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N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide | 923604-59-5

中文名称
——
中文别名
——
英文名称
N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide
英文别名
N-cyclopropylsulfonyl-17-[7-methoxy-8-methyl-2-(4-propan-2-yl-1,3-thiazol-2-yl)quinolin-4-yl]oxy-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxamide
N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide化学式
CAS
923604-59-5
化学式
C38H47N5O7S2
mdl
——
分子量
749.9
InChiKey
JTZZSQYMACOLNN-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

  • 密度:
    1.38
  • 溶解度:
    不溶于水;不溶于乙醇; ≥18.75 mg/mL,溶于 DMSO
  • 颜色/状态:
    White to almost white powder
  • 蒸汽压力:
    5.9X10-27 mm Hg at 25 °C (est)
  • 亨利常数:
    Henry's Law constant = 2.68X10-28 atm-cu m/mol at 25 °C (est)
  • 解离常数:
    pKa1 = 1.61 (imine); pKa2 = 3.77 (amine); pKa3 = 10.80 (secondary amine) (est)

计算性质

  • 辛醇/水分配系数(LogP):
    4.8
  • 重原子数:
    52
  • 可旋转键数:
    8
  • 环数:
    7.0
  • sp3杂化的碳原子比例:
    0.55
  • 拓扑面积:
    194
  • 氢给体数:
    2
  • 氢受体数:
    10

