4-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)(hydroxy)methyl]-N,N-diethylbenzamide | 308110-32-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)(hydroxy)methyl]-N,N-diethylbenzamide
• 英文别名: 4-[(2,2-dimethyl-3H-1-benzofuran-7-yl)-hydroxymethyl]-N,N-diethylbenzamide
• CAS: 308110-32-9
• 化学式: C₂₂H₂₇NO₃
• 分子量: 353.461
• InChiKey: ZHNWKVZERMDYBZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)(hydroxy)methyl]-N,N-diethylbenzamide 在 氯化亚砜 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 13.0h， 生成 4-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)(1-piperazinyl)methyl]-N,N-diethylbenzamide
  参考文献：
  名称：

  New Diarylmethylpiperazines as Potent and Selective Nonpeptidic δ Opioid Receptor Agonists with Increased In Vitro Metabolic Stability

  摘要：

  Nonpeptide delta opioid agonists are analgesics with a potentially improved side-effect and abuse liability profile, compared to classical opioids. Andrews analysis of the NIH nonpeptide lead SNC-80 suggested the removal of substituents not predicted to contribute to binding. This approach led to a simplified lead, N,N-diethyl-4-[phenyl( 1-piperazinyl)methyl]benzamide (1), which retained potent binding affinity and selectivity to the human delta receptor (IC50 = 11 nM, mu/delta = 740, kappa/delta > 900) and potency as a full agonist (EC50 = 36 nM) but had a markedly reduced molecular weight, only one chiral center, and increased in vitro metabolic stability. From this lead, the key pharmacophore groups for delta receptor affinity and activation were more clearly defined by SAR and mutagenesis studies. Further structural modifications on the basis of 1 confirmed the importance of the N,N-diethylbenzamide group and the piperazine lower basic nitrogen for delta binding, in agreement with mutagenesis data. A number of piperazine N-alkyl substituents were tolerated. In contrast, modifications of the phenyl group led to the discovery of a series of diarylmethylpiperazines exemplified by N,N-diethyl-4-[1-piperazinyl(8-quinolinyl)- methyl]benzamide (56) which had an improved in vitro binding profile (IC50 = 0.5 nM, mu/delta = 1239, EC50 = 3.6 nM) and increased in vitro metabolic stability compared to SNC-80.

  DOI：

  10.1021/jm000228x
• 作为产物：
  描述：

  呋喃酚 在 吡啶 、 1,1'-双(二苯基膦)二茂铁 、 palladium diacetate 、 重铬酸吡啶 、 正丁基锂 、 二异丁基氢化铝 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 二氯甲烷 、 二甲基亚砜 、 甲苯 为溶剂， 反应 19.0h， 生成 4-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)(hydroxy)methyl]-N,N-diethylbenzamide
  参考文献：
  名称：

  New Diarylmethylpiperazines as Potent and Selective Nonpeptidic δ Opioid Receptor Agonists with Increased In Vitro Metabolic Stability

  摘要：

  Nonpeptide delta opioid agonists are analgesics with a potentially improved side-effect and abuse liability profile, compared to classical opioids. Andrews analysis of the NIH nonpeptide lead SNC-80 suggested the removal of substituents not predicted to contribute to binding. This approach led to a simplified lead, N,N-diethyl-4-[phenyl( 1-piperazinyl)methyl]benzamide (1), which retained potent binding affinity and selectivity to the human delta receptor (IC50 = 11 nM, mu/delta = 740, kappa/delta > 900) and potency as a full agonist (EC50 = 36 nM) but had a markedly reduced molecular weight, only one chiral center, and increased in vitro metabolic stability. From this lead, the key pharmacophore groups for delta receptor affinity and activation were more clearly defined by SAR and mutagenesis studies. Further structural modifications on the basis of 1 confirmed the importance of the N,N-diethylbenzamide group and the piperazine lower basic nitrogen for delta binding, in agreement with mutagenesis data. A number of piperazine N-alkyl substituents were tolerated. In contrast, modifications of the phenyl group led to the discovery of a series of diarylmethylpiperazines exemplified by N,N-diethyl-4-[1-piperazinyl(8-quinolinyl)- methyl]benzamide (56) which had an improved in vitro binding profile (IC50 = 0.5 nM, mu/delta = 1239, EC50 = 3.6 nM) and increased in vitro metabolic stability compared to SNC-80.

  DOI：

  10.1021/jm000228x

文献信息

• Novel compounds
  申请人：——

  公开号：US20030105110A1

  公开（公告）日：2003-06-05

  Compounds of general formula (I), wherein R 1 selected from phenyl, pyridinyl, thiophenyl, furanyl, imidazolyl, and triazolyl; where each R 1 phenyl ring and R 1 heteroaromatic ring may optionally and independently be further substituted by 1, 2 or 3 substituents selected from straight and branched C 1 -C 6 alkyl, NO 2 , CF 3 , C 1 -C 6 alkoxy, chloro, fluoro, bromo, and iodo.

  通式（I）的化合物，其中R1选自苯基、吡啶基、噻吩基、呋喃基、咪唑基和三唑基；其中每个R1苯环和R1杂环可能且独立地进一步被1、2或3个取自直链和支链C1-C6烷基、NO2、CF3、C1-C6烷氧基、氯、氟、溴和碘的取代基所取代。
• NOVEL COMPOUNDS
  申请人：AstraZeneca AB

  公开号：EP1242410A1

  公开（公告）日：2002-09-25
• US6680318B2
  申请人：——

  公开号：US6680318B2

  公开（公告）日：2004-01-20
• [EN] NOVEL COMPOUNDS<br/>[FR] NOUVEAUX COMPOSES
  申请人：ASTRAZENECA AB

  公开号：WO2001046174A1

  公开（公告）日：2001-06-28

  Compounds of general formula (I), wherein R1 selected from phenyl, pyridinyl, thiophenyl, furanyl, imidazolyl, and triazolyl; where each R1 phenyl ring and R1 heteroaromatic ring may optionally and independently be further substituted by 1, 2 or 3 substituents selected from straight and branched C¿1?-C6 alkyl, NO2, CF3, C1-C6 alkoxy, chloro, fluoro, bromo, and iodo.