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托伐普坦 | 150683-30-0

中文名称
托伐普坦
中文别名
N-[4-[(5R)-7-氯-5-羟基-2,3,4,5-四氢-1-苯并氮杂卓-1-甲酰基]-3-甲基苯基]-2-甲基苯甲酰胺; N-[4-[(5R)-7-氯-5-羟基-2,3,4,5-四氢-1-苯并氮杂卓-1-甲酰基]-3-甲基苯基]-2-甲基苯甲酰胺;托伐坦
英文名称
tolvaptan
英文别名
OPC-41061;7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine;Samsca;7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine;N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide;5-hydroxy-7-chloro-1-[2-methyl-4-(2-methylbenzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine;N-[4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1-benzazepine-1-carbonyl)-3-methylphenyl]-2-methylbenzamide
托伐普坦化学式
CAS
150683-30-0
化学式
C26H25ClN2O3
mdl
——
分子量
448.949
InChiKey
GYHCTFXIZSNGJT-UHFFFAOYSA-N
BEILSTEIN
——
EINECS
——
  • 物化性质
  • 计算性质
  • ADMET
  • 安全信息
  • SDS
  • 制备方法与用途
  • 上下游信息
  • 反应信息
  • 文献信息
  • 表征谱图
  • 同类化合物
  • 相关功能分类
  • 相关结构分类

物化性质

  • 熔点:
    219-222°C
  • 沸点:
    594.4±50.0 °C(Predicted)
  • 密度:
    1.311±0.06 g/cm3(Predicted)
  • 溶解度:
    在DMSO中的溶解度≥15mg/mL
  • 颜色/状态:
    Colorless prisms
  • 蒸汽压力:
    2.05X10-18 mm Hg at 25 °C (est)
  • 稳定性/保质期:

    Stable under recommended storage conditions.

  • 解离常数:
    pKa = 13.84 (est)

计算性质

  • 辛醇/水分配系数(LogP):
    4.8
  • 重原子数:
    32
  • 可旋转键数:
    3
  • 环数:
    4.0
  • sp3杂化的碳原子比例:
    0.23
  • 拓扑面积:
    69.6
  • 氢给体数:
    2
  • 氢受体数:
    3

