氟替卡松 | 90566-53-3

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 肾上腺皮质激素类药
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: 氟替卡松
• 英文名称: fluticasone
• 英文别名: S-(fluoromethyl) (6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthrene-17-carbothioate
• CAS: 90566-53-3
• 化学式: C₂₂H₂₇F₃O₄S
• 分子量: 444.515
• InChiKey: MGNNYOODZCAHBA-GQKYHHCASA-N

物化性质

• 熔点：
  237-239 °C
• 沸点：
  553.2±50.0 °C(Predicted)
• 密度：
  1.37±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于乙腈（少许）、氯仿（少许）
• 蒸汽压力：
  7.45X10-13 mm Hg at 25 °C (est)

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  99.9
• 氢给体数：
  2
• 氢受体数：
  8

ADMET

代谢

[DB08906]和[DB00588]通过细胞色素P450 3A4从肝脏代谢中清除。两者都在FIVE-S-氟甲基碳硫酰基团处水解，形成无活性的代谢物。

[DB08906] and [DB00588] are cleared from hepatic metabolism by cytochrome P450 3A4. Both are hydrolysed at the FIVE-S-fluoromethyl carbothioate group, forming an inactive metabolite.

来源:DrugBank

代谢

丙酸氟替卡松在肝脏中被细胞色素P-450同工酶CYP3A4迅速代谢；主要代谢物是无效的17beta-羧酸衍生物。...在尿液中回收的总放射性中，18%代表丙酸氟替卡松的无效17beta-羧酸衍生物，12%代表一个较少极性的代谢物，其余代表更多极性的代谢物。...丙酸氟替卡松的17beta-羧酸代谢物占粪便排泄的3-40%。

Fluticasone propionate is rapidly metabolized in the liver by the cytochrome P-450 isoenzyme CYP3A4; the principal metabolite is the inactive 17beta-carboxylic acid derivative. ... Of the total radioactivity recovered in urine, 18% represented the inactive 17beta-carboxylic acid derivative of fluticasone propionate, 12% represented a less polar metabolite, and the remainder represented more polar metabolites. ... The 17beta-carboxylic acid metabolite of fluticasone propionate accounted for 3-40% of fecal excretion.

来源:Hazardous Substances Data Bank (HSDB)

代谢

非活性的/17beta-羧酸衍生物/与人类肺细胞质中的糖皮质激素受体的亲和力（大约为1/2000）低于母药，在动物研究中的药理活性可以忽略不计。在体外使用培养的人类肝癌细胞检测到的其他代谢物在人体中尚未检测到。

The inactive /17beta-carboxylic acid derivative/ had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在用人皮肤匀浆体外培养的标记氟替卡松丙酸盐的研究中，没有检测到氟替卡松丙酸盐的代谢物。

No metabolites of fluticasone propionate were detected in an in vitro study of radiolabeled fluticasone propionate incubated in a human skin homogenate.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：外用氟替卡松在哺乳期尚未进行研究。由于只有大量应用最强烈皮质类固醇才可能在母亲体内产生系统性影响，因此短期外用皮质类固醇不太可能通过进入母乳而对哺乳婴儿构成风险。然而，最好还是使用最弱效的药物，并且尽可能在最小面积的皮肤上使用。特别重要的是要确保婴儿的皮肤不直接接触涂抹了药物的区域。只有在婴儿可以直接从皮肤摄入的乳头或乳晕上使用低效皮质类固醇。应该只在水溶性乳膏或凝胶产品上涂抹在乳房上，因为软膏可能会使婴儿通过舔舐接触到高水平的矿物石蜡。如果药物涂抹在乳房或乳头区域，应在哺乳前彻底擦掉任何外用皮质类固醇。 ◉ 对哺乳婴儿的影响：将相对具有较高盐皮质激素活性的皮质类固醇（异氟泼尼松醋酸酯）外用于母亲的乳头，导致其2个月大的哺乳婴儿出现QT间期延长、库欣综合症外貌、严重高血压、生长减缓和电解质异常。这位母亲从婴儿出生起就因为乳头疼痛而使用这种乳膏。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关的已发布信息。

