CN1329379C - Anaerobe resistant compound - Google Patents
Anaerobe resistant compound Download PDFInfo
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- CN1329379C CN1329379C CNB2006100002318A CN200610000231A CN1329379C CN 1329379 C CN1329379 C CN 1329379C CN B2006100002318 A CNB2006100002318 A CN B2006100002318A CN 200610000231 A CN200610000231 A CN 200610000231A CN 1329379 C CN1329379 C CN 1329379C
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The present invention relates to an anaerobe resistant compound, namely 2-methyl-1-(3-azide group-2 hydroxide radical propyl)-5-nitryl-1H-imidazole and a preparation method thereof, and the present invention also relates to a medical compound using the compound as an active component and the application of the compound of the present invention for preparing anaerobe resistant medicines, antitrichomonal medicines and amoeba resistant medicines.
Description
Technical field:
The present invention relates to a kind of new medical compounds, contain their pharmaceutical preparation and preparation method thereof, definite saying so relates to 2-methyl isophthalic acid-(3-cyano-2-hydroxy-propyl group)-5-nitro-1H-imidazolium compounds and preparation method thereof, also relate to the pharmaceutical composition that contains this compound, and their application in preparation anti-anaerobic agent, anti-trichomonal medicine and anti-ameba medicine.
Background technology:
Anerobe is the cell that could survive and breed in oxygen-free environment, under the situation that Abwehrkraft des Koepers descends, can cause severe infections.The medicine that most of anerobe is all had strong anti-microbial activity has nitroimidazoles medicine, paraxin, imipenum/cilastatin, β-Nei Xiananleikangshengsu, beta-lactamase inhibitor etc.
The nitro glyoxaline antimicrobial drug of using clinically has metronidazole, tinidazole, ornidazole, Saikexiaozuo etc. at present.In recent years, discover that clinical isolated anerobe obviously increases the resistant rate of the nitre azole drug of present application, therefore, it is significant to study new nitroimidazoles medicine.
Summary of the invention:
The invention provides a kind of new nitro glyoxaline compound, its chemical structural formula is as follows:
The present invention includes compound in structural formula I,
Described compound comprises its raceme or its optically active isomer, also comprises its pharmacy acceptable salt and/or hydrate, compound of the present invention, and chemical name is: 2-methyl isophthalic acid-(3-cyano-2-hydroxy-propyl group)-5-nitro-1H-imidazoles.
Compound of the present invention, the compound of preferred structure formula II wherein, or its pharmacy acceptable salt and/or hydrate, formula II compound is the optically active compounds monomer, described monomer, preferably described monomer is more than 50%, its enantiomorph is below 50%, and more preferably described monomer is more than 90%, and its enantiomorph is below 10%, described monomer can use conventional monomer separation technology to split, and also can directly use the opticity raw material synthetic.
The invention still further relates to the preparation method of formula I compound, comprising formula III compound and hydrocyanide are reacted the compound that obtains formula I.
The invention still further relates to the preparation method of formula II compound, comprising formula IV compound and hydrocyanide are reacted the compound that obtains formula II.The preferred sodium cyanide of hydrocyanide, potassium cyanide and cuprous cyanide.
Wherein formula III compound and formula IV compound are known compounds as the raw material of product of the present invention, can buy from the market, can also can prepare according to method of the present invention with the technology preparation of existing bibliographical information.
The preparation method of Chinese style I of the present invention and the described compound of formula II, wherein reaction solvent is the polarity organic agent, as methyl alcohol, ethanol, acetonitrile, N, and dinethylformamide, dimethyl sulfoxide (DMSO) etc. and their aqueous solution, preferred alcohols or alcohol/aqueous solution, more preferably methyl alcohol, aqueous ethanolic solution.
And according to some usual methods in field under the present invention, the compound of following formula I of the present invention can generate its pharmacy acceptable salt with acid.Acid can comprise mineral acid or organic acid, and the salt that forms with following acid is particularly preferred: hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, sulfuric acid, phosphoric acid, methylsulfonic acid, ethyl sulfonic acid, toluenesulphonic acids, Phenylsulfonic acid, naphthalene disulfonic acid, formic acid, acetate, propionic acid, lactic acid, trifluoroacetic acid, toxilic acid, citric acid, succsinic acid, glyconic acid, fumaric acid, Tartaric acid, Phenylsulfonic acid, phenylformic acid or tosic acid etc.
