CN1605586A - Alpha-substituted 2-methyl-5-nitroimidazole-1-ethanol derivatives - Google Patents
Alpha-substituted 2-methyl-5-nitroimidazole-1-ethanol derivatives Download PDFInfo
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- CN1605586A CN1605586A CN 200310100057 CN200310100057A CN1605586A CN 1605586 A CN1605586 A CN 1605586A CN 200310100057 CN200310100057 CN 200310100057 CN 200310100057 A CN200310100057 A CN 200310100057A CN 1605586 A CN1605586 A CN 1605586A
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- -1 Alpha-substituted 2-methyl-5-nitroimidazole-1-ethanol Chemical class 0.000 title abstract description 13
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- 229960005495 cefotetan Drugs 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 229960002227 clindamycin Drugs 0.000 description 1
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- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000009112 empiric therapy Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
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- 235000019441 ethanol Nutrition 0.000 description 1
- 238000007046 ethoxylation reaction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
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- 238000004108 freeze drying Methods 0.000 description 1
- 125000005908 glyceryl ester group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
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- 229910052742 iron Inorganic materials 0.000 description 1
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- DBTMGCOVALSLOR-VPNXCSTESA-N laminarin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1O[C@@H]1[C@@H](O)C(O[C@H]2[C@@H]([C@@H](CO)OC(O)[C@@H]2O)O)O[C@H](CO)[C@H]1O DBTMGCOVALSLOR-VPNXCSTESA-N 0.000 description 1
- 229960000433 latamoxef Drugs 0.000 description 1
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- 239000002609 medium Substances 0.000 description 1
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- 239000002245 particle Substances 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
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- 229960002292 piperacillin Drugs 0.000 description 1
- 229940104641 piperacillin / tazobactam Drugs 0.000 description 1
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229940093916 potassium phosphate Drugs 0.000 description 1
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- 239000000047 product Substances 0.000 description 1
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- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
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- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
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- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
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- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an alpha-substituted 2-methyl-5-nitroimidazole-1-ethanol derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and application thereof in preparing anti-anaerobic bacteria medicaments.
Description
Technical field
The pharmaceutical composition that the present invention relates to the 2-methyl-5-nitro imidazoles-1-alcohol derivative and preparation method thereof of alpha-substitution and contain this derivative with and be used to prepare the purposes of anti-anaerobic agent.
Background technology
According to the record of prior art, the chemotherapy of anaerobic infection is usually with empiric treatment (empirical therapy) beginning, because most of anaerobic infections are the polyinfection with aerophil, so the chemotherapy target must be considered the aerophil that coexists simultaneously.Now main anerobe is listed in the table below 1 to the susceptibility of chemotherapeutics.
Table 1 anerobe is to the susceptibility of chemotherapeutics
| Medicine | Fragile plan bacterium | Prey viable bacteria porphyrin bacterium | Fusobacterium | Peptostreptococcus | Clostridium | No brood cell G bacillus |
| Amoxicillin/clavulanate | +++ | +++ | +++ | +++ | +++ | +++ |
| Ampicillin Trihydrate/Sulbactam | +++ | +++ | +++ | +++ | +++ | +++ |
| Ticarcillin/clavulanic acid | +++ | +++ | +++ | +++ | +++ | +++ |
| Piperacillin/tazobactam | +++ | ++/+++ | +++ | +++ | +++ | +++ |
| Cefoperazone/Sulbactam | +++ | +++ | +++ | +++ | + | ++ |
| Imipenum/cilastatin | +++ | +++ | +++ | +++ | +++ | +++ |
| Paraxin | +++ | +++ | +++ | +++ | +++ | +++ |
| Metronidazole | +++ | +++ | +++ | +++ | +++ | -/++ |
| Clindamycin | ++ | ++/+++ | +++ | +++ | ++ | ++/+++ |
| Penicillin G | - | -/+ | +++ | +++ | +++ | +++ |
| Piperacillin | ++ | ++/+++ | +++ | +++ | +++ | +++ |
| Cefoxitin | ++ | ++/+++ | +++ | +++ | ++ | +++ |
| Cefotetan | ++ | ++/+ | ++ | +++ | ++ | ++ |
| Ceftizoxime | ++ | ++/+++ | +++ | +++ | + | ++/+++ |
| Latamoxef | ++ | +/+++ | ++ | +++ | ++ | ++ |
[notes] responsive rate +++: 90%-100%; ++: 70%-89%; +: 50%-69%;-:＜50%
The medicine that most of anerobe is all had strong anti-microbial activity has metronidazole, paraxin, imipenum/Xi Sita β-Nei Xiananleikangshengsu beta-lactamase inhibitor mixture.
