(2R,3S)-4-(4-azidobut-2-ynyl)-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)morpholine | 171243-15-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: (2R,3S)-4-(4-azidobut-2-ynyl)-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)morpholine
• 英文别名: N-(4-Azidobut-2-ynyl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine；(2R,3S)-4-(4-azidobut-2-ynyl)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine
• CAS: 171243-15-5
• 化学式: C₂₄H₂₁F₇N₄O₂
• 分子量: 530.445
• InChiKey: WDPABLGLTMNYIY-KBJGYGKASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  37
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  36.1
• 氢给体数：
  0
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  (2R,3S)-4-(4-azidobut-2-ynyl)-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)morpholine 在 氨 作用下， 以 1,4-二氧六环 为溶剂， 反应 20.0h， 以15%的产率得到1-(5-{[(2R,3S)-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)morpholin-4-yl]methyl}-2H-1,2,3-triazol-4-yl)methanamine
  参考文献：
  名称：

  An Orally Active, Water-Soluble Neurokinin-1 Receptor Antagonist Suitable for Both Intravenous and Oral Clinical Administration

  摘要：

  1-(5-{[(2R,3S)-2-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)morpholin-4-yl]methyl}-2H-1,2,3-triazol-4-yl)-N,N-dimethylmethanamine hydrochloride 3 is a high affinity, orally active, h-NK1 receptor antagonist with a long central duration of action and a solubility in water of > 100 mg/mL. The construction of the 5-dimethylaminomethyl 1,2,3-triazol-4-yl unit, which incorporates the solubilizing group of 3, was accomplished by thermal rearrangement of a propargylic azide in the presence of dimethylamine. Compound 3 is highly effective in pre-clinical tests that are relevant to clinical efficacy in emesis and depression.

  DOI：

  10.1021/jm0109558
• 作为产物：
  描述：

  (2R,3S)-2-[(1R)-1-[3,5-双(三氟甲基)苯基)乙氧基]-3-(4-氟苯基)吗啉 在 sodium azide 、 potassium carbonate 作用下， 以 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 22.0h， 生成 (2R,3S)-4-(4-azidobut-2-ynyl)-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)morpholine
  参考文献：
  名称：

  An Orally Active, Water-Soluble Neurokinin-1 Receptor Antagonist Suitable for Both Intravenous and Oral Clinical Administration

  摘要：

  1-(5-{[(2R,3S)-2-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)morpholin-4-yl]methyl}-2H-1,2,3-triazol-4-yl)-N,N-dimethylmethanamine hydrochloride 3 is a high affinity, orally active, h-NK1 receptor antagonist with a long central duration of action and a solubility in water of > 100 mg/mL. The construction of the 5-dimethylaminomethyl 1,2,3-triazol-4-yl unit, which incorporates the solubilizing group of 3, was accomplished by thermal rearrangement of a propargylic azide in the presence of dimethylamine. Compound 3 is highly effective in pre-clinical tests that are relevant to clinical efficacy in emesis and depression.

  DOI：

  10.1021/jm0109558

文献信息

• [EN] SUBSTITUTED MORPHOLINE DERIVATIVES AND THEIR USE AS THERAPEUTIC AGENTS<br/>[FR] DERIVES DE MORPHOLINE SUBSTITUES ET UNE UTILISATION EN TANT QU'AGENTS THERAPEUTIQUES
  申请人：MERCK SHARP & DOHME LIMITED