ADMET

代谢
在健康受试者单次口服200毫克(推荐剂量的1.3倍)的(14)C-西美瑞韦后,血浆中大部分的放射性(平均:83%)归因于未改变的药物,而血浆中的一部分放射性与代谢物有关(没有主要的代谢物)。在粪便中鉴定的代谢物是通过在大环部分或芳香部分或两者同时进行氧化形成的,以及通过O-脱甲基化后进行氧化形成的。
Following a single oral administration of 200 mg (1.3 times the recommended dosage) (14)C-simeprevir to healthy subjects, the majority of the radioactivity in plasma (mean: 83%) was accounted for by unchanged drug and a small part of the radioactivity in plasma was related to metabolites (none being major metabolites). Metabolites identified in feces were formed via oxidation at the macrocyclic moiety or aromatic moiety or both and by O-demethylation followed by oxidation.
来源:Hazardous Substances Data Bank (HSDB)
代谢
西美瑞韦在肝脏中被代谢。用人肝脏微粒体的体外实验表明,西美瑞韦主要通过肝脏的CYP3A系统进行氧化代谢。不能排除CYP2C8和CYP2C19的参与。与中等或强效的CYP3A抑制剂联合使用可能显著增加西美瑞韦的血浆暴露量,而与中等或强效的CYP3A诱导剂联合使用可能显著降低西美瑞韦的血浆暴露量。
Simeprevir is metabolized in the liver. In vitro experiments with human liver microsomes indicated that simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A system. Involvement of CYP2C8 and CYP2C19 cannot be excluded. Co-administration of Olysio with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir, and co-administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir.
来源:Hazardous Substances Data Bank (HSDB)
代谢
14C-TMC435的体外代谢在鼠、大鼠、兔、猴和人的肝细胞和肝微粒体中被研究。从动物和人体中报告的体外代谢活性较低。在肝细胞中形成了I相代谢物II相结合途径。在体外,母体TMC435的量比任何代谢物都要高得多。已鉴定出20多种代谢物。代谢I相最重要的途径是未改变药物的O-脱甲基化(特别是在动物中)、未改变药物和氧化代谢物的氧化(特别是在猴和人体中),氧化代谢物的葡萄糖苷酸化是II相的主要途径(在人体中较少)。在体外鉴定出的唯一一个人体代谢物在大鼠或狗中没有看到的是M22(氧化未改变的药物),但这个代谢物在大鼠(粪便)中被鉴定出来。体内数据显示,大鼠、狗和人体血浆中的主要成分是母体TMC435。在动物和人体血浆中报告的体内主要代谢物是M18和M21。O-脱甲基-TMC435 M21是在大鼠、狗和人体血浆中发现的唯一共同循环代谢物(M21:平均TMC435血浆的8%,狗中只有少量痕迹),而M18是大鼠和狗血浆中的共同代谢物,但相对于母体化合物,它们的出现浓度较低(M18:在大鼠中为28.9%至12.5%,狗中只有少量痕迹)。在大狗血浆中仅报告了由芳香部分O-脱甲基化和氧化形成的代谢物M18、M21和M8的痕迹。M21代表未改变药物的不到10%,也代表总放射性的不到10%,因此在安全性评估研究中没有评估M21的系统暴露。M21在人体中似乎没有积累。在大鼠胆汁中报告了中等高水平的母体化合物(0.11至17.2%)。在大鼠中,TMC435代谢物主要通过羟基化、O-脱甲基化和葡萄糖苷酸化形成。
The in vitro metabolism of 14C-TMC435 was investigated in hepatocytes and liver microsomes of mouse, rat, rabbit, monkey and human. The metabolic activity reported in vitro from animals and man was low. Phase II conjugation pathways of Phase I metabolites were formed in hepatocytes. Parent TMC435 was found in much greater levels than any metabolite in vitro. More than 20 metabolites were identified. The metabolic Phase I route of highest importance were O-demethylation of unchanged drug (particularly in animals), oxidation of unchanged drug and oxidized metabolites (particularly in monkey and man) and glucuronidation was the major Phase II of oxidized metabolites (less in human). Only one human metabolite identified in vitro not seen in rat or dog was M22 (oxidized unchanged drug) but this metabolite was identified in rat (feces). In vivo data reveals that the main moiety present in plasma of rat, dog and man was parent TMC435. The major metabolites reported in vivo in plasma from animals and human were M18 and M21. O-desmethyl-TMC435 M21 was the only common circulating metabolite found in rat dog and human plasma (M21: 8% of the mean TMC435 plasma and only small traces in dogs), while M18 was common to plasma of rats and dogs but with respect to the parent compound they appeared with low concentrations (M18: between 28.9% and 12.5% in rats, with only small traces in dogs). Only traces of metabolites M18, M21 and M8 formed by O-demethylation and oxidation at the aromatic moiety were reported in dog plasma. M21 represents less than 10% of unchanged drug and also total radioactivity therefore systemic exposure to M21 was not assessed in the safety evaluation studies. M21 did not appear to accumulate in man. In bile from rats, moderately high levels of parent compound were reported (0.11 to 17.2%). TMC435 metabolites in this matrix were formed mainly by hydroxylation and O-demethylation and also by glucuronidation.
