CN102198133A - Application of 8-difluoro methoxy fluoroquinolone and composition thereof to tuberculosis treatment - Google Patents
Application of 8-difluoro methoxy fluoroquinolone and composition thereof to tuberculosis treatment Download PDFInfo
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- CN102198133A CN102198133A CN 201010130632 CN201010130632A CN102198133A CN 102198133 A CN102198133 A CN 102198133A CN 201010130632 CN201010130632 CN 201010130632 CN 201010130632 A CN201010130632 A CN 201010130632A CN 102198133 A CN102198133 A CN 102198133A
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Abstract
The invention relates to an application of 8-difluoro methoxy fluoroquinolone and composition thereof to tuberculosis treatment. The aim of the invention is to provide a new treatment purpose of a compound shown as formula (I), or medicinal salt thereof, or hydrate thereof, especially application of a pharmaceutical composition utilizing the compound as an active component to tuberculosis treatment.
Description
Technical field
The invention belongs to the medical chemistry field, relate to a kind of new purposes of 8-difluoro-methoxy fluoroquinolone compound.More particularly, the present invention relates to 1-cyclopropyl-7-[(S, S)-2,8-diazabicyclo [4,3,0] nonane-8-yl]-6-fluoro-8-difluoro-methoxy-1, the application in treatment tuberculosis of 4-dihydro-4-oxo-3-quinoline carboxylic acid or its pharmaceutical salts, hydrate and compositions thereof.
Background technology
Tuberculosis (TB) is one of serious infectious diseases of the serious harm human health that caused by mycobacterium tuberculosis (MTB).Since the eighties in 20th century, the continuous rising of sickness rate of drug resistance TB, the especially TB of anti-multiple medicines the (MDR-TB) and TB combine with HIV/AIDS the TB epidemic situation are risen once again, become great public health problem and social problem that the whole world is paid close attention to.According to statistics, there are 8,000,000 newly-increased TB patients in the whole world every year, and nearly 3,000,000 people die from tuberculosis, and nearly 1/3 population carries the latent form tubercule bacillus, has potential initiation potential.Regrettably, almost there is not the anti-T B medicine listing of new role mechanism surplus in the of nearly 40 over year, traditional anti-TB medicine, as drug combinations such as streptomycin, isoniazid, rifampicin, ethambutol and pyrazinamide the first lunger of controlling more than 85% is fully recovered, but there are treatment cycle long (greater than 6 months) and the shortcoming invalid to MDR-TB, not strong to the effect of latent form MTB simultaneously, therefore research and develop anti-TB new drug, realization is to the effective treatment and extremely urgent (the external medicine-antibiotic fascicle of control of TB, 2009,30 (1): 19-24).
The fluoroquinolone antibacterial agent thing generally has good pharmacokinetics character, and untoward reaction is less, is fit to long term administration.Wherein some kind has good tuberculosis activity, do not have cross resistance between they and other, the anti-TB medicine in two wires, and MTB is relatively low to its drug resistance incidence rate.The drug resistance TB that The World Health Organization (WHO) released in 1996 handles guide clearly fluoroquinolone antibacterial agent, as ciprofloxacin, ofloxacin and Sparfloxacin as the anti-TB medicine in two wires, use (Chinese Journal of New Drugs with the medication combined use treatment MDR-TB of other anti-TB and to the patient that can not tolerate the anti-TB medicine of a line, 2010,19 (3): 190-198).Wherein, the anti-TB activity of Sparfloxacin is the strongest, but is used by strict restriction because of there is tangible phototoxicity in it.Along with being extensive use of of ciprofloxacin and ofloxacin, MTB increases year by year to the drug resistance of these two kinds, has caused people's very big concern.