  公开号：WO1995018124A1

  公开（公告）日：1995-07-06

  (EN) The present invention relates to compounds of formula (I), wherein R1 is hydrogen, halogen, C1-6¿ alkyl, C¿1-6 alkoxy, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6 alkenyl, C2-6 alkynyl or C1-4 alkyl substituted by C1-4 alkoxy, where Ra and Rb are hydrogen or C1-4 alkyl; R2 is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy substituted by C1-4 alkoxy or CF3; R3 is hydrogen, halogen or CF3; R4 is selected from the definitions of R1; R5 is selected from the definitions of R2; R6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =O, =S or a C1-4 alkyl group, and optionally substituted by an aminoalkyl group; R9a and R9b are hydrogen or C1-4 alkyl, or R9a and R9b are joined to form a C5-7 ring; X is C1-4 alkylene optionally substituted by oxo; and Y is a C1-4 alkyl group optionally substituted by hydroxyl; with the proviso that if Y is C1-4 alkyl, R6 is substituted at least by an aminoalkyl group; and pharmaceutically acceptable salts and prodrugs thereof. The compounds are of particular use in the treatment of pain, inflammation, migraine and emesis.(FR) Composés de formule (I) dans laquelle R1 représente hydrogène, halogène, alkyle C1-6, alcoxy C1-6, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, alcényle C2-6, alcynyle C2-6 ou alkyle C1-4 substitué par alcoxy C1-4, Ra et Rb représentant hydrogène ou alkyle C1-4; R2 représente hydrogène, halogène, alkyle C1-6, alcoxy C1-6 substitué par alcoxy C1-4 ou CF3; R3 représente hydrogène, halogène ou CF3; R4 est sélectionné dans la définition de R1; R5 est sélectionné dans la définition de R2; R6 représente un cycle hétérocyclique à 5 ou 6 éléments contenant 2 ou 3 atomes d'azote éventuellement substitués par =O, =S ou un groupe alkyle C1-4, et éventuellement substitué par un groupe aminoalkyle; R9a et R9b représentant hydrogène ou alkyle C1-4, ou bien R9a et R9b sont joints pour former un cycle C5-7; X représente alkylène C1-4 éventuellement substitué par oxo; et Y représente un groupe alkyle C1-4 éventuellement substitué par hydroxyle, à condition que si Y représente alkyle C1-4, R6 soit substitué par un groupe aminoalkyle; et sels et pro/médicaments pharmaceutiquement acceptables de ces composés. Lesdits composés sont particulièrement utiles pour traiter la douleur, l'inflammation, la migraine et les vomissements.

  本发明涉及公式（I）的化合物，其中R1为氢，卤素，C1-6烷基，C1-6烷氧基，CF3，NO2，CN，SRa，SORa，SO2Ra，CO2Ra，CONRaRb，C2-6烯基，C2-6炔基或C1-4烷基，由C1-4烷氧基取代，其中Ra和Rb为氢或C1-4烷基；R2为氢，卤素，C1-6烷基，由C1-4烷氧基取代，或CF3；R3为氢，卤素或CF3；R4从R1的定义中选择；R5从R2的定义中选择；R6是一个5个或6个成员的杂环环，其中包含2个或3个氮原子，可以选择地由=O，=S或C1-4烷基取代，并可以选择地由氨基烷基取代；R9a和R9b为氢或C1-4烷基，或R9a和R9b连接形成一个C5-7环；X为C1-4烷基，可以选择地由氧代取代；Y为C1-4烷基，可以选择地由羟基取代；前提是如果Y为C1-4烷基，则R6至少被氨基烷基取代；以及其药学上可接受的盐和前药。这些化合物特别适用于治疗疼痛，炎症，偏头痛和呕吐。
• N-oxides of morpholine derivatives and their use as therapeutic agents
  申请人：Merck Sharp & Dohme Limited

  公开号：US05610159A1

  公开（公告）日：1997-03-11

  ##STR1## The present invention relates to morpholine derivatives of the formula (I) and pharmaceutically acceptable salts thereof wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9a, R.sup.9b, X, Y, Z and Het are as defined in the specification; m is 0 or 1; and n is 0 or 1, where the sum total of n+m is 1 or 2. The compounds are of particular use in the treatment of pain, inflammation, migraine, emesis and postherpetic neuralgia.

  本发明涉及公式(I)的吗啡啶衍生物及其药学上可接受的盐，其中R.sup.1，R.sup.2，R.sup.3，R.sup.4，R.sup.5，R.sup.6，R.sup.7，R.sup.9a，R.sup.9b，X，Y，Z和Het如规范中所定义；m为0或1；n为0或1，其中n+m的总和为1或2。这些化合物特别适用于治疗疼痛、炎症、偏头痛、恶心和带状疱疹后神经痛。
• Substituted morpholine derivatives and their use as therapeutic agents
  申请人：Merck Sharp & Dohme Limited

