2-甲氧基-7-氯-10-(4’-羟苯基)胺基苯并[B]-1,5-萘啶 | 81935-60-6

• 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: 2-甲氧基-7-氯-10-(4’-羟苯基)胺基苯并[B]-1,5-萘啶
• 中文别名: 4-[(7-氯-2-甲氧基苯并[b]-1,5-萘-10-吡啶基)氨基]-苯酚；2-甲氧基-7-氯-10-(4'-羟苯基)胺基苯并[B]-1,5-萘啶
• 英文名称: 2-methoxy-7-chloro-10-(4-hydroxyanilino)-benzo[b]-1,5-naphthyridine
• 英文别名: 2-methoxy-7-chloro-10-(4'-hydroxyphenyl)aminobenzo[b]-1,5-naphthyridine；4-((7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino)phenol；2-methoxy-7-chloro-10-(40-hydroxyanilino)-[b]-1,5-naphthyridine；4-[(7-Chloro-2-methoxy-1,5-dihydrobenzo[b][1,5]naphthyridin-10-yl)imino]cyclohexa-2,5-dien-1-one；4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino]phenol
• CAS: 81935-60-6
• 化学式: C₁₉H₁₄ClN₃O₂
• 分子量: 351.792
• InChiKey: OHLFWLUPLZLCGD-UHFFFAOYSA-N

物化性质

• 密度：
  1.438±0.06 g/cm3 (20 ºC 760 Torr)

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  67.3
• 氢给体数：
  2
• 氢受体数：
  5

制备方法与用途

化学性质 

结晶。熔点 258-264℃。

用途 

咯萘啶磷盐酸盐的中间体。

生产方法 

用2-氨基吡啶以混酸硝化，生成2-氨基-5-硝基吡啶，以液碱水解去除氨基，得2-羟基-5-硝基吡啶，然后以三氯氧磷氯化，得2-氯-5-硝基吡啶，将后者与甲醇、甲醇钠回流，醚化得2-甲氧基-5-硝基吡啶，其硝基以铁粉-乙酸还原成氨基，进而与2,4-二氯苯甲酸缩合得5-（5-氯-2-羧基苯胺基）-2-甲氧基吡啶，再在三氯氧磷作用下环合得7,10-二氯-2-甲氧基苯并[b]-1,5-萘啶，最后在硫酸存在下与对氨基苯酚缩合制得该品。

反应信息

• 作为反应物：
  描述：

  2-甲氧基-7-氯-10-(4’-羟苯基)胺基苯并[B]-1,5-萘啶 在 磷酸 作用下， 以 乙醇 、 丙酮 为溶剂， 反应 6.0h， 生成 4-((7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino)-2,6-bis((dimethylamino)methyl)phenol tetraphosphate
  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
• 作为产物：
  描述：

  2-氯-5-硝基吡啶 在 硫酸 、 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 、 甲苯 为溶剂， 反应 6.0h， 生成 2-甲氧基-7-氯-10-(4’-羟苯基)胺基苯并[B]-1,5-萘啶
  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.
• 一种咯萘啶类化合物及其用途
  申请人：中国科学院上海药物研究所

  公开号：CN103570711B

  公开（公告）日：2016-08-03

  本发明提供了一种咯萘啶类化合物，其结构通式如下式I所示，其中R1、R2、R3和R4是作用位点，使得该类化合物具有抑制疟原虫体内PDE的活性。咯萘啶类化合物的结合自由能低于咯萘啶，使得该咯萘啶类化合物有比咯萘啶更高的抑制疟原虫体内PDE的活性，因此具有更强的抗疟活性。
• [EN] TLR7/8 ANTAGONISTS AND USES THEREOF<br/>[FR] ANTAGONISTES DE TLR7/8 ET LEURS UTILISATIONS
  申请人：MERCK PATENT GMBH

  公开号：WO2021257273A1

  公开（公告）日：2021-12-23

  The present invention relates to compounds of the invention and pharmaceutically acceptable compositions thereof, useful as TLR7/8 antagonists.

  本发明涉及本发明化合物及其药学上可接受的组合物，用作TLR7/8拮抗剂。
• Synthesis of carbon-14-labelled pyronaridine tetraphosphate
  作者：Sang Hyun Park、Kannampalli Pradeep、Seung Ho Jang

  DOI：10.1002/jlcr.1456

  日期：2007.12

  Pyronaridine tetraphosphate is an antimalarial drug which is currently being widely investigated for use in the chemotherapy of malaria. We synthesized carbon-14-labelled pyronaridine tetraphosphate (14C-PNDP, 5) by a classical method and also by a microwave irradiation technique for use in biodistribution studies and pharmacokinetic analysis. The application of microwave irradiation facilitated the use of high temperatures resulting in decreased reaction time and employed far less amount of the starting material when compared with the classical method. 14C-PNDP (5) thus synthesized had a chemical purity of >99% as determined by high-performance liquid chromatography (HPLC) and a radiochemical purity of >99% as determined by radio-HPLC. Copyright © 2007 John Wiley & Sons, Ltd.

  四次磷酸吡咯烷酮是一种抗疟药物，目前正被广泛研究用于疟疾化疗。我们采用传统方法和微波辐照技术合成了碳 14 标记的四磷酸吡咯烷酮（14C-PNDP，5），用于生物分布研究和药代动力学分析。与传统方法相比，微波辐照有助于使用高温，从而缩短了反应时间，并大大减少了起始材料的用量。经高效液相色谱法（HPLC）测定，合成的 14C-PNDP (5) 的化学纯度大于 99%，经放射性高效液相色谱法（Radio-HPLC）测定，其放射化学纯度大于 99%。Copyright © 2007 John Wiley & Sons, Ltd. All Rights Reserved.
• Environmentally Responsible and Cost-Effective Synthesis of the Antimalarial Drug Pyronaridine
  作者：Joseph R. A. Kincaid、Rahul D. Kavthe、Juan C. Caravez、Balaram S. Takale、Ruchita R. Thakore、Bruce H. Lipshutz

  DOI：10.1021/acs.orglett.2c00944

  日期：2022.5.13