6-(二氟甲氧基)烟腈 | 1198103-42-2

• 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: 6-(二氟甲氧基)烟腈
• 英文名称: 6-(difluoromethoxy)nicotinonitrile
• 英文别名: 6-(difluoromethoxy)pyridine-3-carbonitrile
• CAS: 1198103-42-2
• 化学式: C₇H₄F₂N₂O
• 分子量: 170.118
• InChiKey: RASGKOKUJVRDAN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  12
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  45.9
• 氢给体数：
  0
• 氢受体数：
  5

安全信息

• 储存条件：
  室温

反应信息

• 作为反应物：
  描述：

  6-(二氟甲氧基)烟腈 在 氢气 、 N,N-二异丙基乙胺 、 三氯氧磷 作用下， 以 甲醇 、 二氯甲烷 为溶剂， -15.0~20.0 ℃ 、310.27 kPa 条件下， 反应 20.0h， 生成 2-(difluoromethoxy)-5-(isocyanomethyl)pyridine
  参考文献：
  名称：

  3-Oxoisoindoline-1-carboxamides: Potent, State-Dependent Blockers of Voltage-Gated Sodium Channel Na_V1.7 with Efficacy in Rat Pain Models

  摘要：

  The voltage-gated sodium channel Na(V)1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective sodium channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure activity relationships, and in vitro and in vivo characterization of a novel series of Na(V)1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na(V)1.7 potency, selectivity over Na(V)1.5, and metabolic stability properties produced several interesting oxoisoindoline carboxamides (16A, 26B, 28, 51, 60, and 62) that were further characterized. The oxoisoindoline carboxamides interacted with the local anesthetics binding site. In spite of this, several compounds showed functional selectivity versus Na(V)1.5 of more than 100-fold. This appeared to be a combination of subtype and state-dependent selectivity. Compound 28 showed concentration-dependent inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation from SNL rats. Compounds 16A and 26B demonstrated concentration-dependent efficacy in preclinical behavioral pain models. The oxoisoindoline carboxamides series described here may be valuable for further investigations for pain therapeutics.

  DOI：

  10.1021/jm300623u
• 作为产物：
  描述：

  2-(二氟甲氧基)-5-溴吡啶 、 zinc(II) cyanide 在 四(三苯基膦)钯 作用下， 以 DMF (N,N-dimethylformamide) 为溶剂， 反应 16.0h， 以73%的产率得到6-(二氟甲氧基)烟腈
  参考文献：
  名称：

  [EN] ISOINDOLINE DERIVATIVES COMPRISING ADDITIONAL HETEROCYCLIC GROUPS AND THEIR USE IN THE TREATMENT OF PAIN DISORDERS
  [FR] DÉRIVÉS ISOINDOLINE COMPRENANT DES GROUPES HÉTÉROCYCLIQUES SUPPLÉMENTAIRES ET LEUR UTILISATION DANS LE TRAITEMENT DE TROUBLES DE LA DOULEUR

  摘要：

  式I的化合物被要求，其中R1是氢；C1-3烷基，可选地由一个或多个取代基独立选择自羟基、C1-3烷氧基和氟代基；C1-3烷氧基，可选地由一个或多个氟代基取代；氰基；羟基或卤素基；m为1,2或3；Het是C5-6杂环芳基，取代为1或2个取代基R2；R2是C1-4烷基；C1-4卤代烷基；C1-4卤代烷氧基；卤素；C1-4烷氧基；或C3-7环烷氧基，可选地由一个或多个氟代基取代；D是C5-6杂环芳基；C3-7杂环烷基；或C3-7环烷基；其中每个D可选择地被一个或多个X4取代；X4是卤素；或C1-3烷基，可选地由一个或多个氟代基取代；C1-3烷基-O-C1-3烷基，可选地由一个或多个氟代基取代；C1-3烷氧基，可选地由一个或多个氟代基取代；氰基；羟基；氧代基；R3 0(C=O)；或R4(C=O)；R3是C1-4烷基；C1-4烷基-O-C1-4烷基；C5-6环烷基；芳基；或芳基-C1-2烷基；R4是C1-4烷基；或C5-6杂环芳基；L1是C1-4烷基；或一个键；而L2是C1-3烷基。该发明的化合物在治疗中有用，如疼痛治疗。

  公开号：

  WO2009145720A1

文献信息

• 3-Oxoisoindoline-1-carboxamides: Potent, State-Dependent Blockers of Voltage-Gated Sodium Channel Na_V1.7 with Efficacy in Rat Pain Models
  作者：Istvan Macsari、Yevgeni Besidski、Gabor Csjernyik、Linda I. Nilsson、Lars Sandberg、Ulrika Yngve、Kristofer Åhlin、Tjerk Bueters、Anders B. Eriksson、Per-Eric Lund、Elisabet Venyike、Sandra Oerther、Karin Hygge Blakeman、Lei Luo、Per I. Arvidsson

