CN100999500A - Onitrodazole precursor drug and its preparation process and use - Google Patents
Onitrodazole precursor drug and its preparation process and use Download PDFInfo
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- CN100999500A CN100999500A CN 200610105187 CN200610105187A CN100999500A CN 100999500 A CN100999500 A CN 100999500A CN 200610105187 CN200610105187 CN 200610105187 CN 200610105187 A CN200610105187 A CN 200610105187A CN 100999500 A CN100999500 A CN 100999500A
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- ornidazole
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Abstract
This invention involves Ornidazole precursor drug and its preparation and use. Ornidazole precursor drugs is obtained by through chemical modification to its structure of the hydroxyl group, can be used in medicinal combination, can be used to treat anaerobic bacteria or protozoan infection diseases.
Description
Technical field:
The present invention relates to the prodrug and preparation method thereof and its purposes of ornidazole at field of medicaments.
Technical background:
Ornidazole is ((±) 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitro imidazoles (Ornidazole, CAS 16773-42-5).Ornidazole is a nitro imidazole derivatives, 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 third generation 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.
Levo-ornidazole ((-) 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitro imidazoles), Chinese patent (CN200510068478.9, CN200510083517.2) has been described it and has been better than ornidazole and (r)-ornidazole aspect some drug side effects such as neurotoxicity.
It is effective ways in the original new drug research that the effective medicine of generally acknowledging is carried out the prodrug design, belongs to present popular Me-too drug research type.The report of the prodrug research of ornidazole is not arranged both at home and abroad at present as yet, and the inventor discloses a kind of prodrug ornidazole phosphate of ornidazole at Chinese patent CN200610041611.6.
Summary of the invention:
The object of the present invention is to provide its structural formula of class ornidazole prodrug to be:
Wherein R is straight chained alkyl, branched-chain alkyl or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxy alkyl, alkyl sulphonyl, aryl sulfonyl, aralkyl alkylsulfonyl, amino-acid residue, a phosphate radical, gen-diphosphate or triphosphate or phosphate radical derivative.
Another object of the present invention provides the preparation method of ornidazole prodrug.
A further object of the present invention provides the medical composition and its use of ornidazole prodrug.
In more detail, the present invention includes hydrate, solvated compounds and the ornidazole prodrug pharmaceutical salts of ornidazole prodrug, hydrate, the solvated compounds of ornidazole prodrug object pharmaceutical salts.
Term alkyl used herein refers to C except that particularly pointing out
1To C
20Saturated chain, branch or ring-type primary, the second month in a season, tertiary hydrocarbon, and specifically comprise methyl, trifluoromethyl, ethyl, propyl group, sec.-propyl, cyclopropyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopentyl, isopentyl, neo-pentyl, hexyl, isohexyl, cyclohexyl, cyclohexyl methyl, 3-methyl amyl, 2,2-dimethylbutyl and 2, the 3-dimethylbutyl.This term comprises and replacing or unsubstituted alkyl.The part that can replace the abovementioned alkyl group is selected from: hydroxyl, amino, alkylamino, arylamino, alkoxyl group, aryloxy, nitro, cyano group, sulfonic acid, sulfate radical, phosphate radical; described part is protected as required or not; perhaps be protected; this is that those skilled in that art are known; for example at Greene etc.; Protective Groups in Organic Synthesis; JohnWiley and Sons; second edition; instruction in 1991, the document is attached to herein hereby by reference.
Term aryl used herein refers to phenyl, xenyl or naphthyl except that particularly pointing out, preferably refer to phenyl.
This term comprises and replacing or unsubstituted part.Aromatic yl group can be selected from one or more following parts and be replaced: hydroxyl, amino, alkylamino, arylamino, alkoxyl group, aryloxy, nitro, cyano group, sulfonic acid, sulfate radical, phosphate radical; described part is protected as required or not; perhaps be protected; this is that those skilled in that art are known; for example at Greene etc.; Protective Groups in OrganicSynthesis; John Wiley and Sons; second edition; instruction in 1991, the document is attached to herein hereby by reference.
