5-(piperidin-4-yloxy)-2-(trifluoromethyl)pyridine | 1353754-94-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 5-(piperidin-4-yloxy)-2-(trifluoromethyl)pyridine
• 英文别名: 5-piperidin-4-yloxy-2-(trifluoromethyl)pyridine
• CAS: 1353754-94-5
• 化学式: C₁₁H₁₃F₃N₂O
• 分子量: 246.232
• InChiKey: PAIIFKWCIPIVHX-UHFFFAOYSA-N

物化性质

• 沸点：
  305.6±42.0 °C(Predicted)
• 密度：
  1.239±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  34.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-(piperidin-4-yloxy)-2-(trifluoromethyl)pyridine 在 氢溴酸 、 palladium diacetate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 sodium t-butanolate 作用下， 以 甲苯 为溶剂， 反应 19.0h， 生成
  参考文献：
  名称：

  Synthesis and Structure–Activity Relationships for Extended Side Chain Analogues of the Antitubercular Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)

  摘要：

  Novel extended side chain nitroimidazooxazine analogues featuring diverse linker groups between two aryl rings were studied as a potential strategy to improve solubility and oral activity against chronic infection by Mycobacterium tuberculosis. Both lipophilic and highly polar functionalities (e.g., carboxamide, alkylamine, piperazine, piperidine, but not sulfonamide) were well tolerated in vitro, and the hydrophilic linkers provided some solubility improvements, particularly in combination with pyridine rings. Most of the 18 compounds further assessed showed high microsomal stabilities, although in the acute infection mouse model, just one stilbene (6-fold) and two pyridine-containing acetylene derivatives (5-fold and >933-fold) gave in vivo efficacies notably superior to the clinical stage compound pretomanid (PA-824). The most efficacious analogue also displayed outstanding in vivo activity in the stringent chronic model (up to 24-fold better than the drug delamanid and 4-fold greater than our previous best phenylpyridine candidate), with favorable pharmacokinetics, including good oral bioavailability in the rat.

  DOI：

  10.1021/jm501608q
• 作为产物：
  描述：

  6-(三氟甲基)吡啶-3-醇 在 三苯基膦 、 三氟乙酸 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 9.0h， 生成 5-(piperidin-4-yloxy)-2-(trifluoromethyl)pyridine
  参考文献：
  名称：

  Structure–Activity Relationships for Amide-, Carbamate-, And Urea-Linked Analogues of the Tuberculosis Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)

  摘要：

  Analogues of clinical tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824), in which the OCH2 linkage was replaced with amide, carbamate, and urea functionality, were investigated as an alternative approach to address oxidative metabolism, reduce lipophilicity, and improve aqueous solubility. Several soluble monoaryl examples displayed moderately improved (similar to 2- to 4-fold) potencies against replicating Mycobacterium tuberculosis but were generally inferior inhibitors under anaerobic (nonreplicating) conditions. More lipophilic biaryl derivatives mostly displayed similar or reduced potencies to these in contrast to the parent biaryl series. The leading biaryl carbamate demonstrated exceptional metabolic stability and a 5-fold better efficacy than the parent drug in a mouse model of acute M. tuberculosis infection but was poorly soluble. Bioisosteric replacement of this biaryl moiety by arylpiperazine resulted in a soluble, orally bioavailable carbamate analogue providing identical activity in the acute model, comparable efficacy to OPC-67683 in a chronic infection model, favorable pharmacokinetic profiles across several species, and enhanced safety.

  DOI：

  10.1021/jm2012276

文献信息

• [EN] OGA INHIBITOR COMPOUNDS<br/>[FR] COMPOSÉS INHIBITEURS D'OGA
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2019243530A1

  公开（公告）日：2019-12-26

  The present invention relates to O-GIcNAc hydrolase (OGA) inhibitors having the structure shown in formula (I). The invention is also directed to pharmaceutical compositions comprising such compounds to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which inhibition of OGA is beneficial, such as tauopathies, in particular Alzheimer's disease or progressive supranuclear palsy; and neurodegenerative diseases accompanied by a tau pathology, in particular amyotrophic lateral sclerosis or frontotemporal lobe dementia caused by C90RF72 mutations. wherein RB is an aromatic heterobicyclic radical selected from the group consisting of (b-1) to (b-6).