来源:Hazardous Substances Data Bank (HSDB)
代谢
在大鼠和狗体内,TMC435最重要的代谢途径是母药的O-脱甲基化,生成M18(大鼠雄性-雌性12.8%-6.4%;狗18.8%)。在大鼠中,其他代谢物是通过M18的氧化和未变化药物的氧化形成的。在狗中,M18进一步氧化为M14和M8,以及未变化药物氧化为M21、M16和M11也被报道为次要途径。人类的代谢轮廓表明,TMC435主要通过两个主要途径代谢:(1)未变化药物的氧化,在环状结构上(M27、M21和M22),或在芳香环上(M26和M16),或两者都有(M23、M24、M25和M11)和(2)未变化药物O-脱甲基化生成M18,然后在大环结构上氧化为M14,在芳香环上氧化为M5,这看起来是人类次要的代谢途径。M21和M22是人类粪便中最重要的代谢物。其他相关代谢物(剂量的1%)是M11、M16、M27和M18。在人类粪便中检测到的所有代谢物都在大鼠和/或狗的体外和/或体内粪便中检测到。参与TMC435代谢的主要CYP酶是CYP3A酶,尽管体外数据表明CYP2C8和CYP2C19也参与了。
The most important metabolic route TMC435 in rat and dog was O-demethylation of the parent drug to M18 (12.8%- 6.4% male-female rats; 18.8% dogs). In rats other metabolites were formed by oxidation of M18 and oxidation of unchanged drug. In dogs, further oxidation of M18 to M14 and M8, and of the unchanged drug to M21, M16 and M11 were also reported as minor routes. The human metabolism profile suggests that TMC435 is mainly metabolized by two main routes, (1) oxidation of unchanged drug, either at the macrocyclic moiety (M27, M21 and M22), or at the aromatic moiety (M26 and M16), or both (M23, M24, M25 and M11) and (2) the O-demethylation of unchanged drug to M18, followed by oxidation on the macrocyclic moiety to M14 and by oxidation on the aromatic moiety to M5, appears to be the secondary metabolic pathway in man. M21 and M22 were the most important metabolites in human faeces. Other relevant metabolites (1% of the dose) were M11, M16, M27 and M18. All metabolites detected in human feces were detected in vitro and/or in vivo in rat and/or dog feces. The main CYP enzymes involved in TMC435 metabolism were CYP3A enzymes although in vitro data suggests the involvement of CYP2C8 and CYP2C19.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 毒性总结
身份和使用:Simeprevir 是一种白色至几乎白色的粉末。Simeprevir 与聚乙二醇干扰素α和利巴韦林联合使用,用于治疗成人有补偿性肝脏疾病(包括肝硬化)的慢性丙型肝炎病毒(HCV)基因型1感染,这些成人之前未接受过治疗(未经治疗)或之前接受干扰素和利巴韦林治疗失败(包括之前无响应、之前部分响应或之前复发)。Simeprevir 必须与聚乙二醇干扰素α(聚乙二醇干扰素α-2a或聚乙二醇干扰素α-2b)和利巴韦林联合使用,不应单独用于治疗慢性HCV感染。 人体暴露和毒性:关于Simeprevir 过量影响的资料非常有限。在健康成人受试者中单次剂量高达600毫克或每日一次剂量高达400毫克,连续5天,以及在成人HCV患者中每日一次200毫克,连续4周,Simeprevir 通常被良好耐受。在动物研究中,Simeprevir 在小鼠中单次剂量高达500毫克/千克,在大鼠中高达1000毫克/千克,在狗中高达160毫克/千克,在猴子中高达300毫克/千克时,也被良好耐受。在动物研究中,Simeprevir 对生命功能(心脏、呼吸和中央神经系统)没有不良影响。在小鼠(长达3个月)、大鼠(长达6个月)、狗(长达9个月)和猴子(长达28天)中进行了Simeprevir的重复剂量口服毒性研究。所有物种都观察到了胃肠道效应。在小鼠、大鼠和/或狗中看到了软便、粘液便或苍白便的高发生率。在小鼠、大鼠和狗的小肠和空肠中注意到了上皮细胞肿胀/空泡化的现象。由于胃排空延迟,在小鼠和大鼠中,化合物配方导致了异常胃内容物和/或腹部膨胀。在小鼠、大鼠和狗中观察到了肝脏效应。这些发现通常伴随着血浆中胆红素和肝酶的增加。在小鼠胚胎胎儿研究中,在高达1000毫克/千克的剂量下,Simeprevir 导致了早期和晚期胎儿死亡以及早期母体死亡,暴露量大约是人类推荐150毫克每日剂量平均AUC的6倍。在暴露量大约是人类推荐每日剂量平均AUC的4倍时,显著降低了胎儿体重,并增加了胎儿骨骼变异。在大鼠的产前和产后研究中,母体动物在妊娠和哺乳期间以高达1000毫克/千克/日的剂量暴露于Simeprevir。在妊娠大鼠中,Simeprevir 在1000毫克/千克/日的剂量下导致早期死亡,对应的暴露量类似于人类推荐150毫克一次每日剂量平均AUC。在暴露量是人类推荐150毫克一次每日剂量平均AUC的0.7倍时,显著减少了体重增加。在大鼠后代中,通过母体给药在子宫内暴露于Simeprevir,并通过母体哺乳给哺乳期幼崽,在母体暴露量类似于人类推荐150毫克一次每日剂量平均AUC时,显著降低了体重,并对身体生长(延迟和小尺寸)和发育(减少运动活动)产生了负面影响。随后的生存、行为和生殖能力未受影响。在大鼠生育研究中,在高达500毫克/千克/日的剂量下,3只雄性大鼠经Simeprevir治疗(24只大鼠中有2只在50毫克/千克/日,1只在500毫克/千克/日)未出现活动精子,睾丸和附睾小,导致其中2只雄性大鼠不育,暴露量大约是人类平均AUC的0.2倍。在包括Ames试验、小鼠淋巴瘤细胞的哺乳动物正向突变试验或体内哺乳动物微核试验在内的一系列体外和体内试验中,Simeprevir 未表现出遗传毒性。
