(3S,5S,6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid | 174956-43-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: (3S,5S,6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid
• 英文别名: (E,3S,5S)-7-[3-(4-fluorophenyl)-1-propan-2-ylindol-2-yl]-3,5-dihydroxyhept-6-enoic acid
• CAS: 174956-43-5
• 化学式: C₂₄H₂₆FNO₄
• 分子量: 411.5
• InChiKey: FJLGEFLZQAZZCD-VVZAMHAXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  82.7
• 氢给体数：
  3
• 氢受体数：
  5

ADMET

代谢

体外数据表明，氟伐他汀的代谢涉及多种细胞色素P450（CYP）同工酶。CYP2C9同工酶主要参与氟伐他汀的代谢（约75%），而CYP2C8和CYP3A4同工酶的参与程度要低得多，即分别大约为5%和大约20%。

In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P450 (CYP) isozymes. CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin (approximately 75%), while CYP2C8 and CYP3A4 isoenzymes are involved to a much less extent, i.e., approximately 5% and approximately 20%, respectively.

来源:Hazardous Substances Data Bank (HSDB)

代谢

氟伐他汀在肝脏中被代谢，主要是通过吲哚环在5和6位置的羟基化。N-脱烷基化和侧链的β-氧化也发生。羟基代谢物具有一些药理活性，但不会在血液中循环。氟伐他汀有两种对映异构体。氟伐他汀的两种对映异构体以类似的方式被代谢。

Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5 and 6 positions. N-dealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood. Fluvastatin has two enantiomers. Both enantiomers of fluvastatin are metabolized in a similar manner.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：氟伐他汀是一种抗胆固醇药物和羟甲戊二酸辅酶A还原酶抑制剂。人类暴露和毒性：已经报道了使用氟伐他汀胶囊和这类药物中的其他药物导致的横纹肌溶解伴急性肾功能衰竭。在使用他汀类药物，包括氟伐他汀的患者中，有罕见报告肝衰竭致死的病例。如果在使用氟伐他汀治疗期间出现严重的肝损伤、临床症状和/或高胆红素血症或黄疸，应立即中断治疗。氟伐他汀胶囊禁用于可能怀孕的妇女。在正常怀孕期间，血清胆固醇和甘油三酯会增加，胆固醇或胆固醇衍生物对胎儿发育至关重要。给孕妇使用氟伐他汀胶囊可能会对胎儿造成伤害。药物不良反应报告显示，与使用他汀类药物有关的精神神经反应的发生，包括行为改变；认知和记忆障碍；睡眠障碍；和性功能障碍。动物研究：在小鼠中以0.3、15和30 mg/kg/天的剂量进行的致癌性研究中发现，在30 mg/kg/天的雄性和雌性小鼠以及15 mg/kg/天的雌性小鼠中，食道鳞状细胞乳头状瘤的数量有统计学意义的增加。在大鼠中以12 mg/kg/天的剂量，在兔中以10 mg/kg/天的剂量，氟伐他汀会延迟骨骼发育。在以下研究中，无论有无代谢活化，均未观察到突变性：使用突变株的沙门氏菌或大肠杆菌的微生物突变试验；BALB/3T3细胞的恶性转化试验；大鼠原代肝细胞的非计划性DNA合成；V79中国仓鼠细胞的染色体畸变；HGPRT V79中国仓鼠细胞。此外，在大鼠或小鼠微核试验中也未观察到突变性。

