N-8-(5-chloro-2-methoxyphenyl)-5,6-dihydro-4H-cyclohepta[1,2-d:3,4-d′]bis(thiazole)-2,8-diamine | 1067637-96-0

• 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: N-8-(5-chloro-2-methoxyphenyl)-5,6-dihydro-4H-cyclohepta[1,2-d:3,4-d′]bis(thiazole)-2,8-diamine
• 英文别名: N2-(5-chloro-2-methoxyphenyl)-7,8-dihydro-6H-cyclohepta[1,2-d:3,4-d']bithiazole-2,2'-diamine；12-N-(5-chloro-2-methoxyphenyl)-3,11-dithia-5,13-diazatricyclo[8.3.0.02,6]trideca-1(10),2(6),4,12-tetraene-4,12-diamine
• CAS: 1067637-96-0
• 化学式: C₁₆H₁₅ClN₄OS₂
• 分子量: 378.906
• InChiKey: DXGPFGKZXAXBEA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  130
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-8-(5-chloro-2-methoxyphenyl)-5,6-dihydro-4H-cyclohepta[1,2-d:3,4-d′]bis(thiazole)-2,8-diamine 、 丁二酸单甲酯酰氯 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 以15%的产率得到methyl 4-((8-((5-chloro-2-methoxyphenyl)amino)-5,6-dihydro-4H-cyclohepta[1,2-d:3,4-d′]bis(thiazole)-2-yl)amino)-4-oxobutanoate
  参考文献：
  名称：

  Constrained Bithiazoles: Small Molecule Correctors of Defective ΔF508–CFTR Protein Trafficking

  摘要：

  Conformationally constrained bithiazoles were previously found to have improved efficacy over nonconstrained bithiazoles for correction of defective cellular processing of the ΔF508 mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. In this study, two sets of constrained bithiazoles were designed, synthesized, and tested in vitro using ΔF508-CFTR expressing epithelial cells. The SAR data demonstrated that modulating the constraining ring size between 7- versus 8-membered in these constrained bithiazole correctors did not significantly enhance their potency (IC50), but strongly affected maximum efficacy (Vmax), with constrained bithiazoles 9e and 10c increasing Vmax by 1.5-fold compared to benchmark bithiazole corr4a. The data suggest that the 7- and 8-membered constrained ring bithiazoles are similar in their ability to accommodate the requisite geometric constraints during protein binding.

  DOI：

  10.1021/jm5007885
• 作为产物：
  描述：

  2-amino-4,5,6,7-tetrahydro-8H-cyclohepta[d]thiazol-8-one 在 溴 、 溶剂黄146 作用下， 以 乙醇 为溶剂， 反应 0.5h， 生成 N-8-(5-chloro-2-methoxyphenyl)-5,6-dihydro-4H-cyclohepta[1,2-d:3,4-d′]bis(thiazole)-2,8-diamine
  参考文献：
  名称：

  Constrained Bithiazoles: Small Molecule Correctors of Defective ΔF508–CFTR Protein Trafficking

  摘要：

  Conformationally constrained bithiazoles were previously found to have improved efficacy over nonconstrained bithiazoles for correction of defective cellular processing of the ΔF508 mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. In this study, two sets of constrained bithiazoles were designed, synthesized, and tested in vitro using ΔF508-CFTR expressing epithelial cells. The SAR data demonstrated that modulating the constraining ring size between 7- versus 8-membered in these constrained bithiazole correctors did not significantly enhance their potency (IC50), but strongly affected maximum efficacy (Vmax), with constrained bithiazoles 9e and 10c increasing Vmax by 1.5-fold compared to benchmark bithiazole corr4a. The data suggest that the 7- and 8-membered constrained ring bithiazoles are similar in their ability to accommodate the requisite geometric constraints during protein binding.

  DOI：

  10.1021/jm5007885

文献信息

• Compounds Having Activity in Correcting Mutant-CFTR Processing and Uses Thereof
  申请人：Kurth Mark J.

