N-(4-氟苄基)-3-氧代-1,1-二苯基四氢-1H-恶唑并[3,4-A]吡嗪-7(3H)-羧酰胺 | 847553-89-3

• 物质功能分类: 生物 - 生物化学试剂 - 拮抗剂
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: N-(4-氟苄基)-3-氧代-1,1-二苯基四氢-1H-恶唑并[3,4-A]吡嗪-7(3H)-羧酰胺
• 中文别名: N-[(4-氟苯基)甲基]四氢-3-氧代-1,1-二苯基-3H-恶唑并[3,4-a]吡嗪-7(1H)-羧酰胺
• 英文名称: SHA 68
• 英文别名: N-[(4-fluorophenyl)methyl]-3-oxo-1,1-diphenyl-5,6,8,8a-tetrahydro-[1,3]oxazolo[3,4-a]pyrazine-7-carboxamide
• CAS: 847553-89-3
• 化学式: C₂₆H₂₄FN₃O₃
• 分子量: 445.493
• InChiKey: SFRQIPRTNYHJHP-UHFFFAOYSA-N

物化性质

• 沸点：
  727.8±60.0 °C(Predicted)
• 密度：
  1.35±0.1 g/cm3(Predicted)
• 溶解度：
  DMF：16 mg/ml； DMSO：14 mg/ml；乙醇：20 mg/ml；乙醇:PBS (pH 7.2)(1:2): 0.33 mg/ml

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  33
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  61.9
• 氢给体数：
  1
• 氢受体数：
  4

制备方法与用途

生物活性

SHA 68 是一种有效的选择性非肽神经肽 S 受体 (NPSR) 拮抗剂，对 NPSR Asn107 和 NPSR Ile107 的 IC50 分别为 22.0 和 23.8 nM。SHA 68 具有有限的血脑屏障 (BBB) 渗透能力和用于神经痛的活性。

靶点

IC50: 22 nM (Asn ¹⁰⁷ ) and 23.8 nM (Ile ¹⁰⁷ )

体内研究

SHA 68 (i.p.; 5 and 50 mg/kg) reduces NPS-induced horizontal activity and vertical rearing and climbing.
SHA 68 (i.v.; 1 mg/kg) has a T _1/2 of 0.74 hours, a CL of 4.29 mL/min/kg, and a V _ss of 2.53 L/kg.
SHA 68 (i.p.; 2.5 mg/kg) has a T _1/2 of 0.43 hours, a CL of 4.56 mL/min/kg.

Animal Model:	Male C57BL/6 mice age 8-12 weeks
Dosage:	5 and 50 mg/kg
Administration:	i.p.
Result:	Reduced NPS-induced horizontal activity and vertical rearing and climbing.

Animal Model:	Male C57BL/6 mice age 8-12 weeks
Dosage:	1 mg/kg (Pharmacokinetic Analysis)
Administration:	i.p.
Result:	Had a T 1/2 of 0.74 hours, a CL of 4.29 mL/min/kg, and a V ss of 2.53 L/kg.

反应信息

• 作为反应物：
  描述：

  N-(4-氟苄基)-3-氧代-1,1-二苯基四氢-1H-恶唑并[3,4-A]吡嗪-7(3H)-羧酰胺 、 碘甲烷 在 sodium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 生成 N-[(4-fluorophenyl)methyl]-N-methyl-3-oxo-1,1-diphenyl-5,6,8,8a-tetrahydro-[1,3]oxazolo[3,4-a]pyrazine-7-carboxamide
  参考文献：
  名称：

  Identifying structural features on 1,1-diphenyl-hexahydro-oxazolo[3,4-a]pyrazin-3-ones critical for Neuropeptide S antagonist activity

