2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine | 159706-39-5

• 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: 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine
• 英文别名: L 742694；5-(((2S,3S)-2-((3,5-bis(trifluoromethyl)benzyl)oxy)-3-phenylmorpholino)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one；L-724,694；2-((3,5-Bis(trifluoromethyl)benzyl)oxy)-3-phenyl-4-((3-oxo-1,2,4-triazol-5-yl)methyl)morpholine；3-[[(2S,3S)-2-[[3,5-bis(trifluoromethyl)phenyl]methoxy]-3-phenylmorpholin-4-yl]methyl]-1,4-dihydro-1,2,4-triazol-5-one
• CAS: 159706-39-5
• 化学式: C₂₂H₂₀F₆N₄O₃
• 分子量: 502.416
• InChiKey: OYKIXMQKLMUJEK-RBUKOAKNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  75.2
• 氢给体数：
  2
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine 在 10percent Pd/C 氢气 、 sodium hexamethyldisilazane 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 2.25h， 生成 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(1-phosphoryl-3-oxo-4H,-1,2,4-triazol-5-yl)methylmorpholine bis(N-methyl-D-glucamine) salt
  参考文献：
  名称：

  Phosphorylated Morpholine Acetal Human Neurokinin-1 Receptor Antagonists as Water-Soluble Prodrugs

  摘要：

  The regioselective dibenzylphosphorylation of 2 followed by catalytic reduction in the presence of N-methyl-D-glucamine afforded 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-(2-phosphoryl-3-oxo-4H,1,2,4-triazolo)methylmorpholine, bis(N-methyl-D-glucamine) salt, 11. Incubation of 11 in rat, dog, and human plasma and in human hepatic subcellular fractions in vitro indicated that conversion to 2 would be expected to occur in vivo most readily in humans during hepatic circulation. Conversion of 11 to 2 occurred rapidly in vivo in the rat and dog with the levels of 11 being undetectable within 5 min after 1 and 8 mg/kg doses iv in the rat and within 15 min after 0.5, 2, and 32 mg/kg doses iv in the dog. Compound 11 has a 10-fold lower affinity for the human NK-1 receptor as compared to 2, but it is functionally equivalent to 2 in preclinical models of NK-1-mediated inflammation in the guinea pig and cisplatin-induced emesis in the ferret, indicating that 11 acts as a prodrug of 2. Based in part on these data, 11 was identified as a novel, water-soluble prodrug of the clinical candidate 2 suitable for intravenous administration in humans.

  DOI：

  10.1021/jm990617v
• 作为产物：
  描述：

  3,5-bis(trifluoromethyl)benzyl trifluoromethanesulfonate 在 ammonium cerium (IV) nitrate 、 L-Selectride 、 potassium carbonate 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 6.5h， 生成 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine
  参考文献：
  名称：

  氮杂-苄基酯重排催化对映选择性合成吗啉酮

  摘要：

  手性吗啉酮是有机合成中的重要组成部分，也是药物化学中的药效团。然而，用于构建这种N , O -杂环的催化对映选择性方法仍然很少。我们在此报告了一种手性磷酸催化的 C3 取代的吗啉酮从芳基/烷基乙二醛和 2-(芳基氨基)ethan-1-ols 的对映选择性合成。该反应通过多米诺 [4 + 2] 杂环化进行，然后是所得环状 α-亚胺鎓半缩醛的 1,2-芳基/烷基位移。它正式代表了前所未有的不对称氮杂-苄基酯重排反应。L-742,694（一种神经激肽-1 受体拮抗剂）的简明合成被记录在案。

  DOI：

  10.1021/jacs.1c03915

文献信息

• Use of substance P antagonists for the treatment of chronic fatigue syndrome and/or fibromyalgia and use of NK-1 receptor antagonists for the treatment of chronic fatigue syndrome
  申请人：——

  公开号：US20030092735A1

  公开（公告）日：2003-05-15

  The invention relates to the pharmaceutical use of specific substance P antagonists, in particular 1-acylpiperidine substance P antagonists, especially N-benzoyl-2-benzyl-4-(azanaphthoyl-amino)-piperidines, e.g. of formula 1 wherein X and Y are each independently of the other N and/or CH and the ring A is unsubstituted or mono- or poly-substituted by substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, nitro and trifluoromethyl; and pharmnaceutically acceptable salts thereof for treatment of chronic fatigue syndrome (CFS) in the absence of serotonin agonist/selective serotonin reuptake inhibitory therapy, or for the treatment of fibromyalgia or associated functional symptoms.

