WO2007082472A1 - Anti-infective quinolone compound, preparation method thereof and use thereof - Google Patents

Abstract

Anti-infective quinolone compound, preparation method thereof and use thereof. The present invention disclosed the pharmaceutically acceptable salt of 6-fluoro-1-methyl-4-oxo-7- (1- piperazinyl) - 4H -[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (I) , which is separated out by solvent crystallization following the reaction of compound (I) with pharmaceutically acceptable acids X 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 (I) 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 pharmaceutically acceptable salt of compound (I), the toxicity of the active compound (I) has been reduced and the safety of its clinic use has been improved.

Description

 Quinolone anti-infective compound, preparation method and use thereof

 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. Background technique

 Indeed

 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.

6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazetino[3,2-a]quinoline-3- Carboxylic acid (UFX, NM394) is a quinolone with a very significant anti-infective effect. 108: p94537d _; 111: pl94791n _; 113: p231357q _; 116: p 41483s; 124: pr8660q _; 128: 123459a 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. A strong antibacterial effect. Since compound i (Li 394) is hardly soluble in water, it affects the use of its drug.

In addition to being difficult to dissolve in water, Li 394 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 1996, 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. There was urinary turbidity in the 30 mg/kg dose, decreased blood gamma globulin in the 10 and 30 mg/kg dose groups, and increased blood urea nitrogen and creatinine in the 10 and 30 mg/kg groups, indicating that renal function has been compromised. In the 10 and 30 mg/kg dose groups, pathological changes occurred in the rats, such as tubular nephropathy, and crystalline substances were found; in the 30 mg/kg dose group, the weight of the kidney and cecum increased; the above changes except blood globulin, Both were reversible, and no significant problems were found in the 3 mg/kg dose group, so the N0AEL of Li 394 to 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 mg/70 kg, which is a very low dose. We know that the normal dose of prisafloxacin is 200-60 mg / Day (in NM394), this result indicates that NM394 intravenous administration is too toxic and has no prospects for clinical application.

 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

 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.

 To achieve the above objects, 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

Wherein X is lactic acid, gluconic acid, hydrochloric acid, methanesulfonic acid, glutamic acid or aspartic acid. Preferably, the compound (I) is lactate or gluconate, which is represented by the following formula:

The nuclear magnetic resonance of compound II or III, ¹³ C R, 3⁄4 MR, and infrared IR (KBr, cnf ¹ ) confirmed its structure as shown in the above formula.

 The compound I of the present invention can be produced by the following method:

 Add 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H- at 0-60 ° C with water or water containing 5~50% by volume of organic solvent as solvent. [1,3]azetidino[3,2-a]quinoline-3-carboxylic acid (i) and a pharmaceutically acceptable acid, the amount of solvent used is 5 to 50 times the weight of the compound (I), stirred 5〜1. 5。 The molar ratio of the molar ratio of the compound (I) and the pharmaceutically acceptable acid is 1: 0. 8~1. 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 comprising quinolone compound I as an active ingredient and comprising 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 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).

 The invention has the following advantages:

1. Provide a class of quinolone compounds with excellent anti-infective effects, the structure is determined, sexual It is stable in nature and 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, vasoactive, and muscle-stimulating tests of the active drug compound (I), NM394, have 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 a compound (working), that is, a pharmaceutically acceptable 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 factors affecting stability, taking compounds II and III as examples

 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.

 1, quality measurement method

 1) Determination of content: According to high performance liquid chromatography (Chinese Pharmacopoeia 2005 two appendix VD) 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, add triethylamine 0. 2 ml, adjust the pH to 6. 0 with phosphoric acid) (40: 60) for the mobile phase; flow rate is 1 0 ml / min; 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 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.

Determination Methods: Compound II about 10mg, accurately weighed, 100ml flask, add the mobile phase amount, sonicated to dissolve and diluted into a solution containing about _50μ β per lml. Precisely measure 20μ1, 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%.