ADMET

代谢
连续给雌性大鼠给药后,托伐普坦的全身暴露量降低。对血清样本中代谢物DM-4103和DM-4107的分析显示,在连续给药后这些代谢物的浓度有所增加,这解释了血清中托伐普坦浓度降低的原因。此外,研究表明,在雌性大鼠连续7天以300 mg/kg/天的剂量给药后,托伐普坦能够诱导肝脏药物代谢酶(细胞色素b5含量和氨基比林N-脱甲基酶活性)。托伐普坦既是MDR1介导运输的底物,也是其抑制剂
Repeated dosing of female rats reduced systemic exposure to tolvaptan. Analysis of the serum samples for metabolites DM-4103 and DM-4107 revealed increases in the concentrations of these metabolites following repeated dosing, and explained the reduction in serum tolvaptan concentrations. Furthermore, tolvaptan was shown to induce hepatic drug-metabolising enzymes (cytochrome b5 content and aminopyrine N-demethylase activity) in female rats after 7 days dosing at 300 mg/kg/day. Tolvaptan was both a substrate for, and inhibitor of, MDR1-mediated transport.
来源:Hazardous Substances Data Bank (HSDB)
代谢
托伐普坦在所有研究物种中都被广泛代谢。在大鼠肝脏匀浆的体外研究中,产生了托伐普坦的多种代谢物。苯并氮杂环的羟基化产生了代谢物DM-4110、DM-4111和DM-4119。苯并氮杂环1号和2号位置之间的键断裂产生了代谢物DM-4103、DM-4104、DM-4105和DM-4107。苯并氮杂环5号位置上羟基的氧化产生了代谢物MOP-21826。
Tolvaptan is extensively metabolized in all species investigated. In vitro studies with rat liver supernatant produced a number of metabolites of tolvaptan. Hydroxylation of the benzazepine ring produced metabolites DM-4110, DM-4111 and DM-4119. Cleavage of the bond between the 1 and 2 positions of the benzazepine ring produced metabolites DM-4103, DM-4104, DM-4105 and DM- 4107. Oxidation of the hydroxyl group at the 5 position in the benzazepine ring produced MOP-21826.
来源:Hazardous Substances Data Bank (HSDB)
代谢
托伐普坦主要(如果不是唯一)通过肝脏的细胞色素P-450(CYP)同工酶3A进行代谢;该药物也是CYP3A的弱抑制剂,并且是P-糖蛋白转运系统的底物和抑制剂。与托伐普坦相比,该药物的代谢产物对人类V2受体的拮抗活性很小或没有。
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.
来源:Hazardous Substances Data Bank (HSDB)
代谢
托伐普坦在人体内通过CYP3A4/5系统广泛代谢,形成了七种代谢物(DM-4103、DM-4104、DM-4105、DM-4107、DM-4110、DM-4111、DM-4119),在一项14C质量平衡研究中,这些代谢物在所有受试者的血浆、尿液和粪便中被检测到。在给予(14)C-托伐普坦后,人血浆中鉴定出13种代谢物。托伐普坦及其鉴定出的代谢物约占总给药放射活性的70%。主要代谢物DM-4103占总剂量的50%以上。DM-4103的终末消除半衰期大约为183小时,多次给药后,DM-4103在第28天出现累积,但在使用临床相关剂量达到的浓度下,这似乎在药理上是无效的。血浆中仅有3%的放射活性归因于未改变的托伐普坦
Tolvaptan is metabolized extensively in humans by the CYP3A4/5 system with seven metabolites (DM-4103, DM-4104, DM-4105, DM-4107, DM-4110, DM-4111, DM-4119) detected in the plasma, urine, and faeces of all subjects in a 14C mass balance study. After administration of (14)C-tolvaptan, 13 metabolites were identified in human plasma. Tolvaptan and identified metabolites accounted for about 70% of administered radioactivity. The predominant metabolite, with >50% of the total dose using the mass balance approach was DM-4103. The terminal elimination half-life of DM-4103 is approximatley 183 hours and after multiple dosing DM-4103 shows accumulation by day 28, but this appears pharmacologically inactive in the concentrations achieved using clinically relevant doses. Only 3% of the radioactivity was due to unchanged tolvaptan in the plasma.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 毒性总结
