3-ethyl-1-oxa-3,8-diazaspiro<4.5>decane-2,4-dione | 26728-09-6

• 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: 3-ethyl-1-oxa-3,8-diazaspiro<4.5>decane-2,4-dione
• 英文别名: 3-ethyl-1-oxa-3,8-diaza-spiro[4.5]decane-2,4-dione；3-Ethyl-1-oxa-3,8-diaza-spiro[4.5]decane-2,4-dione; hydrochloride；3-ethyl-1-oxa-3,8-diazaspiro[4.5]decane-2,4-dione
• CAS: 26728-09-6
• 化学式: C₉H₁₄N₂O₃
• 分子量: 198.222
• InChiKey: CSNDHJHELDEYRP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  燕麦灵 、 3-ethyl-1-oxa-3,8-diazaspiro<4.5>decane-2,4-dione 在 sodium hydride 、 三乙胺 作用下， 生成 4-(2,4-dioxo-3-ethyl-1-oxa-3,8-diazaspiro<4.5>decan-8-yl)-2-bytynyl N-(3-chlorophenyl)carbamate
  参考文献：
  名称：

  Synthesis and structure-activity studies of a series of spirooxazolidine-2,4-diones: 4-oxa-analogs of the muscarinic agonist 2-ethyl-8-methyl-2,8-diazaspiro[4.5]decane-1,3-dione

  摘要：

  A series of spirooxazolidine-2,4-dione derivatives related to the putative M, agonist 2-ethyl-8-methyl-2,8-diazaspiro[4.5]decane-1,3-dione (RS86; 1) were synthesized. The compounds were evaluated as cholinergic agents in in vitro binding assays and in in vivo pharmacological tests including antiamnesic effects using scopolamine-treated mice, hypothermia, and salivation in mice. Four compounds (5a,c,f and 17a) exhibited affinity for cortical M1 receptors and reversed scopolamine-induced impairment of mouse passive avoidance tasks, as did 1. Among these compounds, only 5a exhibited M1-receptor stimulating activity in pithed rats. Structural requirements for muscarinic activity in this series of spirooxazolidine-2,4-dione derivatives were as strict as those reported for spirosuccinimide derivatives including 1. The antiamnesic dose of 3-ethyl-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2,4-dione (5a) was 2 orders of magnitude lower than the doses inducing hypothermia and salivation, in contrast to 1 for which the former dose was only 5-10-fold lower than the latter. These results suggest that the 8-azaspiro[4.5]decane skeleton represents a useful template for designing new muscarinic agonists as antidementia drugs.

  DOI：

  10.1021/jm00068a005
• 作为产物：
  描述：

  1苄基-4-氰基-4-羟基哌啶 在 palladium on activated charcoal 盐酸 、 氢气 、 sodium hydride 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 为溶剂， 4.0~60.0 ℃ 、101.33 kPa 条件下， 反应 1.0h， 生成 3-ethyl-1-oxa-3,8-diazaspiro<4.5>decane-2,4-dione
  参考文献：
  名称：

  Synthesis and structure-activity studies of a series of spirooxazolidine-2,4-diones: 4-oxa-analogs of the muscarinic agonist 2-ethyl-8-methyl-2,8-diazaspiro[4.5]decane-1,3-dione

  摘要：

  A series of spirooxazolidine-2,4-dione derivatives related to the putative M, agonist 2-ethyl-8-methyl-2,8-diazaspiro[4.5]decane-1,3-dione (RS86; 1) were synthesized. The compounds were evaluated as cholinergic agents in in vitro binding assays and in in vivo pharmacological tests including antiamnesic effects using scopolamine-treated mice, hypothermia, and salivation in mice. Four compounds (5a,c,f and 17a) exhibited affinity for cortical M1 receptors and reversed scopolamine-induced impairment of mouse passive avoidance tasks, as did 1. Among these compounds, only 5a exhibited M1-receptor stimulating activity in pithed rats. Structural requirements for muscarinic activity in this series of spirooxazolidine-2,4-dione derivatives were as strict as those reported for spirosuccinimide derivatives including 1. The antiamnesic dose of 3-ethyl-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2,4-dione (5a) was 2 orders of magnitude lower than the doses inducing hypothermia and salivation, in contrast to 1 for which the former dose was only 5-10-fold lower than the latter. These results suggest that the 8-azaspiro[4.5]decane skeleton represents a useful template for designing new muscarinic agonists as antidementia drugs.

  DOI：

  10.1021/jm00068a005

文献信息

• Studies on psychotropic agents. I. Synthesis of 3,8-disubstituted-1-oxa-3,8-diazaspiro(4,5)decan-2,4-dione derivatives.
  作者：YASUTAKA NAGAI、AKIO MAKI、HISASHI KANDA、KAGAYAKI NATSUKA、SUSUMU UMEMOTO

  DOI：10.1248/cpb.24.1179

  日期：——

  A series of 3, 8-disubstituted-1-oxa-3, 8-diazaspiro [4, 5] decan-2, 4-diones (XI) were synthesized for pharmacological testing. 3-Substituted-8-benzyl compounds (IIIb-h), the intermediates of XI, were prepared by the following three methods : 1) condensation of methyl 1-benzyl-4-hydroxyisonipecotate (II) with urea, followed by alkylation, 2) treatment of II with isocyanates and 3) reaction of 1-benzyl-4-cyano-4-piperidinol (I) with isocyanates followed by hydrolysis. The last method was inferior to the other two methods. Reductive debenzylation of III followed by condensation with appropriate halides afforded XI. Among the compounds (XI) synthesized, 8-[3-(2-chlorophenothiazin-10-yl) propyl]-3-methyl compound (XIa) had excellent central nervous system depressing activities.

