(1R,3R)-cis-methyl 2-(chloroacetyl)-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate | 629652-47-7

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 英文名称: (1R,3R)-cis-methyl 2-(chloroacetyl)-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate
• 英文别名: methyl (1R,3R)-1-(4-methoxyphenyl)-N-(2-chloroacetyl)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate；methyl (1R,3R)-2-(2-chloroacetyl)-1-(4-methoxyphenyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate
• CAS: 629652-47-7
• 化学式: C₂₂H₂₁ClN₂O₄
• 分子量: 412.873
• InChiKey: OVIYQPRIMZNGHW-WIYYLYMNSA-N

物化性质

• 熔点：
  223-225 °C(Solv: ethyl ether (60-29-7))
• 沸点：
  616.3±55.0 °C(Predicted)
• 密度：
  1.339±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  71.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (1R,3R)-cis-methyl 2-(chloroacetyl)-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate 在 palladium 10% on activated carbon 、 氢气 、 potassium carbonate 、 三乙胺 作用下， 以 甲醇 、 乙腈 为溶剂， 反应 34.17h， 生成 (6R,12aR)-2-(2-(1-(cyclohexylmethyl)piperidin-4-yl)ethyl)-6-(4-methoxyphenyl)-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]-pyrido[3,4-b]indole-1,4-dione
  参考文献：
  名称：

  4-甲氧基苯基取代四氢-β-咔啉哌嗪二酮类衍 生物及其应用

  摘要：

  本发明涉及一种4‑甲氧基苯基取代四氢‑β‑咔啉哌嗪二酮类衍生物及其应用。具体地，本发明公开了式I所示的化合物或其立体异构体，或其药学上可接受的盐，各基团的定义详见说明书。本发明的化合物具有乙酰胆碱酯酶和磷酸二酯酶5的双重抑制活性，具有良好的血脑屏障透过率。因此，本发明化合物可用于制备治疗和/或预防阿尔茨海默病药物。

  公开号：

  CN108409737B
• 作为产物：
  描述：

  D-色氨酸甲酯 在 碳酸氢钠 、 三氟乙酸 作用下， 以 二氯甲烷 、 氯仿 为溶剂， 生成 (1R,3R)-cis-methyl 2-(chloroacetyl)-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate
  参考文献：
  名称：

  The Discovery of Tadalafil:  A Novel and Highly Selective PDE5 Inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1‘,2‘:1,6]pyrido[3,4-b]indole-1,4-dione Analogues

  摘要：

  Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC50 = 5 nM) with high selectivity for PDE5 vs PDE1-4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil 1.12a showed profound and long-lasting blood pressure lowering activity (30 mmHg/> 7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).

  DOI：

  10.1021/jm0300577

文献信息

• Chemical compounds
  申请人：——

  公开号：US20030225094A1

  公开（公告）日：2003-12-04

  Compounds of the general structural formula (I) and use of the compounds and salts and solvates thereof, as therapeutic agents. 1

  通用结构式（I）的化合物及其盐和溶剂合物的用途，作为治疗剂。
• Design, synthesis and biological activity of β-carboline-based type-5 phosphodiesterase inhibitors
  作者：Graham N. Maw、Charlotte M.N. Allerton、Eugene Gbekor、William A. Million

  DOI：10.1016/s0960-894x(03)00159-8

  日期：2003.4

  The SAR of a series of beta-carboline derived type 5 phosphodiesterase inhibitors has been explored and we have discovered compounds with excellent levels of PDE5 potency and selectivity over PDE6. However, the series exhibits low levels of selectivity over PDE11, a phosphodiesterase with unknown function. (C) 2003 Elsevier Science Ltd. All rights reserved.
• Novel Tadalafil Derivatives Ameliorates Scopolamine-Induced Cognitive Impairment in Mice via Inhibition of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5)
  作者：Wei Ni、Huan Wang、Xiaokang Li、Xinyu Zheng、Manjiong Wang、Jian Zhang、Qi Gong、Dazheng Ling、Fei Mao、Haiyan Zhang、Jian Li

  DOI：10.1021/acschemneuro.8b00014

  日期：2018.7.18

  On the basis of the drug-repositioning and redeveloping strategy, first-generation dual-target inhibitors of acetylcholinesterase (AChE) and phosphodiesterase 5 (PDE5) have been recently reported as a potentially novel therapeutic method for the treatment of Alzheimer's disease (AD), and the lead compound 2 has proven this method was feasible in AD mouse models. In this study, our work focused on exploring alternative novel tadalafil derivatives (3a-s). Among the 19 analogues, compound 3c exhibited good selective dual-target AChE/PDE5 inhibition and good blood-brain barrier (BBB) permeability. Moreover, its citrate (3c center dot Cit) possessed improved water solubility and good effects against scopolamine-induced cognitive impairment with inhibition of cortical AChE activities and enhancement of cAMP response element-binding protein (CREB) phosphorylation ex vivo.
• 4-甲氧基苯基取代四氢-β-咔啉哌嗪二酮类衍 生物及其应用
  申请人：华东理工大学

  公开号：CN108409737B

  公开（公告）日：2020-07-03

  本发明涉及一种4‑甲氧基苯基取代四氢‑β‑咔啉哌嗪二酮类衍生物及其应用。具体地，本发明公开了式I所示的化合物或其立体异构体，或其药学上可接受的盐，各基团的定义详见说明书。本发明的化合物具有乙酰胆碱酯酶和磷酸二酯酶5的双重抑制活性，具有良好的血脑屏障透过率。因此，本发明化合物可用于制备治疗和/或预防阿尔茨海默病药物。
• The Discovery of Tadalafil:  A Novel and Highly Selective PDE5 Inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1‘,2‘:1,6]pyrido[3,4-<i>b</i>]indole-1,4-dione Analogues
  作者：Alain Daugan、Pascal Grondin、Cécile Ruault、Anne-Charlotte Le Monnier de Gouville、Hervé Coste、Jean Michel Linget、Jorge Kirilovsky、François Hyafil、Richard Labaudinière

  DOI：10.1021/jm0300577

  日期：2003.10.1

  Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC50 = 5 nM) with high selectivity for PDE5 vs PDE1-4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil 1.12a showed profound and long-lasting blood pressure lowering activity (30 mmHg/> 7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).