gemifloxacin | 329322-84-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: gemifloxacin
• 英文别名: LB20304；7-[3-(azaniumylmethyl)-4-methoxyiminopyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylate
• CAS: 329322-84-1
• 化学式: C₁₈H₂₀FN₅O₄
• 分子量: 389.386
• InChiKey: ZRCVYEYHRGVLOC-UHFFFAOYSA-N

物化性质

• 沸点：
  638.9±65.0 °C(Predicted)
• 密度：
  1?+-.0.1 g/cm3(Predicted)
• 颜色/状态：
  Off-white, amorphous solid from chloroform-ethanol
• 熔点：
  235-237 °C
• 溶解度：
  In water, 1.31X10+4 mg/L at 25 °C (est)
• 蒸汽压力：
  1.04 mm Hg at 25 °C (est)
• 解离常数：
  pKa1 = 6.4 /COOH/; pKa2 = 9.0 /NH2/

计算性质

• 辛醇/水分配系数(LogP)：
  -0.7
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  121
• 氢给体数：
  2
• 氢受体数：
  10

ADMET

代谢

吉米沙星在肝脏中被有限代谢。在给药后长达4小时之内，未改变的化合物是血浆中检测到的最主要的药物相关成分（大约占65%）。所有形成的代谢物都是少量的（小于给药口服剂量的10%）；主要代谢物包括N-乙酰吉米沙星、吉米沙星的E-异构体和吉米沙星的氨基甲酰葡萄糖苷酸。细胞色素P450酶在吉米沙星的代谢中不起重要作用，且吉米沙星对这些酶的代谢活性没有显著抑制作用。

Gemifloxacin is metabolized to a limited extent by the liver. The unchanged compound is the predominant drug-related component detected in plasma (approximately 65%) up to 4 hours after dosing. All metabolites formed are minor (<10% of the administered oral dose); the principal ones are N-acetyl gemifloxacin, the E-isomer of gemifloxacin and the carbamyl glucuronide of gemifloxacin. Cytochrome P450 enzymes do not play an important role in gemifloxacin metabolism, and the metabolic activity of these enzymes is not significantly inhibited by gemifloxacin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用概要：目前没有关于在哺乳期间使用吉米沙星的临床信息；然而，母乳中的含量似乎很低。由于对婴儿发育中的关节可能产生不良反应的担忧，氟喹诺酮类药物传统上不用于婴儿。然而，最近的研究表明风险很小。母乳中的钙可能防止吸收少量的氟喹诺酮类药物，但现有数据不足以证实或反驳这一说法。在哺乳母亲中使用吉米沙星是可以接受的。然而，最好使用有安全性信息的替代药物。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 ◉ 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:No information is available on the clinical use of gemifloxacin during breastfeeding; however, amounts in breastmilk appear to be low. Fluoroquinolones have traditionally not been used in infants because of concern about adverse effects on the infants' developing joints. However, recent studies indicate little risk. The calcium in milk might prevent absorption of the small amounts of fluoroquinolones in milk, but insufficient data exist to prove or disprove this assertion. Use of gemifloxacin is acceptable in nursing mothers. However, it is preferable to use an alternate drug for which safety information is available. ◉ 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

与华法林可能的药物相互作用（增加凝血酶原时间（PT）、国际标准化比率（INR）和/或出血）。考虑感染性疾病及其伴随的炎症过程、年龄和患者的总体状况也是抗凝活性增加的风险因素。密切监测PT、INR或其他适当的凝血测试。

Possible pharmacologic interaction /with warfarin/ (increased prothrombin time (PT), international normalized ratio (INR), and/or bleeding). Consider that infectious disease and its accompanying inflammatory process, age, and general status of the patient also are risk factors for increased anticoagulation activity. Closely monitor PT, INR, or other suitable coagulation test.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

药物动力学相互作用（减少吉米沙星的吸收）。应在服用硫糖铝前至少2小时服用吉米沙星。

Pharmacokinetic interaction (decreased absorption of gemifloxacin). Gemifloxacin should be taken at least 2 hours before sucralfate.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

