CN101012223A - Ornidazole derivative for treatment, preparing method and use - Google Patents
Ornidazole derivative for treatment, preparing method and use Download PDFInfo
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- CN101012223A CN101012223A CN 200610104890 CN200610104890A CN101012223A CN 101012223 A CN101012223 A CN 101012223A CN 200610104890 CN200610104890 CN 200610104890 CN 200610104890 A CN200610104890 A CN 200610104890A CN 101012223 A CN101012223 A CN 101012223A
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Abstract
The invention discloses a manufacturing method and applying method to treat acterol derivant, which is fit for human and other mammal infected by anaerobe and parasite.
Description
Technical field:
The ornidazole derivative that the present invention relates to be used for the treatment of (especially for the treatment of people and other Mammals anaerobic infections), its application method contains their preparation and their production method.
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.
Summary of the invention:
The object of the present invention is to provide the derivative of the new ornidazole of a class
Another object of the present invention provides a kind of composition that contains the new compound for the treatment of effective dose.
The purposes of a further object of the present invention new compound of the present invention.
The chemical structure that the invention discloses the derivative of the new ornidazole of a class is:
Wherein A is:
Wherein R1 representative is selected from least a of following groups: hydrogen atom, halogen atom replaces or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, alkoxyl group or alkylthio, nitro, cyano group, acyl group, protection or protected hydroxyl not.
R2 is selected from least a of following groups: hydrogen atom, and halogen atom replaces or unsubstituted alkyl alkenyl, cycloalkyl, aryl, alkoxyl group or alkylthio, nitro, cyano group, acyl group, protection or protected hydroxyl not, oxo group and separately with the group of R2 institute bonded carbon atom formation naphthenic ring;
R3 is selected from least a of following groups: hydrogen atom, halogen atom replaces or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, alkoxyl group or alkylthio, nitro, cyano group, acyl group, protection or protected hydroxyl not, oxo group.
R4 represents the amido protecting group, replaces or unsubstituted alkyl, cycloalkyl, alkyl sulphonyl, aryl sulfonyl or aryl.
The derivative of the ornidazole that a class of the present invention is new comprises hydrate, pharmaceutical salts, prodrug, the solvated compounds of this compounds.
The pharmaceutical salts of the derivative of the ornidazole that the present invention's one class is new comprises that usually the known salt that forms at the basic group position comprises the salt that forms with organic acid such as toxilic acid, oxalic acid etc.; The salt that mineral acid example hydrochloric acid, sulfuric acid etc. form;
The prodrug of the derivative of the ornidazole that the present invention's one class is new is the acylations by hydroxyl, alkylation, the compound that phosphorylation or boration effect are derived and obtained.These compounds can be by well-known method.
The derivative of the ornidazole that the present invention's one class is new or pharmaceutical salts, hydrate, prodrug have isomer and the present invention includes these isomer.
The derivative of the ornidazole that the present invention's one class is new adopts the reaction of 2 steps to make:
The first step is to be raw material with the ornidazole, with the epoxide of the reactant aqueous solution system of alkali.
Second the step be with epoxide with
(Compound I I),
Be heated to backflow with methyl alcohol (ethanol, acetonitrile) dissolving, back flow reaction 2～6 hours reclaims methyl alcohol (ethanol, acetonitrile), and it is an amount of to add dehydrated alcohol, is heated to moltenly entirely, filters, and cooling crystallization filters, dry The compounds of this invention.
The preparation method of Compound I I is referring to (CN98810627.2).
The compounds of this invention can the unit dosage form administration, and route of administration can be enteron aisle or non-enteron aisle, as oral, muscle, subcutaneous, nasal cavity etc.
The The compounds of this invention route of administration can be intravenously administrable.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection and acupoint injection therapy etc.
Form of administration can be pharmaceutically acceptable preparations such as tablet, capsule, dispersible tablet, oral liquid, infusion solutions, little pin, freeze-dried powder.
The compounds of this invention can be used for preventing, improving and/or cures the disease that is caused by anaerobic infection; Be particularly suitable for chemotherapeutics active compound as people and animal doctor's usefulness medicine.
The compounds of this invention also can be used for control and is present in the parasite of causing a disease in human body and the animal body.
The compounds of this invention is by the gross weight administration, and its amount is every kg body weight 0.5-600mg, and preferably the consumption of 24h is every kg body weight 1-120mg, also can adopt medication several times.
