WO2007082471A1 - Anti-infective compound, preparation method thereof and use thereof - Google Patents

Abstract

Anti-infective compound, preparation method thereof and use thereof. The present invention disclosed a crystal of 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (II) methanesulfonate, which is separated out by solvent crystallization following the reaction of compound (II) with pharmaceutical methanesulfonic acid using water or water containing organic solvent as solvents. The obtained compound has a definitive structure. It is stable and has confirmed anti-bacterial effect. The water solubility of compound (II) has been improved by this way, and it is convenient to make appropriate dosage forms for clinic use to expand the extension of clinic use. By preparing the methanesulfonate of compound (II), the toxicity of the active compound (II) has been reduced and the safety of its clinic use has been improved.

Description

An infection of the compounds and methods of use and anti Field The present invention relates to a quinolone anti-infective drugs, particularly relates to 6-fluoro --1- methyl --4-- oxo-7- (1-piperazinyl) - 4H- [1, 3] oxetanyl embankment and diltiazem [3, 2- a] quinoline --3- acid methanesulfonate and methods of preparation and use thereof. BACKGROUND OF THE INVENTION Quinolones developed rapidly in recent years antibiotics having a broad spectrum antimicrobial, antibacterial and strong, simple structure, ease of administration, without cross-resistance to other commonly used antibiotics, higher efficacy than the price, and therefore, more more attention to countries, competing to become the production of medicines and hot applications. Marketed quinolone products are dozens of varieties, it is one of the areas of anti-infectives concurrency and most active.

6-fluoro --1- methyl-4-oxo-7- (1_-piperazinyl) - 4H- [1, 3] thiazeto [3, 2 a] quinoline-3-carboxamide acid (UFX, NM394) is a very significant protective effect against infections quinolone, in chemical Abstracts CA _{108: p94537d; 111: pl94791n;} 113: p231357q; 116: p 41483s; 124: pr8660q; 128: 123459a , etc. It reported that it has broad-spectrum antibacterial activity against Gram-positive and Gram-negative bacteria, especially Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, mucus marcescens, Pseudomonas aeruginosa and other bacteria show powerful antibacterial effect. Nippon Shinyaku with Meiji Seika Corporation jointly developed in a 6-fluoro - 1 -methyl-4-oxo-7- (1-piperazinyl) - 4H- [1, 3] thiazeto and [3, 2- _a] quinoline --3- acid II is an oral formulation of the active form of the prodrug, drug named Prulifloxacin. Since the compounds II (NM394) is insoluble in water, so the impact of their drug use.

NM394 addition insoluble in water, which affect the use of the drug, its intravenous toxicity is pharmaceutically acceptable impact reasons, according to the literature large (bandit 394) intravenous dose toxicity UFX. Workers in shida S 1996 Toxicity studies in rats reported that intravenous bandit 394 around the male and female Sprague- Drwlog rats were intravenously at a dose of 3, 10 and 30mg / kg bandit 394, four weeks, 10, 30mg / water consumption and urine of rats displacement kg dose significantly increased urinary sediment found in the crystalline material and small epithelial cells. 30m _g / kg dose of rat urine appears turbid phenomenon, 10

1

And confirm that the 30mg / kg dose group blood Y - paresis, 10 and 30mg / kg mice increased blood urea nitrogen and creatinine, which indicate renal function has been compromised, in addition, and 30mg / kg dose group, 10 rats pathological changes, such as tubular nephropathy, also found that the crystalline substances; 30mg / kg increase in weight of the rat kidney and caecal dose group; and the other changes in blood Y - outer globulin, are reversible, 3mg / kg dose group found no significant problems, it should be N0AEL 394 rats is 3mg / kg.

The study clearly, no adverse reactions dosage is 3mg / kg, a dose equivalent to about law converter 35 m _g / 70kg person, this is a very low dose, we know prulifloxacin normal dose 200-60 mg / day (394 dollars to Korea), the results suggest that NM394 intravenous administration too toxic, no clinical application prospects.