IDENTIFICATION AND USE: Fluvastatin is anticholesteremic agent and hydroxymethylglutaryl-CoA reductase inhibitor. HUMAN EXPOSURE AND TOXICITY: Rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with fluvastatin capsules and other drugs in this class. There have been rare reports of fatal and non-fatal hepatic failure in patients taking statins, including fluvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with fluvastatin, promptly interrupt therapy. Fluvastatin capsules are contraindicated in women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Fluvastatin capsules may cause fetal harm when administered to pregnant women. Adverse drug reaction reports have demonstrated the occurrence of neuropsychiatric reactions associated with statin treatment. They include behavioral alterations; cognitive and memory impairments; sleep disturbance; and sexual dysfunction. ANIMAL STUDIES: The carcinogenicity study conducted in mice at dose levels of 0.3, 15 and 30 mg/kg/day revealed, as in rats, a statistically significant increase in forestomach squamous cell papillomas in males and females at 30 mg/kg/day and in females at 15 mg/kg/day. Fluvastatin produced delays in skeletal development in rats at doses of 12 mg/kg/day and in rabbits at doses of 10 mg/kg/day. No evidence of mutagenicity was observed in vitro, with or without metabolic activation, in the following studies: microbial mutagen tests using mutant strains of Salmonella typhimurium or Escherichia coli; malignant transformation assay in BALB/3T3 cells; unscheduled DNA synthesis in rat primary hepatocytes; chromosomal aberrations in V79 Chinese Hamster cells; HGPRT V79 Chinese Hamster cells. In addition, there was no evidence of mutagenicity in vivo in either a rat or mouse micronucleus test.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

氟伐他汀治疗与1%至5%的患者出现轻度、无症状且通常是暂时的血清转氨酶升高有关，但在超过3倍ULN水平的患者中大约为1%。在大规模前瞻性监测研究的汇总分析中，出现正常以上的ALT升高在多达5%的患者中发生；在氟伐他汀治疗的患者中，ALT水平超过正常上限3倍的发生率为1.1%，而安慰剂接受者为0.3%。这些升高在使用较高剂量氟伐他汀时更为常见。大多数这些升高是自限性的，不需要调整剂量。氟伐他汀是与血清转氨酶升高最相关的他汀类药物，也是与症状性肝损伤最高发生率相关的药物，然而，明显的、临床上可见的氟伐他汀引起的肝损伤仍然非常罕见，估计在使用氟伐他汀的每10,000人年中有1.7例发生。在报告的少数病例中，临床损伤的发病时间在1到4个月之内，损伤模式通常是胆汁淤积性或混合型。皮疹、发热和嗜酸性粒细胞增多不常见。至少有一例具有自身免疫特征的情况被描述。大多数病例在发病后几个月内解决。急性肝衰竭和死亡罕见地归因于氟伐他汀。

Fluvastatin therapy is associated with mild, asymptomatic and usually transient serum aminotransferase elevations in 1% to 5% of patients but in levels above 3 times ULN is approximately 1%. In summary analyses of large scale studies with prospective monitoring, ALT elevations above normal occurred in up to 5% of patients; ALT levels of above 3 times the upper limit of normal (ULN) occurred in 1.1% of fluvastatin treated versus 0.3% of placebo recipients. These elevations were more common with higher doses of fluvastatin. Most of these elevations were self-limited and did not require dose modification. Fluvastatin is the statin most commonly associated with serum aminotransferase elevations and the highest rates of symptomatic liver injury, yet frank, clinically apparent hepatic injury from fluvastatin is still quite rare estimated to occur in 1.7 per 10,000 person years of use. In the few cases that have been reported, the onset of clinical injury has been within 1 to 4 months, the pattern of injury is typically cholestatic or mixed. Rash, fever and eosinophilia are uncommon. At least one case with features of autoimmunity has been described. Most cases resolve within a few months of onset. Rare cases of acute liver failure and death have been attributed to fluvastatin.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：目前没有关于在母乳喂养期间使用氟伐他汀的相关已发表信息。由于担心会干扰婴儿的脂质代谢，共识认为在母乳喂养期间不应使用氟伐他汀。然而，也有人认为对于家族性高胆固醇血症的同型纯合子儿童，从1岁开始就使用他汀类药物，他汀类药物的口服生物利用度较低，对哺乳婴儿的风险很低，尤其是罗苏伐他汀和普伐他汀。[1] 在有更多数据可用之前，可能会优先选择其他药物，特别是在哺乳新生儿或早产儿时。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关已发表信息。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关已发表信息。