  为了进行药理测试，合成了一系列3,8-二取代-1-氧杂-3,8-二氮杂螺[4,5]癸烷-2,4-二酮(XI)。3-取代-8-苄基化合物(IIIb-h)是XI的中间体，通过以下三种方法制备： 1) 甲基1-苄基-4-羟基异哌啶酸酯(II)与尿素缩合，随后进行烷基化 2) 将II与异氰酸酯反应 3) 1-苄基-4-氰基-4-哌啶醇(I)与异氰酸酯反应，然后水解 最后一种方法不如前两种方法。III脱苄基还原后与适当的卤化物缩合得到XI。在合成的化合物(XI)中，8-[3-(2-氯吩噻嗪-10-基)丙基]-3-甲基化合物(XIa)具有优异的中枢神经系统抑制活性。
• Optimizing and characterizing 4-methyl substituted pyrazol-3-carboxamides leading to the peripheral cannabinoid 1 receptor inverse agonist TM38837
  作者：Thomas Högberg、Jean-Marie Receveur、Anthony Murray、Jean-Michel Linget、Pia K. Nørregaard、Paul B. Little、Martin Cooper

  DOI：10.1016/j.bmcl.2023.129572

  日期：2024.1

  with respect to lipophilicity, solubility, CB1 potency, metabolism, distribution to brain and liver, effect on weight loss in diet-induced mice models. A few carboxylic acids and tetrazoles were selected as especially promising with the tetrazole TM38837 subsequently demonstrating impressive efficacy in various animal models of obesity, producing considerable weight loss and improvements on plasma markers

  由相应的 4-氰基甲基吡唑制备了几个系列的用 4-甲基酰胺、4-甲基羧酸和 4-甲基四唑功能化的不同吡唑-3-甲酰胺，并作为大麻素受体 1 (CB1) 拮抗剂和反向激动剂进行了研究，目的是制备化合物与利莫那班相比，CNS（中枢神经系统）介导的副作用更少。对这些化合物的亲脂性、溶解度、CB1 效力、代谢、大脑和肝脏分布以及对饮食诱导小鼠模型体重减轻的影响进行了评估和优化。一些羧酸和四唑被选择为特别有前途的四唑TM38837，随后在各种肥胖动物模型中表现出令人印象深刻的功效，产生显着的体重减轻并改善炎症和葡萄糖稳态的血浆标志物，其剂量显然产生可忽略不计的脑暴露。 TM38837 成为第一个进入临床试验的外周限制性 CB1 拮抗剂或反向激动剂，支持其缺乏 CNS 作用，现在认为非 CNS 介导的功效与高肝脏暴露有关。这为探索非酒精性脂肪肝（NAFLD）和脂肪性肝炎（NASH）等其他适应症提供了机
• NAGAI YASUTAKA; MAKI AKIO; KANDA HISASHI; NATSUKA KAGAYAKI; UMEMOTO SUSUM+, CHEM. AND PHARM. BULL., 1976, 24, NO 6, 1179-1188
  作者：NAGAI YASUTAKA、 MAKI AKIO、 KANDA HISASHI、 NATSUKA KAGAYAKI、 UMEMOTO SUSUM+

  DOI：——

  日期：——
• Synthesis and structure-activity studies of a series of spirooxazolidine-2,4-diones: 4-oxa-analogs of the muscarinic agonist 2-ethyl-8-methyl-2,8-diazaspiro[4.5]decane-1,3-dione
  作者：Shinichi Tsukamoto、Masato Ichihara、Fumikazu Wanibuchi、Shinji Usuda、Kazuyuki Hidaka、Masatomi Harada、Toshinari Tamura

  DOI：10.1021/jm00068a005

  日期：1993.8

  A series of spirooxazolidine-2,4-dione derivatives related to the putative M, agonist 2-ethyl-8-methyl-2,8-diazaspiro[4.5]decane-1,3-dione (RS86; 1) were synthesized. The compounds were evaluated as cholinergic agents in in vitro binding assays and in in vivo pharmacological tests including antiamnesic effects using scopolamine-treated mice, hypothermia, and salivation in mice. Four compounds (5a,c,f and 17a) exhibited affinity for cortical M1 receptors and reversed scopolamine-induced impairment of mouse passive avoidance tasks, as did 1. Among these compounds, only 5a exhibited M1-receptor stimulating activity in pithed rats. Structural requirements for muscarinic activity in this series of spirooxazolidine-2,4-dione derivatives were as strict as those reported for spirosuccinimide derivatives including 1. The antiamnesic dose of 3-ethyl-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2,4-dione (5a) was 2 orders of magnitude lower than the doses inducing hypothermia and salivation, in contrast to 1 for which the former dose was only 5-10-fold lower than the latter. These results suggest that the 8-azaspiro[4.5]decane skeleton represents a useful template for designing new muscarinic agonists as antidementia drugs.