N4-乙基-6-甲氧基-吡啶-3,4-二胺 | 925213-64-5

• 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
• 中文名称: N4-乙基-6-甲氧基-吡啶-3,4-二胺
• 中文别名: N4-乙基-6-甲氧基吡啶-3,4-二胺
• 英文名称: N⁴-ethyl-6-(methyloxy)-3,4-pyridinediamine
• 英文别名: N4-ethyl-6-methoxypyridine-3,4-diamine；4-N-ethyl-6-methoxypyridine-3,4-diamine
• CAS: 925213-64-5
• 化学式: C₈H₁₃N₃O
• mdl: MFCD09832224
• 分子量: 167.211
• InChiKey: CJWFLJHFUOKBOM-UHFFFAOYSA-N

物化性质

• 沸点：
  334.7±42.0 °C(Predicted)
• 密度：
  1.153±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  12
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.375
• 拓扑面积：
  60.2
• 氢给体数：
  2
• 氢受体数：
  4

安全信息

• 海关编码：
  2933399090

反应信息

• 作为反应物：
  描述：

  N4-乙基-6-甲氧基-吡啶-3,4-二胺 在 盐酸 、 三乙胺 、 N,N'-羰基二咪唑 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 11.5h， 生成 (R)-6-cyano-N-(1-(1-ethyl-6-methoxy-1H-imidazo[4,5-c]pyridin-2-yl)ethyl)pyridine-3-sulfonamide
  参考文献：
  名称：

  Identification and Optimization of Benzimidazole Sulfonamides as Orally Bioavailable Sphingosine 1-Phosphate Receptor 1 Antagonists with in Vivo Activity

  摘要：

  We report here a novel series of benzimidazole sulfonamides that act as antagonists of the S1P(1) receptor, identified by exploiting an understanding of the pharmacophore of a high throughput screening (HTS)-derived series of compounds described previously. Lead compound 2 potently inhibits SIP-induced receptor internalization in a cell-based assay (EC50 = 0.05 mu M), but has poor physical properties and metabolic stability. Evolution of this compound through structure-activity relationship development and property optimization led to in vivo probes such as 4. However, this compound was unexpectedly found to be a potent CYP3A inducer in human hepatocytes, and thus further chemistry efforts were directed at addressing this liability. By employing a pregnane X receptor (PXR) reporter gene assay to prioritize compounds for further testing in human hepatocytes, we identified lipophilicity as a key molecular property influencing the likelihood of P450 induction. Ultimately, we have identified compounds such as 46 and 47, which demonstrate the desired S1P(1) antagonist activity while having greatly reduced risk of CYP3A induction in humans. These compounds have excellent oral bioavailability in preclinical species and exhibit pharmacodynamic effects of S1P(1) antagonism in several in vivo models following oral dosing. Relatively modest antitumor activity was observed in multiple xenograft models, however, suggesting that selective S1P(1) antagonists would have limited utility as anticancer therapeutics as single agents.

  DOI：

  10.1021/acs.jmedchem.5b01078
• 作为产物：
  描述：

  2,4-二甲氧基-5-硝基吡啶 在 palladium on activated charcoal 氢气 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 72.0h， 生成 N4-乙基-6-甲氧基-吡啶-3,4-二胺
  参考文献：
  名称：

  Discovery of Aminofurazan-azabenzimidazoles as Inhibitors of Rho-Kinase with High Kinase Selectivity and Antihypertensive Activity

  摘要：

  The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension.

  DOI：

  10.1021/jm060873p

文献信息

• HETEROCYCLYC SULFONAMIDES HAVING EDG-1 ANTAGONISTIC ACTIVITY
  申请人：Grewal Gurmit

  公开号：US20100029643A1

  公开（公告）日：2010-02-04

  The invention relates to chemical compounds of formula (I), (Ia) and (Ib) or pharmaceutically acceptable salts thereof, which possess Edg-1 antagonistic activity and are accordingly useful for their anti-cancer activity and thus in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an anti-cancer effect in a warm-blooded animal, such as man.

