S-(fluoromethyl) (6S,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

• 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
• 英文名称: S-(fluoromethyl) (6S,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
• 化学式: C₂₂H₂₇F₃O₄S
• 分子量: 444.5
• InChiKey: MGNNYOODZCAHBA-AZYZPMHWSA-N

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

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放射标记氟替卡松丙酸盐研究中，未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

哺乳期使用概要：外用氟替卡松在哺乳期间尚未进行研究。由于只有大量使用最强效的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，并且尽可能在最小的皮肤面积上使用。特别是要确保婴儿的皮肤不直接接触到涂抹了药物的区域。只有低效皮质类固醇可以用于乳头或乳晕上，因为婴儿可能会直接从皮肤上摄取药物。应该只用水溶性乳膏或凝胶产品涂抹乳房，因为软膏可能会让婴儿通过舔食接触到高水平的矿物石蜡。如果药物被涂抹在乳房或乳头区域，哺乳前应该彻底擦掉。 对哺乳婴儿的影响：将相对高矿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、生长减少和电解质异常。这位母亲从婴儿出生时起就因为乳头疼痛而使用该乳膏。 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

◉ 母乳喂养期间使用总结：尽管没有测量，吸入型皮质类固醇被母体吸收并分泌到母乳中的量可能太小，不足以影响哺乳婴儿。专家意见认为，吸入型、鼻用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，没有找到相关的已发布信息。

◉ 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名健康志愿者单次口服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无影响。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。

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和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，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。如果患者呕吐，让患者向前倾或将其置于左侧（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。寻求医疗救助。 /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

丙酸氟替卡松从呼吸道和胃肠道吸收差，通过鼻腔吸入药物的水性喷雾剂后。根据间接计算，鼻腔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），且在这些情况下，仅在偶尔的样本中以低浓度出现。

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)

吸收、分配和排泄

来自放射性标记氟替卡松丙酸盐口服给药研究的数据有限，表明该药物从胃肠道吸收不良，在肝脏经历快速的首过代谢。来自一个剂量范围研究初步数据表明，口服给药后，未改变的氟替卡松丙酸盐在血浆中的量随剂量增加而增加，但放射性标记药物的生物利用度平均在1%或以下，口服剂量为1-40毫克。

Limited data from studies in which radiolabeled fluticasone propionate has been administered orally indicate that the drug is poorly absorbed from the GI tract and undergoes rapid first-pass metabolism in the liver. Preliminary data from a dose-ranging study suggests that the amount of unchanged fluticasone propionate in plasma increases with dose following oral administration, but the bioavailability of the radiolabeled drug averaged about 1% or less after oral doses of 1-40 mg.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在少数健康个体口服1毫克或16毫克放射性标记的丙酸氟替卡松后，平均达到大约1.3或9.1纳克/毫升的峰值血浆放射性水平（以丙酸氟替卡松当量表示），分别在0.5-6小时内达到。由于在另外一次口服未标记的丙酸氟替卡松后6小时内，血浆中没有检测到未改变的丙酸氟替卡松，因此假定放射性药物给药后观察到的血浆放射性是丙酸氟替卡松的代谢物。有建议称，这些个体在给药后6-24小时内血浆中存在的小量（50-170皮克/毫升）丙酸氟替卡松可能代表未代谢药物的直肠再吸收。

Following oral administration of 1 or 16 mg of radiolabeled propionylfluticasone in a few healthy individuals, peak plasma radioactivity levels (expressed as fluticasone propionate equivalents) averaging approximately 1.3 or 9.1 ng/mL, respectively, were achieved within 0.5-6 hours. Since no unchanged fluticasone propionate was detected in plasma for up to 6 hours after oral administration of unlabeled fluticasone propionate given on a separate occasion, the plasma radioactivity noted after administration of the radiolabeled drug was presumed to be fluticasone propionate metabolites. It has been suggested that the presence of small amounts (50-170 pg/mL) of fluticasone propionate in plasma from 6-24 hours after the dose in these individuals potentially may represent rectal reabsorption of unmetabolized drug.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

外用皮质类固醇的经皮吸收程度由多种因素决定，包括载体和表皮屏障的完整性。封闭敷料可增强渗透。外用皮质类固醇可以从正常完整的皮肤吸收。皮肤中的炎症和/或其他疾病过程增加经皮吸收。

The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of the epidermal barrier. Occlusive dressing enhances penetration. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为产物：
  描述：

  (6S,9R,10S,11S,13S,16R,17R)-6,9-difluoro-11-hydroxy-17-(((iodomethyl)thio)carbonyl)-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl propionate 以74的产率得到S-(fluoromethyl) (6S,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
  参考文献：
  名称：

  Androstane carbothioates

  摘要：

  分子式为##STR1##的化合物，其中R.sup.1代表氟甲基、氯甲基或溴甲基或2'-氟乙基基团，R.sup.2代表一个COR.sup.6基团，其中R.sup.6是C.sub.1-3烷基或OR.sup.2，而R.sup.3则组成一个16.alpha.，17.alpha.-异丙基二氧基基团；R.sup.3代表氢原子、甲基基团（可以是.alpha.-或.beta.-构型）或亚甲基基团；R.sup.4代表氢、氯或氟原子；R.sup.5代表氢或氟原子，符号代表单键或双键，具有良好的抗炎活性，特别是在局部应用时。公式I的化合物通过酯化、卤代、还原、去保护和在9,11-双键处反应形成9.alpha.-卤代-11.beta.-羟基基团来制备。描述并声明了含有公式I的化合物的制药组合物以及使用这些化合物的方法。

  公开号：

  US04335121A1

文献信息

• 丙酸氟替卡松关键中间体的合成方法
  申请人：中国科学院上海有机化学研究所

  公开号：CN103193844A

  公开（公告）日：2013-07-10

  本发明提供了一种丙酸氟替卡松关键中间体的合成方法，使用环原酸酯(I)开环的策略高效引入17位羟基的丙酰基保护基，一锅煮的高碘酸原位开环和氧化开环的策略构建20位羧酸。所述的中间体（I）具有如下的结构式： 所述的丙酸氟替卡松关键中间体（II）具有如下的结构式： 该工艺解决了空间拥挤的17位羟基选择性保护的问题，步骤未增加，操作和成本都有改善。
• [EN] 17.BETA- (ALPHA-HYDROXY) -ESTERS OF ANDROSTANES AS INTERMEDIATES FOR THE PREPARATION FOR THE PREPARATION OF 17.BETA.-FLUORINATED-ANDROSTANE ESTERS<br/>[FR] ESTERS DE 17-BETA-(ALPHA-HYDROXY) D'ANTROSTANES, UTILISES COMME INTERMEDIAIRES DANS LA PREPARATION D'ESTERS D'ANDROSTANE 15-BETA FLUORES.
  申请人：FARMABIOS SRL

  公开号：WO2004052912A1

  公开（公告）日：2004-06-24

  Process for the preparation of polyhalogenated steroids, in particular of androstanic fluoro derivatives corticosteroids by means of the formation of new androstanic S-hydroxy alkyl or aralkyl-17-carbothioate intermediates.

  制备多卤代类固醇的过程，特别是通过形成新的雄甾烷S-羟基烷基或芳基-17-羧硫酸酯中间体制备雄甾烷氟代皮质类固醇。
• J. Med. Chem. 1994, 37, 3717-3729
  作者：

  DOI：——

  日期：——
• Org. Process Res. Dev. 2014, 18, 928-933
  作者：

  DOI：——

  日期：——