Although EP0315828 and US4, 843, 070 discloses 6-fluoro --1- methyl --4- oxo --7- (1-piperazinyl) 4H- [1, 3] thiazeto [3 , 2-a] quinoline --3--carboxylic acid and its preparation method, but also pointed out some of its pharmaceutically acceptable salts, but does not disclose how to obtain a good water-soluble 6-fluoro --1- methyl --4- oxo-7- (1-piperazinyl) - 4H- [1, 3] thiazeto [3, 2-a] quinoline _3 - carboxylic acid derivative, its scope of application and thus greatly limit. SUMMARY

Object of the present invention is to provide a readily water-soluble, low toxicity and can be administered by injection, the safety of quinolone anti-infective compound and good preparation method and use of the compound.

The present inventors have found that 6-fluoro --1- methyl --4- oxo-7- (1-piperazinyl) - 4H [1, 3] thiazeto [3, 2- a] quinoline --3- acid methanesulfonate is reacted with controlling the reaction conditions to obtain a quinolone compound as a crystalline salt of formula I, the chemical name is 6-fluoro --1- methyl-4-oxo 7- (1-piperazinyl) - 4H- [1, 3] thiazeto [3, 2- a] quinoline-3 - carboxylic acid methanesulfonate:

The crystalline salts have unexpectedly high water solubility, so that the application or use of quinolone anti-infective compound to be significantly widened. For example, the anti-infective composition of the crystalline salt prepared, tablets of one administration of either gastrointestinal, gum hall or granules, may be non-parenteral administration injections, ophthalmic preparations , otic preparations, gynecological formulations or skin external preparation. .

Compound I crystalline powder having the following values ​​(see Figure 1 pattern) X- ray powder diffraction pattern with Cu-Ko-ray measurements obtained in 2Θ, d- spacings and relative intensities (1/1.):

2 Θ d 1/1.

5. 520 15. 99 ± 0. 2 0. 84-1. 00

10.320 + 0.2 8.56 0. 65-0. 78

11. 100 7. 96 ± 0. 2 0. 83-0. 96

14. 040 6. 30 ± 0. 2 0. 42-0. 64

14 420 6.13 0.2 0.5 Soil 24-0. 45

16. 340 5. 42 ± 0. 2 0. 25-0. 46

16. 880 5. 24 ± 0. 2 0. 27-0. 51

17.780 + 0.2 4.98 0. 29-0. 49

18. 740 4. 73 ± 0. 1 0. 46-0. 72

19.820 + 0.1 4.47 0. 39-0. 58

22. 720 3. 91 ± 0. 1 0. 35-0. 63

26.140 + 0.1 3.40 0. 52-1. 00

26. 800 3. 32 ± 0. 1 0. 45-1. 00

NMR _{NMR (DMS0-d 6, 500Hz} ) confirmed the structure of compound I of formula I as described above. IR IR (KBr, cm- ¹⁾ further confirmed the structure shown in the above formula I.

Elemental analysis data produced by the present process to give compound I as follows:

This product is soluble in water and insoluble in methanol, ethanol, acetone and ether.

Preparation of the compounds I of the present invention is achieved by providing the following means: water or an organic solvent-containing 5~50% by volume percent of water as a solution, at 0~60 ° C was added 6-fluoro-1-methyl-4 - oxo-7- (1-piperazinyl) - 4H- [1, 3] thiazeto [3, 2- a] quinoline --3--carboxylic acid (compound II) and methanesulfonic acid , the amount of the solution is 5~50 times the weight of the compound II and dissolved with stirring, 1 ~ by weight of compound II is added: L00 times organic solvent, i.e. precipitated compounds I, II, and the feed molar ratio of methanesulfonic acid 1 : 0. 8~1 5, wherein said organic solvent is either methanol, ethanol, isopropanol, acetone, tetrahydrofuran.

The present invention further provides an anti-infective composition, which is a compound I as an active ingredient quinolones, and contains conventional pharmaceutical carriers. DETAILED parenteral administration may be tablets, capsules, granules, or non-parenteral administration injections, ophthalmic preparations, otic preparations, gynecological preparations, skin external preparations.

The composition can be used for parenteral administration, such as made of capsules, tablets or granules, based on the quinolone compound I with conventional pharmacologically compatible excipients, such as starch, maltose, sucrose, carbonate or calcium phosphate; binders such as starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose; a lubricant such as magnesium stearate or talc; disintegrants such as carboxymethyl calcium or talc mixed powder, prepared by conventional formulation methods. The composition so prepared is usually, Compound I is mixed with at least one of the above carriers or excipients, the compound I as a percentage of the total composition is generally from 0. 1~100% (W / W).

