CAS: 150683-30-0; N-[4-(7-Chloro-5-Hydroxy-2,3,4,5-Tetrahydro-1-Benzazepine-1-Carbonyl)-3-Methylphenyl]-2-Methylbenzamide

该化合物是一种选择性的血管压抑剂V2受体对立物,主要用于治疗低抗体和单细胞主要多细胞肾病(ADPKD)等病症.它是一种小有机分子,其特征是能够抑制血管压抑剂(一种调节肾水保留量的激素)的动作.这种抑制导致尿液产量增加,而钠浓度随后上升.Tolvaptan一般是口服的,以其相对较高的生物利用率而著称.该物质被归类为非对立物,并有一个特殊的分子结构,有助于其药用特性.常见副作用可能包括口渴,口干和潜在的肝功能异常,从而需要在治疗期间定期监测.由于其行动机制,Tolvaptan在管理液体过量条件下特别有利,使其在肾学和内分泌学中成为有价值的治疗剂.

⚠️《2026年兴奋剂目录》
英文名称N-[4-(7-Chloro-5-Hydroxy-2,3,4,5-Tetrahydro-1-Benzazepine-1-Carbonyl)-3-Methylphenyl]-2-Methylbenzamide
中文名称托伐普坦
IUPAC名称N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methyl-benzamide
其它别名1H-1-Benzazepine,benzamide deriv.; 7-Chloro-5-hydroxy-1-(2-methyl-4-(2-methylbenzoylamino)benzoyl)2,3,4,5-tetrahydro-1H-1-benzazepine; Benzamide, N-(4-((7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonyl)-3-methylphenyl)-2-methyl-; (+-)-4'-((7-Chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl) carbonyl)-o-tolu-m-toluidide; N-[4-[(5R)-7-Chloro-5-hydroxy-2,3,4,5-tetrahydro-1-benzazepine-1-carbonyl]-3-methylphenyl]-2-methylbenzamide
CAS编号150683-30-0
MFCD编号:MFCD09838782
EINECS号:691-537-5
FDA UNII编号:21G72T1950
分子式:C26H25ClN2O3
分子量:448.94
产品CID: 731962
产品分类生物化工 → 抑制剂 → G蛋白偶联受体(GPCR & G Protein)

相似结构搜索
InChIKey: GYHCTFXIZSNGJT-UHFFFAOYNA-N
GYHCTFXIZSNGJT-UHFFFAOYSA-N…
计算化学: 氢键受体数3.0氢键供体数2.0可旋转键数3.0

物理性质

熔点219-222 °C
沸点594.4±50.0 °C at 760 mmHg
闪点313.3±30.1 °C
密度1.3±0.1 g/cm3
pKa:13.00±0.70(预测)
PSA:69.64
LogP:4.09
折射率1.664
蒸汽压0.0±1.8 mmHg at 25°C
溶解性DMSO: ≥15mg/mL
外观形态白色至棕褐色粉末
储存条件2-8°C
产品应用该化合物是一种选择性的,竞争性的血管压抑剂V2受体抗体,具有精致的临床前生物活性. 体外研究显示,与V2感应器具有高度的亲近性,有效阻塞了肾脏采集管细胞中由丙基丙胺诱发的丙基苯(CAMP)生产. 在动物模型中,托尔巴潘产生依赖剂量的方形,增加自由排水量,而不会发生严重的电解液损失,并提升了血清钠水平. 心脏衰竭和SIADH模型的临床研究表明,缺水量,尿溶性下降以及等离子钠浓度改善会减少. 托瓦普丹还显示,口服生物利用率和持续的药体动力效应对血压或肾脏体影响最小,支持其治疗功能,以治疗水平衡和低温.

