6-[(2,4-Dimethoxyphenyl)aminomethyl]-2,4-diamino-5-methylpyrido[2,3-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: 6-[(2,4-Dimethoxyphenyl)aminomethyl]-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine
• 英文别名: 6-[(2,4-dimethoxyanilino)methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
• 化学式: C₁₇H₂₀N₆O₂
• 分子量: 340.385
• InChiKey: BLXKKGXDOHABAI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  121
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  聚合甲醛 、 6-[(2,4-Dimethoxyphenyl)aminomethyl]-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine 在 盐酸 、 sodium cyanoborohydride 作用下， 生成 2,4-diamino-5-methyl-6-<(2',4'-dimethoxy-N-methylanilino)methyl>pyrido<2,3-d>pyrimidine hydrochloride
  参考文献：
  名称：

  6-取代的2,4-二氨基-5-甲基吡啶并[2,3-d]嘧啶类化合物是卡氏肺孢子虫和弓形虫的二氢叶酸还原酶的抑制剂，并用作抗肿瘤剂。

  摘要：

  报道了15个6-取代的2，4-二氨基-5-甲基吡啶并[2，3-d]-嘧啶的合成和生物活性。通过修改我们先前报道的程序，可以提高产率合成这些化合物。具体地，合成了在N-10位具有H和CH 3的二甲氧基苯基取代的化合物和具有N-10个乙基，异丙基和炔丙基基团的三甲氧基苯基取代的化合物。这些化合物被评估为卡氏肺孢子虫，弓形虫和大鼠肝脏的二氢叶酸还原酶（DHFR）抑制剂，所选的类似物被评估为弓形虫和培养物中肿瘤细胞生长的抑制剂。与曲美曲塞相比，所有化合物都显示出对弓形虫DHFR的选择性增加（相对于大鼠肝脏DHFR）。通常，对于三甲氧基取代的类似物，将N-10取代基的大小从甲基增加到较大的基团会导致卡氏疟原虫和刚地弓形虫DHFR的选择性和效能降低。对于二甲氧基取代的类似物，N-10甲基化通常会降低效力，但会增加弓形虫DHFR的选择性。为了提高这些类似物的细胞渗透性，还合成了N-10萘基取代的类似物。

  DOI：

  10.1021/jm00010a022
• 作为产物：
  描述：

  2,4-diamino-5-methyl-5-deaza-6-bromomethylpteridine 、 2,4-二甲氧基苯胺 生成 6-[(2,4-Dimethoxyphenyl)aminomethyl]-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine
  参考文献：
  名称：

  Lipophilic Antifolates as Agents against Opportunistic Infections. 1. Agents Superior to Trimetrexate and Piritrexim against Toxoplasma gondii and Pneumocystis carinii in in Vitro Evaluations

  摘要：

  2,4-Diaminopteridines (21 compounds) and 2,4-diamino-5-methyl-5-deazapteridines (34 compounds) along with three 2,4-diamino-5-unsubstituted-5-dieazapteridines and four 2,4-diaminoquinazolines, each with an aryl group attached to the 6-position of the heterocyclic moiety through a two-atom bridge (either CH2NH, CH2N(CH3), CH2S, or CH2CH2), were synthesized and evaluated as inhibitors of the growth of Toxoplasma gondii in culture and as inhibitors of dihydrofolate reductase enzymes from T. gondii, Pneumocystis carinii, and rat liver. Exceptionally high levels of combined potency and selectivity as growth inhibitors of T. gondii and as inhibitors of the microbial enzymes relative to the mammalian enzyme were found among the 5-methyl-5-deazapteridines but not for the other heterocyclic types. Thirty of the 34 5-methyl-5-deaza compounds gave growth inhibition IC50 values lower than that of pyrimethamine (0.4 mu M) with 14 compounds below 0.1 mu M, values that compare favorably with those for piritrexim and trimetrexate (both near 0.02 mu M). As inhibitors of T. gondii DHFR, all but three of the 34 5-methyl-5-deaza compounds gave IC50 values in the order of magnitude with those of piritrexim (0.017 mu M) and trimetrexate (0.010 mu M), and 17 compounds of this group gave IC50 values versus P. carinii DHFR similarly comparable with those of piritrexim (0.031 mu M) and trimetrexate (0.042 mu M). Thirteen of these congeners gave both T. gondii growth inhibition and DHFR inhibition IC50 values of 0.10 mu M or less, thus indicating facile penetration of the cell membrane. Eleven of these inhibitors of both T. gondii growth and DHFR have selectivity ratios (IC50 rat liver divided by IC50 T gondii) of 5 or greater for the parasite DHFR. The highest selectivity ratio of nearly 100 belongs to the 5-methyl-5-deaza compound whose B-substituent is CH2CH2C6H3(OCH3)(2)-2,5. This compound is over 10(3)-fold more selective for T. gondii DHFR than bridge homologue piritrexim (selectivity ratio 0.088), a compound now in clinical trials. The candidate with CH2NHC6H3(CH3)(2)-2,5 in the 6-position gave the highest P. carinii DHFR selectivity ratio of 4.0, which is about 60-fold more selective than trimetrexate (0.071) and 80-fold more selective than piritrexim (0.048) toward this enzyme. The 10 best compounds with respect to potency and selectivity includes six compounds bearing 2,5-disubstituted phenyl groups in the side chain (with little, if any, difference in effects of methyl, methoxy, or ethoxy), two side chains bearing 1-naphthyl groups, and two with 5,6,7,8-tetrahydro-1-naphthyl groups. Bridge groups represented in the 10 choice compounds are CH2NH, CH2N(CH3), CH2CH2, and CH2S. The high levels of both potency and selectivity among these agents suggest that in vivo studies now underway may lead to agents that could replace trimetrexate and piritrexim in treatment of toxoplasmosis and P. carinii pneumonia.