In the same manner, compound III was found to contain 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazepine and [3, 2- a] quinoline-3-carboxylic acid is 58 to 65%. 2) Determination of the pH of the sample: Take Compound II and Compound III, add water to make a solution containing 0.1 g of Compound II or Compound III per 10 ml of water, determined according to law.

 3) 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.

 2, light test

 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.

 The test results show that samples 01 and 02 are basically stable under light conditions.

3, high temperature test

 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.

 The 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.

 4, high humidity test

The samples 01 and 02 were placed under the conditions of 25 ± 2 ° C and a relative humidity of RH 95 ± 5%. 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. Sample time (days) pH value color clarity content%

01 0 4.51 <1 <1 78.2

 5 4.49 <1 <1 77.9

 10 4.50 <1 <1 77.9

 02 0 4.37 <1 <1 62.9

 5 4.35 <1 <1 62.7

 10 4.35 <1 <1 62.5

 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.

 The content of Li 394 mesylate, 匪 394 aspartate, and Li 394 glutamate prepared in the examples of the present invention was measured, and it was found that 匪 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%. 395 glutamate contains 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazetidine [3, 2 - a) Quinoline-3-carboxylic acid is 68 to 72%. The above samples were measured according to the stability test method, and their contents, color, clarity and pH did not change significantly.

 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

Samples 01, 02, 03, 04, and 05 are the compounds II, III, 395 glutamate, 394 394 aspartate, and 394 mesylate provided by the present invention, and sample 06 is 堕394.

test results:

Bacterial name MIC _9Q value (yg/ml)

 06 05 04 03 02 01

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. 05 Klebsiella pneumoniae 0.06 0.07 0.06 0.07 0.08 0.06 Enterobacter cloacae 0.06 0.06 0.05 0.08 0,08 0.05 Test results indicate that the compounds of the invention II, III, Li 394 glutamate, Li 394 aspartate, Sheng 394 mesylate has a broad-spectrum antibacterial effect on Gram-positive and Gram-negative bacteria and sample 匪394, especially against Gram-negative bacteria such as Pseudomonas aeruginosa, Serratia, Enterobacter Shows a powerful antibacterial effect.

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

 Compound II, NM394 lactate, Compound III, NM394 gluconate, or NM394 mesylate, aspartate, and glutamate were used as examples to observe long-term toxicity tests.

 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. fixed with 10% formalin; for liver, kidney, jejunum, cecum, bladder and other organs, conventional Paraffin wax, slice thickness about 4μπι, Η-Ε dye, OLYMPUS BX40 Optical microscope observation. During the recovery period, the remaining animals were taken to make the above observation and detection indicators.

 The results showed that:

No toxicological changes were observed in the 10 mg/kg*bw dose group of each sample. The serum urea nitrogen of some rats in the 30 mg/kg-bw dose group showed an increasing trend. A small amount of urine phosphate crystals were observed in individual rats, but compared with the blank group, animal general observation, blood biochemistry and histopathology No changes in toxicological significance were observed in the examination. The serum urea nitrogen and creatinine of the male rats in the 60mg/kg*bw dose group increased significantly, the urine phosphate crystallized less, and the urine pH value was clear. Significantly decreased, the mild effects of crystalline substances, femoral joints and wrist joints were observed in the urine of individual rats; the renal organ coefficient increased significantly, and some rats showed mild tubular dilatation, mild degeneration of renal tubular epithelium, and renal protein tube Type, cell cast and crystal formation. It indicates that the kidney of the high-dose group has been damaged and has certain toxic effects on the kidney. 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 group, suggesting that intravenous NM394 lactate, NM394 gluconate, or NM394 mesylate, aspartate The toxic effects of salt and glutamate on rats were recoverable, and no delayed toxicity was observed.

