(6R,12aR)-6-benzo[1,3]dioxol-5-yl-2-((R)-1-pyridin-2-ylmethylpyrrolidin-3-yl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (6R,12aR)-6-benzo[1,3]dioxol-5-yl-2-((R)-1-pyridin-2-ylmethylpyrrolidin-3-yl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
• 英文别名: (2R,8R)-2-(1,3-benzodioxol-5-yl)-6-[(3R)-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl]-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione
• 化学式: C₃₁H₂₉N₅O₄
• 分子量: 535.602
• InChiKey: ANDFVHKJKQGFLR-WIISGGPLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  40
• 可旋转键数：
  4
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  91
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  (6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-((R)-1-benzylpyrrolidin-3-yl)-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione 在 palladium on activated charcoal ammonium formate 、 三乙酰氧基硼氢化钠 、 溶剂黄146 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 生成 (6R,12aR)-6-benzo[1,3]dioxol-5-yl-2-((R)-1-pyridin-2-ylmethylpyrrolidin-3-yl)-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：

  Design, synthesis and biological activity of β-carboline-based type-5 phosphodiesterase inhibitors

  摘要：

  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.

  DOI：

  10.1016/s0960-894x(03)00159-8

文献信息

• 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。
• 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.
• [EN] CHIRAL TETRA-HYDRO BETA-CARBOLINE DERIVATIVES, APPLICATIONS THEREOF AS ANTIPARASITIC COMPOUNDS<br/>[FR] DÉRIVÉS CHIRAUX DE TÉTRA-HYDRO BÉTA-CARBOLINE, LEURS APPLICATIONS EN TANT QUE COMPOSÉS ANTIPARASITAIRES
  申请人：UNIV LILLE 2 UNIVERSITE DU DRO

  公开号：WO2008044144A2

  公开（公告）日：2008-04-17

  [EN] The Invention relates to the use of chiral tetra-hydro beta carboline derivatives for the preparation of a pharmaceutical composition for the prevention and/or the treatment of parasitic diseases involving parasites having a phosphodiesterase activity. The invention also relates to some new chiral tetra-hydro beta-carboline derivatives.
  [FR] L'invention concerne des dérivés de tétra-hydro béta carboline utilisés pour la préparation d'une composition pharmaceutique destinée à la prévention et/ou au traitement de maladies parasitaires impliquant des parasites ayant une activité phosphodiestérase. L'invention concerne également certains dérivés chiraux de tétra-hydro béta-carboline.
• Drug-to-Genome-to-Drug, Step 2: Reversing Selectivity in a Series of Antiplasmodial Compounds
  作者：Terence B. Beghyn、Julie Charton、Florence Leroux、Antoine Henninot、Irena Reboule、Paul Cos、Louis Maes、Benoit Deprez

  DOI：10.1021/jm201422e

  日期：2012.2.9

  In a recent paper, we have described the discovery of antimalarial compounds derived from tadalafil, using a drug-to-genome-to-drug approach (J. Med. Chem. 2011, 54 (9), pp 3222-3240). We have shown that these derivatives inhibit the phosphodiesterase activity of Plasmodium falciparum and the parasite growth in culture. In this paper, we describe the optimization of these compounds. A direct consequence of our approach based on gene orthology is the lack of selectivity of the compounds over the original activity on the human target. We demonstrate here that it is possible to take advantage of subtle differences in SAR between HsPDE5 inhibition and antiplasmodial activity to improve significantly the selectivity. In particular, the replacement of the piperonyl group in compound 2 by a dimethozyphenyl group was the best way to optimize selectivity. This observation is consistent with the differences between human and plasmodial sequences in the Q2 pocket receiving this group.