4-[(7-氯-2-甲氧基-1,5-二氢吡啶并[3,2-b]喹啉-10-基)亚氨]-2,6-二(吡咯烷-1-基甲基)环己-2,5-二烯-1-酮磷酸盐 (1:4) | 76748-86-2

• 物质功能分类: 医药中间体 - 杂环化合物 - 吡啶类化合物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 中文名称: 4-[(7-氯-2-甲氧基-1,5-二氢吡啶并[3,2-b]喹啉-10-基)亚氨]-2,6-二(吡咯烷-1-基甲基)环己-2,5-二烯-1-酮磷酸盐 (1:4)
• 中文别名: 4-[(7-氯-2-甲氧基-1,5-二氢吡啶并[3,2-b]喹啉-10-基)亚氨]-2,6-二(吡咯烷-1-基甲基)环己-2,5-二烯-1-酮磷酸盐(1:4)；吡咯烷四磷酸
• 英文名称: pyronaridine tetraphosphate
• 英文别名: 4-((7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino)-2,6-bis(pyrrolidin-1-ylmethyl)phenol tetraphosphate；Pyronaridine phosphate；Pharmakon1600-01502329；4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino]-2,6-bis(pyrrolidin-1-ylmethyl)phenol;phosphoric acid
• CAS: 76748-86-2
• 化学式: C₂₉H₃₂ClN₅O₂*4H₃O₄P
• 分子量: 910.039
• InChiKey: AFQUPAGSIINWCQ-UHFFFAOYSA-N

物化性质

• 熔点：
  233-236° (dec)
• 溶解度：
  醋酸：可溶5mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  5.16
• 重原子数：
  42
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  152
• 氢给体数：
  5
• 氢受体数：
  11

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S26,S36/37,S39
• 危险类别码：
  R63,R22,R41
• WGK Germany：
  2

制备方法与用途

生物活性方面，吡罗喹丁四磷酸盐是一种含有甘露醇的抗疟疾药物，对耐药的镰状疟原虫、间日疟原虫、卵形疟原虫和三日疟原虫均表现出良好的治疗效果。

反应信息

• 作为产物：
  描述：

  2-羟基-5-硝基吡啶 在 磷酸 、 铁粉 、 potassium carbonate 、 溶剂黄146 、 copper(II) oxide 、 三氯氧磷 作用下， 以 乙醇 、 异戊醇 、 N,N-二甲基甲酰胺 、 丙酮 、 甲苯 为溶剂， 生成 4-[(7-氯-2-甲氧基-1,5-二氢吡啶并[3,2-b]喹啉-10-基)亚氨]-2,6-二(吡咯烷-1-基甲基)环己-2,5-二烯-1-酮磷酸盐 (1:4)
  参考文献：
  名称：

  Methnaridine is an orally bioavailable, fast‐killing and long‐acting antimalarial agent that cures Plasmodium infections in mice

  摘要：

  Background and PurposeMalaria is one of the deadliest diseases in the world. Novel chemotherapeutic agents are urgently required to combat the widespread Plasmodium resistance to frontline drugs. Here, we report the discovery of a novel benzonaphthyridine antimalarial, methnaridine, which was identified using a structural optimization strategy.Experimental ApproachAn integrated pharmacological approach was used to evaluate the antimalarial profile of methnaridine. The pharmacokinetic properties of methnaridine were investigated along with the associated safety profile. Host immune response patterns were also analysed.Key ResultsMethnaridine exhibited potent antimalarial activity against P. falciparum (3D7: IC50 = 0.0066 μM; Dd2: IC50 = 0.0056 μM). In P. berghei‐infected mice, oral administration effectively suppressed parasitemia (ED50 = 0.52 mg·kg−1·day−1) and cured the established infection (CD50 = 10.13 mg·kg−1·day−1). These results are equivalent to or better than those of other antimalarial agents in clinical use. Notably, a four‐dose oral regimen at a dosage of 25 mg·kg−1 achieved a complete cure of P. berghei infection in mice. Methnaridine exhibited a rapid parasiticidal profile (PCT99 = 36.0 h) and showed no cross‐resistance to chloroquine. Pharmacokinetic studies revealed that methnaridine is readily absorbed, long‐lasting and slowly cleared. The safety profile of methnaridine is also satisfactory (maximum tolerated dose = 1,125 mg·kg−1). In addition, following methnaridine treatment, infection‐induced Th1 immune response was almost fully alleviated in mice.Conclusion and ImplicationsMethnaridine is an orally bioavailable, fast‐acting and long‐lasting agent with excellent antimalarial properties. Our study highlights the potential of methnaridine for clinical development as a promising antimalarial candidate.

