N-丁基去甲他达拉非 | 171596-31-9

• 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
• 中文名称: N-丁基去甲他达拉非
• 英文名称: (6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-butyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
• 英文别名: (6R,12aR)-6-benzo[1,3]dioxol-5-yl-2-butyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione；N-butyltadalafil；N-Butyl Nortadalafil；(2R,8R)-2-(1,3-benzodioxol-5-yl)-6-butyl-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione
• CAS: 171596-31-9
• 化学式: C₂₅H₂₅N₃O₄
• 分子量: 431.491
• InChiKey: KYRHHTFKIXWPJS-NTKDMRAZSA-N

物化性质

• 熔点：
  209-210 °C(Solv: hexane (110-54-3); toluene (108-88-3))
• 沸点：
  689.5±55.0 °C(Predicted)
• 密度：
  1.41±0.1 g/cm3(Predicted)
• 溶解度：
  氯仿（微溶）、甲醇（微溶、加热）

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  74.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  D-色氨酸甲酯 在 三乙胺 、 三氟乙酸 作用下， 以 乙醇 、 二氯甲烷 、 氯仿 为溶剂， 反应 24.0h， 生成 N-丁基去甲他达拉非
  参考文献：
  名称：

  Drug to Genome to Drug: Discovery of New Antiplasmodial Compounds

  摘要：

  The dominant strategy for discovery of new antimalarial drugs relies on cell-free assays on specific biochemical pathways of Plasmodium falciparum . However, it appears that screening directly on the parasite is a more rewarding approach. The "drug to genome to drug" approach consists of testing a small set of structural analogues of a drug acting on human proteins that have plasmodial orthologues. Both man and plasmodium possess cyclic nucleotide phosphodiesterases (PDEs) that are key players of cell homeostasis. We synthesized and tested 40 analogues of tadalafil, a human PDE5 inhibitor, on P. falciparum in culture and obtained potent inhibitors of parasite growth. We discuss the structure-activity relationships, which support the hypothesis that our compounds kill the parasite via inhibition of plasmodial PDE activity. We also prove that antiplasmodial derivatives inhibit the hydrolysis of cyclic nucleotides of the parasite, validating the cAMP/cGMP pathways as therapeutic targets against Plasmodium falciparum .

  DOI：

  10.1021/jm1014617

文献信息

• Method of inhibiting neoplastic cells with tetracyclic pyrido[3,4-B] indole derivatives
  申请人：——

  公开号：US20020035111A1

  公开（公告）日：2002-03-21

  A method for inhibiting neoplasia, particularly cancerous and precancerous lesions by exposing the affected cells to pyrido[3,4b]indoles.

  一种通过将受影响的细胞暴露于吡啶并［3,4b］吲哚来抑制肿瘤，特别是癌症和癌前病变的方法。
• 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).
• TETRACYCLIC DERIVATIVES, PROCESS OF PREPARATION AND USE
  申请人：ICOS CORPORATION

  公开号：EP0740668B1

  公开（公告）日：1998-07-29
• US6025494A
  申请人：——

  公开号：US6025494A

  公开（公告）日：2000-02-15
• US6143746A
  申请人：——

  公开号：US6143746A

  公开（公告）日：2000-11-07