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

 FIELD OF THE INVENTION 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-[3,2-a]quinoline-3-carboxylic acid mesylate, preparation method and use thereof. BACKGROUND OF THE INVENTION Quinolones are antibacterial drugs that have been rapidly developed 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. It has become the hot spot drug for competing production and application. There are dozens of quinolone products on the market, and it is one of the most active areas of anti-infective drugs.

6-fluoro- 1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazetino[3,2 a]quinoline-3-carboxylate Acid (UFX, NM394) is a quinolone with a very significant anti-infective effect, 108 in the Chemical Abstracts CA, p94537d _, 111: pl94791n _, 113: p231357q _, 116: p 41483s, 124: pr8660q _, 128: 123459a, etc. It has been reported in the literature that it has a broad-spectrum antibacterial effect against Gram-positive bacteria and Gram-negative bacteria, especially for bacteria such as Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, Serratia marcescens, and Pseudomonas aeruginosa. Strong antibacterial effect. Japan New Drug Company and Meiji Fruit Co., Ltd. jointly developed 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazetidine And [3, 2- _a ] quinoline-3-carboxylic acid II is an oral preparation of a prodrug of the active substance, and the drug name is Prulifloxacin. Since Compound II (NM394) is insoluble in water, it affects the use of its drug.

In addition to being insoluble in water, NM394 affects the use of its drugs. The high toxicity of intravenous injection is also the cause of its medicinal use. According to the literature, UFX (匪394) is highly toxic. In 2009, Shida S reported the results of a toxicity study of 394 weeks of intravenous infusion in rats. Male and female Sprague-Drwlog rats were given intravenously at doses of 3, 10, and 30 mg/kg, for a period of four weeks, 10, 30 mg. The water consumption and urinary excretion of the rats in the /kg dose were significantly increased, and crystalline substances and small epithelial cells were found in the urine precipitate. Urine turbidity occurred in rats at 30 m _g / kg dose, 10

1

Confirmation In the 30 mg/kg dose group, blood Y-globulin decreased, and in the 10 and 30 mg/kg groups, blood urea nitrogen and creatinine increased, indicating that renal function has been impaired. In addition, pathology occurred in rats in the 10 and 30 mg/kg dose groups. Changes, such as tubular nephropathy, and the discovery of crystalline substances; the weight of the kidney and cecum of the 30 mg/kg dose group increased; the above changes were reversible except for blood Y-globulin, and the 3 mg/kg dose group did not. An obvious problem was found, so the N0AEL of 394 pairs of rats should be 3 mg/kg.

The above studies clearly indicated that the dose without adverse reactions was 3 mg/kg, and the dose conversion rule was equivalent to about 35 m _g / 70 kg, which is a very low dose. We know that the normal dose of prisafloxacin is 200-60 mg. / Day (in 394 liters), this result indicates that NM394 intravenous toxicity is too much, there is no prospect of clinical application.

 6-Fluoro-1-methyl-4-oxo-7-(1-piperazinyl) 4H-[1,3]thiazetetane[3] is disclosed in EP 0 315 828 and US Pat. No. 4,843,070. , 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- Oxo-7-(1-piperazinyl)-4H-[1,3]thiazetino[3,2-a]quinoline-3-carboxylic acid derivative, thus its application range is greatly affected limit. Summary of the invention

 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 inventors of the present invention found that 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H[1,3]thiazetetane[3, 2- a] quinoline-3-carboxylic acid is reacted with methanesulfonate to control the reaction conditions, and a quinolone compound crystal salt represented by the following formula I is obtained, and its chemical name is 6-fluoro-1-methyl-4-oxo -7-(1-Piperazinyl)-4H-[1,3]thiazetino[3,2-a]quinoline-3-carboxylic acid methanesulfonate:

The crystalline salt has an unexpectedly high water solubility, so that the use or application range of the anti-infective quinolone compound is greatly broadened. For example, an anti-infective pharmaceutical composition prepared from such a crystalline salt may be a tablet for gastrointestinal administration, a capsule or granule, or an injection for parenteral administration or an ophthalmic preparation. , otic preparations, gynecological preparations or external preparations for skin. .

