1-(3-methoxy-4-hydroxyethoxy-5-iodophenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione | 154544-30-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-(3-methoxy-4-hydroxyethoxy-5-iodophenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione
• 英文别名: 1-[4-(2-hydroxyethoxy)-3-iodo-5-methoxyphenyl]-4-(3,4,5-trimethoxyphenyl)butane-1,4-dione
• CAS: 154544-30-6
• 化学式: C₂₂H₂₅IO₈
• 分子量: 544.34
• InChiKey: DWOKTSXOJGXCQJ-UHFFFAOYSA-N

物化性质

• 沸点：
  671.0±55.0 °C(Predicted)
• 密度：
  1.473±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  31
• 可旋转键数：
  12
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  101
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  1-(3-methoxy-4-hydroxyethoxy-5-iodophenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione 在 sodium tetrahydroborate 、 三氟化硼乙醚 、 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 40.5h， 生成 [2-[2-(4-chlorophenyl)sulfanylethoxy]-3-methoxy-5-[(2S,5S)-5-(3,4,5-trimethoxyphenyl)oxolan-2-yl]phenyl]methanamine
  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
• 作为产物：
  描述：

  5-碘香兰素 在 3-苄基羟乙基甲基噻唑氯化锂 、 sodium hydride 、 三乙胺 作用下， 反应 36.5h， 生成 1-(3-methoxy-4-hydroxyethoxy-5-iodophenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione
  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/或免疫紊乱的制药配方，特别是那些由血小板活化因子（“PAF”）或5-脂氧合酶产物介导的疾病。在一个实施例中，该配方是一种基本无水的软膏，含有从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2,5-二芳基吡咯烷等化合物组成的活性剂，以及一个增效剂组合，其中包含一个或多个C3-18酯，如琥珀酸二乙酯、碳酸丙二酯、己二酸二异丙酯和三乙酰甘油。在另一个实施例中，该配方是一种乳霜、凝胶、乳液、油剂等，含有晶体形式的活性剂。该发明还涵盖了该活性剂的新晶体形式，以及使用这些配方治疗患有炎症和/或免疫紊乱的个体的方法。还包括异丙醇（IPA）用于增强活性剂和制药配方的稳定性。
• Compounds and methods for the treatment of inflammatory and immune disorders
  申请人：——

  公开号：US20020177723A1

  公开（公告）日：2002-11-28

  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 are disclosed that reduce the chemotaxis and respiratory burst leading to the formation of damaging oxygen radicals of polymorphonuclear leukocytes during an inflammatory or immune response. The compounds exhibit this biological activity by acting as PAF receptor antagonists, by inhibiting the enzyme 5-lipoxygenase, or by exhibiting dual activity, i. e., by acting as both a PAF receptor antagonist and inhibitor of 5-lipoxygenase. A method to treat disorders mediated by PAF or leukotrienes is also disclosed, that includes administering an effective amount of one or more of the above-identified compounds or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

  本文披露了以下化合物：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，这些化合物可以减少多形核白细胞在炎症或免疫反应中的趋化和呼吸爆发，从而减少有害氧自由基的形成。这些化合物通过作为PAF受体拮抗剂、抑制5-脂氧合酶酶或表现出双重活性即同时作为PAF受体拮抗剂和5-脂氧合酶抑制剂来表现出这种生物活性。本文还披露了一种治疗PAF或白三烯介导的疾病的方法，包括在药学上可接受的载体中投与上述化合物或其药学上可接受的盐的有效量。
• Compounds and methods for the treatment of cardiovascular, inflammatory
  申请人：Cytomed, Inc.

  公开号：US05463083A1

  公开（公告）日：1995-10-31

  2,5-Diaryl tetrahydrofurans, 2,5-diaryl tetrahydrothiophenes, 1,3-diaryl cyclopentanes are disclosed that reduce the chemotaxis and respiratory burst leading to the formation of damaging oxygen radicals of polymorphonuclear leukocytes during an inflammatory or immune response. The compounds exhibit this biological activity by acting as PAF receptor antagonists, by inhibiting the enzyme 5-lipoxygenase, or by exhibiting dual activity, i,e., by acting as both a PAF receptor antagonist and inhibitor of 5-lipoxygenase. Also disclosed is a method to treat disorders mediated by PAF and/or leukotrienes that includes administering an effective amount of one or more of the above-identified compounds or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, to a patient in need of such therapy.