Anti-infective composition comprising a compound I of the present invention is provided, may also be used for parenteral administration, such as an injection, 'ophthalmic preparations, otic preparations, gynecological preparations, skin external preparations and the like. Compound I ratio of the total composition is generally 0. 1~100% (W / W).

The present invention has the following advantages:

1, provides a superior anti-inflammatory effects of quinolone compounds, their structure determined, stable, soluble in water, can be conveniently prepared in various dosage forms suitable for clinical use.

2. Preparation of the production process of the present invention is simple, rational and low production cost.

3, an increase of new varieties antiinfective formulations, improved pharmaceutical active compound ([pi) i.e. the water-soluble NM394, vein irritation, muscle stimulation test indicate that the compounds of the present invention is suitable for intravenous and intramuscular, expanding clinical application.

4, by preparing compound (II) methanesulfonate i.e. NM394, NM394 reduced toxicity of the active material, the increase in clinical drug safety. Advantageous effects of the present invention will be described below by test examples.

Test Example 1: Stability test factors present invention provides compound I

Test sample: 01 cases, see Sample 2 provided the following embodiment, the compounds provided by the test method of the present invention:

1, mass measurement method

1) Determination method: high performance liquid chromatography (Chinese Pharmacopoeia 2005 Appendix VD) determination.

Chromatographic conditions and system suitability test: octadecylsilane bonded silica as a filler; acetonitrile - 0. 005mol / l sodium dihydrogen phosphate solution (take 0. 005mol / l sodium dihydrogen phosphate solution 100ml, was added triethylamine amine 0. 2 ml, pH adjusted to 6.0 with phosphoric acid) (40: 60) as mobile phase; flow rate 1. 0ml / min; detection wavelength 278nm. Number of theoretical plates 6_ fluoro - 1 -methyl-4-oxo-7- (1-piperazinyl) - 4H- [1, 3] thiazeto [3, 2- a] quinolin morpholine --3- the carboxylic acid should not be less than 2000; 6-fluoro - 1 -methyl-4-oxo --7- (1-piperazinyl) - 4H- [1, 3] thiazeto and [3, 2-a] quinoline --3- acid peak and the adjacent impurity separation should meet the requirements.

Determination Methods: Compound I about 10m _g, accurately weighed, 100ml flask, add the mobile phase amount of ultrasound treatment to dissolve and dilute made solution containing about 50μ per lml. The precise amount of 20μ1, into the liquid chromatograph, record the chromatograms; Another 6-fluoro --1- methyl-4-oxo --7- (1-piperazinyl) - 4Η- [1, 3] diltiazem oxetanyl embankment and [3, 2- a] quinoline --3--carboxylic acid (reference) about 10mg, the same method. By external standard method with peak area calculation, that is, too. Compound I containing 6-fluoro - 1 - methyl --4- oxo-7- (1-piperazinyl) - 4Η- [1, 3] oxetanyl embankment and diltiazem [3, 2- a] quinolin morpholine --3- acid is 75~81%.

Methods for determination of pH 2) Sample: The solution of compound I, per 10ml of water was added an aqueous solution containing 0. lg of Compound I is made, according to the determination.

3) clarity and color of the sample: of compound I, per 10ml of water was added water to make a solution containing 0. lg of compound I, according to the determination.

2, the test light

The sample 01 is placed under the tester medicament light, light intensity 4500LX ± 500LX, for 5, 10 days after sampling observe the color, pH measurement, clarity, content. The results in the table below. Sample Time (days) pH value of the color content of clarified%

010 2.89 <1 <1 79.5

5 2.90 <1 <1 79.4

10 2.91 <1 <1 79.3

The results showed that 01 samples were stable under illumination.

3, high-temperature test

The samples were placed in 01 incubator 60Ό placed observe the color sample 5, after 10 days, the PH value measurement, clarity, content. The results in the table below.

The results show that the sample 01 is placed at a high temperature product content, color, clarity and no significant changes in pH value, so this product is stable.

4, humidity test

The samples were placed in 01 persons 25 persons 2 ° C RH95 5% relative humidity conditions, placing observe the color sample 5, after 10 days, pH measurement, clarity, content. The results in the table below.

The results show that the product is placed in a high humidity content, color, clarity and no significant changes in pH value, so this product is stable.

