WO2007082472A1 - Composé de quinolone anti-infectueux, son procédé de préparation et son utilisation - Google Patents

Composé de quinolone anti-infectueux, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2007082472A1
WO2007082472A1 PCT/CN2007/000180 CN2007000180W WO2007082472A1 WO 2007082472 A1 WO2007082472 A1 WO 2007082472A1 CN 2007000180 W CN2007000180 W CN 2007000180W WO 2007082472 A1 WO2007082472 A1 WO 2007082472A1
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Prior art keywords
compound
acid
infective
preparation
quinolone
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PCT/CN2007/000180
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English (en)
Chinese (zh)
Inventor
Mao Chen
Shaoxuan Zhu
Xuebin Liu
Lizhen Zheng
Shuwen Xu
Danqing Liu
Original Assignee
Guangzhou Baiyunshan Pharmaceutical Co., Ltd. Guangzhou Baiyunshan Pharmaceutical Factory
Guangzhou Pharmaceutical Industrial Research Institute
Guangzhou Baiyunshan Pharmaceutical Co., Ltd. Guangzhou Baiyunshan Chemical Pharmaceutical Factory
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Priority claimed from CN 200610033033 external-priority patent/CN101003541A/zh
Priority claimed from CN 200610033034 external-priority patent/CN101003542A/zh
Priority claimed from CN 200610033042 external-priority patent/CN101003543A/zh
Priority claimed from CNA2006100330280A external-priority patent/CN101003540A/zh
Priority claimed from CN 200610033039 external-priority patent/CN101003534A/zh
Application filed by Guangzhou Baiyunshan Pharmaceutical Co., Ltd. Guangzhou Baiyunshan Pharmaceutical Factory, Guangzhou Pharmaceutical Industrial Research Institute, Guangzhou Baiyunshan Pharmaceutical Co., Ltd. Guangzhou Baiyunshan Chemical Pharmaceutical Factory filed Critical Guangzhou Baiyunshan Pharmaceutical Co., Ltd. Guangzhou Baiyunshan Pharmaceutical Factory
Publication of WO2007082472A1 publication Critical patent/WO2007082472A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a quinolone anti-infective drug, in particular to 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazepine
  • a pharmaceutically acceptable salt of alkano[3,2-a]quinoline-3-carboxylic acid a process for its preparation and its use.
  • Quinolones are antibacterial drugs that have developed rapidly in recent years. They have broad antibacterial spectrum, strong antibacterial activity, simple structure, convenient administration, no cross-resistance with other commonly used antibacterial drugs, and high cost-effectiveness. The more attention is paid to this. There are dozens of varieties of quinolone products that have been marketed, and it is one of the most active areas for the development of anti-infective drugs.
  • Li 394 affects the use of its drugs.
  • the high toxicity of intravenous injection is also the cause of its medicinal use.
  • UFX ⁇ 394
  • Ishida S reported a 394-week toxicity study in rats. Male and female Sprague-Drwlog rats were given M394 at doses of 3, 10, and 30 mg/kg for four weeks, 10, 30 mg/kg.
  • the water consumption and urinary excretion of the rats in the dose were significantly increased, and crystalline substances and small epithelial cells were found in the urine precipitate.
  • 6-Fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazetetane is disclosed in EP 0 315 828 and US Pat. No. 4,843,070. 3, 2- a] quinoline-3-carboxylic acid and its preparation method, also pointed out some pharmaceutically acceptable salts thereof, but did not disclose how to obtain 6-fluoro-1 -methyl-4 with good water solubility -oxo-7-(1-piperazinyl)-4H-[1,3]thiazetino[3,2-a]quinoline-3-carboxylic acid derivative, thus having a wide range of applications Restricted. Summary of the invention
  • An object of the present invention is to provide an anti-infective quinolone compound which is easily soluble in water, can be administered by injection, has low toxicity and is safe, and a preparation method and use thereof.
  • the present invention provides a class of quinolone anti-infective compounds which are 6-fluoro-: L-methyl-4-oxo-7-(1-piperazinyl)-4H- [ 1, 3] thiazetanazo[3,2- a]quinoline-3-carboxylate
  • X is lactic acid, gluconic acid, hydrochloric acid, methanesulfonic acid, glutamic acid or aspartic acid.
  • the compound (I) is lactate or gluconate, which is represented by the following formula:
  • the compound I of the present invention can be produced by the following method:
  • the organic solvent is any one of methanol, ethanol, isopropanol, acetone, and tetrahydrofuran; and the pharmaceutically acceptable acid is lactic acid, gluconic acid, hydrochloric acid, methanesulfonic acid, glutamic acid or aspartic acid.
