(1S,3R)-甲基-1,2,3,4-四氢-1-(3,4-亚甲二氧基苯基)-9H-吡啶并[3,4-b]吲哚-3-羧酸酯 | 171596-42-2

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 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
• 中文名称: (1S,3R)-甲基-1,2,3,4-四氢-1-(3,4-亚甲二氧基苯基)-9H-吡啶并[3,4-b]吲哚-3-羧酸酯
• 中文别名: 他达拉非杂质7
• 英文名称: (1S,3R)-1-(benzo[1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester
• 英文别名: methyl (1S,3R)-1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate；(1S,3R)-Methyl-1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate；methyl (1S,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate
• CAS: 171596-42-2
• 化学式: C₂₀H₁₈N₂O₄
• 分子量: 350.374
• InChiKey: LIPVUDSNGRJSQE-QAPCUYQASA-N

物化性质

• 熔点：
  83-85°C
• 沸点：
  531.0±50.0 °C(Predicted)
• 密度：
  1.359±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于丙酮（少许）、氯仿（少许）、乙酸乙酯（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  72.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (1S,3R)-甲基-1,2,3,4-四氢-1-(3,4-亚甲二氧基苯基)-9H-吡啶并[3,4-b]吲哚-3-羧酸酯 在 碳酸氢钠 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 49.0h， 生成 顺式-ent-他达拉非
  参考文献：
  名称：

  Synthesis and SAR of tetracyclic pyrroloquinolones as phosphodiesterase 5 inhibitors

  摘要：

  The synthesis of the fused tetracyclic pyrroloquinolones 9a-i in four steps is described. The PDE5 inhibitory activities of these compounds, their selectivities against PDE1, PDE2, PDE3, PDE4 and PDE6, the preclinical pharmacokinetic assessments and the in vivo efficacy in increasing intracavernosal pressure are presented and discussed. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2003.12.044
• 作为产物：
  描述：

  (1S,3S)-1-(1,3-苯并二氧戊环-5-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯 在 palladium 10% on activated carbon 、 氢气 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 N,N-二异丙基乙胺 作用下， 以 乙腈 为溶剂， 60.0~81.0 ℃ 、111.47 kPa 条件下， 反应 31.0h， 生成 (1S,3R)-甲基-1,2,3,4-四氢-1-(3,4-亚甲二氧基苯基)-9H-吡啶并[3,4-b]吲哚-3-羧酸酯
  参考文献：
  名称：

  Highly stereoselective transformation of (1S,3S)-cis-1,3-disubstituted tetrahydro-β-carbolines into (1S,3R)-trans-1,3-disubstituted tetrahydro-β-carbolines: an improved asymmetric synthesis of tadalafil from l-tryptophan

  摘要：

  An efficient and general method for the highly stereoselective transformation of (1S,3S)-cis-1,3-disubstituted 1,2,3,4-tetrahydro-beta-carbolines (THBCs) into (15,3R)-trans-1,3-disubstituted THBCs is described. The method contains the following three steps: the enantiomerically pure (1S,3S)-cis-1,3-disubstituted THBCs 1 were first converted into (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 by N-1-naphthylmethylation/benzylation; (15,3S)-cis-1,2,3-trisubstituted THBCs 2 were then converted into (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 in high yields and with high stereoselectivities via a base-catalyzed epimerization at C-3; (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 were subsequently converted into (15,3R)-trans-1,3-disubstituted THBCs 4 after reductive removal of the 1-naphthylmethyl/benzyl group. In addition, as an application of this method, an improved and highly stereoselective synthesis of the PDE5 inhibitor tadalafil (Cialis (R)) starting from natural and less expensive L-tryptophan was developed. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetasy.2013.06.006

文献信息

• [EN] NOVEL DUAL MODE OF ACTION SOLUBLE GUANYLATE CYCLASE ACTIVATORS AND PHOSPHODIESTERASE INHIBITORS AND USES THEREOF<br/>[FR] NOUVEAUX ACTIVATEURS DE LA GUANYLATE CYCLASE SOLUBLE À DOUBLE MODE D'ACTION ET INHIBITEURS DE PHOSPHODIESTÉRASE ET LEURS UTILISATIONS
  申请人：TOPADUR PHARMA AG

  公开号：WO2021245192A1

  公开（公告）日：2021-12-09

  The present invention relates to compounds of formula (I), or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein said compound of formula (I) comprises at least one covalently bound -ONO2 or -ONO moiety and at most four covalently bound -ONO2 or -ONO moieties, and wherein AR, R1, X, R3 and R4 are as defined in claim 1; and pharmaceutical compositions thereof, and their use in methods of treating or preventing a disease alleviated by inhibition of PDE5 in a human or in a non-human mammal.

