7-chloro-2-(1,1-difluoroethyl)-5-methyl[1,2,4]triazolo[1,5-a] pyrimidine | 1281860-67-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 三唑并嘧啶类
• 英文名称: 7-chloro-2-(1,1-difluoroethyl)-5-methyl[1,2,4]triazolo[1,5-a] pyrimidine
• 英文别名: 7-chloro-2-(1,1-difluoroethyl)-5-methyl[1,2,4]triazolo[1,5-a]pyrimidine；7-Chloro-2-(1,1-difluoroethyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine
• CAS: 1281860-67-0
• 化学式: C₈H₇ClF₂N₄
• 分子量: 232.62
• InChiKey: VPYFEHOXUIAQFS-UHFFFAOYSA-N

物化性质

• 密度：
  1.57±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  43.1
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-氨基茚 、 7-chloro-2-(1,1-difluoroethyl)-5-methyl[1,2,4]triazolo[1,5-a] pyrimidine 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以85%的产率得到2-(1,1-difluoroethyl)-N-(2,3-dihydro-1H-inden-2-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine
  参考文献：
  名称：

  Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity

  摘要：

  Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor I (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen.

  DOI：

  10.1021/acs.jmedchem.6b00275
• 作为产物：
  描述：

  2,3-Diamino-6-methyl-4(3H)-pyrimidinone 在 sodium ethanolate 、 三氯氧磷 作用下， 反应 5.0h， 生成 7-chloro-2-(1,1-difluoroethyl)-5-methyl[1,2,4]triazolo[1,5-a] pyrimidine
  参考文献：
  名称：

  NEW SUBSTITUTED TRIAZOLOPYRIMIDINES AS ANTI-MALARIAL AGENTS

  摘要：

  本发明涉及三唑吡咯嘧啶衍生物在制造用于预防或治疗疟疾的药物方面的用途。具体而言，本发明涉及三唑吡咯嘧啶衍生物，用于制备用于抑制疟原虫增殖的药物配方。

  公开号：

  EP3072894A1

文献信息

• [EN] NEW SUBSTITUTED TRIAZOLOPYRIMIDINES AS ANTI-MALARIAL AGENTS<br/>[FR] NOUVELLES TRIAZOLOPYRIMIDINES SUBSTITUÉES UTILISÉES COMME AGENTS ANTI-PALUDISME
  申请人：UNIV TEXAS

  公开号：WO2016151521A1

  公开（公告）日：2016-09-29

  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.

  本发明涉及三唑嘧啶衍生物在制造用于预防或治疗疟疾的药物中的应用。具体而言，本发明涉及三唑嘧啶衍生物，其可用于制备药物配方，以抑制疟原虫的增殖。
• 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.

  抑制寄生性二氢乳酸脱氢酶酶（DHOD）的酶抑制剂是治疗疟疾的候选药物。这种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：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。
• [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
• Structure-Guided Lead Optimization of Triazolopyrimidine-Ring Substituents Identifies Potent <i>Plasmodium falciparum</i> Dihydroorotate Dehydrogenase Inhibitors with Clinical Candidate Potential
  作者：Jose M. Coteron、María Marco、Jorge Esquivias、Xiaoyi Deng、Karen L. White、John White、Maria Koltun、Farah El Mazouni、Sreekanth Kokkonda、Kasiram Katneni、Ravi Bhamidipati、David M. Shackleford、Iñigo Angulo-Barturen、Santiago B. Ferrer、María Belén Jiménez-Díaz、Francisco-Javier Gamo、Elizabeth J. Goldsmith、William N. Charman、Ian Bathurst、David Floyd、David Matthews、Jeremy N. Burrows、Pradipsinh K. Rathod、Susan A. Charman、Margaret A. Phillips

  DOI：10.1021/jm200592f

  日期：2011.8.11

  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.