◉ Summary of Use during Lactation:Topical fluticasone has not been studied during breastfeeding. Since only extensive application of the most potent corticosteroids may cause systemic effects in the mother, it is unlikely that short-term application of topical corticosteroids would pose a risk to the breastfed infant by passage into breastmilk. However, it would be prudent to use the least potent drug on the smallest area of skin possible. It is particularly important to ensure that the infant's skin does not come into direct contact with the areas of skin that have been treated. Only the lower potency corticosteroids should be used on the nipple or areola where the infant could directly ingest the drugs from the skin. Only water-miscible cream or gel products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins via licking. Any topical corticosteroid should be wiped off thoroughly prior to nursing if it is being applied to the breast or nipple area. ◉ Effects in Breastfed Infants:Topical application of a corticosteroid with relatively high mineralocorticoid activity (isofluprednone acetate) to the mother's nipples resulted in prolonged QT interval, cushingoid appearance, severe hypertension, decreased growth and electrolyte abnormalities in her 2-month-old breastfed infant. The mother had used the cream since birth for painful nipples. ◉ 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

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用概要：尽管没有进行测量，吸入型皮质类固醇被母体吸收进入血液和分泌到母乳中的量可能太小，不足以影响哺乳的婴儿。专家意见认为，吸入、鼻腔和口服皮质类固醇在哺乳期间使用是可以接受的。另见氟替卡松，外用。 ◉ 对哺乳婴儿的影响：任何皮质类固醇均无报告有影响。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关已发布信息。

◉ Summary of Use during Lactation:Although not measured, the amounts of inhaled corticosteroids absorbed into the maternal bloodstream and excreted into breastmilk are probably too small to affect a breastfed infant. Expert opinion considers inhaled, nasal and oral corticosteroids acceptable to use during breastfeeding. See also Fluticasone, Topical. ◉ Effects in Breastfed Infants:None reported with any corticosteroid. ◉ 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

在一项健康受试者中进行的一项药物相互作用研究中，发现利托那韦（一种高度有效的细胞色素P450 3A4抑制剂）可以显著增加血浆中氟替卡松丙酸酯的暴露量，导致血清皮质醇浓度显著降低。

A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在一项安慰剂对照的交叉研究中，8名健康志愿者单次吸入氟替卡松丙酸盐，并与多次剂量的酮康唑达到稳态，结果导致血浆中氟替卡松丙酸盐的暴露量增加，血浆皮质醇AUC减少，对尿液中皮质醇的排泄没有影响。当氟替卡松丙酸盐与酮康唑和其他已知的强效细胞色素P450 3A4抑制剂联合使用时，应谨慎行事。

In a placebo-controlled crossover study in 8 healthy volunteers, coadministration of a single dose of orally inhaled fluticasone propionate with multiple doses of ketoconazole to steady state resulted in increased plasma fluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. Caution should be exercised when fluticasone propionate is coadministered with ketoconazole and other known potent cytochrome P450 3A4 inhibitors.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中毒物清除。如果患者停止呼吸，开始人工呼吸，最好使用需求阀复苏器、袋阀面罩装置或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果发生呕吐，让患者前倾或置于左侧（如果可能的话，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗帮助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

鼻内暴露[DB08906]会导致患者吞下更大剂量的药物。然而，吸收不良且代谢率高，因此全身暴露可以忽略不计，鼻内生物利用度为0.50%，口服生物利用度为1.26%。吸入生物利用度为13.9%。一项对24名健康白人男性的研究表明，吸入生物利用度为6.3-18.4%。[DB00588]的鼻内生物利用度小于2%，口服生物利用度小于1%。鼻内暴露导致大部分剂量被吞下。[DB00588]的局部吸收非常低，但可能会根据多种因素（包括皮肤的完整性以及炎症或疾病的存在）而变化。一项对24名健康白人男性的研究表明，吸入生物利用度为9.0%。

Intranasal exposure of [DB08906] results in patients swallowing a larger portion of the dose. However, absorption is poor and metabolism is high, therefore there is negligible systemic exposure with a nasal bioavailability of 0.50% and oral bioavialability of 1.26%. Inhaled bioavailability is 13.9%. A study of 24 healthy Caucasian males showed an inhaled bioavailability of 6.3-18.4%. Intranasal bioavailability of [DB00588] is <2%, and oral bioavailability is <1%. Intranasal exposure results in the majority of the dose being swallowed. Topical absorption of [DB00588] is very low but can change depending on a number of factors including integrity of the skin and the presence of inflammation or disease. A study of 24 healthy Caucasian males showed an inhaled bioavailability of 9.0%.