Experiment 2: Antimicrobial Test of Compound I of the present invention is provided, the lowest concentration measuring MIC. Test Methods: General plate dilution method in vitro antibacterial test

Sample 02 is a compound _II,; sample 01, the compounds I of the present invention is provided.

test results:

Bacterial name MIC90 values ​​(g / ml)

Samples 02 samples 01 gold aureus 0.5 0.5

Streptococcus pneumoniae 2 ^ 2.2

4 3.9

f less 0.25 0.25

Pseudomonas aeruginosa 2 2.0

Escherichia coli 0.06 0.06

Klebsiella pneumoniae ^ 0.06 0.07

0.06 0.06

Test results indicate that compounds I also have a broad antibacterial spectrum against Gram-positive bacteria and gram-negative bacteria with the compound II, especially Pseudomonas aeruginosa, Serratia, Enterobacter and other Gram-negative bacteria exhibit powerful antibacterial effect.

Test Example 3, continuous intravenous administration of 28 days toxicity test:

80 test using SD rats, weight and sex by animals were randomly divided into 4 groups, 20 per group, male and female. Provided compound I (M394 mesylate) 10, 30, 60mg / kg dose groups three and a blank control group, tail vein injection, once a day for 4 weeks, the recovery observed for 2 weeks. Daily observation of general health status, statistics weekly body weight, food consumption, taking the end of the administration half of the animals are bled and urine was collected for blood biochemistry, electrolytes, urinalysis testing, while generally do necropsy were sacrificed for pathological examination, and taking femur, wrist cartilage, femoral articular cartilage, brain (cerebrum, cerebellum, brainstem), spinal cord (cervical, thoracic, lumbar), pituitary, thymus, thyroid, parathyroid, esophagus, salivary glands, stomach, duodenum , ileum, colon, liver, gallbladder, kidney, adrenal, spleen, pancreas, trachea, lung, aorta, heart, epididymis, testes, ovaries, uterus, prostate, breast, sciatic nerve, bladder, ocular (eye examination found abnormal) , optic, local administration (tail vein), the sternum (bone and bone marrow), lymph nodes (mesenteric lymph nodes) and other fixed with 10% formalin; organs of liver, kidneys, jejunum, cecum, bladder drawn first, conventional paraffin section, slice thickness of about 4μιη, Η-Ε staining, OLYMPUS BX40 optical microscopy Observed. The remaining animals for recovery to take the observation and detection index.

The results showed that:,

lOmg / kg'bw dose rats urine pH decreased slightly, no toxicologically significant changes. 30 mg / kg * bw portion rat serum urea nitrogen dose groups increased, reducing the pH of the urine of male rats. In Serum urea nitrogen and creatinine 60mg / kg * bw dose groups increased significantly, decreased urine pH, urine seen in mildly affected individual rats crystalline material of the hip joint and wrist; kidney organ coefficient significantly rise, tubular mild expansion, mild renal tubular epithelial degeneration, renal protein casts, crystals and cell tube portion rats had formed. Showed that the high dose group rat kidney has been damaged, the kidneys have a certain toxicity. In the recovery period, the animals in each treatment group and biochemical examination histopathological examination showed no changes have toxicological significance, suggesting NM394 methanesulfonate rats induced toxicity is recoverable, no delayed toxicity .

Based on the above findings, intravenous injection of NM394 methanesulfonate nontoxic dose response of rats is 30 mg / kg »bW o

Results of this study and the results of different studies Ishida toxic injection around NM394 S (1996) reported in rats were intravenously: NM394 mainly in the nephrotoxic effects (10, 30mg / kg-bw dose group appeared renal toxicity, blood urea nitrogen and creatinine significantly increased, but its toxicity is reversible; non-toxic-effect dose was 3 mg / kg, bw); but decreased urine pH NM394 methanesulfonate 10 mg / kg * bw dose group showed only, not other significant observed symptoms of poisoning, while the same dose of NM394 nephropathy occurs, and the crystalline material urinary blood urea nitrogen and creatinine increased significantly, which is 60 mg / kg «bw dose NM394 mesylate changes consistent , to approach the degree of change in 60 mg / kg «bw dose of this sulfonate with ΝΜ394 a 30mg / kg * bw of NM394 addition to the above symptoms, the phenomenon also appeared turbid urine and blood γ- globulin reduced.

