CN102199147A - Nitroimidazole derivative in therapy - Google Patents
Nitroimidazole derivative in therapy Download PDFInfo
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- CN102199147A CN102199147A CN2011100756246A CN201110075624A CN102199147A CN 102199147 A CN102199147 A CN 102199147A CN 2011100756246 A CN2011100756246 A CN 2011100756246A CN 201110075624 A CN201110075624 A CN 201110075624A CN 102199147 A CN102199147 A CN 102199147A
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Abstract
The invention relates to a nitroimidazole derivative used in therapy, and provides a compound of formula (I) or its pharmaceutical salt: wherein R1 can be taken as saturated or unsaturated straight chain, branched chain alkyl or cyclic alkyl with the carbon number from 1 to 10, R2, R3 can represent alkyl or form rings, the ring can be the ring from three-membered ring to ten-membered ring, the ring is capable of connecting with one or a plurality of same or different substituents; the rings formed by R2, R3 are capable of forming heterocycles, the heterocycle is capable of containing 0 to 5 same or different heteroatom substitutions; X expresses ion or group with negative electricity, which concretely can be halogen negative ion, organic acid radical, inorganic acid radical. According to the invention, the nitroimidazole derivative is used for treating the diseases caused by anaerobic infection or protozoans infection.
Description
Technical field:
Nitro imidazole derivatives that the present invention relates to be used for the treatment of (especially for the treatment of people and other Mammals anaerobic infections or protozoan infection) and pharmaceutical composition thereof, and their preparation method and application.
Technical background:
Many nitro glyoxaline compounds are known.For example: metronidazole, tinidazole, ornidazole etc. all have the excellent antibiotic activity.Ornidazole is the medicine that a kind of powerful anaerobe resistant and protozoacide infect, and also is that newly the curative effect of development is higher behind metronidazole, the course of treatment is shorter, tolerance is better, the wider nitro imidazole derivatives of distribution in the body.The anti-microbial effect of ornidazole is to be reduced into amino by the nitro in its molecule in oxygen-free environment, or interacts by the formation and the cellular constituent of free radical, thereby causes the death of microorganism.
The first-elected clinically at present microbiotic of the treatment of anaerobic infection.Anerobe often has resistance to aminoglycosides antibiotics.Most of anerobes are except that bacteroides fragilis, all to the penicillin G sensitivity.The antimicrobial spectrum and the penicillin G of lincomycin are similar, can select for use during to penicillin anaphylaxis as patient.Paraxin almost comprises that to all anerobes bacteroides fragilis is all effective, but shortcoming is that myelosuppressive danger is arranged.Anerobe is variant to the susceptibility of tsiklomitsin, erythromycin and paraxin, and in therapeutic process, develop immunity to drugs rapidly, clindamycin is better than lincomycin to the curative effect of anaerobic infection, but it is the same with lincomycin, causes fatal pseudomembranous colitis sometimes.In present antimicrobial drug, the first-elected ornidazole that curative effect is best.
(ornidazole ONZ) is third generation nitro glyoxaline microbiotic to ornidazole, and such microbiotic is only at anaerobic infection, and protozoon, trichomonacide etc.Its mechanism of action is, makes the nitro by molecule be reduced into amino in oxygen-free environment, or the formation by free radical, makes the structural break of acceptor helical tissue, blocks it and transcribes and duplicate and become feeble and die.This class of past infects uses metronidazole, tinidazole control always.After the ornidazole introducing was clinical, the researchist found that compare with nitroimidazoles medicines such as tinidazole, metronidazoles, the anti-infective advantage of these product is more obvious.This be because, the ornidazole duration of efficacy is long, it is 14.4 hours that its blood plasma is eliminated transformation period, is higher than 8.4 hours and 12.7 hours of tinidazole of metronidazole, can reduce patient's medicining times, convenient use; Mutagenesis and teratogenesis are lower than metronidazole and tinidazole; Aspect anti anaerobic bacteria infection, the minimum inhibitory concentration of ornidazole and minimum bactericidal concentration are all less than metronidazole and tinidazole, and curative effect is better than metronidazole and tinidazole; Local application's curative effect is better than metronidazole and tinidazole.
