(S)-2-(tert-butoxycarbonylamino)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propanoic acid | 158574-73-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-2-(tert-butoxycarbonylamino)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propanoic acid
• 英文别名: (2S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid
• CAS: 158574-73-3
• 化学式: C₁₆H₂₁NO₆
• 分子量: 323.346
• InChiKey: SLFSRSMNPFXTCT-NSHDSACASA-N

物化性质

• 沸点：
  498.8±45.0 °C(Predicted)
• 密度：
  1?+-.0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  94.1
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (S)-2-(tert-butoxycarbonylamino)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propanoic acid 在 isobutyl chloroformate 、 氢溴酸 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 6.5h， 生成 (S)-3-(tert-butoxycarbonylamino)-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxobutyl acetate
  参考文献：
  名称：

  Design and Preparation of a Potent Series of Hydroxyethylamine Containing β-Secretase Inhibitors That Demonstrate Robust Reduction of Central β-Amyloid

  摘要：

  A series of potent hydroxyethyl amine (HEA) derived inhibitors of beta-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogues that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS beta-amyloid (A beta) in Sprague-Dawley rats following oral administration.

  DOI：

  10.1021/jm300119p
• 作为产物：
  描述：

  (S)-methyl 2-(tert-butoxycarbonylamino)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propanoate 在 lithium hydroxide monohydrate 、 盐酸 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 2.0h， 以2.93 g的产率得到(S)-2-(tert-butoxycarbonylamino)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propanoic acid
  参考文献：
  名称：

  Design and Preparation of a Potent Series of Hydroxyethylamine Containing β-Secretase Inhibitors That Demonstrate Robust Reduction of Central β-Amyloid

  摘要：

  A series of potent hydroxyethyl amine (HEA) derived inhibitors of beta-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogues that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS beta-amyloid (A beta) in Sprague-Dawley rats following oral administration.

  DOI：

  10.1021/jm300119p

文献信息

• Studies on Neurokinin Antagonists. 4. Synthesis and Structure-Activity Relationships of Novel Dipeptide Substance P Antagonists: N2-[(4R)-4-Hydroxy-1-[(1-methyl-1H-indol-3-yl)carbonyl]-L-prolyl]-N-methyl-N-(phenylmethyl)-3-(2-naphthyl)-L-alaninamide and Its Related Compounds
  作者：Daijiro Hagiwara、Hiroshi Miyake、Norihiro Igari、Masako Karino、Yasue Maeda、Takashi Fujii、Masaaki Matsuo

  DOI：10.1021/jm00039a022

  日期：1994.6

  As an extension of our studies on discovering a novel substance P (SP) antagonist, we modified the previously reported dipeptide, N-2-[N-2-(1H-indol-3-ylcarbonyl)-L-lysyl]-N-methyl-N-(phenylmethyl)-L-phenylalaninamide (2b). The lysine part in 2b was first optimized to a (2S,4R)hydroxyproline derivative (3h),which is 2-fold more potent than 2b in [H-3]SP binding assay using guinea pig lung membranes. Next we modified the 1H-indol-3-ylcarbonyl part in 3h. Introduction; of a methyl group at the indole nitrogen enhanced the oral activity, while retaining the binding activity. Finally, we modified the phenylalanine part to culminate in the most potent compound 7k (FK888), which is a potent SP antagonist with NK1 selectivity as well as oral activity.
• Design and Preparation of a Potent Series of Hydroxyethylamine Containing β-Secretase Inhibitors That Demonstrate Robust Reduction of Central β-Amyloid
  作者：Matthew M. Weiss、Toni Williamson、Safura Babu-Khan、Michael D. Bartberger、James Brown、Kui Chen、Yuan Cheng、Martin Citron、Michael D. Croghan、Thomas A. Dineen、Joel Esmay、Russell F. Graceffa、Scott S. Harried、Dean Hickman、Stephen A. Hitchcock、Daniel B. Horne、Hongbing Huang、Ronke Imbeah-Ampiah、Ted Judd、Matthew R. Kaller、Charles R. Kreiman、Daniel S. La、Vivian Li、Patricia Lopez、Steven Louie、Holger Monenschein、Thomas T. Nguyen、Lewis D. Pennington、Claire Rattan、Tisha San Miguel、E.Allen Sickmier、Robert C. Wahl、Paul H. Wen、Stephen Wood、Qiufen Xue、Bryant H. Yang、Vinod F. Patel、Wenge Zhong

  DOI：10.1021/jm300119p

  日期：2012.11.8

  A series of potent hydroxyethyl amine (HEA) derived inhibitors of beta-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogues that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS beta-amyloid (A beta) in Sprague-Dawley rats following oral administration.