 The 2Θ, d-plane spacing and relative intensity (1/1.) in the X-ray powder diffraction pattern of the crystalline powder of Compound I measured by Cu-Ko ray have the following values (see Figure 1 for the spectrum):

 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 soil 0. 2 0. 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 4. 98 + 0. 2 0. 29-0. 49

 18. 740 4. 73 ± 0. 1 0. 46-0. 72

 19. 820 4. 47 + 0. 1 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

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

 The elemental analysis data of Compound I prepared by this method are as follows:

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

The preparation method of the compound I provided by the invention is achieved by the following methods: The organic solvent has a volume percentage of 5 to 50% of water as a solution, and 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1, is added at 0 to 60 °C. 3] thiazetazo[3,2-a]quinoline-3-carboxylic acid (compound II) and methanesulfonic acid, the amount of the solution used is 5 to 50 times the weight of the compound II, after stirring and dissolving, The organic solvent is methanol and ethanol. The organic solvent is methanol or ethanol. The organic solvent is methanol and ethanol. The organic solvent is methanol and ethanol. Any one of isopropyl alcohol, acetone, and tetrahydrofuran.

 The present invention also provides an anti-infective pharmaceutical composition comprising a quinolone compound I as an active ingredient and a conventional pharmaceutical carrier. Specifically, it 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 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, sucrose, carbonic acid. Calcium or calcium phosphate; binders such as starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose; lubricants such as magnesium stearate or talc; decomposers such as carboxymethyl calcium or talc The powder phase is mixed and prepared by a conventional formulation method. 1〜100% ( W / W ) The ratio of the compound I to the total composition is generally 0. 1~100% (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).

 The invention has the following advantages:

 1. Provide a quinolone compound with excellent anti-infective effect. Its structure is determined, its properties are stable, and it is easily soluble in water. It can be conveniently prepared into various suitable dosage forms for clinical use.

 2. The preparation and production process of the invention is simple and reasonable, and the production cost is low.

 3. New varieties of anti-infective drug preparations have been added, and the water-soluble, vascular-stimulated, muscle-stimulating test of the active drug compound (Π), NM394, has been improved, indicating that the compound of the present invention is suitable for intramuscular injection and intravenous injection, and expands the clinical application range.

4. By preparing compound (II), that is, the mesylate salt of NM394, the toxicity of the active substance NM394 is lowered, and the safety of clinical use is increased. The beneficial effects of the present invention will be described below by way of test examples.

 Test Example 1 : Experiment on the influence factors of the stability of the compound I provided by the present invention

 Test sample: See sample 01 provided in Example 2 below, which is the compound test method provided by the present invention:

 1, quality measurement method

 1), content determination method: According to high performance liquid chromatography (Chinese Pharmacopoeia 2005 two appendix V D) determination.

 Chromatographic conditions and system suitability test: using octadecylsilane bonded silica as a filler; acetonitrile - 0. 005mol / l sodium dihydrogen phosphate solution (take 0. 005mol / l sodium dihydrogen phosphate solution 100ml, plus three The amine is 0. 2 ml, and the pH is adjusted to 6. 0) (40: 60) with a mobile phase; the flow rate is 1.0 ml/min; and the detection wavelength is 278 nm. The number of theoretical plates is 6_fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazetino[3,2- a]quina The carboxylic acid-3-carboxylic acid meter should not be less than 2000; 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazetidine The resolution of the [3, 2-a] quinoline-3-carboxylic acid peak and the adjacent impurity peak should meet the requirements.

