3-(6-methoxypyridin-3-yl)-5-(4-methylsulfonylphenyl)pyridin-2-amine | 1314882-43-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 3-(6-methoxypyridin-3-yl)-5-(4-methylsulfonylphenyl)pyridin-2-amine
• 英文别名: 3-(6-Methoxy-3-pyridyl)-5-(4-methylsulfonylphenyl)pyridin-2-amine
• CAS: 1314882-43-3
• 化学式: C₁₈H₁₇N₃O₃S
• 分子量: 355.417
• InChiKey: MPUUTGILUJDKKP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  104
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-(6-methoxypyridin-3-yl)-5-(4-methylsulfonylphenyl)pyridin-2-amine 在 potassium carbonate 、 三氟乙酸 、 sodium nitrite 作用下， 以 四氢呋喃 、 水 、 二甲基亚砜 为溶剂， 反应 18.08h， 生成 2-ethoxy-6'-methoxy-5-(4-(methylsulfonyl)phenyl)-3,3'-bipyridine
  参考文献：
  名称：

  Structure–Activity-Relationship Studies around the 2-Amino Group and Pyridine Core of Antimalarial 3,5-Diarylaminopyridines Lead to a Novel Series of Pyrazine Analogues with Oral in Vivo Activity

  摘要：

  Replacement of the pyridine core of antimalarial 3,5-diaryl-2-aminopyridines led to the identification of a novel series of pyrazine analogues with potent oral antimalarial activity. However, other changes to the pyridine core and replacement or substitution of the 2-amino group led to loss of antimalarial activity. The 3,5-diaryl-2-arninopyrazine series showed impressive in vitro antiplasmodial activity against the K1 (multidrug resistant) and NF54 (sensitive) strains of Plasmodium falciparum in the nanomolar IC50 range of 6-94 nM while also demonstrating good in vitro metabolic stability in human liver microsomes. In the Plasmodium berghei mouse model, this series generally exhibited good efficacy at low oral doses. One of the frontrunner compounds, 4, displayed potent in vitro antiplasmodial activity with IC50 values of 8.4 and 10 nM against the K1 and NF54 strains, respectively. When evaluated in P. berghei-infected mice, compound 4 was completely curative at an oral dose of 4 x 10 mg/kg.

  DOI：

  10.1021/jm401278d
• 作为产物：
  描述：

  2-氨基-5-溴吡啶 在 bis-triphenylphosphine-palladium(II) chloride 、 碘 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 二甲基亚砜 为溶剂， 反应 36.0h， 生成 3-(6-methoxypyridin-3-yl)-5-(4-methylsulfonylphenyl)pyridin-2-amine
  参考文献：
  名称：

  Structure–Activity-Relationship Studies around the 2-Amino Group and Pyridine Core of Antimalarial 3,5-Diarylaminopyridines Lead to a Novel Series of Pyrazine Analogues with Oral in Vivo Activity

  摘要：

  Replacement of the pyridine core of antimalarial 3,5-diaryl-2-aminopyridines led to the identification of a novel series of pyrazine analogues with potent oral antimalarial activity. However, other changes to the pyridine core and replacement or substitution of the 2-amino group led to loss of antimalarial activity. The 3,5-diaryl-2-arninopyrazine series showed impressive in vitro antiplasmodial activity against the K1 (multidrug resistant) and NF54 (sensitive) strains of Plasmodium falciparum in the nanomolar IC50 range of 6-94 nM while also demonstrating good in vitro metabolic stability in human liver microsomes. In the Plasmodium berghei mouse model, this series generally exhibited good efficacy at low oral doses. One of the frontrunner compounds, 4, displayed potent in vitro antiplasmodial activity with IC50 values of 8.4 and 10 nM against the K1 and NF54 strains, respectively. When evaluated in P. berghei-infected mice, compound 4 was completely curative at an oral dose of 4 x 10 mg/kg.

  DOI：

  10.1021/jm401278d

文献信息

• Alternative solid-state forms of a potent antimalarial aminopyridine: X-ray crystallographic, thermal and solubility aspects
  作者：Dyanne L. Cruickshank、Yassir Younis、Nicholas M. Njuguna、Dennis S. B. Ongarora、Kelly Chibale、Mino R. Caira

  DOI：10.1039/c3ce41798k

  日期：——

  3-(6-Methoxypyridin-3-yl)-5-(4-methylsulfonyl phenyl)-pyridin-2-amine (MMP) is a member of a novel class of orally active antimalarial drugs. This aminopyridine molecule has shown potent in vitro antiplasmodial activity and in vivo antimalarial activity in Plasmodium berghei-infected mice. The aqueous solubility of this molecule is, however, limited. Thus investigations aimed at improving the physicochemical properties, including solubility, of MMP were accordingly conducted. Five salts of MMP were formed with co-former molecules saccharin, salicylic acid, fumaric acid, oxalic acid and suberic acid, but a cocrystal was obtained when the co-former adipic acid was employed. All these new multi-component systems have been fully characterised using X-ray diffraction and thermal methods. Semi-quantitative, turbidimetric solubility tests in a phosphate-buffered saline solution at a pH of 7.4 were performed on the salts and the cocrystal of MMP. The saccharinate salt, fumarate salt and the cocrystal of MMP proved to have greater solubility than MMP itself. This work illustrates the importance of screening and modifying candidate drug compounds in their preliminary stages of development.