But ornidazole also has some shortcomings.Liken water-soluble lowly, take back dizziness and gastrointestinal upset, can also cause untoward reactions such as hepatocellular damage, lupoid hepatitis, peripheral neurophaty once in a while.
Summary of the invention:
The object of the present invention is to provide a kind of new nitro glyoxaline compound.
R wherein
1For containing carbon number is 1～10 saturated or undersaturated straight chained alkyl, branched-chain alkyl or cyclic alkyl;
R2, R3 can independently represent alkyl; R2 R3 also can form ring, and described ring can be that ternary arrives ten-ring, also can connect one or several identical or different substituted radicals on the ring.
The ring that R2, R3 form can form heterocycle, and heterocycle can contain 0～5 identical or different heteroatoms and replace.
X represents electronegative ion or group, specifically can be halogen anion, organic acid, inorganic acid radical.
More detailed compound of the present invention comprises its pharmaceutical salts and their hydrate and prodrug.
The invention provides the production method of above-mentioned formula I compound and pharmaceutical salts thereof, concrete steps are by shown in down:
The preferred methylene dichloride of the solvent of step 1; Temperature of reaction 0-50 ℃;
The solvent of step 2 is methyl alcohol, ethanol; Temperature of reaction is 10-70 ℃;
The solvent of step 3 is methyl alcohol, ethanol, methylene dichloride, temperature of reaction 0-70 ℃;
The negatively charged ion of this compound (X) can be changed in the following manner, specifically is the example explanation with the acetate.
Adopt Levo-ornidazole or (r)-ornidazole to replace the racemization ornidazole can prepare the isomer of above-claimed cpd as starting raw material.
The preparation of the prodrug of above-claimed cpd can adopt method chemically commonly used with the hydroxylic moiety acylations, alkylation, phosphorylation or sulfonylation.
Compound of the present invention is useful, because they have pharmacologically active in comprising human animal.Particularly this compound is useful aspect treatment or prevention anaerobic infection and protozoan infection.For example: 1. be used for trichomonal men and women's urogenital infections.2. be used for the intestines that ameba causes, liver amoeba parasitosis (comprising amebic dysentery, amebic liver abscess).3. be used for giardiasis.4. be used for anaerobic infection: as septicemia, meningitis, operating rear wound infection, puerperal sepsis, septic abortion, endometritis and responsive microbial other infection.5. be used to prevent various operations back anaerobic infection.
Another object of the present invention is to provide a kind of and contain the pharmaceutical composition of (I) compound, and the application of said composition in preparation anti-anaerobic agent, anti-trichomonal medicine and anti-ameba medicine.
The weight content that contains formula (I) compound in the composition of the present invention is 0.01～99%, it is 10～2000mg that wherein preferred per unit preparation (as every, every bottle, every bag) contains formula (I) compound, further preferred 50～1200mg, more preferably 100mg～1000mg.
Pharmaceutical composition of the present invention is useful, because they have pharmacologically active in comprising human animal.Particularly this compound is useful aspect treatment or prevention anaerobic infection, anti-trichomonal infection and anti-ameba infection.For example: 1. be used for trichomonal men and women's urogenital infections.2. be used for the intestines that ameba causes, liver amoeba parasitosis (comprising amebic dysentery, amebic liver abscess).3. be used for giardiasis.4. be used for anaerobic infection: as septicemia, meningitis, operating rear wound infection, puerperal sepsis, septic abortion, endometritis and responsive microbial other infection.5. be used to prevent various operations back anaerobic infection.
Pharmaceutical composition provided by the invention is as activeconstituents and pharmaceutically acceptable carrier with formula (I) compound.
Pharmaceutical composition of the present invention can be prepared as the gastrointestinal administration preparation, also can be prepared as the parenteral administration preparation.
Gastrointestinal administration preparation of the present invention can be tablet, dispersible tablet, capsule, granule, oral liquid, syrup, preferred tablet, dispersible tablet, capsule.