Determination method: Take about 10m _{g of} compound I, accurately weigh it, put it into a 100ml volumetric flask, add the appropriate amount of mobile phase, sonicate and dissolve and dilute to make a solution containing about 50μ per lml. Precisely measure 20μ1, inject into the liquid chromatograph, record the chromatogram; take 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4Η-[1,3] sulfur nitrogen Heterocyclic butyrazino[3,2-a]quinoline-3-carboxylic acid (control) was about 10 mg, determined by the same method. According to the external standard method, the peak area is calculated. Compound I contains 6-fluoro-1- 1 -methyl-4-oxo-7-(1-piperazinyl)-4-yl-[1,3]thiazepine-[3,2- a]quina The porphyrin-3-carboxylic acid is 75 to 81%.

 2) Determination of pH of the sample: Take Compound I, add water to make a solution containing 0.1 g of Compound I per 10 ml of water, and determine according to law.

 3) Clarity and color of the sample: Take Compound I, add water to make a solution containing 0.1 g of Compound I per 10 ml of water, and determine according to law.

 2, light test

Sample 01 was placed under a medical light tester, and the light intensity was 4500 LX ± 500 LX. After 5 and 10 days of storage, the color was measured, and the pH, clarity, and content were measured. See the table below for the results. Sample time (days) pH value color clarity content%

 01 0 2. 89 < 1 <1 79. 5

 5 2. 90 < 1 < 1 79. 4

 10 2. 91 < 1 < 1 79. 3

 The test results show that sample 01 is substantially stable under illumination conditions.

3, high temperature test

 Sample 01 was placed in a 60-inch incubator, placed for 5, 10 days, and samples were taken to observe the color, pH, clarity, and content. See the table below for the results.

 The test results show that the sample 01 has no obvious change in content, color, clarity and pH value when it is placed at high temperature, so the product is stable.

 4, high humidity test

 The sample 01 was placed under a condition of 25 ± 2 ° C relative humidity RH 95 ± 5%, and placed for 5, 10 days, and the color was measured, and the pH, clarity, and content were measured. See the table below for the results.

 The 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.

 Test 2: The bacteriostatic test of the compound I provided by the present invention, the minimum concentration of M I C was determined. Test method: In vitro bacteriostasis test using conventional plate double dilution method

Sample 01, which is a compound I provided by the present invention _{; and} sample 02, is a compound II.

test results:

 Bacterial name MIC90 value (g/ml)

Sample 02 sample 01 Staphylococcus 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

 The test results show that Compound I has a broad-spectrum antibacterial effect on Gram-positive bacteria and Gram-negative bacteria and Compound II, especially for Gram-negative bacteria such as Pseudomonas aeruginosa, Serratia, Enterobacter and the like. Strong antibacterial effect.

Test Example 3. Continuous intravenous administration 28-day toxicity test:

Eighty SD rats were randomly divided into 4 groups according to animal weight and sex, 20 in each group, half male and half female. Compound I (M394 mesylate) 10, 30, 60 mg / kg three dose groups and a blank control group, tail vein injection, once a day, continuous administration for 4 weeks, resume observation 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. fixed with 10% formalin; for liver, kidney, jejunum, cecum, bladder and other organs, conventional Paraffin wax, slice thickness about 4μηη, Η-Ε dyeing, OLYMPUS BX40 optical microscopy Observed. During the recovery period, the remaining animals were taken to make the above observation and detection indicators.

 The results showed that:,

 In the lOmg/kg 'bw dose group, the urine pH was slightly decreased, and no toxicological changes were observed. The serum urea nitrogen of some rats in the 30 mg/kg*bw dose group increased, and the urine pH of male rats decreased. In the 60mg/kg*bw group, the serum urea nitrogen and creatinine were significantly increased, the urine pH was decreased, and the mild effects of crystal material, femoral joint and wrist joint were observed in the urine of individual rats; Ascending, some rats developed mild tubular dilatation, mild degeneration of renal tubular epithelium, renal protein cast, cell tubular type and crystal formation. It indicates that the kidneys of rats in the high-dose group have been damaged and have certain toxic effects on the kidneys. At the end of the recovery period, no toxicological changes were observed in the blood biochemical examination and histopathological examination of the animals in each administration group, suggesting that the toxicity of NM394 mesylate to rats was recoverable, and no delayed toxicity was observed. .