Preferred plan is that the amount that gives one or more active compounds of the present invention once a day is the 1-250mg/kg body weight, and preferred dose is the 1-16mg/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 and compound used therefor 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 embodiment 1 1-[3-(2, the 6-dimethylated morpholinyl)-2-hydroxypropyl] preparation of 2-methyl-5-nitro imidazoles (compd A)
220g racemization ornidazole is dissolved in the 600ml methylene dichloride, stirs down, add 20% NaOH solution 500ml, control reaction temperature is-10～30 ℃, reacts separatory 1 hour, collect dichloromethane layer, add anhydrous sodium sulfate drying, the evaporated under reduced pressure methylene dichloride gets epoxide 153g.
Epoxide 183g is dissolved in the 500ml methyl alcohol, is heated to backflow, add 2,6-thebaine 100g, back flow reaction 2～6h reclaims methyl alcohol, and residue filters with dehydrated alcohol 200ml heating for dissolving, the filtrate cooling crystallization filters, and gets faint yellow crystalline solid 142g compd A.
Embodiment 2 1-[3-(1-methyl-2,3-dihydro-1H-5 pseudoindoyl)-2-hydroxypropyl] preparation of 2-methyl-5-nitro imidazoles (compd B)
According to the same procedure preparation of embodiment 1, different is that 3-dihydro-1H-5 isoindole replaces 2, the 6-thebaine with 1-methyl-2.
Embodiment 3 1-[3-[4-(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl isophthalic acid-piperazinyl]-the 2-hydroxypropyl]-preparation of 2-methyl-5-nitro imidazoles (Compound C)
According to the same procedure preparation of embodiment 1, different is to replace 2 with 4-(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl isophthalic acid-piperazine, the 6-thebaine.
Embodiment 4: the preparation method of compd A sheet
Prescription:
Compd A 100g
Starch 60g
Microcrystalline Cellulose 105g
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 compd A, the Microcrystalline Cellulose of 40g 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 5: the preparation of compd A sodium-chlor transfusion
Prescription:
Compd A 10.0g
Sodium-chlor 89g
Water for injection 10L
Make 10000ml
Method for making: take by weighing the compd A and the sodium-chlor of recipe quantity, add injection water 10L, stir, transferring pH with Citric Acid is 6.0; 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 compd A sodium-chlor.
Embodiment 6: the preparation of compd A injection liquid
Prescription:
Compd A 10.0g
Water for injection 1000ml
Make 1000ml
Method for making: take by weighing the compd A of recipe quantity, add injection water 1000ml, stir, transferring pH with the acid of structure rafter is 6.0; 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 10ml ampoule, and 100 ℃ of flowing steams were sterilized 45 minutes, promptly got the compd A injection liquid.
Embodiment 7: the preparation of injection compd A
Prescription: compd A 10.0g
Water for injection 1000ml
Make 100 bottles
Compd A dissolves with water for injection, transfer pH to add needle-use activated carbon absorption 30 minutes after 6.0 with Citric Acid 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 the injection compd A.
Test 1: The compounds of this invention and ornidazole studies on acute toxicity;
With the ornidazole is the anxious poison test of mouse of contrast medicine
Mouse tail vein injection LD
50:
Ornidazole LD
50: 314mg/kg
The LD of compd A
50: 1232mg/kg LD
50Average fiducial limit: 1232 ± 98.37mg/kg
The LD of compd B
50: 1108mg/kg LD
50Average fiducial limit: 1108 ± 91.99mg/kg
The LD of Compound C
50: 1009mg/kg LD
50Average fiducial limit: 1009 ± 96.12mg/kg
Test shows that the toxicity of The compounds of this invention is less than ornidazole.
Test 2: The compounds of this invention and the research of ornidazole antibacterial activity in vitro;
| Bacteroides fragilis (ug/ml) | The Gooch genera bacillus | |||
| MIC | MBC | MIC | MBC | |
| Compd A | 1 | 1 | 2 | 3 |
| Compd B | 1.5 | 2 | 3 | 2 |
| Compound C | 2 | 1 | 2 | 2 |
| Ornidazole | 2 | 4 | 5 | 7 |
Test shows that the in-vitro antibacterial effect of The compounds of this invention is better than ornidazole.