Parenteral administration preparation of the present invention can be infusion preparation, injection and injection freeze-dried powder, can also be the vagina administration preparation, the preferred effervescent tablet of vagina administration preparation, gelifying agent or suppository.
The infusion preparation of formula (I) compound and the preparation method of injection mix formula (I) compound to contact with water for injection, perhaps with the intravenously administrable acceptable auxiliary, after osmotic pressure regulator, pH regulator agent mixing contact, contact with water for injection again, realize obtaining by following step:
A. formula (I) compound is added the dissolving of injection water, add medicine acceptable carrier mixing, add the amount of injection water to regulation;
B. accent or not adjust pH;
C. filter;
D. embedding;
E. sterilization.
Described osmotic pressure regulator is selected from an alkali metal salt, sodium-chlor, Repone K, borax, the boric acid of glucose, glucose, perhaps their mixture.
Described pH regulator agent is selected from hydrochloric acid, sodium hydroxide, Citric Acid, lactic acid, phosphoric acid salt or citrate buffer etc.
The preparation method of the injection freeze-dried powder of formula (I) compound contains following a few step:
A. preparating liquid: formula (I) compound is added the dissolving of injection water, add the amount of injection water to regulation;
B. accent or not adjust pH;
C. depyrogenation: in the solution of step b, add the heating of injection gac and filtered in 20 minutes;
D. degerming: the filtrate of step c is carried out Sterile Filtration with sterilization filter;
E. can: carry out sterile filling with the control antibiotic bottle;
F. freeze-drying: under cryogenic vacuum, carry out lyophilize.
Pharmaceutical composition of the present invention can be used for preventing, improving and/or cures the disease that is caused by anaerobic infection or protozoan infection; Be particularly suitable for using medicine as people and animal doctor.
Composition of the present invention is by the gross weight administration, and its amount is 1-100mg for every kg body weight with the amount of formula (I) compound, and preferably the consumption of 24h is every kg body weight 1-20mg, also can adopt medication several times.
Preferred plan is that the amount that gives the present composition once a day is the 1-50mg/kg body weight, and preferred dose is the 3-20mg/kg body weight.In order to meet people or ideal occlusion regimen for animals, the difference of the visual state of an illness weight of this dosage, treatment difficulty or ease fluctuates up and down, or follows the doctor's advice.
Typical compound of the present invention is as follows:
Below in conjunction with embodiment the present invention is described in further detail, but should understands the non-scope that only limits to these embodiment of scope of the present invention.
Embodiment 1: the preparation of compd A
With 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitro imidazoles (ornidazole) 220g, be dissolved in and slowly drip 20% sodium hydroxide 250ML in the 500ml methylene dichloride, stirring at room reaction 40 minutes, separatory, the organic layer drying, evaporated under reduced pressure solvent, residue 151g; Residue 500ML ethanolic soln slowly adds tetramethyleneimine 70g, and 50 ℃ were reacted 6 hours, termination reaction, and evaporated under reduced pressure solution, residue gets solid 92g with ethanol/re-crystallizing in ethyl acetate; The 92g solid is dissolved in 500ml methyl alcohol, stirs down and drip methyl iodide 55g, room temperature reaction disappears to raw material point, and evaporated under reduced pressure gets compd A 140g.
Purity: 98.3% chromatographic condition C18 chromatographic column (250mm * 46mm, 5 μ m), moving phase is acetonitrile-water (40: 60), and column temperature is 30 ℃, and the detection wavelength is 310nm.
Preparation with the compd A hydrochloride
With compd A 30g ethanol: acetone=200ml dissolving in 1: 1, dripping hydrochloric acid to pH value is about 2, stirring and crystallizing 1 hour, filtration, dry the hydrochloride 9g of compd A.
The preparation of the S type isomer of compd A
Preparing different according to the preparation method of preparation compd A is to replace ornidazole with Levo-ornidazole.
The preparation of the R type isomer of compd A
Preparing different according to the preparation method of preparation compd A is to replace ornidazole with (r)-ornidazole.