In addition, the present invention also comprises the prodrug of The compounds of this invention.According to the present invention, prodrug is the derivative of the compound of formula I and formula II, they self may have more weak active or even do not have activity, but after administration, (for example by metabolism, solvolysis or other mode) is converted to corresponding biologically active form under physiological condition.
The present invention includes pharmaceutical composition, said composition contains the compound of following formula I or formula II or its pharmacy acceptable salt as activeconstituents, and pharmaceutically acceptable carrier.Compound of the present invention can be used in combination with other activeconstituentss, as long as they do not produce other disadvantageous effects, for example anaphylaxis, hemolytic reaction, local excitation.
Pharmaceutical composition of the present invention can be mixed with any suitable formulation, for example: oral preparations (as tablet, capsule, oral liquid, suspensoid, pill, granule), injection preparation (as aseptic powder, lyophilized powder, liquid drugs injection, transfusion, emulsion, liposome); Topical formulations (for example ointment, solution and suppository etc.).The present composition can be prepared according to the method for knowing in this area.
The carrier that is used for pharmaceutical composition of the present invention is the available common type of pharmaceutical field, comprising: the tackiness agent that oral preparations is used, lubricant, disintegrating agent, solubility promoter, thinner, stablizer, suspension agent, correctives etc.; The solubility promoter that injectable formulation is used, stablizer, sanitas, physiological saline, glucose, water for injection etc.; The matrix that topical formulations is used, thinner, lubricant, sanitas etc.Pharmaceutical preparation can oral administration or parenteral mode (for example intravenously, subcutaneous, intraperitoneal, intravaginal or part) administration, if medicine is unsettled under the stomach condition, it can be mixed with enteric coated tablets.
And, the compound of following formula I or formula II is used for patient's clinical dosage and can suitably adjusts according to activeconstituents therapeutic efficiency and bioavailability, their metabolism and discharge rate and patient's age, sex, the disease phase in vivo, therefore, therapeutic dose of the present invention can have large-scale variation.In general, the actual active drug quantity that can be according to the present invention be contained in the last preparation in medicinal compound or the composition, in addition suitable adjustment to reach the requirement of its treatment significant quantity, is finished the purpose that the present invention treats anaerobic infection.Usually be the patient of 75kg for body weight, institute's administration per daily dose is 1.0mg/kg～40mg/kg, preferred 2mg/kg～20mg/kg.Above-mentioned effective dose can be according to doctor or pharmacist's guidance, with the single dose form administration or divide several times administration (being preferably to six time) at certain intervals.
The dosage of above activeconstituents will be different because of prescription.Yet, if necessary, also can depart from above-mentioned consumption, this depends on experimenter's to be treated type and body weight, individual behavior to medicine, the character of disease and type and the administration time or the interval of seriousness, preparation and administration.
Following synthetic route 1 has been described the preparation of formula I compound of the present invention, and all raw materials all are the method preparation known by the method for describing in these synoptic diagram, by the organic chemistry filed those of ordinary skill or commercially available.This method is that the organic chemistry filed those of ordinary skill is known.The optically active isomer of its Chinese style I compound is the formula III compound that formula II compound can at first make corresponding S type and R type by the epoxy chloropropane of selecting S-(+) and R-(-), again with sodium cyanide reaction (route 2 and 3).
Route 3
The beneficial effect of The compounds of this invention is described with experimental data below.
Test 1
Adopt method known to a person of ordinary skill in the art that compound of the present invention has been carried out external anti-anaerobic activity and measure (seeing Table 1), select the clinical separation anerobe of 121 strains for use, adopt agar dilution to detect the minimal inhibitory concentration (MIC) of embodiment 1～3 compound and contrast medicine metronidazole and tinidazole, the results are shown in Table 1.