IDENTIFICATION AND USE: Simeprevir is a white to almost white powder. Simeprevir is used in conjunction with peginterferon alfa and ribavirin for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in adults with compensated liver disease (including cirrhosis) who are treatment-naive (previously untreated) or in whom prior treatment with interferon and ribavirin failed (including those with prior null response, prior partial response, or prior relapse). Simeprevir must be used in conjunction with peginterferon alfa (peginterferon alfa-2a or peginterferon alfa-2b) and ribavirin and should not be used alone for the treatment of chronic HCV infection. HUMAN EXPOSURE AND TOXICITY: Very few data are available on the effects of overdose to simeprevir. Simeprevir was generally well tolerated when given as single doses up to 600 mg or once daily doses up to 400 mg for 5 days in healthy adult subjects, and as 200 mg once daily for 4 weeks in adult patients with HCV. ANIMAL STUDIES: Simeprevir was well tolerated after single doses up to 500 mg/kg in mice, 1000 mg/kg in rats, 160 mg/kg in dogs and 300 mg/kg in monkeys. There were no adverse effects of simeprevir on vital functions (cardiac, respiratory and central nervous system) in animal studies. Repeat dose oral toxicity studies with simeprevir were conducted in mice (up to 3 months), rats (up to 6 months), dogs (up to 9 months), and monkeys (up to 28 days). Gastrointestinal effects were observed in all species. A higher incidence of soft, mucoid or pale feces was seen in mice, rats and/or dogs. The presence of swelling/vacuolization of apical enterocytes in the duodenum and jejunum was noted in mice, rats and dogs. The compound formulation caused abnormal stomach contents and/or abdominal distention, in mice and rats, as a result of delayed gastric emptying. Liver effects were observed in mice, rats and dogs. These findings were often accompanied by increases in bilirubin, and liver enzymes in plasma. In a mouse embryofetal study at doses up to 1000 mg/kg, simeprevir resulted in early and late in utero fetal losses and early maternal deaths at an exposure approximately 6 times higher than the mean AUC in humans at the recommended 150 mg daily dose. Significantly decreased fetal weights and an increase in fetal skeletal variations were seen at exposures approximately 4 times higher than the mean AUC in humans at the recommended daily dose. In a rat pre- and postnatal study, maternal animals were exposed to simeprevir during gestation and lactation at doses up to 1000 mg/kg/day. In pregnant rats, simeprevir resulted in early deaths at 1000 mg/kg/day corresponding to exposures similar to the mean AUC in humans at the recommended 150 mg once daily dose. Significant reduction in body weight gain was seen at an exposure 0.7 times the mean AUC in humans at the recommended 150 mg once daily dose. The developing rat offspring exhibited significantly decreased body weight and negative effects on physical growth (delay and small size) and development (decreased motor activity) following simeprevir exposure in utero (via maternal dosing) and during lactation (via maternal milk to nursing pups) at a maternal exposure similar to the mean AUC in humans at the recommended 150 mg once daily dose. Subsequent survival, behavior and reproductive capacity were not affected. In a rat fertility study at doses up to 500 mg/kg/day, 3 male rats treated with simeprevir (2/24 rats at 50 mg/kg/day and 1/24 rats at 500 mg/kg/day) showed no motile sperm, small testes and epididymides, and resulted in infertility in 2 out of 3 of the male rats at approximately 0.2 times the mean AUC in humans. Simeprevir was not genotoxic in a series of in vitro and in vivo tests including the Ames test, the mammalian forward mutation assay in mouse lymphoma cells or the in vivo mammalian micronucleus test.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 肝毒性