 According to the above results, the intravenous dose of NM394 lactate, NM394 gluconate, or NM394 mesylate, aspartate and glutamate was 30 mg/kg «bW o

 The results of this study are different from those reported by Ishida. S (1996) for the intravenous toxicity of NM394 in 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 effects were reversible; its non-toxic dose was 3 mg/kg*bw). However, 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 ΝΜ394 lactate. The 60 mg/kg 'bw dose group of ΝΜ 394 gluconate, or ΝΜ 394 mesylate, aspartate and glutamate was more severe.

 Based on the above results, 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.

 Test Example 4: Vaso-excitation, muscle stimulation test:

。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Another 3 rabbits were used as blank controls, and the same amount of sodium chloride injection was administered to both the left and right ears. Inject once a day, Give 3 consecutive days. Four rabbits in each test group were examined by necropsy at 48 hours after the last administration, and two rabbits were necropsy in the blank control group, leaving rabbits to recover for 14 days. The results of visual observation and pathological examination showed that the high and low concentration test solutions of mesylate, aspartate, lactate, glutamate and gluconate showed no obvious abnormal changes in rabbit ears; At the end of the observation, no obvious abnormal changes were observed in the eyes and pathological examination of the rabbit ears.

 2, 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 technical solutions of the present invention are further illustrated by the following examples, and the present invention is not limited to the following embodiments. ■ Example 1-1 Preparation of NM394 lactate (compound Π)

5Kg的针用活性碳,搅拌搅拌。 Adding 5KgNM394 (compound i), adding lactic acid 2. 8Kg, stirring for 60 minutes, adding 0. 5Kg needle with activated carbon, stirring After 15 minutes, it was filtered into a 500 L crystallization tank; the reaction tank was washed with 10 L of water and filtered into a 500 L crystallization tank. Under stirring, about 400 L of isopropanol was added dropwise to the crystallization tank, and isopropanol was added over 3 hours to precipitate a solid. The mixture was stirred at 15 to 20 ° C for 2 hours, filtered, washed once with 20 L of isopropyl alcohol, and dried under vacuum at 35 to 40 °C. Obtained 9. lKg of compound II.

The nuclear magnetic ' ^:i CNMR, 3⁄4 NMR (D ₂ 0, 500 Hz) data are as follows:

Carbon number δ„ D ₂ 0

 1 72.484 6.111, s, lH

2 164.009

The IR (KBr, cm - ') data are as follows: 1698 (m, V o. carboxylic acid), 1628 (s, v _{c =} ketone), 1628-1500 (m, s, v _c=c (aromatic ring, Aromatic heterocycles>), 1457 (m, δ m), 1397 (m, δ. carboxylic acid)

 Sample element analysis

 The sample was measured by Cu-Kct ray and the 2 Θ, d-plane spacing and relative intensity in the X-ray powder diffraction pattern were 1/1. Has the following values:

 5.100 17.3125 1.00

 10.240 8.6311 0.76

 22.560 3.9378 0.19

 25. 80 3. 928 0.23

 Example 1 - 2 Preparation of NM394 Gluconate (Compound ΙΠ)

15~20 °C, 50L water and 5L isopropanol were added to the 100L reaction tank, then 10kg of compound II was added, 13L of 50% gluconic acid aqueous solution was added dropwise with stirring, stirred for 30 minutes, 0.5g needle was added with activated carbon, and stirred. 15 minutes, filtered to 500L crystallization tank; 10L water washing anti The tank should be filtered and filtered into a 500L crystallization tank. The crystallizer was stirred, and 400 L of isopropanol was added dropwise thereto, and isopropanol was added thereto for 4 hours to precipitate a solid. The mixture was stirred at 15 to 20 ° C for 2 hours, filtered, washed once with 20 L of isopropyl alcohol, and dried under vacuum at 35 to 40 ° C. 8. 9kg of compound I was obtained.

