2-[4-(dimethylamino)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid | 285552-83-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 2-[4-(dimethylamino)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid
• 英文别名: [2-(4-dimethylamino)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid；2-[4-(Dimethylamino)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid；2-[4-(dimethylamino)phenyl]-1,3-dioxoisoindole-5-carboxylic acid
• CAS: 285552-83-2
• 化学式: C₁₇H₁₄N₂O₄
• 分子量: 310.309
• InChiKey: STVUXSXNROPWJG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  77.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  α-(aminomethyl)-4-[2-(1-methylethoxy)phenyl]-1-piperazineethanol 、 2-[4-(dimethylamino)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid 在 4-二甲氨基吡啶 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以26%的产率得到2-[4-(dimethylamino)phenyl]-2,3-dihydro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide
  参考文献：
  名称：

  Design, Synthesis, and Structure−Activity Relationships of Phthalimide-Phenylpiperazines:  A Novel Series of Potent and Selective α_1a-Adrenergic Receptor Antagonists

  摘要：

  Beginning from the screening hit and literature alpha(1)-adrenergic compounds, a hybridized basic skeleton A was proposed as the pharmacophore for potent and selective alpha(1a)-AR antagonists. Introduction of a hydroxy group to increase the flexibility afforded B which served as the screening model and resulted in the identification of the second-generation lead 1. Using the Topliss approach, a number of potent and selective alpha(1a)-AR antagonists were discovered. In all cases, binding affinity and selectivity at the alpha(1a)-AR of S-hydroxy enantiomers were higher than those of the R-hydroxy enantiomers. As compared to the des-hydroxy analogues, the S-hydroxy enantiomers had slightly lower binding affinity at alpha(1a)-AR but gained more than 2-fold selectivity for alpha(1a)-AR over alpha(1b)-AR, and 2- to 6-fold selectivity for alpha(1a)-AR over alpha(1d)-AR. They also had less cross activities against a panel of 25-35 peripheral and CNS receptors. The S-hydroxy enantiomers 23 and 24 (K-i = 0.29 nM, 0.33 nM; alpha(1b)/alpha(1a) >5690, >6060; alpha(1d)/alpha(1a) = 186, 158, respectively) were slightly less potent but much more selective at alpha(1a)-AR than tamsulosin (K-i = 0.13 nM, alpha(1d)/alpha(1a)= 14.8, alpha(1d)/alpha(1a) = 1.4). In the functional assay, the S-hydroxy enantiomers 20, 23, and 24 were less potent than tamsulosin in inhibiting contractions of rat prostate tissue but more selective in the inhibition of tissue contractions of rat prostate versus rat aorta. Compound 24 was selected as the development candidate for the treatment of BPH.

  DOI：

  10.1021/jm9905918
• 作为产物：
  描述：

  N,N-二甲基-对苯二胺 、 偏苯三酸酐 以 溶剂黄146 为溶剂， 反应 16.0h， 以71%的产率得到2-[4-(dimethylamino)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid
  参考文献：
  名称：

  Phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia

  摘要：

  这项发明涉及到一系列Formula II的替代哌嗪，以及其对映体。这些化合物在制药组合物的制造中是有用的。

  公开号：

  US06362338B1

文献信息

• Phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia
  申请人：Ortho-McNeil Pharmaceutical, Inc.

  公开号：US06362338B1

  公开（公告）日：2002-03-26

  This invention relates to a series of substituted piperazines of Formula II, as well as enantiomers thereof These compounds are useful in the manufacture of pharmaceutical compositions.

  这项发明涉及到一系列Formula II的替代哌嗪，以及其对映体。这些化合物在制药组合物的制造中是有用的。
• An improved synthesis of enantiomerically pure RWJ 69442, a development candidate for the treatment of benign prostatic hyperplasia
  作者：Gee-Hong Kuo、Catherine Prouty、William V. Murray、Rekha D. Shah

  DOI：10.1002/jhet.5570380433

  日期：2001.7

  This report describes an improved synthesis of enantiomerically pure (S)-2-[4-(Dimethylamino)phenyl]-2,3-dihydro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)-phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide (RWJ 69442), a potent and selective αla-adrenergic receptor antagonist for the treatment of benign prostatic hyperplasia. The synthesis highlights less hazardous reagents, easier purification

  该报告描述了对映体纯的（S）-2- [4-（二甲基氨基）苯基] -2,3-二氢-N- [2-羟基-3- [4- [2-（1-甲基乙氧基） -苯基] -1-哌嗪基〕丙基〕-1,3-二氧代-1- ħ -异吲哚-5-甲酰胺（RWJ 69442），一个有效的和选择性α拉-肾上腺素能受体拮抗剂用于治疗良性前列腺增生的治疗。该合成突出显示了较少的危险试剂，更易于纯化和更高的对映体纯度。所述Ñ苄基N-叔丁氧羰基胺6可以作为对映体纯的手性结构单元为不对称合成。
• Design, Synthesis, and Structure−Activity Relationships of Phthalimide-Phenylpiperazines:  A Novel Series of Potent and Selective α₁_a-Adrenergic Receptor Antagonists
  作者：Gee-Hong Kuo、Catherine Prouty、William V. Murray、Virginia Pulito、Linda Jolliffe、Peter Cheung、Sally Varga、Mary Evangelisto、Jian Wang

  DOI：10.1021/jm9905918

  日期：2000.6.1

  Beginning from the screening hit and literature alpha(1)-adrenergic compounds, a hybridized basic skeleton A was proposed as the pharmacophore for potent and selective alpha(1a)-AR antagonists. Introduction of a hydroxy group to increase the flexibility afforded B which served as the screening model and resulted in the identification of the second-generation lead 1. Using the Topliss approach, a number of potent and selective alpha(1a)-AR antagonists were discovered. In all cases, binding affinity and selectivity at the alpha(1a)-AR of S-hydroxy enantiomers were higher than those of the R-hydroxy enantiomers. As compared to the des-hydroxy analogues, the S-hydroxy enantiomers had slightly lower binding affinity at alpha(1a)-AR but gained more than 2-fold selectivity for alpha(1a)-AR over alpha(1b)-AR, and 2- to 6-fold selectivity for alpha(1a)-AR over alpha(1d)-AR. They also had less cross activities against a panel of 25-35 peripheral and CNS receptors. The S-hydroxy enantiomers 23 and 24 (K-i = 0.29 nM, 0.33 nM; alpha(1b)/alpha(1a) >5690, >6060; alpha(1d)/alpha(1a) = 186, 158, respectively) were slightly less potent but much more selective at alpha(1a)-AR than tamsulosin (K-i = 0.13 nM, alpha(1d)/alpha(1a)= 14.8, alpha(1d)/alpha(1a) = 1.4). In the functional assay, the S-hydroxy enantiomers 20, 23, and 24 were less potent than tamsulosin in inhibiting contractions of rat prostate tissue but more selective in the inhibition of tissue contractions of rat prostate versus rat aorta. Compound 24 was selected as the development candidate for the treatment of BPH.