◉ Summary of Use during Lactation:No relevant published information exists on the use of fluvastatin during breastfeeding. Because of a concern with disruption of infant lipid metabolism, the consensus is that fluvastatin should not be used during breastfeeding. However, others have argued that children homozygous for familial hypercholesterolemia are treated with statins beginning at 1 year of age, that statins have low oral bioavailability, and risks to the breastfed infant are low, especially with rosuvastatin and pravastatin.[1] Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

肌病病例，包括横纹肌溶解症，已经报告了与秋水仙碱联合使用氟伐他汀的情况，在开具氟伐他汀与秋水仙碱联合处方的时应谨慎。

Cases of myopathy, including rhabdomyolysis, have been reported with fluvastatin coadministered with colchicine, and caution should be exercised when prescribing fluvastatin with colchicine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在使用香豆素类抗凝剂的同时服用其他HMG-CoA还原酶抑制剂的患者中，已经报道了出血和/或凝血酶原时间增加的情况。因此，当开始使用氟伐他汀钠或更改氟伐他汀钠剂量时，接受华法林型抗凝剂治疗的患者应密切监测其凝血酶原时间。

Bleeding and/or increased prothrombin times have been reported in patients taking coumarin anticoagulants concomitantly with other HMG-CoA reductase inhibitors. Therefore, patients receiving warfarin-type anticoagulants should have their prothrombin times closely monitored when fluvastatin sodium is initiated or the dosage of fluvastatin sodium is changed.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

基于动物数据，氟伐他汀在母乳中的比例约为2:1（母乳：血浆）。

/MILK/ Based on animal data, fluvastatin is present in breast milk in a 2:1 ratio (milk:plasma).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

服用胶囊后，氟伐他汀在不到1小时内达到峰值浓度。服用10毫克剂量后的绝对生物利用度为24%（范围9%至50%）。

Following oral administration of the capsule, fluvastatin reaches peak concentrations in less than 1 hour. The absolute bioavailability is 24% (range 9% to 50%) after administration of a 10 mg dose.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

氟伐他汀与血浆蛋白的结合率为98%。平均分布容积（VDss）估计为0.35 L/kg。在治疗浓度下，华法林、水杨酸和格列本脲不会影响氟伐他汀的蛋白结合。

Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VDss) is estimated at 0.35 L/kg. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

氟伐他汀以氟伐他汀钠缓释片80毫克的形式给药，在空腹条件下、低脂餐后或低脂餐后2.5小时，大约在3小时内达到峰值浓度。缓释片的平均相对生物利用度大约为29%（范围：9%至66%），与空腹条件下给药的氟伐他汀即释胶囊相比。高脂餐后给药会延迟吸收（Tmax：6小时）并使缓释片的生物利用度提高约50%。然而，高脂餐后氟伐他汀钠缓释片达到的最大浓度低于单次剂量或每日两次40毫克氟伐他汀胶囊后的峰值浓度。

Fluvastatin administered as fluvastatin sodium extended-release 80 mg tablets reaches peak concentration in approximately 3 hours under fasting conditions, after a low fat meal, or 2.5 hours after a low fat meal. The mean relative bioavailability of the extended-release tablet is approximately 29% (range: 9% to 66%) compared to that of the fluvastatin immediate-release capsule administered under fasting conditions. Administration of a high fat meal delayed the absorption (Tmax: 6 hr) and increased the bioavailability of the extended-release tablet by approximately 50%. However, the maximum concentration of fluvastatin sodium extended-release tablets seen after a high fat meal is less than the peak concentration following a single dose or twice daily dose of the 40 mg fluvastatin capsule.

来源:Hazardous Substances Data Bank (HSDB)

文献信息

• Process for the synthesis of N-methyl-N-phenylaminoacrolein
  申请人：Clariant Life Science Molecules (Italia) SpA

  公开号：EP1477474A1

  公开（公告）日：2004-11-17

  A process is disclosed for manufacturing N-methyl-N-phenylaminoacrolein of formula (I) which comprises reacting N-methylformanilide and an alkyl vinyl ether of formula (III) wherein R is a C3-C4 alkyl, said process being characterized in that the reaction between N-methylformanilide and said alkyl vinyl ether of formula (III) is carried out in the presence of phosgene, diphosgene or triphosgene in a solvent selected from dioxane, acetonitrile and/or chlorobenzene.