The data of nuclear magnetic ¹³ and NMR (DMS0-d ₆ , D ₂ 0 , 500 Hz) are as follows:

The sample was measured by Cu-Κα ray and the X-ray powder diffraction pattern was taken between 2Θ and d-planes. The distance and relative intensity have the following values:

 2Θ d 1/1.

 9.32 9.48 0.37

 17.9 4.95 0.51

 18.920 4.68 0.26

 22.6 3.93 0.32

 25.94 3.43 1.00

 27.46 3.26 0.31

 27.88 3.19 0.30

 Example 1 - 3 Preparation of NM394 methanesulfonate

 50L of water and 5L of ethanol were added to the 100L reaction tank, 10Kg of M394 (compound i) was added at 15 to 20 ° C, 2.8 Kg of methanesulfonic acid was added dropwise with stirring, and the mixture was stirred for 30 minutes. The other steps were the same as those in Example 1 -1. 8.7 Kg NM 394 methanesulfonate.

Nuclear magnetic ¹ H NMR (DMS0-d ₆ , D ₂ 0 , 500 Hz)

Infrared IR KB cm- ¹ ) data are as follows: 1698 (m, v _{c = 0} carboxylic acid), 1628 (s, v _{c = 0} ketone), 1628-1500 (m, s, v _{c = c} (aromatic ring, aromatic) Heterocycle)), 1457 (m,

S _CH3 ), 1397 (m, δ ₀ carboxylic acid).

。 。 。 。 。 。 。 ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ ΝΜ 匪 匪 匪 匪 匪 匪 匪 匪 匪 85 85 85 85 85 85 85 85 85 85 , stirring for 1 hour, adding 0. 5K _g needle with activated carbon, stirring for 20 minutes, filtering and decarburization; the filtrate was pressed into a sterile room 500L crystallizing tank through a 0.22 μm ultrafiltration membrane. Water 10 L washes the reaction tank and piping and is also pressed 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 sterilized powder of the compound II was obtained in a vacuum of 0. 5K _g .

The obtained sample was subjected to nuclear magnetic ¹ H NMR (D ₂ O, 500 Hz) data, and the X Θ, d-plane spacing and relative intensity of the X-ray minute diffraction pattern measured by Cu- Κ α ray were 1/1. Same as 1-1.

 Example 2-2 Preparation of NM394 Gluconate (Compound ΠΙ)

5kg, 0. 5kg, adding 0. 5kg, stirring 1 hour, adding 0. 5kg The needle was stirred with activated carbon for 60 minutes, and decarburized by filtration; the filtrate was pressed into a sterile chamber 1000 L crystallization tank through a 0.22 μM ultrafiltration membrane. Water 15 L washes the reaction tank and piping and is also pressed into the crystallization tank. The mixture was stirred, and acetone 650 L was added dropwise thereto, and acetone was added over 5 hours to precipitate a solid. The mixture was stirred at 0 to 5 ° C for 5 hours, filtered, and washed with acetone 30 L X 2 twice, and dried at 35 to 40 ° C under vacuum. A sterile powder of Compound III was obtained in an amount of 8. 4 kg.

The obtained sample was subjected to nuclear magnetic ¹ H NMR (DMSO-d ₆ , D ₂ o, 500 Hz) data, and the X Θ, d-plane spacing, and relative intensity 1/1 of the X-ray powder diffraction pattern measured by Cu-I ray. Same as 1-2.

The lactic acid 3. 2g, lactic acid was added dropwise with agitation of 0. 5g, lactic acid was added to the mixture. Stir for 30 minutes, add 0. 5g needle with activated carbon, stir 15 minutes, decarburization by filtration; wash the three-necked flask with 10 ml of water and filter. The filtrate was combined into a 500 ml three-necked flask, and 350 ml of ethanol was added dropwise with stirring, 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, and washed with anhydrous ethanol 2 Ctal once, and dried under vacuum at 35 to 40 ° C. 7.2 g of compound II.

