肺孢子虫，弓形虫和大鼠肝脏中二氢叶酸还原酶的抑制剂，这是针对发现兼具高酶选择性和高效力的亲脂性非经典抗叶酸药物的一项较大努力的一部分。在所测试的六个类似物中，对弓形虫DHFR最有效和最具选择性的是2,4-二氨基-6-[（3'，4'，5'-三甲氧基-N-甲基苯胺基）甲基]吡啶基[3,2- dd嘧啶（7），IC50为0。0047 microM（针对该酶）与0.026 microM（针对大鼠肝酶）相比。7对刚地弓形虫DHFR的效价与曲美

  DOI：

  10.1021/jm00014a014

文献信息

• Nonclassical 2,4-Diamino-8-deazafolate Analogues as Inhibitors of Dihydrofolate Reductases from Rat Liver, <i>Pneumocystis carinii</i>, and <i>Toxoplasma gondii</i>
  作者：Aleem Gangjee、Yuanming Zhu、Sherry F. Queener、Paula Francom、Arthur D. Broom

  DOI：10.1021/jm950918e

  日期：1996.1.1

  trichlorophenyl-substituted analogues with H or CH3 at the N10 position and methyl and trifluoromethyl phenyl ketone analogues with H, CH3, and CH2C identical to CH at the N10 position were synthesized. The S10 and N10 alpha- and beta-naphthyl analogues along with the N10 CH3 analogues were also synthesized. These compounds were evaluated as inhibitors of dihydrofolate reductases (DHFR) from Pneumocystis carinii (pc)

  报道了42个6-取代的2,4-二氨基吡啶并[3,2-d]嘧啶（2,4-二氨基-8-脱氮叶酸酯类似物）的合成和生物活性。与以前的经典类似物相比，使用我们先前报告的方法改进后的化合物以更高的产率合成。具体地，S-苯基-; 单-，二-和三甲氧基苯基-; 合成了在N10位置具有H或CH3的单，二和三氯苯基取代的类似物，以及在N10位置具有与CH相同的H，CH3和CH2C的甲基和三氟甲基苯基酮类似物。还合成了S10和N10α-和β-萘基类似物以及N10 CH3类似物。这些化合物被评估为卡氏肺孢子虫（pc）和弓形虫（tg）的二氢叶酸还原酶（DHFR）抑制剂。确定相对于大鼠肝（r1）DHFR作为哺乳动物参考酶的选择性比。针对pcDHFR，对于2,4-二氨基-6-[[（N-甲基-2'-萘基氨基）甲基]吡啶[3,2-d]嘧啶（28），IC50值范围从0.038 x 10-6 M到5.5 x 2,4-二氨基-6
• 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。
• 2,4-Diaminopyrido[3,2-d]pyrimidine Inhibitors of Dihydrofolate Reductase from Pneumocystis carinii and Toxoplasma gondii
  作者：Andre Rosowsky、Ronald A. Forsch、Sherry F. Queener

  DOI：10.1021/jm00014a014

  日期：1995.7

  Six previously unknown 2,4-diamino-6-(anilinomethyl)- and 2,4-diamino-6-[(N-methylanilino)-methyl]pyrido[3,2-d]pyrimidines (5-10) were synthesized from 2,4-diamino-6-(bromomethyl)-pyrido[3,2-d]pyrimidine hydrobromide (11.HBr) by treatment with the appropriate aniline or N-methylaniline in dimethylformamide at room temperature, with or without NaHCO3 present. Compounds 5-10 were tested as inhibitors

  由以下化合物合成了六个先前未知的2,4-二氨基-6-（苯胺基甲基）-和2,4-二氨基-6-[（N-甲基苯胺基）-甲基]吡啶基[3,2-d]嘧啶（5-10）通过在室温下在存在或不存在NaHCO3的条件下，用适当的苯胺或N-甲基苯胺在二甲基甲酰胺中处理，来制备2,4-二氨基-6-（溴甲基）-吡啶并[3,2-d]嘧啶氢溴酸盐（11.HBr）。测试了化合物5-10作为卡氏肺孢子虫，弓形虫和大鼠肝脏中二氢叶酸还原酶的抑制剂，这是针对发现兼具高酶选择性和高效力的亲脂性非经典抗叶酸药物的一项较大努力的一部分。在所测试的六个类似物中，对弓形虫DHFR最有效和最具选择性的是2,4-二氨基-6-[（3'，4'，5'-三甲氧基-N-甲基苯胺基）甲基]吡啶基[3,2- dd嘧啶（7），IC50为0。0047 microM（针对该酶）与0.026 microM（针对大鼠肝酶）相比。7对刚地弓形虫DHFR的效价与曲美