识别和使用:托伐普坦是一种白色结晶粉末,被制成口服片剂。托伐普坦精氨酸加压素抗利尿激素)V2受体的拮抗剂。它用于治疗血液中含量过低。人类暴露和毒性:在健康受试者中,单次口服剂量高达480毫克的托伐普坦和每日一次连续5天多达300毫克的剂量下都能很好地耐受。对于托伐普坦中毒没有特定的解毒剂。急性过量的征兆和症状可以预期为药理作用的过度表现:血清浓度升高、多尿、口渴和脱/低血容量。然而,长期使用托伐普坦可能导致严重甚至致命的肝脏损伤。2013年,美国食品和药物管理局(FDA)确定该药物使用时间不应超过30天,并且不应在有潜在肝脏疾病的病人中使用,因为它可能引起肝脏损伤,可能需要肝移植或导致死亡。在一项针对常染色体显性多囊肾病患者长期使用托伐普坦的安慰剂对照和开放标签扩展研究中,观察到了因托伐普坦引起的严重肝脏损伤病例。托伐普坦治疗应该在医院环境中开始或重新开始,以便可以密切监测血清浓度和治疗效果。过快纠正低血症可能导致渗透性脱髓鞘综合征,表现为言语不清、缄默、吞咽困难、乏力、情感变化、痉挛性四肢轻瘫、癫痫发作、昏迷或死亡。在易感患者中,包括那些严重营养不良、酗酒或晚期肝病的患者,建议更慢的纠正速度。抗利尿激素分泌不当综合征患者或基线血清浓度非常低的患者可能存在血清浓度过快纠正的风险。托伐普坦在无法感知或适当地对口渴作出反应的患者以及低血容量性低血症的患者中是禁忌的。托伐普坦主要(如果不是唯一的话)通过肝细胞色素P-450(CYP)同工酶3A代谢;该药物也是CYP3A的弱抑制剂,并且是P-糖蛋白转运系统的底物和抑制剂。与托伐普坦相比,该药物的代谢物对人类V2受体的拮抗活性很小或没有。动物研究:在大鼠和狗中给予托伐普坦的急性毒性较低。在大鼠和狗的重复剂量研究中,发现的结果通常与托伐普坦的药理作用有关,包括增加尿量、降低尿渗量和增加饮量。也观察到了体重减轻和血液学和临床化学参数的改变,但在恢复期间是可逆的。在长达两年的口服托伐普坦给雄性和雌性大鼠中,没有增加肿瘤的发生率。在一项针对雄性和雌性大鼠的生育研究中,与对照组相比,托伐普坦与较少的黄体和植入有关。在器官形成期间给怀孕兔子口服托伐普坦,与母体体重增加和食物消耗的减少有关。也观察到了流产、胚胎-胎儿死亡、胎儿小眼症、开眼睑、腭裂、短肢和骨骼畸形。在体外(细菌反向突变试验和中国仓鼠肺成纤维细胞染色体畸变试验)和体内(大鼠微核试验)测试系统中,托伐普坦基因毒性的测试结果为阴性。
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.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 肝毒性
在上市前的临床试验中,托伐普坦并未导致血清酶平升高或临床上明显的肝损伤。然而,在一小部分接受托伐普坦治疗的肝硬化患者中,报告了肝衰竭恶化和门脉高压并发症的情况。这些并发症包括静脉曲张出血、肝性脑病和黄疸恶化。在许多试验中,这些并发症的发生率并未明显高于接受安慰剂治疗的对照组。最近,在针对ADPKD患者长期治疗的大型注册试验中,服用托伐普坦的患者血清转酶升高的发生率为4%至5%,而对照组仅为1%。此外,大约有0.1%的接受治疗的患者出现了临床上明显的肝损伤。发病时间从3个月到9个月不等(案例1),但偶尔也会在长期治疗期间出现(案例2)。临床表现是隐匿性发展疲劳、恶心和腹痛,随后出现深色尿、黄疸和瘙痒。血清酶升高的模式通常是肝细胞型或混合型,肝脏活检显示急性肝炎伴轻度胆汁淤积。所有患者在停止治疗后恢复,通常在停止治疗1到3个月内没有残留损伤的证据。未发现免疫过敏特征和自身抗体。在治疗期间,几例患者在重新用药后迅速复发,表现为血清酶平显著升高,但出现黄疸的患者并未再次暴露。治疗期间临床上明显肝损伤的发生率是ADPKD长期托伐普坦治疗正式批准延迟的原因之一。自从批准使用并更广泛使用以来,偶尔仍有临床上明显肝损伤的报告,至少有一例导致了肝移植。有趣的是,大多数肝损伤的报道与其用于常染色体显性多囊肾病有关,而不是用于低血症。这可能是由于治疗持续时间,但也可能与用于减缓多囊肾病进展的略高剂量有关。
In prelicensure clinical trials, tolvaptan was not implicated in causing serum enzyme elevations or clinically apparent liver injury. However, instances of worsening of hepatic failure and complications of portal hypertension were reported in a small proportion of patients with cirrhosis treated with tolvaptan. These complications included variceal hemorrhage, hepatic encephalopathy and worsening of jaundice. In many trials, however, the frequency of these complications was not significantly greater than in placebo treated controls. More recently, in large registration trials of long term therapy in patients with ADPKD, serum aminotransferase elevations occurred in 4% to 5% of patients on tolvaptan, compared to only 1% of controls. Furthermore, clinically apparent liver injury occurred in approximately 0.1% of treated patients. The time to onset of illness ranged from 3 to 9 months (Case 1), but occasionally arose during long term therapy (Case 2). The clinical presentation was with the insidious development of fatigue, nausea and abdominal pain followed by dark urine, jaundice