8-Methoxy-3-[4-(2-methyl-3-phenyl-allyl)-piperazin-1-ylmethyl]-3a, 4-dihydro-3H-chromeno[4,3-c]isoxazole-7-carboxylic acid ethylamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: 8-Methoxy-3-[4-(2-methyl-3-phenyl-allyl)-piperazin-1-ylmethyl]-3a, 4-dihydro-3H-chromeno[4,3-c]isoxazole-7-carboxylic acid ethylamide
• 英文别名: N-ethyl-8-methoxy-3-[[4-[(E)-2-methyl-3-phenylprop-2-enyl]piperazin-1-yl]methyl]-3a,4-dihydro-3H-chromeno[4,3-c][1,2]oxazole-7-carboxamide
• 化学式: C₂₉H₃₆N₄O₄
• 分子量: 504.629
• InChiKey: LDHSQSUKPUMHKQ-XSFVSMFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  37
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  75.6
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  7-bromo-8-methoxy-3-[[4-(2-methyl-3-phenylprop-2-enyl)piperazin-1-yl]methyl]-3a,4-dihydro-3H-chromeno[4,3-c][1,2]oxazole 、 异氰酸乙酯 在 正丁基锂 、 盐酸 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 3.0h， 以10%的产率得到8-Methoxy-3-[4-(2-methyl-3-phenyl-allyl)-piperazin-1-ylmethyl]-3a, 4-dihydro-3H-chromeno[4,3-c]isoxazole-7-carboxylic acid ethylamide
  参考文献：
  名称：

  [EN] C-SUBSTITUTED TRICYCLIC ISOXAZOLINE DERIVATIVES AND THEIR USE AS ANTI-DEPRESSANTS
  [FR] DERIVES D'ISOXAZOLINE TRICYCLIQUES SUBSTITUES SUR LE CARBONE, ET LEUR UTILISATION COMME ANTIDEPRESSIFS

  摘要：

  该发明涉及根据式(I)的取代三环异噁唑啉衍生物，其药学上可接受的酸或碱盐，其立体化异构体以及其N-氧化物形式，更具体地是三环二氢苯并异噁唑啉，二氢喹啉异噁唑啉，二氢萘异噁唑啉和二氢苯并硫杂苯并异噁唑啉衍生物，其在三环部分的苯基上至少有一个通过碳-碳键连接到苯基的基团，以及它们的制备方法，包含它们的药物组合物以及它们作为药物的用途，特别是用于治疗抑郁症、焦虑症、运动障碍、精神病、帕金森病和包括厌食症和暴食症在内的体重紊乱，其中所有变量在权利要求书第1项中定义。(I) 这些化合物被惊人地显示具有选择性的5-羟色胺（5-HT）再摄取抑制剂活性，结合额外的α2-肾上腺素受体拮抗剂活性，并显示出强大的抗抑郁和/或抗焦虑活性和/或抗精神病活性和/或体重控制活性，而不具有镇静作用。另外，鉴于它们具有选择性的5-羟色胺（5-HT）再摄取抑制剂以及α2-肾上腺素受体拮抗剂活性，根据本发明的化合物也适用于治疗和/或预防在其中单独的活性或所述活性的组合可能具有治疗用途的疾病。

  公开号：

  WO2004016621A1

文献信息

• C-substituted tricyclic isoxazoline derivatives and their use as anti-depressants
  申请人：Andres-Gil Ignacio Jose

  公开号：US20050256119A1

  公开（公告）日：2005-11-17

  The invention concerns substituted tricyclic isoxazoline derivatives according to Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof and the N-oxide form thereof, more in particular tricyclic dihydrobenzopy-ranoisoxazoline, dihydroquinolinoisoxazoline, dihydronaphthalenoisoxazoline and dihydrobenzothiopyranoisoxazoline derivatives substituted on the phenylpart of the tricyclic moiety with at least one radical that is attached to the phenyl radical by a carbon-carbon bond as well as processes for their preparation, pharmaceutical compositions comprising them and their use as a medicine, in particular for treating depression, anxiety, movement disorders, psychosis, Parkinson's disease and body weight disorders including anorexia nervosa and bulimia, wherin all variables are defined in claim 1 . (I) The compounds have surprisingly been shown to have selective serotonine (5-HT) reuptake inhibitor activity in combination with additional α 2 -adrenocptor antagonist activity and show a strong antidepressant and/or anxiolytic activity and/or antipsychotic and/or a body weight control activity without being sedative. Also, in view of their selective serotonine (5-HT) reuptake inhibitor as well as α 2 -adrenoceptor antagonist activity, compounds according to the invention are also suitable for treatment and/or prophylaxis in diseases where either one of the activities alone or the combination of said activities may be of therapeutic use.