 Based on the above results, the amount of NM394 mesylate intravenously administered to rats was 30 mg/kg»bW o

 The results of this study are different from those reported by Ishida. S (1996) for intravenous injection of NM394 around rats: NM394 is mainly characterized by nephrotoxicity (10, 30 mg/kg-bw dose group, nephrotoxicity, blood urea nitrogen) And creatinine increased significantly, but its toxic effect is reversible; its non-toxic dose is 3 mg / kg, bw); but NM394 mesylate 10 mg / kg * bw dose group only showed a decrease in urine pH, not Other obvious symptoms of poisoning were observed, and nephropathy, urinary crystalline substances, and blood urea nitrogen and creatinine were significantly increased in the same dose of NM394, which was consistent with the change in the 60 mg/kg «bw dose group of NM394 mesylate. In addition to the above symptoms, NM394 at 30 mg/kg*bw also showed turbidity and decreased blood gamma globulin, which was similar to the change in the 60 mg/kg «bw dose group of ΝΜ394 mesylate.

According to the above results, intravenous NM394 mesylate salt is a non-toxic reagent for rats. The amount is 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. Test Example 4, Vaso Stimulation, Muscle Stimulation Experiment:

1. Vascular irritancy test: 2 rabbits were used for the test drug, and the left rabbit ears were given a high concentration test solution 1. 2 mg/mL, and the right rabbit ears were given a corresponding low concentration test solution 0.4 mg/mL. Another rabbit was taken as a blank control, and the right and left ears were given an equal 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 macroscopic observation showed that the 高 394 methanesulfonate high and low concentration test solution showed no irritating phenomenon, the rabbit ear blood vessel contour was clear, the rabbit ear thickness was uniform, and no obvious abnormal changes were observed.

2. Muscle irritation test: 2 rabbits were used for each test substance, 1.2 mg/mL of high concentration test solution was administered to the left femoral muscle, and 0.4 mg/mL of low concentration test solution of the corresponding test substance was administered to the right femoral muscle. 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. Visual observation showed that the NM394 mesylate high concentration test solution was mildly irritating to the deep muscle tissue of the rabbit injection site, mainly showing the occurrence of scattered needle-like bleeding points, but no significant abnormal changes were observed in the low concentration of the test solution. BRIEF DESCRIPTION OF THE DRAWINGS

 BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an X-ray powder diffraction pattern of Compound I provided in Example 1.

 The technical solutions of the present invention are further illustrated by the following examples, and 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 Minute, filter into 500L crystallization tank; wash the reaction tank with 10L water, filter to 500L W

 In the crystallization tank. Under stirring, about 350 L of isopropanol was added dropwise to the crystallization tank, and isopropanol was added over 3 hours to precipitate a solid. Incubation 5~: UTC was stirred for 2 hours, filtered, washed once with 20 L of isopropyl alcohol, and dried under vacuum at 35 to 40 °C. 8.7 Kg of Compound I was obtained.

Nuclear magnetic 'HNMR (DMS0-d ₆ , D ₂ 0 , 500Hz)

Infrared 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, aromatic heterocyclic) ), 1457 (m,

), 1397 (m, S _QI1 carboxylic acid)

 The product element analysis results are as follows:

 Analytical project C H N S measured value 52.11 4.86 9.56 7.39

52.21 4.79 9.64 7.28 Calculated value 52.17 4.81 9.61 7.32 The product has a 2 Θ, d-plane spacing and a relative intensity of 1/1 in the X-ray powder diffraction pattern measured by Cu-Kct ray. 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