  • the quinolone anti-infective compound obtained by the present invention is easily soluble in water, but is insoluble in methanol, absolute ethanol, acetone and diethyl ether.
  • the present invention also provides an anti-infective pharmaceutical composition
  • an anti-infective pharmaceutical composition comprising quinolone compound I as an active ingredient and comprising a conventional pharmaceutical carrier.
  • a conventional pharmaceutical carrier may be a tablet, a capsule, a granule for gastrointestinal administration, or an injection for parenteral administration, an ophthalmic preparation, an otic preparation, a gynecological preparation, or an external preparation for skin.
  • the active ingredient of the above anti-infective pharmaceutical composition is preferably 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazetidine and [ 3,2-a]quinoline-3-carboxylic acid lactate or gluconate.
  • the above anti-infective pharmaceutical composition can be used for gastrointestinal administration, such as capsules, tablets or granules, and is a quinolone compound I and a conventional pharmacologically compatible excipient such as starch, maltose, and sucrose. , calcium carbonate or calcium phosphate; binders such as starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose; lubricants such as magnesium stearate or talc; decomposition agents such as carboxymethyl calcium Or talc powder is mixed and prepared by a conventional preparation method.
  • the composition is usually prepared by mixing the compound I with at least one of the above-mentioned carriers or excipients, and the ratio of the compound I to the total composition is generally 0.1 to 100% (W/W).
  • the anti-infective pharmaceutical composition of the compound I provided by the present invention can also be used for parenteral administration such as injections, ophthalmic preparations, otic preparations, gynecological preparations, external preparations for skin and the like.
  • the ratio of the compound I to the entire composition is generally from 0.1 to 100% (W/W).
  • Test Samples Samples 01 and 02, which are the compounds II and III provided by the present invention, were prepared by the examples 1 to 1, 1 _2, respectively.
  • the number of theoretical plates is 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazetino[3,2- a]quina
  • the porphyrin-3-carboxylic acid meter should be not less than 2000; 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazetidine
  • the degree of separation of the [3,2-a]quinoline-3-carboxylic acid peak and the adjacent impurity peak should meet the requirements.
  • Compound II about 10mg, accurately weighed, 100ml flask, add the mobile phase amount, sonicated to dissolve and diluted into a solution containing about 50 ⁇ ⁇ per lml. Precisely measure 20 ⁇ 1, inject into the liquid chromatograph, record the chromatogram; take another 10mg of 394 (commercially available, reference), and measure it by the same method. According to the external standard method, the peak area is calculated.
  • Compound II contains 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazepine-[3,2- a]quina
  • the porphyrin-3-carboxylic acid is 75 to 80%.
  • Clarity and color of the sample Take Compound II or Compound III, add water to make a solution containing 0.1 g of Compound II or Compound III per 10 ml of water, and determine according to law.
  • Samples 01 and 02 were placed under a medical light tester, and the light intensity was 4500 LX ⁇ 500 LX. After 5 and 10 days, samples were taken to observe the color, pH, clarity, and content. See the table below for the results.
  • Samples 01 and 02 were placed in an incubator at 60 ° C, and after 5 and 10 days, samples were taken to observe the color, and the pH, clarity, and content were measured. See the table below for the results.
  • test results show that the samples 01 and 02 have no significant changes in content, color, clarity and pH at high temperature, so the product is stable.
  • test results show that the product has no obvious change in content, color, clarity and pH value when placed in high humidity, so the product is stable.
  • Li 394 mesylate, ⁇ 394 aspartate, and Li 394 glutamate prepared in the examples of the present invention was measured, and it was found that ⁇ 394 mesylate contained 6-fluoro-1-methyl.
  • 4-Oxo-7-(1-piperazinyl)-4H-[1,3]thiazetino[3,2-a]quinoline-3-carboxylic acid is 75 to 81%.
  • Aspartate contains 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazetidine [3, 2- a] quinoline-3-carboxylic acid is 69 to 74%.
  • Test Example 2 Inhibition test, the minimum concentration of M I C was determined.
