6-chloro-3,4-dihydro-4-(phenylethynyl)-4-(trifluoromethyl)-2(1H)-quinazolinone | 214287-66-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 6-chloro-3,4-dihydro-4-(phenylethynyl)-4-(trifluoromethyl)-2(1H)-quinazolinone
• 英文别名: 7-chloro-4-phenylethylnyl-4-trifluoromethyl-3,4-dihydroquinazolin-2-one；(+/-)-6-chloro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone；6-Chloro-4-(phenylethynyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1h)-one；6-chloro-4-(2-phenylethynyl)-4-(trifluoromethyl)-1,3-dihydroquinazolin-2-one
• CAS: 214287-66-8
• 化学式: C₁₇H₁₀ClF₃N₂O
• 分子量: 350.727
• InChiKey: AUCQXBRRUPAGQY-UHFFFAOYSA-N

物化性质

• 熔点：
  104-107 °C
• 沸点：
  435.3±45.0 °C(Predicted)
• 密度：
  1.48±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  41.1
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  1-(2-氨基-5-氯苯基)-2,2,2-三氟乙酮 在 三氟化硼乙醚 作用下， 以 四氢呋喃 、 xylene 为溶剂， 生成 6-chloro-3,4-dihydro-4-(phenylethynyl)-4-(trifluoromethyl)-2(1H)-quinazolinone
  参考文献：
  名称：

  Expanded-Spectrum Nonnucleoside Reverse Transcriptase Inhibitors Inhibit Clinically Relevant Mutant Variants of Human Immunodeficiency Virus Type 1

  摘要：

  摘要：针对鉴定对K103N突变型人类免疫缺陷病毒（HIV）具有增强效力且保持一日一次剂量的药代动力学一致性的扩展谱非核苷类逆转录酶抑制剂的研究项目已经取得成果，发现了4-环丙炔基-4-三氟甲基-3,4-二氢-2(1H)喹唑啉酮DPC 961和DPC 963，以及4-环丙烯基-4-三氟甲基-3,4-二氢-2(1H)喹唑啉酮DPC 082和DPC 083用于临床开发。DPC 961、DPC 963、DPC 082和DPC 083均对野生型病毒、K103N和L100I单突变变种以及许多多种氨基酸替换的HIV-1突变体表现出低纳摩尔级别的效力。这种高度的效力与口服生物利用度高度结合，如在恒河猴和黑猩猩中展示的那样，并且具有可以导致显著药物自由水平的血浆血清蛋白结合。

  DOI：

  10.1128/aac.43.12.2893

文献信息

• Expanded-Spectrum Nonnucleoside Reverse Transcriptase Inhibitors Inhibit Clinically Relevant Mutant Variants of Human Immunodeficiency Virus Type 1
  作者：Jeffrey W. Corbett、Soo S. Ko、James D. Rodgers、Susan Jeffrey、Lee T. Bacheler、Ronald M. Klabe、Sharon Diamond、Chii-Ming Lai、Shelley R. Rabel、Jo Anne Saye、Stephen P. Adams、George L. Trainor、Paul S. Anderson、Susan K. Erickson-Viitanen

  DOI：10.1128/aac.43.12.2893

  日期：1999.12

  A research program targeted toward the identification of expanded-spectrum nonnucleoside reverse transcriptase inhibitors which possess increased potency toward K103N-containing mutant human immunodeficiency virus (HIV) and which maintain pharmacokinetics consistent with once-a-day dosing has resulted in the identification of the 4-cyclopropylalkynyl-4-trifluoromethyl-3,4-dihydro-2(1 H )quinazolinones DPC 961 and DPC 963 and the 4-cyclopropylalkenyl-4-trifluoromethyl-3,4-dihydro-2(1 H )quinazolinones DPC 082 and DPC 083 for clinical development. DPC 961, DPC 963, DPC 082, and DPC 083 all exhibit low-nanomolar potency toward wild-type virus, K103N and L100I single-mutation variants, and many multiply amino acid-substituted HIV type 1 mutants. This high degree of potency is combined with a high degree of oral bioavailability, as demonstrated in rhesus monkeys and chimpanzees, and with plasma serum protein binding that can result in significant free levels of drug.