MSDS等安全信息

GHS符号GHS08
警示词Warning
危险描述H362-H361
防范说明P201-P260-P263-P264-P270-P308+P313-P201-P202-P281-P308+P313-P405-P501
UN编号NONH for all modes of transport
安全声明IDENTIFICATION AND USE: Tolvaptan is a white crystalline powder that is formulated into oral tablets. Tolvaptan is an antagonist of arginine vasopressin (antidiuretic hormone) V2 receptors. It is used to treat low sodium levels in the blood. HUMAN EXPOSURE AND TOXICITY: Tolvaptan was well tolerated in healthy subjects at single oral doses up to 480 mg and multiple doses up to 300 mg once daily for 5 days. There is no specific antidote for tolvaptan intoxication. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst, and dehydration/hypovolemia. However, chronic administration of tolvaptan can cause serious and potentially fatal liver injury. In 2013, the U.S. Food and Drug Administration (FDA) determined that the drug should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially requiring liver transplant or death. In a placebo-controlled and open label extension study of chronically administered tolvaptan in patients with autosomal dominant polycystic kidney disease, cases of serious liver injury attributed to tolvaptan were observed. Tolvaptan therapy should be initiated or reinitiated only in a hospital setting, where serum sodium concentrations and therapeutic response can be monitored closely. Too rapid correction of hyponatremia may cause osmotic demyelination syndrome, resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, or death. Slower rates of correction may be advisable in susceptible patients, including those with severe malnutrition, alcoholism, or advanced liver disease. Patients with syndrome of inappropriate secretion of antidiuretic hormone or very low baseline serum sodium concentrations may be at increased risk for too rapid correction of serum sodium concentration. Tolvaptan is contraindicated in patients who are unable to sense or appropriately respond to thirst and in those with hypovolemic hyponatremia. Tolvaptan is mainly, if not exclusively, metabolized in the liver by cytochrome P-450 (CYP) isoenzyme 3A; the drug also is a weak inhibitor of CYP3A and a substrate and inhibitor of the P-glycoprotein transport system. Compared with tolvaptan, metabolites of the drug have little or no antagonist activity for human V2 receptors. ANIMAL STUDIES: Tolvaptan had low acute toxicity when administered to rats and dogs. In repeated dose studies in rats and dogs, findings were generally related to the pharmacological effect of tolvaptan and consisted of increased urine volume, decreased urine osmolality and increased water consumption. Decreased body weight and alterations in hematological and clinical chemistry parameters were also seen but were reversible during a recovery period. Up to two years of oral administration of tolvaptan to male and female rats did not increase the incidence of tumors. In a fertility study in male and female rats, tolvaptan was associated with fewer corpora lutea and implants compared to controls. Oral administration of tolvaptan to pregnant rabbits during organogenesis was associated with reductions in maternal body weight gain and food consumption. Abortions, increased incidences of embryo-fetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia, and skeletal malformations were also observed. Tolvaptan tested negative for genotoxicity in in vitro (bacterial reverse mutation assay and chromosomal aberration test in Chinese hamster lung fibroblast cells) and in vivo (rat micronucleus assay) test systems.
WGK Germany3

上下游产品

合成工艺路线路线简述

合成目标产物 Tolvaptan 主要起始原料 5-Dehydro Tolvaptan
(文献来源)合成步骤主要原料 5-Dehydro Tolvaptan

4-溴-2-甲基苯甲酸置于甲醇,Sodium Tetrahydroborate,Potassium Phosphate,氯化亚砜体系中,用四氢呋喃,N,N-二甲基甲酰胺,甲苯用作溶剂,化学反应 7.0H,反应生成托伐普坦
参考文献: Intermediates And Processes For The Preparation Of Tolvaptan And Its Derivatives[fr] Intermédiaires Et Procédés Pour La Préparation De Tolvaptan Et De Ses Dérivés
标题: Intermediates And Processes For The Preparation Of Tolvaptan And Its Derivatives[fr] Intermédiaires Et Procédés Pour La Préparation De Tolvaptan Et De Ses Dérivés
摘要:本发明涉及用于合成托瓦普坦及其衍生物的新中间体,以及涉及所述中间体的制备过程.

