tert-butyl 1-(4-(difluoromethoxy)phenyl)-3-methyl-1H-pyrazole-4-carboxylate | 1576240-69-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: tert-butyl 1-(4-(difluoromethoxy)phenyl)-3-methyl-1H-pyrazole-4-carboxylate
• 英文别名: Tert-butyl 1-[4-(difluoromethoxy)phenyl]-3-methylpyrazole-4-carboxylate；tert-butyl 1-[4-(difluoromethoxy)phenyl]-3-methylpyrazole-4-carboxylate
• CAS: 1576240-69-1
• 化学式: C₁₆H₁₈F₂N₂O₃
• 分子量: 324.327
• InChiKey: PXDNPMCDJGPQHJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  53.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  乙酰乙酸叔丁酯 、 (4-(difluoromethoxy)phenyl)hydrazine hydrochloride 、 N,N-二甲基甲酰胺二甲基缩醛 在 对甲苯磺酸 、 三乙胺 作用下， 以 水 为溶剂， 反应 0.25h， 以65 mg的产率得到tert-butyl 1-(4-(difluoromethoxy)phenyl)-3-methyl-1H-pyrazole-4-carboxylate
  参考文献：
  名称：

  [EN] PYRAZOLE CARBOXAMIDE DERIVATIVES AS TAAR MODULATORS FOR USE IN THE TREATMENT OF SEVERAL DISORDERS, SUCH AS DEPRESSION, DIABETES AND PARKINSON'S DISEASE
  [FR] DÉRIVÉS DE PYRAZOLE-CARBOXAMIDE EN TANT QUE MODULATEURS DE TAAR POUR UTILISATION DANS LE TRAITEMENT DE PLUSIEURS TROUBLES, TELS QUE LA DÉPRESSION, LE DIABÈTE ET LA MALADIE DE PARKINSON

  摘要：

  本发明涉及以下式（I）的化合物，其中R1是苯基，可以被卤素、较低烷基、较低环烷基、较低烷氧基、氰基、被卤素取代的较低烷基、被羟基取代的较低烷基、被卤素取代的较低烷氧基或被羟基取代的较低烷氧基；或是吡啶-2、3或4-基，可以被卤素、较低烷基、较低环烷基、氰基、被卤素取代的较低烷基、被羟基取代的较低烷基、较低烷氧基、被卤素取代的较低烷氧基或被羟基取代的较低烷氧基取代；或是嘧啶-2、4或5-基，可以被卤素、较低烷基、较低环烷基、被羟基取代的较低烷基或被卤素取代的较低烷基取代；或是吡嗪-2-基，可以被卤素、较低烷基、较低环烷基、被卤素取代的较低烷基、被羟基取代的较低烷基或氰基取代；或是2,2-二氟苯并[d][1,3]二氧杂环-5-基，或是噻唑基，可以被被卤素取代的较低烷基取代；R2是氢或较低烷基；R3是氢、氨基或较低烷基；Z是键，-CH2-或-O-；或其药学上适用的酸盐。现已发现，式I的化合物对追踪胺相关受体（TAARs）有很好的亲和力，尤其是对TAAR1。这些化合物可用于治疗抑郁症、焦虑症、双相情感障碍、注意力缺陷多动障碍（ADHD）、与压力相关的障碍、精神分裂症等精神障碍、帕金森病等神经系统疾病、阿尔茨海默病等神经退行性疾病、癫痫、偏头痛、高血压、物质滥用以及代谢障碍，如进食障碍、糖尿病、糖尿病并发症、肥胖症、血脂异常、能量消耗和吸收障碍、体温稳态障碍、睡眠和昼夜节律障碍，以及心血管疾病。

  公开号：

  WO2014041007A1

文献信息

• PYRAZOLE CARBOXAMIDE COMPOUNDS AND USES THEREOF
  申请人：Hoffmann-La Roche Inc.

