5-(氯甲基)-2,4-二甲基吡啶 | 856851-22-4

• 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: 5-(氯甲基)-2,4-二甲基吡啶
• 英文名称: 5-chloromethyl-2,4-dimethyl-pyridine
• 英文别名: 5-Chlormethyl-2,4-dimethyl-pyridin；5-(Chloromethyl)-2,4-dimethylpyridine
• CAS: 856851-22-4
• 化学式: C₈H₁₀ClN
• mdl: MFCD18262039
• 分子量: 155.627
• InChiKey: WHMJNCNCWTYNLV-UHFFFAOYSA-N

物化性质

• 熔点：
  151-152 °C
• 沸点：
  244.7±35.0 °C(Predicted)
• 密度：
  1.088±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  10
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.375
• 拓扑面积：
  12.9
• 氢给体数：
  0
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  5-(氯甲基)-2,4-二甲基吡啶 在 sodium hydride 作用下， 以 四氢呋喃 、 二甲基亚砜 为溶剂， 生成 2-(4,6-Dimethylpyridin-3-yl)-3-oxobutanenitrile
  参考文献：
  名称：

  Design of 2,5-Dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylaminopyrazolo[1,5-a]pyrimidine (NBI 30775/R121919) and Structure−Activity Relationships of a Series of Potent and Orally Active Corticotropin-Releasing Factor Receptor Antagonists

  摘要：

  We have previously shown that 3-phenylpyrazolo[1,5-a]pyrimidines exemplified by 8 were potent antagonists of the human corticotropin-releasing factor-1 receptor. A series of 3-pyridylpyrazolo[1,5-a]pyrimidines 15, 25-30, 34, and 35 containing a weakly basic pyridine ring at the 3-position of the bicyclic nucleus was designed to reduce lipophilicity from the initial leads such as 7. Here, we showed that these 3-pyridyl compounds exhibited potent antagonists at the human CRF1, receptor. Moreover, the hydrophilic and weakly basic pyridine moiety increased the water solubility of some analogues. Compound 26h exhibited good binding affinity at the human CRF1 receptor with a K-i value of 3.5 nM. As a functional antagonist, it dose-dependently inhibited CRF-stimulated cAMP production in cells expressing the CRF1 receptor [IC50 = 50 nM), and CRF-stimulated ACTH release from cultured rat pituitary cells [IC50 = 20 nM). 26h had a log P value of 4.9 and water solubility of greater than 10 mg/mL. Pharmacokinetic studies in rats showed that 26h was orally bioavailable and able to penetrate into the brain. 26h has been demonstrated in vivo efficacy in animal behavioral models that measure anxiolytic activity. These results suggest that analogues from this series were potent CRF1, receptor antagonists with proper physicochemical properties and good pharmacokinetic profiles. 26h was developed into a clinical compound and exhibited efficacy in patients with major depression.

  DOI：

  10.1021/jm040058e
• 作为产物：
  描述：

  (4,6-Dimethyl-[3]pyridyl)-methanol 在 氯化亚砜 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 生成 5-(氯甲基)-2,4-二甲基吡啶
  参考文献：
  名称：

  口服活性催产素拮抗剂的开发：1-（1- [1- [4- [1-（2-甲基-1-氧吡啶基-3-基甲基）哌啶-4-基氧基] -2-甲氧基苯甲酰基]哌啶-4-基）的研究-1,4-二氢苯并[d] [1,3]恶嗪-2-酮（L-372,662）和相关的吡啶。

  摘要：

  先前报道的催产素拮抗剂L-371,257（2）在其乙酰基哌啶末端进行了修饰，以结合各种吡啶N-氧化物基团。这种修饰导致鉴定出具有改善的药代动力学和优异的口服生物利用度的化合物。吡啶N-氧化物系列的实例为L-372,662（30），在体外和体内（大鼠体内静脉AD50 = 0.71 mg / kg）（Ki = 4.1 nM，克隆的人催产素受体）均具有良好的效价。口服生物利用度（在大鼠中为90％，在狗中为96％），良好的水溶解度（在pH 5.2下> 8.5 mg / mL）应有利于静脉内给药的制剂以及对人精氨酸加压素受体的优异选择性。在这类催产素拮抗剂中，在中央苯甲酰基环上引入5-氟取代基可增强体外和体内效能，但不利于这些化合物的药代动力学。尽管在化合物30的吡啶环周围的亲脂取代在体外具有更高的亲和力，但是这种取代基是代谢缺陷，并导致体内的不足。研究了两种防止这种新陈代谢的方法，即增加循环限制和