The external anti-anaerobic activity of table 1 embodiment compound
| The bacterium name | The bacterial strain number | MIC (μg/ml) | Tinidazole | Metronidazole | Embodiment 1 | Embodiment 2 | Embodiment 3 |
| Bacterioide | 26 | MIC 50 MIC 90The MIC scope | 0.5 1.0 0.25-8.0 | 0.5 1.0 0.25-8.0 | 0.25 0.5 0.125-4.0 | 0.25 0.5 0.125-4.0 | 0.25 0.5 0.125-8.0 |
| Prey is irrigated bacterium | 25 | MIC 50 MIC 90The MIC scope | 0.5 1.0 0.125-16 | 0.5 1.0 0.125-16 | 0.25 0.5 0.125-8.0 | 1.0 4.0 0.5-32 | 0.25 0.5 0.125-4.0 |
| Peptostreptococcus | 20 | MIC 50 MIC 90The MIC scope | 0.5 1.0 0.25-8.0 | 0.5 1.0 0.25-8.0 | 0.5 1.0 0.25-8.0 | 0.125 0.25 0.06-2.0 | 0.25 0.5 0.125-4.0 |
| Fusobacterium | 30 | MIC 50 MIC 90The MIC scope | 0.5 1.0 0.25-8.0 | 0.5 1.0 0.125-8.0 | 1.0 2.0 0.25-4.0 | 0.5 1.0 0.06-2.0 | 2.0 8.0 0.5-32 |
| Clostridium | 20 | MIC 50 MIC 90The MIC scope | 0.5 1.0 0.125-8.0 | 0.5 1.0 0.125-8.0 | 0.5 2.0 0.125-16.0 | 0.25 0.5 0.125-8.0 | 0.5 1.0 0.25-16.0 |
The result shows that The compounds of this invention has good antibacterial activity in vitro to multiple anerobe, quite or be better than metronidazole and tinidazole.
Test 2
Adopt Kunming kind small white mouse, with clinical separation bacteroides fragilis, peptostreptococcus respectively infecting mouse prepare the abdominal cavity infection model, and carry out the endogenous protective test with the positive contrast medicine of ornidazole.The results are shown in Table 2
Table 2 embodiment compound is to the endogenous protective test-results of infecting mouse
| Embodiment chemical combination | Oral ED 50(mg/kg) | Intravenously administrable ED 50(mg/kg) | ||
| Bacteroides fragilis | Peptostreptococcus | Bacteroides fragilis | Peptostreptococcus | |
| 1 | 6 | 12 | 10 | 15 |
| 2 | 5 | 13 | 7 | 10 |
| 3 | 9 | 18 | 12 | 18 |
| Ornidazole | 12 | 24 | 9 | 20 |
Test-results shows that The compounds of this invention all is better than the reference substance ornidazole to the provide protection of infecting mouse
Test 3
With the Kunming mouse is experimental animal, and male and female half and half are irritated stomach and intravenous administration, and the embodiment compound has been carried out preliminary studies on acute toxicity, the results are shown in Table 3.
Table 3 acute toxicity test in mice
| Be subjected to the reagent product | Route of administration | Solvent | LD 50Value (mg/kg) |
| Embodiment 1 | Oral administration | 0.4％CMC | 6000 |
| Intravenously administrable | The 30%DMSO sodium chloride injection | 700 | |
| Embodiment 2 | Oral administration | 0.4％CMC | 8000 |
| Intravenously administrable | The 30%DMSO sodium chloride injection | 1000 | |
| Embodiment 3 | Oral administration | 0.4％CMC | 5000 |
| Intravenously administrable | The 30%DMSO sodium chloride injection | 600 | |
| Ornidazole | Oral administration | 0.4％CMC | 1500 |
| Intravenously administrable | The 30%DMSO sodium chloride injection | 550 |
The result shows that The compounds of this invention mouse vein and oral administration acute toxicity all are lower than ornidazole.
Compound according to following formula I of the present invention and formula II has anti-microbial effect to multiple anerobe, and is better than metronidazole and tinidazole; Experiment shows that the provide protection to infecting mouse is better than ornidazole in the body; Acute toxicity test shows that the toxicity of its mouse vein and oral administration is lower than ornidazole.Therefore, they can be as the medicine of preparation treatment anaerobic infection.