Below be the chemical structural formula of typical compound of the present invention:
Ornidazole acetic ester Levo-ornidazole acetic ester (r)-ornidazole acetic ester
Ornidazole propionic ester Levo-ornidazole propionic ester (r)-ornidazole propionic ester
Ornidazole benzoic ether Levo-ornidazole benzoic ether (r)-ornidazole benzoic ether
Ornidazole benzene sulfonate Levo-ornidazole benzene sulfonate (r)-ornidazole benzene sulfonate
Ornidazole methanesulfonates Levo-ornidazole methanesulfonates (r)-ornidazole methanesulfonates
Ornidazole cetylate Levo-ornidazole cetylate (r)-ornidazole cetylate
The prodrug of ornidazole of the present invention is the acylations by hydroxyl, alkylation, the compound that phosphorylation or sulfoacylation obtain.
Pharmaceutical composition provided by the invention is that pharmaceutical salts with ornidazole prodrug or prodrug is as activeconstituents and pharmaceutically acceptable carrier.
Form of administration can be pharmaceutically acceptable preparations such as tablet, capsule, dispersible tablet, oral liquid, infusion solutions, little pin, freeze-dried powder.
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.
The prodrug of ornidazole of the present invention is by the gross weight administration, and its amount is every kg body weight 1-100mg, and preferably the consumption of 24h is every kg body weight 1-50mg, also can adopt medication several times.
Preferred plan is that the amount that gives the Levo-ornidazole prodrug once a day is the 1-50mg/kg body weight, and preferred dose is the 3-50mg/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.
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 Levo-ornidazole acetic ester
Levo-ornidazole 110g is dissolved in the exsiccant ethyl acetate 500ml solution, dripping acetyl chloride 90ml, control reaction temperature is at 10-20 ℃, liquid phase control reaction is to the peak that does not have Levo-ornidazole substantially, and the reclaim under reduced pressure ethyl acetate is under the cooling, slowly add pure water 600ml, slowly adding 10% sodium carbonate solution adjust pH is 5.0, is evaporated to dried, add ethanol 500ml, filter, add 500ml sherwood oil, freezing crystallization in the filtrate, filter, get Levo-ornidazole acetic ester 91g.
[purity: 98.8%, chromatographic condition: moving phase is the potassium dihydrogen phosphate (transferring pH with triethylamine is 6.0)=35: 65 of methyl alcohol: 0.05mol/L; Chromatographic column: Kromasil C18 5u, 250 * 4.6mm; ]
Embodiment 2: the preparation of Levo-ornidazole propionic ester
Levo-ornidazole 110g is dissolved in the exsiccant ethyl acetate 500ml solution, drips propionyl chloride 100ml, control reaction temperature is at 10-20 ℃, liquid phase control reaction is to the peak that does not have Levo-ornidazole substantially, and the reclaim under reduced pressure ethyl acetate is under the cooling, slowly add pure water 600ml, slowly adding 10% sodium carbonate solution adjust pH is 5.0, is evaporated to dried, add ethanol 500ml, filter, add 500ml sherwood oil, freezing crystallization in the filtrate, filter, get Levo-ornidazole propionic ester 97g.
[purity: 99.1%, chromatographic condition: moving phase is the potassium dihydrogen phosphate (transferring pH with triethylamine is 6.0)=35: 65 of methyl alcohol: 0.05mol/L; Chromatographic column: Kromasil C18 5u, 250 * 4.6mm; ]
Embodiment 3: the preparation of Levo-ornidazole benzoic ether
Levo-ornidazole 110g is dissolved in the exsiccant ethyl acetate 500ml solution, drips Benzoyl chloride 120ml, control reaction temperature is at 10-20 ℃, liquid phase control reaction is to the peak that does not have Levo-ornidazole substantially, and the reclaim under reduced pressure ethyl acetate is under the cooling, slowly add pure water 600ml, slowly adding 10% sodium carbonate solution adjust pH is 5.0, is evaporated to dried, add ethanol 500ml, filter, add 500ml sherwood oil, freezing crystallization in the filtrate, filter, get Levo-ornidazole benzoic ether 109g.
