4-氨基-1-甲基-3-正丙基-1H-吡唑-5-甲酰胺 | 1357160-72-5

• 物质功能分类: 原料药 - 抑制剂
• 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: 4-氨基-1-甲基-3-正丙基-1H-吡唑-5-甲酰胺
• 英文名称: URB937
• 英文别名: cyclohexylcarbamic acid 3′–carbamoyl–6–hydroxybiphenyl–3–yl ester；N-cyclohexyl-carbamic acid 3'-(aminocarbonyl)-6-hydroxy[1,1'- biphenyl]-3-yl ester；N-cyclohexyl-carbamic acid, 3'-(aminocarbonyl)-6-hydroxy[1,10-biphenyl]-3-yl ester；cyclohexylcarbamic acid 3'-carbamoyl-6-hydroxybiphenyl-3-yl ester；URB 937；URB-937；3'-Carbamoyl-6-hydroxybiphenyl-3-yl cyclohexylcarbamate；[3-(3-carbamoylphenyl)-4-hydroxyphenyl] N-cyclohexylcarbamate
• CAS: 1357160-72-5
• 化学式: C₂₀H₂₂N₂O₄
• 分子量: 354.406
• InChiKey: CMEQHOXCIGFZNJ-UHFFFAOYSA-N

物化性质

• 沸点：
  562.8±50.0 °C(Predicted)
• 密度：
  1.31±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO：可溶15mg/mL，澄清

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  102
• 氢给体数：
  3
• 氢受体数：
  4

安全信息

• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H317,H319

反应信息

• 作为反应物：
  描述：

  4-氨基-1-甲基-3-正丙基-1H-吡唑-5-甲酰胺 在 三氧化硫吡啶 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 以44%的产率得到ammonium cyclohexylcarbamic acid 3′-carbamoyl-6-sulfatebiphenyl-3-yl ester
  参考文献：
  名称：

  Synthesis and Structure–Activity Relationship Studies of O-Biphenyl-3-yl Carbamates as Peripherally Restricted Fatty Acid Amide Hydrolase Inhibitors

  摘要：

  The peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor URB937 (3, cyclohexylcarbamic acid 3'-carbamoyl-6-hydroxybiphenyl-3-yl ester) is extruded from the brain and spinal cord by the Abcg2 efflux transporter. Despite its inability to enter the central nervous system (CNS), 3 exerts profound antinociceptive effects in mice and rats, which result from the inhibition of FAAH in peripheral tissues and the consequent enhancement of anandamide signaling at CB1 cannabinoid receptors localized on sensory nerve endings. In the present study, we examined the structure-activity relationships (SAP.) for the biphenyl region of compound 3, focusing on the carbamoyl and hydroxyl groups in the distal and proximal phenyl rings. Our SAR studies generated a new series of peripherally restricted FAAH inhibitors and identified compound 35 (cyclohexylcarbamic acid 3'-carbamoyl-5-hydroxybiphenyl-3-yl ester) as the most potent brain-impermeant FAAH inhibitor disclosed to date.

  DOI：

  10.1021/jm4007017
• 作为产物：
  描述：

  4-(苄氧基)-3-溴苯甲醛 在 四(三苯基膦)钯 、 palladium 10% on activated carbon 氢气 、 sodium methylate 、 sodium carbonate 、 三乙胺 、 间氯过氧苯甲酸 作用下， 以 乙醇 、 二氯甲烷 、 水 、 乙酸乙酯 、 甲苯 、 乙腈 为溶剂， 20.0~50.0 ℃ 、405.33 kPa 条件下， 反应 97.0h， 生成 4-氨基-1-甲基-3-正丙基-1H-吡唑-5-甲酰胺
  参考文献：
  名称：