 Add 50L of water and 15L of acetone to the reaction tank, add 10Kg of compound II at 10~15°C, add 2.8Kg of methanesulfonic acid with stirring, stir for 1 hour, add 0.5Kg of needle with activated carbon, stir for 20 minutes, filter off Carbon; The filtrate was pressed into a sterile chamber 500L crystallization tank through a 0.22 μm ultrafiltration membrane. Water 10L Washing the reaction tank and piping, and also pressing into the crystallization tank. After stirring, 350 L of acetone was added dropwise, and acetone was added over 4 hours to precipitate a solid. The mixture was stirred at 0 to 5 ° C for 5 hours, filtered, and washed twice with acetone 30 LX 2 and dried under vacuum at 35 to 40 ° C. A sterile powder of Compound I 8, 8, Kg was obtained.

Nuclear magnetic ¹ H匪R (DMS0-d _s , D ₂ 0, 500 Hz), infrared IR (KBr, cm- ¹ ), and X-ray powder diffraction data are the same as in Example 1. Example 3

Add 50 ml of water to a 100 ml three-necked flask, add 10 g of compound II at 0 to 5 ° C, add 4. l _{g of} methanesulfonic acid with stirring, stir for 30 minutes, add 0.5 g of needle with activated carbon, and stir for 15 minutes. Filter decarburization; wash the three-necked flask with 10 ml of water and filter. The filtrate was combined into a 500 ml three-necked flask and stirred. Next, 350 ml of ethanol was added dropwise, and the mixed solution was added over 2 hours to precipitate a solid. The mixture was stirred at 15 to 20 ° C for 2 hours, filtered, washed once with 20 ml of absolute ethanol, and dried under vacuum at 35 to 40 ° C. 6. g of compound I.

Nuclear magnetic ¹ H NMR (DMS0-d ₆ , D ₂ 0 , 500 Hz), infrared IR (KBr, cm ^-1 ), and X-ray powder diffraction data were 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, Stir for 15 minutes, filter for decarburization; wash the three-necked flask with 10 ml of water and filter. The filtrate was combined into a 500 ml three-necked flask. Under stirring, 1000 ml of acetone was added dropwise, and acetone was added over 4 hours to precipitate a solid. The mixture was stirred at 15 to 20 ° C for 2 hours, filtered, and washed with acetone 20 ml once, and dried at 35 to 40 ° C under vacuum. 5. g of compound I was obtained. Example 5

 2克针用活性碳,搅拌搅拌。 Add a mixture of 0. 2g of the activated carbon, stir, add 0g of the compound II, add 5g of the compound II. 15 minutes, decarburization by filtration; wash the three-necked flask with 10 ml of water and filter. The filtrate was combined into a 250 ml three-necked flask, stirred at room temperature, and 500 ml of tetrahydrofuran was added dropwise thereto, and tetrahydrofuran was added over 2 hours to precipitate a solid. Insulation 15~2 (TC stirring for 2 hours, filtration, acetone 20 ml once, 35~40 ° C vacuum drying, 2. lg compound I. Example 6

5克针用活性碳。 In a 100ml three-necked flask with the addition of 15ml of water and 25ml of tetrahydrofuran, at 25~30 ° C, 10 _{g of the} compound II, stirring with the addition of methane sulfonic acid 2. 3g, stirring for 60 minutes, adding 0. 5 _g needle with activated carbon Stir for 15 minutes, filter for decarburization; wash the three-necked flask with 10 ml of water and filter. The filtrate was combined into a 100 ml three-necked flask, and 10 ml of acetone was added dropwise with stirring, and acetone was added for 10 minutes to precipitate a solid. 5克化合物1。 I. Ig. Example 7

Add 100L of water to the reaction tank, add 10Kg of compound hydrazine at 10~15 °C, stir Add 2.8Kg of methanesulfonic acid dropwise, stir for 1 hour, add 0.5K _{g of} needle with activated carbon, stir for 20 minutes, filter and decarburize; filter the filtrate through 0.22 μηι ultrafiltration membrane, and put the solution into the freeze dryer to freeze the compound to obtain the compound. I lyophilized powder of 8.4Kg.