and pruritus. The pattern of serum enzyme elevations was typically hepatocellular or mixed, and liver biopsy showed an acute hepatitis with mild cholestasis. All patients recovered after stopping therapy, generally within 1 to 3 months of stopping therapy without evidence of residual injury. Immunoallergic features and autoantibodies were not found. Rapid recurrence on rechallenge was demonstrated in several patients with marked serum enzyme elevations during therapy, but patients with jaundice were not reexposed. The frequency of clinically apparent liver injury during therapy was one reason for the delay of formal approval of long term tolvaptan therapy for ADPKD. Since its approval and more wide-spread use, occasion reports of clinically apparent liver injury have continued to appear, at least one of which led to liver transplantation. Interestingly, most instances of liver injury have been reported with its use in autosomal dominant polycystic kidney disease rather than hyponatremia. Reasons for this are probably the duration of therapy, but also may relate to the slightly higher doses used to decrease progress in polycystic kidney disease.
来源:LiverTox
毒理性
  • 药物性肝损伤
化合物:托伐普坦
Compound:tolvaptan
来源:Drug Induced Liver Injury Rank (DILIrank) Dataset
毒理性
  • 药物性肝损伤
药物性肝损伤标注:最令人关注的药物性肝损伤
DILI Annotation:Most-DILI-Concern
来源:Drug Induced Liver Injury Rank (DILIrank) Dataset
毒理性
  • 药物性肝损伤
严重程度等级:8
Severity Grade:8
来源:Drug Induced Liver Injury Rank (DILIrank) Dataset
吸收、分配和排泄
在一项研究中,给予10-124 mL/min肌酐清除率的肾功能障碍患者单次剂量60毫克的托伐普坦,与对照组相比,严重肾损害患者的托伐普坦血浆AUC和Cmax增加不到两倍。血清的峰值增加为5-6 mEq/L,与肾功能无关,但是托伐普坦对血清的影响在严重肾损害患者中起效和消失较慢。
In a study in patients with creatinine clearances ranging from 10-124 mL/min administered a single dose of 60 mg tolvaptan, AUC and Cmax of plasma tolvaptan were less than doubled in patients with severe renal impairment relative to the controls. The peak increase in serum sodium was 5-6 mEq/L, regardless of renal function, but the onset and offset of tolvaptan's effect on serum sodium were slower in patients with severe renal impairment.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
在健康受试者中,对单次剂量高达480毫克和每日一次多次剂量高达300毫克的托伐普坦的药代动力学进行了研究。曲线下面积(AUC)与剂量成正比增加。然而,在服用剂量大于或等于60毫克后,Cmax的增加与剂量不成正比。托伐普坦的药代动力学特性具有立体特异性,稳态时S-(-)对R-(+)对映体的比率约为3。托伐普坦的绝对生物利用度未知。至少40%的剂量以托伐普坦或代谢物的形式被吸收。托伐普坦的峰浓度在给药后2到4小时观察到。食物不影响托伐普坦生物利用度。体外数据表明托伐普坦是P-gp的底物和抑制剂托伐普坦在血浆中高度蛋白结合(99%)并分布到大约3 L/kg的表观分布容积中。托伐普坦完全通过非肾途径消除,主要是通过CYP 3A代谢。口服给药后,清除率约为4 mL/min/kg,终末相半衰期约为12小时。托伐普坦的积累因子为每日一次给药方案为1.3,低谷浓度达到或超过峰浓度的16%,提示主导半衰期略短于12小时。受试者之间托伐普坦的峰浓度和平均暴露量有显著差异,变异系数百分比介于30%至60%之间。