  [EN] PERIPHERALLY RESTRICTED FAAH INHIBITORS
  [FR] INHIBITEURS DE LA FAAH À RESTRICTION PÉRIPHÉRIQUE

  摘要：

  公开号：

  WO2012015704A3

文献信息

• [EN] INHIBITORS OF FATTY ACID AMIDE HYDROLASE (FAAH) ENZYME WITH IMPROVED ORAL BIOAVAILABILITY AND THEIR USE AS MEDICAMENTS<br/>[FR] INHIBITEURS DE L'ENZYME HYDROLASE DES AMIDES D'ACIDES GRAS (FAAH) AVEC UNE MEILLEURE BIODISPONIBILITÉ ORALE ET LEUR UTILISATION COMME MÉDICAMENTS
  申请人：UNIV CALIFORNIA

  公开号：WO2015157313A1

  公开（公告）日：2015-10-15

  Described herein, inter alia, are compositions and methods useful for inhibiting fatty acid amide hydrolase.

  本文描述了用于抑制脂肪酸酰胺酶的组合物和方法。
• META-SUBSTITUTED BIPHENYL PERIPHERALLY RESTRICTED FAAH INHIBITORS
  申请人：The Regents of the University of California

  公开号：US20140288170A1

  公开（公告）日：2014-09-25

  The present invention provides methods of making and using peripherally restricted inhibitors of fatty acid amide hydrolase (FAAH). The present invention provides compounds and compositions that suppress FAAH activity and increases anandamide levels outside the central nervous system (CNS). The present invention also sets forth methods for inhibiting FAAH as well as methods for treating conditions such as, but not limited to, pain, inflammation, immune disorders, dermatitis, mucositis, the over reactivity of peripheral sensory neurons, neurodermatitis, and an overactive bladder. Accordingly, the invention also provides compounds, methods, and pharmaceutical compositions for treating conditions in which the selective inhibition of peripheral FAAH (as opposed to CNS FAAH) would be of benefit.

  本发明提供了制备和使用周边限制性脂肪酸酰胺水解酶（FAAH）抑制剂的方法。本发明提供了抑制FAAH活性并增加中枢神经系统（CNS）外的芳香酰胺水平的化合物和组合物。本发明还提出了抑制FAAH的方法以及治疗疼痛、炎症、免疫紊乱、皮炎、口腔炎、周围感觉神经过度反应、神经性皮炎和过度活跃膀胱等疾病的方法。因此，本发明还提供了用于治疗选择性抑制周围FAAH（而不是CNS FAAH）将有益的情况下的化合物、方法和制药组合物。
• PERIPHERALLY RESTRICTED FAAH INHIBITORS
  申请人：Piomelli Daniele

  公开号：US20130217764A1

  公开（公告）日：2013-08-22

  Peripherally restricted inhibitors of fatty acid amide hydrolase (FAAH) are provided. The compounds can suppress FAAH activity and increases anandamide levels outside the central nervous system (CNS). Despite their relative inability to access brain and spinal cord, the compounds attenuate behavioral responses indicative of persistent pain in rodent models of inflammation and peripheral nerve injury, and suppresses noxious stimulus-evoked neuronal activation in spinal cord regions implicated in nociceptive processing. CBi receptor blockade prevents these effects. Accordingly, the invention also provides methods, and pharmaceutical compositions for treating conditions in which the inhibition of peripheral FAAH would be of benefit. The compounds of the invention are according to the formula (I): in which R 1 is a polar group. In some embodiments, R 1 is selected from the group consisting of hydroxy and the physiologically hydro lysable esters thereof. R 2 and R 3 are independently selected from the group consisting of hydrogen and substituted or unsubstituted hydrocarbyl; each R 4 is independently selected from the group consisting of halogen and substituted or unsubstituted hydrocarbyl and n is an integer from 0 to 4; each R 5 is independently selected from the group consisting of halo and substituted or unsubstituted hydrocarbyl and m is an integer from 0 to 3; and R 6 is substituted or unsubstituted cyclohexyl; and the pharmaceutically acceptable salts thereof.

