4-氨基螺[苯并二氢吡喃-2,4-哌啶]-1-羧酸叔丁酯盐酸盐 | 1243481-60-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 中文名称: 4-氨基螺[苯并二氢吡喃-2,4-哌啶]-1-羧酸叔丁酯盐酸盐
• 英文名称: tert-Butyl 4-aminospiro[chroman-2,4'-piperidine]-1'-carboxylate hydrochloride
• 英文别名: tert-butyl 4-aminospiro[3,4-dihydrochromene-2,4'-piperidine]-1'-carboxylate;hydrochloride
• CAS: 1243481-60-8
• 化学式: C₁₈H₂₆N₂O₃*ClH
• 分子量: 354.877
• InChiKey: IYEWEOVWGXSXQF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.66
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  64.8
• 氢给体数：
  2
• 氢受体数：
  4

安全信息

• 海关编码：
  2934999090

反应信息

• 作为反应物：
  描述：

  7-吲哚甲酸 、 4-氨基螺[苯并二氢吡喃-2,4-哌啶]-1-羧酸叔丁酯盐酸盐 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 tert-butyl 4-(1H-indole-7-carboxamido)spiro[chroman-2,4'-piperidine]-1'-carboxylate
  参考文献：
  名称：

  DNA-Encoded Library Technology-Based Discovery, Lead Optimization, and Prodrug Strategy toward Structurally Unique Indoleamine 2,3-Dioxygenase-1 (IDO1) Inhibitors

  摘要：

  We report the discovery of a novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor class through the affinity selection of a previously unreported indole-based DNA-encoded library (DEL). The DEL exemplar, spiro-chromane 1, had moderate IDO1 potency but high in vivo clearance. Series optimization quickly afforded a potent, low in vivo clearance lead 11. Although amorphous 11 was highly bio-available, crystalline 11 was poorly soluble and suffered disappointingly low bio-availability because of solubility-limited absorption. A prodrug approach was deployed and proved effective in discovering the highly bio-available phosphonooxymethyl 31, which rapidly converted to 11 in vivo. Obtaining crystalline 31 proved problematic, however; thus salt screening was performed in an attempt to circumvent this obstacle and successfully delivered greatly soluble and bio-available crystalline tris-salt 32. IDO1 inhibitor 32 is characterized by a low calculated human dose, best-in-class potential, and an unusual inhibition mode by binding the IDO1 heme-free (apo) form.

  DOI：

  10.1021/acs.jmedchem.9b01799
• 作为产物：
  描述：

  4-氧代-2-螺(N-叔丁基哌啶-4-基)-吡喃 在 盐酸 、 titanium(IV) tetraethanolate 、 sodium tetrahydroborate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 为溶剂， 反应 47.5h， 生成 4-氨基螺[苯并二氢吡喃-2,4-哌啶]-1-羧酸叔丁酯盐酸盐
  参考文献：
  名称：

  DNA-Encoded Library Technology-Based Discovery, Lead Optimization, and Prodrug Strategy toward Structurally Unique Indoleamine 2,3-Dioxygenase-1 (IDO1) Inhibitors

  摘要：

  We report the discovery of a novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor class through the affinity selection of a previously unreported indole-based DNA-encoded library (DEL). The DEL exemplar, spiro-chromane 1, had moderate IDO1 potency but high in vivo clearance. Series optimization quickly afforded a potent, low in vivo clearance lead 11. Although amorphous 11 was highly bio-available, crystalline 11 was poorly soluble and suffered disappointingly low bio-availability because of solubility-limited absorption. A prodrug approach was deployed and proved effective in discovering the highly bio-available phosphonooxymethyl 31, which rapidly converted to 11 in vivo. Obtaining crystalline 31 proved problematic, however; thus salt screening was performed in an attempt to circumvent this obstacle and successfully delivered greatly soluble and bio-available crystalline tris-salt 32. IDO1 inhibitor 32 is characterized by a low calculated human dose, best-in-class potential, and an unusual inhibition mode by binding the IDO1 heme-free (apo) form.

  DOI：

  10.1021/acs.jmedchem.9b01799