tert-butyl 2-(3-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate | 1225276-08-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: tert-butyl 2-(3-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate
• CAS: 1225276-08-3
• 化学式: C₂₀H₂₉NO₃
• 分子量: 331.455
• InChiKey: YYYCWFSQOVBWLH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  38.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  tert-butyl 2-(3-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate 在 盐酸 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 乙腈 为溶剂， 生成 N-(3,4-dimethylisoxazol-5-yl)-2-(3-methoxyphenyl)-7-azaspiro[3.5]nonane-7-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
• 作为产物：
  描述：

  7-叔丁氧基羰基-7-氮杂螺[3.5]-2-壬醇 在 nickel(II) iodide 、 四溴化碳 、 三苯基膦 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 异丙醇 为溶剂， 生成 tert-butyl 2-(3-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate
  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] AZASPIROCYCLES AS MONOACYLGLYCEROL LIPASE MODULATORS<br/>[FR] AZASPIROCYCLES SERVANT DE MODULATEURS DE LA MONOACYLGLYCÉROL LIPASE
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2021191390A1

  公开（公告）日：2021-09-30

  Azaspirocycle compounds of Formula (I), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, pharmaceutical compositions containing them, methods of making them, and methods of using them including methods for treating disease states, disorders, and conditions associated with MGL modulation, such as those associated with pain, psychiatric disorders, neurological disorders (including, but not limited to major depressive disorder, treatment resistant depression, anxious depression, autism spectrum disorders, Asperger syndrome, bipolar disorder), cancers and eye conditions: wherein X, R1, R2a, R2b, R3, m, n, o, and p are defined herein.

  式(I)的Azaspirocycle化合物，以及其药学上可接受的盐、同位素、N-氧化物、溶剂合物和立体异构体，含有它们的药物组合物，制备它们的方法，以及使用它们的方法，包括用于治疗与MGL调节相关的疾病状态、紊乱和症状的方法，例如与疼痛、精神紊乱、神经紊乱（包括但不限于重度抑郁症、治疗抵抗性抑郁症、焦虑性抑郁症、自闭症谱系障碍、阿斯伯格综合症、双相情感障碍）、癌症和眼部疾病相关的方法：其中X、R1、R2a、R2b、R3、m、n、o和p在此处定义。
• 7-AZASPIRO[3.5]NONANE-7-CARBOXAMIDE COMPOUNDS
  申请人：Long Scott A.

  公开号：US20100113465A1

  公开（公告）日：2010-05-06

  Provided herein are 7-azaspiro[3.5]nonane-7-carboxamide compounds and the pharmaceutically acceptable salts of such compounds useful in treating diseases or conditions associated with fatty acid amide hydrolase (FAAH) activity, conditions including including acute pain, chronic pain, neuropathic pain, nociceptive pain, inflammatory pain, cancer and cancer 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7-azaspiro[3.5]nonane-7-carboxamide化合物及其药用可接受盐，用于治疗与脂肪酸酰胺水解酶（FAAH）活性相关的疾病或症状，包括急性疼痛、慢性疼痛、神经病性疼痛、伤害性疼痛、炎症性疼痛、癌症及癌症疼痛、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、膀胱过度活跃、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。
• [EN] 7-AZASPIRO [3.5] NONANE-7-CARBOXAMIDE COMPOUNDS AS MODULATORS OF FATTY ACID AMIDE HYDROLASE<br/>[FR] COMPOSÉS 7-AZASPIRO[3.5]NONANE-7-CARBOXAMIDE COMME MODULATEURS DE L'HYDROLASE D'AMIDES D'ACIDES GRAS
  申请人：PFIZER

  公开号：WO2010049841A1

  公开（公告）日：2010-05-06

  Provided herein are 7-azaspiro[3.5]nonane-7-carboxamide compounds and the pharmaceutically acceptable salts of such compounds useful in treating diseases or conditions associated with fatty acid amide hydrolase (FAAH) activity, conditions including including acute pain, chronic pain, neuropathic pain, nociceptive pain, inflammatory pain, cancer and cancer 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7-azaspiro[3.5]nonane-7-carboxamide化合物及其药学上可接受的盐，用于治疗与脂肪酸酰胺水解酶（FAAH）活性相关的疾病或症状，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、癌症和癌痛、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、银屑病、多发性硬化症、脑血管疾病、脑损伤、胃肠道疾病、高血压或心血管疾病。
• 7-azaspiro [3.5]nonane-7-carboxamide compounds as modulators of fatty acid amide hydrolase
  申请人：Pfizer Inc.

  公开号：EP2358704A1

  公开（公告）日：2011-08-24
• AZASPIROCYCLES AS MONOACYLGLYCEROL LIPASE MODULATORS
  申请人：Janssen Pharmaceutica NV

  公开号：US20220081428A1

  公开（公告）日：2022-03-17

  Azaspirocycle compounds of Formula (I), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, pharmaceutical compositions containing them, methods of making them, and methods of using them including methods for treating disease states, disorders, and conditions associated with MGL modulation, such as those associated with pain, psychiatric disorders, neurological disorders (including, but not limited to major depressive disorder, treatment resistant depression, anxious depression, autism spectrum disorders, Asperger syndrome, bipolar disorder), cancers and eye conditions: wherein X, R 1 , R 2a , R 2b , R 3 , m, n, o, and p are defined herein.