(3RS)-N-(3,4-dimethylisoxazol-5-yl)-3-[3-(trifluoromethyl)phenyl]-1-oxa-8-azaspiro[4.5]decane-8-carboxamide | 1227473-05-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂螺癸烷衍生物
• 英文名称: (3RS)-N-(3,4-dimethylisoxazol-5-yl)-3-[3-(trifluoromethyl)phenyl]-1-oxa-8-azaspiro[4.5]decane-8-carboxamide
• 英文别名: N-(3,4-dimethyl-1,2-oxazol-5-yl)-3-[3-(trifluoromethyl)phenyl]-1-oxa-8-azaspiro[4.5]decane-8-carboxamide
• CAS: 1227473-05-3
• 化学式: C₂₁H₂₄F₃N₃O₃
• 分子量: 423.435
• InChiKey: XYOQQHFNJRSRQD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  30
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  67.6
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  N-叔丁氧羰基-1-氧杂-8-氮杂螺[4.5]癸烷-3-醇 在 nickel(II) iodide 、 盐酸 、 四溴化碳 、 N,N-二异丙基乙胺 、 三苯基膦 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 异丙醇 、 乙腈 为溶剂， 生成 (3RS)-N-(3,4-dimethylisoxazol-5-yl)-3-[3-(trifluoromethyl)phenyl]-1-oxa-8-azaspiro[4.5]decane-8-carboxamide
  参考文献：
  名称：

  Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 2. Discovery of 7-azaspiro[3.5]nonane urea PF-04862853, an orally efficacious inhibitor of fatty acid amide hydrolase (FAAH) for pain

  摘要：

  Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase responsible for the degradation of fatty acid amide signaling molecules such as endocannabinoid anandamide (AEA), which has been shown to possess cannabinoid-like analgesic properties. Herein we report the optimization of spirocyclic 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane urea covalent inhibitors of FAAH. Using an iterative design and optimization strategy, lead compounds were identified with a remarkable reduction in molecular weight and favorable CNS drug like properties. 3,4-Dimethylisoxazole and 1-methyltetrazole were identified as superior urea moieties for this inhibitor class. A dual purpose in vivo efficacy and pharmacokinetic screen was designed to be the key decision enabling experiment affording the ability to move quickly from compound synthesis to selection of preclinical candidates. On the basis of the remarkable potency, selectivity, pharmacokinetic properties and in vivo efficacy, PF-04862853 (15p) was advanced as a clinical candidate. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.08.048

文献信息

• [EN] 1-OXA-8-AZASPIRO [4, 5 ] DECANE- 8 -CARBOXAMIDE COMPOUNDS AS FAAH INHIBITORS<br/>[FR] 1-OXA-8-AZASPIRO[4.5]DÉCANE-8-CARBOXAMIDES EN TANT QU'INHIBITEURS DE FAAH
  申请人：PFIZER

  公开号：WO2010058318A1

  公开（公告）日：2010-05-27

  Provided herein are 1-oxa-8-azaspiro[4.5]decane-8-carboxamide compounds of formula I wherein Ar1, Ar2, R1, R2, R3 and R4 are as defined herein and the pharmaceutically acceptable salts of such compounds useful in treating diseases or conditions associated with fatty acid amide hydrolase (FAAH) activity, conditions including acute pain, chronic pain, neuropathic pain, nociceptive pain, inflammatory pain, fibromyalgia, rheumatoid arthritis, inflammatory bowel disease, lupus, diabetes, allergic asthma, vascular inflammation, urinary incontinence, overactive bladder, emesis, cognitive disorders, anxiety, depression, sleeping disorders, eating disorders, movement disorders, glaucoma, psoriasis, multiple sclerosis, cerebrovascular disorders, brain injury, gastrointestinal disorders, hypertension, or cardiovascular disease.