  摘要：

  A series of 7-substituted 1,1-diphenyl-hexahydro-oxazolo[3,4-a]pyrazin-3-ones were synthesized and tested for Neuropeptide S (NPS) antagonist activity. A concise synthetic route was developed, which features a DMAP catalyzed carbamate formation. 4-Fluorobenzyl urea (1c) and benzyl urea (1d) were identified as the most potent antagonists among the compounds examined. Structure-activity relationships (SARs) demonstrate that a 7-position urea functionality is required for potent antagonist activity and alkylation of the urea nitrogen (1e) or replacement with carbon or oxygen (5a) results in reduced potency. In addition, compounds with alpha-methyl substitution (1b) or elongated alkyl chains (1h and 1j) had reduced potency, indicating a limited tolerance for 7-position substituents. (c) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2008.05.098
• 作为产物：
  描述：

  (1,4-dibenzyl-piperazin-2-yl)-diphenyl-methanol 在 盐酸 、 4-二甲氨基吡啶 、 三乙胺 作用下， 以 四氢呋喃 、 乙醚 、 二氯甲烷 为溶剂， 20.0 ℃ 、317.17 kPa 条件下， 反应 31.0h， 生成 N-(4-氟苄基)-3-氧代-1,1-二苯基四氢-1H-恶唑并[3,4-A]吡嗪-7(3H)-羧酰胺
  参考文献：
  名称：

  Identification of Neuropeptide S Antagonists: Structure–Activity Relationship Studies, X-ray Crystallography, and in Vivo Evaluation

  摘要：

  Modulation of the neuropeptide S (NPS) system has been linked to a variety of CNS disorders such as panic disorder, anxiety, sleeping disorders, asthma, obesity, PTSD, and substance abuse. In this study, a series of diphenyltetrahydro-1H-oxazolo[3,4-α]pyrazin-3(5H)-ones were synthesized and evaluated for antagonist activity at the neuropeptide S receptor. The absolute configuration was determined by chiral resolution of the key synthetic intermediate, followed by analysis of one of the individual enantiomers by X-ray crystallography. The R isomer was then converted to a biologically active compound (34) that had a Ke of 36 nM. The most potent compound displayed enhanced aqueous solubility compared with the prototypical antagonist SHA-68 and demonstrated favorable pharmacokinetic properties for behavioral assessment. In vivo analysis in mice indicated a significant blockade of NPS induced locomotor activity at an ip dose of 50 mg/kg. This suggests that analogs having improved drug-like properties will facilitate more detailed studies of the neuropeptide S receptor system.

  DOI：

  10.1021/cn500113c

文献信息

• Synthesis and Pharmacological in Vitro and in Vivo Profile of 3-Oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-<i>a</i>]pyrazine-7-carboxylic Acid 4-Fluoro-benzylamide (SHA 68), a Selective Antagonist of the Neuropeptide S Receptor
  作者：Naoe Okamura、Stephen A. Habay、Joanne Zeng、A. Richard Chamberlin、Rainer K. Reinscheid

  DOI：10.1124/jpet.107.135103

  日期：2008.6

  Neuropeptide S (NPS) has been shown to modulate arousal, sleep wakefulness, anxiety-like behavior, and feeding after central administration of the peptide agonist to mice or rats. We report here the chemical synthesis and pharmacological characterization of SHA 66 (3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4- a ]pyrazine-7-carboxylic acid benzylamide) and SHA 68 (3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4- a ]pyrazine-7-carboxylic acid 4-fluoro-benzylamide), two closely related bicyclic piperazines with antagonistic properties at the NPS receptor (NPSR). The compounds block NPS-induced Ca2+ mobilization, and SHA 68 shows displaceable binding to NPSR in the nanomolar range. The antagonistic activity of SHA 68 seems to be specific because it does not affect signaling at 14 unrelated G protein-coupled receptors. Analysis of pharmacokinetic parameters of SHA 68 demonstrates that the compound reaches pharmacologically relevant levels in plasma and brain after i.p. administration. Furthermore, peripheral administration of SHA 68 in mice (50 mg/kg i.p.) is able to antagonize NPS-induced horizontal and vertical activity as well as stereotypic behavior. Therefore, SHA 68 could be a useful tool to characterize physiological functions and pharmacological parameters of the NPS system in vitro and in vivo.

