4-Amino-2,6-bis(pyrrolidinomethyl)phenol-trihydrochlorid | 85236-52-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-Amino-2,6-bis(pyrrolidinomethyl)phenol-trihydrochlorid
• 英文别名: 4-amino-2,6-bis(pyrrolidin-1-ylmethyl)phenol trihydrochloride；Phenol, 4-amino-2,6-bis(1-pyrrolidinylmethyl)-, hydrochloride；4-amino-2,6-bis(pyrrolidin-1-ylmethyl)phenol;hydrochloride
• CAS: 85236-52-8
• 化学式: C₁₆H₂₅N₃O*3ClH
• 分子量: 384.777
• InChiKey: OKJGXEVZKFNUQO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.59
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  52.7
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-Chlorthieno[3,4-c]chinolin 、 4-Amino-2,6-bis(pyrrolidinomethyl)phenol-trihydrochlorid 以 乙二醇乙醚 为溶剂， 反应 9.0h， 以49.4%的产率得到4-(Thieno[3,4-c]chinolin-4-yl)amino-2,6-bis(pyrrolidinomethyl)phenol-trihydrochlorid
  参考文献：
  名称：

  Goerlitzer; Gabriel; Jomaa, Pharmazie, 2006, vol. 61, # 11, p. 901 - 907

  摘要：

  DOI：
• 作为产物：
  描述：

  3,5-bis<(N-pyrrolidinyl)methyl>-4-hydroxyacetanilide 在 盐酸 作用下， 反应 4.0h， 以85%的产率得到4-Amino-2,6-bis(pyrrolidinomethyl)phenol-trihydrochlorid
  参考文献：
  名称：

  Goerlitzer; Kramer; Meyer, Pharmazie, 2004, vol. 59, # 4, p. 243 - 250

  摘要：

  DOI：

文献信息

• 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。
• Pharmacophore Based Synthesis of 3-Chloroquinoxaline-2-carboxamides as Serotonin3 (5-HT3) Receptor Antagonist
  作者：Radhakrishnan Mahesh、Ramachandran Venkatesha Perumal、Pandi Vijaya Pandi

  DOI：10.1248/bpb.27.1403

  日期：——

  A series of 3-chloroquinoxaline-2-carboxamides were designed and prepared by the condensation of 3-chloro-2-quinoxaloylchloride with appropriate Mannich bases of the p-aminophenol in the microwave environment. The synthesized compounds were evaluated for serotonin3 (5-HT3) receptor antagonistic activities in longitudinal muscle-myenteric plexus (LMMP) preparation from guinea pig ileum against the 5-HT3 agonist, 2-methyl-5-HT. Compound 3g exhibited comparable 5-HT3 antagonistic activity (pA2 6.4) to that of standard antagonist Ondansetron (pA2 6.9), while the other compounds exhibited mild to moderate 5-HT3 antagonistic activities.

  在微波环境下，通过 3-氯-2-喹喔啉盐酸盐与对氨基苯酚的适当曼尼希碱缩合，设计并制备了一系列 3-氯喹喔啉-2-羧酰胺。评估了合成化合物在豚鼠回肠纵肌-肠肌丛（LMMP）制备过程中对 5-HT3 激动剂 2-甲基-5-HT 的 5-羟色胺3（5-HT3）受体拮抗活性。化合物 3g 的 5-HT3 拮抗活性（pA2 6.4）与标准拮抗剂昂丹司琼（pA2 6.9）相当，而其他化合物则表现出轻度至中度的 5-HT3 拮抗活性。
• Benzo[c][2,7]naphthyridin-5-yl-arylamine &#8211; Phenol-Mannich-Basen vom Amodiaquin-, Cycloquin- und Pyronaridin-Typ
  作者：Goerlitzer、Enge、Jones、Jomaa、Wiesner

