N-苯基-4-(3-苯基-1,2,4-噻二唑-5-基)-1-哌嗪甲酰胺 | 681136-29-8

• 物质功能分类: 生物化工 - 抑制剂 - 代谢(Metabolism)
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 中文名称: N-苯基-4-(3-苯基-1,2,4-噻二唑-5-基)-1-哌嗪甲酰胺
• 英文名称: JNJ-1661010
• 英文别名: 4-(3-phenyl-[1,2,4]thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide；N-phenyl-4-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine-1-carboxamide；1-Piperazinecarboxamide, N-phenyl-4-(3-phenyl-1,2,4-thiadiazol-5-yl)-
• CAS: 681136-29-8
• 化学式: C₁₉H₁₉N₅OS
• 分子量: 365.459
• InChiKey: BHBOSTKQCZEAJM-UHFFFAOYSA-N

物化性质

• 密度：
  1.340±0.06 g/cm3(Predicted)
• 溶解度：
  在DMSO中的溶解度≥28mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  89.6
• 氢给体数：
  1
• 氢受体数：
  5

安全信息

• WGK Germany：
  1
• 储存条件：
  存储于4°C环境下

制备方法与用途

生物活性

JNJ-1661010是一种有效的，选择性的FAAH抑制剂。

其IC50分别为10 nM（大鼠）和12 nM（人类），作用于FAAH-1比作用于FAAH-2选择性高100倍以上。

体外研究

FAAH预与JNJ-1661010孵育表明，该抑制剂与活性部位的相互作用具有缓慢可逆性，并在高温下会加速。LC-ESI-MS检测显示，JNJ-1661010是一种共价的、基于机制的底物抑制剂。它与FAAH中的苯基噻二唑对接于疏水性隧道中，而其苯脲部分则嵌入FAAH的亲水性口袋。

体内研究

在20 mg/kg腹腔注射下，JNJ-1661010能至少抑制大鼠大脑85%的FAAH活性长达4小时。这导致了脂质乙醇酰胺在脑中的积累。此剂量依赖性地逆转了温和热损伤（MTI）小鼠和大鼠模型中的触觉异常疼痛，最大效应出现在给药后30分钟时约为90%。JNJ-1661010 (20 mg/kg) 在脊髓神经结扎损伤大鼠模型中于给药30分钟后逆转了60.8%的触觉异常疼痛。

在50 mg/kg腹腔注射下，JNJ-1661010显著减弱了大鼠角叉菜胶炎性疼痛模型中的痛觉过敏。血浆峰值浓度为26.9 μM（ Tmax = 0.75 h），脑中最高浓度则为6.04 μM（Tmax = 2 h）。同时，JNJ-1661010还抑制了大鼠大脑中FAAH的活性，并增加了脑组织中的AEA水平。

靶点

目标：

Target	Value
FAAH (rat)	10 nM
FAAH (human)	12 nM

反应信息

• 作为产物：
  描述：

  4-(3-chloro-[1,2,4]thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide 、 苯硼酸 生成 N-苯基-4-(3-苯基-1,2,4-噻二唑-5-基)-1-哌嗪甲酰胺
  参考文献：
  名称：

  N-heteroarylpiperazinyl ureas as modulators of fatty acid amide hydrolase

  摘要：

  描述了某些N-杂环芳基哌嗪基脲化合物，这些化合物可用作FAAH抑制剂。这些化合物可以用于制备药物组合物，并用于治疗由脂肪酰胺水解酶(FAAH)活性介导的疾病状态、紊乱和情况的方法。因此，这些化合物可以用于治疗焦虑、疼痛、炎症、睡眠障碍、进食障碍或运动障碍(如多发性硬化症)。

  公开号：

  US20070004741A1

文献信息

• [EN] MODULATORS OF FATTY ACID AMIDE HYDROLASE<br/>[FR] MODULATEURS DE L'AMIDE HYDROLASE D'ACIDE GRAS
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2011139951A1