Based on the above findings, intravenous injection of NM394 methanesulfonate nontoxic dose response in rats of 30 mg / kg * bw. Rats were injected intravenously and the reported reaction NM394 nontoxic dose of 3mg / kg-bw, pharmaceutical compounds of the present invention, the reaction is greatly reduced toxicity. Test Example 4, vascular stimulation, muscle stimulation experiment:

1, Vascular stimulation test: The test drug with rabbit 2, the left rabbit ear administering a high concentration of test solution 1. 2mg / mL, to give the corresponding right rabbit ear low concentration test solution 0. 4mg / mL. Another rabbit as a blank control, an equal amount of right and left ears were given sodium chloride injection. Injections given once a day, for 3 consecutive days. 48 hours after the last administration autopsy. The results show visually observed, methanesulfonate high bandit 394, the low concentration of the test solution no irritation phenomena, rabbit ear blood vessel crisper, rabbit ear thickness uniformity, no obvious abnormalities.

2, muscle irritation test: Each rabbit was again purified by two, the left vastus administering a high concentration of the test solution 1.2mg / mL, the right vastus low concentration test solution to give the corresponding sample object is 0.4mg / mL. Another rabbit as a blank control, the left and right sides were treated with an equivalent amount vastus sodium chloride injection. Injections given once a day, for 3 consecutive days. 48 hours after the last administration autopsy. The results show visually observed, NM394 mesylate high concentration of the test solution in rabbits deep muscle tissue injection site with mild irritation, mainly for dispersion of acicular bleeding occurs, a low concentration of the test solution but no obvious abnormalities. ; BRIEF DESCRIPTION

1 is a X- ray powder diffraction pattern of Compound I is provided in Example 1 embodiment.

The following aspect of the invention is further illustrated by way of example, the present invention is not limited to the following embodiments. detailed description

Example 1

100L 50L reaction tank is added with water and ethanol 5L, 10K _g of Compound II was added at 15~20 ° C, added dropwise with stirring methanesulfonic acid 2. 8Kg, stirred for 30 minutes, 0. 5Kg needle with activated carbon, stirred for 15 min, filtered into the crystallizer 500L; the reaction tank was washed with 10L of water, filtered to 500L W is

Crystallization tank. Under stirring, added dropwise to about crystallizer isopropanol 350L, 3 hours + End isopropanol, and the precipitated solid. Insulation 5~: UTC stirred for 2 hours, filtered, washed once with 20L of isopropanol, and dried in vacuo at 35~40 ° C. 8.7Kg give compound I.

NMR _{'HNMR (DMS0-d 6,} D 2 0, 500Hz)

IR IR (KBr, cnT) data are as _{follows: 1698 (m, v c =} Q -carboxylic acid), 1628 (sc = ₀ ketone), 1628-1500 (m, s, v c = c ( aromatic ring, an aromatic heterocycle) ), 1457 (m,

), 1397 (m, S _QI1 carboxylic acid)

Product elemental analysis results are as follows:

CHNS analysis project measured value 4.86 9.56 7.39 52.11%

52.21 4.79 9.64 7.28 Calcd X- ray powder diffraction pattern 4.81 9.61 7.32 52.17% Cu- Kct ray measurements product was obtained in 2 Θ, d- spacings and relative intensities 1/1. It has the following values:

2 Θ d 1/1.

5.520 15.99 0.84

10.320 8.56 0.74

11.100 • 7.96 0.83

14.040 6.30 0.58

14.420 6.13 0.31

16.340 5.42 0.32

16.880 5.24 0.40

17.780 4 98 0.49

18.740 4.73 0.46

19.820 4.47 0.46

22.720 3.90 0.38

26.140 3.40 1.00

26.800 3.32 0.74

'Example 2

50L of water was added to the reaction vessel and 15L of acetone was added 10Kg Compound II at 10~15 ° C, 2.8Kg of methanesulfonic acid was added dropwise with stirring, stirred for 1 hour, was added 0.5Kg needle with activated carbon, stirred for 20 minutes, filtered off carbon; the filtrate was 0.22 μ m membrane into a sterile pressure chamber 500L crystallizer. 10L reaction tank was washed with water and pipes, is also pressed into the crystallizer. Open stirring, acetone was added dropwise 350L, 4 hours + End acetone to precipitate a solid. Insulation 0~5 ° C for 5 hours, filtered, washed twice with acetone 30LX2, 35~40 ° C and dried in vacuo. Sterile powders to obtain Compound I 8, 4Kg.