在大规模随机对照试验中,simeprevir并未与治疗期间血清酶水平升高或临床明显的肝损伤的病例增多有关联。Simeprevir会导致血清间接胆红素轻微升高,一些患者出现了明显的黄疸,但胆红素升高通常是轻微的、短暂的,并未与血清转氨酶或碱性磷酸酶水平的变化相关。然而,在获得批准并更广泛使用后,simeprevir至少与一例急性肝炎(案例1)有关。发病潜伏期为7周,损伤模式为肝细胞型,没有免疫过敏或自身免疫特征。停止治疗后,恢复迅速而完全。 此外,simeprevir与其他药物联合使用时,还与急性、看似自发的丙型肝炎相关肝硬化失代偿病例有关。simeprevir相对于其他联合使用的丙型肝炎抗病毒药物的角色常常不清楚。在使用聚乙二醇干扰素和利巴韦林联合治疗丙型肝炎肝硬化时,simeprevir联合治疗期间肝失代偿的比率大约为2%至3%,而与索非布韦联合使用时为0.5%至1.0%。由于存在失代偿的风险,接受抗病毒方案治疗(包括全口服和干扰素基础方案)的肝硬化患者应在治疗的前4周特别监测肝脏疾病恶化的迹象。这种并发症在肝疾病更严重的患者、Child B级肝硬化和有肝失代偿既往史的患者中可能更常见。 损伤机制的几率评分:D(可能是易感个体临床明显肝损伤的罕见原因)。 损伤机制 simeprevir可能引起肝损伤的机制尚不清楚。它主要通过肝脏的细胞色素P450系统代谢,主要是CYP 3A,并且是药物转运蛋白P-糖蛋白和OATP1Ba/3以及外排转运蛋白MDR1、MRP2和BSEP的抑制剂,这可能是部分患者出现间接高胆红素血症的原因。Simeprevir与药物相互作用有关,并且可能提高某些他汀类药物的水平。simeprevir联合治疗时发生的失代偿可能是药物的直接作用,或者是快速根除丙型肝炎感染的常见并发症。最后,失代偿的发作可能只是偶然的,与抗病毒治疗无关。
In large randomized controlled trials, simeprevir was not linked to an increased rate of serum enzyme elevations during treatment or with instances of clinically apparent liver injury. Simeprevir causes a mild increase in serum indirect bilirubin and some patients became visibly jaundiced, but the bilirubin elevations were generally mild, transient and not associated with changes in serum aminotransferase or alkaline phosphatase levels. After its approval and more wide scale use, however, simeprevir has been implicated in at least one case of an acute hepatitis (Case 1). The latency to onset was 7 weeks and pattern of injury was hepatocellular without immunoallergic or autoimmune features. Recovery was rapid and complete once therapy was stopped. In addition, simeprevir, in combination with other agents, has been linked to instances of acute, seemingly spontaneous decompensation of HCV related cirrhosis. The role of simeprevir as opposed to the other HCV antivirals used in combination was often unclear. Rates of hepatic decompensation during simeprevir combination therapy of cirrhosis due to hepatitis C was approximately 2% to 3% when combined with peginterferon and ribavirin, and 0.5% to 1.0% when used with sofosbuvir. Because of the risk of decompensation, patients with cirrhosis who are treated with antiviral regimens (both all-oral and interferon based) should be monitored for evidence of worsening liver disease, particularly during the first 4 weeks of treatment. This complication is probably more common in patients with more advanced liver disease, Child’s Class B cirrhosis and those with a previous history of liver decompensation. Likelihood score: D (possible rare cause of clinically apparent liver injury in susceptible individuals). Mechanism of Injury The mechanism by which simeprevir might cause liver injury is not known. It is metabolized in the liver largely via the cytochrome P450 system, predominantly CYP 3A and it is an inhibitor of the drug transporters P-glycoprotein and OATP1Ba/3 and the efflux transporters MDR1, MRP2 and BSEP, perhaps accounting for the indirect hyperbilirubinemia that occurs in some patients. Simeprevir is associated with drug-drug interactions and it can raise levels of some statins. The decompensation that occurs with simeprevir combination therapy may be due to a direct effect of the agent, or else represent a usual complication of the rapid eradication of HCV infection. Finally, the episodes of decompensation may be incidental and unrelated to the antiviral therapy.