Nitro glyoxaline antimicrobial drug, commercially available compound have metronidazole (R is H), and (R is CH to ornidazole
2Cl) and secnidazole (R is CH
3).Particularly metronidazole (metronidazole) is as sterilant, its anaerobe resistant spectrum is wide, extremely sensitive to bacteroides fragilis, Eubacterium, clostridium perfringens, to dyspepsiacoccus, peptostreptococcus, product melanocyte Prey viable bacteria, porphyrin Zymomonas mobilis medium sensitivity, relatively poor to no brood cell's gram-positive bacillus susceptibility.Oral absorption is good, T
Max1-2h, widely distributed in vivo, can enter saliva, milk, fester, also can infiltrate in the cerebrospinal fluid.T
1/28h, most of by draining in the urine, discharge through ight soil on a small quantity.Be mainly used in microbial system of above-mentioned anaerobism and local infection.Antimicrobial spectrum, the anti-microbial effect of tinidazole (tinidazole) are identical with metronidazole, and the transformation period is than the long (T of metronidazole
1/212-14h), treatment abdominal cavity, pelvic cavity and postoperative anaerobic infection all obtain satisfactory effect.Can adopt the single dose treatment.
Summary of the invention
The object of the present invention is to provide a kind of new compound with anaerobe resistant characteristic.
Another object of the present invention is to provide a kind of method for preparing general formula of the present invention (I) new compound.
A further object of the present invention is to provide a kind of composition that contains invention general formula (I) new compound for the treatment of effective dose, and,
The present invention also aims to provide the purposes of general formula of the present invention (I) new compound.
In order to finish purpose of the present invention, the present invention relates to following technical scheme:
The content of being put down in writing according to the present invention The present invention be more particularly directed to the compound of general formula (I) representative and hydrate or the solvated compounds or the pharmacy acceptable salt of general formula (I) compound.
Wherein R is CH
2F, CHF
2, CF
3,
The invention still further relates to the preparation method of general formula (I) compound, it comprises: with formula II compound with
Reaction:
Or with the formula III compound with
Obtain described compound.
The invention still further relates to a kind of pharmaceutical composition, it is characterized in that containing treat effective dose above-claimed cpd as activeconstituents and pharmaceutically acceptable carrier.
The compounds of this invention can be used to prepare anti-anaerobic agent.
This shows, the present invention relates to the 2-methyl-5-nitro imidazoles-1-alcohol derivative of alpha-substitution of general formula (I) expression and hydrate or the solvate or the pharmacy acceptable salt of general formula (I) compound.The invention still further relates to the pharmaceutical composition that contains these compounds that has fabulous anaerobe resistant characteristic and have tight security.
Wherein R is CH
2F, CHF
2, CF
3,
Known 2-methyl-5-nitro imidazoles-1-alcohol compound has good anti-anaerobic activity.The inventor finds that some specific alpha-substitution-2-methyl-5-nitro imidazoles-1-alcohol compound has than better pharmacological action of existing medicine and lower toxicity, has finished the present invention thus.
With the compound of general formula (I) expression can by formula II compound with
Reaction.
Or by formula III with
Prepared in reaction.
Be typically, pharmaceutical composition of the present invention can prepare according to methods known in the art.When being used for this purpose, if desired, effective constituent and one or more solids or liquid medicine vehicle and/or assistant agent can be combined, make and can be used as suitable administration form or the dosage form that people's medicine uses.
Pharmaceutical composition of the present 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, oral mucosa, skin, peritonaeum or rectum etc.
The route of administration of pharmaceutical composition of the present invention can be drug administration by injection.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and acupoint injection therapy etc.
Form of administration can be liquid dosage form, solid dosage.As liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other formulations are tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, lyophilized injectable powder etc. for example.