 Example 3-2 Preparation of NM394 Gluconate (Compound ΠΙ) 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 Π) In a 100 ml three-necked flask, 40 ml of water and 2 ml of ethanol were added, 10 g of Li 394 (compound i) was added at 10 to 15 ° C, and lactic acid was added dropwise with stirring. 05g, 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 ΠΙ) 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 Π) In a 100 ml three-necked flask, 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克, 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. 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. 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. 2. 3 g of compound II were obtained.

 Example 5-2 Preparation of NM394 gluconate (Compound ΠΙ) 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 5-3 Preparation of NM394 Glutamate

5〜60 C, 100ml three-necked flask was added 20ml of water and 20ml of methanol, then added 5g of compound II, stirred with glutamic acid 2. 2g, stirred for 45 minutes, the other with the same example 5-1 07000180

3.8 g of NM394 glutamate.

The nuclear magnetic ' ³ C NMR, ^ NMR C ^ O, 500 Hz) data are as follows:

The infrared IR (KBr, cn ¹ ) data is as follows: 1695 (m, v _c= . Ketone), 1628-1499 (S, v _c=c (aromatic, aromatic)), 1457 (m, δ _α , ₃ ), 1397 (S, S. carboxylic acid)

 Example 6-1 Preparation of NM394 lactate (Compound Π) In a 100 ml three-necked flask, 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克, 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. 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 over 10 minutes to precipitate a solid. The mixture was stirred at 15 to 20 ° C for 2 hours, filtered, and washed with acetone 10 ml once, and dried at 35 to 40 ° C under vacuum. 2. 2. g of compound II was obtained.

 Example 6-2 Preparation of NM394 Gluconate (Compound ΙΠ) 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克化合物III。 The acid solution of the aqueous solution of 13.1L.

5K, the mixture is stirred for 1 hour, and added to 0. 5K. 5K, the mixture is stirred for 1 hour, 0. 5K _g needle with activated carbon, stirred for 20 minutes, filtered decarburization; the filtrate was 0. 22 μ πι ultrafiltration, freeze solution was placed in a lyophilizer one thousand, to give compound II lyophilized powder 8. 9Kg.

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

 Add 20g 394 (Compound I) to 200ml of water at 15~20°C, add 58ml of 3% hydrochloric acid with stirring, stir for 20 minutes, dissolve the solid, filter, wash with 30ml of water, combine the filtrate, add 2500ml of acetone under stirring, add dropwise The HCl (Compound I) hydrochloride salt 13. 5g. The HCl (Compound I) hydrochloride salt was obtained.

 Example 9 Preparation of NM394 Aspartate

0~5 ° C, 150 L of water was added to the reaction tank, and 10 kg of aspartic acid was added, and the mixture was added dropwise with stirring. W

3% hydrochloric acid, 74 L, stirring for 1 hour, adding 1. 0 kg of needle with activated carbon, stirring for 15 minutes, decarburization by filtration; the filtrate was pressed into a sterile chamber 500 L crystallization tank through a 0.22 μm ultrafiltration membrane. Water 10 L washes the reaction tank and piping and is also pressed into the crystallization tank. After stirring, 60 L of a 5% aqueous sodium hydroxide solution was added dropwise, and the addition was completed in 3 hours, and a solid was gradually precipitated during the dropwise addition. After the sodium hydroxide solution was added, the mixture was stirred at 0 to 5 ° C for 3 hours, filtered, washed twice with anhydrous ethanol 50 LX 2 , and dried under vacuum at 35 to 40 Torr. Aseptic aspartic acid powder 8. 4kg ₀

The magnetic resonance ¹³ CNMR, ^l HNMR (D ₂ 0, 500 Hz) data are as follows:

Infrared ΙίΚΚΒΓ, αη— ¹ ) data are as follows: 1695 (m, V c=. carboxylic acid), 1628 (S, vc=. ketone), 1628-1499 (S, v _c=c (aromatic ring, aromatic heterocyclic ring) ), 1457 (m, δ _α . ₁₃ ), 1397 (S, δ. carboxylic acid)

 Example 10 Preparation of Injection

9%氯化。 The 5% chlorination of the compound 0 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤 过滤0. 9% sodium chloride solution to a total amount of 10L, determine the content, check the clarity, fill into a 100ml infusion bottle, press the aluminum cap and sterilize at 121 °C for 20min.