  本发明涉及特定物质 P 拮抗剂的药物用途，特别是 1-酰基哌啶物质 P 拮抗剂，尤其是 N-苯甲酰基-2-苄基-4-（偶氮萘甲酰氨基）-哌啶，如式 1 其中 X 和 Y 各自独立地为 N 和/或 CH，环 A 未被取代或被选自由低级烷基、低级烷氧基、卤素、硝基和三氟甲基组成的组的取代基单取代或多取代；及其药学上可接受的盐，用于在缺乏血清素激动剂/选择性血清素再摄取抑制疗法的情况下治疗慢性疲劳综合征（CFS），或用于治疗纤维肌痛或相关功能症状。
• Phosphorylated Morpholine Acetal Human Neurokinin-1 Receptor Antagonists as Water-Soluble Prodrugs
  作者：Jeffrey J. Hale、Sander G. Mills、Malcolm MacCoss、Conrad P. Dorn、Paul E. Finke、Richard J. Budhu、Robert A. Reamer、Su-Er W. Huskey、Debra Luffer-Atlas、Brian J. Dean、Erin M. McGowan、William P. Feeney、Shuet-Hing Lee Chiu、Margaret A. Cascieri、Gary G. Chicchi、Marc M. Kurtz、Sharon Sadowski、Elzbieta Ber、F. David Tattersall、Nadia M. J. Rupniak、Angela R. Williams、Wayne Rycroft、Richard Hargreaves、Joseph M. Metzger、D. Euan MacIntyre

  DOI：10.1021/jm990617v

  日期：2000.3.1

  The regioselective dibenzylphosphorylation of 2 followed by catalytic reduction in the presence of N-methyl-D-glucamine afforded 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-(2-phosphoryl-3-oxo-4H,1,2,4-triazolo)methylmorpholine, bis(N-methyl-D-glucamine) salt, 11. Incubation of 11 in rat, dog, and human plasma and in human hepatic subcellular fractions in vitro indicated that conversion to 2 would be expected to occur in vivo most readily in humans during hepatic circulation. Conversion of 11 to 2 occurred rapidly in vivo in the rat and dog with the levels of 11 being undetectable within 5 min after 1 and 8 mg/kg doses iv in the rat and within 15 min after 0.5, 2, and 32 mg/kg doses iv in the dog. Compound 11 has a 10-fold lower affinity for the human NK-1 receptor as compared to 2, but it is functionally equivalent to 2 in preclinical models of NK-1-mediated inflammation in the guinea pig and cisplatin-induced emesis in the ferret, indicating that 11 acts as a prodrug of 2. Based in part on these data, 11 was identified as a novel, water-soluble prodrug of the clinical candidate 2 suitable for intravenous administration in humans.
• Catalytic Enantioselective Synthesis of Morpholinones Enabled by Aza-Benzilic Ester Rearrangement
  作者：Yu-Ping He、Hua Wu、Qian Wang、Jieping Zhu

  DOI：10.1021/jacs.1c03915

  日期：2021.5.19

  building block in organic synthesis and a pharmacophore in medicinal chemistry. However, catalytic enantioselective methods for the construction of this N,O-heterocycle remain scarce. We report herein a chiral phosphoric acid-catalyzed enantioselective synthesis of C3-substituted morpholinones from aryl/alkylglyoxals and 2-(arylamino)ethan-1-ols. The reaction proceeds through a domino [4 + 2] heteroannulation

  手性吗啉酮是有机合成中的重要组成部分，也是药物化学中的药效团。然而，用于构建这种N , O -杂环的催化对映选择性方法仍然很少。我们在此报告了一种手性磷酸催化的 C3 取代的吗啉酮从芳基/烷基乙二醛和 2-(芳基氨基)ethan-1-ols 的对映选择性合成。该反应通过多米诺 [4 + 2] 杂环化进行，然后是所得环状 α-亚胺鎓半缩醛的 1,2-芳基/烷基位移。它正式代表了前所未有的不对称氮杂-苄基酯重排反应。L-742,694（一种神经激肽-1 受体拮抗剂）的简明合成被记录在案。