3-isobutyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)imidazolidine-2,4-dione | 1228594-56-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 英文名称: 3-isobutyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)imidazolidine-2,4-dione
• 英文别名: 3-Isobutyl-1-(4-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)benzyl)imidazolidine-2,4-dione；3-(2-methylpropyl)-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]imidazolidine-2,4-dione
• CAS: 1228594-56-6
• 化学式: C₂₀H₂₉BN₂O₄
• 分子量: 372.272
• InChiKey: QXZPKGFRAUVPCJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.41
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  59.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-isobutyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)imidazolidine-2,4-dione 、 C₁₁H₁₅BrFN₃ 在 四(三苯基膦)钯 、 potassium carbonate 作用下， 以 乙醇 、 甲苯 为溶剂， 生成
  参考文献：
  名称：

  大麻素CB 2受体激动剂的结构动力学关系研究表明，其对停留时间的取代基特异性亲脂作用

  摘要：

  图形化的抽象图。没有可用的字幕。摘要十年前，引入了药物靶标停留时间模型，该模型描述了配体在其蛋白靶标上的结合动力学的重要性。从那时起，它已成功应用于包括GPCR在内的多种蛋白质靶标，用于开发解离动力学较慢（即较长的靶标停留时间）以提高体内功效或具有较短的停留时间以防止靶标相关侧的先导化合物。效果。迄今为止，该模型尚未用于大麻素CB2受体（CB2R）的新型选择性配体的设计和药理学评估，该选择性配体具有治疗组织损伤和炎性疾病的潜力。在这里，我们研究了理化性质之间的关系，两种不同的信号转导途径中的结合动力学和功能活性，即G蛋白激活和b-arrestin募集。我们合成了24个类似物3-环丙基-1-（4-（6-（（1,1-二氧硫代吗啉代）甲基）-5-氟吡啶-2-基）苄基）咪唑烷-2-，4-二酮（LEI101），以前报道过体内活性和CB2R选择性激动剂，具有不同的碱性和亲脂性。我们发现，由于烷基取代基

  DOI：

  10.1016/j.bcp.2018.03.018
• 作为产物：
  描述：

  2-[(4-溴苯基)甲基氨基]乙酰胺 在 4-二甲氨基吡啶 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 potassium acetate 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 48.0h， 生成 3-isobutyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)imidazolidine-2,4-dione
  参考文献：
  名称：

  大麻素CB 2受体激动剂的结构动力学关系研究表明，其对停留时间的取代基特异性亲脂作用

  摘要：

  图形化的抽象图。没有可用的字幕。摘要十年前，引入了药物靶标停留时间模型，该模型描述了配体在其蛋白靶标上的结合动力学的重要性。从那时起，它已成功应用于包括GPCR在内的多种蛋白质靶标，用于开发解离动力学较慢（即较长的靶标停留时间）以提高体内功效或具有较短的停留时间以防止靶标相关侧的先导化合物。效果。迄今为止，该模型尚未用于大麻素CB2受体（CB2R）的新型选择性配体的设计和药理学评估，该选择性配体具有治疗组织损伤和炎性疾病的潜力。在这里，我们研究了理化性质之间的关系，两种不同的信号转导途径中的结合动力学和功能活性，即G蛋白激活和b-arrestin募集。我们合成了24个类似物3-环丙基-1-（4-（6-（（1,1-二氧硫代吗啉代）甲基）-5-氟吡啶-2-基）苄基）咪唑烷-2-，4-二酮（LEI101），以前报道过体内活性和CB2R选择性激动剂，具有不同的碱性和亲脂性。我们发现，由于烷基取代基