药物动力学相互作用/与丙磺舒/(减少吉米沙星清除)。

Pharmacokinetic interaction /with probenecid/ (decreased clearance of gemifloxacin).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

药物动力学相互作用（减少吉米沙星的吸收）。含有锌、镁或铁等金属阳离子的膳食补充剂（例如，多种维生素、硫酸亚铁）应在服用吉米沙星前至少3小时或服用后2小时服用。

Pharmacokinetic interaction (decreased absorption of gemifloxacin). Dietary supplements containing metal cations such as zinc, magnesium, or iron (e.g., multivitamins, ferrous sulfate) should be taken at least 3 hours before or 2 hours after gemifloxacin.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

吉米沙星以口服片剂形式给药时，能迅速从胃肠道吸收。口服片剂给药后0.5到2小时观察到吉米沙星的血浆峰浓度，320毫克片剂的绝对生物利用度平均约为71%（95%置信区间为60%-84%）。对健康受试者重复口服320毫克剂量后，吉米沙星的最大血浆浓度（Cmax）和系统药物暴露（AUC (0-24)）的均值±标准差分别为1.61±0.51微克/毫升（范围0.70-2.62微克/毫升）和9.93±3.07微克·小时/毫升（范围4.71-20.1微克·小时/毫升）。在患有呼吸道和泌尿道感染的患者（n=1423）中，使用群体药代动力学分析确定了类似的系统药物暴露估计值（几何平均AUC (0-24)，8.36微克·小时/毫升；范围3.2-47.7微克·小时/毫升）。

Gemifloxacin, given as an oral tablet, is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations of gemifloxacin were observed between 0.5 and 2 hours following oral tablet administration and the absolute bioavailability of the 320 mg tablet averaged approximately 71% (95% CI 60%-84%). Following repeat oral doses of 320 mg to healthy subjects, the mean + or - SD maximal gemifloxacin plasma concentrations (Cmax) and systemic drug exposure (AUC (0-24)) were 1.61 + or - 0.51 ug/mL (range 0.70-2.62 ug/mL) and 9.93 + or - 3.07 ug.hr/mL (range 4.71-20.1 ug.hr/mL), respectively. In patients with respiratory and urinary tract infections (n=1423), similar estimates of systemic drug exposure were determined using a population pharmacokinetics analysis (geometric mean AUC (0-24), 8.36 ug.hr/mL; range 3.2 -47.7 ug.hr/mL).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

吉米沙星在健康受试者的体外血浆蛋白结合率大约为60%至70%，且与浓度无关。在重复给药后，健康老年和年轻受试者的体内血浆蛋白结合率范围为55%至73%，且不受年龄影响。肾功能损害并不显著影响吉米沙星的蛋白结合。吉米沙星的血药浓度与血浆浓度之比为1.2:1。Vdss/F的几何平均值为4.18 L/kg（范围，1.66 - 12.12 L/kg）。口服给药后，吉米沙星在体内广泛分布。吉米沙星在支气管肺泡灌洗液中的浓度超过其在血浆中的浓度。吉米沙星能很好地渗透到肺组织和液体中。

In vitro binding of gemifloxacin to plasma proteins in healthy subjects is approximately 60 to 70% and is concentration independent. After repeated doses, the in vivo plasma protein binding in healthy elderly and young subjects ranged from 55% to 73% and was unaffected by age. Renal impairment does not significantly affect the protein binding of gemifloxacin. The blood-to-plasma concentration ratio of gemifloxacin was 1.2:1. The geometric mean for Vdss/F is 4.18 L/kg (range, 1.66 - 12.12 L/kg). Gemifloxacin is widely distributed throughout the body after oral administration. Concentrations of gemifloxacin in bronchoalveolar lavage fluid exceed those in the plasma. Gemifloxacin penetrates well into lung tissue and fluids.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