来源:DrugBank

吸收、分配和排泄

• 消除途径

[DB08906]在粪便中消除≥90%，在尿液中消除1-2%。[DB00588]主要在粪便中消除，尿液中的消除量小于5%。

[DB08906] is eliminated ≥90% in the feces and 1-2% in the urine. [DB00588] is mainly eliminated in the feces with <5% eliminated in the urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

608L在静脉给药[DB08906]的稳态下。其他报告显示稳态下的平均分布容积为661L。一项对24名健康白人男性的研究表明，静脉给药后稳态下的分布容积为704L。静脉给药[DB00588]的分布容积为4.2L/kg。一项对24名健康白人男性的研究表明，静脉给药后稳态下的分布容积为577L。

608L at steady state for intravenous administration of [DB08906]. Other reports suggest the mean volume of distribution at steady state is 661L. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 704L following intravenous administration. The volume of distribution of intravenous [DB00588] is 4.2L/kg. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 577L following intravenous administration.

来源:DrugBank

吸收、分配和排泄

• 清除

57.8升/小时用于[DB08906]。一项对24名健康白人男性的研究表明，静脉给药后的清除率为71.8升/小时。1093毫升/分钟用于[DB00588]。一项对24名健康白人男性的研究表明，静脉给药后的清除率为63.9升/小时。

57.8L/h for [DB08906]. A study of 24 healthy Caucasian males showed a clearance of 71.8L/h following intravenous administration. 1093mL/min for [DB00588]. A study of 24 healthy Caucasian males showed a clearance of 63.9L/h following intravenous administration.

来源:DrugBank

吸收、分配和排泄

丙酸氟替卡松从呼吸道和胃肠道的吸收较差，通过鼻腔吸入药物的水性喷雾后，根据间接计算，鼻内丙酸氟替卡松的绝对系统生物利用度小于2%。鼻内给予皮质类固醇的大部分剂量会被吞咽，并在肝脏经历广泛的首过代谢。在接受丙酸氟替卡松治疗2-3周的季节性过敏性鼻炎患者中，只有在推荐剂量被超过时，血浆浓度才高于检测限（50 pg/mL），而且在这种情况下，只是偶尔在低浓度的样本中。

Fluticasone propionate is poorly absorbed from the respiratory and GI tracts following nasal inhalation of the drug as an aqueous spray. Based on indirect calculations, intranasal fluticasone propionate has an absolute systemic bioavailability of less than 2%. A major portion of an intranasal dose of corticosteroids is swallowed and undergoes extensive first-pass metabolism in the liver. In patients with allergic rhinitis receiving intranasal fluticasone propionate for 2-3 weeks, plasma concentrations were above the level of detection of the assay (50 pg/mL) only when recommended dosages were exceeded, and in those instances, only in occasional samples at low concentrations.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

糖皮质激素 氟替卡松是一种强效吸入型糖皮质激素，其作用类似布地奈德。适用于哮喘和哮喘性支气管炎。

药理作用 氟替卡松是一种局部作用的强效糖皮质激素，具有显著的抗炎活性。它几乎不被口服吸收（<1%），经过鼻腔吸入给药后能迅速减轻哮喘症状。其血浆浓度很低，大多数患者未检测到其全身性效应，因此对下丘脑-垂体-肾上腺轴的影响较小。尽管如此，不同个体之间存在较大差异，应使用最小有效剂量以控制症状。

不良反应 氟替卡松的不良反应较为罕见，但长期大剂量使用仍可能导致全身性反应（参考氢化可的松）。

1. 气雾剂：非常罕见口腔及咽喉念珠菌病。用药后用清水漱口可能有所帮助；若有症状，可用抗真菌药物治疗并继续使用。
2. 声嘶是某些病人吸入后的常见不良反应，建议用药后用清水漱口。
3. 极为罕见异常支气管痉挛，应立即使用速效支气管扩张剂，并停止使用该气雾剂。

药物相互作用

1. 氟替卡松与酮康唑、利托那韦等强效CYP3A4酶抑制药合用时，血药浓度、生物利用度及全身不良反应发生率会增加。
2. 与安非拉酮合用会导致癫痫发作阈值降低，因此应避免同时使用。

反应信息

• 作为反应物：
  描述：

  氟替卡松 在 水 、 过碘酸 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 以97.6%的产率得到6,9-二氟-11,17-二羟基-16-甲基-3-氧代雄甾-1,4-二烯-17-羧酸
  参考文献：
  名称：

