(+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N-hydroxyureidyl)methylphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: (+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N-hydroxyureidyl)methylphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran
• 英文别名: 3-[[2-[2-(4-chlorophenyl)sulfanylethoxy]-3-methoxy-5-[(2S,5S)-5-(3,4,5-trimethoxyphenyl)oxolan-2-yl]phenyl]methyl]-1-hydroxy-1-methylurea
• 化学式: C₃₁H₃₇ClN₂O₈S
• 分子量: 633.162
• InChiKey: LZVBMKDVEPGGFK-DQEYMECFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  43
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  133
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  5-碘香兰素 在 sodium tetrahydroborate 、 三氟化硼乙醚 、 3-苄基羟乙基甲基噻唑氯化锂 、 sodium hydride 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 氯仿 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 79.0h， 生成 (+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N-hydroxyureidyl)methylphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran
  参考文献：
  名称：

  (±)-trans-2-[3-Methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N- hydroxyureidyl)methylphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (CMI-392), a Potent Dual 5-Lipoxygenase Inhibitor and Platelet-Activating Factor Receptor Antagonist

  摘要：

  By incorporating an N-hydroxyurea functionality onto diaryltetrahydrofurans, a novel series of compounds was investigated as dual 5-lipoxygenese (5-LO) inhibitor and platelet-activating factor (PAF) receptor antagonist. These dual functional compounds were evaluated in vitro for 5-LO inhibition in RBL cell extracts and human whole blood, and PAF receptor antagonism in a receptor binding assay. PAF-induced hemoconcentration and arachidonic acid-and TPA-induced ear edema in mice were used to determine in vivo activities. The structure-activity relationship analysis to define a preclinical lead is presented. (+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N-hydroxyureidyl)methylphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (40, CMI-392) was selected for further study. In the arachidonic acid-induced mouse ear edema model, 40 was more potent than either zileuton (a 5-LO inhibitor) or BN 50739 (a PAF receptor antagonist), and it demonstrated the same inhibitory effect as a physical combination of the latter two agents. These results suggest that a single compound which both inhibits leukotriene synthesis and blocks PAF receptor binding may provide therapeutic advantages over single-acting agents. The clinical development of compound 40 is in progress.

  DOI：

  10.1021/jm980046r

文献信息

• PHARMACEUTICAL FORMULATIONS USEFUL TO TREAT INFLAMMATORY AND IMMUNE DISORDERS
  申请人：——

  公开号：US20030008914A1

  公开（公告）日：2003-01-09

  A pharmaceutical formulation is provided for the treatment of inflammatory and/or immune disorders, particularly those mediated by platelet activating factor (“PAF”) or a product of 5-lipoxygenase. The formulation, in one embodiment, is an essentially anhydrous ointment containing an active agent selected from the group consisting of 2,5-diaryl tetrahydrofurans, 2,5-diaryl tetrahydrothiophenes, 2,4-diaryl tetrahydrofurans, 2,4-diaryl tetrahydrothiophenes, 1,3-diaryl cyclopentanes, 2,4-diaryl pyrrolidines, and 2,5-diaryl pyrrolidines, and an enhancer composition containing one or more C 3-18 esters such as diethyl succinate, propylene carbonate, diisopropyl adipate and glyceryl triacetate. In another embodiment, the formulation is a cream, gel, lotion, oil, or the like, containing the: active agent in crystalline form. The invention also encompasses the novel crystalline form of the active agent, and methods for using the formulations to treat individuals with inflammatory and/or immune disorders. Also encompassed is use of isopropyl alcohol (IPA) to enhance stability of the active agent and pharmaceutical formulations.

  提供了一种用于治疗炎症和/或免疫性疾病的药物配方，特别是那些通过血小板活化因子（“PAF”）或5-脂氧合酶产物介导的疾病。在一种实施例中，该配方是一种基本无水的软膏，含有从以下组中选择的活性剂：2,5-二芳基四氢呋喃，2,5-二芳基四氢噻吩，2,4-二芳基四氢呋喃，2,4-二芳基四氢噻吩，1,3-二芳基环戊烷，2,4-二芳基吡咯烷和2,5-二芳基吡咯烷，以及一种增强剂组合物，其中包含一种或多种C3-18酯，例如琥珀酸二乙酯，丙烯酸三元醇酯，己二酸二异丙酯和三乙酰甘油酯。在另一种实施例中，该配方是一种含有晶体形式的活性剂的乳霜、凝胶、润肤液、油剂或类似物。该发明还包括活性剂的新晶体形式，以及使用该配方治疗具有炎症和/或免疫性疾病的个体的方法。该发明还包括使用异丙醇（IPA）增强活性剂和制药配方的稳定性。
• Ram; Balram; Ram, S. Raghu, Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2003, vol. 42, # 9, p. 2063 - 2068
  作者：Ram、Balram、Ram, S. Raghu

  DOI：——

  日期：——
• (±)-<i>trans</i>-2-[3-Methoxy-4-(4-chlorophenylthioethoxy)-5-(<i>N</i>-methyl-<i>N</i>- hydroxyureidyl)methylphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (CMI-392), a Potent Dual 5-Lipoxygenase Inhibitor and Platelet-Activating Factor Receptor Antagonist
  作者：Xiong Cai、Ralph T. Scannell、David Yaeger、Md. Sajjat Hussoin、David B. Killian、Changgeng Qian、Joseph Eckman、San-Bao Hwang、Lynn Libertine-Garahan、C. Grace Yeh、Stephen H. Ip、T. Y. Shen

  DOI：10.1021/jm980046r

  日期：1998.5.1

  By incorporating an N-hydroxyurea functionality onto diaryltetrahydrofurans, a novel series of compounds was investigated as dual 5-lipoxygenese (5-LO) inhibitor and platelet-activating factor (PAF) receptor antagonist. These dual functional compounds were evaluated in vitro for 5-LO inhibition in RBL cell extracts and human whole blood, and PAF receptor antagonism in a receptor binding assay. PAF-induced hemoconcentration and arachidonic acid-and TPA-induced ear edema in mice were used to determine in vivo activities. The structure-activity relationship analysis to define a preclinical lead is presented. (+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N-hydroxyureidyl)methylphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (40, CMI-392) was selected for further study. In the arachidonic acid-induced mouse ear edema model, 40 was more potent than either zileuton (a 5-LO inhibitor) or BN 50739 (a PAF receptor antagonist), and it demonstrated the same inhibitory effect as a physical combination of the latter two agents. These results suggest that a single compound which both inhibits leukotriene synthesis and blocks PAF receptor binding may provide therapeutic advantages over single-acting agents. The clinical development of compound 40 is in progress.