Pharmaceutical composition of the present invention can be made ordinary preparation, also can be sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For the unit form of administration is made tablet, can be extensive use of various carrier well known in the art.Example about carrier is, for example thinner and absorption agent are as starch, dextrin, calcium sulfate, lactose, N.F,USP MANNITOL, sucrose, sodium-chlor, glucose, urea, lime carbonate, white bole, Microcrystalline Cellulose, pure aluminium silicate etc.; Wetting agent and tackiness agent are as water, glycerine, polyoxyethylene glycol, ethanol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, Xylo-Mucine, lac, methylcellulose gum, potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent, for example dry starch, alginates, agar powder, laminaran, sodium bicarbonate and Citric Acid, lime carbonate, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.; Disintegration inhibitor, for example sucrose, Tristearoylglycerol, theobroma oil, hydrogenation wet goods; Absorption enhancer, for example quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, for example talcum powder, silicon-dioxide, W-Gum, stearate, boric acid, whiteruss, polyoxyethylene glycol etc.Tablet further can also be made coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
For pill is made in the administration unit, can be extensive use of various carrier well known in the art.Example about carrier is, for example thinner and absorption agent are as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talcum powder etc.; Tackiness agent is as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or batter etc.; Disintegrating agent is as agar powder, dry starch, alginates, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.
For suppository is made in the administration unit, can be extensive use of various carrier well known in the art.Example about carrier is, for example the ester of polyoxyethylene glycol, Yelkin TTS, theobroma oil, higher alcohols, higher alcohols, gelatin, semi-synthetic glyceryl ester etc.
For capsule is made in the administration unit, effective constituent is mixed with above-mentioned various carriers, and the mixture that will obtain thus places hard gelatine capsule or soft capsule.Also effective constituent can be made microcapsule, be suspended in and form suspensoid in the aqueous medium, in the hard capsule of also can packing into or make injection and use.
For example, composition of the present invention is made injection preparation, as solution, suspensoid solution, emulsion, lyophilized injectable powder, this preparation can be moisture or non-water, can contain acceptable carrier, thinner, tackiness agent, lubricant, sanitas, tensio-active agent or dispersion agent on a kind of and/or multiple pharmacodynamics.Can be selected from water, ethanol, polyoxyethylene glycol, 1 as thinner, the isooctadecanol of ammediol, ethoxylation, the isooctadecanol of polyoxyization, Polyoxyethylene Sorbitol Fatty Acid Esters etc.In addition, ooze injection liquid, can in injection preparation, add proper amount of sodium chloride, glucose or glycerine, in addition, can also add conventional solubility promoter, buffer reagent, pH regulator agent etc. in order to prepare etc.These auxiliary materials are that this area is commonly used
In addition, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives, sweeting agent or other material.
Composition of the present invention can be used for the treatment of microbial whole body of anaerobism or the local infection that Mammals comprises the people.
The dosage of compound of the present invention or medicinal compositions depends on many factors, for example to prevent or treat the character and the severity of disease, the sex of patient or animal, age, body weight, personality and individual reaction, route of administration, administration number of times etc., therefore therapeutic dose of the present invention can have large-scale variation.In general, the using dosage of pharmacy composition of the present invention is well known to a person skilled in the art.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 to the about 75 kilograms of patients of body weight, the per daily dose of institute's administration be the 0.5mg/kg body weight extremely
The 40mg/kg body weight, preferred 4mg/kg body weight 20mg/kg body weight.Above-mentioned dosage can the single dose form or be divided into several, for example two, three or four dosage form administrations, this is subject to the dosage regimen of administration doctor's clinical experience.
In external, body, all shown good anaerobe resistant effect by the compound of general formula (I) expression of the present invention preparation.
Embodiment
Routine embodiment will be described in more detail the present invention down, be not to be interpreted as it is limitation of the present invention.