In healthy subjects the pharmacokinetics of tolvaptan after single doses of up to 480 mg and multiple doses up to 300 mg once daily have been examined. Area under the curve (AUC) increases proportionally with dose. After administration of doses > or = 60 mg, however, Cmax increases less than proportionally with dose. The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. The absolute bioavailability of tolvaptan is unknown. At least 40% of the dose is absorbed as tolvaptan or metabolites. Peak concentrations of tolvaptan are observed between 2 and 4 hours post-dose. Food does not impact the bioavailability of tolvaptan. In vitro data indicate that tolvaptan is a substrate and inhibitor of P-gp. Tolvaptan is highly plasma protein bound (99%) and distributed into an apparent volume of distribution of about 3 L/kg. Tolvaptan is eliminated entirely by non-renal routes and mainly, if not exclusively, metabolized by CYP 3A. After oral dosing, clearance is about 4 mL/min/kg and the terminal phase half-life is about 12 hours. The accumulation factor of tolvaptan with the once-daily regimen is 1.3 and the trough concentrations amount to > or = 16% of the peak concentrations, suggesting a dominant half-life somewhat shorter than 12 hours. There is marked inter-subject variation in peak and average exposure to tolvaptan with a percent coefficient of variation ranging between 30 and 60%.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
在任何原因引起的低血症患者中,托伐普坦的清除率降低至大约2 mL/min/kg。中重度肝功能损害或充血性心力衰竭会降低托伐普坦的清除率并增加其分布容积,但这些变化在临床上并不显著。在肌酐清除率在79到10 mL/min之间的受试者以及肾功能正常的患者中,托伐普坦的暴露和反应没有差异。
In patients with hyponatremia of any origin the clearance of tolvaptan is reduced to about 2 mL/min/kg. Moderate or severe hepatic impairment or congestive heart failure decrease the clearance and increase the volume of distribution of tolvaptan, but the respective changes are not clinically relevant. Exposure and response to tolvaptan in subjects with creatinine clearance ranging between 79 and 10 mL/min and patients with normal renal function are not different.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
在健康的受试者中,单次给予Samsca 60 mg后,利尿和增加的效果在给药后2到4小时内出现。在给药后4到8小时之间观察到大约6 mEq的血清增加和大约9 mL/min的尿排泄率增加的峰值效应;因此,药理活性滞后于托伐普坦的血浆浓度。大约60%的血清峰值效应在给药后24小时内持续,但此时尿排泄率不再升高。高于60 mg托伐普坦的剂量不会进一步增加利尿或血清。在推荐的15到60 mg每日一次的剂量范围内,托伐普坦的效果似乎仅限于利尿和由此产生的浓度增加。
In healthy subjects receiving a single dose of Samsca 60 mg, the onset of the aquaretic and sodium increasing effects occurs within 2 to 4 hours post-dose. A peak effect of about a 6 mEq increase in serum sodium and about 9 mL/min increase in urine excretion rate is observed between 4 and 8 hours post-dose; thus, the pharmacological activity lags behind the plasma concentrations of tolvaptan. About 60% of the peak effect on serum sodium is sustained at 24 hours post-dose, but the urinary excretion rate is no longer elevated by this time. Doses above 60 mg tolvaptan do not increase aquaresis or serum sodium further. The effects of tolvaptan in the recommended dose range of 15 to 60 mg once daily appear to be limited to aquaresis and the resulting increase in sodium concentration.
来源:Hazardous Substances Data Bank (HSDB)