 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 11 Preparation of Injection

 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 12 Preparation of Injection

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.

 Compound II was replaced by compound III, and the amount of compound III was changed to 156 g, the rest being the same as above.

 Example 13 Preparation of powder injection

。 126g / bottle, 0. 189g / bottle, 0. 252g / bottle, 0. 315g / bottle, 0. 378 _g , 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.

 Example 14 Preparation of powder injection

 A sterile powder of the compound II obtained in Example 7-1 was prepared by the method of Example 13.

 Example 15 Preparation of tablets

Prescription: Compound 126g per 1000 tablets, lactose l, 9 _g , 10% PVP solution 10ml, magnesium citrate 0. 52g

Preparation: 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.

 Example 16 Preparation of Capsules

 Prescription (1000 prescriptions): 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 replaced with Compound III, and the rest was the same as above to prepare a capsule of the compound hydrazine.

 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.

 Example 17 Preparation of granules

 Prescription: Compound II 126g, dextrin 120g, sucrose sugar 280g,

 Preparation: The compound II and sucrose obtained in Example 1 to 1 were pulverized into a fine powder, mixed, and granulated by a wet method, and dried at 60 ° C, sufficiently dried, and dispensed.

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,

 Example 18 Preparation of Eye Drops

Prescription: Compound II 3. 78 _g , sodium chloride 0. 9g, boric acid buffer solution, phenylethyl alcohol 3g, water amount, a total of 1000ml

Preparation: The compound II obtained in Example 1-1 and sodium chloride were added to 600 ml of distilled water. 0 After completely dissolved under stirring, add boric acid buffer solution to adjust the pH of the solution to 6.5; additionally take phenylethyl alcohol, add 200 ml of boiling distilled water to dissolve; mix the above two solutions, add distilled water to a total amount of 1000 ml, stir well, Filtered with 0.22 μηηι microporous membrane, filled, tightly sealed, sterilized by 10CTC for 30 minutes, steamed, and dispensed.

 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.

 Example 19 Preparation of ear drops

 Prescription: Compound II 12. 6g, ethanol 300ml, glycerol 300ml, water amount, a total of 1000ml. Preparation: Take 12. 6g of compound II obtained in Example 1-1 dissolved in 200ml of water for injection, add 300ml of ethanol and 200ml of glycerin, then Add water for injection to a total amount of 1000 ml, stir well, filter with 0.22 μ microporous membrane, and fill.

 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.

 Example 20 Preparation of suppository

 Prescription: Compound II 12. 6g

 Cocoa butter 200g 100 capsules

 Preparation: 200g of cocoa butter, heated and melted on a water bath (temperature controlled below 50 )), taking the compound II fine powder obtained in Example 1-1 12. 6g (over 100 mesh sieve) 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.

 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.

 Example 21 Preparation of Ointment

Prescription: 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.

Preparation: 126 g of the compound II obtained in Example 1-1 was dissolved in 300 ml of water, and then an aqueous solution of sodium lauryl sulfate, glycerin, triethanolamine, ethyl p-hydroxybenzoate and compound II was added, and heated to the whole on a water bath. Dissolve, and let the temperature be around 70 ° C; take stearic acid, Bai Fan Shilin and glyceryl monostearate, heated to full melting, until the temperature drops to about 70 ° C, slowly add the above solution under constant stirring, and continue to stir until the emulsification is complete, condensation, that is.

 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 匪 394 glutamate was prepared.

 Compound II was changed to 394 aspartate, and the amount was changed to 138 g, and the same as above, an ointment containing 394 oxalate as a salt was prepared. Industrial applicability

 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.