  DOI：10.1021/jm300623u

  日期：2012.8.9

  The voltage-gated sodium channel Na(V)1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective sodium channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure activity relationships, and in vitro and in vivo characterization of a novel series of Na(V)1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na(V)1.7 potency, selectivity over Na(V)1.5, and metabolic stability properties produced several interesting oxoisoindoline carboxamides (16A, 26B, 28, 51, 60, and 62) that were further characterized. The oxoisoindoline carboxamides interacted with the local anesthetics binding site. In spite of this, several compounds showed functional selectivity versus Na(V)1.5 of more than 100-fold. This appeared to be a combination of subtype and state-dependent selectivity. Compound 28 showed concentration-dependent inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation from SNL rats. Compounds 16A and 26B demonstrated concentration-dependent efficacy in preclinical behavioral pain models. The oxoisoindoline carboxamides series described here may be valuable for further investigations for pain therapeutics.
• [EN] ISOINDOLINE DERIVATIVES COMPRISING ADDITIONAL HETEROCYCLIC GROUPS AND THEIR USE IN THE TREATMENT OF PAIN DISORDERS<br/>[FR] DÉRIVÉS ISOINDOLINE COMPRENANT DES GROUPES HÉTÉROCYCLIQUES SUPPLÉMENTAIRES ET LEUR UTILISATION DANS LE TRAITEMENT DE TROUBLES DE LA DOULEUR
  申请人：ASTRAZENECA AB

  公开号：WO2009145720A1

  公开（公告）日：2009-12-03

  Compounds of formula I are claimed wherein R1 is hydrogen; C1-3 alkyl, optionally substituted by one or more substituents independently selected from hydroxy, C1-3 alkoxy andfluoro; C1-3 alkoxy, optionally substituted by one or morefluoro; cyano; hydroxy or halo; m is 1,2 or 3; Het is C5-6 heteroaryl substituted by 1 or 2 substituents R2; R2 is C1-4 alkyl; C1-4 haloalkyl;C 1-4 haloalkoxy; halo; C1-4 alkoxy; or C3-7 cycloalkyloxy, optionally substituted by one or morefluoro; D is C5-6 heteroaryl; C3-7 heterocycloalkyl; or C3-7 cycloalkyl; wherein each D may optionally be substituted by one or more X4; X4 is halo; or C1-3 alkyl, optionally substituted by one or morefluoro; C1-3 alkyl-O-C1-3 alkyl, optionally substituted by one or morefluoro; C1-3 alkoxy, optionally substituted by one or morefluoro; cyano; hydroxy; oxo; R3 0(C=O); or R4(C=O); R3 is C1-4 alkyl; C1-4 alkyl-O-C1-4 alkyl; C5-6 cycloalkyl; aryl; or aryl-C1-2 alkyl; R4 is C1-4 alkyl; or C5-6 heteroaryl; L1is C1-4 alkylene; or a bond; and L2 is C1-3 alkylene. Compounds of the invention are useful in therapy, such as pain therapy.

  式I的化合物被要求，其中R1是氢；C1-3烷基，可选地由一个或多个取代基独立选择自羟基、C1-3烷氧基和氟代基；C1-3烷氧基，可选地由一个或多个氟代基取代；氰基；羟基或卤素基；m为1,2或3；Het是C5-6杂环芳基，取代为1或2个取代基R2；R2是C1-4烷基；C1-4卤代烷基；C1-4卤代烷氧基；卤素；C1-4烷氧基；或C3-7环烷氧基，可选地由一个或多个氟代基取代；D是C5-6杂环芳基；C3-7杂环烷基；或C3-7环烷基；其中每个D可选择地被一个或多个X4取代；X4是卤素；或C1-3烷基，可选地由一个或多个氟代基取代；C1-3烷基-O-C1-3烷基，可选地由一个或多个氟代基取代；C1-3烷氧基，可选地由一个或多个氟代基取代；氰基；羟基；氧代基；R3 0(C=O)；或R4(C=O)；R3是C1-4烷基；C1-4烷基-O-C1-4烷基；C5-6环烷基；芳基；或芳基-C1-2烷基；R4是C1-4烷基；或C5-6杂环芳基；L1是C1-4烷基；或一个键；而L2是C1-3烷基。该发明的化合物在治疗中有用，如疼痛治疗。