安全信息

  • WGK Germany:
    3
  • 危险品运输编号:
    NONH for all modes of transport
  • 储存条件:
    | 冰箱 |

SDS

SDS:950f655fc1b930d1c1a82915141f8a82
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制备方法与用途

托伐普坦简介

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,减少重吸收,增加尿液中游离的排泄,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:

  1. 以化合物2-氨基-5-氯苯甲酸甲酯为原料,与对甲苯磺酸进行基保护反应。
  2. 然后与丁酸乙酯反应生成化合物2。通过Dieckmann缩合关环成苯并氮杂卓的母环3。
  3. 在酸性条件下脱去羧酸乙酯,得到化合物4,在多聚磷酸溶液中去除对甲苯磺酸保护基生成化合物5。该化合物是托伐普坦的关键中间体。
  4. 通过一系列反应合成最终产品。
生物活性

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血症模型中,Tolvaptan改善了低血症症状,并提高了器官份保留率,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血症模型中,Tolvaptan明显升高无电解质的间隙(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。

上下游信息

  • 上游原料
    中文名称 英文名称 CAS号 化学式 分子量
  • 下游产品
    中文名称 英文名称 CAS号 化学式 分子量
    • 1
    • 2

反应信息

  • 作为反应物:
    描述:
    托伐普坦四氮唑 、 5%-palladium/activated carbon 、 氢气 、 sodium hydroxide 作用下, 以 甲醇乙醇二氯甲烷 为溶剂, 反应 3.08h, 生成
    参考文献:
    名称:
    [EN] BENZOAZEPINE COMPOUND-CONTAINING PHARMACEUTICAL COMPOSITION
    [FR] COMPOSITION PHARMACEUTIQUE CONTENANT UN COMPOSÉ DE BENZOAZÉPINE
    摘要:
    提供了一种减少托瑞洛芬副作用的方法。具体而言,该方法提供了一种药物组合物,其中包括由式(1)表示的化合物或其金属盐,该药物组合物的使用是以该化合物或其金属盐以经血管途径在10分钟或更长时间内输注4至20毫克的剂量。
    公开号:
    WO2020196816A1
  • 作为产物:
    描述:
    4-溴-2-甲基苯甲酸甲醇 、 sodium tetrahydroborate 、 potassium phosphate氯化亚砜 作用下, 以 四氢呋喃N,N-二甲基甲酰胺甲苯 为溶剂, 反应 7.0h, 生成 托伐普坦
    参考文献:
    名称:
    [EN] 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。
    公开号:
    WO2021249877A1
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文献信息

  • DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
    申请人:BAYER PHARMA AKTIENGESELLSCHAFT
    公开号:US20160221965A1
    公开(公告)日:2016-08-04
    The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.
    本申请涉及新颖的2,5-二取代6-(三甲基)嘧啶-4(3H)-酮衍生物,其制备方法,其单独或与其他药物联合用于治疗和/或预防疾病,以及用于制备治疗和/或预防疾病的药物,特别是用于治疗和/或预防心血管、肾脏、炎症和纤维化疾病。
  • [EN] PROCESS FOR PREPARING TOLVAPTAN INTERMEDIATES<br/>[FR] PROCÉDÉ DE PRÉPARATION D'INTERMÉDIAIRES DE TOLVAPTAN
    申请人:HETERO RESEARCH FOUNDATION
    公开号:WO2012046244A1
    公开(公告)日:2012-04-12
    The present invention provides a novel process for the preparation of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one. The present invention also provides an improved process for the preparation of 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. The present invention further provides an improved process for the preparation of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine.
    本发明提供了一种新型的制备7--2,3,4,5-四氢-1H-1-苯并哌啶-5-酮的方法。本发明还提供了一种改进的制备7--1-(2-甲基-4-硝基苯甲酰)-5-氧代-2,3,4,5-四氢-1H-1-苯并哌啶的方法。本发明还提供了一种改进的制备7--1-[2-甲基-4-[(2-甲基苯甲酰)基]苯甲酰]-5-氧代-2,3,4,5-四氢-1H-1-苯并哌啶的方法。
  • PROCESS FOR PREPARING TOLVAPTAN INTERMEDIATES
    申请人:Reddy Bandi Parthasaradhi
    公开号:US20130190490A1
    公开(公告)日:2013-07-25
    The present invention provides a novel process for the preparation of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one. The present invention also provides an improved process for the preparation of 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. The present invention further provides an improved process for the preparation of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine.
    本发明提供了一种新型的制备7--2,3,4,5-四氢-1H-1-苯并哌啶-5-酮的方法。本发明还提供了一种改进的制备7--1-(2-甲基-4-硝基苯甲酰)-5-氧代-2,3,4,5-四氢-1H-1-苯并哌啶的方法。本发明还提供了一种改进的制备7--1-[2-甲基-4-[(2-甲基苯甲酰)基]苯甲酰]-5-氧代-2,3,4,5-四氢-1H-1-苯并哌啶的方法。
  • [EN] VASOPRESSIN RECEPTOR ANTAGONISTS AND PRODUCTS AND METHODS RELATED THERETO<br/>[FR] ANTAGONISTES DU RÉCEPTEUR DE LA VASOPRESSINE, PRODUITS ET PROCÉDÉS ASSOCIÉS
    申请人:BLACKTHORN THERAPEUTICS INC
    公开号:WO2019050988A1
    公开(公告)日:2019-03-14
    Compounds are provided that antagonize vasopressin receptors, particularly the V1a receptor products containing such compounds, as well as to methods of their use and synthesis. Such compounds have the structure of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: (I) wherein Q1, Q2, Q3, R2a, R2b, R3 and X are as defined herein.
    提供了拮抗加压素受体的化合物,特别是含有这些化合物的V1a受体产品,以及它们的使用和合成方法。这些化合物具有以下结构的结构(I),或其药学上可接受的异构体、消旋体、合物、溶剂合物、同位素或盐:(I)其中Q1、Q2、Q3、R2a、R2b、R3和X如本文所定义。
  • SUBSTITUTED BIPIPERIDINYL DERIVATIVES
    申请人:Bayer Pharma Aktiengesellschaft
    公开号:US20160318866A1
    公开(公告)日:2016-11-03
    The invention relates to novel substituted bipiperidinyl derivatives, to processes for their preparation, to their use for the treatment and/or prevention of diseases and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of diabetic microangiopathies, diabetic ulcers on the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microvascular heart disorders, peripheral and cardiac vascular disorders, thromboembolic disorders and ischaemias, peripheral circulatory disturbances, Raynaud's phenomenon, CREST syndrome, microcirculatory disturbances, intermittent claudication, and peripheral and autonomous neuropathies.
    该发明涉及新型取代的双哌啶生物,涉及它们的制备方法,涉及它们用于治疗和/或预防疾病以及用于制备治疗和/或预防疾病的药物的用途,特别是用于治疗和/或预防糖尿病微血管病变、四肢糖尿病溃疡,特别是促进糖尿病足溃疡愈合、糖尿病心力衰竭、糖尿病冠状微血管心脏疾病、外周和心脏血管疾病、血栓栓塞疾病和缺血、外周循环障碍、雷诺现象、CREST综合征、微循环障碍、间歇性跛行以及外周和自主神经病变的治疗和/或预防。
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同类化合物