  DOI：

  10.1111/bph.15268

文献信息

• Synthesis of [²H]- and [¹³C]-labeled pyronaridine tetraphosphate-an antimalarial drug
  作者：Sang Hyun Park、Yeon Jun Jeong、Kannampalli Pradeep

  DOI：10.1002/jlcr.1568

  日期：2009.2

  The increasing prevalence of strains of Plasmodium falciparum resistant to chloroquine and other antimalarial drugs, necessitates the need for developing novel antimalarial drugs with a potent pharmacological activity. Pyronaridine tetraphosphate (PNDP) is one such drug that is currently undergoing preclinical and clinical trials for use in a chemotherapy treatment of malaria. The present investigation was carried out with the objective of synthesizing carbon-13 [13C]- and deuterium [2H]-labeled PNDP for use in studying the ADME and pharmacokinetics of the drug. Here, we present a methodology to synthesize [13C]- and [2H]-PNDP using a microwave irradiation technique as this method was found to be more advantageous than the classical method. The labeled compounds thus synthesized had a chemical purity of >99% as determined by HPLC and were also found to be relatively stable up to 3 months when stored under standard conditions. Further they also revealed satisfactory instrumental analysis data. Copyright © 2008 John Wiley & Sons, Ltd.

  恶性疟原虫对氯喹和其他抗疟药物的耐药性日益普遍，这迫切需要开发具有强效药理活性的新型抗疟药物。吡咯尼群四磷酸酯（PNDP）就是这样一种药物，目前正在进行用于疟疾化疗治疗的临床前和临床试验。本研究旨在合成用于研究药物ADME和药代动力学的碳-13（¹³C）和氘（²H）标记的PNDP。在此，我们介绍了一种使用微波辐照技术合成[¹³C]和[²H]PNDP的方法，因为这种方法比经典方法更有优势。合成的标记化合物通过HPLC测定的化学纯度>99%，并且在标准储存条件下发现相对稳定，可达3个月。此外，它们还显示出令人满意仪器分析数据。版权所有©2008 John Wiley & Sons, Ltd.
• 一种制备咯萘啶的方法
  申请人：上海迪赛诺药业有限公司

  公开号：CN103373995B

  公开（公告）日：2016-04-27

  本发明涉及一种制备咯萘啶的方法，具体地，本发明公开了一种高纯度的咯萘啶的制备方法，包括步骤：在惰性溶剂中，将式II化合物与式III化合物的酸式盐反应，从而形成式I咯萘啶；其中，n为1～3。本发明所述方法具有合成路线短，反应条件温和，操作简单，产品收率高、纯度高、杂质1和杂质2的含量低，成本低等特点，适合工业化生产。
• Improved Manufacturing Process for Pyronaridine Tetraphosphate
  作者：Dong Won Lee、Seung Kyu Lee、Jun Ho Cho、Seung Soo Yoon

  DOI：10.5012/bkcs.2014.35.2.521

  日期：2014.2.20

  Pyronaridine tetraphosphate (1) is a well-known antimalarial drug. However, it required a carefully optimized production process for the manufacture of pyronaridine tetraphosphate. Each step of its manufacturing process was reinvestigated. For the cyclization of 4-chloro-2-(6-methoxy-pyridin-3-yl-amino)-benzoic acid 6 to 7,10-dichloro-2-methoxybenzo[b]-1,5-naphthyridine 5, an improved process was developed to eliminated critical process impurity (BIA). By the redesign of the formation of triphosphate salt, the purity as API grade was increased. Thus, a robust manufacturing process with an acceptable process performance has been developed to produce high quality pyronaridine tetraphosphate.

  四次磷酸吡咯烷酮（1）是一种著名的抗疟药物。然而，生产四磷酸吡咯烷酮需要经过精心优化的生产工艺。我们对其生产过程的每个步骤都进行了重新研究。在将 4-氯-2-(6-甲氧基吡啶-3-基氨基)-苯甲酸 6 环化为 7,10-二氯-2-甲氧基苯并[b]-1,5-萘啶 5 的过程中，开发了一种改进的工艺，以消除关键工艺杂质（BIA）。通过重新设计三磷酸盐的形成过程，提高了原料药等级的纯度。因此，我们开发出了一种稳健的生产工艺，其工艺性能可以接受，可以生产出高质量的四磷酸吡萘啶。
• Compound for treatment of myotonic dystrophy type 1
  申请人：Universitat De València, Estudi General

  公开号：EP3034074A1

  公开（公告）日：2016-06-22

  The present invention relates to a compound, or a salt thereof, and a pharmaceutical composition comprising said compound, or a salt thereof, for use in the prevention and/or treatment of myotonic dystrophy type 1 in a patient, in particular by reducing the levels of autophagy and apoptosis that are elevated in myotonic muscular dystrophy type 1.

  本发明涉及一种化合物或其盐，以及包含所述化合物或其盐的药物组合物，用于预防和/或治疗患者的肌营养不良症1型，特别是通过降低肌营养不良症1型中升高的自噬和细胞凋亡水平。
• A Novel Process for Antimalarial Drug Pyronaridine Tetraphosphate
  作者：Yu Liu、Zixue Zhang、Anfei Wu、Xiaoli Yang、Yong Zhu、Nan Zhao

  DOI：10.1021/op400357f

  日期：2014.2.21

  A novel process for preparation of pyronaridine tetraphosphate, an antimalarial drug substance, is reported. The overall yields are 54% and >99.8% (including five chemical steps). Formation and control of possible impurities are also described.