来源:LiverTox
毒理性
  • 相互作用
体外实验中,西美瑞韦是P-糖蛋白(P-gp)的底物和抑制剂。同时使用西美瑞韦和P-gp底物的药物可能会导致这些药物浓度增加。
In vitro, simeprevir is a substrate and inhibitor of P-glycoprotein (P-gp) transport. Concomitant use of simeprevir with drugs that are P-gp substrates may result in increased concentrations of such drugs.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 相互作用
与环孢素的药代动力学相互作用(增加环孢素浓度)。与西美瑞韦同时使用时,不需要调整环孢素的剂量;建议常规监测环孢素浓度。
Pharmacokinetic interaction with cyclosporine (increased cyclosporine concentrations). Cyclosporine dosage adjustments are not needed when used concomitantly with simeprevir; routine monitoring of cyclosporine concentrations is recommended.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 相互作用
辛伐他汀(单次剂量40毫克)与西美瑞韦(每日一次150毫克,连续使用10天)同时使用,由于西美瑞韦抑制了OATP1B1和/或CYP3A4,导致辛伐他汀的AUC(药时曲线下面积)增加了1.5倍。如果辛伐他汀与西美瑞韦同时使用,应谨慎调整辛伐他汀的剂量,并使用最低必需剂量的辛伐他汀;应对患者进行安全性监测。
Concomitant use of simvastatin (single 40-mg dose) and simeprevir (150 mg once daily for 10 days) resulted in a 1.5-fold increase in simvastatin AUC due to inhibition of OATP1B1 and/or CYP3A4 by simeprevir. If simvastatin is used concomitantly with simeprevir, dosage of simvastatin should be titrated carefully and the lowest necessary dosage of simvastatin used; the patient should be monitored for safety.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
西美普韦被血浆蛋白广泛结合(大于99.9%),主要与白蛋白结合,其次是与α1-酸性糖蛋白结合。在肾或肝功能损害的患者中,血浆蛋白结合并不会显著改变。
Simeprevir is extensively bound to plasma proteins (greater than 99.9%), primarily to albumin and, to a lesser extent, alfa 1-acid glycoprotein. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
使用食物给予健康受试者西美普韦,分别在高脂肪、高热量(928千卡)和正常热量(533千卡)的早餐后,相对生物利用度(AUC)分别增加了61%和69%,吸收分别延迟了1小时和1.5小时。由于生物利用度增加,Olysio应在食物伴随下服用。食物的类型不影响西美普韦的暴露。
Administration of simeprevir with food to healthy subjects increased the relative bioavailability (AUC) by 61% and 69% after a high-fat, high-caloric (928 kcal) and normal-caloric (533 kcal) breakfast, respectively, and delayed the absorption by 1 hour and 1.5 hours, respectively. Due to increased bioavailability, Olysio should be administered with food. The type of food does not affect exposure to simeprevir.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
消除西美普韦的方式是通过胆汁排泄。肾脏清除在其消除过程中不起重要作用。在健康受试者单次口服200毫克(14)C-西美普韦后,平均有91%的总放射性在粪便中回收。少于1%的给药剂量在尿液中回收。粪便中未改变的西美普韦平均占给药剂量的31%。
Elimination of simeprevir occurs via biliary excretion. Renal clearance plays an insignificant role in its elimination. Following a single oral administration of 200 mg (14)C-simeprevir to healthy subjects, on average 91% of the total radioactivity was recovered in feces. Less than 1% of the administered dose was recovered in urine. Unchanged simeprevir in feces accounted for on average 31% of the administered dose.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
在动物中,西美瑞韦在肠道和肝脏(在大鼠中肝脏:血液的比例为29:1)组织中广泛分布。体外数据和基于生理的药代动力学建模与模拟表明,人类肝脏摄取由OATP1B1/3介导。
In animals, simeprevir is extensively distributed to gut and liver (liver:blood ratio of 29:1 in rat) tissues. In vitro data and physiologically-based pharmacokinetic modeling and simulations indicate that hepatic uptake in humans is mediated by OATP1B1/3.
来源:Hazardous Substances Data Bank (HSDB)