The preparation of compd A prodrug is that example is described as follows with the phosphoric acid ester:
Compd A 20g is dissolved in slowly drips phosphorus oxychloride 10g in the 100ml tetrahydrofuran (THF), dripped stirring reaction 2 hours, solvent evaporated slowly adds the frozen water hydrolysis, and evaporate to dryness gets the phosphoric acid ester of compd A.
Embodiment 2: the preparation of compd B.
With 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitro imidazoles 220g, be dissolved in and slowly drip 20% sodium hydroxide 250ML in the 500ml methylene dichloride, stirring at room reaction 40 minutes, separatory, organic layer drying, evaporated under reduced pressure solvent, residue 151g; Residue 500ML ethanolic soln slowly adds morphine quinoline 80g, and 50 ℃ were reacted 10 hours, termination reaction, and evaporated under reduced pressure solution, the residue re-crystallizing in ethyl acetate gets solid 53g; The 53g solid is dissolved in 500ml methyl alcohol, stirs down and drip methyl iodide 30g, room temperature reaction disappears to raw material point, and evaporated under reduced pressure gets compd A 82g.
Purity: 98.1% chromatographic condition C18 chromatographic column (250mm * 46mm, 5 μ m), moving phase is acetonitrile-water (40: 60), and column temperature is 30 ℃, and the detection wavelength is 310nm.
Preparation with compd B vitriol
With compd A 30g ethanol: acetone=200ml dissolving in 1: 1, the sulphuric acid soln of Dropwise 5 0% to pH value is about 2, stirring and crystallizing 1 hour, filtration, dry the vitriol 9g of compd B.
Embodiment 3: the preparation of Compound C.
With 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitro imidazoles 220g, be dissolved in and slowly drip 20% sodium hydroxide 250ML in the 500ml methylene dichloride, stirring at room reaction 40 minutes, separatory, organic layer drying, evaporated under reduced pressure solvent, residue 151g; Residue 500ML ethanolic soln slowly adds morphine quinoline 80g, and 50 ℃ were reacted 10 hours, termination reaction, and evaporated under reduced pressure solution, the residue re-crystallizing in ethyl acetate gets solid 53g; The 53g solid is dissolved in 500ml methyl alcohol, stirs dripping bromine propane 45g down, room temperature reaction disappears to raw material point, and evaporated under reduced pressure gets Compound C 87g.
Purity: 97.5% chromatographic condition C18 chromatographic column (250mm * 46mm, 5 μ m), moving phase is acetonitrile-water (40: 60), and column temperature is 30 ℃, and the detection wavelength is 310nm.
Embodiment 4: the preparation of Compound D.
With 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitro imidazoles (ornidazole) 220g, be dissolved in and slowly drip 20% sodium hydroxide 250ML in the 500ml methylene dichloride, stirring at room reaction 40 minutes, separatory, the organic layer drying, evaporated under reduced pressure solvent, residue 151g; Residue 500ML ethanolic soln slowly adds pyrrolidone 72g, and 50 ℃ were reacted 6 hours, termination reaction, and evaporated under reduced pressure solution, residue gets solid 83g with ethanol/re-crystallizing in ethyl acetate; The 80g solid is dissolved in 500ml methyl alcohol, stirs dripping bromine butane 60g down, room temperature reaction disappears to raw material point, and evaporated under reduced pressure gets Compound D 121g.
Purity: 98.3% chromatographic condition C18 chromatographic column (250mm * 46mm, 5 μ m), moving phase is acetonitrile-water (40: 60), and column temperature is 30 ℃, and the detection wavelength is 310nm.
Embodiment 5: the preparation of compd E
Compd B is dissolved in the ethanol, slowly adds KOH, stirring at room reaction 2 hours is filtered, and it is 7-8 that filtrate slowly adds acetic acid accent pH, and solvent evaporated gets compd E.
Embodiment 6: the preparation of compound F 17-hydroxy-corticosterone
With 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitro imidazoles (ornidazole) 220g, be dissolved in and slowly drip 20% sodium hydroxide 250ML in the 500ml methylene dichloride, stirring at room reaction 40 minutes, separatory, the organic layer drying, evaporated under reduced pressure solvent, residue 149g; Residue 500ML ethanolic soln slowly adds diethylamine 65g, and 50 ℃ were reacted 6 hours, termination reaction, and evaporated under reduced pressure solution, residue gets solid 82g with ethanol/re-crystallizing in ethyl acetate; The 82g solid is dissolved in 500ml methyl alcohol, stirs down and drip methyl iodide 50g, room temperature reaction disappears to raw material point, and evaporated under reduced pressure gets compd A 130g.