Hu etc. discover, the Tuberculosis in vitro nuclear activity of new fluoroquinolone antibacterial agent Moxifloxacin obviously is better than ciprofloxacin, ofloxacin and levofloxacin, it not only has clear and definite bactericidal activity to poky MTB, and stay bacterium also to show to holding of tolerance high concentration rifampicin and effectively kill activity (AntimicrobAgents Chemother, 2003,47 (2): 653-657).Mouse infection MTB Study of model is the result show, with the isoniazid in the Moxifloxacin alternate standard therapeutic scheme, its course of treatment can be by foreshortened to 4 months in 6 months (Am JRespir Crit Care Med, 2006,174 (1): 94-101).
Chemical compound shown in the formula (I) is the chemical compound of being found by Inst. of Medicinal Biological Technology, Chinese Academy of Medical Sciences and Zhejiang Medicine Co's joint study with outstanding broad spectrum antibiotic activity, chemistry 1-cyclopropyl-7-[(S by name, S)-2,8-diazabicyclo [4,3,0] nonane-8-yl]-6-fluoro-8-difluoro-methoxy-1,4-dihydro-4-oxo-3-quinoline carboxylic acid (CN:ZL200410033956.8; PCT/CN2005/00489).
The inventor has estimated the compound or pharmaceutically acceptable salt thereof shown in the formula (I), the hydrate antibacterial activity to the mycobacterium tuberculosis that comprises clinical separation strain first.Final find that it has beyond thought strong anti-mycobacteria activity, compare to have more superior Killing Mycobacterium Tuberculosis activity with existing clinical usefulness one line antituberculotics (as rifampicin), two wires tuberculosis fluoroquinolones (as ciprofloxacin etc.).
Summary of the invention
A kind of new therapeutic use that the purpose of this invention is to provide the compound or pharmaceutically acceptable salt thereof shown in the formula (I), hydrate, particularly it is as the application of pharmaceutical composition in treatment tuberculosis of active component.
Compound or pharmaceutically acceptable salt thereof shown in the formula that pharmaceutical composition of the present invention contains (I), the weight ratio of hydrate in compositions are 0.1～99.9%, and the weight ratio of medicine acceptable carrier in compositions is 0.1～99.9%.Pharmaceutical composition exists to be fit to medicinal dosage form.Medicinal preparation is tablet, sugar coated tablet, film coated tablet, enteric coated tablet, slow releasing tablet, capsule, hard capsule, soft capsule, slow releasing capsule, powder.
Pharmaceutical composition of the present invention, as dosage form, the effective dose of the compound or pharmaceutically acceptable salt thereof shown in the formula that contains in every dose (I), hydrate is 0.1～1000mg, described every dose refers to, each preparation unit, as every of tablet, capsular every, also can refer to each taking dose, as take 100mg at every turn.
But pharmaceutical composition of the present invention can use solid carrier when being prepared into the solid pharmaceutical preparation of powder, tablet dispersion powder, capsule, cachet form.Spendable solid carrier is preferably one or more materials that are selected from diluent, flavoring agent, solubilizing agent, lubricant, suspending agent, binding agent, the extender etc., or can be encapsulating substance.Suitable solid carrier comprises magnesium carbonate, magnesium stearate, Pulvis Talci, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethyl cellulose, cocoa butter etc.Because they are easy to administration, tablet, the best oral solid formulation of representative such as powder, cachet and capsule.
In order to be easy to administration and dosage homogeneous, it is particularly advantageous that the said medicine preparation is mixed with dosage unit form.The dosage unit form of preparation refers to be suitable for the physical separation unit as single dose, and each unit contains the active component of the good scheduled volume of the calculating that produces desired therapeutic effect.This dosage unit form can be packaged form, as tablet, capsule be contained in tubule or bottle in powder.
Though the amount of contained active component can change in the dosage unit form, generally, be adjusted in 1～800mg scope according to the effectiveness of selected active component.
When the compound or pharmaceutically acceptable salt thereof shown in the formula (I), hydrate are used as the medicine of treatment m tuberculosis infection, preferably give the amount of 6～14mg/kg body weight in the phase I.But dosage can change along with the seriousness of the infection of patient's needs, desire treatment, selected compounds etc.