  公开（公告）日：2011-11-10

  4-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperazine-1 -carboxylic acid (4-chloro-pyridin-3-yl)-amide is described, which is useful as a FAAH modulator. 4-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperazine-1 -carboxylic acid (4-chloro-pyridin-3-yl)-amide may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity, such as anxiety, pain, inflammation, sleep disorders, eating disorders, energy metabolism disorders, and movement disorders (e.g., multiple sclerosis). A method of synthesizing 4- (2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperazine-1 -carboxylic acid (4- chloro-pyridin-3-yl)-amide is also disclosed.

  描述了4-(2,2-二氟苯并[1,3]二噁英-5-基甲基)-哌嗪-1-羧酸(4-氯吡啶-3-基)-酰胺，该化合物可用作FAAH调节剂。4-(2,2-二氟苯并[1,3]二噁英-5-基甲基)-哌嗪-1-羧酸(4-氯吡啶-3-基)-酰胺可用于制备药物组合物，并用于治疗由脂肪酰胺水解酶(FAAH)活性介导的疾病状态、紊乱和情况，如焦虑、疼痛、炎症、睡眠障碍、进食障碍、能量代谢紊乱和运动障碍(例如多发性硬化)。还公开了合成4-(2,2-二氟苯并[1,3]二噁英-5-基甲基)-哌嗪-1-羧酸(4-氯吡啶-3-基)-酰胺的方法。
• Amide Compound
  申请人：Matsumoto Takahiro

  公开号：US20080312226A1

  公开（公告）日：2008-12-18

  There is provided a FAAH inhibitor and a prophylactic or therapeutic agent for cerebrovascular disorders or sleep disorders comprising it. The prophylactic or therapeutic agent comprises a compound of the formula (I 0 ): R 1 —C—R 2 —R 3 —R 4 (I 0 ) wherein Z is oxygen or sulfur; R 1 is aryl which may be substituted, or a heterocyclic group which may be substituted; R 1a is a hydrogen atom, a hydrocarbon group which may be substituted, hydroxyl, etc.; R 2 is piperidin-1,4-diyl which may be substituted, or piperazin-1,4-diyl which may be substituted; R 3 is a group formed by eliminating two hydrogen atoms from a 5-membered aromatic heterocyclic group having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, which may be further substituted, —CO—, etc.; and R 4 is a hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted; or a salt thereof.

  提供了一种FAAH抑制剂和预防或治疗脑血管疾病或睡眠障碍的药物，其中预防或治疗剂包括化合物(I0)的一种：R1-C-R2-R3-R4(I0)，其中Z为氧或硫；R1为芳基，可以被取代，或者是可以被取代的杂环基；R1a为氢原子，可以被取代的碳氢基，羟基等；R2为可以被取代的哌啶-1,4-二基，或者可以被取代的哌嗪-1,4-二基；R3为从具有1到3个氮、氧和硫杂原子的5元芳香杂环基中消除两个氢原子形成的基团，可以进一步被取代，-CO-等；R4为可以被取代的碳氢基或者可以被取代的杂环基；或其盐。
• Amide compound
  申请人：Takeda Pharmaceutical Company Limited

  公开号：US07851473B2

  公开（公告）日：2010-12-14

  There is provided a FAAH inhibitor and a prophylactic or therapeutic agent for cerebrovascular disorders or sleep disorders comprising it. The prophylactic or therapeutic agent comprises a compound of the formula (I0): wherein Z is oxygen or sulfur; R1 is aryl which may be substituted, or a heterocyclic group which may be substituted; R1a is a hydrogen atom, a hydrocarbon group which may be substituted, hydroxyl, etc.; R2 is piperidin-1,4-diyl which may be substituted, or piperazin-1,4-diyl which may be substituted; R3 is a group formed by eliminating two hydrogen atoms from a 5-membered aromatic heterocyclic group having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, which may be further substituted, —CO—, etc.; and R4 is a hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted; or a salt thereof.