  DOI：

  10.1016/j.bcp.2018.03.018

文献信息

• 1-(BIPHENYL-4-YLMETHYL)IMIDAZOLIDINE-2,4-DIONE
  申请人：van der Stelt Marcelis

  公开号：US20100144723A1

  公开（公告）日：2010-06-10

  The invention relates to A 1-(biphenyl-4-ylmethyl)imidazolidine-2,4-dione derivative having the general Formula I wherein R 1 is H, (C 1-6 )alkyl (optionally substituted with oxo, OR 4 , COOR 5 , halogen or CN), (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 3-6 )cycloalkyl or (C 3-6 )cycloalkyl(C 1-3 )alkyl; R 2 and R 2 ′ are independently H or (C 1-3 )alkyl; or R 2 and R 2 ′ form together with the carbon atom to which they are bound a (C 3-5 )cycloalkyl group; R 3 represents H or 1 to 4 F substituents; Y represents or NR 8 R 9 ; X represents CHR 6 , CF 2 , O, S, SO or SO 2 ; R 4 and R 5 are (C 1-6 )alkyl; R 6 is H, OR 7 or CN; R 7 is (C 1-3 )alkyl; R 8 is (C 5-7 )cycloalkyl comprising a heteroatom selected from O, S, SO and SO 2 ; R 9 is H or (C 1-4 )alkyl; o and m represent the ortho or meta position of the substituent Y—CH 2 ; or a pharmaceutically acceptable salt thereof; as well as to the use of said 1-(biphenyl-4-ylmethyl)imidazolidine-2,4-dione derivatives in the treatment of pain such as for example peri-operative pain, chronic pain, neuropathic pain, cancer pain and pain and spasticity associated with multiple sclerosis.

  该发明涉及具有通式I的1-(联苯基-4-基甲基)咪唑烷二酮衍生物，其中R1为H，(C1-6)烷基（可选地取代为氧代、OR4、COOR5、卤素或CN），(C2-6)烯基，(C2-6)炔基，(C3-6)环烷基或(C3-6)环烷基(C1-3)烷基；R2和R2'独立地为H或(C1-3)烷基；或R2和R2'与它们连接的碳原子一起形成一个(C3-5)环烷基基团；R3代表H或1至4个F取代基；Y代表或NR8R9；X代表CHR6，CF2，O，S，SO或SO2；R4和R5为(C1-6)烷基；R6为H，OR7或CN；R7为(C1-3)烷基；R8为含有来自O、S、SO和SO2的杂原子的(C5-7)环烷基；R9为H或(C1-4)烷基；o和m表示取代基Y-CH2的邻位或间位；或其药学上可接受的盐；以及所述1-(联苯基-4-基甲基)咪唑烷二酮衍生物在治疗疼痛方面的应用，例如围手术期疼痛、慢性疼痛、神经痛、癌症疼痛以及与多发性硬化症相关的疼痛和痉挛。
• 1-(4-(PYRIDIN-2-YL)BENZYL)IMIDAZOLIDINE-2,4-DIONE DERIVATIVES
  申请人：van der Stelt Marcelis

  公开号：US20100144724A1

  公开（公告）日：2010-06-10

  The invention relates to 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative having the general Formula I wherein R 1 is H, (C 1-6 )alkyl (optionally substituted with oxo, (C 1-3 )alkyloxy, (C 1-3 )alkyloxycarbonyl, halogen or CN), (C 3-6 )cycloalkyl or (C 3-6 )cycloalkyl(C 1-3 )alkyl, each cycloalkyl ring optionally comprising a heteroatom selected from O and S; R 2 and R 3 are independently H or (C 1-3 )alkyl; or R 2 and R 3 form together with the carbon atom to which they are bound a (C 3-5 )cycloalkyl group; R 4 is H or 1 to 3 F substituents; R 5 is H or 1 to 4 F substituents; R 6 and R 7 are independently H or F; X represents R 8 , OR 8 , NR 8 R 9 , R 8 is (C 5-7 )cycloalkyl optionally comprising a heteroatom selected from O, S, SO and SO 2 ; R 9 is H or (C 1-4 )alkyl; R 10 represents 1-3 substituents independently selected from H, (C 1-3 )alkyl, halogen, oxo, CN and CF 3 ; Y is CF 2 , O, S, SO or SO 2 ; or a pharmaceutically acceptable salt thereof, to pharmaceutical compositions comprising the same, as well as to the use of said 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives in the treatment of pain such as for example peri-operative pain, chronic pain, neuropathic pain, cancer pain and pain and spasticity associated with multiple sclerosis.