  本文提供了式I的1-氧-8-氮杂螺[4.5]癸烷-8-羧酰胺化合物，其中Ar1、Ar2、R1、R2、R3和R4如本文所定义，并且这些化合物的药用盐在治疗与脂肪酸酰胺水解酶（FAAH）活性相关的疾病或症状方面具有用处，这些症状包括急性疼痛、慢性疼痛、神经痛、伤害性疼痛、炎症性疼痛、纤维肌痛、类风湿性关节炎、炎症性肠病、狼疮、糖尿病、过敏性哮喘、血管炎症、尿失禁、膀胱过度活动、呕吐、认知障碍、焦虑、抑郁、睡眠障碍、进食障碍、运动障碍、青光眼、牛皮癣、多发性硬化、脑血管疾病、脑损伤、胃肠道疾病、高血压或心血管疾病。
• 1-OXA-8-Azaspiro [4,5] Decabe-8-Carboxamide Compounds as FAAH Inhibitors
  申请人：Long Scott Allen

  公开号：US20110230493A1

  公开（公告）日：2011-09-22

  Provided herein are 1-oxa-8-azaspiro[4.5]decane-8-carboxamide compounds of formula I wherein Ar 1 , Ar 2 , R 1 , R 2 , R 3 and R 4 are as defined herein and the pharmaceutically acceptable salts of such compounds useful in treating diseases or conditions associated with fatty acid amide hydrolase (FAAH) activity, conditions including acute pain, chronic pain, neuropathic pain, nociceptive pain, inflammatory pain, fibromyalgia, rheumatoid arthritis, inflammatory bowel disease, lupus, diabetes, allergic asthma, vascular inflammation, urinary incontinence, overactive bladder, emesis, cognitive disorders, anxiety, depression, sleeping disorders, eating disorders, movement disorders, glaucoma, psoriasis, multiple sclerosis, cerebrovascular disorders, brain injury, gastrointestinal disorders, hypertension, or cardiovascular disease.

  本文提供了式I的1-氧-8-氮杂螺[4.5]癸烷-8-羧酰胺化合物，其中Ar1，Ar2，R1，R2，R3和R4如本文所定义，并且此类化合物的药物可接受的盐在治疗与脂肪酸酰胺水解酶（FAAH）活性相关的疾病或病症中有用，包括急性疼痛，慢性疼痛，神经病理性疼痛，伤害性疼痛，炎症性疼痛，纤维肌痛，类风湿性关节炎，炎症性肠病，狼疮，糖尿病，过敏性哮喘，血管炎症，尿失禁，膀胱过度活动，呕吐，认知障碍，焦虑，抑郁，睡眠障碍，进食障碍，运动障碍，青光眼，牛皮癣，多发性硬化症，脑血管疾病，脑损伤，胃肠疾病，高血压或心血管疾病。
• 1-OXA-8-AZASPIRO [4, 5] DECANE- 8 -CARBOXAMIDE COMPOUNDS AS FAAH INHIBITORS
  申请人：Pfizer Inc.

  公开号：EP2367830A1

  公开（公告）日：2011-09-28
• Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 2. Discovery of 7-azaspiro[3.5]nonane urea PF-04862853, an orally efficacious inhibitor of fatty acid amide hydrolase (FAAH) for pain
  作者：Marvin J. Meyers、Scott A. Long、Matthew J. Pelc、Jane L. Wang、Scott J. Bowen、Barbara A. Schweitzer、Mark V. Wilcox、Joseph McDonald、Sarah E. Smith、Susan Foltin、Jeanne Rumsey、Young-Sun Yang、Mark C. Walker、Satwik Kamtekar、David Beidler、Atli Thorarensen

  DOI：10.1016/j.bmcl.2011.08.048

  日期：2011.11

  Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase responsible for the degradation of fatty acid amide signaling molecules such as endocannabinoid anandamide (AEA), which has been shown to possess cannabinoid-like analgesic properties. Herein we report the optimization of spirocyclic 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane urea covalent inhibitors of FAAH. Using an iterative design and optimization strategy, lead compounds were identified with a remarkable reduction in molecular weight and favorable CNS drug like properties. 3,4-Dimethylisoxazole and 1-methyltetrazole were identified as superior urea moieties for this inhibitor class. A dual purpose in vivo efficacy and pharmacokinetic screen was designed to be the key decision enabling experiment affording the ability to move quickly from compound synthesis to selection of preclinical candidates. On the basis of the remarkable potency, selectivity, pharmacokinetic properties and in vivo efficacy, PF-04862853 (15p) was advanced as a clinical candidate. (C) 2011 Elsevier Ltd. All rights reserved.