CN101302201A - Nitroimidazole derivate for therapy - Google Patents
Nitroimidazole derivate for therapy Download PDFInfo
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- CN101302201A CN101302201A CNA2008100181904A CN200810018190A CN101302201A CN 101302201 A CN101302201 A CN 101302201A CN A2008100181904 A CNA2008100181904 A CN A2008100181904A CN 200810018190 A CN200810018190 A CN 200810018190A CN 101302201 A CN101302201 A CN 101302201A
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- Prior art keywords
- ornidazole
- levo
- compound
- nitroimidazole
- ester hydrochloride
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Abstract
The invention relates to nitroimidazole derivative used for treatment. The structure of the derivative is R1-O-L, wherein, R1 refers to a non hydroxyl group in one of ornidazole enantiomers; and L refers to an acyl of amino acid or -COCH2CH2COOR2. The nitroimidazole compound of the invention has strong functions of preventing anaerobic formers and protozoan infection, has good metabolism stability and long acting time, increases the bioavailability and reduces the drug toxicity.
Description
Technical field:
This invention relates to the nitro imidazole derivatives (especially for the treatment of people and other Mammals anaerobic infections) that is used for the treatment of, and its application method contains their preparation and their production method.
Technical background:
Many nitro glyoxaline compounds are known.For example: metronidazole, tinidazole, ornidazole etc. all have the excellent antibiotic activity.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, CN200510083571.2) has been described it and has been better than ornidazole and (r)-ornidazole aspect some drug side effects such as neurotoxicity.
Levo-ornidazole itself is water-soluble low especially, must be with recombiner to reach satisfied water soluble preparation.Yet the one-tenth mark that people always expect to reduce prescription is so that reduce the issuable side reaction of patient, and Chinese patent CN200610166893.2 has related to the phosphoric acid ester of this compounds.
Summary of the invention:
The object of the present invention is to provide a kind of derivative of this compounds newly.
Its structure is: R
1-O-L.
R
1Expression
L represent in the amino acid acyl moiety or
Wherein preferred amino acids comprises: glycine, L-Ala, Methionin, leucine, Isoleucine, Xie Ansuan, phenylalanine.
R
2Expression hydrogen sodium or potassium.
The invention provides the production method of above-mentioned formula I compound and pharmaceutical salts thereof: with the esterification of formula II compound
R
1OH (II)，
R wherein
1As above-mentioned definition;
Esterification process is: with formula (II) with through the amino acid (as: Boc amino acid, Fmoc amino acid) of overprotection amino, carry out the O-acylation, the preparation intermediate gets formula I compound with intermediate deprotection base again.
The method for preparing its succinate is: formula (II) with the solvent dissolving, with the succinyl dichloride reaction, is prepared into intermediate.Then above-mentioned intermediate is hydrolyzed, promptly gets the Levo-ornidazole succinate.
Action solvent is an ethyl acetate, acetonitrile, tetrahydrofuran (THF), acetone, methylene dichloride, chloroform etc., temperature of reaction is-50-50 ℃, and preferred 25-40 ℃.
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.
Pharmaceutical composition provided by the invention is as activeconstituents and pharmaceutically acceptable carrier with compound of the present invention.
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.
Compound 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 1-20mg, also can adopt medication several times.
Preferred plan is that the amount that gives The compounds of this invention 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.
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.
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 glycinate
With Levo-ornidazole 220 grams (1mol), be dissolved in the 2000ml ethyl acetate, add triphenyl phosphorus 262.3g (1mol), BOC-glycine 175.2g (1mol), stir and drip diethyl azodiformate (DEAD) 174.2g (1mol) room temperature reaction 5h down, filter, feed exsiccant HCl gas in the filtrate to saturated, stirring at room 5h separates out a large amount of white solids, filters, filter cake washs with amount of ethyl acetate, dry levo-ornidazole phosphate hydrochloride 153.5g.
Levo-ornidazole phosphate hydrochloride 100g is restrained with after 500 milliliters of dissolved in purified water, slowly drip saturated sodium carbonate solution to pH be 7 to 7.5, with three each 500ml of ethyl acetate extraction, united extraction liquid, add anhydrous sodium sulfate drying, evaporated under reduced pressure gets Levo-ornidazole glycinate 71 grams.
The preparation of embodiment 2 (r)-ornidazole glycinates
Same procedure according to embodiment 1 prepares the (r)-ornidazole glycinate, and different is to replace Levo-ornidazole with (r)-ornidazole.