  该发明涉及具有一般式I的1-(4-(吡啶-2-基)苄基)咪唑啉二酮衍生物，其中R1为H，(C1-6)烷基（可选择地取代为氧代、(C1-3)烷氧基、(C1-3)烷氧羰基、卤素或CN），(C3-6)环烷基或(C3-6)环烷基(C1-3)烷基，每个环烷基环可选择包含从O和S中选择的杂原子; R2和R3分别为H或(C1-3)烷基; 或R2和R3与它们连接的碳原子一起形成(C3-5)环烷基基团; R4为H或1至3个F取代基; R5为H或1至4个F取代基; R6和R7分别为H或F; X代表R8，OR8，NR8R9，R8为(C5-7)环烷基，可选择包含从O、S、SO和SO2中选择的杂原子; R9为H或(C1-4)烷基; R10代表1-3个取代基，独立选择自H、(C1-3)烷基、卤素、氧代、CN和CF3; Y为CF2、O、S、SO或SO2;或其药学上可接受的盐，以及包含该类化合物的药物组合物，以及所述1-(4-(吡啶-2-基)苄基)咪唑啉二酮衍生物在治疗疼痛中的用途，例如围手术期疼痛、慢性疼痛、神经性疼痛、癌症疼痛以及与多发性硬化相关的疼痛和痉挛。
• 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives
  申请人：MSD OSS B.V.

  公开号：US08143246B2

  公开（公告）日：2012-03-27

  The invention relates to 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative having the general Formula I wherein R1 is H, (C1-6)alkyl (optionally substituted with oxo, (C1-3)alkyloxy, (C1-3)alkyloxycarbonyl, halogen or CN), (C3-6)cycloalkyl or (C3-6)cycloalkyl(C1-3)alkyl, each cycloalkyl ring optionally comprising a heteroatom selected from O and S; R2 and R3 are independently H or (C1-3)alkyl; or R2 and R3 form together with the carbon atom to which they are bound a (C3-5)cycloalkyl group; R4 is H or 1 to 3 F substituents; R5 is H or 1 to 4 F substituents; R6 and R7 are independently H or F; X represents R8, OR8, NR8R9, R8 is (C5-7)cycloalkyl optionally comprising a heteroatom selected from O, S, SO and SO2; R9 is H or (C1-4)alkyl; R10 represents 1-3 substituents independently selected from H, (C1-3)alkyl, halogen, oxo, CN and CF3; Y is CF2, O, S, SO or SO2; or a pharmaceutically acceptable salt thereof, to pharmaceutical compositions comprising the same, as well as to the use of said 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives in the treatment of pain such as for example peri-operative pain, chronic pain, neuropathic pain, cancer pain and pain and spasticity associated with multiple sclerosis.

  本发明涉及一种具有通式I的1-(4-(吡啶-2-基)苯基)咪唑啉-2,4-二酮衍生物，其中R1为H，(C1-6)烷基（可选地取代氧代，(C1-3)烷氧基，(C1-3)烷氧羰基，卤素或CN），(C3-6)环烷基或(C3-6)环烷基(C1-3)烷基，每个环烷基环可选地包含选自O和S的杂原子；R2和R3独立地为H或(C1-3)烷基；或R2和R3与它们结合的碳原子一起形成(C3-5)环烷基；R4为H或1至3个F取代基；R5为H或1至4个F取代基；R6和R7独立地为H或F；X代表R8，OR8，NR8R9，R8为(C5-7)环烷基，可选地包含选自O、S、SO和SO2的杂原子；R9为H或(C1-4)烷基；R10代表1-3个取代基，独立地选自H，(C1-3)烷基，卤素，氧代，CN和CF3；Y为CF2，O，S，SO或SO2；或其药学上可接受的盐，以及含有它们的制药组合物，以及在治疗疼痛，例如围手术期疼痛，慢性疼痛，神经病性疼痛，癌症疼痛和与多发性硬化症相关的疼痛和痉挛中使用所述1-(4-(吡啶-2-基)苯基)咪唑啉-2,4-二酮衍生物。
• Structural basis of selective cannabinoid CB2 receptor activation
  作者：Xiaoting Li、Hao Chang、Jara Bouma、Laura V. de Paus、Partha Mukhopadhyay、Janos Paloczi、Mohammed Mustafa、Cas van der Horst、Sanjay Sunil Kumar、Lijie Wu、Yanan Yu、Richard J. B. H. N. van den Berg、Antonius P. A. Janssen、Aron Lichtman、Zhi-Jie Liu、Pal Pacher、Mario van der Stelt、Laura H. Heitman、Tian Hua