Those skilled in the art can determine to be suitable for the preferred dose of certain situation according to a conventional method.Generally, the amount of begin treatment is lower than the optimal dose of active component, increases dosage then gradually, up to reaching optimum therapeuticing effect.For simplicity, total daily dose can be divided into several parts, divides administration for several times.
As mentioned above, compound or pharmaceutically acceptable salt thereof shown in the formula (I), hydrate not only obviously are better than being widely used at present a clinical line antituberculotics rifampicin and two wires tuberculosis fluoroquinolone antibacterial agent thing ciprofloxacin to the activity of mycobacterium tuberculosis, also are better than the strongest fluoroquinolone antibacterial agent thing Moxifloxacin of tuberculosis activity.
Below by test data beneficial effect of the present invention is described:
External anti-mycobacteria activity test
The tuberculosis activity of the compound or pharmaceutically acceptable salt thereof shown in the formula (I), hydrate is to represent by measuring its minimal inhibitory concentration to mycobacterium tuberculosis type strain H37Rv ATCC 27294 and clinical separation strain 09710 (MIC, μ g/mL).In this test, compare medicine with ciprofloxacin and Moxifloxacin and a line antituberculotics rifampicin.Minimal inhibitory concentration is measured as follows: aseptic 48 orifice plates (the special-purpose microtest plate of tulase quick medicine-sensitive), by the drug sensitive test designing requirement, each hole adds the medicine with 2 times of concentration culture medium (improvement Michaelis 7H9 fluid medium) dilution respectively.Each chemical compound make debita spissitudo first solution, be diluted to two times of concentration of each compound used therefor with culture medium (2 *), every kind of each 10 gradient of chemical compound, add the every hole 100 μ L of 48 orifice plates, the final concentration of investigational agent is respectively 128,64,32 ... 0.25 μ g/mL (measuring clinical separation strain 09710) or 5.12,2.56,1.28 ... 0.01 μ g/mL (bioassay standard strain H37RvATCC 27294).Clinical separation strain 09710 and type strain H37Rv ATCC 27294,100 μ l are inoculated in every hole, and every pore fungi amount is 4 * 10
-3Mg.Every plate is all established 2 growth positive control hole and two growth negative control holes with the alternative culture medium of distilled water of not containing antimicrobial drug, and 48 orifice plates are added a cover the back on every side with the adhesive tape sealing, places wet box to hatch for 37 ℃.Observe positive growth control hole and negative growth control hole after the 3rd day, when observing both clear and definite difference being arranged, quantity and form to each test hole bacterial growth are observed, and judge that inhibition or drug resistance also write down the result, after the 7th day again observed and recorded once confirm.The concentration of contained drug minimum is minimal inhibitory concentration (MIC) in the control wells of asepsis growth.Measurement result is listed in table 1.
Chemical compound mesylate, ciprofloxacin, Moxifloxacin and rifampicin shown in table 1 formula (I) is to the active * of 2 strain mycobacterias
* mycobacteria trace quick medicine-sensitive test method determination directly perceived
Chemical compound mesylate shown in the formula (I) is respectively ciprofloxacin, Moxifloxacin and rifampicin 8 times, 2 times and 4 times to the external activity of mycobacterium tuberculosis type strain H37Rv ATCC 27294, is respectively ciprofloxacin, Moxifloxacin and rifampicin 32 times, 2 times and 8 times to the external activity of clinical separation strain 09710.
Oral acute toxicity test
Be the compound or pharmaceutically acceptable salt thereof shown in the mensuration formula (I), the oral acute toxicity of hydrate, it has been carried out acute toxicity testing, to contain the compound or pharmaceutically acceptable salt thereof shown in the formula (I) of variable concentrations, the oral male mice that awards of solution of hydrate, dosage is the 0.1ml/10g body weight, the dead Mus that counts respectively after 7 days is measured, and calculates the median lethal dose(LD 50) (LD of each chemical compound with the Bliss program
50).The results are shown in Table 2.
