2-(1,1-difluoroethyl)-5-methyl-N-[4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine | 1281861-06-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-(1,1-difluoroethyl)-5-methyl-N-[4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine
• 英文别名: 2-(1,1-difluoroethyl)-5-methyl-N-[4-(trifluoromethyl)phenyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine；DSM267
• CAS: 1281861-06-0
• 化学式: C₁₅H₁₂F₅N₅
• 分子量: 357.286
• InChiKey: CUCVTDOXQYMYKL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  55.1
• 氢给体数：
  1
• 氢受体数：
  9

制备方法与用途

一种有效的选择性恶性疟原虫二氢乳清酸脱氢酶(PfDHODH)抑制剂，其IC50值为53 nM；该化合物不抑制人体酶，并且对Pf 3D7的EC50值为14 nM。与DSM265相比，它具有更好的药物样特性和物种选择性，同时保持了良好的功效和药代动力学特性。已完成寄生虫感染一期临床试验。

反应信息

• 作为产物：
  描述：

  2,3-Diamino-6-methyl-4(3H)-pyrimidinone 在 sodium ethanolate 、 三氯氧磷 作用下， 以 乙醇 为溶剂， 反应 1.5h， 生成 2-(1,1-difluoroethyl)-5-methyl-N-[4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine
  参考文献：
  名称：

  Structure-Guided Lead Optimization of Triazolopyrimidine-Ring Substituents Identifies Potent Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors with Clinical Candidate Potential

  摘要：

  Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chemistry program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compound has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmaco-kinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compound toward clinical candidate status.

  DOI：

  10.1021/jm200592f

文献信息

• NEW SUBSTITUTED TRIAZOLOPYRIMIDINES AS ANTI-MALARIAL AGENTS
  申请人：BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM

  公开号：US20180065968A1

  公开（公告）日：2018-03-08

  The present invention is related to a use of triazolopyrimidine derivatives in the manufacture of a medicament for preventing or treating malaria. Specifically, the present invention is related to triazolopyrimidine derivatives useful for the preparation of a pharmaceutical formulation for the inhibition of malaria parasite proliferation.

  本发明涉及在制造预防或治疗疟疾药物中使用三唑嘧啶衍生物的用途。具体而言，本发明涉及用于制备药物配方以抑制疟原虫增殖的三唑嘧啶衍生物。
• Method of Using PI3K and MEK Modulators
  申请人：Aftab Dana T.

  公开号：US20120302545A1

  公开（公告）日：2012-11-29

  The invention provides methods of treating cancer with a combination of compounds which inhibit kinases, more specifically MEK and PI3K.

  该发明提供了一种使用抑制激酶的化合物组合治疗癌症的方法，更具体地说是MEK和PI3K。
• ANTIMALARIAL AGENTS THAT ARE INHIBITORS OF DIHYDROOROTATE DEHYDROGENASE
  申请人：Rathod Pradipsinh K.

  公开号：US20120302586A1

  公开（公告）日：2012-11-29

  Inhibitors of parasitic dihydroorotate dehydrogenase enzyme (DHOD) are candidate therapeutics for treating malaria. Illustrative of such therapeutic agents include the compound: and a triazolopyrimidine class of compounds that conform to Formula IX: and their solvates, stereoisomers, tautomers and pharmaceutically acceptable salts.

  抑制寄生虫脱氢酶酶（DHOD）的药物是治疗疟疾的候选治疗药物。这类治疗药物的例子包括化合物：以及符合公式IX的三唑嘧啶类化合物及其溶剂化物、立体异构体、互变异构体和药学上可接受的盐。
• Antimalarial agents that are inhibitors of dihydroorotate dehydrogenase
  申请人：Rathod Pradipsinh K.

  公开号：US09238653B2

  公开（公告）日：2016-01-19

  Inhibitors of parasitic dihydroorotate dehydrogenase enzyme (DHOD) are candidate therapeutics for treating malaria. Illustrative of such therapeutic agents include the compound: and a triazolopyrimidine class of compounds that conform to Formula IX: and their solvates, stereoisomers, tautomers and pharmaceutically acceptable salts.

  寄生性二氢乳酸脱氢酶酶（DHOD）的抑制剂是治疗疟疾的候选治疗药物。这种治疗剂的例子包括化合物：以及符合公式IX的三唑嘧啶类化合物：以及它们的溶剂化物、立体异构体、互变异构体和药学上可接受的盐。
• [EN] ANTIMALARIAL AGENTS THAT ARE INHIBITORS OF DIHYDROOROTATE DEHYDROGENASE<br/>[FR] AGENTS ANTIPALUDIQUES INHIBITEURS DE LA DIHYDRO-OROTATE DÉSHYDROGÉNASE
  申请人：UNIV TEXAS

  公开号：WO2011041304A3

  公开（公告）日：2011-08-04