  DOI：

  10.1021/jm950760y

文献信息

• Lipophilic Antifolates as Agents against Opportunistic Infections. 1. Agents Superior to Trimetrexate and Piritrexim against <i>Toxoplasma gondii</i> and <i>Pneumocystis carinii</i> in <i>in Vitro</i> Evaluations
  作者：James R. Piper、Cheryl A. Johnson、Charles A. Krauth、Ronald L. Carter、Carla A. Hosmer、Sherry F. Queener、Susan E. Borotz、Elmer R. Pfefferkorn

  DOI：10.1021/jm950760y

  日期：1996.3.15

  2,4-Diaminopteridines (21 compounds) and 2,4-diamino-5-methyl-5-deazapteridines (34 compounds) along with three 2,4-diamino-5-unsubstituted-5-dieazapteridines and four 2,4-diaminoquinazolines, each with an aryl group attached to the 6-position of the heterocyclic moiety through a two-atom bridge (either CH2NH, CH2N(CH3), CH2S, or CH2CH2), were synthesized and evaluated as inhibitors of the growth of Toxoplasma gondii in culture and as inhibitors of dihydrofolate reductase enzymes from T. gondii, Pneumocystis carinii, and rat liver. Exceptionally high levels of combined potency and selectivity as growth inhibitors of T. gondii and as inhibitors of the microbial enzymes relative to the mammalian enzyme were found among the 5-methyl-5-deazapteridines but not for the other heterocyclic types. Thirty of the 34 5-methyl-5-deaza compounds gave growth inhibition IC50 values lower than that of pyrimethamine (0.4 mu M) with 14 compounds below 0.1 mu M, values that compare favorably with those for piritrexim and trimetrexate (both near 0.02 mu M). As inhibitors of T. gondii DHFR, all but three of the 34 5-methyl-5-deaza compounds gave IC50 values in the order of magnitude with those of piritrexim (0.017 mu M) and trimetrexate (0.010 mu M), and 17 compounds of this group gave IC50 values versus P. carinii DHFR similarly comparable with those of piritrexim (0.031 mu M) and trimetrexate (0.042 mu M). Thirteen of these congeners gave both T. gondii growth inhibition and DHFR inhibition IC50 values of 0.10 mu M or less, thus indicating facile penetration of the cell membrane. Eleven of these inhibitors of both T. gondii growth and DHFR have selectivity ratios (IC50 rat liver divided by IC50 T gondii) of 5 or greater for the parasite DHFR. The highest selectivity ratio of nearly 100 belongs to the 5-methyl-5-deaza compound whose B-substituent is CH2CH2C6H3(OCH3)(2)-2,5. This compound is over 10(3)-fold more selective for T. gondii DHFR than bridge homologue piritrexim (selectivity ratio 0.088), a compound now in clinical trials. The candidate with CH2NHC6H3(CH3)(2)-2,5 in the 6-position gave the highest P. carinii DHFR selectivity ratio of 4.0, which is about 60-fold more selective than trimetrexate (0.071) and 80-fold more selective than piritrexim (0.048) toward this enzyme. The 10 best compounds with respect to potency and selectivity includes six compounds bearing 2,5-disubstituted phenyl groups in the side chain (with little, if any, difference in effects of methyl, methoxy, or ethoxy), two side chains bearing 1-naphthyl groups, and two with 5,6,7,8-tetrahydro-1-naphthyl groups. Bridge groups represented in the 10 choice compounds are CH2NH, CH2N(CH3), CH2CH2, and CH2S. The high levels of both potency and selectivity among these agents suggest that in vivo studies now underway may lead to agents that could replace trimetrexate and piritrexim in treatment of toxoplasmosis and P. carinii pneumonia.
• 6-Substituted 2,4-Diamino-5-methylpyrido[2,3-d]pyrimidines as Inhibitors of Dihydrofolate Reductases from Pneumocystis carinii and Toxoplasma gondii and as Antitumor Agents
  作者：Aleem Gangjee、Anil Vasudevan、Sherry F. Queener、Roy L. Kisliuk

  DOI：10.1021/jm00010a022

  日期：1995.5

  analogues, increasing the size of the N-10 substituent from a methyl group to larger groups resulted in a decrease in selectivity and potency for both P. carinii and T. gondii DHFR. For the dimethoxy-substituted analogues, N-10 methylation in general decreased potency but increased selectivity for T. gondii DHFR. In an attempt to improve the cell penetration of these analogues, the N-10 naphthyl-substituted

  报道了15个6-取代的2，4-二氨基-5-甲基吡啶并[2，3-d]-嘧啶的合成和生物活性。通过修改我们先前报道的程序，可以提高产率合成这些化合物。具体地，合成了在N-10位具有H和CH 3的二甲氧基苯基取代的化合物和具有N-10个乙基，异丙基和炔丙基基团的三甲氧基苯基取代的化合物。这些化合物被评估为卡氏肺孢子虫，弓形虫和大鼠肝脏的二氢叶酸还原酶（DHFR）抑制剂，所选的类似物被评估为弓形虫和培养物中肿瘤细胞生长的抑制剂。与曲美曲塞相比，所有化合物都显示出对弓形虫DHFR的选择性增加（相对于大鼠肝脏DHFR）。通常，对于三甲氧基取代的类似物，将N-10取代基的大小从甲基增加到较大的基团会导致卡氏疟原虫和刚地弓形虫DHFR的选择性和效能降低。对于二甲氧基取代的类似物，N-10甲基化通常会降低效力，但会增加弓形虫DHFR的选择性。为了提高这些类似物的细胞渗透性，还合成了N-10萘基取代的类似物。