N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-4-yl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide | 1044587-93-0

• 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
• 英文名称: N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-4-yl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide
• 英文别名: N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridin-4-yl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide
• CAS: 1044587-93-0
• 化学式: C₂₆H₂₂Cl₃F₃N₂O₃
• 分子量: 573.826
• InChiKey: WYLPBGSDNSBKPW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.9
• 重原子数：
  37
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  71.4
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  3,3,3-三氟-2-羟基-2-甲基丙酸 、 6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine 在 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-4-yl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide
  参考文献：
  名称：

  Discovery ofN-[(4R)-6-(4-Chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]-5-methyl-1H-pyrazole-3-carboxamide (MK-5596) as a Novel Cannabinoid-1 Receptor (CB1R) Inverse Agonist for the Treatment of Obesity

  摘要：

  This paper describes the discovery of N-[(4R)-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]-5-methyl-1H-pyrazole-3-carboxamide (MK-5596, 12c) as a novel cannabinoid-1 receptor (CB1R) inverse agonist for the treatment of obesity. Structure activity relationship (SAR) studies of lead compound 3, which had off-target hERG (human ether-a-go-go related gene) inhibition activity, led to the identification of several compounds that not only had attenuated hERG inhibition activity but also were subject to glucuronidation in vitro providing the potential for multiple metabolic clearance pathways. Among them, pyrazole 12c was found to be a highly selective CB1R inverse agonist that reduced body weight and food intake in a DIO (diet-induced obese) rat model through a CB1R-mediated mechanism. Although 12c was a substrate of P-glycoprotein (P-gp) transporter, its high in vivo efficacy in rodents, good pharmacokinetic properties in preclinical species, good safety margins, and its potential for a balanced metabolism profile in man allowed for the further evaluation of this compound in the clinic.

  DOI：

  10.1021/jm100023j

文献信息

• Substituted pyrano[2,3-B]pyridine derivatives as cannabinoid-1 receptor modulators
  申请人：Debenham John S.

  公开号：US20080207666A1

  公开（公告）日：2008-08-28

  Novel compounds of the structural formula (I) are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, Alzheimer's disease, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, Huntington's disease movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, as well as the treatment of asthma, constipation, chronic intestinal pseudo-obstruction, cirrhosis of the liver, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and the promotion of wakefulness.

  结构式（I）的新化合物是大麻素-1（CB1）受体的拮抗剂和/或反向激动剂，并可用于治疗、预防和抑制CB1受体介导的疾病。本发明的化合物可用作中枢作用药物，治疗精神病、记忆障碍、认知障碍、阿尔茨海默病、偏头痛、神经病、神经炎性疾病，包括多发性硬化症和吉兰-巴雷综合征，以及病毒性脑炎、脑血管意外和头部创伤的炎症后遗症、焦虑症、压力、癫痫、帕金森病、亨廷顿病运动障碍和精神分裂症。这些化合物还可用于治疗物质滥用障碍、肥胖或进食障碍，以及哮喘、便秘、慢性肠假性梗阻、肝硬化、非酒精性脂肪肝病（NAFLD）、非酒精性脂肪性肝炎（NASH）和促进清醒。
• SUBSTITUTED PYRANO [2, 3 - B]PYRIDINE DERIVATIVES AS CANNABINOID-1 RECEPTOR MODULATORS
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP2109615B1

  公开（公告）日：2011-03-09
• US7999107B2
  申请人：——

  公开号：US7999107B2

  公开（公告）日：2011-08-16
• Discovery of<i>N</i>-[(4<i>R</i>)-6-(4-Chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2<i>H</i>-pyrano[2,3-<i>b</i>]pyridin-4-yl]-5-methyl-1<i>H</i>-pyrazole-3-carboxamide (MK-5596) as a Novel Cannabinoid-1 Receptor (CB1R) Inverse Agonist for the Treatment of Obesity
  作者：Lin Yan、Pei Huo、John S. Debenham、Christina B. Madsen-Duggan、Julie Lao、Richard Z. Chen、Jing Chen Xiao、Chun-Pyn Shen、D. Sloan Stribling、Lauren P. Shearman、Alison M. Strack、Nancy Tsou、Richard G. Ball、Junying Wang、Xinchun Tong、Thomas J. Bateman、Vijay B. G. Reddy、Tung M. Fong、Jeffrey J. Hale

  DOI：10.1021/jm100023j

  日期：2010.5.27

  This paper describes the discovery of N-[(4R)-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]-5-methyl-1H-pyrazole-3-carboxamide (MK-5596, 12c) as a novel cannabinoid-1 receptor (CB1R) inverse agonist for the treatment of obesity. Structure activity relationship (SAR) studies of lead compound 3, which had off-target hERG (human ether-a-go-go related gene) inhibition activity, led to the identification of several compounds that not only had attenuated hERG inhibition activity but also were subject to glucuronidation in vitro providing the potential for multiple metabolic clearance pathways. Among them, pyrazole 12c was found to be a highly selective CB1R inverse agonist that reduced body weight and food intake in a DIO (diet-induced obese) rat model through a CB1R-mediated mechanism. Although 12c was a substrate of P-glycoprotein (P-gp) transporter, its high in vivo efficacy in rodents, good pharmacokinetic properties in preclinical species, good safety margins, and its potential for a balanced metabolism profile in man allowed for the further evaluation of this compound in the clinic.