tert-butyl-3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate | 209530-76-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 英文名称: tert-butyl-3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate
• 英文别名: tert-Butyl 3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate
• CAS: 209530-76-7
• 化学式: C₁₉H₂₇N₃O₃
• 分子量: 345.442
• InChiKey: ZBTCTIDRZAHCCK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  53.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl-3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 1.5h， 以91%的产率得到3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one
  参考文献：
  名称：

  Synthesis of [123I]-8-[4-[2-(5-iodothienyl)]-4-oxobutyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one: A potential dopamine D2 receptor radioligand for SPECT

  摘要：

  [I-123]-8-[4-[2-(5-Iodothienyl)]-4-oxobutyl]-3-methyl-1 phenyl-1,3,8-triazaspiro[4.5]-decan-4-one ((1) under bar)) has been synthesized as a potential ligand for dopamine D-2 receptors. This new compound proved to be moderate in lipophilicity (log P = 3.14) and exhibited high affinity (Ki = 1.9 nM) for the dopamine D-2 receptor as well as good selectivity for D-2 versus serotonin 5HT(2) receptors (Ki 5HT(2)/D-2 = 16.7) in vitro. The corresponding radioligand, I-123-(1) under bar, was synthesized from a thienyl tributylstannane precursor using oxidative iododestannylation methods. The radiochemical yield was 64-808 EOS (n = 5) and the purified product was >99% radiochemically purity with a specific activity >3,500 mCi/mu mol(>129,500 MBq/mu mol).

  DOI：

  10.1002/(sici)1099-1344(199805)41:5<363::aid-jlcr90>3.0.co;2-b
• 作为产物：
  描述：

  1-苯基-1,3,8-三唑螺环(4,5)十烷-4-酮 在 sodium hydride 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 26.17h， 生成 tert-butyl-3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate
  参考文献：
  名称：

  Synthesis of [123I]-8-[4-[2-(5-iodothienyl)]-4-oxobutyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one: A potential dopamine D2 receptor radioligand for SPECT

  摘要：

  [I-123]-8-[4-[2-(5-Iodothienyl)]-4-oxobutyl]-3-methyl-1 phenyl-1,3,8-triazaspiro[4.5]-decan-4-one ((1) under bar)) has been synthesized as a potential ligand for dopamine D-2 receptors. This new compound proved to be moderate in lipophilicity (log P = 3.14) and exhibited high affinity (Ki = 1.9 nM) for the dopamine D-2 receptor as well as good selectivity for D-2 versus serotonin 5HT(2) receptors (Ki 5HT(2)/D-2 = 16.7) in vitro. The corresponding radioligand, I-123-(1) under bar, was synthesized from a thienyl tributylstannane precursor using oxidative iododestannylation methods. The radiochemical yield was 64-808 EOS (n = 5) and the purified product was >99% radiochemically purity with a specific activity >3,500 mCi/mu mol(>129,500 MBq/mu mol).

  DOI：

  10.1002/(sici)1099-1344(199805)41:5<363::aid-jlcr90>3.0.co;2-b

文献信息

• [EN] SUBSTITUTED SPIROCYDIC INHIBITORS OF AUTOTAXIN<br/>[FR] INHIBITEURS SPIROCYCLIQUES SUBSTITUÉS DE L'AUTOTAXINE
  申请人：X RX DISCOVERY INC

  公开号：WO2015154023A1

  公开（公告）日：2015-10-08

  The present invention relates to compounds according to Formula 1 and pharmaceutically acceptable salts, synthesis, intermediates, formulations, and methods of disease treatment therewith, including cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus, mediated at least in part by ATX.

  本发明涉及根据公式1的化合物以及可药用的盐、合成方法、中间体、制剂以及用它们治疗疾病的方法，包括癌症、淋巴细胞归巢、慢性炎症、神经性疼痛、纤维化疾病、血栓形成和由ATX介导的胆汁淤积性瘙痒。
• Novel Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry
  作者：John W. Cuozzo、Matthew A. Clark、Anthony D. Keefe、Anna Kohlmann、Mark Mulvihill、Haihong Ni、Louis M. Renzetti、Daniel I. Resnicow、Frank Ruebsam、Eric A. Sigel、Heather A. Thomson、Ce Wang、Zhifeng Xie、Ying Zhang

  DOI：10.1021/acs.jmedchem.0c00688

  日期：2020.7.23

  with a number of human diseases including idiopathic pulmonary fibrosis (IPF). We screened a single DNA-encoded chemical library (DECL) of 225 million compounds and identified a series of potent inhibitors. Optimization of this series led to the discovery of compound 1 (X-165), a highly potent, selective, and bioavailable small molecule. Cocrystallization of compound 1 with human autotaxin demonstrated

  分泌的磷酸二酯酶自分泌生物素的活性产生炎症信号分子LPA，并与许多人类疾病有关，包括特发性肺纤维化（IPF）。我们筛选了一个含有2.25亿种化合物的单一DNA编码化学文库（DECL），并确定了一系列有效的抑制剂。该系列产品的优化导致发现化合物1（X-165），这是一种高效，选择性和生物利用度高的小分子。化合物1与人自分泌紫杉醇的共结晶表明，它具有一种新颖的结合模式，既占据了疏水口袋，又占据了自分泌紫杉醇活性位点附近的通道。化合物1在纳摩尔水平上抑制人和小鼠血浆中LPA的产生，并在人肺纤维化的小鼠模型中显示出功效。成功完成IND启用研究后，化合物1被FDA批准用于I期临床试验。这些结果表明DECL命中可以很容易地优化为临床候选。
• Substituted spirocyclic inhibitors of autotaxin
  申请人：X-Rx, Inc.

  公开号：US10011601B2

  公开（公告）日：2018-07-03

  The present invention relates to compounds according to Formula 1 and pharmaceutically acceptable salts, synthesis, intermediates, formulations, and methods of disease treatment therewith, including cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus, mediated at least in part by ATX.

  本发明涉及根据式 1 的化合物和药学上可接受的盐、合成、中间体、制剂以及用其治疗疾病的方法，包括至少部分由 ATX 介导的癌症、淋巴细胞归巢、慢性炎症、神经性疼痛、纤维化疾病、血栓形成和胆汁淤积性瘙痒症。
• SUBSTITUTED SPIROCYDIC INHIBITORS OF AUTOTAXIN
  申请人：X-RX, Inc.

  公开号：EP3125895A1

  公开（公告）日：2017-02-08
• SUBSTITUTED SPIROCYCLIC INHIBITORS OF AUTOTAXIN
  申请人：X-RX, INC.

  公开号：US20170166568A1

  公开（公告）日：2017-06-15

  The present invention relates to compounds according to Formula 1 and pharmaceutically acceptable salts, synthesis, intermediates, formulations, and methods of disease treatment therewith, including cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus, mediated at least in part by ATX.