¹ H NMR bandit _{R (DMS0-d s, D} 2 0, 500Hz), infrared IR (KBr, cm- ^1), X- ray powder diffraction data and the same as in Example 1. Example 3

In a three-necked 100ml flask was added 50ml of water, 10g of compound II at 0~5 ° C, methanesulfonic acid dropwise with stirring at 4. l _g, stirred for 30 minutes, was added 0.5g needle with activated carbon, stirred for 15 minutes, decarburization filtered; washed with water 10ml 3-necked flask, and filtered. The filtrates were combined into a three-necked 500ml flask with stirring was added dropwise 350 ml of ethanol, 2 hours + End mixed solution to precipitate a solid. Insulation 15~20 ° C for 2 hours, filtered, washed with anhydrous ethanol 20ml once, and dried in vacuo 35~40 ° C. 6. 9g to give compound I.

NMR _{^{1 HNMR (DMS0- d 6, D}} 2 0, 500Hz), infrared IR (KBr, cm ^-1), X- ray powder diffraction data and the same as in Example 1. Example 4

In a three-necked 100ml flask was added 40ml of water and 5ml of ethanol, 10g of compound II at 10~15 ° C, added dropwise with stirring methanesulfonic acid 2. 5g, stirred for 20 minutes, was added 0. 5 _g needle with activated carbon, stirred for 15 minutes, filtered decarburization; 3-necked flask washed with 10ml water, and filtered. The combined filtrates to 500ml three-necked flask, with stirring, a solution of acetone 1000ml, 4 hours + End acetone to precipitate a solid. Insulation 15~20 ° C for 2 hours, filtered, washed with 20ml of acetone once, and dried in vacuo 35~40 ° C. 5. 9g to give compound I. Example 5

In a three-necked 100ml flask was added 200ml of water and 50ml of methanol, 5g of compound II at 55~60 ° C, methanesulfonic acid was added dropwise with stirring under 1. lg, stirred for 30 minutes, activated carbon was added 0. 2g needle, stirring 15 minutes, filtered decarburization; 3-necked flask washed with 10ml water, and filtered. The combined filtrate was taken to 250ml three-necked flask, stirred at room temperature, tetrahydrofuran was added dropwise 500ml, 2 hours + End of tetrahydrofuran, and the precipitated solid. Insulation 15~2 (TC stirred for 2 hours, filtered, washed with 20ml of acetone once, 35~40 ° C and dried in vacuo to give 2. lg compound I. Example 6

In a three-necked 100ml flask was added 25ml of tetrahydrofuran and 15ml of water, 10 _g of Compound II was added at 25~30 ° C, added dropwise with stirring methanesulfonic acid 2. 3g, stirred for 60 minutes, was added 0. 5 _g of activated carbon needle , stirred for 15 minutes, filtered decarburization; 3-necked flask washed with 10ml water, and filtered. The combined filtrates to 100ml three-necked flask, with stirring, acetone was added dropwise 10ml, 10 minutes plus End acetone to precipitate a solid. Insulation 15~20 ° C for 2 hours, filtered, washed with 10ml of acetone once, 35~40 ° C and dried in vacuo to afford compound I. 2. 5g Example 7

100L was added in a reaction tank of water, was added compound Π 10Kg at 10~15 ° C, 2.8Kg of methanesulfonic acid was added dropwise with stirring, stirred for 1 hour, 0.5K _g needle with activated carbon, stirred for 20 minutes, filtered decarburization ; the filtrate was 0.22 μηι ultrafiltration, freeze solution was placed in a lyophilizer one thousand, to give lyophilized powder of compound I 8.4Kg.