  • Test method In vitro bacteriostasis test using conventional plate double dilution method
  • Staphylococcus aureus 0. 5 0. 5 0.6 0.5 0.8 0. 4 Streptococcus pneumoniae ⁇ 2 ⁇ 2. 2 2.2 2.3 2.5 ⁇ 2. 1 Enterococcus faecalis 4 3. 9 ⁇ 4.5 4.4 ⁇ 4.5 4 ⁇ 2 Mucus Serratia 0. 25 0. 25 0.25 0.26 0.29 0. 23 Pseudomonas aeruginosa 2 ⁇ 2. 0 2.0 2.1 2.2 1. 8 Escherichia coli 0. 06 0 ⁇ 06 0.06 0.07 0.08 0.
  • Test Example 3 Continuous intravenous administration 28-day toxicity test:
  • the long-toxicity test of each sample used 120 SD rats, which were randomly divided into 4 groups according to animal weight and sex, 30 in each group, half male and half female. Three dose groups of 10, 30, 60 mg/kg and one blank control group were administered respectively, and the tail vein was administered once a day for 4 weeks, and the observation was resumed for 2 weeks. The general condition observation was performed every day, and the body weight and food intake were counted once a week. At the end of the administration, half of the animals were collected for blood collection and urine was collected for blood biochemistry, electrolytes, urine analysis, and bloodletting and necropsy were performed for gross pathological examination.
  • Femur wrist cartilage, femoral articular cartilage, brain (brain, cerebellum, brain stem), spinal cord (neck, chest, lumbar), pituitary, thymus, thyroid, parathyroid, esophagus, salivary gland, stomach, duodenum , ileum, colon, liver, gallbladder, kidney, adrenal gland, spleen, pancreas, trachea, lung, aorta, heart, epididymis, testis, ovary, uterus, prostate, breast, sciatic nerve, bladder, eye (when abnormalities are found in ophthalmology) , optic nerve, local administration (tail vein), sternum (bone and bone marrow), lymph nodes (mesenteric lymph nodes), etc.
  • brain brain
  • cerebellum brain stem
  • spinal cord neck, chest, lumbar
  • pituitary thymus, thyroid, parathyroid, esophagus, salivary gland, stomach, duodenum , ileum
  • the intravenous dose of NM394 lactate, NM394 gluconate, or NM394 mesylate, aspartate and glutamate was 30 mg/kg «bW o
  • NM394 is mainly characterized by nephrotoxicity (10, 30 mg/kg.bw dose group, nephrotoxicity, blood urea nitrogen) And creatinine increased significantly, but its toxic effects were reversible; its non-toxic dose was 3 mg/kg*bw).
  • NM394 lactate, NM394 gluconate, or NM394 mesylate, aspartate and glutamate 10 mg/kg*bw groups there was no toxicological change in the rats in the NM394 lactate, NM394 gluconate, or NM394 mesylate, aspartate and glutamate 10 mg/kg*bw groups.
  • a dose of NM394 showed a significant increase in nephropathy, urinary crystalline substances, and blood urea nitrogen and creatinine, which was associated with intravenous injection of NM394 lactate, NM394 gluconate, or NM394 mesylate, aspartate, and glutamate.
  • the change of salt in the 60 mg/kg-bw dose group was basically the same, while the 30 mg/kg*bw NM394 showed urinary turbidity and blood gamma globulin reduction in addition to the above symptoms, which was more than intravenous ⁇ 394 lactate.
  • the 60 mg/kg 'bw dose group of ⁇ 394 gluconate, or ⁇ 394 mesylate, aspartate and glutamate was more severe.
  • the intoxication dose of intravenous NM394 lactate, NM394 gluconate, or NM394 mesylate, aspartate and glutamate to rats was 30 mg/kg*bw.
  • the non-toxic reaction dose of intravenous NM394 in rats reported in the literature is 3 mg/kg.bw, and the toxicity of the drug compound of the present invention is greatly reduced.
  • muscle stimulation test 2 rabbits in each test object, the left femoral muscle was given a high concentration of test solution 1.2mg / mL, the right femoral muscle was given the corresponding test substance low concentration test solution 0.4mg / mL . Another rabbit was used as a blank control, and the right and left lateral femoral muscles were given the same amount of sodium chloride injection. The drug was administered once a day for 3 consecutive days. The necropsy was performed 48 hours after the last administration. The results of visual observation and pathological examination showed that there were no obvious abnormal changes in the high concentration test solution and low concentration test solution of gluconate, aspartate, methanesulfonate, lactate or glutamate of NM394. detailed description
  • the sample was measured by Cu-Kct ray and the 2 ⁇ , d-plane spacing and relative intensity in the X-ray powder diffraction pattern were 1/1. Has the following values:
  • the sample was measured by Cu- ⁇ ray and the X-ray powder diffraction pattern was taken between 2 ⁇ and d-planes.