[purity: 98.3%, chromatographic condition: moving phase is the potassium dihydrogen phosphate (transferring pH with triethylamine is 6.0)=35: 65 of methyl alcohol: 0.05mol/L; Chromatographic column: Kromasil C18 5u, 250 * 4.6mm; ]
Embodiment 4: the preparation of Levo-ornidazole benzene sulfonate
Levo-ornidazole 110g is dissolved in the exsiccant ethyl acetate 500ml solution, drips benzene sulfonyl chloride 125ml, control reaction temperature is at 10-20 ℃, liquid phase control reaction is to the peak that does not have Levo-ornidazole substantially, and the reclaim under reduced pressure ethyl acetate is under the cooling, slowly add pure water 600ml, slowly adding 10% sodium carbonate solution adjust pH is 5.0, is evaporated to dried, add ethanol 500ml, filter, add 500ml sherwood oil, freezing crystallization in the filtrate, filter, get Levo-ornidazole benzene sulfonate 112g.
[purity: 98.7%, chromatographic condition: moving phase is the potassium dihydrogen phosphate (transferring pH with triethylamine is 6.0)=35: 65 of methyl alcohol: 0.05mol/L; Chromatographic column: Kromasil C18 5u, 250 * 4.6mm; ]
Embodiment 5: the preparation of Levo-ornidazole methanesulfonates
Levo-ornidazole 110g is dissolved in the exsiccant ethyl acetate 500ml solution, drips methylsulfonyl chloride 98ml, control reaction temperature is at 10-20 ℃, liquid phase control reaction is to the peak that does not have Levo-ornidazole substantially, and the reclaim under reduced pressure ethyl acetate is under the cooling, slowly add pure water 600ml, slowly adding 10% sodium carbonate solution adjust pH is 5.0, is evaporated to dried, add ethanol 500ml, filter, add 500ml sherwood oil, freezing crystallization in the filtrate, filter, get Levo-ornidazole methanesulfonates 89g.
[purity: 98.6%, chromatographic condition: moving phase is the potassium dihydrogen phosphate (transferring pH with triethylamine is 6.0)=35: 65 of methyl alcohol: 0.05mol/L; Chromatographic column: Kromasil C18 5u, 250 * 4.6mm; ]
Embodiment 6: the preparation of Levo-ornidazole cetylate
Levo-ornidazole 110g is dissolved in the exsiccant ethyl acetate 500ml solution, drips palmityl chloride 181ml, control reaction temperature is at 10-20 ℃, liquid phase control reaction is to the peak that does not have Levo-ornidazole substantially, and the reclaim under reduced pressure ethyl acetate is under the cooling, slowly add pure water 600ml, slowly adding 10% sodium carbonate solution adjust pH is 5.0, is evaporated to dried, add ethanol 500ml, filter, add 500ml sherwood oil, freezing crystallization in the filtrate, filter, get Levo-ornidazole cetylate 176g.
[purity: 99.3%, chromatographic condition: moving phase is the potassium dihydrogen phosphate (transferring pH with triethylamine is 6.0)=35: 65 of methyl alcohol: 0.05mol/L; Chromatographic column: Kromasil C18 5u, 250 * 4.6mm; ]
Embodiment 7: can prepare raceme, the dextrorotatory form of the foregoing description compound according to the method described above, different is to replace Levo-ornidazole with racemization ornidazole and (r)-ornidazole.
Embodiment 8: the preparation of Levo-ornidazole acetic ester sheet.
Prescription:
Levo-ornidazole acetic ester 300g
Starch 100g
Microcrystalline Cellulose 85g
Magnesium stearate 20g
Make 1000
Method for making: take by weighing Levo-ornidazole acetic ester, the Microcrystalline Cellulose of 100g 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 magnesium stearate, mix eventually, survey intermediate content, stator is heavy; Compressing tablet.