  公开号：US20150218131A1

  公开（公告）日：2015-08-06

  The present invention relates to compounds of formula wherein R 1 is phenyl, optionally substituted by halogen, lower alkyl, lower cycloalkyl, lower alkoxy, cyano, lower alkyl substituted by halogen, lower alkyl substituted by hydroxy, lower alkoxy substituted by halogen or lower alkoxy substituted by hydroxy; or is pyridine-2, 3 or 4-yl, optionally substituted by halogen, lower alkyl, lower cycloalkyl, cyano, lower alkyl substituted by halogen, lower alkyl substituted by hydroxy, lower alkoxy, lower alkoxy substituted by halogen or lower alkoxy substituted by hydroxyl; or is pyrimidin-2, 4 or 5-yl, optionally substituted by halogen, lower alkyl, lower cycloalkyl, lower alkyl substituted by hydroxy or lower alkyl substituted by halogen; or is pyrazin-2-yl, optionally substituted by halogen, lower alkyl, lower cycloalkyl, lower alkyl substituted by halogen, lower alkyl substituted by hydroxy or cyano; or is 2,2-difluorobenzo[d][1,3]dioxol-5-yl, or is thiazolyl, optionally substituted by lower alkyl substituted by halogen; R 2 is hydrogen or lower alkyl; R 3 is hydrogen, amino or lower alkyl; Z is a bond, —CH 2 — or —O—; or to a pharmaceutically suitable acid addition salt thereof. It has now been found that the compounds of formulas I have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1. The compounds may be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

  本发明涉及以下式的化合物： 其中， R1是苯基，可以被卤素、低烷基、低环烷基、低烷氧基、氰基、被卤素取代的低烷基、被羟基取代的低烷基、被卤素取代的低烷氧基或被羟基取代的低烷氧基；或是吡啶-2、3或4-基，可以被卤素、低烷基、低环烷基、氰基、被卤素取代的低烷基、被羟基取代的低烷基、低烷氧基、被卤素取代的低烷氧基或被羟基取代的低烷氧基取代； 或是嘧啶-2、4或5-基，可以被卤素、低烷基、低环烷基、被羟基取代的低烷基或被卤素取代的低烷基取代； 或是吡唑-2-基，可以被卤素、低烷基、低环烷基、被卤素取代的低烷基、被羟基取代的低烷基或氰基取代； 或是2,2-二氟苯并[d][1,3]二氧杂环-5-基； 或是噻唑基，可以被被卤素取代的低烷基取代； R2是氢或低烷基； R3是氢、氨基或低烷基； Z是键，-CH2-或-O-； 或是其药学上适宜的酸盐。 现已发现，式I的化合物对微量胺基关联受体(TAARs)具有良好的亲和力，尤其是对TAAR1。 该化合物可用于治疗抑郁症、焦虑症、双相情感障碍、注意力缺陷多动障碍(ADHD)、压力相关障碍、精神疾病如精神分裂症、神经疾病如帕金森病、神经退行性疾病如阿尔茨海默病、癫痫、偏头痛、高血压、物质滥用和代谢性疾病如进食障碍、糖尿病、糖尿病并发症、肥胖症、血脂异常、能量消耗和吸收障碍、体温稳态障碍、睡眠和昼夜节律障碍以及心血管疾病的治疗。
• PYRAZOLE CARBOXAMIDE DERIVATIVES AS TAAR MODULATORS FOR USE IN THE TREATMENT OF SEVERAL DISORDERS, SUCH AS DEPRESSION, DIABETES AND PARKINSON'S DISEASE
  申请人：F.Hoffmann-La Roche AG

  公开号：EP2895477A1

  公开（公告）日：2015-07-22
• PYRAZOLE CARBOXAMIDE DERIVATIVES AS TAAR MODULATORS FOR USE IN THE TREATMENT OF SEVERAL DISORDERS, SUCH AS DEPRESSION, DIABETES AND PARKINSON'S DISEASE.
  申请人：F. Hoffmann-La Roche AG

