6-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrazin-2-amine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并二恶烷
• 英文名称: 6-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrazin-2-amine
• 英文别名: 6-(4-tert-butylphenyl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)pyrazin-2-amine
• 化学式: C₂₂H₂₃N₃O₂
• 分子量: 361.444
• InChiKey: BJVNWCGYGFLIFA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  56.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  4-叔丁基苯硼酸 在 tris-(dibenzylideneacetone)dipalladium(0) 、 四(三苯基膦)钯 potassium carbonate 、 sodium t-butanolate 、 2-二环己膦基-2'-(N,N-二甲胺)-联苯 作用下， 以 1,4-二氧六环 、 甲苯 为溶剂， 反应 0.66h， 生成 6-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrazin-2-amine
  参考文献：
  名称：

  Novel Vanilloid Receptor-1 Antagonists:  1. Conformationally Restricted Analogues of trans-Cinnamides

  摘要：

  The vanilloid receptor-1 (VR1 or TRPV1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role as an integrator of multiple pain-producing stimuli. From a high-throughput screening assay, measuring calcium uptake in TRPV1-expressing cells, we identified an N-aryl trans-cinnamide (AMG9810, compound 9) that acts as a potent TRPV1 antagonist. We have demonstrated the antihyperalgesic properties of 9 in vivo and have also reported the discovery of novel, orally bioavailable cinnamides derived from this lead. Herein, we expand our investigations and describe the synthesis and biological evaluation of a series of conformationally constrained analogues of the s-cis conformer of compound 9. These investigations resulted in the identification of 4-amino- and 4-oxopyrimidine cores as suitable isosteric replacements for the trans-acrylamide moiety. The best examples from this series, pyrimidines 79 and 74, were orally bioavailable and exhibited potent antagonism of both rat (IC50 = 4.5 and 0.6 nM, respectively) and human TRPV1 (IC50 = 7.4 and 3.7 nM, respectively). In addition, compound 74 was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo in the capsaicin-induced hypothermia model in rats; however, it was ineffective at preventing thermal hyperalgesia induced by complete Freund's adjuvant in rats.

  DOI：

  10.1021/jm070189q

文献信息

• Vanilloid receptor ligands and their use in treatments
  申请人：Chen Ning

  公开号：US20050153984A1

  公开（公告）日：2005-07-14

  Compounds having the general structure and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.

  具有一般结构和组成的化合物，用于治疗急性、炎症性和神经病性疼痛、牙痛、普通头痛、偏头痛、群集性头痛、混合性血管和非血管综合征、紧张型头痛、一般炎症、关节炎、风湿性疾病、骨关节炎、炎症性肠病、炎症性眼疾、炎症性或不稳定的膀胱疾病、牛皮癣、带有炎症成分的皮肤疾病、慢性炎症病症、炎症性疼痛和相关的过敏性痛觉和触觉过敏、神经病性疼痛和相关的过敏性痛觉和触觉过敏、糖尿病性神经病疼痛、烧伤后神经痛、交感神经维持性疼痛、感觉缺失综合征、哮喘、上皮组织损伤或功能障碍、单纯疱疹、呼吸、泌尿、胃肠或血管区域内脏动力障碍、伤口、烧伤、过敏性皮肤反应、瘙痒、白癜风、一般胃肠疾病、胃溃疡、十二指肠溃疡、腹泻、坏死剂诱导的胃病变、毛发生长、血管运动或过敏性鼻炎、支气管疾病或膀胱疾病。
• VANILLOID RECEPTOR LIGANDS AND THEIR USE IN TREATMENTS
  申请人：AMGEN INC.

  公开号：EP1670794A2

  公开（公告）日：2006-06-21
• US7390907B2
  申请人：——

  公开号：US7390907B2

  公开（公告）日：2008-06-24
• [EN] VANILLOID RECEPTOR LIGANDS AND THEIR USE IN TREATMENTS<br/>[FR] LIGANDS DE RECEPTEUR VANILLOIDE ET LEUR UTILISATION DANS CERTAINS TRAITEMENTS
  申请人：AMGEN INC

  公开号：WO2005033105A2

  公开（公告）日：2005-04-14

  Compounds having the general structure formula (I) and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.
• Novel Vanilloid Receptor-1 Antagonists:  1. Conformationally Restricted Analogues of <i>trans</i>-Cinnamides
  作者：Mark H. Norman、Jiawang Zhu、Christopher Fotsch、Yunxin Bo、Ning Chen、Partha Chakrabarti、Elizabeth M. Doherty、Narender R. Gavva、Nobuko Nishimura、Thomas Nixey、Vassil I. Ognyanov、Robert M. Rzasa、Markian Stec、Sekhar Surapaneni、Rami Tamir、Vellarkad N. Viswanadhan、James J. S. Treanor

  DOI：10.1021/jm070189q

  日期：2007.7.1

  The vanilloid receptor-1 (VR1 or TRPV1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role as an integrator of multiple pain-producing stimuli. From a high-throughput screening assay, measuring calcium uptake in TRPV1-expressing cells, we identified an N-aryl trans-cinnamide (AMG9810, compound 9) that acts as a potent TRPV1 antagonist. We have demonstrated the antihyperalgesic properties of 9 in vivo and have also reported the discovery of novel, orally bioavailable cinnamides derived from this lead. Herein, we expand our investigations and describe the synthesis and biological evaluation of a series of conformationally constrained analogues of the s-cis conformer of compound 9. These investigations resulted in the identification of 4-amino- and 4-oxopyrimidine cores as suitable isosteric replacements for the trans-acrylamide moiety. The best examples from this series, pyrimidines 79 and 74, were orally bioavailable and exhibited potent antagonism of both rat (IC50 = 4.5 and 0.6 nM, respectively) and human TRPV1 (IC50 = 7.4 and 3.7 nM, respectively). In addition, compound 74 was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo in the capsaicin-induced hypothermia model in rats; however, it was ineffective at preventing thermal hyperalgesia induced by complete Freund's adjuvant in rats.