Purity: 97.5% chromatographic condition C18 chromatographic column (250mm * 46mm, 5 μ m), moving phase is acetonitrile-water (40: 60), and column temperature is 30 ℃, and the detection wavelength is 310nm.
Embodiment 7: the preparation method of compd B sheet
Prescription:
Method for making: prepare 4% Vltra tears (E-30) solution, standby.Taking by weighing 20g starch, to put 105 ℃ of dryings 5 hours standby.Take by weighing compd B, the Microcrystalline Cellulose of 60g starch and recipe quantity, mixing was pulverized 80 mesh sieves., granulate with 20 mesh sieves, material system softwood with 4% Vltra tears (E-30) solution in 50-60 ℃ of moisture content about 3% that is dried in the particle.Cross the whole grain of 20 mesh sieves, add dry starch (105 ℃ drying 5 hours), the magnesium stearate of recipe quantity, mix eventually, survey intermediate content, stator is heavy; Compressing tablet.
Embodiment 8: the preparation of Compound D sodium-chlor transfusion
Prescription:
Compound D 500g
Sodium-chlor 89g
Water for injection 10L
Make 10000ml
Method for making: take by weighing the Compound D and the sodium-chlor of recipe quantity, add injection water 10L, stirring and transferring pH is 5.0; Add 0.1% gac in above-mentioned solution, stir, placed 15 minutes, 5 microns titanium rods take off charcoal, filter through the millipore filtration essence of 0.45 micron of filter cartridge and 0.22 micron again; Embedding is in the 100ml glass infusion bottle, and 115 ℃ of flowing steams were sterilized 30 minutes, promptly gets the transfusion of Compound D sodium-chlor.
Embodiment 9: the preparation of Compound C injection liquid
Prescription:
Compound C 250g
Water for injection 1000ml
Make 1000ml
Method for making: take by weighing the Compound C of recipe quantity, add injection water 1000ml, stirring and transferring pH is 8.0; Add 0.1% gac in above-mentioned solution, stir, placed 15 minutes, 5 microns titanium rods take off charcoal, filter through the millipore filtration essence of 0.45 micron of filter cartridge and 0.22 micron again; Embedding promptly gets the Compound C injection liquid in the 10ml ampoule.
Embodiment 10: the hydrochloride preparation of injection compd B
Prescription: compd B 500
Water for injection 1000ml
Make 100 bottles
With the hydrochloride of compd B with the water for injection dissolving after, transferring pH is about 7, add needle-use activated carbon absorption 30 minutes after carbon removal, Sterile Filtration (0.22 μ m), after testing, be sub-packed in after filtrate is up to specification in the control microbiotic cillin bottle, place in the vacuum freezing drying oven and carried out lyophilize 48 hours, add a cover butyl rubber plug, and roll the hydrochloride that the envelope aluminium lid promptly gets the injection compd B.
Embodiment 11: pharmacodynamic study
Anaerobe resistant research adopts agar plate dilution method to measure compd A, compd B, the Compound C MIC to 11 kind of 207 strain anerobe
50Value, and observe of the influence of different bacterium concentration to MIC, measure their minimal bactericidal concentration (MBC) with the test tube doubling dilution.With the Quality Control bacterial strain of peptostreptococcus anaerobius, actinomyces israelii, porphyromonas gingivalis, bacteroides fragilis and clinical isolating peptostreptococcus anaerobius, clostridium perfringens, bacteroides fragilis, the oral antibacterial activity in vivo of the general Salmonella infecting mouse of product melanochrome model determination.In the experiment with the positive contrast of Levo-ornidazole.
