(1R,3R)-(2-chloroacetyl)-1-(2,2-difluorobenzo[1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester | 1018815-45-6

• 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)-(2-chloroacetyl)-1-(2,2-difluorobenzo[1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester
• 英文别名: (1R,3R)-2-(2-chloro-acetyl)-1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester；(1R,3R)-methyl 2-(2-chloroacetyl)-1-(2,2-difluorobenzo[d]-dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4,-b]indole-3-carboxylate；methyl (1R,3R)-2-(2-chloroacetyl)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate
• CAS: 1018815-45-6
• 化学式: C₂₂H₁₇ClF₂N₂O₅
• 分子量: 462.837
• InChiKey: MYHOJUDBOTXCPV-FOIQADDNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  80.9
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (1R,3R)-(2-chloroacetyl)-1-(2,2-difluorobenzo[1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester 、 甲胺-D5 以 甲醇 为溶剂， 反应 17.0h， 生成 (6R,12aR)-6-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-2-trideuteromethyl-1,4-dione
  参考文献：
  名称：

  Novel pharmaceutical compounds

  摘要：

  本发明涉及替代他达拉非的衍生物，在苯并二氧杂环戊二烷环的氧原子之间的亚甲基碳原子上取代氟，并且可选地进一步用氘原子取代正常丰富的氢，以及用13C取代正常丰富的12C。这些化合物是选择性的PDE5抑制剂，并具有有利的生物制药和药代动力学性质。该发明还提供了包含这些化合物的组合物和治疗对PDE5抑制有响应的疾病和症状的方法，单独或与其他药物联合使用。

  公开号：

  US20070037815A1
• 作为产物：
  描述：

  D-色氨酸甲酯盐酸盐 在 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 氯仿 为溶剂， 反应 17.0h， 生成 (1R,3R)-(2-chloroacetyl)-1-(2,2-difluorobenzo[1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester
  参考文献：
  名称：

  Drug-to-Genome-to-Drug, Step 2: Reversing Selectivity in a Series of Antiplasmodial Compounds

  摘要：

  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.

  DOI：

  10.1021/jm201422e

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。
• Novel pharmaceutical compounds
  申请人：Tung Roger

  公开号：US20070037815A1

  公开（公告）日：2007-02-15

  The present invention relates to derivatives of tadalafil, substituted with fluorine on the methylene carbon atom situated between the oxygens of the benzodioxol ring, and optionally further substituted with deuterium atoms in place of normally abundant hydrogen, and 13 C in place of normally abundant 12 C. These compounds are selective PDE5 inhibitors and possess advantageous biopharmaceutical and pharmacokinetic properties. The invention further provides compositions comprising these compounds and methods of treating diseases and conditions that are responsive to PDE5 inhibition, alone and in combination with additional agents.

  本发明涉及替代他达拉非的衍生物，在苯并二氧杂环戊二烷环的氧原子之间的亚甲基碳原子上取代氟，并且可选地进一步用氘原子取代正常丰富的氢，以及用13C取代正常丰富的12C。这些化合物是选择性的PDE5抑制剂，并具有有利的生物制药和药代动力学性质。该发明还提供了包含这些化合物的组合物和治疗对PDE5抑制有响应的疾病和症状的方法，单独或与其他药物联合使用。
• 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.