N-(4-羟基戊烷酰基)-N-{[2'-(2H-四唑-5-基)-4-联苯基]甲基}-L-缬氨酸 | 188259-69-0

• 物质功能分类: 医药中间体 - 原料药中间体
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: N-(4-羟基戊烷酰基)-N-{[2'-(2H-四唑-5-基)-4-联苯基]甲基}-L-缬氨酸
• 中文别名: 4-羟基缬沙坦；4-羟基缬沙坦(对非对映体的混合物)
• 英文名称: 4-Hydroxyvalsartan
• 英文别名: Valeryl-4-hydroxyvalsartan；(2S)-2-[4-hydroxypentanoyl-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]amino]-3-methylbutanoic acid
• CAS: 188259-69-0
• 化学式: C₂₄H₂₉N₅O₄
• 分子量: 451.525
• InChiKey: ICSQZMPILLPFKC-XLDIYJRPSA-N

物化性质

• 熔点：
  130-132°C
• 溶解度：
  少许溶于甲醇

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  33
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  132
• 氢给体数：
  3
• 氢受体数：
  7

ADMET

代谢

4-羟基-缬沙坦是缬沙坦已知的人体代谢物。

4-hydroxy-valsartan is a known human metabolite of valsartan.

来源:NORMAN Suspect List Exchange

制备方法与用途

应用

缬沙坦可选择性地阻断血管紧张素II与AT1受体的结合，导致血管扩张，并减少醛固酮分泌。最近的临床研究表明，缬沙坦在急性血管事件后的患者群体中具有额外的益处。由于血小板活化在冠状血管和脑血管闭塞中起关键作用，而AT1受体存在于血小板表面，研究评估了缬沙坦及其主要肝代谢物4-羟基戊酰基缬沙坦对具有多重血管疾病危险因素个体的血小板的体外作用。4-羟基缬沙坦是缬沙坦的一种代谢产物。

制备

在20毫升二甲苯中的8.64克(S)-2-[(2′-氰基-联苯-4-基甲基)-(4-氧代-戊酰基)-氨基]-3-甲基-丁酸苄酯与12.71克Tributyltinazid(Aldrich)回流28小时后，用0.5N氢氧化钠水溶液处理混合物。将水相用醚洗涤，并将醚相用水萃取一次。合并的水相用浓盐酸水溶液酸化、用二氯甲烷萃取、用水洗涤、混悬入活性炭、过滤、用硫酸钠干燥、浓缩并真空干燥，得到产物(S)-3-甲基-2-{(4-氧代-戊酰基)-[2′-(1H-四唑-5-基)-联苯-4-基甲基]-氨基}-丁酸苄酯，为棕色泡沫。

在160毫升四氢呋喃中的7.9克(S)-3-甲基-2-{(4-氧代-戊酰基)-[2′-(1H-四唑-5-基)-联苯-4-基甲基]-氨基}-丁酸苄酯，于常压、室温下，在1.5克披批钯碳(10％)存在下进行氢化，直至达到饱和。将混合物过滤并真空浓缩，得到(S)-3-甲基-2-{(4-氧代-戊酰基)-[2′-(1H-四唑-5-基)-联苯-4-基甲基]-氨基}-丁酸，为几乎白色的泡沫。

反应信息

• 作为产物：
  描述：

  4-羰基戊酰氯 在 palladium on activated charcoal sodium tetrahydroborate 、 N,N-二异丙基乙胺 、 三正丁基叠氮化锡 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 xylene 为溶剂， 生成 N-(4-羟基戊烷酰基)-N-{[2'-(2H-四唑-5-基)-4-联苯基]甲基}-L-缬氨酸
  参考文献：
  名称：

  Pharmacokinetics, disposition and biotransformation of [14C]-radiolabelled valsartan in healthy male volunteers after a single oral dose

  摘要：

  1. The disposition of valsartan, a potent angiotensin II receptor antagonist, was investigated in six healthy male volunteers. They each received a single oral dose of 80 mg of a C-14-labelled preparation as a neutral buffered solution.2. Peak concentrations of radioactivity and valsartan in plasma measured Ih after dosing showed rapid onset of absorption. The results of this study combined with other available data indicate that at least 51% of the dose was absorbed.3. Valsartan was the predominant radioactive compound in plasma. Elimination of valsartan and radioactivity was fast and multiexponential. beta-Half-lives of 6 +/- 1 h were observed. In a terminal elimination phase, low radioactivity levels decreased with a half-life of 81 +/- 33 h. A minor, pharmacologically inactive metabolite (valeryl-4-hydroxy-valsartan; M1) was detected in the plasma at rime points later than 2 h after dosing, representing approximately 11% of the AUC((24 h)) of plasma radioactivity.4. The bulk of the dose was excreted within 4 days. The total excretion within 7 days amounted to 99 +/- 1% of dose. Faecal excretion was predominant (86 +/- 5% of dose). Valsartan was largely excreted unchanged (81 +/- 5% of the dose in the excreta). The predominant clearance mechanism appeared to be direct elimination via bile. 5. An inactive metabolite, M1, was formed by oxidative biotransformation and accounted for 9 +/- 3% of the dose in the excreta.

