N-(5,6-Dimethoxy-indan-2-yl)-N-propyl-2-thiophen-2-yl-acetamide | 745060-18-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 茚满类
• 英文名称: N-(5,6-Dimethoxy-indan-2-yl)-N-propyl-2-thiophen-2-yl-acetamide
• 英文别名: N-(5,6-dimethoxy-2,3-dihydro-1H-inden-2-yl)-N-propyl-2-thiophen-2-ylacetamide
• CAS: 745060-18-8
• 化学式: C₂₀H₂₅NO₃S
• 分子量: 359.489
• InChiKey: MNHHZSWIKPVZKQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  25
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  67
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(5,6-Dimethoxy-indan-2-yl)-N-propyl-2-thiophen-2-yl-acetamide 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 为溶剂， 反应 3.5h， 以63%的产率得到(5,6-Dimethoxy-indan-2-yl)-propyl-(2-thiophen-2-yl-ethyl)-amine
  参考文献：
  名称：

  Dopamine D₃ Receptor Antagonists. 1. Synthesis and Structure−Activity Relationships of 5,6-Dimethoxy-N-alkyl- and N-Alkylaryl-Substituted 2-Aminoindans

  摘要：

  5,6-Dimethoxy-2-(N-dipropyl)-aminoindan (3, PNU-99194A) was found to be a selective dopamine D-3 receptor antagonist with potential antipsychotic properties in animal models. To investigate the effects of nitrogen substitution on structure-activity relationships, a series of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans were synthesized and evaluated in vitro for binding affinity and metabolic stability. The results indicate that substitution at the amine nitrogen of the 2-aminoindans is fairly limited to the di-N-propyl group in order to achieve selective D-3 antagonists. Thus, combinations of various alkyl groups were generally inactive at the D-3 receptor. Although substitution with an N-alkylaryl or N-alkylheteroaryl group yields compounds with potent D-3 binding affinity, the D-2 affinity is also enhanced, resulting in a less than 4-fold preference for the D-3 receptor site, and no improvements in metabolic stability were noted. A large-scale synthesis of the D-3 antagonist 3 has been developed that has proven to be reproducible with few purification steps. The improvements include the use of 3,4-dimethoxybenzaldehyde as a low-cost starting material to provide the desired 5,6-dimethoxy-1-indanone 5c in good overall yield (65%) and the formation of a soluble silyl oxime 17 that was reduced efficiently with BH3. Me2S. The resulting amino alcohol was alkylated and then deoxygenated using a Lewis acid and Et3SiH to give the desired product 3 in good overall yield of (similar to 65%) from the indanone 5c.

  DOI：

  10.1021/jm010145w
• 作为产物：
  描述：

  3-(3,4-dimethoxy-phenyl)-propionyl chloride 在 10percent Pd/C 盐酸 、 lithium aluminium tetrahydride 、 三氯化铝 、 亚硝酸丁酯 、 氰基磷酸二乙酯 、 硫酸 、 氢气 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 溶剂黄146 为溶剂， 20.0~40.0 ℃ 、344.75 kPa 条件下， 反应 42.5h， 生成 N-(5,6-Dimethoxy-indan-2-yl)-N-propyl-2-thiophen-2-yl-acetamide
  参考文献：
  名称：

  Dopamine D₃ Receptor Antagonists. 1. Synthesis and Structure−Activity Relationships of 5,6-Dimethoxy-N-alkyl- and N-Alkylaryl-Substituted 2-Aminoindans

  摘要：

  5,6-Dimethoxy-2-(N-dipropyl)-aminoindan (3, PNU-99194A) was found to be a selective dopamine D-3 receptor antagonist with potential antipsychotic properties in animal models. To investigate the effects of nitrogen substitution on structure-activity relationships, a series of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans were synthesized and evaluated in vitro for binding affinity and metabolic stability. The results indicate that substitution at the amine nitrogen of the 2-aminoindans is fairly limited to the di-N-propyl group in order to achieve selective D-3 antagonists. Thus, combinations of various alkyl groups were generally inactive at the D-3 receptor. Although substitution with an N-alkylaryl or N-alkylheteroaryl group yields compounds with potent D-3 binding affinity, the D-2 affinity is also enhanced, resulting in a less than 4-fold preference for the D-3 receptor site, and no improvements in metabolic stability were noted. A large-scale synthesis of the D-3 antagonist 3 has been developed that has proven to be reproducible with few purification steps. The improvements include the use of 3,4-dimethoxybenzaldehyde as a low-cost starting material to provide the desired 5,6-dimethoxy-1-indanone 5c in good overall yield (65%) and the formation of a soluble silyl oxime 17 that was reduced efficiently with BH3. Me2S. The resulting amino alcohol was alkylated and then deoxygenated using a Lewis acid and Et3SiH to give the desired product 3 in good overall yield of (similar to 65%) from the indanone 5c.

  DOI：

  10.1021/jm010145w

文献信息

• Dopamine D₃ Receptor Antagonists. 1. Synthesis and Structure−Activity Relationships of 5,6-Dimethoxy-<i>N</i>-alkyl- and <i>N</i>-Alkylaryl-Substituted 2-Aminoindans
  作者：Susanne R. Haadsma-Svensson、Kerry A. Cleek、Dac M. Dinh、J. Neil Duncan、Christopher L. Haber、Rita M. Huff、Mary E. Lajiness、Nanette F. Nichols、Martin W. Smith、Kjell A. Svensson、Matt J. Zaya、Arvid Carlsson、Chiu-Hong Lin

  DOI：10.1021/jm010145w

  日期：2001.12.1

  5,6-Dimethoxy-2-(N-dipropyl)-aminoindan (3, PNU-99194A) was found to be a selective dopamine D-3 receptor antagonist with potential antipsychotic properties in animal models. To investigate the effects of nitrogen substitution on structure-activity relationships, a series of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans were synthesized and evaluated in vitro for binding affinity and metabolic stability. The results indicate that substitution at the amine nitrogen of the 2-aminoindans is fairly limited to the di-N-propyl group in order to achieve selective D-3 antagonists. Thus, combinations of various alkyl groups were generally inactive at the D-3 receptor. Although substitution with an N-alkylaryl or N-alkylheteroaryl group yields compounds with potent D-3 binding affinity, the D-2 affinity is also enhanced, resulting in a less than 4-fold preference for the D-3 receptor site, and no improvements in metabolic stability were noted. A large-scale synthesis of the D-3 antagonist 3 has been developed that has proven to be reproducible with few purification steps. The improvements include the use of 3,4-dimethoxybenzaldehyde as a low-cost starting material to provide the desired 5,6-dimethoxy-1-indanone 5c in good overall yield (65%) and the formation of a soluble silyl oxime 17 that was reduced efficiently with BH3. Me2S. The resulting amino alcohol was alkylated and then deoxygenated using a Lewis acid and Et3SiH to give the desired product 3 in good overall yield of (similar to 65%) from the indanone 5c.