The oral acute toxicity of the mice of table 2 experimental compound
| Experimental compound | LD 50(mg/kg) |
| Chemical compound shown in the formula (I) | ＞4000 |
| Chemical compound mesylate shown in the formula (I) | ＞4000 |
| Chemical compound monohydrate shown in the formula (I) | ＞4000 |
Experimental result shows that the toxicity of the compound or pharmaceutically acceptable salt thereof shown in the formula (I), hydrate is very low, is fit to very much medicinal.
The specific embodiment
In following examples, will more specifically explain the present invention.But should be understood that the following example to be intended to the present invention is described and scope of the present invention is not constituted any restriction.
Embodiment 1 coated tablet
The label prescription:
Chemical compound mesylate 10.0g shown in the formula (I)
Lactose 50.0g
Starch 40.0g
Hyprolose 4.0g
10% polyvidone is an amount of
Magnesium stearate 0.5g
Get the mentioned component mix homogeneously, the granulate that sieves after the granulation, dry, tabletting is made 100 labels.Coating fluid prescription: Opadry (Opadry) 5g, an amount of coating of 80% ethanol.
Embodiment 2 capsules
Prescription:
Chemical compound monohydrate 100g shown in the formula (I)
Starch 10g
Carboxymethyl starch sodium 20g
Low-substituted hydroxypropyl cellulose 10g
Tween 80 is an amount of
Polyvinylpyrrolidone 5% ethanol liquid is an amount of
Sodium lauryl sulphate 8g
1000 of No. 0 gastric-dissolved capsules
Make 1000 capsules
Preparation method:
Get the recipe quantity supplementary material, sieve respectively, add 5% polyvinylpyrrolidone alcohol liquid and Tween 80 system soft material,, under 15 ℃ of room temperatures, dry with the granulation of 20 mesh sieves, add sodium lauryl sulphate, mix homogeneously is by the 0.27g/S gastric-dissolved capsule of packing into No. 0, sample examination, the stripping limit is Q=80%, and content should be 90～110% of labelled amount.
Though above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (7)
1. the 8-difluoro-methoxy fluoroquinolone compound of a formula (1) structure or its pharmaceutical composition application in preparation treatment tuberculosis.
2. the described application of claim 1, wherein said chemical compound comprises its pharmaceutical salts, hydrate.
3. the application of claim 1 is characterized in that, every dose of consumption of described formula (I) compound or pharmaceutically acceptable salt thereof, hydrate is 0.1mg～1000mg.
4. the application of claim 1 is characterized in that, described pharmaceutical composition is tablet, sugar coated tablet, film coated tablet, enteric coated tablet, slow releasing tablet, capsule, hard capsule, soft capsule, slow releasing capsule, granule, pill, powder.
5. the application of claim 1 is characterized in that, described tuberculosis comprises active tuberculosis, single resistant tuberculosis, many resistant tuberculosis, anti-multiple medicines tuberculosis and extensive anti-multiple medicines tuberculosis.
6. the application of claim 1 is characterized in that, described tuberculosis comprises pulmonary tuberculosis, the outer tuberculosis of lung.
7. the application of claim 6 is characterized in that, the outer tuberculosis of described lung comprises other organs except that lung that caused by tubercule bacillus, as skeleton, joint, lymph node, intestinal tuberculosis.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2010101306321A CN102198133B (en) | 2010-03-24 | 2010-03-24 | Application of 8-difluoro methoxy fluoroquinolone and composition thereof to tuberculosis treatment |
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| CN102198133B CN102198133B (en) | 2012-11-21 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1563004A (en) * | 2004-04-21 | 2005-01-12 | 中国医学科学院医药生物技术研究所 | Compound of quinolone carboxylic acid, preparation method and medicinal usage |
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2010
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1563004A (en) * | 2004-04-21 | 2005-01-12 | 中国医学科学院医药生物技术研究所 | Compound of quinolone carboxylic acid, preparation method and medicinal usage |
Non-Patent Citations (1)
| Title |
|---|
| 《中国抗生素杂志》 20060930 刘九雨等 莫西沙星8-二氟甲氧基类似物的合成与体内外抗菌作用 559-563 1-7 第31卷, 第9期 * |
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