  本文披露了2,5-二芳基四氢呋喃、2,5-二芳基四氢噻吩、1,3-二芳基环戊烷等化合物，可通过作为PAF受体拮抗剂、抑制5-脂氧合酶酶或表现出双重活性（即作为PAF受体拮抗剂和5-脂氧合酶抑制剂）的方式，减少中性粒细胞在炎症或免疫反应中的趋化和呼吸爆发，从而防止有害氧自由基的形成。此外，本文还揭示了一种治疗PAF和/或白三烯介导疾病的方法，包括向需要该疗法的患者投予上述化合物或其药学上可接受的盐的有效量，可选配以药学上可接受的载体。
• Compounds and methods for the treatment of inflammatory and immune
  申请人：CytoMed, Inc.

  公开号：US05648486A1

  公开（公告）日：1997-07-15

  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 are disclosed that reduce the chemotaxis and respiratory burst leading to the formation of damaging oxygen radicals of polymorphonuclear leukocytes during an inflammatory or immune response. The compounds exhibit this biological activity by acting as PAF receptor antagonists, by inhibiting the enzyme 5-lipoxygenase, or by exhibiting dual activity, i.e., by acting as both a PAF receptor antagonist and inhibitor of 5-lipoxygenase. A method to treat disorders mediated by PAF or leukotrienes is also disclosed, that includes administering an effective amount of one or more of the above-identified compounds or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

  本发明揭示了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2,5-二芳基吡咯烷等化合物，它们能够减少在炎症或免疫反应期间多形核白细胞的趋化和呼吸爆发，从而降低有害氧自由基的生成。这些化合物通过作为PAF受体拮抗剂、抑制5-脂氧合酶酶或表现出双重活性，即既作为PAF受体拮抗剂又作为5-脂氧合酶的抑制剂来展示这种生物活性。本发明还揭示了一种治疗由PAF或白三烯介导的疾病的方法，该方法包括在药学上可接受的载体中投给上述任意一种或多种化合物或其药学上可接受的盐的有效量。
• Compounds and methods for the treatment of cardiovascular inflammatory
  申请人：Cytomed, Inc.

  公开号：US05741809A1

  公开（公告）日：1998-04-21

  2,5-Diaryl tetrahydrofurans, 2,5-diaryl tetrahydrothiophenes, 1,3-diaryl cyclopentanes are disclosed that reduce the chemotaxis and respiratory burst leading to the formation of damaging oxygen radicals of polymorphonuclear leukocytes during an inflammatory or immune response. The compounds exhibit this biological activity by acting as PAF receptor antagonists, by inhibiting the enzyme 5-lipoxygenase, or by exhibiting dual activity, i.e., by acting as both a PAF receptor antagonist and inhibitor of 5-lipoxygenase. Also disclosed is a method to treat disorders mediated by PAF and/or leukotrienes that includes administering an effective amount of one or more of the above-identified compounds or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, to a patient in need of such therapy.

  本文披露了2,5-二芳基四氢呋喃、2,5-二芳基四氢噻吩、1,3-二芳基环戊烷等化合物，可减少炎症或免疫反应期间多形核白细胞的趋化和呼吸爆发，从而减少有害氧自由基的形成。这些化合物通过作为PAF受体拮抗剂、抑制5-脂氧合酶酶或表现出双重活性，即作为PAF受体拮抗剂和5-脂氧合酶抑制剂来表现出这种生物活性。本文还披露了一种治疗PAF和/或白三烯介导的疾病的方法，包括向需要这种治疗的患者施用上述化合物或其药学上可接受的盐的有效量，可选择在药学上可接受的载体中施用。