6-[2-(3,4,5-Trimethoxyphenyl)vinyl]pyridino[2,3-d]pyrimidine-2,4-diamine | 186414-88-0

• 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-(3,4,5-Trimethoxyphenyl)vinyl]pyridino[2,3-d]pyrimidine-2,4-diamine
• 英文别名: 6-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]pyrido[2,3-d]pyrimidine-2,4-diamine
• CAS: 186414-88-0
• 化学式: C₁₈H₁₉N₅O₃
• 分子量: 353.381
• InChiKey: CUPAUTLMZBTYGL-SNAWJCMRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  118
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  三氟乙酸 、 6-[2-(3,4,5-Trimethoxyphenyl)vinyl]pyridino[2,3-d]pyrimidine-2,4-diamine 在 palladium on activated charcoal 氢气 作用下， 以 甲醇 为溶剂， 反应 24.0h， 以59%的产率得到(+/-)-2,4-diamino-6-[2-(3',4',5'-trimethoxyphenyl)ethyl]-5,6,7,8-tetrahydro-8H-pyrido[2,3-d]pyrimidine trifluoroacetate salt
  参考文献：
  名称：

  Synthesis and Dihydrofolate Reductase Inhibitory Activities of 2,4-Diamino-5-deaza and 2,4-Diamino-5,10-dideaza Lipophilic Antifolates

  摘要：

  Two series of nonclassical antifolates (2,4-diamino-5-deaza compounds 2-5 and 5,10-dideaza compounds 6-13) were synthesized as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (pc) and Toxoplasma gondii (tg) organisms that are responsible for fatal opportunistic infections in AIDS patients. Rat liver (rl) DHFR served as the mammalian reference enzyme to determine selectivity. Syntheses of the target 5-deaza compounds were achieved by initial construction of the pivaloyl-protected 2,4-diamino-6-bromopyrido[2,3-d]-pyrimidine 17 via a cyclocondensation of 2,4,6-triaminopyrimidine with bromomalonaldehyde. Sequential Heck coupling of 17 with styrene followed by ozonolysis afforded the g-formyl derivative 19. Reductive amination of 19 with 3,4,5-trimethoxyaniline afforded the N10-H analog. The NIO-Me and NIO-Et analogs were synthesized by nucleophilic displacement of the 6-bromomethyl derivative 22 (obtained from the g-formyl derivative 19 by reduction and bromination) with the appropriate N-alkylaniline. The trans-5,10-dideaza analogs 6-8 were synthesized via a Heck coupling of the appropriate methoxystyrene with 17, and selective reduction of the resulting 9,10-double bond afforded target compounds 9-11. Further reduction to the tetrahydro derivatives afforded analogs 12 and 13. The 5-deaza NIO-Me 3,4,5-trimethoxy analog 3 maintained the best balance of potency and selectivity against both tgDHFR and pcDHFR. Compared to trimethoprim, compound 3 was only slightly less selective but was 300-fold more potent against tgDHFR. The 5,10-dideaza analogs were generally less potent and selective than the 5-deaza compounds.

  DOI：

  10.1021/jm9606913
• 作为产物：
  描述：

  2,4-bis(pivaloylamino)-6-bromopyrido<2,3-d>pyrimidine 在 palladium diacetate 、 copper(l) iodide 、 氨 、 三乙胺 、 三(邻甲基苯基)磷 作用下， 以 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 120.0h， 生成 6-[2-(3,4,5-Trimethoxyphenyl)vinyl]pyridino[2,3-d]pyrimidine-2,4-diamine
  参考文献：
  名称：

  Synthesis and Dihydrofolate Reductase Inhibitory Activities of 2,4-Diamino-5-deaza and 2,4-Diamino-5,10-dideaza Lipophilic Antifolates

  摘要：

  Two series of nonclassical antifolates (2,4-diamino-5-deaza compounds 2-5 and 5,10-dideaza compounds 6-13) were synthesized as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (pc) and Toxoplasma gondii (tg) organisms that are responsible for fatal opportunistic infections in AIDS patients. Rat liver (rl) DHFR served as the mammalian reference enzyme to determine selectivity. Syntheses of the target 5-deaza compounds were achieved by initial construction of the pivaloyl-protected 2,4-diamino-6-bromopyrido[2,3-d]-pyrimidine 17 via a cyclocondensation of 2,4,6-triaminopyrimidine with bromomalonaldehyde. Sequential Heck coupling of 17 with styrene followed by ozonolysis afforded the g-formyl derivative 19. Reductive amination of 19 with 3,4,5-trimethoxyaniline afforded the N10-H analog. The NIO-Me and NIO-Et analogs were synthesized by nucleophilic displacement of the 6-bromomethyl derivative 22 (obtained from the g-formyl derivative 19 by reduction and bromination) with the appropriate N-alkylaniline. The trans-5,10-dideaza analogs 6-8 were synthesized via a Heck coupling of the appropriate methoxystyrene with 17, and selective reduction of the resulting 9,10-double bond afforded target compounds 9-11. Further reduction to the tetrahydro derivatives afforded analogs 12 and 13. The 5-deaza NIO-Me 3,4,5-trimethoxy analog 3 maintained the best balance of potency and selectivity against both tgDHFR and pcDHFR. Compared to trimethoprim, compound 3 was only slightly less selective but was 300-fold more potent against tgDHFR. The 5,10-dideaza analogs were generally less potent and selective than the 5-deaza compounds.

  DOI：

  10.1021/jm9606913

文献信息

• Synthesis and Dihydrofolate Reductase Inhibitory Activities of 2,4-Diamino-5-deaza and 2,4-Diamino-5,10-dideaza Lipophilic Antifolates
  作者：Aleem Gangjee、Rajesh Devraj、Sherry F. Queener

  DOI：10.1021/jm9606913

  日期：1997.2.1

  Two series of nonclassical antifolates (2,4-diamino-5-deaza compounds 2-5 and 5,10-dideaza compounds 6-13) were synthesized as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (pc) and Toxoplasma gondii (tg) organisms that are responsible for fatal opportunistic infections in AIDS patients. Rat liver (rl) DHFR served as the mammalian reference enzyme to determine selectivity. Syntheses of the target 5-deaza compounds were achieved by initial construction of the pivaloyl-protected 2,4-diamino-6-bromopyrido[2,3-d]-pyrimidine 17 via a cyclocondensation of 2,4,6-triaminopyrimidine with bromomalonaldehyde. Sequential Heck coupling of 17 with styrene followed by ozonolysis afforded the g-formyl derivative 19. Reductive amination of 19 with 3,4,5-trimethoxyaniline afforded the N10-H analog. The NIO-Me and NIO-Et analogs were synthesized by nucleophilic displacement of the 6-bromomethyl derivative 22 (obtained from the g-formyl derivative 19 by reduction and bromination) with the appropriate N-alkylaniline. The trans-5,10-dideaza analogs 6-8 were synthesized via a Heck coupling of the appropriate methoxystyrene with 17, and selective reduction of the resulting 9,10-double bond afforded target compounds 9-11. Further reduction to the tetrahydro derivatives afforded analogs 12 and 13. The 5-deaza NIO-Me 3,4,5-trimethoxy analog 3 maintained the best balance of potency and selectivity against both tgDHFR and pcDHFR. Compared to trimethoprim, compound 3 was only slightly less selective but was 300-fold more potent against tgDHFR. The 5,10-dideaza analogs were generally less potent and selective than the 5-deaza compounds.