Claims

Rights request

 1. A quinolone anti-infective compound having the structure of formula (I),

The compound is 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazepine[3,2-a]quinoline A pharmaceutically acceptable salt of 3-carboxylic acid, wherein X is lactic acid, gluconic acid, hydrochloric acid, methanesulfonic acid, glutamic acid or aspartic acid.

 The quinolone anti-infective compound according to claim 1, wherein the compound is 6-fluoro-1-methyl-4-oxo-7- (1-) having the formula (II) Piperazinyl) - 4H- [1, 3] thiazetanazo[3,2- a]quinoline-3-carboxylic acid lactate:

The quinolone anti-infective compound according to claim 1, wherein the compound is 6-fluoro-1-methyl-4-oxo-7-(1-) having the formula (III) Piperazinyl) - 4H - [1, 3] thiazepine-[3,2- a]quinoline-3-carboxylic acid gluconate:

The quinolone anti-infective compound according to claim 2, wherein the crystalline powder of the compound has a 2 Θ, d-plane spacing and relative in an X-ray powder diffraction pattern measured by Cu-Kct ray. The intensity has the following values:

 5.100 17.3125±0.2 1.00±0.1

 10.240 8.6311±0.2 0.76±0.1

 22.560 3.9378±0.2 0.19±0.1

 25.480 3.4928±0.2 0.23±0.1

 The quinolone anti-infective compound according to claim 3, wherein the crystalline powder of the compound has a 2 Θ, d-plane spacing and relative in an X-ray powder diffraction pattern measured by Cu-Κα ray. The intensity has the following values:

 2Θ d m.

 9.32 9.48±0.2 0.37±0.1

 17.9 4.95±0.2 0.51±0.1

 18.920 4.68±0.2 0.26±0.1

 22.6 3.93±0.1 0.32±0.1

 25.94 3.43±0.1 1.00±0.1

 27.46 3.26±0.1 0.31±0.1

 27.88 3.19±0.1 0.30±0.1

 A method for preparing a quinolone anti-infective compound according to any one of claims 1 to 5, which is characterized in that the method uses water or a solvent containing 5 to 50% by volume of organic solvent as a solvent. , adding 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazetino[3, 2 at 0~60 °C - a) quinoline-3-carboxylic acid (i) and a pharmaceutically acceptable acid, the amount of the solvent used is 5 to 50 times the weight of the compound (I), and after stirring and dissolved, 1 to 100 times the weight of the compound (I) is added. The organic solvent, that is, the precipitation compound (I), the compound (I) and the pharmaceutically acceptable acid are fed in a molar ratio of 1: 0.8 to 1.5, wherein the organic solvent is methanol, ethanol, isopropanol, acetone, tetrahydrofuran. Any of them.

The method for preparing a quinolone anti-infective compound (I) according to claim 6, wherein the pharmaceutically acceptable acid is lactic acid, gluconic acid, hydrochloric acid, methanesulfonic acid, glutamic acid or aspartame

A quinolone anti-infective pharmaceutical composition comprising the quinolone compound (I) according to any one of claims 1 to 5 as an active ingredient, and comprising a conventional pharmaceutically acceptable carrier.

 The quinolone anti-infective pharmaceutical composition according to claim 8, wherein the quinolone compound (I) is 6-fluoro-1-methyl-4-oxo-7-(1-piperidyl). Lactate or gluconate of thiazino) - 4H - 1, 3] thiazepine[3,2- a]quinoline-3-carboxylic acid.

 The quinolone anti-infective pharmaceutical composition according to claim 8 or 9, which is a tablet for gastrointestinal administration, a capsule or a granule.

 The quinolone anti-infective pharmaceutical composition according to claim 8 or 9, which is a parenteral injection, an ophthalmic preparation, an otic preparation, a gynecological preparation or an external preparation for skin. .