Embodiment 9:: the preparation of revolving the transfusion of ornidazole acetic ester sodium-chlor
Prescription:
Levo-ornidazole acetic ester 30g
Sodium-chlor 89g
Water for injection 10L
Make 10000ml
Method for making: the Levo-ornidazole acetic ester and the sodium-chlor that take by weighing recipe quantity, add injection water 10L, stir, molten clear, transferring pH with citric acid is 3.5, adds 0.1% gac in above-mentioned solution, stir, placed 15 minutes, 5 microns titanium rods take off charcoal, again through the smart filter of the millipore filtration of 0.45 micron of filter cartridge and 0.22 micron; Embedding is in the 100ml glass infusion bottle, and 105 ℃ of flowing steams were sterilized 45 minutes, promptly gets the transfusion of Levo-ornidazole acetic ester sodium-chlor.
Embodiment 10: the preparation of Levo-ornidazole acetic ester injection liquid
Prescription:
Levo-ornidazole acetic ester 30g
Water for injection 1000ml
Make 1000ml
Method for making: take by weighing the Levo-ornidazole acetic ester of recipe quantity, add injection water 1000ml, stir, molten clear, transferring pH with citric acid is 3.5; 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 10ml ampoule, and 100 ℃ of flowing steams were sterilized 45 minutes, promptly got its injection liquid.
Embodiment 11: the preparation of injection Levo-ornidazole acetic ester
Prescription: Levo-ornidazole acetic ester 30g
Water for injection 100ml
Make 100 bottles
The Levo-ornidazole acetic ester that takes by weighing recipe quantity dissolves with water for injection, after 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 envelope aluminium lid promptly get its freeze-dried preparation.
Claims (3)
1, the prodrug of ornidazole and pharmaceutical salts thereof, hydrate, solvated compounds:
Wherein R is straight chained alkyl, branched-chain alkyl or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxy alkyl, alkyl sulphonyl, aryl sulfonyl, aralkyl alkylsulfonyl, amino-acid residue, a phosphate radical, gen-diphosphate or triphosphate or phosphate radical derivative.
2, a kind of pharmaceutical composition, it is characterized in that containing treat effective dose compound according to claim 1 as activeconstituents and pharmaceutically acceptable carrier.
3,, be used for the medicine that production for treating anti anaerobic bacteria infection and protozoacide infect according to the purposes of the described pharmaceutical composition of claim 2.
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| CN 200610105187 CN100999500A (en) | 2006-12-18 | 2006-12-18 | Onitrodazole precursor drug and its preparation process and use |
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| CN 200610105187 CN100999500A (en) | 2006-12-18 | 2006-12-18 | Onitrodazole precursor drug and its preparation process and use |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2793871A4 (en) * | 2011-12-23 | 2015-07-22 | Auckland Uniservices Ltd | Compounds and methods for selective imaging and/or ablation |
| CN107235911A (en) * | 2016-03-28 | 2017-10-10 | 陕西合成药业股份有限公司 | A kind of purposes of 2- methyl-4-nitro iminazoles derivative and preparation method thereof and Pharmaceutical composition |
| CN107365272A (en) * | 2016-05-12 | 2017-11-21 | 陕西合成药业股份有限公司 | A kind of novel imidazole class compound and preparation method thereof and application medically |
| CN112778363A (en) * | 2019-11-05 | 2021-05-11 | 华创合成制药股份有限公司 | Nitro imidazole azole derivative, preparation method and application thereof |
-
2006
- 2006-12-18 CN CN 200610105187 patent/CN100999500A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2793871A4 (en) * | 2011-12-23 | 2015-07-22 | Auckland Uniservices Ltd | Compounds and methods for selective imaging and/or ablation |
| CN107235911A (en) * | 2016-03-28 | 2017-10-10 | 陕西合成药业股份有限公司 | A kind of purposes of 2- methyl-4-nitro iminazoles derivative and preparation method thereof and Pharmaceutical composition |
| CN107365272A (en) * | 2016-05-12 | 2017-11-21 | 陕西合成药业股份有限公司 | A kind of novel imidazole class compound and preparation method thereof and application medically |
| CN112778363A (en) * | 2019-11-05 | 2021-05-11 | 华创合成制药股份有限公司 | Nitro imidazole azole derivative, preparation method and application thereof |
| CN112778363B (en) * | 2019-11-05 | 2024-03-15 | 华创合成制药股份有限公司 | Nitroimidazole derivative and preparation method and application thereof |
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Open date: 20070718 |