Compound of the present invention has the chemical sproof effect that resists currently available products, and efficient, low toxicity, and Stability Analysis of Structures, the optical density height is fit to suitability for industrialized production, has good biological activity.
Embodiment:
Embodiment is intended to set forth rather than limit the scope of the invention.The proton nmr spectra of compound is measured with BrukerARX-300, and mass spectrum is measured with Agilent 1100 LC/MSD: agents useful for same is analytical pure or chemical pure.
The preparation of preparation example 1 2-methyl isophthalic acid-(3-chloro-2-hydroxypropyl)-5-nitro-1H-imidazoles
In ethyl acetate 150mL, add 2-methyl-5-nitro imidazoles 12.7g (0.1mol), be cooled to 0-5 ℃.Add aluminum trichloride (anhydrous) 20.0g (0.15mol), control reaction temperature is not higher than 10 ℃ in batches.Finish,, drip off the back and continue 0-5 ℃ of reaction 4 hours in 0-10 ℃ of dropping epoxy chloropropane 13.9g (0.15mol) in reaction solution.Reaction is finished, and frozen water 50mL is slowly added in the reaction solution, and the control reacting liquid temperature is lower than 30 ℃, stirred 1 hour, and filtered filtrate Dropwise 5 0% dilute sulphuric acid, transfer to pH to 1.0, then, in mixed solution, drip strong aqua and transfer to pH to 3-4, separate out solid, filter, gained filtrate transfers to pH to 7.0-7.5 with strong aqua, tell ethyl acetate layer, use anhydrous sodium sulfate drying, evaporated under reduced pressure, with 50% ethanol/water recrystallization, get white powder 11.4g, yield 52.5%.
The preparation of preparation example 2 S-(-)-2-methyl isophthalic acid-(3-chloro-2-hydroxypropyl)-5-nitro-1H-imidazoles
In ethyl acetate 150mL, add 2-methyl-5-nitro imidazoles 12.7g (0.1mol), be cooled to 0-5 ℃.Add aluminum trichloride (anhydrous) 20.0g (0.15mol), control reaction temperature is not higher than 10 ℃ in batches.Finish, in reaction solution, drip S-(+)-epoxy chloropropane 13.9g (0.15mol) in 0-10 ℃, drip off the back and continue 0-5 ℃ of reaction 4 hours.Reaction is finished, frozen water 50mL is slowly added in the reaction solution, and the control reacting liquid temperature is lower than 30 ℃, stirs 1 hour, filter, filtrate Dropwise 5 0% dilute sulphuric acid transfers to pH to 1.0, then, in mixed solution, drip strong aqua and transfer to pH to 3-4, separate out solid, filter, gained filtrate transfers to pH to 7.0-7.5 with strong aqua, tell ethyl acetate layer, use anhydrous sodium sulfate drying, evaporated under reduced pressure is with 50% ethanol/water recrystallization, get white powder S-(-)-2-methyl isophthalic acid-(3-chloro-2-hydroxypropyl)-5-nitro-1H-imidazoles 10.4g, yield 47.7%, mp.90-96 ℃, MS m/z:220.0[M+H]
+
The preparation of preparation example 3R-(+)-2-methyl isophthalic acid-(3-chloro-2-hydroxypropyl)-5-nitro-1H-imidazoles
With 2-methyl-5-nitro imidazoles 12.7g (0.1mol) and R-(-)-epoxy chloropropane 13.9g (0.15mol) is raw material, preparation method according to embodiment 4, synthetic white powder R-(+)-2-methyl isophthalic acid-(3-chloro-2-the hydroxypropyl)-5-nitro-1H-imidazoles 9.8g that obtains, yield 44.7%, mp:90-96 ℃, MS m/z:219.9[M+H]
+
The preparation of embodiment 1 2-methyl isophthalic acid-(3-cyano-2-hydroxy-propyl group)-5-nitro-1H-imidazoles
In 85% aqueous ethanolic solution 500mL, add 2-methyl isophthalic acid-(3-chloro-2-hydroxypropyl)-5-nitro-1H-imidazoles 100g (0.46mol) and potassium cyanide 35.5g (0.55mol), stir reflux, thin layer monitoring.Reaction finishes, reaction solution is cooled to room temperature, the most of ethanol of pressure reducing and steaming, residual solution is put into refrigerator overnight, separates out solid, suction filtration, the a spot of absolute ethanol washing of filter cake, drying gets 2-methyl isophthalic acid-(3-cyano-2-hydroxy-propyl group)-5-nitro-1H-imidazoles 58.0g, yield 60%, MS m/z:211[M+H]
+,
1H-NMR:(DMSO): 2.45 (s, 3H), 2.77 (dd, 1H, J=6.4,16.9Hz), 2.86 (dd, 1H, J=4.8,16.9Hz), 4.06 (m, 1H), 4.17 (dd, 1H, J=9.5,14.0Hz), 4.46 (dd, 1H, J=2.8,14.0Hz), 5.88 (d, 1H, J=5.3Hz), 8.04 (s, 1H).