吉米沙星及其代谢物通过双重排泄途径排出。在健康受试者口服吉米沙星后，平均（±SD）61±9.5%的剂量以未改变药物和代谢物的形式排入粪便中，36±9.3%排入尿液中。在重复给予320毫克剂量后，平均（±SD）肾清除率大约为11.6±3.9 L/小时（范围4.6-17.6 L/小时），这表明主动分泌参与了吉米沙星的肾排泄。在健康受试者稳态下服用320毫克后，平均（±SD）血浆消除半衰期大约为7±2小时（范围4-12小时）。

Gemifloxacin and its metabolites are excreted via dual routes of excretion. Following oral administration of gemifloxacin to healthy subjects, a mean (+ or - SD) of 61 + or - 9.5% of the dose was excreted in the feces and 36 + or - 9.3% in the urine as unchanged drug and metabolites. The mean (+ or - SD) renal clearance following repeat doses of 320 mg was approximately 11.6 + or - 3.9 L/hr (range 4.6-17.6 L/hr), which indicates active secretion is involved in the renal excretion of gemifloxacin. The mean (+ or - SD) plasma elimination half-life at steady state following 320 mg to healthy subjects was approximately 7 + or - 2 hours (range 4-12 hours).

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  gemifloxacin 在 水 作用下， 生成 7-[3-(aminomethyl)-4-(methoxyimino)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid monohydrate
  参考文献：
  名称：

  WO2006/134608

  摘要：

  公开号：
• 作为产物：
  描述：

  8-(3-(aminomethyl)-4-(methoxyimino)pyrrolidin-1-yl)-6-cyclopropyl-9-fluoro-4-oxo-4,6-dihydro-2H-1l3,2l4-[1,3,2]dioxaborinino[5,6-c][1,8]naphthyridine-2,2-diyl diacetate 在 sodium hydroxide 、 水 、 盐酸 作用下， 以 乙腈 为溶剂， 反应 1.25h， 生成 gemifloxacin
  参考文献：
  名称：

  WO2006/134608

  摘要：

  公开号：

文献信息

• Experimental and computational study on the enantioseparation of four chiral fluoroquinolones by capillary electrophoresis with sulfated‐β‐cyclodextrin as chiral selector
  作者：Qianyun Ma、Wei Cong、Ye Liu、Zikai Geng、Ying Lin、Zhaokun Wang

  DOI：10.1002/chir.23340

  日期：2021.9

  In this work, enantioseparation of four chiral fluoroquinolones (FQs), namely, ofloxacin, gemifloxacin, lomefloxacin, and gatifloxacin, was achieved by capillary electrophoresis with sulfated-β-cyclodextrin (S-β-CD) as chiral selector. Factors affecting the enantiomeric resolution, such as the concentrations of S-β-CD, BGE pH conditions, and the buffer types and concentrations, were optimized and discussed

  在这项工作中，以硫酸化-β-环糊精 (S-β-CD) 作为手性选择剂，通过毛细管电泳实现了四种手性氟喹诺酮类 (FQ) 的对映体分离，即氧氟沙星、吉米沙星、洛美沙星和加替沙星。优化和讨论了影响对映体分辨率的因素，例如 S-β-CD 的浓度、BGE pH 条件以及缓冲液类型和浓度。发现由 30 g/L S-β-CD 和 30-mM 磷酸盐组成的 BGE 在 pH 4.0 下适用于氧氟沙星和吉米沙星的对映体拆分，而在 pH 3.0 下的相同 BGE 则适用于洛美沙星和加替沙星的对映体分离。pH 依赖性实验表明，四种 FQ 对映体的分离分辨率受 BGE pH 显着影响，这被认为与对映异构体和手性选择器之间不同的静电吸引力有关。为了验证这一推测，分子对接研究被用于进一步研究 S-β-CD 的对映体识别机制。分子模型表明疏水作用和氢键参与了主客体包含，但静电引力通过增加个体对映体和 S-β-CD 之
• Biochemical Characterization of New Gemifloxacin Schiff Base (GMFX-o-phdn) Metal Complexes and Evaluation of Their Antimicrobial Activity against Some Phyto- or Human Pathogens
  作者：Hazem S. Elshafie、Sadeek A. Sadeek、Ippolito Camele、Amira A. Mohamed