The external anaerobe resistant MIC of compd A as a result
50Be 0.02～0.3mgL
-1, MIC
90Be 0.05～1mgL
-1The external anaerobe resistant MIC of compd B
50Be 0.015～0.2mgL
-1, MIC
90Be 0.05～1mgL
-1The external anaerobe resistant MIC of Compound C
50Be 0.01～0.5mgL
-1, MIC
90Be 0.05～1mgL
-1Morpholine nitre azoles MIC
50Be 0.045～1.0mgL
-1, MIC
90Be 0.1～15mgL
-1Ornidazole MIC
50Be 0.065～1.5mgL
-1, MIC
90Be 0.2～20mgL
-1Studies show that the compound of invention is better than morpholine nitre azoles and ornidazole to the anti-anaerobic activity of bacterium.
Anti-trichomonal and the research of anti-amoeba insect infection, compd A, compd B, Compound C clinical isolating Trichomonas hominis and the Ah crust of histolytica cadelle in the solution of 5ug/ml all have the good restraining effect, and Trichomonas hominis and the Ah crust of histolytica cadelle are all effectively killed.
Claims (3)
1. the pharmaceutical salts of the compound of general formula (I) or its hydrate and they and their prodrug:
R wherein
1For containing carbon number is 1～10 saturated or undersaturated straight chained alkyl, branched-chain alkyl or cyclic alkyl;
R2, R3 can independently represent alkyl; R2 R3 also can form ring, and described ring can be that ternary arrives ten-ring, also can connect one or several identical or different substituted radicals on the ring.
The ring that R2, R3 form can form heterocycle, and heterocycle can contain 0～5 identical or different heteroatoms and replace.
X represents electronegative ion or group, specifically can be halogen anion, organic acid, inorganic acid radical.
2. a medicinal compositions is characterized in that, contain the treatment effective dose according to claim 1 compound as activeconstituents and pharmaceutically acceptable carrier.
3. according to the purposes of the described pharmaceutical composition of claim 3, be used for the medicine that production for treating anti anaerobic bacteria infection or protozoacide infect.
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| CN2011100756246A CN102199147A (en) | 2011-03-19 | 2011-03-19 | Nitroimidazole derivative in therapy |
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| CN2011100756246A CN102199147A (en) | 2011-03-19 | 2011-03-19 | Nitroimidazole derivative in therapy |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104829541A (en) * | 2015-05-05 | 2015-08-12 | 江苏豪森药业股份有限公司 | High selectivity and high purity method for preparing morinidazole |
| CN104844522A (en) * | 2015-05-05 | 2015-08-19 | 江苏豪森药业股份有限公司 | Morinidazole crystal and preparation method and medical application thereof |
| CN114478494A (en) * | 2020-10-26 | 2022-05-13 | 南京锐志生物医药有限公司 | Derivative of nitroimidazole compound, pharmaceutical composition, preparation method and application thereof |
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| CN101250185A (en) * | 2008-03-31 | 2008-08-27 | 四川百利药业有限责任公司 | Pyrrone nidazole ester compound as well as preparation method and usage thereof |
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| CN1433414A (en) * | 1999-12-24 | 2003-07-30 | 应用研究系统Ars股份公司 | Benzazole derivatives and their use as JNK modulators |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104829541A (en) * | 2015-05-05 | 2015-08-12 | 江苏豪森药业股份有限公司 | High selectivity and high purity method for preparing morinidazole |
| CN104844522A (en) * | 2015-05-05 | 2015-08-19 | 江苏豪森药业股份有限公司 | Morinidazole crystal and preparation method and medical application thereof |
| CN104844522B (en) * | 2015-05-05 | 2017-07-25 | 江苏豪森药业集团有限公司 | Morpholine nitre azoles crystal and preparation method thereof and medical usage |
| CN114478494A (en) * | 2020-10-26 | 2022-05-13 | 南京锐志生物医药有限公司 | Derivative of nitroimidazole compound, pharmaceutical composition, preparation method and application thereof |
| CN114478494B (en) * | 2020-10-26 | 2023-10-27 | 南京锐志生物医药有限公司 | Derivatives of nitroimidazole compounds, pharmaceutical composition, preparation method and application thereof |
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Application publication date: 20110928 |