  本发明涉及式(I)的化合物，或其药学上可接受的盐、溶剂或水合物，其中所述式(I)的化合物至少包括一个共价结合的-ONO2或-ONO基团，最多包括四个共价结合的-ONO2或-ONO基团，其中AR、R1、X、R3和R4如权利要求1所定义；以及其药物组合物，以及它们在治疗或预防通过抑制人类或非人类哺乳动物中的PDE5而缓解的疾病的方法中的使用。
• Potassium Superoxide as an Alternative Reagent for Winterfeldt Oxidation of β-Carbolines
  作者：Weiqin Jiang、Xuqing Zhang、Zhihua Sui

  DOI：10.1021/ol0271279

  日期：2003.1.1

  Potassium superoxide was examined as an alternative oxidation reagent for the Winterfeldt reaction. KO(2) was found to be superior to the original Winterfeldt protocol for base-sensitive substrates. [reaction--see text]

  研究了过氧化钾作为温特费尔特反应的替代氧化剂。发现KO（2）优于原始的Winterfeldt协议用于碱敏底物。[反应-见文字]
• Cyclic gmp-specific phosphodiesterase inhibitors
  申请人：——

  公开号：US20030225093A1

  公开（公告）日：2003-12-04

  Compounds of 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 Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer’s Disease
  作者：Fei Mao、Huan Wang、Wei Ni、Xinyu Zheng、Manjiong Wang、Keting Bao、Dazheng Ling、Xiaokang Li、Yixiang Xu、Haiyan Zhang、Jian Li

  DOI：10.1021/acschemneuro.7b00345

  日期：2018.2.21

  drug discovery strategies of repurposing and redeveloping existing drugs, a series of novel tadalafil derivatives were rationally designed, synthesized, and evaluated to seek dual-target AChE/PDE5 inhibitors as good candidate drugs for Alzheimer’s disease (AD). Among these derivatives, 1p and 1w exhibited excellent selective dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier

  通过重新利用和重新开发现有药物的药物发现策略，合理地设计，合成和评估了一系列新型他达拉非衍生物，以寻找双靶点AChE / PDE5抑制剂作为阿尔茨海默氏病（AD）的良好候选药物。在这些衍生物中，1p和1w表现出优异的选择性双靶AChE / PDE5抑制活性和改善的血脑屏障（BBB）渗透性。重要的是1w·Cit（柠檬酸盐为1w）可以逆转东pol碱诱导的AD小鼠的认知功能障碍，并在增强体内cAMP反应元件结合蛋白（CREB）磷酸化方面表现出优异的作用，这是记忆形成和突触可塑性的关键因素。此外，与hAChE和hPDE5A的1w分子对接模拟证实了我们的设计策略是合理的。总而言之，我们的研究提供了一种潜在的选择性双靶AChE / PDE5抑制剂，作为治疗AD的良好候选药物，它也可以被视为小分子探针，以验证体内新颖的AD治疗方法。
• CHIRAL TETRA-HYDRO BETA-CARBOLINE DERIVATIVES AND APPLICATIONS THEREOF AS ANTIPARASITIC COMPOUNDS
  申请人：Université de Lille 2 Droit et Santé

  公开号：EP1914235A1

  公开（公告）日：2008-04-23

  The invention relates to the use of chiral tetra-hydro β-carboline derivatives of formula (I) for the preparation of pharmaceutical composition for the prevention and/or the treatment of parasitic diseases involving parasites having a phosphodiesterase activity: or a pharmaceutically acceptable salt thereof, in which: - R1 and R2, identical or different, represent a hydrogen atom or a fluorine atom; - k is an integer equal to 0 or 1; - R3 is selected from the group consisting of: ■ a phenyl ring optionally substituted ■ a 3'-N-pyridine ring optionally substituted - R4 is a group selected in the group consisting of the following groups: -NH-A-R5, -NHC(O)-R5 and the groups of formulas (II-a) to (II-c) below: The invention also relates to some new chiral tetra-hydro β-carboline derivatives.

  该发明涉及使用手性四氢β-咔啉衍生物的化学式(I)来制备用于预防和/或治疗涉及具有磷酸二酯酶活性的寄生虫引起的寄生虫疾病的药物组合物，或其药用盐，其中：- R1和R2，相同或不同，代表氢原子或氟原子；- k为0或1的整数；- R3从以下群组中选择：■ 可选择取代的苯环■ 可选择取代的3'-N-吡啶环- R4是从以下群组中选择的一个基团：-NH-A-R5，-NHC(O)-R5和下面的化学式(II-a)到(II-c)的基团：该发明还涉及一些新的手性四氢β-咔啉衍生物。

表征谱图