1-(2,6-Dimethyl-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester | 439287-50-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: 1-(2,6-Dimethyl-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester
• 英文别名: tert-butyl 1-[(2,6-dimethylphenyl)carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate
• CAS: 439287-50-0
• 化学式: C₂₃H₂₈N₂O₃
• 分子量: 380.487
• InChiKey: XHIYZFRIISJEHH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(2,6-Dimethyl-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 在 盐酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以71%的产率得到
  参考文献：
  名称：

  Synthesis and structure–activity relationships of potential anticonvulsants based on 2-piperidinecarboxylic acid and related pharmacophores

  摘要：

  Using N-(2,6-dimethyl)phenyl-2-piperidinecarboxamide (1) and N-(alpha -methylbenzyl)-2-piperidinecarboxamide (2) as structural leads, a variety of analogues were synthesised and evaluated for anticonvulsant activity in the MES test in mice. In the N-benzyl series, introduction of 3-Cl, 4-Cl, 3,4-Cl-2, or 3-CF3 groups on the aromatic ring led to an increase in MES activity. Replacement of the alpha -methyl group by either i-Pr or benzyl groups enhanced MES activity with no increase in neurotoxicity. Substitution on the piperidine ring nitrogen led to a decrease in MES activity and neurotoxicity, while reduction of the amide carbonyl led to a complete loss of activity. Movement of the carboxamide group to either the 3- or 4-positions of the piperidine ring decreased MES activity and neurotoxicity. Incorporation of the piperidine ring into a tetrahydroisoquinoline or diazahydrinone nucleus led to increased neurotoxicity. In the N-(2,6-dimethyl)phenyl series, opening of the piperidine ring between the 1- and 6-positions gave the active norleucine derivative 75 (ED50 = 5.8 mg kg(-1), TD50 = 36.4 mg kg(-1), PI = 6.3). Replacement of the piperidine ring of I by cycloalkane (cyclohexane, cyclopentane, and cyclobutane) resulted in compounds with decreased MES activity and neurotoxicity, whereas replacement of the piperidine ring by a 4-pyridyl group led to a retention of MES activity with a comparable PI. Simplification of the 2-piperidinecarboxamide nucleus of 1 into a glycinecarboxamide nucleus led to about a six-fold decrease in MES activity. The 2,6-dimethylanilides were the most potent compounds in the MES test in each group of compounds evaluated, and compounds 50 and 75 should be useful leads in the development of agents for the treatment of tonic-clonic and partial seizures in man. (C) 2001 Editions scientifiques et medicales Elsevier SAS.

  DOI：

  10.1016/s0223-5234(00)01206-x
• 作为产物：
  描述：

  1,2,3,4-四氢异喹啉-1-羧酸 在 N-甲基吗啉 、 sodium hydroxide 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 叔丁醇 为溶剂， 反应 1.08h， 生成 1-(2,6-Dimethyl-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Synthesis and structure–activity relationships of potential anticonvulsants based on 2-piperidinecarboxylic acid and related pharmacophores

  摘要：

  Using N-(2,6-dimethyl)phenyl-2-piperidinecarboxamide (1) and N-(alpha -methylbenzyl)-2-piperidinecarboxamide (2) as structural leads, a variety of analogues were synthesised and evaluated for anticonvulsant activity in the MES test in mice. In the N-benzyl series, introduction of 3-Cl, 4-Cl, 3,4-Cl-2, or 3-CF3 groups on the aromatic ring led to an increase in MES activity. Replacement of the alpha -methyl group by either i-Pr or benzyl groups enhanced MES activity with no increase in neurotoxicity. Substitution on the piperidine ring nitrogen led to a decrease in MES activity and neurotoxicity, while reduction of the amide carbonyl led to a complete loss of activity. Movement of the carboxamide group to either the 3- or 4-positions of the piperidine ring decreased MES activity and neurotoxicity. Incorporation of the piperidine ring into a tetrahydroisoquinoline or diazahydrinone nucleus led to increased neurotoxicity. In the N-(2,6-dimethyl)phenyl series, opening of the piperidine ring between the 1- and 6-positions gave the active norleucine derivative 75 (ED50 = 5.8 mg kg(-1), TD50 = 36.4 mg kg(-1), PI = 6.3). Replacement of the piperidine ring of I by cycloalkane (cyclohexane, cyclopentane, and cyclobutane) resulted in compounds with decreased MES activity and neurotoxicity, whereas replacement of the piperidine ring by a 4-pyridyl group led to a retention of MES activity with a comparable PI. Simplification of the 2-piperidinecarboxamide nucleus of 1 into a glycinecarboxamide nucleus led to about a six-fold decrease in MES activity. The 2,6-dimethylanilides were the most potent compounds in the MES test in each group of compounds evaluated, and compounds 50 and 75 should be useful leads in the development of agents for the treatment of tonic-clonic and partial seizures in man. (C) 2001 Editions scientifiques et medicales Elsevier SAS.

  DOI：

  10.1016/s0223-5234(00)01206-x

文献信息

• Synthesis and structure–activity relationships of potential anticonvulsants based on 2-piperidinecarboxylic acid and related pharmacophores
  作者：Bin Ho、A Michael Crider、James P Stables

  DOI：10.1016/s0223-5234(00)01206-x

  日期：2001.3

  Using N-(2,6-dimethyl)phenyl-2-piperidinecarboxamide (1) and N-(alpha -methylbenzyl)-2-piperidinecarboxamide (2) as structural leads, a variety of analogues were synthesised and evaluated for anticonvulsant activity in the MES test in mice. In the N-benzyl series, introduction of 3-Cl, 4-Cl, 3,4-Cl-2, or 3-CF3 groups on the aromatic ring led to an increase in MES activity. Replacement of the alpha -methyl group by either i-Pr or benzyl groups enhanced MES activity with no increase in neurotoxicity. Substitution on the piperidine ring nitrogen led to a decrease in MES activity and neurotoxicity, while reduction of the amide carbonyl led to a complete loss of activity. Movement of the carboxamide group to either the 3- or 4-positions of the piperidine ring decreased MES activity and neurotoxicity. Incorporation of the piperidine ring into a tetrahydroisoquinoline or diazahydrinone nucleus led to increased neurotoxicity. In the N-(2,6-dimethyl)phenyl series, opening of the piperidine ring between the 1- and 6-positions gave the active norleucine derivative 75 (ED50 = 5.8 mg kg(-1), TD50 = 36.4 mg kg(-1), PI = 6.3). Replacement of the piperidine ring of I by cycloalkane (cyclohexane, cyclopentane, and cyclobutane) resulted in compounds with decreased MES activity and neurotoxicity, whereas replacement of the piperidine ring by a 4-pyridyl group led to a retention of MES activity with a comparable PI. Simplification of the 2-piperidinecarboxamide nucleus of 1 into a glycinecarboxamide nucleus led to about a six-fold decrease in MES activity. The 2,6-dimethylanilides were the most potent compounds in the MES test in each group of compounds evaluated, and compounds 50 and 75 should be useful leads in the development of agents for the treatment of tonic-clonic and partial seizures in man. (C) 2001 Editions scientifiques et medicales Elsevier SAS.