The preparation of embodiment 2 R-2-methyl isophthalic acids-(3-cyano-2-hydroxy-propyl group)-5-nitro-1H-imidazoles
With S-(-)-2-methyl isophthalic acid-(3-chloro-2-hydroxypropyl)-5-nitro-1H-imidazoles and potassium cyanide is starting raw material, according to synthetic R-2-methyl isophthalic acid-(3-azido--2-the hydroxypropyl)-5-nitro-1H-imidazoles that obtains of the preparation method of embodiment 4.
The preparation of embodiment 3 S-2-methyl isophthalic acids-(3-cyano-2-hydroxy-propyl group)-5-nitro-1H-imidazoles
With R-(+)-2-methyl isophthalic acid-(3-chloro-2-hydroxypropyl)-5-nitro-1H-imidazoles and sodium cyanide is starting raw material, according to synthetic S-2-methyl isophthalic acid-(3-azido--2-the hydroxypropyl)-5-nitro-1H-imidazoles that obtains of the preparation method of embodiment 4.
The preparation of embodiment 4 embodiment 1 compound tablet (250mg/ sheet)
Get embodiment 1 compound 250g, starch 30g, 2%HPMC aqueous solution 80ml, carboxymethylstach sodium 15g, Magnesium Stearate 2g, according to following steps:
A, preparation 2%HPMC solution are an amount of, standby;
B, former, auxiliary material is suitably dry crosses 100 mesh sieves respectively, and is standby;
C, take by weighing former, auxiliary material by recipe quantity.After embodiment 1 compound, starch, carboxymethylstach sodium mixed, add 2%HPMC solution and make softwood, with 20 mesh sieve system wet granulars;
D, wet granular cool after the drying slightly in about 3 hours of 55 ℃ of dryings, add Magnesium Stearate, with whole of 20 mesh sieves; Measure content, it is heavy to calculate sheet;
E, select 10mm dimple form drift compressing tablet for use, make 1000.
F, inspection after construction, qualified after, packing warehouse-in.
The preparation of embodiment 5 embodiment 2 compound dispersible tablets
Get following component:
Embodiment 2 compound 250g
Pregelatinized Starch 50g
Microcrystalline Cellulose 50g
Sodium starch glycolate 20g
The about 90ml of the 2%HPMC aqueous solution
Micropowder silica gel 20g
Stevia glucoside 18g
Magnesium Stearate 2g
Make 1000
Be prepared according to following steps:
A, preparation 2%HPMC solution are an amount of, standby.
B, former, auxiliary material is suitably dry crosses 100 mesh sieves respectively, and is standby.
C, take by weighing former, auxiliary material by recipe quantity.After embodiment 2 compounds, pregelatinized Starch, Microcrystalline Cellulose, carboxymethylstach sodium, stevia glucoside mixed, add 2%HPMC solution and make softwood, with 20 mesh sieve system wet granulars.
D, wet granular cool after the drying slightly in 55 ℃ of dryings 3 hours, add micropowder silica gel, Magnesium Stearate, with whole of 20 mesh sieves.Measure content, it is heavy to calculate sheet.
E, select 11mm dimple form drift compressing tablet for use, 1000.