  • the distance and relative intensity have the following values:
  • the obtained sample was subjected to nuclear magnetic 1 H NMR (D 2 O, 500 Hz) data, and the X ⁇ , d-plane spacing and relative intensity of the X-ray minute diffraction pattern measured by Cu- ⁇ ⁇ ray were 1/1. Same as 1-1.
  • the obtained sample was subjected to nuclear magnetic 1 H NMR (DMSO-d 6 , D 2 o, 500 Hz) data, and the X ⁇ , d-plane spacing, and relative intensity 1/1 of the X-ray powder diffraction pattern measured by Cu-I ray. Same as 1-2.
  • Example 3-2 Preparation of NM394 Gluconate (Compound ⁇ ) The lactic acid was added dropwise with stirring to an aqueous solution of dropwise addition of 50% gluconic acid 13. 2 L, and the remaining Example 3-1 gave 6. 9 g of Compound III.
  • Example 4 -1 Preparation of NM394 Lactate (Compound ⁇ )
  • 10 g of Li 394 Compound i
  • lactic acid was added dropwise with stirring.
  • stirring for 20 minutes stirring for 20 minutes
  • adding 0. 5g needle with activated carbon stirring for 15 minutes
  • filtering decarburization washing the three-necked flask with 10ml of water, and filtering.
  • the filtrate was combined into a 500 ml three-necked flask, and 1000 ml of acetone was added dropwise with stirring, and acetone was added over 4 hours to precipitate a solid.
  • Incubate at 15 ⁇ 20 C for 2 hours, filter, wash with acetone 20 ml once, and dry at 35 ⁇ 40 °C. 8. 7 g of compound II were obtained.
  • Example 4 - 2 Preparation of NM394 gluconate (Compound ⁇ ) The lactic acid was added dropwise with stirring to a solution of 19 L of a 50% aqueous solution of gluconic acid, and the remaining Example 4-1 gave 7.4 g of Compound III.
  • Example 5 - 1 Preparation of NM394 Lactate (Compound ⁇ )
  • 200 ml of water and 50 ml of methanol were added, and 5 g of Li 394 (compound i) was added at 55 to 60 ° C, and lactic acid was added dropwise with stirring. 3 ⁇ , stirring for 30 minutes, adding 0. 2g needle with activated carbon, stirring for 15 minutes, filtering decarburization; washing the three-necked flask with 10ml of water, and filtering.
  • Example 5-2 Preparation of NM394 gluconate (Compound ⁇ ) The lactic acid was added dropwise with stirring to an aqueous solution of 50% gluconic acid. 5. 1 L, and the same as the same Example 5 to give 3. 4 g of Compound III.
  • Example 6-1 Preparation of NM394 lactate (Compound ⁇ )
  • 15 ml of water and 25 ml of tetrahydrofuran were added, and 10 g of NM394 (compound i) was added at 25 to 30 ° C, and lactic acid was added dropwise with stirring. 16 ⁇ , stirring for 60 minutes, adding 0. 5g needle with activated carbon, stirring for 15 minutes, filtering decarburization; washing the three-necked flask with 10ml of water, and filtering.
  • Example 6-2 Preparation of NM394 Gluconate (Compound ⁇ ) 25 ⁇ 30 ° C, 30 ml of three-necked flask was added with 30 ml of water and 10 ml of tetrahydrofuran, then 10 g of Li 394 (compound i) was added, and 50% glucose was added dropwise with stirring. 5 ⁇ III ⁇ The acid solution of the aqueous solution of 13.1L.
  • Example 7-2 Preparation of NM394 gluconate (compound oxime) 10 ⁇ 15 ° C, 100 L of water was added to the reaction tank, and then 10 kg of blue 394 (compound i) was added, and an aqueous solution of 50% gluconic acid was added dropwise with stirring. 9L, stirred for 1.5 hours, activated carbon was added 1. 0kg needle, stirred for 20 minutes, with the rest of the compound obtained in Example 7-1 III sterile lyophilized powder 9. 2kg 0 hydrochloride of Example 8 NM394 embodiment
  • the compound hydrazine was changed to the compound III, and the amount of the compound III was changed to 15.6 g, and the rest was the same as above.
  • Compound II was changed to Li 394 mesylate salt and the amount was changed to 25.6 g, the rest being the same as above.
  • Compound II was changed to Li 394 glutamate and the amount was changed to 14.2 g, the rest being the same as above.