  DOI：10.1691/ph.2007.2.6574

  日期：——

  2,5-Dichlor-4-methyl-benzo[c][2,7]naphthyridin (1) reagierte mit aromatischen Aminen selektiv unter Substitution in 5-Position zu den Amidinen 2. Das 4-Aminophenol 2c konnte auch durch Etherspaltung von 2b dargestellt werden. Die Struktur von 2c wurde durch Röntgenkristallanalyse bewiesen. Aminomethylierung von 2c lieferte das Amodiaquin-Analogon 3. Durch Umsetzung von 1 mit Phenol-Mannich-Base-Hydrochloriden wurden die mono- und bisaminomethylierten Derivate 4 und 5 erhalten. Die Verbindungen 3–5 wurden auf Wirksamkeit gegen Malaria mit einem Chloroquin-sensitiven und -resistenten Plasmodium-falciparum-Stamm in vitro getestet. Die besten Aktivitäten zeigten die Pyronaridin-analogen Substanzen 5a und 5b mit IC50-Werten um 200 nM. Benzo[c][2,7]naphthyridine-5-yl-arylamines – phenol Mannich bases of the amodiaquine-, cycloquine- and pyronaridine-type 2,5-Dichloro-4-methyl-benzo[c][2,7]naphthyridine (1) reacted with aromatic amines selectively by substitution at the 5-position to yield the amidines 2. The 4-aminophenol 2c could also be synthesized by cleavage of the ether 2b. The structure of 2c was proved by X-ray crystal analysis. Aminomethylation of 2c yielded the amodiaquine analogue 3. The mono- and bisaminomethylated derivatives 4 and 5 were obtained by reaction of compound 1 with phenol Mannich base hydrochlorides. Compounds 3–5 were tested in vitro for antimalarial activity using chloroquine-sensitive and resistant Plasmodium-falciparum strains. The highest activities were shown by the pyronaridine-type compounds 5a and 5b with IC50 values of approximately 200 nM.

  2,5-二氯-4-甲基-苯并[c][2,7]萘啶（1）通过 5 位取代 2 位芳香胺，与芳香胺发生反应。4-Aminophenol 2c 也可以通过 2b 的醚化作用而生成。2c 的结构是通过伦琴晶体分析得出的。2c 的氨甲基化产生了氨基二氢喹啉类似物 3。通过将 1 与苯酚-曼尼希-碱-氢氯化物混合，得到了单氨基和双氨基甲基衍生物 4 和 5。在体外测试中，3-5 号衍生物可与对氯喹敏感和对氯喹有抗药性的疟疾疟原虫结合。5a 和 5b 的最佳活性显示，它们的 IC50 值均为 200 nM。苯并[c][2,7]萘啶-5-基芳基胺-苯酚 阿莫地喹型、环喹型和吡萘啶型 2,5-二氯-4-甲基苯并[c][2,7]萘啶（1）的曼尼希碱通过在 5 位上的取代选择性地与芳香胺反应生成酰胺 2。通过裂解醚 2b 也可以合成 4-氨基苯酚 2c。X 射线晶体分析证明了 2c 的结构。对 2c 进行氨基甲基化可得到阿莫地喹类似物 3。化合物 1 与苯酚曼尼希碱盐酸盐反应得到了单氨基甲基化和双氨基甲基化衍生物 4 和 5。使用对氯喹敏感和耐药的疟原虫菌株对化合物 3-5 进行了体外抗疟活性测试。活性最高的是吡萘啶类化合物 5a 和 5b，其 IC50 值约为 200 nM。
• Methnaridine is an orally bioavailable, fast‐killing and long‐acting antimalarial agent that cures <i>Plasmodium</i> infections in mice
  作者：Weisi Wang、Junmin Yao、Zhuo Chen、Yiming Sun、Yuqing Shi、Yufen Wei、Hejun Zhou、Yingfang Yu、Shizhu Li、Liping Duan

  DOI：10.1111/bph.15268

  日期：2020.12

  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.
• 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.