F, inspection after construction, qualified after, packing warehouse-in.
The preparation of embodiment 6 embodiment, 1 compound capsules (125mg/ grain)
Get following component:
Embodiment 1 compound 125g
Starch 15g
Lactose 15g
The about 40ml of the 2%HPMC aqueous solution
Sodium starch glycolate 7.5g
Magnesium Stearate 1g
Make 1000
Carry out according to following steps:
A, preparation 2%HPMC solution are an amount of, standby.
B, former, auxiliary material is suitably dry crosses 100 mesh sieves respectively, and is standby.
C, take by weighing former, auxiliary material by recipe quantity.After embodiment 1 compound, starch, lactose, carboxymethylstach sodium mixed, add 2%HPMC solution system softwood, with 20 mesh sieve system wet granulars.
D, wet granular cool after the drying slightly in about 3 hours of 55 ℃ of dryings, add Magnesium Stearate, with whole of 20 mesh sieves.Measure content, calculate loading amount.
E, select 2# capsule shell can particle for use, 1000 of capsules.
F, with capsule polishing, dedusting.
G, inspection after construction, qualified after, packing warehouse-in.
The preparation of embodiment 7 embodiment, 1 compound effervescent tablets (250mg/ sheet)
Get following component:
Embodiment 1 compound 250g
Lactose 100g
Boric acid 92g
Sodium bicarbonate 120g
Hydroxypropylcellulose 20g
Magnesium stearate 15g
Polyvidone 5g
95% ethanol 100ml
Make 1000
Carry out according to following steps:
A, supplementary material is sieved, standby;
B, polyvidone is dissolved in 95% ethanol, standby;
C, with embodiment 1 compound, lactose, sodium bicarbonate 95% ethanolic soln system softwood, granulation with polyvidone;
D, mixing that c is obtained with hydroxypropylcellulose, magnesium stearate;
E, compressing tablet get 1000.
The preparation of embodiment 8 embodiment, 1 compound effervescent tablets (500mg/ piece)
Get following component:
Embodiment 1 compound 500g
Vitamin-E 1.5g
Lactic acid 30g
Semi-synthetic fatty acid glyceride (36 type) 860g
Make 1000 pieces
Carry out according to following steps:
A, embodiment 1 raw materials of compound medicinal powder is broken, it is standby to cross 100 mesh sieves;
B, take by weighing supplementary material by recipe quantity;
C, get 36 type semi-synthetic fatty acid glyceride, put heat fused in 55～60 ℃ of water-baths;
D, embodiment 1 compound fine powder, lactic acid, the vitamin-E that will pulverize and cross 100 mesh sieves add in the 36 type semi-synthetic fatty acid glyceride of above-mentioned fusing, with adding with stirring to mixing, irritate mould, solidify, and wipe the demoulding off;
E, mensuration content;
F, pack 1000 pieces of finished products.
The preparation of embodiment 9 embodiment 2 compound injections (250mg/ props up).
Get following component:
Embodiment 2 compound 250g
Ethanol 2.5L
0.1mol/L an amount of adjust pH to 3.5 of hydrochloric acid soln
Water for injection adds to 5L
Make 1000
Carry out according to following steps:
A, embodiment 2 compounds are added dissolve with ethanol, regulate pH value, add and inject water to specified amount;
B, in the soup of step a, add the injection gac and filtered in 20 minutes in 60～70 ℃ of heating;
1000 of c, embeddings;
D, pressure sterilizing.