  • Compound II was changed to 394 aspartate, and the amount was changed to 13.8 g, the rest being the same as above.
  • Example 1 The 12.6 g of the compound II obtained in Example 1 to 1 was added to 2 L of a 5% glucose solution at 15 to 20 ° C, and after stirring and dissolved, it was prepared in the same manner as in Example 10.
  • Compound II was replaced by compound III, and the amount of compound III was changed to 15.6 g, the rest being the same as above.
  • Compound II was replaced with Compound Li 394 glutamate, and the amount of NM394 glutamate was changed to 14.2 g, the rest being the same as above.
  • Example 1-1 126 g of the compound II obtained in Example 1-1 was added to 500 ml of water for injection at 15 to 20 ° C, stirred and dissolved, and 5 g of the needle was added with activated carbon, stirred for 10 minutes, and decarburized by filtration; preparation.
  • Example 2-1 the sterile powder of the compound II obtained in Example 2-1 was aseptically divided into 0. 126g / bottle, 0. 189g / bottle, 0. 252g / bottle, 0. 315g / bottle, 0. 378 g / bottle, 0. 504 g / bottle or 0. 630 g / bottle, a sterile powder injection preparation of Compound I is obtained.
  • Compound II was replaced with Compound III, Li 394 mesylate, Li 394 glutamate, Li 394 Aspartate, Wax 394 hydrochloride, and the rest as above.
  • a sterile powder of the compound II obtained in Example 7-1 was prepared by the method of Example 13.
  • Example 1-1 The compound II obtained in Example 1-1 was sprayed with a lactose in a fluidized bed granulator for 10 minutes, mixed, and then sprayed into a 10% PVP solution at a wind speed of about 120 m/hr. It is about 2 ⁇ 3ml/min, and is dried by hot air at 60°C for about 15 minutes. After mixing with magnesium stearate, it is tableted and coated.
  • the compound II is prepared by the compound II.
  • the compound is used in the form of a compound of the formula III.
  • the compound is used in an amount of 156 g, the amount of the compound is 156 g, the lactose is 1. 5 g, the 10% PVP solution is 10 ml, and the magnesium stearate is 0.52 g. tablet.
  • Compound II is 126g, microcrystalline cellulose 40g, sodium carboxymethyl starch 50g, magnesium stearate 3. 4g
  • Preparation Take the original and auxiliary materials in the prescription, mix well and fill them into the No. 4 empty capsules.
  • Compound II was changed to Li 394 mesylate salt, and the amount was changed to 128 g, and the rest was the same, and a capsule containing Li 394 mesylate was prepared.
  • Compound II was replaced with Lan 394 glutamate, and the amount was changed to 142 g, and the rest was the same as above, and a capsule containing Li 394 glutamate was prepared.
  • Compound II was changed to 394 aspartate, and the amount was changed to 138 g, and the same as above, a capsule containing NM394 aspartate was prepared.
  • Compound II was replaced with Compound III, and a granule of Compound III was prepared as follows. Prescription: Compound II 156g, dextrin 115 g, sucrose 280g,
  • the compound II was replaced with the compound III, and the amount of the compound III was changed to 4.7 g, and the rest was the same, and an eye drop containing the compound III was prepared.
  • the compound hydrazine was replaced with the compound III, and the amount of the compound III was changed to 15.6 g, and the same as above, an ear drop containing the compound III was prepared.
  • the compound II was replaced with the compound III, and the amount of the compound III was changed to 15.6 g, and the same as above, a suppository containing the compound III was prepared.
  • Compound II 126g 85g of stearic acid, white petrolatum 170 g, glyceryl monostearate, lauryl sulfate alkyl with 2g, glycerol 100g, triethanolamine 4g, ethylparaben lg, water, amount of 1000g.
  • the compound II was replaced with the compound III, and the amount of the compound III was changed to 156 g, and the same as above, an ointment containing the compound III was prepared.
  • Compound II was replaced with M394 mesylate salt, and the amount was changed to 128 g, and the same as above, an ointment containing NM394 mesylate was prepared.
  • Compound II was changed to NM394 glutamate, and the amount was changed to 142 g, and the same as above, an ointment containing ⁇ 394 glutamate was prepared.
  • the series of quinolone anti-infective drugs provided by the invention has the structures, stable properties, exact antibacterial effect, improved water solubility of the active pharmaceutical compound (I), and can be conveniently prepared into various suitable dosage forms for clinical use.