 Example 8 Preparation of Injection

 25.6 g of the compound I obtained in Example 1 was added to 5 L of a 0.9% sodium chloride solution at 15 to 20 ° C, and after stirring and dissolved, 0.3 g of a needle was added with activated carbon, stirred for 10 minutes, and decarburized by filtration; using 0.45 μηι Filter the membrane, filter with 0.22 μηη filter, add 0.9% sodium chloride solution to the total amount of 10L, measure the content, check the clarity, fill into the 100ml infusion bottle, press the rolled aluminum cover, 121 °C Sterilize for 20 min. Example 9 Preparation of Injection

 12.8 g of the compound I obtained in Example 1 was added to 2 L of a 5% glucose solution at 15 to 20 ° C, stirred and dissolved, and 0.3 g of a needle was added with activated carbon, stirred for 10 minutes, and decarburized by filtration; a filter of 0.45 m was used. Filter and filter with 0.22 μηι filter, add 5 ° /. Glucose solution to a total of 10L, determine the content, check the clarity, fill the 100ml infusion bottle, press the aluminum cap, 121. C kill bacteria for 20min. Example 10 Preparation of Injection

 The compound I obtained in Example 1 was added to 500 ml of water for injection at 15 to 20 ° C, stirred and dissolved, and then 5 g of the needle was added with activated carbon, stirred for 10 minutes, and decarburized by filtration; 0.45 μπτ filter was filtered, and 0.22 was further used. Filter through μπι filter, add water for injection to a total of lOOOOml, determine the content, check the clarity, fill with nitrogen in a 10ml ampoule, and sterilize for 20rain at 121Ό. Example 11 Preparation of powder injection

 The sterile powder of Compound I obtained in Example 2 was dispensed under sterile conditions into 0.128 g/bottle, 0.192 g/bottle, 0.256 g/bottle, 0.320 g/bottle, 0.384 g/bottle, 0.512 g/bottle or 0.640 g / bottle, a sterile powder injection preparation of Compound I was obtained. Example 12 Preparation of Injection

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

 Prescription (per 1,000 tablets): Compound I 128 g, lactose 1. 9 g, 10% PVP solution 10 ml, magnesium stearate 0. 52 g.

 Preparation: The compound I obtained in Example 1 and lactose were air-dried 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. 2~3ml/min, 60°C hot air flow for about 15 minutes, add magnesium stearate to mix, press, and coat. Example 14 Preparation of Capsules

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

 Preparation: Take the original and auxiliary materials in the prescription, mix well and fill them into the No. 4 empty capsules. Example 15 Preparation of granules

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

 Preparation: The compound I obtained in Example 1 and sucrose were pulverized into fine powder, mixed, and granulated by a wet method, placed under 60 Torr, sufficiently dried, and dispensed. Example 16 Preparation of Eye Drops

 Prescription: Compound I 3.84g, sodium chloride 0.9g, boric acid buffer solution, phenylethyl alcohol 3g, 7 , a total of 1000 ml c

 Preparation: The compound I obtained in Example 1 and sodium chloride was added to 600 ml of distilled water, and dissolved completely after stirring, and the pH of the solution was adjusted to be 6.5 by adding a boric acid buffer solution. Further, phenylethyl alcohol was added, and 200 ml of boiling distilled water was added to dissolve it. Mix the above two solutions, add distilled water to a total amount of 1000ml, stir well, filter with 0.22 μππ microporous membrane, fill, seal tightly, sterilize with 10CTC for 30 minutes, steam sterilization, dispense , that is. Example 17 Preparation of ear drops

 Where: Compound I 12.8g, ethanol 300 ml, glycerin 300 ml, water 3⁄43⁄4, total 1000 ml