The preparation of embodiment 10 embodiment 3 compound freeze-dried powders (125mg/ props up)
Get following component:
Embodiment 3 compound 125g
N.F,USP MANNITOL 125g
0.1mol/L an amount of adjust pH to 2.5 of hydrochloric acid soln
Water for injection 3000mL
Make 1000 bottles
Carry out according to following steps:
A, preparating liquid: take by weighing recipe quantity embodiment 3 compounds, N.F,USP MANNITOL, add injection water 2400mL, an amount of adjust pH to 2.5 of 0.1mol/L hydrochloric acid soln makes dissolving;
B, depyrogenation: add injection gac (activated carbon dosage be cumulative volume 0.1～0.3%) in the above-mentioned soup,, filter, collect filtrate 60～70 ℃ of heating 20 minutes;
C, degerming: above-mentioned filtrate is carried out degerming by aseptic method with sterilization filter filter, with 0.22 μ m millipore filtration;
1000 bottles of d, cans;
E, freeze-drying: pre-freeze below-40 ℃ 1.5～2 hours, under-25 ℃, 1.33Pa (0.01 holder) vacuum tightness, distil then, remove after 90% at free water content, after heat drying (top temperature must not above 30 ℃) treats that temperature curve and vacuum curve overlap respectively, promptly can be considered freeze-drying and finish, jump a queue entirely automatically in the freeze drying box.
F, seal and add aluminium lid.
Claims (10)
1, the compound of formula I structure, its raceme or optically active isomer, or its pharmacy acceptable salt and/or hydrate.
According to the compound of claim 1, it is characterized in that 2, wherein said optically active isomer is the compound of formula II, or its pharmacy acceptable salt and/or hydrate.
3, according to each compound in claim 1 or 2, it is characterized in that described pharmacy acceptable salt is mineral acid or organic acid salt, described optically active isomer is the optically active compounds monomer, wherein said monomer is more than 50%, and its enantiomorph is below 50%.
4, a kind of medicinal compositions is characterized in that, contains in claim 1 or 2 each described compound or its pharmacy acceptable salt and/or hydrate as activeconstituents and pharmaceutically acceptable carrier.
5, each described compound or its pharmacy acceptable salt and/or the hydrate application in the preparation anti-anaerobic agent in the claim 1 or 2.
6, according to the preparation method of the described compound of claim 1, it is characterized in that, comprise formula III compound and hydrocyanide are reacted the step that obtains formula I compound.
7, according to the preparation method of the described compound of claim 2, it is characterized in that, comprise formula IV compound and hydrocyanide are reacted the step that obtains formula II compound.
According to claim 7 or 8 described preparation methods, it is characterized in that 8, wherein said hydrocyanide is sodium cyanide, potassium cyanide or cuprous cyanide.
According to claim 7 or 8 described preparation methods, it is characterized in that 9, reaction is to carry out in the aqueous solution of polar organic solvent or polar organic solvent.
According to the preparation method of claim 9, it is characterized in that 10, wherein said polar organic solvent is ethanol or methyl alcohol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100002318A CN1329379C (en) | 2006-01-06 | 2006-01-06 | Anaerobe resistant compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100002318A CN1329379C (en) | 2006-01-06 | 2006-01-06 | Anaerobe resistant compound |
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| CN1800167A CN1800167A (en) | 2006-07-12 |
| CN1329379C true CN1329379C (en) | 2007-08-01 |
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| CNB2006100002318A Expired - Fee Related CN1329379C (en) | 2006-01-06 | 2006-01-06 | Anaerobe resistant compound |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1651415A (en) * | 2004-11-29 | 2005-08-10 | 南京圣和药业有限公司 | Preparation and purification method of ornidazole optical antipode |
| CN1686117A (en) * | 2005-04-28 | 2005-10-26 | 南京圣和药业有限公司 | Application of levoornidazole in preparation of anti anaerobic bacteria infection medicine |
| CN1709245A (en) * | 2005-07-08 | 2005-12-21 | 南京圣和药业有限公司 | Use of levo-ornidazole for preparing anti-parasitic-infectious drug |
-
2006
- 2006-01-06 CN CNB2006100002318A patent/CN1329379C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1651415A (en) * | 2004-11-29 | 2005-08-10 | 南京圣和药业有限公司 | Preparation and purification method of ornidazole optical antipode |
| CN1686117A (en) * | 2005-04-28 | 2005-10-26 | 南京圣和药业有限公司 | Application of levoornidazole in preparation of anti anaerobic bacteria infection medicine |
| CN1709245A (en) * | 2005-07-08 | 2005-12-21 | 南京圣和药业有限公司 | Use of levo-ornidazole for preparing anti-parasitic-infectious drug |
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| CN1800167A (en) | 2006-07-12 |
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