AMG 628 | 862269-93-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: AMG 628
• 英文别名: N-[4-(6-{4-[(R)-1-(4-fluorophenyl)ethyl]piperazin-1-yl}pyrimidin-4-yloxy)benzothiazol-2-yl]acetamide；N-(4-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide；N-[4-(6-{4-[(1R)-1-(4-fluorophenyl)ethyl]piperazine-1-yl}pyrimidin-4-yloxy)benzothiazol-2-yl]acetamide；Acetamide, N-(4-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2-benzothiazolyl)-；N-[4-[6-[4-[(1R)-1-(4-fluorophenyl)ethyl]piperazin-1-yl]pyrimidin-4-yl]oxy-1,3-benzothiazol-2-yl]acetamide
• CAS: 862269-93-0
• 化学式: C₂₅H₂₅FN₆O₂S
• 分子量: 492.577
• InChiKey: QUHZTEMPQQZPNB-MRXNPFEDSA-N

物化性质

• 熔点：
  249 °C
• 密度：
  1.370±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  112
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  (R)-1-(4-氟苯基)乙胺 在 氢溴酸 、 sodium carbonate 、 N,N-二异丙基乙胺 、 对羟基苯甲酸 作用下， 以 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 反应 73.5h， 生成 AMG 628
  参考文献：
  名称：

  Novel Vanilloid Receptor-1 Antagonists:  3. The Identification of a Second-Generation Clinical Candidate with Improved Physicochemical and Pharmacokinetic Properties

  摘要：

  Based on the previously reported clinical candidate, AMG 517 (compound 1), a series of related piperazinylpyrimidine analogues were synthesized and evaluated as antagonists of the vanilloid 1 receptor (VR1 or TRPV1). Optimization of in vitro potency and physicochemical and pharmacokinetic properties led to the discovery of (R)-N-(4-(6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide (16p), a potent TRPV1 antagonist [rTRPV1(CAP) IC50 = 3.7 nM] with excellent aqueous solubility (>= 200 mu g/mL in 0.01 N HCl) and a reduced half-life (rat t(1/2) = 3.8 h, dog t(1/2) = 2.7 h, monkey t(1/2) = 3.2 h) as compared to AMG 517. In addition, compound 16p was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo (ED50 = 1.9 mg/kg, p.o. in the capsaicin-induced flinch model in rats) and was also effective at reducing thermal hyperalgesia induced by complete Freund's adjuvant in rats (MED = 1 mg/kg, p.o). Based on its improved overall profile, compound 16p (AMG 628) was selected as a second-generation candidate for further evaluation in human clinical trials as a potential new treatment for chronic pain.

  DOI：

  10.1021/jm070191h

文献信息

• Vanilloid receptor ligands and their use in treatments
  申请人：Wang Hui-Ling

  公开号：US20050176726A1

  公开（公告）日：2005-08-11

  Pyrimidine ethers 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.

  嘌呤醚及含有它们的组合物，用于治疗急性、炎症性和神经痛、牙痛、普通头痛、偏头痛、集群头痛、混合血管和非血管综合症、紧张性头痛、一般炎症、关节炎、风湿病、骨关节炎、炎症性肠道疾病、炎症性眼部疾病、炎症性或不稳定的膀胱疾病、牛皮癣、伴有炎症成分的皮肤问题、慢性炎症症状、炎症性疼痛及相关的过敏性疼痛和触痛、神经痛及相关的过敏性疼痛和触痛、糖尿病性神经病痛、烧灼性疼痛、交感神经维持性疼痛、感觉缺失综合症、哮喘、上皮组织损伤或功能障碍、单纯疱疹、呼吸、泌尿生殖、胃肠或血管区域内脏运动障碍、伤口、烧伤、过敏性皮肤反应、瘙痒、白癜风、一般胃肠道紊乱、胃溃疡、十二指肠溃疡、腹泻、由坏死剂引起的胃损伤、毛发生长、血管运动性或过敏性鼻炎、支气管疾病或膀胱疾病。
• [EN] PYRIMIDINE DERIVATIVES FOR USE AS VANILLOID RECEPTOR LIGANDS AND THEIR USE IN THE TREATMENT OF PAIN<br/>[FR] DERIVES DE PYRIMIDINE UTILISES COMME LIGANDS DE RECEPTEUR DE VANILLOIDE ET LEUR UTILISATION DANS LE TRAITEMENT DE LA DOULEUR
  申请人：AMGEN INC

  公开号：WO2005077944A1

  公开（公告）日：2005-08-25

  Pyrimidine ethers and compositions containing them, fo use as vanilloid receptor ligands 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. Wherein R1 - R4 and X are as defined in the claims.

  含有嘧啶醚化合物的组合物，用作vanilloid受体配体，用于治疗急性、炎症性和神经病理性疼痛、牙痛、普通头痛、偏头痛、群集性头痛、混合血管和非血管综合症、紧张性头痛、一般炎症、关节炎、风湿病、骨关节炎、炎症性肠病、炎症性眼病、炎症性或不稳定膀胱疾病、牛皮癣、具有炎症成分的皮肤疾病、慢性炎症状态、炎症性疼痛及相关的高敏性和触痛、神经病理性疼痛及相关的高敏性和触痛、糖尿病性神经病疼痛、交感神经维持的疼痛、去神经症候群、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运动障碍、创伤、烧伤、过敏性皮肤反应、瘙痒、白癜风、一般胃肠道疾病、胃溃疡、十二指肠溃疡、腹泻、坏死性剂引起的胃病变、毛发生长、血管运动性或过敏性鼻炎、支气管疾病或膀胱疾病。其中R1-R4和X的定义如权利要求中所述。
• Practical Synthesis of a Vanilloid Receptor-1 Antagonist
  作者：Oliver R. Thiel、Charles Bernard、Tony King、Mina Dilmeghani-Seran、Tracy Bostick、Robert D. Larsen、Margaret M. Faul

  DOI：10.1021/jo8002216

  日期：2008.5.1

  Small molecule TRPV1 antagonists have been a recent focus in the search for pain treatment agents. We herein describe a practical and scalable synthesis of AMG 628 (1), a bis-substituted pyrimidine derivative that was identified as a highly efficacious agent, suitable for clinical development. Highlights of our approach include a practical route to a substituted benzothiazole, a scalable synthesis of an enantiopure piperazine fragment, and identification of conditions for selective coupling reactions on 2,6-dichloropyrimidine, to access the active pharmaceutical ingredient in high purity and overall yield.
• PYRIMIDINE DERIVATIVES FOR USE AS VANILLOID RECEPTOR LIGANDS AND THEIR USE IN THE TREATMENT OF PAIN
  申请人：AMGEN INC.

  公开号：EP1720868A1

  公开（公告）日：2006-11-15
• USE OF TRPV1 RECEPTOR ANTAGONISTS FOR TREATING DRY EYE AND OCULAR PAIN
  申请人：Yanni John M.

  公开号：US20090131449A1

  公开（公告）日：2009-05-21

  Methods of treating symptoms of dry eye by administering inhibitors of transient receptor potential cation channel, subfamily V, member 1 (TRPV1) are disclosed. Methods of preventing or alleviating ocular pain by administering TRPV1 inhibitors are also disclosed.