安全信息

  • 危险性防范说明:
    P280,P305+P351+P338
  • 危险性描述:
    H302

SDS

SDS:5ad1f2fc8d50c910b219702b6b4a7dc6
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制备方法与用途

生物活性

Simeprevir(TMC-435, TMC-435350)是一种竞争性、可逆的、非共价结合的大环HCV NS3/4A蛋白酶抑制剂,直接抑制HCV病毒。它对genotypes 1a、1b、2、4、5和6的HCV NS3/4A的平均IC50值小于13 nM,而对genotype 3的IC50值为37 nM。

靶点
Target Value
HCV NS3/4A protease ()

反应信息

  • 作为反应物:
    描述:
    18-[2-(4-Isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-2,15-dioxo-3,14-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 、 环丙磺酰胺N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide 生成 N-[18-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yl-oxy]-2,15-dioxo-3,14-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carbonyl] (cyclopropyl)sulfonamide
    参考文献:
    名称:
    Macrocyclic inhibitors of hepatitis C virus
    摘要:
    公式(I)的HCV复制抑制剂,以及N-氧化物,盐和立体异构体,其中每个虚线代表一个可选的双键; X为N,CH,其中X带有双键时为C; R1为—OR7,—NH—SO2R8; R2为氢,且当X为C或CH时,R2也可以是C1-6烷基; R3为氢,C1-6烷基,C1-6烷氧基C1-6烷基,C3-7环烷基; R4为芳基或杂环基; n为3、4、5或6; R5为卤素,C1-6烷基,羟基,C1-6烷氧基,苯基或杂环基; R6为C1-6烷氧基或二甲基氨基; R7为氢; 芳基; 杂环基; C3-7环烷基,可选地用C1-6烷基取代; 或C1-6烷基,可选地用C3-7环烷基,芳基或杂环基取代; R8为芳基; 杂环基; C3-7环烷基,可选地用C1-6烷基取代; 或C1-6烷基,可选地用C3-7环烷基,芳基或杂环基取代; 芳基为苯基,可选地用一个、两个或三个取代基取代;杂环基为含有1至4个氮、氧和硫杂原子的5或6成员饱和、部分不饱和或完全不饱和的杂环环,可选地用一个、两个或三个取代基取代; 包含化合物(I)的制药组合物和制备化合物(I)的过程也提供。还提供了公式(I)的HCV抑制剂与利托那韦的生物利用度组合。
    公开号:
    US08741926B2
  • 作为产物:
    描述:
    17-[2-(4-Isopropylthiazole-2-yl)-7-methoxy-8-methyl quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid 、 N,N'-羰基二咪唑环丙磺酰胺1,8-二氮杂双环[5.4.0]十一碳-7-烯氮气二氯甲烷盐酸 、 Brine 、 magnesium sulfate乙酸乙酯 作用下, 以 四氢呋喃 为溶剂, 反应 17.0h, 以afforded 314 mg of an off-white solid which的产率得到N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide
    参考文献:
    名称:
    Macrocyclic inhibitors of hepatitis C virus
    摘要:
    HCV复制抑制剂的化学式(I),其N-氧化物、盐和立体异构体,其中每个虚线代表一个可选的双键;X为N,CH,其中X带有双键时为C;R1为—OR7或—NH—SO2R8;R2为氢,当X为C或CH时,R2也可以是C1-6烷基;R3为氢,C1-6烷基,C1-6烷氧基C1-6烷基或C3-7环烷基;R4为芳基或杂环基;n为3、4、5或6;R5为卤素、C1-6烷基、羟基、C1-6烷氧基、苯基或杂环基;R6为C1-6烷氧基或二甲氨基;R7为氢、芳基、杂环基、C3-7环烷基,可选地用C1-6烷基取代;或C1-6烷基,可选地用C3-7环烷基、芳基或杂环基取代;R8为芳基、杂环基、C3-7环烷基,可选地用C1-6烷基取代;或C1-6烷基,可选地用C3-7环烷基、芳基或杂环基取代;芳基为苯基,可选地用一个、两个或三个取代基取代;杂环基为含有1至4个氮、氧和硫杂原子的5或6成员饱和、部分不饱和或完全不饱和的杂环环,可选地用一个、两个或三个取代基取代;含有化合物(I)的药物组合物和制备化合物(I)的方法。还提供了与利托那韦的HCV抑制剂的生物利用度组合。
    公开号:
    US08153800B2
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文献信息