(βS)-β-氨基-4-(4-羟基苯氧基)-3,5-二碘苯甲丙醇 (S,S)-邻甲苯基-DIPAMP (S)-(-)-7'-〔4(S)-(苄基)恶唑-2-基]-7-二(3,5-二-叔丁基苯基)膦基-2,2',3,3'-四氢-1,1-螺二氢茚 (S)-盐酸沙丁胺醇 (S)-3-(叔丁基)-4-(2,6-二甲氧基苯基)-2,3-二氢苯并[d][1,3]氧磷杂环戊二烯 (S)-2,2'-双[双(3,5-三氟甲基苯基)膦基]-4,4',6,6'-四甲氧基联苯 (S)-1-[3,5-双(三氟甲基)苯基]-3-[1-(二甲基氨基)-3-甲基丁烷-2-基]硫脲 (R)富马酸托特罗定 (R)-(-)-盐酸尼古地平 (R)-(-)-4,12-双(二苯基膦基)[2.2]对环芳烷(1,5环辛二烯)铑(I)四氟硼酸盐 (R)-(+)-7-双(3,5-二叔丁基苯基)膦基7''-[((6-甲基吡啶-2-基甲基)氨基]-2,2'',3,3''-四氢-1,1''-螺双茚满 (R)-(+)-7-双(3,5-二叔丁基苯基)膦基7''-[(4-叔丁基吡啶-2-基甲基)氨基]-2,2'',3,3''-四氢-1,1''-螺双茚满 (R)-(+)-7-双(3,5-二叔丁基苯基)膦基7''-[(3-甲基吡啶-2-基甲基)氨基]-2,2'',3,3''-四氢-1,1''-螺双茚满 (R)-(+)-4,7-双(3,5-二-叔丁基苯基)膦基-7“-[(吡啶-2-基甲基)氨基]-2,2”,3,3'-四氢1,1'-螺二茚满 (R)-3-(叔丁基)-4-(2,6-二苯氧基苯基)-2,3-二氢苯并[d][1,3]氧杂磷杂环戊烯 (R)-2-[((二苯基膦基)甲基]吡咯烷 (R)-1-[3,5-双(三氟甲基)苯基]-3-[1-(二甲基氨基)-3-甲基丁烷-2-基]硫脲 (N-(4-甲氧基苯基)-N-甲基-3-(1-哌啶基)丙-2-烯酰胺) (5-溴-2-羟基苯基)-4-氯苯甲酮 (5-溴-2-氯苯基)(4-羟基苯基)甲酮 (5-氧代-3-苯基-2,5-二氢-1,2,3,4-oxatriazol-3-鎓) (4S,5R)-4-甲基-5-苯基-1,2,3-氧代噻唑烷-2,2-二氧化物-3-羧酸叔丁酯 (4S,4''S)-2,2''-亚环戊基双[4,5-二氢-4-(苯甲基)恶唑] (4-溴苯基)-[2-氟-4-[6-[甲基(丙-2-烯基)氨基]己氧基]苯基]甲酮 (4-丁氧基苯甲基)三苯基溴化磷 (3aR,8aR)-(-)-4,4,8,8-四(3,5-二甲基苯基)四氢-2,2-二甲基-6-苯基-1,3-二氧戊环[4,5-e]二恶唑磷 (3aR,6aS)-5-氧代六氢环戊基[c]吡咯-2(1H)-羧酸酯 (2Z)-3-[[(4-氯苯基)氨基]-2-氰基丙烯酸乙酯 (2S,3S,5S)-5-(叔丁氧基甲酰氨基)-2-(N-5-噻唑基-甲氧羰基)氨基-1,6-二苯基-3-羟基己烷 (2S,2''S,3S,3''S)-3,3''-二叔丁基-4,4''-双(2,6-二甲氧基苯基)-2,2'',3,3''-四氢-2,2''-联苯并[d][1,3]氧杂磷杂戊环 (2S)-(-)-2-{[[[[3,5-双(氟代甲基)苯基]氨基]硫代甲基]氨基}-N-(二苯基甲基)-N,3,3-三甲基丁酰胺 (2S)-2-[[[[[((1S,2S)-2-氨基环己基]氨基]硫代甲基]氨基]-N-(二苯甲基)-N,3,3-三甲基丁酰胺 (2S)-2-[[[[[[((1R,2R)-2-氨基环己基]氨基]硫代甲基]氨基]-N-(二苯甲基)-N,3,3-三甲基丁酰胺 (2-硝基苯基)磷酸三酰胺 (2,6-二氯苯基)乙酰氯 (2,3-二甲氧基-5-甲基苯基)硼酸 (1S,2S,3S,5S)-5-叠氮基-3-(苯基甲氧基)-2-[(苯基甲氧基)甲基]环戊醇 (1S,2S,3R,5R)-2-(苄氧基)甲基-6-氧杂双环[3.1.0]己-3-醇 (1-(4-氟苯基)环丙基)甲胺盐酸盐 (1-(3-溴苯基)环丁基)甲胺盐酸盐 (1-(2-氯苯基)环丁基)甲胺盐酸盐 (1-(2-氟苯基)环丙基)甲胺盐酸盐 (1-(2,6-二氟苯基)环丙基)甲胺盐酸盐 (-)-去甲基西布曲明 龙蒿油 龙胆酸钠 龙胆酸叔丁酯 龙胆酸 龙胆紫-d6 龙胆紫