Stable under recommended storage conditions.
托伐普坦是由日本大冢公司开发的药物,于2009年经美国FDA批准上市,主要用于治疗心力衰竭等患者。其商品名为苏麦卡。托伐普坦合成路线中的苯并七元环构建是主要难点之一。
药理作用血管加压素是人体调节水平衡最重要的激素,受渗透压感受器和压力感受器双重调控。托伐普坦是一种苯氮杂卓类衍生物,与V2受体的亲和力是V1a受体的29倍以上,约为天然精氨酸加压素的1.8倍。该药物通过与集合管上的V2受体结合并阻断其活性,促进AQP2从内膜脱落,减少水重吸收,增加尿液中游离水的排泄,降低容量负荷。托伐普坦还能抑制cAMP生成和积聚,升高血浆钠离子浓度,并帮助多余的水分通过尿液排出。
此外,托伐普坦对多囊肾的治疗机制在于它能抑制多囊肾细胞内cAMP的积累,从而减少囊液分泌,进而抑制囊肿生长。
适应症托伐普坦也是目前唯一用于肝硬化低钠血症的普坦类药物。研究表明,血管加压素受体V2、V3在垂体和异位促肾上腺皮质激素(ACTH)瘤中有过度表达。选择性V2、V3受体拮抗剂可能具有治疗这些肿瘤的作用,但这一结论仍需进一步研究证实。
制备托伐普坦的合成过程包括以下几个关键步骤:
Tolvaptan是一种选择性的、竞争性精氨酸加压素受体2拮抗剂,IC50为1.28µM,并抑制AVP-诱导的血小板聚集。它在人类V(2)受体结合中比V(1a)高29倍,且不表现出对V(1B)受体的抑制作用。
靶点Tolvaptan的作用靶点为血管加压素受体2,IC50值为3 nM。
体外研究在健康和患病动物中,Tolvaptan表现出显著的夜尿症。它还能浓度依赖性地抑制ADPKD细胞中精氨酸加压素诱导的cAMP产生(IC50为0.1 nM),并抑制AVP引起的ERK信号传导和细胞增殖。此外,该药物能降低在三维胶原基质内培养的ADPKD细胞体外生长囊肿。
体内研究在大鼠急性及慢性低钠血症模型中,Tolvaptan改善了低钠血症症状,并提高了器官水份保留率,防止了死亡。它降低了心脏前负荷,未对肾功能、全身血流动力学或循环神经激素产生不利影响。在人类多囊肾病(PKD)动物模型中,该药物导致肾脏重量减轻以及囊肿纤维化和体积的减小。
此外,在大鼠急性及慢性低钠血症模型中,Tolvaptan明显升高无电解质水的间隙(E-CH(2)O),并增加尿精氨酸加压素(AVP)在心脏衰竭大鼠中的排泄。
中文名称 | 英文名称 | CAS号 | 化学式 | 分子量 |
---|---|---|---|---|
7-氯-1-[2-甲基-4-[(2-甲基苯甲酰)氨基]苯甲酰基]-5-氧代-2,3,4,5-四氢-1H-1-苯并氮杂卓 | 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine | 137973-76-3 | C26H23ClN2O3 | 446.933 |
1-(4-氨基-2-甲基苯甲酰基)-7-氯-1,2,3,4-四氢-5H-1-苯并氮杂卓-5-酮 | 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine | 137977-97-0 | C18H17ClN2O2 | 328.798 |
7-氯-1,2,3,4-四氢-1-(2-甲基-4-硝基苯甲酰基)-5H-1-苯并氮杂卓-5-酮 | 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine | 137982-91-3 | C18H15ClN2O4 | 358.781 |
托伐普坦杂质30 | 7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-benzazepine | 1310357-40-4 | C10H12ClNO | 197.664 |
中文名称 | 英文名称 | CAS号 | 化学式 | 分子量 |
---|---|---|---|---|
—— | 4-amino-(2-methylphenyl)(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]-azepin-1-yl)methanone | 1432725-24-0 | C18H19ClN2O2 | 330.814 |
—— | 7-chloro-5-hydroxy-1-[4-[(2-methylbenzoyl)amino]benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine | —— | C25H23ClN2O3 | 434.922 |
—— | 7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-5-methylthiomethoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine | 1094837-52-1 | C28H29ClN2O3S | 509.069 |
—— | Dibenzyl [7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-2,3,4,5-tetrahydro-1-benzazepin-5-yl] phosphite | 1056613-14-9 | C40H38ClN2O5P | 693.179 |
—— | Ditert-butyl [7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-2,3,4,5-tetrahydro-1-benzazepin-5-yl] phosphite | 1056613-08-1 | C34H42ClN2O5P | 625.145 |
—— | {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} chloroacetate | 1094837-36-1 | C28H26Cl2N2O4 | 525.431 |
—— | 7-chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 4-chlorobutyrate | 1094837-42-9 | C30H30Cl2N2O4 | 553.485 |
—— | {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}(2-chloroethyl)carbamate | 1094837-55-4 | C29H29Cl2N3O4 | 554.473 |
—— | chloromethyl {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} carbonate | 1094837-49-6 | C28H26Cl2N2O5 | 541.431 |
—— | {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} hexadecanoate | 1094837-35-0 | C42H55ClN2O4 | 687.363 |
—— | {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} succinate | 1094837-24-7 | C30H29ClN2O6 | 549.023 |
—— | methyl {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethylthio} acetate | 1094837-32-7 | C31H31ClN2O6S | 595.116 |
—— | {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethylthio} acetic acid | 1094837-31-6 | C30H29ClN2O6S | 581.089 |
—— | N-(4-(7-chloro-5-hydroxy-2,3,4-trihydro-5-deutero-1H-benzo[b]azepine-1-carbonyl)-3-methylphenyl)-2-methylbenzamide | 1296212-17-3 | C26H25ClN2O3 | 449.941 |
—— | 7-chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 4-(4-acetylpiperazin-1-yl)butyrate | 1094837-43-0 | C36H41ClN4O5 | 645.198 |
—— | methyl {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethylsulfonyl}-acetate | 1094837-33-8 | C31H31ClN2O8S | 627.115 |
7-氯-1-[2-甲基-4-[(2-甲基苯甲酰)氨基]苯甲酰基]-5-氧代-2,3,4,5-四氢-1H-1-苯并氮杂卓 | 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine | 137973-76-3 | C26H23ClN2O3 | 446.933 |
—— | N-(4-(7-chloro-2,3-dihydro-5-hydroxy-4,4,5-trideutero-1H-benzo[b]azepine-1-carbonyl)-3-methylphenyl)-2-methylbenzamide | 1296212-18-4 | C26H25ClN2O3 | 451.925 |
—— | 7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 3-[2-(bis-benzyloxy-phosphoryloxy)-4,6-dimethyl-phenyl]-3-methyl-butyrate | 1094837-46-3 | C53H54ClN2O8P | 913.447 |