2-chloro-4,5-bis(4-methoxyphenyl)-2-(4-methylpiperazin-1-yl)thiazole

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 2-chloro-4,5-bis(4-methoxyphenyl)-2-(4-methylpiperazin-1-yl)thiazole
• 英文别名: 4,5-Bis(4-methoxyphenyl)-2-(4-methylpiperazin-1-yl)thiazole；4,5-bis(4-methoxyphenyl)-2-(4-methylpiperazin-1-yl)-1,3-thiazole
• 化学式: C₂₂H₂₅N₃O₂S
• 分子量: 395.525
• InChiKey: ZIBPFPDJVNOBOW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  66.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  N-甲基哌嗪 、 2-chloro-4,5-bis(4-methoxyphenyl)thiazole 反应 6.0h， 以50.2%的产率得到2-chloro-4,5-bis(4-methoxyphenyl)-2-(4-methylpiperazin-1-yl)thiazole
  参考文献：
  名称：

  Antiplatelet Agents Based on Cyclooxygenase Inhibition without Ulcerogenesis. Evaluation and Synthesis of 4,5-Bis(4-methoxyphenyl)-2-substituted-thiazoles

  摘要：

  The syntheses, biological evaluations, and structure-activity relationships of a series of 4,5-bis-( 4-methoxyphenyl)-2-substituted-thiazoles as potent antiplatelet agents with vasodilatory activity are described. 2-Guanidino-4,5-bis(4-methoxyphenyl) thiazole (3), designed from two parent compounds (itazigrel and timegadine), showed inhibitory activity of malondialdehyde (MDA, IC50 = 31 mu M) production which is formed from the cyclooxygenase (CO)-catalyzed oxygenation of arachidonic acid in the synthesis of prostanoids in platelets, with vasodilatory activity (ED(50) 2.0 mu M). Further structure-activity relationship studies on 3 culminated in the preparation of 4,5-bis(4-methoxyphenyl)-2-[(1-methylpiperazin-4-yl)carbonyl] thiazole (10a, FR122047) which exhibited potent inhibitory activity on MDA synthesis in vitro (IC50 = 0.088 mu M) and platelet aggregation in guinea pigs ex vivo (100% inhibition even 6 h after 1.0 mg/kg administration) with vasodilatory activity in vitro (ED(50) = 6.2 mu M). Moreover, 10a demonstrated no ulcerogenesis effect in rats even at 100 mg/kg dosage (safety margin in rats is more than 70 while that of aspirin is only 1.2) in spite of its potent CO inhibition (IC50 = 0.43 mu M(14)), while the use of aspirin, a CO inhibitor and the most popular thromboembolic drug, is restricted by the side effect.(8) Pharmacokinetic studies on 10a have revealed that 10a is detectable in platelet-rich plasma but not in platelet-poor plasma 1 day after oral administration, which indicates that 10a tends to be localized in platelets. This property could be responsible for its low toxicity and reduction of side effects in clinical studies.

  DOI：

  10.1021/jm00034a017

文献信息

• Thiazole compounds, processes for the preparation thereof, and pharmaceutical composition comprising the same
  申请人：FUJISAWA PHARMACEUTICAL CO., LTD.

  公开号：EP0377457A1

  公开（公告）日：1990-07-11

  The present invention relates to new thiazole compounds and pharmaceutically acceptable salts thereof which have pharmacological activities, processes for preparation thereof, a pharmaceutical composition comprising the same same and a use of the same.

  本发明涉及具有药理活性的新噻唑化合物及其药学上可接受的盐、其制备工艺、包含相同物质的药物组合物以及相同物质的用途。
• US5217971A
  申请人：——

  公开号：US5217971A

  公开（公告）日：1993-06-08
• Antiplatelet Agents Based on Cyclooxygenase Inhibition without Ulcerogenesis. Evaluation and Synthesis of 4,5-Bis(4-methoxyphenyl)-2-substituted-thiazoles
  作者：Akito Tanaka、Hiroyoshi Sakai、Yukio Motoyama、Takatoshi Ishikawa、Hisashi Takasugi

  DOI：10.1021/jm00034a017

  日期：1994.4

  The syntheses, biological evaluations, and structure-activity relationships of a series of 4,5-bis-( 4-methoxyphenyl)-2-substituted-thiazoles as potent antiplatelet agents with vasodilatory activity are described. 2-Guanidino-4,5-bis(4-methoxyphenyl) thiazole (3), designed from two parent compounds (itazigrel and timegadine), showed inhibitory activity of malondialdehyde (MDA, IC50 = 31 mu M) production which is formed from the cyclooxygenase (CO)-catalyzed oxygenation of arachidonic acid in the synthesis of prostanoids in platelets, with vasodilatory activity (ED(50) 2.0 mu M). Further structure-activity relationship studies on 3 culminated in the preparation of 4,5-bis(4-methoxyphenyl)-2-[(1-methylpiperazin-4-yl)carbonyl] thiazole (10a, FR122047) which exhibited potent inhibitory activity on MDA synthesis in vitro (IC50 = 0.088 mu M) and platelet aggregation in guinea pigs ex vivo (100% inhibition even 6 h after 1.0 mg/kg administration) with vasodilatory activity in vitro (ED(50) = 6.2 mu M). Moreover, 10a demonstrated no ulcerogenesis effect in rats even at 100 mg/kg dosage (safety margin in rats is more than 70 while that of aspirin is only 1.2) in spite of its potent CO inhibition (IC50 = 0.43 mu M(14)), while the use of aspirin, a CO inhibitor and the most popular thromboembolic drug, is restricted by the side effect.(8) Pharmacokinetic studies on 10a have revealed that 10a is detectable in platelet-rich plasma but not in platelet-poor plasma 1 day after oral administration, which indicates that 10a tends to be localized in platelets. This property could be responsible for its low toxicity and reduction of side effects in clinical studies.