  公开号：EP2895477B1

  公开（公告）日：2017-11-01
• US9487501B2
  申请人：——

  公开号：US9487501B2

  公开（公告）日：2016-11-08
• [EN] PYRAZOLE CARBOXAMIDE DERIVATIVES AS TAAR MODULATORS FOR USE IN THE TREATMENT OF SEVERAL DISORDERS, SUCH AS DEPRESSION, DIABETES AND PARKINSON'S DISEASE<br/>[FR] DÉRIVÉS DE PYRAZOLE-CARBOXAMIDE EN TANT QUE MODULATEURS DE TAAR POUR UTILISATION DANS LE TRAITEMENT DE PLUSIEURS TROUBLES, TELS QUE LA DÉPRESSION, LE DIABÈTE ET LA MALADIE DE PARKINSON
  申请人：HOFFMANN LA ROCHE

  公开号：WO2014041007A1

  公开（公告）日：2014-03-20

  The present invention relates to compounds of formula (I) wherein R1 is phenyl, optionally substituted by halogen, lower alkyl, lower cycloalkyl, lower alkoxy, cyano, lower alkyl substituted by halogen, lower alkyl substituted by hydroxy, lower alkoxy substituted by halogen or lower alkoxy substituted by hydroxy; or is pyridine-2, 3 or 4-yl, optionally substituted by halogen, lower alkyl, lower cycloalkyl, cyano, lower alkyl substituted by halogen, lower alkyl substituted by hydroxy, lower alkoxy, lower alkoxy substituted by halogen or lower alkoxy substituted by hydroxyl; or is pyrimidin-2, 4 or 5-yl, optionally substituted by halogen, lower alkyl, lower cycloalkyl, lower alkyl substituted by hydroxy or lower alkyl substituted by halogen; or is pyrazin-2-yl, optionally substituted by halogen, lower alkyl, lower cycloalkyl, lower alkyl substituted by halogen, lower alkyl substituted by hydroxy or cyano; or is 2,2-difluorobenzo[d][l,3]dioxol-5-yl, or is thiazolyl, optionally substituted by lower alkyl substituted by halogen; R2 is hydrogen or lower alkyl; R3 is hydrogen, amino or lower alkyl; Z is a bond, -CH2- or -O-; or to a pharmaceutically suitable acid addition salt thereof. It has now been found that the compounds of formulas I have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1. The compounds may be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

  本发明涉及以下式（I）的化合物，其中R1是苯基，可以被卤素、较低烷基、较低环烷基、较低烷氧基、氰基、被卤素取代的较低烷基、被羟基取代的较低烷基、被卤素取代的较低烷氧基或被羟基取代的较低烷氧基；或是吡啶-2、3或4-基，可以被卤素、较低烷基、较低环烷基、氰基、被卤素取代的较低烷基、被羟基取代的较低烷基、较低烷氧基、被卤素取代的较低烷氧基或被羟基取代的较低烷氧基取代；或是嘧啶-2、4或5-基，可以被卤素、较低烷基、较低环烷基、被羟基取代的较低烷基或被卤素取代的较低烷基取代；或是吡嗪-2-基，可以被卤素、较低烷基、较低环烷基、被卤素取代的较低烷基、被羟基取代的较低烷基或氰基取代；或是2,2-二氟苯并[d][1,3]二氧杂环-5-基，或是噻唑基，可以被被卤素取代的较低烷基取代；R2是氢或较低烷基；R3是氢、氨基或较低烷基；Z是键，-CH2-或-O-；或其药学上适用的酸盐。现已发现，式I的化合物对追踪胺相关受体（TAARs）有很好的亲和力，尤其是对TAAR1。这些化合物可用于治疗抑郁症、焦虑症、双相情感障碍、注意力缺陷多动障碍（ADHD）、与压力相关的障碍、精神分裂症等精神障碍、帕金森病等神经系统疾病、阿尔茨海默病等神经退行性疾病、癫痫、偏头痛、高血压、物质滥用以及代谢障碍，如进食障碍、糖尿病、糖尿病并发症、肥胖症、血脂异常、能量消耗和吸收障碍、体温稳态障碍、睡眠和昼夜节律障碍，以及心血管疾病。