6-[(3,4,5-Trimethoxyanilino)methyl]pyrido[2,3-d]pyrimidine-2,4-diamine | 174655-08-4

• 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-[(3,4,5-Trimethoxyanilino)methyl]pyrido[2,3-d]pyrimidine-2,4-diamine
• CAS: 174655-08-4
• 化学式: C₁₇H₂₀N₆O₃
• 分子量: 356.384
• InChiKey: NBXFVGDELMEKSA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  130
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  甲酸 、 6-[(3,4,5-Trimethoxyanilino)methyl]pyrido[2,3-d]pyrimidine-2,4-diamine 在 乙酸酐 作用下， 反应 48.0h， 以86%的产率得到N-(2,4-Diamino-pyrido[2,3-d]pyrimidin-6-ylmethyl)-N-(3,4,5-trimethoxy-phenyl)-formamide
  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 、 三乙胺-硼烷 、 sodium methylate 、 臭氧 、 溶剂黄146 、 三乙胺 、 三(邻甲基苯基)磷 作用下， 以 甲醇 、 二氯甲烷 、 溶剂黄146 、 乙腈 为溶剂， 反应 106.0h， 生成 6-[(3,4,5-Trimethoxyanilino)methyl]pyrido[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

• Antimycobacterial Activities of 2,4-Diamino-5-Deazapteridine Derivatives and Effects on Mycobacterial Dihydrofolate Reductase
  作者：William J. Suling、Lainne E. Seitz、Vibha Pathak、Louise Westbrook、Esther W. Barrow、Sabrina Zywno-van-Ginkel、Robert C. Reynolds、J. Robert Piper、William W. Barrow

  DOI：10.1128/aac.44.10.2784-2793.2000

  日期：2000.10

  were active against MAC NJ168 at concentrations of < or =13 microg/ml. Depending on the MAC strain used, 81 to 87% had MICs of < or =1.3 microg/ml. Twenty-one derivatives were >100-fold more active against MAC rDHFR than against human rDHFR. In general, selectivity was dependent on the composition of the two-atom bridge at position 6 and the attached aryl group with substitutions at the 2' and 5' positions

  开发用于鸟分枝杆菌复合体 (MAC) 感染的新抗分枝杆菌药物对于同时感染人类免疫缺陷病毒的人来说尤其重要。本研究的目的是评估 2, 4-diamino-5-methyl-5-deazapteridines (DMDPs) 对 MAC 的体外活性，并评估它们对 MAC 二氢叶酸还原酶重组酶 (rDHFR) 的活性。最初评估了 77 种 DMDP 衍生物对一到三株 MAC（NJ168、NJ211 和/或 NJ3404）的体外活性。用 10 倍稀释的药物和比色法（Alamar Blue）微量稀释肉汤测定法测定 MIC。还确定了 MAC rDHFR 50% 抑制浓度与人 rDHFR 的抑制浓度。蝶啶部分第 5 位的取代基包括 -CH(3)、-CH(2)CH(3) 和 -CH(2)OCH(3) 基团。此外，不同的取代和未取代的芳基通过 -CH(2)NH、-CH(2)N(CH(3))、-CH(2)CH(2)
• US5508281A
  申请人：——

  公开号：US5508281A

  公开（公告）日：1996-04-16
• US6114339A
  申请人：——

  公开号：US6114339A

  公开（公告）日：2000-09-05
• 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.