(3R,5S)-氟伐他汀钠盐 | 94061-80-0

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 中文名称: (3R,5S)-氟伐他汀钠盐
• 英文名称: fluvastatin sodium
• 英文别名: fluvastatin sodium salt；(3R,5S)-Fluvastatin Sodium Salt；sodium;(E,3R,5S)-7-[3-(4-fluorophenyl)-1-propan-2-ylindol-2-yl]-3,5-dihydroxyhept-6-enoate
• CAS: 94061-80-0
• 化学式: C₂₄H₂₅FNO₄*Na
• 分子量: 433.455
• InChiKey: ZGGHKIMDNBDHJB-NRFPMOEYSA-M

物化性质

• 熔点：
  >150°C (dec.)
• 溶解度：
  溶于DMSO、甲醇、水
• 蒸汽压力：
  1.91X10-16 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions. /Fluvastatin sodium hydrate/
• 分解：
  Hazardous decomposition products formed under fire conditions - Carbon oxides, nitrogen oxides (NOx), hydrogen fluoride, sodium oxides. /Fluvastatin sodium hydrate/
• 解离常数：
  pKa = 4.5 (carboxy) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  31
• 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：
  85.5
• 氢给体数：
  2
• 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同工酶的参与程度则要低得多，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-氧化也会发生。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相似的方式被代谢。

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

• 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。氟伐他汀是最常与血清转氨酶升高和症状性肝损伤最高发生率相关的他汀类药物，然而，氟伐他汀引起的明显、临床上可见的肝损伤仍然相当罕见，估计在使用10,000人年中有1.7例发生。在报告的少数病例中，临床损伤的发作通常在1到4个月内，损伤模式通常是胆汁淤积性或混合性。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。

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.

来源:LiverTox

毒理性

• 相互作用

肌肉病，包括横纹肌溶解症，在使用氟伐他汀与秋水仙碱联合治疗时已有报道，因此在开具氟伐他汀与秋水仙碱联合处方时应谨慎。

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

服用香豆素类抗凝剂的同时使用其他HMG-CoA还原酶抑制剂的患者中，已经报告了出血和/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)

毒理性

• 相互作用

非诺伐他汀与苯妥英钠联合使用增加了苯妥英钠的暴露量。当开始非诺伐他汀治疗或更改非诺伐他汀剂量时，患者应继续适当监测。

Concomitant administration of fluvastatin and phenytoin increased phenytoin exposures. Patients should continue to be monitored appropriately when fluvastatin therapy is initiated or when fluvastatin dose is changed.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

非诺贝特和格列本脲的联合用药增加了格列本脲的暴露。正在联合使用格列本脲和非诺贝特的病人应继续适当监测。

Concomitant administration of fluvastatin and glyburide increased glyburide exposures. Patients on concomitant therapy of glyburide and fluvastatin should continue to be monitored appropriately.

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

非诺伐他汀缓释片 80 毫克在空腹条件下、低脂餐后或低脂餐后 2.5 小时达到峰值浓度大约需要 3 小时。与空腹条件下给药的非诺伐他汀即释胶囊相比，缓释片的平均相对生物利用度大约为 29%（范围：9% 至 66%）。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，高脂餐后非诺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剂量的 40 毫克非诺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)

制备方法与用途

(3R,5S)-Fluvastatin ((3R,5S)-XU 62-320) 硫酸盐是 Fluvastatin 的 3R,5S 异构体。Fluvastatin (XU 62-320 自由酸) 是第一个完全合成的、竞争性 HMG-CoA 还原酶抑制剂，其 IC50 值为 8 nM。Fluvastatin 能通过依赖 Nrf2 的抗氧化途径保护血管平滑肌细胞免受氧化应激的影响。

反应信息

• 作为反应物：
  描述：

  (3R,5S)-氟伐他汀钠盐 在 sodium hydrogen sulfate 作用下， 以 水 、 乙酸乙酯 为溶剂， 生成 fluvastatin
  参考文献：
  名称：

  Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase

  摘要：

  本发明提供了物质组合物、试剂盒和它们在治疗MAP激酶相关疾病和/或HMG-CoA还原酶相关疾病中的应用的方法。具体而言，本发明提供了用于通过抑制p38α MAP激酶和/或HMG-CoA还原酶来治疗动物主体的炎症和/或心血管疾病的组合物，以及提供这些组合物的配方和给药方式。本发明还提供了用于有理设计MAP激酶、HMG-CoA还原酶或两者的抑制剂的方法，用于实施本发明。

  公开号：

  US20050261354A1
• 作为产物：
  描述：

  (E)-3-[3-(4-氟苯基)-1-异丙基吲哚-2-基]丙烯醛 在 sodium hydroxide 、 sodium tetrahydroborate 、 二乙基甲氧基硼烷 、 双氧水 、 碳酸氢钠 作用下， 以 乙醇 为溶剂， 反应 18.08h， 生成 (3R,5S)-氟伐他汀钠盐
  参考文献：
  名称：

  Asymmetric synthesis of 3,5-dihydroxy-6(E)-heptenoate-containing HMG-CoA reductase inhibitors