  • Vaso-irritation, muscle stimulation tests indicate that the compounds of the present invention are suitable for intramuscular injection and intravenous injection, expand the range of clinical applications, and increase new varieties of anti-infective pharmaceutical preparations.
  • the present invention reduces the toxicity of the active substance compound (I) by preparing a pharmaceutically acceptable salt of the compound (I), and increases the safety of clinical use. Further, the production process of the present invention is simple and reasonable, has low production cost, and has industrial applicability.

Abstract

L'invention concerne un composé de quinolone anti-infectieux, son procédé de préparation et son utilisation. L'invention concerne également un sel pharmaceutiquement acceptable d'acide 6-fluoro-1-methyl-4-oxo-7- (1- piperazinyl) - 4H -[1,3]thiazeto[3,2-a]quinoline-3-carboxylique (I) séparé par cristallisation d'un solvant, suivie d'une réaction du composé (I) avec des acides pharmaceutiquement acceptables à l'aide d'eau ou d'eau contenant un solvant organique comme solvant. Le composé obtenu présente une structure définitive, est stable et possède un effet antibactérien confirmé. La solubilité de l'eau du composé (I) a été améliorée de la manière précitée, ce qui convient pour produire des formes de dosage appropriées pour un usage clinique afin d'étendre son utilisation. La préparation du sel pharmaceutiquement acceptable du composé (I) permet de réduire la toxicité du composé actif (I) et d'améliorer la sécurité de son usage clinique.
PCT/CN2007/000180 2006-01-18 2007-01-18 Composé de quinolone anti-infectueux, son procédé de préparation et son utilisation WO2007082472A1 (fr)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
CN200610033028.0 2006-01-18
CN200610033039.9 2006-01-18
CN200610033042.0 2006-01-18
CN200610033034.6 2006-01-18
CN 200610033033 CN101003541A (zh) 2006-01-18 2006-01-18 一种广谱抗菌化合物及其用途
CN200610033033.1 2006-01-18
CN 200610033034 CN101003542A (zh) 2006-01-18 2006-01-18 一种广谱杀菌化合物及其用途
CN 200610033042 CN101003543A (zh) 2006-01-18 2006-01-18 一种抗感染化合物及其用途
CNA2006100330280A CN101003540A (zh) 2006-01-18 2006-01-18 一种抗感染化合物和用途
CN 200610033039 CN101003534A (zh) 2006-01-18 2006-01-18 一种抗菌化合物及其用途

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2009121303A1 (fr) * 2008-04-03 2009-10-08 广州白云山制药股份有限公司广州白云山制药总厂 Sels pharmaceutiquement acceptables de la quinolone, un anti-infectieux
CN102584859A (zh) * 2011-12-31 2012-07-18 广州医药工业研究院 乳酸左旋尤利沙星晶体及其制备方法和用途

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CN1033055A (zh) * 1987-11-07 1989-05-24 日本新药株式会社 喹啉羧酸衍生物
US4843070A (en) * 1986-05-14 1989-06-27 Nippon Shinyaku Co., Ltd. Substituted thiazetoquinoline-3-carboxylic acids and pharmaceutically acceptable salts thereof

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US4843070A (en) * 1986-05-14 1989-06-27 Nippon Shinyaku Co., Ltd. Substituted thiazetoquinoline-3-carboxylic acids and pharmaceutically acceptable salts thereof
CN1033055A (zh) * 1987-11-07 1989-05-24 日本新药株式会社 喹啉羧酸衍生物

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009121303A1 (fr) * 2008-04-03 2009-10-08 广州白云山制药股份有限公司广州白云山制药总厂 Sels pharmaceutiquement acceptables de la quinolone, un anti-infectieux
EP2258705A1 (fr) * 2008-04-03 2010-12-08 Guangzhou Baiyunshan Pharmaceutical Co. Ltd. Guangzhou Baiyunshan Pharmaceutica Factory Sels pharmaceutiquement acceptables de la quinolone, un anti-infectieux
EP2258705A4 (fr) * 2008-04-03 2011-03-30 Guangzhou Baiyunshan Pharmaceutical Co Ltd Guangzhou Baiyunshan Pharmaceutica Factory Sels pharmaceutiquement acceptables de la quinolone, un anti-infectieux
CN102584859A (zh) * 2011-12-31 2012-07-18 广州医药工业研究院 乳酸左旋尤利沙星晶体及其制备方法和用途
CN102584859B (zh) * 2011-12-31 2014-08-20 广州医药工业研究院 乳酸左旋尤利沙星晶体及其制备方法和用途

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