  神经肽 S（Neuropeptide S，NPS）已被证明可以调节小鼠或大鼠的觉醒、睡眠觉醒、焦虑样行为和摄食。我们在此报告 SHA 66（3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a ]pyrazine-7-carboxylic acid benzylamide）和 SHA 68（3-oxo-1、1-二苯基-四氢噁唑并[3,4- a ]吡嗪-7-羧酸 4-氟苯甲酰胺）和 SHA 68（3-氧代-1, 1-二苯基-四氢噁唑并[3,4- a ]吡嗪-7-羧酸 4-氟苯甲酰胺），这是两种密切相关的双环哌嗪类化合物，具有拮抗 NPS 受体（NPSR）的特性。这两种化合物能阻断 NPS 诱导的 Ca2+ 迁移，SHA 68 与 NPSR 的结合在纳摩尔范围内具有可置换性。SHA 68 的拮抗活性似乎是特异性的，因为它不会影响 14 种不相关的 G 蛋白偶联受体的信号传导。对 SHA 68 药代动力学参数的分析表明，静脉注射后，该化合物在血浆和大脑中达到了药理相关水平。此外，给小鼠外周注射 SHA 68（50 毫克/千克 i.p.）能够拮抗 NPS 引起的水平和垂直活动以及刻板行为。因此，SHA 68 可以作为一种有用的工具，用于描述 NPS 系统在体外和体内的生理功能和药理参数。
• Bicyclic piperazine compound and use thereof
  申请人：Fukatsu Kohji

  公开号：US20070072865A1

  公开（公告）日：2007-03-29

  The present invention provides a compound represented by the formula: wherein R 1 is an acyl group, R 2 is a hydrocarbon group which may be substituted or the like, R 3 is a hydrocarbon group which may be substituted or the like, R 4 is a hydrocarbon group which may be substituted or the like, n is from 0 to 4, and X is an oxygen atom, a sulfur atom or the like, or a salt thereof. The invention also provides a compound which has a TGR23 antagonist activity and thus is useful for prevention and treatment of cancer.

  本发明提供一种化合物，其化学式为：其中，R1是酰基，R2是烃基，可以被取代或类似物，R3是烃基，可以被取代或类似物，R4是烃基，可以被取代或类似物，n为0至4，X为氧原子、硫原子或类似物或其盐。本发明还提供一种具有TGR23拮抗活性的化合物，因此可用于预防和治疗癌症。
• BICYCLIC PIPERAZINE COMPOUND AND USE THEREOF
  申请人：Takeda Pharmaceutical Company Limited

  公开号：EP1661898A1

  公开（公告）日：2006-05-31

  The present invention provides a compound represented by the formula: wherein R1 is an acyl group, R2 is a hydrocarbon group which may be substituted or the like, R3 is a hydrocarbon group which may be substituted or the like, R4 is a hydrocarbon group which may be substituted or the like, n is from 0 to 4, and X is an oxygen atom, a sulfur atom or the like, or a salt thereof. The invention also provides a compound which has a TGR23 antagonist activity and thus is useful for prevention and treatment of cancer.

  本发明提供了一种由式表示的化合物： 其中 R1 是酰基，R2 是可被取代的烃基或类似物，R3 是可被取代的烃基或类似物，R4 是可被取代的烃基或类似物，n 是 0 至 4，X 是氧原子、硫原子或类似物，或其盐。本发明还提供了一种化合物，它具有 TGR23 拮抗剂活性，因此可用于预防和治疗癌症。
• COMPOSITION AND METHOD FOR NEUROPEPTIDE S RECEPTOR (NPSR) ANTAGONISTS
  申请人：Research Triangle Institute

  公开号：EP2788359B1

  公开（公告）日：2017-03-01
• US7795267B2
  申请人：——

  公开号：US7795267B2

  公开（公告）日：2010-09-14