  本发明提供了周围限制的脂肪酸酰胺酶（FAAH）抑制剂。这些化合物可以抑制FAAH活性并增加中枢神经系统（CNS）外的阿那and胺水平。尽管它们相对无法进入大脑和脊髓，但这些化合物可以减弱炎症和周围神经损伤啮齿动物模型中表现持续性疼痛的行为反应，并抑制与伤害处理有关的脊髓区域的神经元激活。CB1受体阻断可以防止这些效应。因此，本发明还提供了治疗抑制周围FAAH会有益的疾病的方法和制药组合物。本发明的化合物符合以下公式（I）：其中R1是极性基团。在某些实施例中，R1选择自羟基和其生理上可水解的酯。R2和R3分别选择自氢和取代或未取代的烃基；每个R4独立选择自卤素和取代或未取代的烃基，n为0到4的整数；每个R5独立选择自卤素和取代或未取代的烃基，m为0到3的整数；R6是取代或未取代的环己基；以及其药物可接受的盐。
• Peripherally restricted FAAH inhibitors
  申请人：Piomelli Daniele

  公开号：US09187413B2

  公开（公告）日：2015-11-17

  Peripherally restricted inhibitors of fatty acid amide hydrolase (FAAH) are provided. The compounds can suppress FAAH activity and increases anandamide levels outside the central nervous system (CNS). Despite their relative inability to access brain and spinal cord, the compounds attenuate behavioral responses indicative of persistent pain in rodent models of inflammation and peripheral nerve injury, and suppresses noxious stimulus-evoked neuronal activation in spinal cord regions implicated in nociceptive processing. CBi receptor blockade prevents these effects. Accordingly, the invention also provides methods, and pharmaceutical compositions for treating conditions in which the inhibition of peripheral FAAH would be of benefit. The compounds of the invention are according to the formula (I): in which R1 is a polar group. In some embodiments, R1 is selected from the group consisting of hydroxy and the physiologically hydro lysable esters thereof. R2 and R3 are independently selected from the group consisting of hydrogen and substituted or unsubstituted hydrocarbyl; each R4 is independently selected from the group consisting of halogen and substituted or unsubstituted hydrocarbyl and n is an integer from 0 to 4; each R5 is independently selected from the group consisting of halo and substituted or unsubstituted hydrocarbyl and m is an integer from 0 to 3; and R6 is substituted or unsubstituted cyclohexyl; and the pharmaceutically acceptable salts thereof.

  提供了周边限制性脂肪酸酰胺酶（FAAH）抑制剂。这些化合物可以抑制FAAH活性并增加中枢神经系统（CNS）外的阿南胺水平。尽管它们相对无法进入大脑和脊髓，但这些化合物可以减弱炎症和周围神经损伤啮齿动物模型中持续性疼痛的行为反应，并抑制与伤害性刺激处理相关的脊髓区域的神经元活化。CBi受体阻断可以防止这些效应。因此，本发明还提供了治疗抑制周围FAAH有益的疾病的方法和制药组合物。本发明的化合物符合以下公式（I）：其中R1是极性基团。在某些实施例中，R1选自羟基和其生理可水解酯。R2和R3独立地选自氢和取代或未取代的烃基；每个R4独立地选自卤素和取代或未取代的烃基，n是0到4的整数；每个R5独立地选自卤素和取代或未取代的烃基，m是0到3的整数；R6是取代或未取代的环己基；以及其药学上可接受的盐。
• Inhibitors of fatty acid amide hydrolase (FAAH) enzyme with improved oral bioavailability and their use as medicaments
  申请人：THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

  公开号：US10435355B2

  公开（公告）日：2019-10-08

  Described herein, inter alia, are compositions and methods useful for inhibiting fatty acid amide hydrolase.

  本文特别描述了用于抑制脂肪酸酰胺水解酶的组合物和方法。