  DOI：

  10.1021/jm9800797

文献信息

• Development of Orally Active Oxytocin Antagonists:  Studies on 1-(1-{4-[1-(2-Methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy]-2- methoxybenzoyl}piperidin-4-yl)-1,4-dihydrobenz[<i>d</i>][1,3]oxazin-2-one (L-372,662) and Related Pyridines
  作者：Ian M. Bell、Jill M. Erb、Roger M. Freidinger、Steven N. Gallicchio、James P. Guare、Maribeth T. Guidotti、Rita A. Halpin、Doug W. Hobbs、Carl F. Homnick、Michelle S. Kuo、Edward V. Lis、David J. Mathre、Stuart R. Michelson、Joseph M. Pawluczyk、Douglas J. Pettibone、Duane R. Reiss、Stanley Vickers、Peter D. Williams、Carla J. Woyden

  DOI：10.1021/jm9800797

  日期：1998.6.1

  The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N-oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned

  先前报道的催产素拮抗剂L-371,257（2）在其乙酰基哌啶末端进行了修饰，以结合各种吡啶N-氧化物基团。这种修饰导致鉴定出具有改善的药代动力学和优异的口服生物利用度的化合物。吡啶N-氧化物系列的实例为L-372,662（30），在体外和体内（大鼠体内静脉AD50 = 0.71 mg / kg）（Ki = 4.1 nM，克隆的人催产素受体）均具有良好的效价。口服生物利用度（在大鼠中为90％，在狗中为96％），良好的水溶解度（在pH 5.2下> 8.5 mg / mL）应有利于静脉内给药的制剂以及对人精氨酸加压素受体的优异选择性。在这类催产素拮抗剂中，在中央苯甲酰基环上引入5-氟取代基可增强体外和体内效能，但不利于这些化合物的药代动力学。尽管在化合物30的吡啶环周围的亲脂取代在体外具有更高的亲和力，但是这种取代基是代谢缺陷，并导致体内的不足。研究了两种防止这种新陈代谢的方法，即增加循环限制和
• PYRIDINE DERIVATIVE AND APPLICATION THEREOF
  申请人：Medshine Discovery Inc.

  公开号：EP4159730A1

  公开（公告）日：2023-04-05

  Disclosed are a series of compounds having pyridine structures or pharmaceutically acceptable salts thereof, and an application thereof in the preparation of drugs for the treatment of related diseases. Specifically, disclosed is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

  本发明公开了一系列具有吡啶结构的化合物及其药用盐和在制备治疗相关疾病的药物中的应用。具体来说，本发明公开了一种由式(I)表示的化合物或其药用盐。
• Tsuda et al., Pharmaceutical Bulletin, 1953, vol. 1, p. 122,125
  作者：Tsuda et al.

  DOI：——

  日期：——
• Design of 2,5-Dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylaminopyrazolo[1,5-<i>a</i>]pyrimidine (NBI 30775/R121919) and Structure−Activity Relationships of a Series of Potent and Orally Active Corticotropin-Releasing Factor Receptor Antagonists
  作者：Chen、Keith M. Wilcoxen、Charles Q. Huang、Yun-Feng Xie、James R. McCarthy、Thomas R. Webb、Yun-Fei Zhu、John Saunders、Xin-Jun Liu、Ta-Kung Chen、Haig Bozigian、Dimitri E. Grigoriadis

  DOI：10.1021/jm040058e

  日期：2004.9.1

  We have previously shown that 3-phenylpyrazolo[1,5-a]pyrimidines exemplified by 8 were potent antagonists of the human corticotropin-releasing factor-1 receptor. A series of 3-pyridylpyrazolo[1,5-a]pyrimidines 15, 25-30, 34, and 35 containing a weakly basic pyridine ring at the 3-position of the bicyclic nucleus was designed to reduce lipophilicity from the initial leads such as 7. Here, we showed that these 3-pyridyl compounds exhibited potent antagonists at the human CRF1, receptor. Moreover, the hydrophilic and weakly basic pyridine moiety increased the water solubility of some analogues. Compound 26h exhibited good binding affinity at the human CRF1 receptor with a K-i value of 3.5 nM. As a functional antagonist, it dose-dependently inhibited CRF-stimulated cAMP production in cells expressing the CRF1 receptor [IC50 = 50 nM), and CRF-stimulated ACTH release from cultured rat pituitary cells [IC50 = 20 nM). 26h had a log P value of 4.9 and water solubility of greater than 10 mg/mL. Pharmacokinetic studies in rats showed that 26h was orally bioavailable and able to penetrate into the brain. 26h has been demonstrated in vivo efficacy in animal behavioral models that measure anxiolytic activity. These results suggest that analogues from this series were potent CRF1, receptor antagonists with proper physicochemical properties and good pharmacokinetic profiles. 26h was developed into a clinical compound and exhibited efficacy in patients with major depression.