anhydrous (R,S)-7-(3-aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid | 210353-54-1

• 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: anhydrous (R,S)-7-(3-aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
• 英文别名: gemifloxacin；anhydrous 7-(3-aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid；7-(3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid；(R,S)-7-(3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate；(R,S)-7-(3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid；(R,S)-7-(3-aminomethyl-4-syn-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid；7-[(4E)-3-(aminomethyl)-4-methoxyiminopyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid
• CAS: 210353-54-1
• 化学式: C₁₈H₂₀FN₅O₄
• 分子量: 389.386
• InChiKey: ZRCVYEYHRGVLOC-HMAPJEAMSA-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，未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，未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）。考虑到感染性疾病及其伴随的炎症过程、年龄和患者的整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）。吉米沙星应在服用硫糖铝至少2小时前服用。

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/(降低吉米沙星的清除率)。

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（例如，多种维生素、硫酸亚铁）的膳食补充剂应在服用吉米沙星前至少3小时或后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，吉米沙星的平均±标准差最大血浆浓度（Cmax）和系统药物暴露（AUC (0-24)）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比率为1.2:1。表观分布容积（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脏排泄。在健康受试者服用320毫克达到稳态后，平均（±SD）血浆消除半衰期约为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：

  anhydrous (R,S)-7-(3-aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid 在 甲烷磺酸 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 3.0h， 以91%的产率得到gemifioxacin mesylate
  参考文献：
  名称：

  PROCESS FOR PRODUCTION OF NAPHTHYRIDINE-3-CARBOXYLIC ACID DERIVATIVES

  摘要：

  公开号：

  EP1214321B1
• 作为产物：
  描述：

  环丙基萘啶羧酸 、 3-aminomethylpyrrolidin-4-one O-methyloxime dihydrochloride 在 三乙胺 作用下， 以 水 、 乙腈 为溶剂， 反应 23.25h， 以78.8%的产率得到anhydrous (R,S)-7-(3-aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
  参考文献：
  名称：

  PROCESS FOR PRODUCTION OF NAPHTHYRIDINE-3-CARBOXYLIC ACID DERIVATIVES

  摘要：

  公开号：

  EP1214321B1

文献信息

• [EN] NEW PROCESS FOR PREPARING 4-AMINOMETHYL-3-ALKOXYIMINOPYRROLIDINE METHANESULFONATE<br/>[FR] NOUVEAU PROCEDE DE PREPARATION DE 4-AMINOMETHYL-3-ALCOXYIMINOPYRROLIDINE METHANESULPHONATE
  申请人：LG LIFE SCIENCES LTD

  公开号：WO2004092129A1

  公开（公告）日：2004-10-28

  The present invention relates to a process for the preparation of 4-aminomethyl-3-alkoxyiminopyrrolidine methanesulfonate, a key intermediate of quinolone antibiotics. According to the process of the present invention, the total number of steps has been shortened to 2-3 steps, the solid separation is not required, and the use of costly chemicals, particularly (BOC)2O (t-butoxycarbonyl anhydride), several organic solvents and reactants, is eliminated.

  本发明涉及一种制备喹诺酮类抗生素关键中间体4-氨基甲基-3-烷氧基亚胺吡咯啉甲磺酸盐的方法。根据本发明的方法，总步骤数量缩短至2-3步，无需固体分离，消除了使用昂贵化学品，特别是(BOC)2O（叔丁氧羰基酸酐）、多种有机溶剂和反应物。
• [EN] PROCESS FOR PREPARING ACID SALTS OF GEMIFLOXACIN<br/>[FR] PROCEDE DE PREPARATION DE SELS ACIDES DE GEMIFLOXACINE
  申请人：LG LIFE SCIENCES LTD

  公开号：WO2003087100A1

  公开（公告）日：2003-10-23

  The present invention relates to a process for preparing acid salts of Gemifloxacin, a quinolone type antibiotic agent having potent antimicrobial activity. The process according to the present invention can provide advantages such as simplicity of process, improvement of productivity and improvement of yield, and the like by reducing conventional three-step process to two-step process.

  本发明涉及一种制备盐酸吉米沙星的方法，吉米沙星是一种喹诺酮类抗生素，具有强大的抗微生物活性。本发明的方法可以通过将传统的三步法简化为两步法，提供工艺简单、生产率提高和产率提高等优点。
• BACTERIAL TOPOISOMERASE I INHIBITORS WITH ANTIBACTERIAL ACTIVITY
  申请人：The Florida International University Board of Trustees

  公开号：US20180079757A1

  公开（公告）日：2018-03-22

  The present invention provides compounds as bacterial topoisomerase inhibitors with antibacterial activity. The present invention also provides pharmaceutical compositions comprising at least one of the compounds and methods of using the compounds and pharmaceutical compositions as antibacterial agents for treating infectious diseases.

  本发明提供了一种具有抗菌活性的细菌拓扑异构酶抑制剂化合物。本发明还提供了包含至少一种该化合物的药物组合物以及使用该化合物和药物组合物作为抗菌剂治疗传染病的方法。
• Process for the preparation of amorphous gemifloxacin
  申请人：Hetero Drugs Limited

  公开号：EP2161269A1

  公开（公告）日：2010-03-10

  A process for the preparation of amorphous gemifloxacin comprising preparing a solution of gemifloxacin in dimethylformamide or methylene chloride, and isolating amorphous gemifloxacin from the solution.

  一种制备非晶态吉米沙星的方法，包括制备二甲基甲酰胺或氯甲烷中的吉米沙星溶液，并从溶液中分离非晶态吉米沙星。
• GEMIFLOXACIN PROCESS AND POLYMORPHS
  申请人：PARTHASARADHI REDDY Bandi

  公开号：US20110136855A1

  公开（公告）日：2011-06-09

  The present invention provides a novel process for the preparation of gemifloxacin and its pharmaceutically acceptable acid addition salts in high yield. The present invention also relates to novel polymorphs of gemifloxacin free base and its hydrates to the processes for their preparation and to pharmaceutical compositions comprising them. The present invention also relates to infusion solutions of gemifloxacin and to processes for their preparation. Thus, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphth-yridine-3-carboxylic acid is reacted with a mixture of acetic anhydride, acetic acid and boric acid to give borane compound, which is then treated with 4-Aminomethyl-3-methoxyimino-pyrrolidinium dimethanesulfonate in presence of triethylamine, followed by treatment with 3.5% sodium hydroxide solution to give gemifloxacin free base.

  本发明提供了一种制备吉米沙星及其药学上可接受的酸盐的新方法，其产率高。本发明还涉及吉米沙星游离碱的新多晶形态及其水合物的制备方法，以及包含它们的制药组合物。本发明还涉及吉米沙星的输注溶液及其制备方法。因此，7-氯-1-环丙基-6-氟-4-氧代-1,4-二氢-1,8-萘啉-3-羧酸与乙酸酐、乙酸和硼酸混合物反应，得到硼烷化合物，然后在三乙胺的存在下，用4-氨基甲基-3-甲氧基亚胺吡咯烷二甲磺酸盐处理，随后用3.5％的氢氧化钠溶液处理，得到吉米沙星游离碱。