  • POLYMORPHIC FORMS OF A MACROCYCLIC INHIBITOR OF HCV
    申请人:Stokbroekx Sigrid Carl Maria
    公开号:US20100029715A1
    公开(公告)日:2010-02-04
    Provided are crystalline forms of the compound of formula (I), which is a macrocyclic inhibitor of HCV, processes for the preparation thereof, and pharmaceutical compositions comprising these crystalline forms.
    提供了公式(I)化合物的晶体形式,该化合物是HCV的大环抑制剂,其制备过程以及包含这些晶体形式的制药组合物。
  • Macrocyclic inhibitors of hepatitis c virus
    申请人:Simmen Kenneth Alan
    公开号:US20090281140A1
    公开(公告)日:2009-11-12
    Inhibitors of HCV replication of formula (I) and the N-oxides, salts, and stereoisomers, wherein each dashed line represents an optional double bond; X is N, CH and where X bears a double bond it is C; R 1 is —OR 7 , —NH—SO 2 R 8 ; R 2 is hydrogen, and where X is C or CH, R 2 may also be C 1-6 alkyl; R 3 is hydrogen, C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, C 3-7 cycloalkyl; R 4 is aryl or Het; n is 3, 4, 5, or 6; R 5 is halo, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, phenyl, or Het; R 6 is C 1-6 alkoxy, or dimethylamino; R 7 is hydrogen; aryl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or with Het; R 8 is aryl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or with Het; aryl is phenyl optionally substituted with one, two or three substituents; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.
    公式(I)及其N-氧化物,盐和立体异构体的HCV复制抑制剂,其中每个虚线表示一个可选的双键; X是N,CH,其中X带有双键时是C; R1是-OR7,-NH-SO2R8; R2是氢,当X为C或CH时,R2也可以是C1-6烷基; R3是氢,C1-6烷基,C1-6烷氧基C1-6烷基,C3-7环烷基; R4是芳基或杂环基; n为3、4、5或6; R5是卤素,C1-6烷基,羟基,C1-6烷氧基,苯基或杂环基; R6是C1-6烷氧基或二甲基氨基; R7是氢; 芳基; 杂环基; C3-7环烷基,可选地用C1-6烷基取代; 或C1-6烷基,可选地用C3-7环烷基,芳基或杂环基取代; R8是芳基; 杂环基; C3-7环烷基,可选地用C1-6烷基取代; 或C1-6烷基,可选地用C3-7环烷基,芳基或杂环基取代; 芳基是苯基,可选地用一个、两个或三个取代基取代; 杂环基是一个含有1-4个氮、氧和硫杂原子的5或6元饱和、部分不饱和或完全不饱和的杂环环,可选地用一个、两个或三个取代基取代; 包含化合物(I)的药物组合物和制备化合物(I)的过程也提供。还提供了公式(I)的HCV抑制剂与利托那韦的生物利用度组合。
  • Macrocyclic Inhibitors Of Hepatitis C Virus
    申请人:Simmen Kenneth Alan
    公开号:US20110295012A1
    公开(公告)日:2011-12-01
    Inhibitors of HCV replication of formula (I) and the N-oxides, salts, and stereoisomers, wherein each dashed line represents an optional double bond; X is N, CH and where X bears a double bond it is C; R 1 is —OR 7 or —NH—SO 2 R 8 ; R 2 is hydrogen, and where X is C or CH, R 2 may also be C 1-6 alkyl; R 3 is hydrogen, C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, or C 3-7 cycloalkyl; R 4 is aryl or Het; n is 3, 4, 5, or 6; R 5 is halo, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, phenyl, or Het; R 6 is C 1-6 alkoxy or dimethylamino; R 7 is hydrogen; aryl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or with Het; R 8 is aryl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or with Het; aryl is phenyl optionally substituted with one, two or three substituents; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.
    公式(I)的HCV复制抑制剂及其N-氧化物,盐和立体异构体,其中每个虚线表示可选的双键;X为N,CH,其中X带有双键时为C;R1为—OR7或—NH—SO2R8;R2为氢,其中X为C或CH时,R2也可以是C1-6烷基;R3为氢,C1-6烷基,C1-6烷氧基C1-6烷基或C3-7环烷基;R4为芳基或杂环基;n为3、4、5或6;R5为卤素,C1-6烷基,羟基,C1-6烷氧基,苯基或杂环基;R6为C1-6烷氧基或二甲基氨基;R7为氢,芳基,杂环基,C3-7环烷基,可选地用C1-6烷基取代;或C1-6烷基,可选地用C3-7环烷基,芳基或杂环基取代;R8为芳基,杂环基,C3-7环烷基,可选地用C1-6烷基取代;或C1-6烷基,可选地用C3-7环烷基,芳基或杂环基取代;芳基为苯基,可选地用一个、两个或三个取代基取代;杂环基为含有1到4个氮、氧和硫杂原子的5或6成员饱和、部分不饱和或完全不饱和的杂环环,可选地用一个、两个或三个取代基取代;包含化合物(I)的药物组合物和制备化合物(I)的方法。还提供了公式(I)的HCV抑制剂与利托那韦的生物利用度组合。
  • Polymorphic forms of a macrocyclic inhibitor of HCV
    申请人:Tibotec Pharmaceuticals Ltd.
    公开号:US08143402B2
    公开(公告)日:2012-03-27
    Provided are crystalline forms of the compound of formula (I), which is a macrocyclic inhibitor of HCV, processes for the preparation thereof, and pharmaceutical compositions comprising these crystalline forms.
    提供了化合物(I)的晶体形式,该化合物是HCV的大环抑制剂,其制备过程以及包含这些晶体形式的药物组合物。
  • Macrocylic inhibitors of hepatitis C virus
    申请人:Tibotec Pharmaceuticals Ltd.
    公开号:US08349869B2
    公开(公告)日:2013-01-08
    Inhibitors of HCV replication of formula (I) and the N-oxides, salts, and stereoisomers, wherein each dashed line represents an optional double bond; X is N, CH and where X bears a double bond it is C; R1 is —OR7, —NH—SO2R8; R2 is hydrogen, and where X is C or CH, R2 may also be C1-6alkyl; R3 is hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl, C3-7cycloalkyl; R4 is aryl or Het; n is 3, 4, 5, or 6; R5 is halo, C1-6alkyl, hydroxy, C1-6alkoxy, phenyl, or Het; R6 is C1-6alkoxy, or dimethylamino; R7 is hydrogen; aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; R8 is aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; aryl is phenyl optionally substituted with one, two or three substituents; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.
    公式(I)及其N-氧化物,盐和立体异构体的HCV复制抑制剂,其中每个虚线表示可选的双键; X为N,CH,其中X带有双键时为C; R1为—OR7,—NH—SO2R8; R2为氢,其中X为C或CH时,R2也可以是C1-6烷基; R3为氢,C1-6烷基,C1-6烷氧基C1-6烷基,C3-7环烷基; R4为芳基或杂环基; n为3、4、5或6; R5为卤素,C1-6烷基,羟基,C1-6烷氧基,苯基或杂环基; R6为C1-6烷氧基或二甲氨基; R7为氢,芳基,杂环基,C3-7环烷基,可选地被C1-6烷基取代; 或C1-6烷基,可选地被C3-7环烷基,芳基或杂环基取代; R8为芳基,杂环基,C3-7环烷基,可选地被C1-6烷基取代; 或C1-6烷基,可选地被C3-7环烷基,芳基或杂环基取代; 芳基为苯基,可选地被一、二或三个取代基取代; 杂环基是一个5或6成员的饱和,部分不饱和或完全不饱和的杂环环,其中包含1到4个从氮,氧和硫中选择的杂原子,并可选地被一个,两个或三个取代基取代; 包含化合物(I)的制药组合物和制备化合物(I)的过程。还提供了公式(I)的HCV抑制剂与利托那韦的生物利用度组合。
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