Preparation Example 8 injections

Take the embodiment obtained in Example 1 25.6g of Compound I was added to 15~20 ° C 5L 0.9% sodium chloride solution. After stirring to dissolve, was added 0.3g needle with activated carbon, stirred for 10 minutes, filtered decarburization; with 0.45μηι membrane filter, and then 0.22 μιη membrane filter, plus 0.9% sodium chloride solution to a total volume of 10L, the content of the measurement, inspection clarity, filled into infusion bottles 100ml, tamponade rolled aluminum cap, 121 ° C sterilization 20min. Preparation Example 9 Injection of

Take the embodiment obtained in Example 1 12.8g of Compound I was added to 15~20 ° C in 2L of 5% glucose solution, stirred and dissolved, was added 0.3g needle with activated carbon, stirred for 10 minutes, filtered decarburization; filter with 0.45 m filtered, and then 0.22 μηι membrane filter, plus 5 ° /. Glucose solution to a total volume of 10L, the content of the measurement, inspection clarity, filled into infusion bottles 100ml, aluminum rolling tamponade cap 121. C sterilization 20min. Example 10 Preparation of injections embodiment

Take the embodiment obtained in Example 1 was added to 128g of Compound I of water for injection in 500ml 15~20 ° C and dissolved with stirring, was added 5g of activated carbon needle, stirred for 10 minutes, filtered decarburization; 0.45μπτ membrane filtration, and then 0.22 μπι membrane filter, to the total amount of water for injection lOOOOml, determination of inspection clarity, the potting nitrogen to 10ml of bottle security berkelium, 121Ό sterilization 20rain. Example 11 Preparation of powder

Take a sterile powder of Compound I obtained in Example 2 was dispensed into 0.128g / bottle, 0.192g / bottle, 0.256g / bottle, 0.320g / bottle, 0.384g / bottle, 0.512g / vial under aseptic conditions or 0.640g / bottle, sterile powders to give compound I injectable preparation. Example 12 Preparation of injections embodiment

Sterile powder of Compound I obtained in Example 7 embodiment taken under sterile conditions into dispensed 0.128g / bottle, 0.192g / bottle, 0.256g / bottle, 0.320 _g / bottle, 0.384g / bottle, 0.512g / bottle or 0.640g / bottle, a sterile lyophilized powder injectable preparation of compound I. Example 13 Preparation of tablets embodiment

Prescription (1k amount): Compound I 128g, lactose 1. 9g, 10% PVP solution 10ml, magnesium stearate 0. 52g.

Preparation: Take 1 of the compound obtained in Example I is mixed with lactose in a fluid bed granulator hair for 10 minutes to mix, and then injected into a solution of 10% PVP, the wind speed of about 120 m / h, the speed is about injected 2~3ml / min, 60 ° C hot air dry in about 15 minutes, magnesium stearate is added after mixing, tabletting, coating derived. Example 14 Preparation of capsules embodiment

Prescription (a prescription amount of a): Compound I 128g, microcrystalline cellulose 40g, starch carboxymethylcellulose within ¾ ^ 50 _g, stearyl vine 3.4g.

Preparation: The formulation of raw materials, after fully mixed, filled into empty capsules No. 4, that is, too. Granules prepared in Example 15

Prescription: Compound I 128g, dextrin 120g, sucrose sugar 280g.

: Compound I and sucrose obtained in Example 1 of the embodiment taken pulverized into powder, mixing, wet granulation to, underlying 60Ό, sufficiently dried, packaging, i.e., too. Example 16 Preparation of eye drops

Prescription: Compound I 3.84g, NaCl 0.9g, an appropriate amount of borate buffer solution, phenylethyl alcohol 3g, 7, a total of 1000 ml c

: Compound I obtained in Example 1 and sodium chloride were added to 600ml embodiment taken distilled water and completely dissolved under stirring, was added boric acid buffer solution to adjust the solution to pH 6.5; taken phenylethanol Further, 200ml of distilled water was added to dissolve the boiling ; the above two solutions were mixed, add distilled water to a total volume of 1000ml, stir with a 0. 22 μ πι filter membrane, filling, sealing strict, 10CTC sterilized 30 minutes to the circulation steam sterilization, packaging , that is, too. Preparation Example 17 ear drops

Prescription: Compound I 12.8g, ethanol 300 ml, glycerol 300 ml, water ¾¾, a total of 1000 ml

Preparation: Take embodiment 12. 8g Compound I obtained in Example 1 was dissolved in 200ml water for injection, and 300ml of ethanol was added 2.00 mL of glycerin, water for injection was further added to a total volume of 1000ml, stir with a 0. 22 μ millipore filtering, filling, that is, too. Example 18 Preparation of suppositories

Prescription: Compound 1 12. 8g, cocoa butter 200g, 100 were made.