Claims (4)
- Derivative and the optically active isomer and the racemic modification of 1 formula [I] ornidazole:
Wherein A is:Wherein R1 representative is selected from least a of following groups: hydrogen atom, and halogen atom replaces or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, alkoxyl group or alkylthio, nitro, cyano group, acyl group, protection or protected hydroxyl not;R2 is selected from least a of following groups: hydrogen atom, and halogen atom replaces or unsubstituted alkyl alkenyl, cycloalkyl, aryl, alkoxyl group or alkylthio, nitro, cyano group, acyl group, protection or protected hydroxyl not, oxo group and separately with the group of R2 institute bonded carbon atom formation naphthenic ring;R3 is selected from least a of following groups: hydrogen atom, and halogen atom replaces or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, alkoxyl group or alkylthio, nitro, cyano group, acyl group, protection or protected hydroxyl not, oxo group;R4 represents the amido protecting group, replaces or unsubstituted alkyl, cycloalkyl, alkyl sulphonyl, aryl sulfonyl or aryl. - 2 hydrates, pharmaceutical salts, prodrug, solvated compounds according to right 1 described compound.
- 3 one kinds of pharmaceutical compositions, it is characterized in that containing treat effective dose compound according to claim 1 as activeconstituents and pharmaceutically acceptable carrier.
- 4, be used to prepare the purposes of anti-anaerobic agent and anti-parasite medicine according to the described compound of claim 1.
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| CN 200610104890 CN101012223A (en) | 2006-11-13 | 2006-11-13 | Ornidazole derivative for treatment, preparing method and use |
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| CN 200610104890 CN101012223A (en) | 2006-11-13 | 2006-11-13 | Ornidazole derivative for treatment, preparing method and use |
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| WO2014100734A1 (en) * | 2012-12-21 | 2014-06-26 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
| US8906900B2 (en) | 2012-12-21 | 2014-12-09 | Epizyme, Inc. | PRMT5 inhibitors and uses thereof |
| US8940726B2 (en) | 2012-12-21 | 2015-01-27 | Epizyme, Inc. | PRMT5 inhibitors and uses thereof |
| US8993555B2 (en) | 2012-12-21 | 2015-03-31 | Epizyme, Inc. | PRMT5 inhibitors and uses thereof |
| US9365555B2 (en) | 2012-12-21 | 2016-06-14 | Epizyme, Inc. | PRMT5 inhibitors and uses thereof |
| 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 |
| US10653693B2 (en) | 2014-08-04 | 2020-05-19 | Epizyme, Inc. | PRMT5 inhibitors and uses thereof |
| CN112209881A (en) * | 2020-10-19 | 2021-01-12 | 西南大学 | Emodin azole alcohol compound and 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 |
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2006
- 2006-11-13 CN CN 200610104890 patent/CN101012223A/en active Pending
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| US9765068B2 (en) | 2012-12-21 | 2017-09-19 | Epizyme, Inc. | PRMT5 inhibitors and uses thereof |
| US10150758B2 (en) | 2012-12-21 | 2018-12-11 | Epizyme, Inc. | PRMT5 inhibitors and uses thereof |
| US8940726B2 (en) | 2012-12-21 | 2015-01-27 | Epizyme, Inc. | PRMT5 inhibitors and uses thereof |
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| US10980794B2 (en) | 2012-12-21 | 2021-04-20 | Epizyme, Inc. | PRMT5 inhibitors and uses thereof |
| US9908887B2 (en) | 2012-12-21 | 2018-03-06 | Epizyme, Inc. | PRMT5 inhibitors and uses thereof |
| WO2014100734A1 (en) * | 2012-12-21 | 2014-06-26 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
| US8906900B2 (en) | 2012-12-21 | 2014-12-09 | Epizyme, Inc. | PRMT5 inhibitors and uses thereof |
| US10307413B2 (en) | 2012-12-21 | 2019-06-04 | Epizyme, Inc. | Tetrahydro- and dihydro-isoquinoline PRMT5 inhibitors and uses thereof |
| US10391089B2 (en) | 2012-12-21 | 2019-08-27 | Epizyme, Inc. | PRMT5 inhibitors and uses therof |
| US10653693B2 (en) | 2014-08-04 | 2020-05-19 | Epizyme, Inc. | PRMT5 inhibitors and uses thereof |
| 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 |
| CN112209881A (en) * | 2020-10-19 | 2021-01-12 | 西南大学 | Emodin azole alcohol compound and preparation method and application thereof |
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| 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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Open date: 20070808 |