  DOI：10.3390/ijms23042110

  日期：——

  lone pair of electrons) (the absent of peak corresponding to ν(COOH) at 1715 cm−1, the shift of azomethine group peak from 1633 cm−1 to around 1570 cm−1, the signal at 11 ppm of COOH and the presence of the chloride ions outside the complex sphere). Thermal analyses (TG-DTG/DTA) exhibited that the decaying of the metal complexes exists in three steps with the final residue metal oxide. The obtained data

  通过 Fe(III)、pleCo(II)、Zn(II) 和 Zr(IV) 与希夫碱吉米沙星与邻苯二胺反应 (GMFX-o-phdn) 的反应合成了四种新型配体金属配合物，并进行了研究他们的生物活性。进行了元素分析、FT-IR、1H NMR、紫外-可见光、摩尔电导、熔点、磁化率和热分析以确保螯合过程。对果核褐霉、黄曲霉、意大利青霉、灰葡萄孢、大肠杆菌、蜡状芽孢杆菌、荧光假单胞菌和铜绿假单胞菌进行了抗菌活性。采用ABTS法体外评价自由基清除活性(RSA%)。 FT-IR光谱表明GMFX-o-phdn通过羧酸基团的氧和偶氮甲碱基团的氮以四齿形式与金属离子螯合。红外、1H NMR和摩尔电导率数据表明，GMFX-o-phdn作为中性四齿配体（N2O2）通过羧基的两个氧原子（带负电荷的氧）和羧基的两个氮原子与金属离子发生反应。偶氮甲碱基团（每个氮含有一对孤对电子）（在 1715 cm−1 处没有对应于
• SALT OF NAPHTHYRIDINE CARBOXYLIC ACID DERIVATIVE
  申请人：KIM Ae Ri

  公开号：US20100240694A1

  公开（公告）日：2010-09-23

  7-(3-Aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate and hydrates thereof, processes for their preparation, pharmaceutical compositions comprising them, and their use in antibacterial therapy.

  7-(3-氨甲基-4-甲氧亚胺吡咯烷-1-基)-1-环丙基-6-氟-4-氧代-1,4-二氢-1,8-萘啶-3-羧酸甲磺酸盐及其水合物，其制备方法，包括它们的制药组合物以及它们在抗菌治疗中的应用。
• 吉米沙星侧链化合物的制备方法
  申请人：北京阳光诺和药物研究股份有限公司

  公开号：CN113773240B

  公开（公告）日：2022-05-31

  本发明公开了一种吉米沙星侧链化合物的制备方法。所述制备方法包括如下步骤：S1、1‑N‑叔丁氧羰基‑4‑氰基‑3‑吡咯烷酮与甲氧基胺盐酸盐进行反应得到式(Ⅴ)所示化合物；S2、在惰性气氛中，在10～50℃的温度下、在钯碳存在的条件下，式(Ⅴ)所示化合物在0.1～0.5Mpa氢气氛围下进行加氢还原反应1～3h；再加入Boc酸酐，于10～50℃和0.1～0.5Mpa的条件下继续进行加氢还原反应4～8h，得到式(Ⅵ)所示化合物；S3、式(Ⅵ)所示化合物与酸反应脱除保护基，即得式(Ⅰ)所示吉米沙星侧链化合物。本发明制备方法，工艺简单，反应条件非常温和，很容易实现；(2)原料价格低廉，成本低；(3)开创一种新的、有效的吉米沙星侧链的合成工艺路线。
• Salt of naphthyridine carboxylic acid derivative
  申请人：LG Life Sciences Ltd.

  公开号：EP1179533B1

  公开（公告）日：2004-01-14