The preparation of embodiment 3 Levo-ornidazole succinates
Levo-ornidazole 110g is dissolved in the exsiccant ethyl acetate 500ml solution, drip succinyl dichloride 150ml, 20-38 ℃ of control reaction * temperature, liquid phase control reaction is to the peak that does not have Levo-ornidazole substantially, the reclaim under reduced pressure ethyl acetate gets intermediate, and cooling down, slowly add pure water 600ml, hydrolysis reaction 1 hour, slowly adding 10% sodium carbonate solution adjust pH is 5.0, is evaporated to dried, add methyl alcohol 500ml, filter, add in the filtrate 500ml (sherwood oil: ethyl acetate=1: 1), freezing crystallization, filter, get Levo-ornidazole succinate 97g.
The preparation of embodiment 4 Levo-ornidazole succinate sodium
100g Levo-ornidazole succinate with 90% dissolve with methanol, is slowly added yellow soda ash and produces to there being bubble, add the 1000ml dehydrated alcohol again, freezing crystallization filters, and obtains white Levo-ornidazole succinate sodium solid 72g.(purity: 99.2%, 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 C185u, 250 * 4.6mm; )
Embodiment 5: the preparation method of Levo-ornidazole glycine ester hydrochloride sheet
Prescription:
Levo-ornidazole glycine ester hydrochloride 300g
Starch 80g
Microcrystalline Cellulose 120g
Magnesium stearate 2.0g
Vltra tears (E-30) (4% solution) is an amount of
Make 1000
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 Levo-ornidazole glycine ester hydrochloride, 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 6: the preparation of Levo-ornidazole glycine ester hydrochloride sodium-chlor transfusion
Prescription:
Levo-ornidazole glycine ester hydrochloride 300g
Sodium-chlor 89g
Water for injection 10L
Make 10000ml
Method for making: take by weighing the Levo-ornidazole glycine ester hydrochloride and the sodium-chlor of recipe quantity, add injection water 10L, stir; 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 Levo-ornidazole glycine ester hydrochloride sodium-chlor.
Embodiment 7: the preparation of Levo-ornidazole glycine ester hydrochloride
Prescription:
Levo-ornidazole glycine ester hydrochloride 300g
Water for injection 1000ml
Make 1000ml
Method for making: take by weighing the Levo-ornidazole glycine ester hydrochloride of recipe quantity, add injection water 1000ml, stir dissolving; 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 left Levo-ornidazole glycine ester hydrochloride injection liquid.Embodiment 8: the preparation of injection Levo-ornidazole glycine ester hydrochloride
Prescription: Levo-ornidazole glycine ester hydrochloride 300g
Water for injection 1000ml
Make 100 bottles
The Levo-ornidazole glycine ester hydrochloride with adding needle-use activated carbon absorption 30 minutes after the water for injection dissolving 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 injection Levo-ornidazole glycine ester hydrochloride.
Claims (3)
1. the compound of general formula (I) or its hydrate:
R
1Expression
L represent in the amino acid acyl moiety or
R2 represents hydrogen sodium or potassium.
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 anaerobe resistant and protozoacide infect.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100181904A CN101302201A (en) | 2008-05-14 | 2008-05-14 | Nitroimidazole derivate for therapy |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100181904A CN101302201A (en) | 2008-05-14 | 2008-05-14 | Nitroimidazole derivate for therapy |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101302201A true CN101302201A (en) | 2008-11-12 |
Family
ID=40112320
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008100181904A Pending CN101302201A (en) | 2008-05-14 | 2008-05-14 | Nitroimidazole derivate for therapy |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106467494A (en) * | 2015-08-21 | 2017-03-01 | 陕西合成药业股份有限公司 | Amino-acid ester soluble derivative of laevo-ornidazole and application thereof |
| CN114478392A (en) * | 2020-10-26 | 2022-05-13 | 南京锐志生物医药有限公司 | Ester prodrug of anti-anaerobic bacteria compound, pharmaceutical composition, preparation method and 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 |
-
2008
- 2008-05-14 CN CNA2008100181904A patent/CN101302201A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106467494A (en) * | 2015-08-21 | 2017-03-01 | 陕西合成药业股份有限公司 | Amino-acid ester soluble derivative of laevo-ornidazole and application thereof |
| CN114478392A (en) * | 2020-10-26 | 2022-05-13 | 南京锐志生物医药有限公司 | Ester prodrug of anti-anaerobic bacteria compound, pharmaceutical composition, preparation method and 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 |
| CN114478392B (en) * | 2020-10-26 | 2023-09-29 | 南京锐志生物医药有限公司 | Ester prodrug of anti-anaerobic 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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Open date: 20081112 |