Preparation: The cocoa butter 200g, heated and melted in a water bath (temperature control 5CTC less), powder of compound I obtained in Example 1 of the embodiment '12. 8g (100 mesh pass) was added to melted cocoa butter, the edge was added with stirring, the drug uniformly dispersed in the matrix, and then dumped into the cooled suppository mold coated with a lubricant, the Calibrating be solidified, open mold, packing, ie. Example 12 Preparation external skin preparation according to the

Prescription: Compound I 128g, 85g of stearic acid, 170g of white petrolatum, glyceryl monostearate 43g, sodium alkyl with twelve 2g, glycerol 100g, triethanolamine 4g, X ethylparaben inch lg, the amount of water, a total of 1000g.

Preparation: 128g taken Compound I obtained in Example 1 was dissolved in 300ml of water, then take sodium lauryl sulfate, glycerin, triethanolamine, an aqueous solution of acetic acid aliphatic hydroxy compound and heating on a water bath until dissolved, and a temperature of about 70 ° C; another stearate, glycerol monostearate and white petrolatum was heated to melt all, until the temperature dropped to 70 ° C, was slowly added a solution of the item under constant stirring, and continue stirring to emulsify complete condensation, i.e., too. Industrial Applicability The present invention provides a quinolone anti-infective drug, having determined the structure, stability, antimicrobial efficacy, improved water-soluble active pharmaceutical compound ([pi) can be conveniently prepared by a variety of suitable dosage forms in clinical practice. Vascular stimulation, muscle stimulation test indicate that the compounds of the present invention is suitable for intravenous and intramuscular, expanding clinical application, adds new varieties antiinfective formulations. The present invention is by preparing compound (II) methanesulfonate, reduced toxicity active substance (II), an increase of clinical drug safety. Further preparation of the present invention production process is simple, rational, low production cost, having industrial applicability.

Claims

Rights request

1. A compound having the structural formula infection (I), anti-structure, the chemical name of the compound is 6-fluoro --1- methyl --4- oxo --7- (1-piperazinyl) -4Η- [ 1, 3] thiazeto [3, 2- a] quinoline-3-carboxylic acid methanesulfonate:

Wherein, X- ray powder diffraction pattern agent crystalline powder of the compound obtained by Cu-K a-ray measurements in 2 Θ, d- spacings and relative intensities have the following values:

2 Θ d 1/1.

5.520 15.99 ± 0.2 0. 84-1. 00

10.320 8. 56 ± 0. 2 0. 65-0. 78

11.100 7. 96 ± 0. 2 0. 83-0. 96

14.040 6. 30 ± 0. 2 0. 42-0. 64

14.420 6. 13 ± 0. 2 0. 24-0. 45

16.340 + 0.2 5.42 0. 25-0. 46

16.880 5. 24 ± 0. 2 0. 27-0. 51

17.780 4. 98 ± 0. 2 0. 29-0. 49

18.740 + 0.1 4.73 0. 46-0. 72

19.820 + 0.1 4.47 0. 39-0. 58

22.720 3. 91 ± 0. 1 0. 35-0. 63

26.140 3. 40 ± 0. 1 0. 52-1. 00

26.800 3. 32 ± 0. 1 0. 45-1. 00

2. A preparation as claimed in claim 1, the anti-compound of infection, characterized in that water or an organic solvent containing 5~50% by volume percent of water as solvent, at 0~60 ° C was added 6 - fluoro --1 - methyl - 4-oxo - 7- (l- piperazinyl) - 4H- [1, 3] thiazeto [3,2-a] quinoline --3- carboxylic acid (II) and methanesulfonic acid, the solvent in an amount of the compound (II) 5~50 times the weight of dissolved with stirring, was added the compound (Π) 1~100 times the weight of the organic solvent, i.e., a precipitated compound (the I), compound (II) and the molar ratio of methanesulfonic acid feed is 1: 0.8~1.5, wherein said organic solvent is arbitrary - methanol, ethanol, isopropanol, acetone, tetrahydrofuran

3 An anti-infective composition, the composition comprising an anti-infective compound as claimed in claim 1 as an active ingredient, and containing conventional pharmaceutically acceptable carriers.

4, according to claim 3 of said anti-infective composition, characterized in that the composition is a parenteral administration, tablets, capsules or granules.

5, according to claim 3 of said anti-infective composition, characterized in that the composition is a non parenteral administration injections, ophthalmic preparations, otic preparations, gynecological formulations or skin external preparation.