  公开号：US05612337A1

  公开（公告）日：1997-03-18

  The present invention relates to compounds of formula (I), wherein R.sup.1 is hydrogen, halogen, C.sub.1-6 C alkyl, C.sub.1-6 alkoxy, CF.sub.3, NO.sub.2, CN, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a, CO.sub.2 R.sup.a, CONR.sup.a R.sup.b, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl or C.sub.1-4 alkyl substituted by C.sub.1-4 alkoxy, where R.sup.a and R.sup.b are hydrogen or C.sub.1-4 alkyl; R.sup.2 is hydrogen, halogen, C .sub.1-6 alkyl, C.sub.1-6 alkoxy substituted by C.sub.1-4 alkoxy or CF.sub.3 ; R.sup.3 is hydrogen, halogen or CF.sub.3 ; R.sup.4 is selected from the definitions of R.sup.1 ; R.sup.5 is selected from the definitions of R.sup.2 ; R.sup.6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by .dbd.O, .dbd.S or a C.sub.1-4 alkyl group, and optionally substituted by an aminoalkyl group; R.sup.9a and R.sup.9b are hydrogen or C.sub.1-4 alkyl, or R.sup.9a and R.sup.9b are joined to form a C.sub.5-7 ring; X is C.sub.1-4 alkylene optionally substituted by oxo; and Y is a C.sub.1-4 alkyl group optionally substituted by hydroxyl; with the proviso that if Y is C.sub.1-4 alkyl, R.sup.6 is substituted at least by an aminoalkyl group; and pharmaceutically acceptable salts and prodrugs thereof. The compounds are of particular use in the treatment of pain, inflammation, migraine and emesis.

  本发明涉及式(I)的化合物，其中R.sup.1是氢、卤素、C.sub.1-6烷基、C.sub.1-6烷氧基、CF.sub.3、NO.sub.2、CN、SR.sup.a、SOR.sup.a、SO.sub.2R.sup.a、CO.sub.2R.sup.a、CONR.sup.aR.sup.b、C.sub.2-6烯基、C.sub.2-6炔基或C.sub.1-4烷基，其被C.sub.1-4烷氧基取代，其中R.sup.a和R.sup.b是氢或C.sub.1-4烷基；R.sup.2是氢、卤素、C.sub.1-6烷基、被C.sub.1-4烷氧基取代的C.sub.1-6烷氧基或CF.sub.3；R.sup.3是氢、卤素或CF.sub.3；R.sup.4是从R.sup.1的定义中选择的；R.sup.5是从R.sup.2的定义中选择的；R.sup.6是一个含有2或3个氮原子的5元或6元杂环，可以选择地被.dbd.O、.dbd.S或C.sub.1-4烷基取代，并可以选择地被氨基烷基取代；R.sup.9a和R.sup.9b是氢或C.sub.1-4烷基，或者R.sup.9a和R.sup.9b结合形成一个C.sub.5-7环；X是可选择地被氧代取代的C.sub.1-4烷基；而Y是可选择地被羟基取代的C.sub.1-4烷基，但前提是如果Y是C.sub.1-4烷基，则R.sup.6至少被一个氨基烷基取代；以及其药学上可接受的盐和前药。这些化合物在治疗疼痛、炎症、偏头痛和恶心方面特别有用。
• Tachykinin antagonist and an opioid analgesic effective at treating pain
  申请人：Merck Sharp & Dohme Limited

  公开号：US05880132A1

  公开（公告）日：1999-03-09

  This invention relates to methods and compositions for treating pain and nociception in a patient by administering a combination of a piperidine tachykinin antagonist and an opioid analgesic.

  本发明涉及一种通过给予哌啶类快速激肽拮抗剂和阿片类镇痛药的组合物治疗患者的疼痛和痛觉敏感性的方法和组合物。
• Use of a tachykinin antagonist and a muscarinic antagonist and/or an
  申请人：Merck Sharp & Dohme Ltd.

  公开号：US06140324A1

  公开（公告）日：2000-10-31

  The present invention relates to the use of a tachykinin antagonist and a muscarinic antagonist and/or an antihistamine for the treatment or prevention of motion sickness. There is also provided pharmaceutical compositions and products comprising a tachykinin antagonist and a muscarinic antagonist and/or an antihistamine.

  本发明涉及使用速激肽拮抗剂和毒蕈碱受体拮抗剂和/或抗组胺药物治疗或预防晕动病。同时还提供包含速激肽拮抗剂和毒蕈碱受体拮抗剂和/或抗组胺药物的制药组合物和产品。