海关参考信息

2902600000-乙苯
2903919090-氯苯
2905121000-正丙醇
2905130000-正丁醇
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详情请参考：📖 海关编码查询和海关进出口税则

专利信息

专利号:US-12247037-B2
优先权日:2018-12-12
标题:1-(2,6-diazaspiro[3.3]heptan-6-yl)-5,6-dihydro-4h-benzo[f][1,2,4]triazolo[4,3-A][1,4]diazepine derivatives and related compounds as vasopressin antagonists for the treatment of neuro-psychological disorders
发明人：BRANDT GARY
权利人:NEUMORA THERAPEUTICS INC
摘要:The present invention relates to 1-(2,6-diazaspiro[3.3]heptan-6-yl)-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine derivatives and related compounds of Formula (I): wherein A, B, G, R1, R1b, RiC, R2 and X are as defined herein. The present compounds are vasopressin receptor antagonists (in particular of the Via receptor) for the treatment of neuro-psychological disorders, such as e.g. autism, anxiety, stress-related disorders, depression, schizophrenia or bipolar disorder. The present description discloses the synthesis of exemplary compounds, as well as pharmacological data thereof (e.g. pages 71 to 246; examples 1 to 49; tables 1 to 5). An exemplary compound is e.g. 8-chloro-1-(2-(5-fluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-6-yl)-5-methyl-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine (example 1, compound no. 1).

专利号:WO-2021249877-A1
优先权日:2020-06-08
标题 :Intermediates and processes for the preparation of tolvaptan and its derivatives
发明人：VIGO DANIELE; CAPUTO FRANCESCO; COLOMBO FRANCESCO
权利人:CAMBREX PROFARMACO MILANO S R L
摘要:The present invention relates to new intermediates for the synthesis of Tolvaptan and of its derivatives and a process for its preparation involving said intermediates.

专利号:JP-H11503328-A
优先权日:1995-04-11
标题:Improved enzymatic synthesis of oligosaccharides

专利号:CN-113264885-B
优先权日:2021-05-29
标题:Synthesis of tolvaptan degradation derivative

专利号:IT-UB20160256-A1
优先权日:2016-01-15
标题 :ESTERIFIED WATER-BASED HYDRO-PERSONS DERIVATIVES AND THEIR USE IN THE SYNTHESIS OF TOLVAPTAN

专利号:CN-113264885-A
优先权日:2021-05-29
标题:A kind of synthesis of tolvaptan degradation derivatives

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主要参考文献

1: Kakeshita K, Imamura T, Hida Y, Onoda H, Koike T, Kinugawa K. Trajectory of Urine Parameters by Adding Herbal Kampo Medicine Goreisan to Tolvaptan in Patients with Congestive Heart Failure. J Clin Med. 2024 Dec 11;13(24):7523. doi: 10.3390/jcm13247523.
745:151256. doi: 10.1016/j.bbrc.2024.151256. Epub 2024 Dec 28. 14(12):e088317. doi: 10.1136/bmjopen-2024-088317.
6: Martínez González Á, González Nunes M, Rodeiro Escobar P, Llópiz Castedo J, Cabaleiro Loureiro A, Martínez Espinosa RP, Ruades Patiño R, Lorenzo Canda G, Aguayo Arjona J, Rodríguez Zorrilla S. Comparative study of the effectiveness of tolvaptan versus urea in patients with hyponatremia caused by SIADH. Rev Clin Esp (Barc). 2024 Dec

合成参考文献

参考文献:10.1182/blood-2011-04-347328
摘要:Blumenfeld JD, Tepler J, Mauer A, Coller B, Bichet DG, Smith B. Tolvaptan inhibition of desmopressin effects on coagulation factors in a patient with decreased von Willebrand factor and polycystic kidney disease. Blood. 2011 Jul 14;118(2):474–6.
摘要:Stiefelhagen P. [Heart and kidney failure combined. Trouble seldom comes alone]. MMW Fortschr Med. 2011 Jun 30;153(26-28):12–4.