  DOI：

  10.1080/004982597240767

文献信息

• Use of valsartan or its metabolite to inhibit platelet aggregation
  申请人：Malinin Alex

  公开号：US20050197372A1

  公开（公告）日：2005-09-08

  The invention relates to a method of inhibiting platelet aggregation comprising administering a therapeutically effective amount of an ARB or its metabolite, especially Valsartan or its metabolite valeryl 4-hydroxy valsartan. Conditions to be treated by inhibition of platelet aggregation include acute myocardial infarction, ischemic stroke, angina pectoris, acute coronary syndromes, TIA (transient ischemic attacks, or acute cerebrovascular syndromes), heart failure, chest pain of ischemic etiology, syndrome X, thromboembolism, pulmonary hypertension, diabetes mellitus, peripheral vascular disease, deep vein thrombosis, arterial thrombosis of any vessel, catheter thrombotic occlusion or reocclusion.

  本发明涉及一种抑制血小板聚集的方法，包括给予治疗有效量的ARB或其代谢物，特别是Valsartan或其代谢物valeryl 4-hydroxy valsartan。需要通过抑制血小板聚集来治疗的疾病包括急性心肌梗塞、缺血性卒中、心绞痛、急性冠状动脉综合症、短暂性脑缺血发作（TIA，或急性脑血管综合征）、心力衰竭、缺血性胸痛、X综合症、血栓栓塞、肺动脉高压、糖尿病、周围血管疾病、深静脉血栓形成、任何血管的动脉血栓形成、导管血栓闭塞或再闭塞。
• USE OF VALSARTAN OR ITS METABOLITE TO IN HIBIT PLATELET AGGREGATION
  申请人：Malinin Alex

  公开号：US20100048654A1

  公开（公告）日：2010-02-25

  The invention relates to a method of inhibiting platelet aggregation comprising administering a therapeutically effective amount of an ARB or its metabolite, especially Valsartan or its metabolite valeryl 4-hydroxy valsartan. Conditions to be treated by inhibition of platelet aggregation include acute myocardial infarction, ischemic stroke, angina pectoris, acute coronary syndromes, TIA (transient ischemic attacks, or acute cerebrovascular syndromes), heart failure, chest pain of ischemic etiology, syndrome X, thromboembolism, pulmonary hypertension, diabetes mellitus, peripheral vascular disease, deep vein thrombosis, arterial thrombosis of any vessel, catheter thrombotic occlusion or reocclusion.

  本发明涉及一种抑制血小板聚集的方法，包括给予治疗有效量的ARB或其代谢物，特别是Valsartan或其代谢物Valeryl 4-羟基Valsartan。通过抑制血小板聚集来治疗的疾病包括急性心肌梗死、缺血性卒中、心绞痛、急性冠状动脉综合征、TIA（短暂性缺血性发作，或急性脑血管综合征）、心力衰竭、缺血性胸痛、X综合征、血栓栓塞、肺动脉高压、糖尿病、外周血管疾病、深静脉血栓形成、任何血管的动脉血栓形成、导管血栓性闭塞或再闭塞。
• USE OF THE METABOLITE OF VALSARTAN TO INHIBIT PLATELET AGGREGATION
  申请人：Novartis AG

  公开号：EP1505965B1

  公开（公告）日：2006-08-02
• USE OF VALSARTAN OT ITS METABOLITE TO INHIBIT PLATELET AGGREGATION
  申请人：Novartis AG

  公开号：EP1505965A1

  公开（公告）日：2005-02-16
• [EN] USE OF VALSARTAN OT ITS METABOLITE TO INHIBIT PLATELET AGGREGATION<br/>[FR] UTILISATION DE VALSARTAN OU DE SON METABOLITE POUR INHIBER L'AGREGATION PLAQUETTAIRE
  申请人：NOVARTIS AG

  公开号：WO2003094915A1

  公开（公告）日：2003-11-20

  The invention relates to a method of inhibiting platelet aggregation comprising administering a therapeutically effective amount of an ARB or its metabolite, especially Valsartan or its metabolite valeryl 4-hydroxy valsartan. Conditions to be treated by inhibition of platelet aggregation include acute myocardial infarction, ischemic stroke, angina pectoris, acute coronary syndromes, TIA (transient ischemic attacks, or acute cerebrovascular syndromes), heart failure, chest pain of ischemic etiology, syndrome X, thromboembolism, pulmonary hypertension, diabetes mellitus, peripheral vascular disease, deep vein thrombosis, arterial thrombosis of any vessel, catheter thrombotic occlusion or reocclusion.