2-(1-cyanopropan-2-yl)-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline-1-carboxamide | 1198163-51-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 2-(1-cyanopropan-2-yl)-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline-1-carboxamide
• 英文别名: 2-(1-cyanopropan-2-yl)-3-oxo-N-[[4-(trifluoromethoxy)phenyl]methyl]-1H-isoindole-1-carboxamide
• CAS: 1198163-51-7
• 化学式: C₂₁H₁₈F₃N₃O₃
• 分子量: 417.387
• InChiKey: FDVHTMPORAQXDN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  82.4
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  1-(异氰基甲基)-4-(三氟甲氧基)苯 、 1-cyanopropan-2-aminium 2,2,2-trifluoroacetate 、 邻羧基苯甲醛 在 三乙胺 作用下， 以 甲醇 为溶剂， 以12%的产率得到2-(1-cyanopropan-2-yl)-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline-1-carboxamide
  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

文献信息

• [EN] ISOINDOLINE DERIVATIVES COMPRISING A CYANO GROUP AND THEIR USE IN THE TREATMENT OF PAIN DISORDERS<br/>[FR] DÉRIVÉS D'ISO-INDOLINE COMPRENANT UN GROUPE CYANO ET LEUR UTILISATION DANS LE TRAITEMENT DE TROUBLES DE LA DOULEUR
  申请人：ASTRAZENECA AB

  公开号：WO2009145719A1

  公开（公告）日：2009-12-03

  Compounds of formula I are claimed, wherein R1 is hydrogen, C1_3alkyl, C1_3alkoxy, cyano, hydroxy or halo; and wherein said C1-3alkyl is optionally substituted by one or more substituents independently selected from hydroxy, C1_3alkoxy andfluoro; and said C1_3alkoxy is optionally substituted by one or more fluoro; m is 1, 2 or 3; R2 and R3 is each and independently selected from hydrogen, C1-4haloalkyl, C1-4haloalkoxy, halo, C1-4alkoxy, C1-4alkyl and C3_7Cycloalkyloxy; wherein said C3_7cycloalkyloxy is optionally substituted by one or more fluoro; and R2 and R3 may not both be hydrogen; L1 is C1-4alkylene, pentylene, or C3-6 cycloalkylene, wherein said C1-4alkylene, pentylene or C3-6 cycloalkylene may be optionally substituted by one or more X4; X4 is fluoro, C1_3alkyl, C3_7Cycloalkyl, C1_3alkylOCi_3alkyl, C1_3alkoxy, cyano, hydroxy, R4O(C=O)-, R4NR5(C=O)-, R4O(C=O)NR5-, R4NR5(C=O)NR5-, R4(C=O)O-, R4(C=O)NR5-, R4NR5(C=O)O-, R4NR5(C=O)NR5-, C5-6 heteroaryl(C=O), or C5-6 heteroaryl; R4 is C1-4 alkylOC1-4 alkyl, C5-6 cycloalkyl, aryl, or aryl-C1-2 alkyl; R5 is H or methyl; and wherein said C1-3 alkylOC1-3alkyl, C1-3alkoxy and C1-4alkylsulfonyl is optionally substituted by one or more fluoro; L2 is C1-3 alkylene, optionally substituted by one or more X4; as well as pharmaceutically acceptable salt, or isomer thereof, or a salt of said isomer. Compounds of the invention are useful in therapy, such as pain therapy.

  公式I的化合物被声明，其中R1是氢，C1_3烷基，C1_3烷氧基，氰基，羟基或卤素; 其中所述的C1-3烷基可以选择地被一个或多个独立选择自羟基，C1_3烷氧基和氟代基的取代基所取代; 所述的C1_3烷氧基可以选择地被一个或多个氟代基所取代; m为1、2或3; R2和R3分别且独立地选择自氢，C1-4卤代烷基，C1-4卤代烷氧基，卤素，C1-4烷氧基，C1-4烷基和C3_7环烷氧基; 其中所述的C3_7环烷氧基可以选择地被一个或多个氟代基所取代; R2和R3不能同时为氢; L1为C1-4烷基，戊烷基或C3-6环烷基，其中所述的C1-4烷基，戊烷基或C3-6环烷基可以选择地被一个或多个X4所取代; X4为氟代基，C1_3烷基，C3_7环烷基，C1_3烷基氧C1_3烷基，C1_3烷氧基，氰基，羟基，R4O(C=O)-，R4NR5(C=O)-，R4O(C=O)NR5-，R4NR5(C=O)NR5-，R4(C=O)O-，R4(C=O)NR5-，R4NR5(C=O)O-，R4NR5(C=O)NR5-，C5-6杂环芳基(C=O)，或C5-6杂环芳基; R4为C1-4烷氧基C1-4烷基，C5-6环烷基，芳基，或芳基-C1-2烷基; R5为H或甲基; 其中所述的C1-3烷氧基C1-3烷基，C1-3烷氧基和C1-4烷基磺酰基可以选择地被一个或多个氟代基所取代; L2为C1-3烷基，可以选择地被一个或多个X4所取代; 以及药学上可接受的盐，或其异构体，或所述异构体的盐。本发明的化合物在治疗中很有用，如疼痛治疗。
• 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.