  摘要：

  DOI：

  10.1016/s0040-4020(97)00686-8
• 作为试剂：
  描述：

  (+/-)7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl)-3,5-dihydroxy heptenoic acid monosodium salt 在 异丙醇 、 (3R,5S)-氟伐他汀钠盐 、 乙醇 作用下， 以 乙醇 为溶剂， 反应 4.0h， 以Thus 1.4 g of anhydrous amorphous fluvastatin sodium salt is obtained (yield 70%)的产率得到(3R,5S)-氟伐他汀钠盐
  参考文献：
  名称：

  Anhydrous amorphous form of fluvastatin sodium

  摘要：

  本发明涉及一种新型的无水非晶态形式的双[(E)[4-(4-氟苯基)异丙基[甲基（甲磺酰基）氨基]嘧啶基](3R,5S)-3,5-二羟基庚烯酸]钙盐（罗伐司汀钙盐）、(±)7-(3-(4-氟苯基)-1-(1-甲基乙基)-1H-吲哚-2-基)3,5-二羟基庚烯酸单钠盐（氟伐他汀钠盐）和双[(E)-3,5-二羟基-7-[4′-(4″-氟苯基)-2′-环丙基-喹啉-3′-庚-6-烯酸]钙盐（匹伐他汀钙盐）的制备方法，含有它们的药物组合物以及使用它们的治疗方法。所得到的罗伐司汀钙盐、匹伐他汀钙盐和氟伐他汀钠盐是已知的有价值的药物，可用于治疗高脂血症和高胆固醇血症。

  公开号：

  US07241800B2

文献信息

• [EN] CATHEPSIN CYSTEINE PROTEASE INHIBITORS<br/>[FR] INHIBITEURS DE PROTÉASES À CYSTÉINE DE TYPE CATHEPSINES
  申请人：MERCK SHARP & DOHME

  公开号：WO2015054038A1

  公开（公告）日：2015-04-16

  This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.

  这项发明涉及一类新型化合物，它们是半胱氨酸蛋白酶抑制剂，包括但不限于对卡特普辛K、L、S和B的抑制剂。这些化合物可用于治疗需要抑制骨吸收的疾病，如骨质疏松症。
• Dibenzyl Amine Compounds and Derivatives
  申请人：Chang George

  公开号：US20070213371A1

  公开（公告）日：2007-09-13

  Dibenzyl amine compounds and derivatives, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including humans.

  二苯基胺化合物及其衍生物，含有这种化合物的药物组合物以及使用这种化合物提高某些血浆脂质水平，包括高密度脂蛋白胆固醇，并降低其他一些血浆脂质水平，如低密度脂蛋白胆固醇和甘油三酯，并据此治疗由高密度脂蛋白胆固醇水平低和/或低密度脂蛋白胆固醇和甘油三酯水平高加重的疾病，如动脉粥样硬化和心血管疾病在某些哺乳动物，包括人类。
• [EN] FTO INHIBITORS<br/>[FR] INHIBITEURS DE FTO
  申请人：NAT INST OF BIOLOGICAL SCIENCES BEIJING

  公开号：WO2016206573A1

  公开（公告）日：2016-12-29

  The invention provides compounds that inhibit FTO (fat mass and obesity), including pharmaceutically acceptable salts, hydrides and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof, particularly obesity, with an effective amount of the compound or composition, and detecting a resultant improvement in the person's health or condition.

  这项发明提供了抑制FTO（脂肪质量和肥胖）的化合物，包括药用可接受的盐、氢化物和立体异构体。这些化合物用于制备药物组合物，以及制备和使用的方法，包括使用有效量的化合物或组合物治疗有需要的人，特别是肥胖症，并检测人的健康或状况的改善。
• [EN] ERK INHIBITORS<br/>[FR] INHIBITEURS D'ERK
  申请人：MERCK SHARP & DOHME

  公开号：WO2016100050A1

  公开（公告）日：2016-06-23

  The present invention provides a compound of Formula (I) or the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are ERK2 inhibitors. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and a pharmaceutically acceptable carrier. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and an effective amount of at least one other pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent), and a pharmaceutically acceptable carrier.

  本发明提供了一种化合物(I)或其药学上可接受的盐、酯和前药，这些化合物是ERK2抑制剂。该发明还提供了一种包括至少一种化合物(I)和药学上可接受的载体的有效量的药物组合物。该发明还提供了一种包括至少一种化合物(I)的有效量和至少一种其他药学活性成分的有效量（例如，化疗药物等）以及药学上可接受的载体的药物组合物。
• FACTOR XIA-INHIBITING PYRIDOBENZAZEPINE AND PYRIDOBENZAZOCINE DERIVATIVES
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US20170275282A1

  公开（公告）日：2017-09-28

  The invention relates to substituted pyridobenzazepine and pyridobenzazocine derivatives and to processes for preparation thereof, and also to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially of cardiovascular disorders, preferably thrombotic or thromboembolic disorders, and oedemas, and also ophthalmic disorders.

  这项发明涉及取代的吡啶苯并脑和吡啶苯并哌啶衍生物，以及其制备方法，还涉及将其用于生产用于治疗和/或预防疾病的药物，特别是心血管疾病，最好是血栓性或血栓栓塞性疾病，水肿，以及眼科疾病。