Preparation: 12. 8g of Compound I obtained in Example 1 was dissolved in 200ml of water for injection, Add 300 ml of ethanol and 2.00 ml of glycerin, add water for injection to a total amount of 1000 ml, stir well, filter with 0.22 μm microfiltration membrane, and fill. Example 18 Preparation of suppository

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

 Preparation: 200 g of cocoa butter was heated and melted on a water bath (temperature controlled below 5 CTC), and the fine powder of Compound I obtained in Example 1 was taken. 12.8 g (over 100 mesh sieve) was added to the melted cocoa butter. Stirring is carried out to uniformly disperse the drug in the matrix, and then poured into a bolt which is cooled and coated with a lubricant, which is to be solidified, then flattened, opened, and packaged. Example 12 Preparation of topical skin preparation

 Prescription: Compound I 128g, stearic acid 85g, white petrolatum 170g, glyceryl monostearate 43g, sodium decyl sulfate 2g, glycerol 100g, triethanolamine 4g, X-hydroxy hydroxybenzoate lg, water amount, A total of 1000g.

 Preparation: 128 g of Compound I obtained in Example 1 was dissolved in 300 ml of water, and then an aqueous solution of sodium lauryl sulfate, glycerin, triethanolamine, ethyl p-hydroxybenzoate and Compound 1 was placed, and heated to a total dissolution in a water bath. And the temperature is about 70 ° C; another take stearic acid, white petrolatum and glyceryl monostearate, heated to full melting, until the temperature drops to about 70 ° C, slowly add the above solution with constant stirring, And continue to stir until the emulsification is complete, condensation, that is. Industrial Applicability The present invention provides a quinolone anti-infective drug which has a structure-determined, stable property, and has an antibacterial effect, and improves the water solubility of the active drug compound (Π), and can be conveniently prepared into various suitable dosage forms. In the clinic. Vaso-irritation, muscle stimulation tests indicate that the compounds of the present invention are suitable for intramuscular and intravenous injections, expand the range of clinical applications, and increase new varieties of anti-infective pharmaceutical preparations. The preparation of the mesylate salt of the compound (II) by the invention reduces the toxicity of the active substance (II) and increases the safety of clinical use. In addition, the preparation and production process of the invention is simple and reasonable, the production cost is low, and the industrial applicability is obtained.

Claims

Rights request

 An anti-infective compound having the structure of the formula (I), the chemical name of which is 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4Η-[ 1, 3]thiazetino[3,2-a]quinoline-3-carboxylic acid mesylate:

 It is characterized in that the 2 Θ, d-plane pitch and relative intensity in the X-ray line powder diffraction pattern of the crystalline powder of the compound measured by Cu-K a ray 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 5. 42 + 0. 2 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 4. 73 + 0. 1 0. 46-0. 72

 19.820 4. 47 + 0. 1 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 method for preparing an anti-infective compound according to claim 1, characterized in that water or a solvent containing 5 to 50% by volume of organic solvent is used as a solvent, and 6-60 ° C is added to 6 - Fluoro-1-methyl-4-oxo-7-(l-piperazinyl)-4H- [1,3]thiazepine[3,2-a]quinoline-3-carboxylic acid (II) and methanesulfonic acid, the amount of the solvent used is 5 to 50 times the weight of the compound (II), and after stirring and dissolved, the organic solvent is added in an amount of 1 to 100 times by weight of the compound (Π), thereby precipitating the compound (I), the compound The molar ratio of (II) to methanesulfonic acid is 1: 0.8~1.5, wherein the organic solvent is any of methanol, ethanol, isopropanol, acetone, tetrahydrofuran~

An anti-infective pharmaceutical composition comprising the anti-infective compound of claim 1 as an active ingredient and comprising a conventional pharmaceutical carrier.

The anti-infective pharmaceutical composition according to claim 3, which is a tablet, capsule or granule for gastrointestinal administration.

The anti-infective pharmaceutical composition according to claim 3, which is a parenteral injection, an ophthalmic preparation, an otic preparation, a gynecological preparation or an external preparation for skin.