  本发明涉及具有式(I)所示结构的O-GIcNAc水解酶（OGA）抑制剂。该发明还涉及包含这种化合物的药物组合物、制备这种化合物和组合物的方法，以及利用这种化合物和组合物预防和治疗抑制OGA有益的疾病，如tau病变，特别是阿尔茨海默病或进行性上核性麻痹；以及伴有tau病理的神经退行性疾病，特别是由C90RF72突变引起的肌萎缩侧索硬化或额颞叶痴呆症。其中RB是从（b-1）到（b-6）组成的芳香杂双环基团。
• OGA INHIBITOR COMPOUNDS
  申请人：Janssen Pharmaceutica NV

  公开号：US20210122763A1

  公开（公告）日：2021-04-29

  The present invention relates to O-GlcNAc hydrolase (OGA) inhibitors. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which inhibition of OGA is beneficial, such as tauopathies, in particular Alzheimer's disease or progressive supranuclear palsy; and neurodegenerative diseases accompanied by a tau pathology, in particular amyotrophic lateral sclerosis or frontotemporal lobe dementia caused by C9ORF72 mutations.
• Structure–Activity Relationships for Amide-, Carbamate-, And Urea-Linked Analogues of the Tuberculosis Drug (6<i>S</i>)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5<i>H</i>-imidazo[2,1-<i>b</i>][1,3]oxazine (PA-824)
  作者：Adrian Blaser、Brian D. Palmer、Hamish S. Sutherland、Iveta Kmentova、Scott G. Franzblau、Baojie Wan、Yuehong Wang、Zhenkun Ma、Andrew M. Thompson、William A. Denny

  DOI：10.1021/jm2012276

  日期：2012.1.12

  Analogues of clinical tuberculosis drug (6S)-2-nitro-6-[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824), in which the OCH2 linkage was replaced with amide, carbamate, and urea functionality, were investigated as an alternative approach to address oxidative metabolism, reduce lipophilicity, and improve aqueous solubility. Several soluble monoaryl examples displayed moderately improved (similar to 2- to 4-fold) potencies against replicating Mycobacterium tuberculosis but were generally inferior inhibitors under anaerobic (nonreplicating) conditions. More lipophilic biaryl derivatives mostly displayed similar or reduced potencies to these in contrast to the parent biaryl series. The leading biaryl carbamate demonstrated exceptional metabolic stability and a 5-fold better efficacy than the parent drug in a mouse model of acute M. tuberculosis infection but was poorly soluble. Bioisosteric replacement of this biaryl moiety by arylpiperazine resulted in a soluble, orally bioavailable carbamate analogue providing identical activity in the acute model, comparable efficacy to OPC-67683 in a chronic infection model, favorable pharmacokinetic profiles across several species, and enhanced safety.
• Synthesis and Structure–Activity Relationships for Extended Side Chain Analogues of the Antitubercular Drug (6<i>S</i>)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5<i>H</i>-imidazo[2,1-<i>b</i>][1,3]oxazine (PA-824)
  作者：Brian D. Palmer、Hamish S. Sutherland、Adrian Blaser、Iveta Kmentova、Scott G. Franzblau、Baojie Wan、Yuehong Wang、Zhenkun Ma、William A. Denny、Andrew M. Thompson

  DOI：10.1021/jm501608q

  日期：2015.4.9

  Novel extended side chain nitroimidazooxazine analogues featuring diverse linker groups between two aryl rings were studied as a potential strategy to improve solubility and oral activity against chronic infection by Mycobacterium tuberculosis. Both lipophilic and highly polar functionalities (e.g., carboxamide, alkylamine, piperazine, piperidine, but not sulfonamide) were well tolerated in vitro, and the hydrophilic linkers provided some solubility improvements, particularly in combination with pyridine rings. Most of the 18 compounds further assessed showed high microsomal stabilities, although in the acute infection mouse model, just one stilbene (6-fold) and two pyridine-containing acetylene derivatives (5-fold and >933-fold) gave in vivo efficacies notably superior to the clinical stage compound pretomanid (PA-824). The most efficacious analogue also displayed outstanding in vivo activity in the stringent chronic model (up to 24-fold better than the drug delamanid and 4-fold greater than our previous best phenylpyridine candidate), with favorable pharmacokinetics, including good oral bioavailability in the rat.