  本发明涉及根据式(I)的取代三环异噁唑啉衍生物、其药学上可接受的酸或碱加成盐、其立体化学异构体形式和其N-氧化物形式，特别是三环二氢苯并吡喃异噁唑啉、二氢喹啉异噁唑啉、二氢萘并异噁唑啉和二氢苯并噻吩异噁唑啉衍生物、二氢萘异噁唑啉和二氢苯并硫吡喃异噁唑啉衍生物，在三环分子的苯基部分被至少一个通过碳-碳键与苯基相连的基取代，以及它们的制备工艺、包含它们的药物组合物和它们作为药物的用途，特别是用于治疗抑郁症、焦虑症、运动障碍、精神病、帕金森病和体重障碍，包括神经性厌食症和贪食症，其中所有变量均在权利要求中定义 1 .(I) 令人惊奇的是，这些化合物具有选择性血清素（5-HT）再摄取抑制剂活性，与额外的 α 2 -肾上腺素拮抗剂的活性，并显示出强烈的抗抑郁和/或抗焦虑活性和/或抗精神病和/或体重控制活性，而没有镇静作用。此外，鉴于它们具有选择性血清素（5-HT）再摄取抑制剂和α 2 -肾上腺素受体拮抗剂的活性，根据本发明的化合物也适用于治疗和/或预防疾病，在这些疾病中，单独的一种活性或上述活性的组合可能具有治疗作用。
• C-SUBSTITUTED TRICYCLIC ISOXAZOLINE DERIVATIVES AND THEIR USE AS ANTI-DEPRESSANTS
  申请人：JANSSEN PHARMACEUTICA N.V.

  公开号：EP1537124B1

  公开（公告）日：2007-08-01
• Ｃ−置換三環式イソオキサゾリン誘導体及び抗−うつ薬としてのそれらの使用
  申请人：ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ

  公开号：JP4681295B2

  公开（公告）日：2005-12-08
• US7465741B2
  申请人：——

  公开号：US7465741B2

  公开（公告）日：2008-12-16
• [EN] C-SUBSTITUTED TRICYCLIC ISOXAZOLINE DERIVATIVES AND THEIR USE AS ANTI-DEPRESSANTS<br/>[FR] DERIVES D'ISOXAZOLINE TRICYCLIQUES SUBSTITUES SUR LE CARBONE, ET LEUR UTILISATION COMME ANTIDEPRESSIFS
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2004016621A1

  公开（公告）日：2004-02-26

  The invention concerns substituted tricyclic isoxazoline derivatives according to Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof and the N-oxide form thereof, more in particular tricyclic dihydrobenzopyranoisoxazoline, dihydroquinolinoisoxazoline , dihydronaphthalenoisoxazoline and dihydrobenzothiopyranoisoxazoline derivatives substituted on the phenylpart of the tricyclic moiety with at least one radical that is attached to the phenyl radical by a carbon-carbon bond as well as processes for their preparation, pharmaceutical compositions comprising them and their use as a medicine, in particular for treating depression, anxiety, movement disorders, psychosis, Parkinson's disease and body weight disorders including anorexia nervosa and bulimia, wherin all variables are defined in Claim 1. (I) The compounds have surprisingly been shown to have selective serotonine (5-HT) reuptake inhibitor activity in combination with additional α2-adrenoceptor antagonist activity and show a strong anti-depressant and/or anxiolytic activity and/or antipsychotic and/or a body weight control activity without being sedative. Also, in view of their selective serotonine (5-HT) reuptake inhibitor as well as α2-adrenoceptor antagonist activity, compounds according to the invention are also suitable for treatment and/or prophylaxis in diseases where either one of the activities alone or the combination of said activities may be of therapeutic use.

  该发明涉及根据式(I)的取代三环异噁唑啉衍生物，其药学上可接受的酸或碱盐，其立体化异构体以及其N-氧化物形式，更具体地是三环二氢苯并异噁唑啉，二氢喹啉异噁唑啉，二氢萘异噁唑啉和二氢苯并硫杂苯并异噁唑啉衍生物，其在三环部分的苯基上至少有一个通过碳-碳键连接到苯基的基团，以及它们的制备方法，包含它们的药物组合物以及它们作为药物的用途，特别是用于治疗抑郁症、焦虑症、运动障碍、精神病、帕金森病和包括厌食症和暴食症在内的体重紊乱，其中所有变量在权利要求书第1项中定义。(I) 这些化合物被惊人地显示具有选择性的5-羟色胺（5-HT）再摄取抑制剂活性，结合额外的α2-肾上腺素受体拮抗剂活性，并显示出强大的抗抑郁和/或抗焦虑活性和/或抗精神病活性和/或体重控制活性，而不具有镇静作用。另外，鉴于它们具有选择性的5-羟色胺（5-HT）再摄取抑制剂以及α2-肾上腺素受体拮抗剂活性，根据本发明的化合物也适用于治疗和/或预防在其中单独的活性或所述活性的组合可能具有治疗用途的疾病。