  一种丙酸氟替卡松的合成方法

  摘要：

  本发明实施例提供了一种丙酸氟替卡松的合成方法，所述方法包括：硫代酯化反应：在反应釜中加入第一中间体、第一有机碱、二甲氨基硫代甲酰氯、碘化钠、以及第一有机溶剂，反应完毕后，加入极性非质子溶剂和水，降温析晶，过滤、洗涤、烘干得到第二中间体；醇解反应：在反应釜中加入第二中间体、第一无机碱、以及第二有机溶剂，反应完毕后，加入水，或者水和萃取剂进行萃取，然后取水相滴加盐酸，析晶后，过滤、洗涤、烘干得到第三中间体；取代成酯反应：在反应釜中加入第三中间体、第二无机碱、以及第三有机溶剂，加入氟溴甲烷，然后滴加盐酸，析晶后，过滤、洗涤、烘干得到丙酸氟替卡松。本发明实施例可以实现低成本生产，反应收率及纯度较高。

  公开号：

  CN110698530A
• 作为产物：
  描述：

  S-iodomethyl 6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate 在 silver fluoride 作用下， 以 乙腈 为溶剂， 反应 3.0h， 以82%的产率得到氟替卡松
  参考文献：
  名称：

  丙酸氟替卡松相关物质的合成

  摘要：

  6. (a) W. Vetter 和 J. Wu, Chemosphere 52,423 (2003)；(b) EL Teuten、BE Pedler、AN Hangsterfer 和 CM Reddy，Environ。污染。144,336 (2006)；(c) EL Teuten、R. SaintLouis、BE Pedler、L. Xu、E. Pelletier 和 C. M. Reddy，Mar. Polfur。公牛。52,572 (2006)；(d) W. Vetter, S. Gaul, D. Olbrich 和 C. Gaus, Chemosphere 66,201 1 (2007); (e) EL Teuten 和 CM Reddy，Environ。污染。145,668 (2007)；(f) K. Pangallo、RK Nelson、EL Teuten、BE Pedler 和

  DOI：

  10.1080/00304940809458122

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-(三氟甲基)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] S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES<br/>[FR] COMPOSÉS DE S-NITROSOMERCAPTO ET DÉRIVÉS APPARENTÉS
  申请人：GALLEON PHARMACEUTICALS INC

  公开号：WO2009151744A1

  公开（公告）日：2009-12-17

  The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.

  本发明涉及基于巯基和S-亚硝基巯基的SNO化合物及其衍生物，以及它们在治疗正常呼吸控制缺失方面的用途，包括治疗与睡眠、肥胖、某些药物和其他医疗状况相关的呼吸暂停和低通气。
• [EN] NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS<br/>[FR] NOUVEAUX COMPOSÉS ET COMPOSITIONS PHARMACEUTIQUES LES COMPRENANT POUR LE TRAITEMENT DE TROUBLES INFLAMMATOIRES
  申请人：GALAPAGOS NV

  公开号：WO2017012647A1

  公开（公告）日：2017-01-26

  The present invention discloses compounds according to Formula (I), wherein R1, R3, R4, R5, L1, and Cy are as defined herein. The present invention also provides compounds, methods for the production of said compounds of the invention, pharmaceutical compositions comprising the same and their use in allergic or inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 and/or interferons. The present invention also methods for the prevention and/or treatment of the aforementioned diseases by administering a compound of the invention.

  本发明公开了根据式（I）的化合物，其中R1、R3、R4、R5、L1和Cy如本文所定义。本发明还提供了该发明的化合物、制备该化合物的方法、包括相同化合物的药物组合物以及它们在过敏或炎症症状、自身免疫疾病、增殖性疾病、移植排斥、涉及软骨周转障碍的疾病、先天软骨畸形和/或与IL6和/或干扰素过度分泌相关的疾病中的使用。本发明还提供了通过给予该发明的化合物来预防和/或治疗上述疾病的方法。
• [EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020257998A1

  公开（公告）日：2020-12-30

  Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.

  提供了一种将细胞毒性药物与一个侧链连接分子结合的共轭物。它提供了制备细胞毒性分子与细胞结合配体的共轭物的侧链连接方法，以及在靶向治疗癌症、感染和免疫性疾病中使用该共轭物的方法。
• [EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020006722A1

  公开（公告）日：2020-01-09

  A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.

  一种新型的交联细胞毒剂，吡咯苯并二氮杂环二聚体（PBD）衍生物，以及它们与细胞结合分子的结合物，一种制备这些结合物的方法以及这些结合物的治疗用途。