  提供了一种FAAH抑制剂和用于预防或治疗脑血管疾病或睡眠障碍的预防性或治疗性制剂，它包括公式（I0）的化合物：其中Z是氧或硫；R1是取代的芳基或取代的杂环基；R1a是氢原子、可取代的碳氢基、羟基等；R2是可取代的哌啶-1,4-二基或可取代的哌嗪-1,4-二基；R3是由1至3个从氮、氧和硫中选择的杂原子构成的5-成员芳香杂环基消去两个氢原子形成的基团，它可以进一步取代，-CO-等；R4是可取代的碳氢基或可取代的杂环基；或其盐。
• MODULATORS OF FATTY ACID AMIDE HYDROLASE
  申请人：Keith John M.

  公开号：US20130053398A1

  公开（公告）日：2013-02-28

  4-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperazine-1-carboxylic acid (4-chloro-pyridin-3-yl)-amide is described, which is useful as a FAAH modulator. 4-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperazine-1-carboxylic acid (4-chloro-pyridin-3-yl)-amide may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity, such as anxiety, pain, inflammation, sleep disorders, eating disorders, energy metabolism disorders, and movement disorders (e.g., multiple sclerosis). A method of synthesizing 4-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperazine-1-carboxylic acid (4-chloro-pyridin-3-yl)-amide is also disclosed.

  本文描述了一种4-(2,2-二氟苯并[1,3]二噁英-5-甲基)-哌嗪-1-羧酸(4-氯吡啶-3-基)-酰胺，该物质可用作FAAH调节剂。4-(2,2-二氟苯并[1,3]二噁英-5-甲基)-哌嗪-1-羧酸(4-氯吡啶-3-基)-酰胺可用于制备药物组合物和治疗由脂肪酸酰胺水解酶(FAAH)活性介导的疾病状态、紊乱和情况的方法，例如焦虑、疼痛、炎症、睡眠障碍、进食障碍、能量代谢紊乱和运动障碍(例如多发性硬化症)。本文还揭示了一种合成4-(2,2-二氟苯并[1,3]二噁英-5-甲基)-哌嗪-1-羧酸(4-氯吡啶-3-基)-酰胺的方法。
• AMIDE COMPOUND
  申请人：Takeda Pharmaceutical Company Limited

  公开号：EP1813606A1

  公开（公告）日：2007-08-01

  There is provided a FAAH inhibitor and a prophylactic or therapeutic agent for cerebrovascular disorders or sleep disorders comprising it. The prophylactic or therapeutic agent comprises a compound of the formula (I0): wherein Z is oxygen or sulfur; R1 is aryl which may be substituted, or a heterocyclic group which may be substituted; R1a is a hydrogen atom, a hydrocarbon group which may be substituted, hydroxyl, etc.; R2 is piperidin-1,4-diyl which may be substituted, or piperazin-1,4-diyl which may be substituted; R3 is a group formed by eliminating two hydrogen atoms from a 5-membered aromatic heterocyclic group having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, which may be further substituted, -CO-, etc.; and R4 is a hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted; or a salt thereof.

  本发明提供了一种 FAAH 抑制剂和一种用于脑血管疾病或睡眠障碍的预防或治疗剂。该预防或治疗剂包括式（I0）化合物： 其中 Z 是氧或硫；R1 是可被取代的芳基或可被取代的杂环基团；R1a 是氢原子、可被取代的烃基、羟基等。R2 是可被取代的哌啶-1,4-二基或可被取代的哌嗪-1,4-二基；R3 是通过从具有 1 至 3 个选自氮、氧和硫的杂原子的 5 元芳香杂环基团中消除两个氢原子而形成的基团，该基团可被进一步取代、-CO- 等；以及 R4 是可被取代的烃基或可被取代的杂环基；或其盐。