  公开号：US20100273839A1

  公开（公告）日：2010-10-28

  The invention provides compositions, pharmaceutical preparations and methods for increasing activity of a mutant cystic fibrosis transmembrane conductance regulator protein (mutant-CFTR). The compositions pharmaceutical preparations and methods are useful for the study and treatment of disorders associated with mutant-CFTR, such as cystic fibrosis. The compositions and pharmaceutical preparations of the invention may comprise one or more bithiazole-containing compounds of the invention, or an analog or derivative thereof.

  本发明提供了用于增加突变囊性纤维化跨膜传导调节因子蛋白（突变CFTR）活性的组合物、制药制剂和方法。该组合物、制药制剂和方法可用于突变CFTR相关的疾病的研究和治疗，如囊性纤维化。本发明的组合物和制药制剂可以包含本发明的一种或多种双噻唑含有化合物，或其类似物或衍生物。
• Potent <i>s-cis</i>-Locked Bithiazole Correctors of ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator Cellular Processing for Cystic Fibrosis Therapy
  作者：Gui Jun Yu、Choong L. Yoo、Baoxue Yang、Michael W. Lodewyk、Liping Meng、Tamer T. El-Idreesy、James C. Fettinger、Dean J. Tantillo、A. S. Verkman、Mark J. Kurth

  DOI：10.1021/jm800533c

  日期：2008.10.9

  N-(5-(2-(5-Chloro-2-methoxyphenylamino)thiazol-4-yl)-4-methylthiazol-2-yl)pivalamide 1 (compound 15jf) was found previously to correct defective cellular processing of the cystic fibrosis protein Delta F508-CFTR. Eight C4'-C5 C,C-bond-controlling bithiazole analogues of 1 were designed, synthesized, and evaluated to establish that constraining rotation about the bithiazole-tethering has a significant effect on corrector activity. For example, constraining the C4'-C5 bithiazole tether in the s-cis conformation [N-(2-(5-chloro-2-methoxyphenylamino)-7,8-dihydro-6H-cyclohepta[1,2-d:3,4-d']bithiazole-2'-yl)pivalamide, 29] results in improved corrector activity. Heteroatom placement in the bithaizole core is also critical as evidenced by the decisive loss of corrector activity with s-cis constrained N-(2-(5-chloro-2-methoxyphenylamino)-5,6-dihydro-4H-cyclohepta[1,2-d:3,4-d]bithiazole-2'-yl)pivalamide 33. In addition, computational models were utilized to examine the conformational preferences for select model systems. Following our analysis, the "s-cis-locked" cycloheptathiazolothiazole 29 was found to be the most potent bithiazole corrector, with an IC(50) Of similar to 450 nM.
• US8389736B2
  申请人：——

  公开号：US8389736B2

  公开（公告）日：2013-03-05
• Constrained Bithiazoles: Small Molecule Correctors of Defective ΔF508–CFTR Protein Trafficking
  作者：Keith C. Coffman、Huy H. Nguyen、Puay-Wah Phuan、Brandi M. Hudson、Gui J. Yu、Alex L. Bagdasarian、Deanna Montgomery、Michael W. Lodewyk、Baoxue Yang、Choong L. Yoo、A. S. Verkman、Dean J. Tantillo、Mark J. Kurth

  DOI：10.1021/jm5007885

  日期：2014.8.14

  Conformationally constrained bithiazoles were previously found to have improved efficacy over nonconstrained bithiazoles for correction of defective cellular processing of the ΔF508 mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. In this study, two sets of constrained bithiazoles were designed, synthesized, and tested in vitro using ΔF508-CFTR expressing epithelial cells. The SAR data demonstrated that modulating the constraining ring size between 7- versus 8-membered in these constrained bithiazole correctors did not significantly enhance their potency (IC50), but strongly affected maximum efficacy (Vmax), with constrained bithiazoles 9e and 10c increasing Vmax by 1.5-fold compared to benchmark bithiazole corr4a. The data suggest that the 7- and 8-membered constrained ring bithiazoles are similar in their ability to accommodate the requisite geometric constraints during protein binding.