  3-(6-甲氧基吡啶-3-基)-5-(4-甲磺酰基苯基)-吡啶-2-胺（MMP）是一种新型口服抗疟药物。这种氨基吡啶分子在体外抗疟活性和体内抗疟活性方面都表现出了很强的效力，在感染了伯格希疟原虫的小鼠体内也是如此。然而，这种分子的水溶性有限。因此，我们进行了旨在改善 MMP 的理化性质（包括溶解性）的研究。与共聚物分子糖精、水杨酸、富马酸、草酸和亚琥珀酸一起形成了五种 MMP 盐，但在使用共聚物己二酸时得到了一种共晶体。使用 X 射线衍射和热学方法对所有这些新的多组分系统进行了全面鉴定。在 pH 值为 7.4 的磷酸盐缓冲盐溶液中，对 MMP 的盐类和共晶体进行了半定量、比浊溶解度测试。结果表明，MMP 的蔗糖盐、富马酸盐和共晶体的溶解度高于 MMP 本身。这项工作说明了在候选药物的初步开发阶段对其进行筛选和改良的重要性。
• NEW ANTI-MALARIAL AGENTS
  申请人：Witty Michael John

  公开号：US20120295905A1

  公开（公告）日：2012-11-22

  The present invention is related to a use of aminopyridine derivatives in the manufacture of a medicament for preventing or treating malaria. Specifically, the present invention is related to aminopyridine derivatives useful for the preparation of a pharmaceutical formulation for the inhibition of malaria parasite proliferation.

  本发明涉及氨基吡啶衍生物在制造预防或治疗疟疾药物方面的用途。具体而言，本发明涉及氨基吡啶衍生物，可用于制备制药配方，以抑制疟原虫的增殖。
• Anti-malarial agents
  申请人：Witty Michael John

  公开号：US09024033B2

  公开（公告）日：2015-05-05

  The present invention is related to a use of aminopyridine derivatives in the manufacture of a medicament for preventing or treating malaria. Specifically, the present invention is related to aminopyridine derivatives useful for the preparation of a pharmaceutical foimulation for the inhibition of malaria parasite proliferation.

  本发明涉及氨基吡啶衍生物在制造预防或治疗疟疾的药物中的应用。具体而言，本发明涉及氨基吡啶衍生物，用于制备药物配制物，以抑制疟原虫的增殖。
• [EN] NEW ANTI-MALARIAL AGENTS<br/>[FR] NOUVEAUX AGENTS ANTIPALUDIQUES
  申请人：MEDICINES FOR MALARIA VENTURE MMV

  公开号：WO2011086531A3

  公开（公告）日：2011-09-29
• Preparation and Physicochemical Characterization of an Inclusion Complex Between Dimethylated β-Cyclodextrin and a Drug Lead From a New Class of Orally Active Antimalarial 3,5-Diaryl-2-Aminopyridines
  作者：Laurelle M. Joseph、Kelly Chibale、Mino R. Caira

  DOI：10.1016/j.xphs.2016.07.030

  日期：2016.11

  Cyclodextrins (CDs) were used to increase the aqueous solubility of a recently discovered orally active 3,5-diaryl-2-aminopyridine antimalarial drug lead (MMP). Phase-solubility studies using beta-CD, hydroxypropyl-beta-CD, and heptakis(2,6-di-O-methyl)-beta-CD (DIMEB) as potential solubilizers for MMP yielded solubility enhancement factors of 17, 49, and 65, respectively, at 25 degrees C with CD concentrations similar to 20 mM. A crystalline complex, DIMEB, MMP, 2H(2)O, was prepared and characterized by thermal and single-crystal X-ray analyses. The latter technique revealed preferential encapsulation of the hydrophobic methylsulfonylphenyl moiety of MMP within the CD cavity and protrusion of the more polar methoxypyridinyl and aminopyridine residues from the cavity. This inclusion mode results in a DIMEB complex with a new packing arrangement and an intricate network of intermolecular hydrogen bonds linking guest residues that protrude from 21-related host cavities. A summary of the results of the performance of the inclusion complex in preliminary pharmacokinetic and efficacy tests in mouse models is provided. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.