  摘要：针对鉴定对K103N突变型人类免疫缺陷病毒（HIV）具有增强效力且保持一日一次剂量的药代动力学一致性的扩展谱非核苷类逆转录酶抑制剂的研究项目已经取得成果，发现了4-环丙炔基-4-三氟甲基-3,4-二氢-2(1H)喹唑啉酮DPC 961和DPC 963，以及4-环丙烯基-4-三氟甲基-3,4-二氢-2(1H)喹唑啉酮DPC 082和DPC 083用于临床开发。DPC 961、DPC 963、DPC 082和DPC 083均对野生型病毒、K103N和L100I单突变变种以及许多多种氨基酸替换的HIV-1突变体表现出低纳摩尔级别的效力。这种高度的效力与口服生物利用度高度结合，如在恒河猴和黑猩猩中展示的那样，并且具有可以导致显著药物自由水平的血浆血清蛋白结合。
• Structural and Rate Studies of the 1,2-Additions of Lithium Phenylacetylide to Lithiated Quinazolinones:  Influence of Mixed Aggregates on the Reaction Mechanism
  作者：Timothy F. Briggs、Mark D. Winemiller、David B. Collum、Rodney L. Parsons,、Akin H. Davulcu、Gregory D. Harris、Joseph M. Fortunak、Pat N. Confalone

  DOI：10.1021/ja0305813

  日期：2004.5.1

  The 1,2-addition of lithium phenylacetylide (PhCCLi) to quinazolinones was investigated using a combination of structural and rate studies. (6)Li, (13)C, and (19)F NMR spectroscopies show that deprotonation of quinazolinones and phenylacetylene in THF/pentane solutions with lithium hexamethyldisilazide affords a mixture of lithium quinazolinide/PhCCLi mixed dimer and mixed tetramer along with PhCCLi

  结合结构和速率研究，研究了苯乙炔锂 (PhCCLi) 与喹唑啉酮的 1,2-加成反应。(6)Li、(13)C 和 (19)F NMR 光谱表明，喹唑啉酮和苯乙炔在 THF/戊烷溶液中与六甲基二硅肼锂脱质子化，得到喹唑啉锂/PhCCLi 混合二聚体和混合四聚体与 PhCCLi 二聚体的混合物。尽管混合四聚体在用于结构研究的高混合聚集体浓度和低温下占主导地位，但混合二聚体在低总混合聚集体浓度、高 THF 浓度和用于研究 1,2-加成的环境温度下是主要形式. 使用 (19)F NMR 光谱监测反应速率揭示了对混合二聚体的一级依赖性，对 THF 的零级依赖性，以及对 PhCCLi 浓度的半阶依赖性。速率定律与向混合二聚体中添加溶解的 PhCCLi 单体一致。对 PhCCLi 的 1,2-加成到 O 保护的喹唑啉酮的研究表明通过三溶剂化 PhCCLi 单体进行反应。
• Inhibition of Clinically Relevant Mutant Variants of HIV-1 by Quinazolinone Non-Nucleoside Reverse Transcriptase Inhibitors
  作者：Jeffrey W. Corbett、Soo S. Ko、James D. Rodgers、Lisa A. Gearhart、Nicholas A. Magnus、Lee T. Bacheler、Sharon Diamond、Susan Jeffrey、Ronald M. Klabe、Beverly C. Cordova、Sena Garber、Kelly Logue、George L. Trainor、Paul S. Anderson、Susan K. Erickson-Viitanen

  DOI：10.1021/jm990580e

  日期：2000.5.1

  A series of 4-alkenyl and 4-alkynyl-3,4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones were found to be potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) of human immunodeficiency virus type-1 (HIV-1). The 4-alkenyl-3,4-dihydro-4-(trifluoromethyl) quinazolinones DPC 082 and DPC 083 and the 4-alkynyl-3,4-dihydro-4-(trifluoromethyl) (LK)-quinazolinones DPC 961 and DPC 963 were found to exhibit low nanomolar potency toward wild-type RF virus (IC90 = 2.0, 2.1, 2.0, and 1.3 nM, respectively) and various single and many multiple amino acid substituted HIV-1 mutant viruses.-The increased potency is combined with favorable plasma serum protein binding as demonstrated by improvements in the percent free drug in human plasma when compared to efavirenz: 3.0%, 2.0%, 1.5% 2.8%, and 0.2- 0.5% for DPC 082, DPC 083, DPC 961, DPC 963, and efavirenz, respectively.