  公开了一种制备式(I)的N-甲基-N-苯基氨基丙烯醛的方法，该方法包括反应N-甲基甲酰苯胺和式(III)的烷基乙烯醚，其中R为C3-C4烷基，其特征在于在二恶烷、乙腈和/或氯化苯等溶剂中，在光气、二光气或三光气的存在下，进行N-甲基甲酰苯胺和式(III)的烷基乙烯醚之间的反应。
• Separation And Manipulation Of A Chiral Object
  申请人：Kibar Osman

  公开号：US20080262240A1

  公开（公告）日：2008-10-23

  Among other things, to cause directional motion of chiral objects in a mixture in a chamber, a field is rotated relative, to a chamber to cause rotation of the chiral objects. The rotation of the objects causes them to move directionally based on their chirality.

  在混合物室中，为了使手性物体产生定向运动，需要旋转一个场，相对于室内旋转手性物体。物体的旋转会根据它们的手性定向移动。
• Synthesis of N-methyl-N-phenylaminoacrolein
  申请人：Clariant Life Science Molecules (Italia) S.p.A.

  公开号：US20040229958A1

  公开（公告）日：2004-11-18

  A process is disclosed for manufacturing N-methyl-N-phenylaminoacrolein of formula (I) 1 which comprises reacting N-methylformanilide and an alkyl vinyl ether of formula (III) 2 wherein R is a C 3 -C 4 alkyl, said process being characterized in that the reaction between N-methylformanilide and said alkyl vinyl ether of formula (III) is carried out in the presence of phosgene, diphosgene or triphosgene in a solvent selected from dioxane, acetonitrile and/or chlorobenzene.

  本发明公开了一种制备式(I)的N-甲基-N-苯基氨基丙烯醛的方法，其中包括将N-甲基甲酰苯胺和式(III)的烷基乙烯醚反应，其中R是C3-C4烷基。该方法的特点在于，在二恶烷、乙腈和/或氯苯等溶剂中，在光气、双光气或三光气的存在下进行N-甲基甲酰苯胺和式(III)的烷基乙烯醚的反应。
• NEUROGENESIS BY MUSCARINIC RECEPTOR MODULATION
  申请人：Barlow Carrolee

  公开号：US20070049576A1

  公开（公告）日：2007-03-01

  The instant disclosure describes methods for treating diseases and conditions of the central and peripheral nervous system by stimulating or increasing neurogenesis. The disclosure includes compositions and methods based on muscarinic receptor modulation, such as via inhibition of acetylcholine esterase (AChE) activity, alone or in combination with another neurogenic agent to stimulate or activate the formation of new nerve cells.

  该即时披露描述了通过刺激或增加神经发生来治疗中枢神经系统和外周神经系统的疾病和病症的方法。该披露包括基于毒蕈碱受体调节的组合物和方法，例如通过抑制乙酰胆碱酯酶（AChE）活性，单独或与另一种神经生成剂结合以刺激或激活新神经细胞的形成。
• Use of cyclooxygenase inhibitors and antimuscarinic agents for the treatment of incontinence
  申请人：Pharmacia Corporation

  公开号：EP1915992A1

  公开（公告）日：2008-04-30

  The present invention provides a method for the use of a cyclooxygenase-2 inhibitor in combination with an anti-muscarinic agent, for the treatment or prophylaxis of interstitial cystitis in a subject in need of such treatment or prevention, comprising administering to the subject an effective amount of the cyclooxygenase-2 inhibitor and the anti-muscarinic agent.

  本发明提供了一种将环氧化酶-2 抑制剂与抗毒蕈碱类药物结合使用的方法，用于治疗或预防需要治疗或预防的受试者的间质性膀胱炎，包括向受试者施用有效量的环氧化酶-2 抑制剂和抗毒蕈碱类药物。