  DOI：10.1038/s41467-023-37112-9

  日期：——

  Cannabinoid CB₂ receptor (CB₂R) agonists are investigated as therapeutic agents in the clinic. However, their molecular mode-of-action is not fully understood. Here, we report the discovery of LEI-102, a CB₂R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CB₂R activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies. We identify key residues for CB₂R activation. Highly lipophilic HU308 and the endocannabinoids, but not the more polar LEI-102, APD371, and CP55,940, reach the binding pocket through a membrane channel in TM1-TM7. Favorable physico-chemical properties of LEI-102 enable oral efficacy in a chemotherapy-induced nephropathy model. This study delineates the molecular mechanism of CB₂R activation by selective agonists and highlights the role of lipophilicity in CB₂R engagement. This may have implications for GPCR drug design and sheds light on their activation by endogenous ligands.

  摘要大麻素 CB2 受体（CB2R）激动剂被研究用作临床治疗药物。然而，人们对它们的分子作用模式并不完全了解。在此，我们报告了发现的一种 CB2R 激动剂 LEI-102，并将其与其他三种 CBR 配体（APD371、HU308 和 CP55,940）结合使用，通过结合动力学、定点突变和冷冻电镜研究来研究 CB2R 的选择性激活。我们确定了激活 CB2R 的关键残基。高亲脂性的 HU308 和内源性大麻素，而非极性较强的 LEI-102、APD371 和 CP55,940，可通过 TM1-TM7 的膜通道到达结合口袋。LEI-102 具有良好的物理化学特性，可在化疗诱导的肾病模型中发挥口服疗效。这项研究描述了选择性激动剂激活 CB2R 的分子机制，并强调了亲脂性在 CB2R 参与中的作用。这可能会对 GPCR 药物设计产生影响，并揭示了内源性配体对它们的激活作用。
• Discovery and Optimization of 1-(4-(Pyridin-2-yl)benzyl)imidazolidine-2,4-dione Derivatives As a Novel Class of Selective Cannabinoid CB2 Receptor Agonists
  作者：Mario van der Stelt、Jos Cals、Silvia Broeders-Josten、Jean Cottney、Antoon A. van der Doelen、Marcel Hermkens、Vera de Kimpe、Angela King、Jan Klomp、Julia Oosterom、Ilse Pols-de Rooij、Jeroen de Roos、Martin van Tilborg、Susan Boyce、James Baker

  DOI：10.1021/jm200916p

  日期：2011.10.27

  Here, we report the identification and optimization of 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives as a novel chemotype with selective cannabinoid CB2 receptor agonist activity. 1 is a potent and selective cannabinoid CB2 receptor agonist (hCB2 pEC(50) = 8.6). The compound was found to be metabolically unstable, which resulted in low oral bioavailability in rat (F-po = 4%) and possessed off-target activity at the hERG ion channel (pK(i), = 5.5). Systematic modification of physicochemical properties, such as lipophilicity and basicity, was used to optimize the pharmacokinetic profile and hERG affinity of this novel class of cannabinoid CB2 receptor agonists. This led to the identification of 44 as a potent, selective, and orally bioavailable cannabinoid CB2 receptor agonist (hCB2 pEC(50) = 8.0; hERG pK(i) < 4; F-po = 100%), which was active in a rat spinal nerve ligation model of neuropathic pain.