  该发明涉及化学式（I），（Ia）和（Ib）或其药学上可接受的盐的化合物，其具有Edg-1拮抗活性，因此在抗癌活性和人或动物体的治疗方法中有用。该发明还涉及制造上述化学化合物的过程，含有它们的制药组合物以及在制造用于在温血动物（如人）中产生抗癌效果的药物的制造中使用它们。
• HETEROCYCLYC SULFONAMIDES HAVING EDG-I ANTAGONISTIC ACTIVITY
  申请人：AstraZeneca AB

  公开号：EP2094670A1

  公开（公告）日：2009-09-02
• [EN] HETEROCYCLYC SULFONAMIDES HAVING EDG-I ANTAGONISTIC ACTIVITY<br/>[FR] SULFONAMIDES HÉTÉROCYCLIQUES À ACTIVITÉ ANTAGONISTE DE EDG-1
  申请人：ASTRAZENECA AB

  公开号：WO2008056150A1

  公开（公告）日：2008-05-15

  [EN] The invention relates to chemical compounds of formula (I), (Ia) and (Ib) or pharmaceutically acceptable salts thereof, which possess Edg-1 antagonistic activity and are accordingly useful for their anti-cancer activity and thus in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an anti-cancer effect in a warm-blooded animal, such as man.
  [FR] L'invention porte sur des composés chimiques de formule (I), (Ia) et (Ib) ou sur des sels pharmaceutiquement acceptables de ceux-ci, qui possèdent une activité antagoniste de Edg-1 et sont en conséquence utiles pour leur activité anti-cancer et donc dans des procédés de traitement du corps humain ou animal. L'invention porte également sur des procédés de fabrication desdits composés chimiques, sur des compositions pharmaceutiques les contenant et sur leur utilisation dans la fabrication de médicaments utilisés pour produire un effet anti-cancer chez un animal à sang chaud, tel que l'homme.
• Discovery of Aminofurazan-azabenzimidazoles as Inhibitors of Rho-Kinase with High Kinase Selectivity and Antihypertensive Activity
  作者：Robert A. Stavenger、Haifeng Cui、Sarah E. Dowdell、Robert G. Franz、Dimitri E. Gaitanopoulos、Krista B. Goodman、Mark A. Hilfiker、Robert L. Ivy、Jack D. Leber、Joseph P. Marino,、Hye-Ja Oh、Andrew Q. Viet、Weiwei Xu、Guosen Ye、Daohua Zhang、Yongdong Zhao、Larry J. Jolivette、Martha S. Head、Simon F. Semus、Patricia A. Elkins、Robert B. Kirkpatrick、Edward Dul、Sanjay S. Khandekar、Tracey Yi、David K. Jung、Lois L. Wright、Gary K. Smith、David J. Behm、Christopher P. Doe、Ross Bentley、Zunxuan X. Chen、Erding Hu、Dennis Lee

  DOI：10.1021/jm060873p

  日期：2007.1.1

  The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension.
• Identification and Optimization of Benzimidazole Sulfonamides as Orally Bioavailable Sphingosine 1-Phosphate Receptor 1 Antagonists with in Vivo Activity
  作者：Edward J. Hennessy、Vibha Oza、Ammar Adam、Kate Byth、Lillian Castriotta、Gurmit Grewal、Geraldine A. Hamilton、Victor M. Kamhi、Paula Lewis、Danyang Li、Paul Lyne、Linda Öster、Michael T. Rooney、Jamal C. Saeh、Li Sha、Qibin Su、Shengua Wen、Yafeng Xue、Bin Yang

  DOI：10.1021/acs.jmedchem.5b01078

  日期：2015.9.10

  We report here a novel series of benzimidazole sulfonamides that act as antagonists of the S1P(1) receptor, identified by exploiting an understanding of the pharmacophore of a high throughput screening (HTS)-derived series of compounds described previously. Lead compound 2 potently inhibits SIP-induced receptor internalization in a cell-based assay (EC50 = 0.05 mu M), but has poor physical properties and metabolic stability. Evolution of this compound through structure-activity relationship development and property optimization led to in vivo probes such as 4. However, this compound was unexpectedly found to be a potent CYP3A inducer in human hepatocytes, and thus further chemistry efforts were directed at addressing this liability. By employing a pregnane X receptor (PXR) reporter gene assay to prioritize compounds for further testing in human hepatocytes, we identified lipophilicity as a key molecular property influencing the likelihood of P450 induction. Ultimately, we have identified compounds such as 46 and 47, which demonstrate the desired S1P(1) antagonist activity while having greatly reduced risk of CYP3A induction in humans. These compounds have excellent oral bioavailability in preclinical species and exhibit pharmacodynamic effects of S1P(1) antagonism in several in vivo models following oral dosing. Relatively modest antitumor activity was observed in multiple xenograft models, however, suggesting that selective S1P(1) antagonists would have limited utility as anticancer therapeutics as single agents.