Embodiment 1
Preparation α-methyl fluoride-2-methyl-5-nitro imidazoles-1-ethanol
With 2-methyl-5-nitro imidazoles (10g), formic acid (100ml) drops in the reaction flask and stirs, and makes dissolving, is chilled to 5～10 ℃, divide 5 times and add epoxy fluoro-propane (10ml) vitriol oil (5ml), each 2 hours at interval, finish in stirring at room 48 hours, slowly add yellow soda ash (8g), reclaim under reduced pressure formic acid is to most, add entry (120ml) and be heated to 80 ℃, put coldly, filter, washing, filtrate is transferred to pH8 with ammoniacal liquor, extract, merge with ethyl acetate (100ml * 5), water 50ml washes, drying, the reclaim under reduced pressure ethyl acetate is to most, and it is The compounds of this invention 1 that column chromatography purification gets white solid (6g).Its proton magnetic resonance (PMR) data are:
1HNMR(CD
3Cl)δ2.57(3H，s)δ4.25～4.35(2H，m)δ4.84～4.71(3H，m)δ7.92(1H，s)
Embodiment 2
Preparation alpha-difluoromethyl-2-methyl-5-nitro imidazoles-1-ethanol
Prepare alpha-difluoromethyl-2-methyl-5-nitro imidazoles-1-ethanol according to embodiment 1 identical method, different is to replace the epoxy fluoro-propane with the difluoro propylene oxide, prepares compound 2 of the present invention.Its proton magnetic resonance (PMR) data are:
1HNMR(CD
3Cl)δ2.55(3H，s)δ4.25～4.30(2H，m)δ4.46～4.70(2H，m)δ7.90(1H，s)
Embodiment 3
Preparation α-trifluoromethyl-2-methyl-5-nitro imidazoles-1-ethanol
Prepare α-trifluoromethyl-2-methyl-5-nitro imidazoles-1-ethanol according to embodiment 1 identical method, different is to replace the epoxy fluoro-propane with trifluoro-epoxy propane, prepares compound 3 of the present invention.Its proton magnetic resonance (PMR) data are:
1HNMR(CD
3Cl)δ2.53(3H，s)δ4.25～4.31(1H，m)δ4.43～4.46(1H，m)δ4.78～4.83(1H，m)δ7.89(1H，s)
Embodiment 4
Preparation α-(4-hydroxy piperidine-1-yl) methyl-2-methyl-5-nitro imidazoles-1-ethanol
With 1-(2, the 3-epoxypropyl)-and 2-methyl-5-nitro imidazoles (10g), 4-hydroxy piperidine (10g), acetonitrile 100ml refluxed 2 hours, the reclaim under reduced pressure acetonitrile, add entry 100ml, be heated to molten entirely, filtered while hot, put cold, filter, washing, it is The compounds of this invention 4 that oven dry obtains off-white color solid (11g).Its proton magnetic resonance (PMR) data are:
1HNMR(CD
3Cl)δ1.49～1.58(2H，m)δ1.83～1.89(2H，m)δ2.14～2.86(6H，m)δ2.52(3H，s)δ3.69～3.73(1H，m)δ3.95～4.06(2H，m)δ4.51～4.55(1H，m)δ7.92(1H，s)
Embodiment 5
Preparation α-(piperazine-1-yl) methyl-2-methyl-5-nitro imidazoles-1-ethanol
Prepare α-(piperazine-1-yl) methyl-2-methyl-5-nitro imidazoles-1-ethanol according to embodiment 4 identical methods, different is to replace the 4-hydroxy piperidine with piperazine, prepares compound 5 of the present invention.Its proton magnetic resonance (PMR) data are:
1HNMR(CD
3Cl)δ2.25～2.63(10H，m)δ2.49(3H，s)δ4.05～4.15(2H，m)δ4.60～4.65(1H，m)δ7.95(1H，s)
Embodiment 6
Preparation α-(4-methylpiperazine-1-yl) methyl-2-methyl-5-nitro imidazoles-1-ethanol
Prepare α-(4-methylpiperazine-1-yl) methyl-2-methyl-5-nitro imidazoles-1-ethanol according to embodiment 4 identical methods, different is to replace the 4-hydroxy piperidine with methylpiperazine, prepares compound 6 of the present invention.Its proton magnetic resonance (PMR) data are:
1HNMR(CD
3Cl)δ2.20(3H，s)δ2.48(3H，s)δ2.28～2.52(10H，m)δ4.03～4.11(2H，m)δ4.55～4.61(1H，m)δ7.94(1H，s)
Embodiment 7
Preparation α-(morphine quinoline-1-yl) methyl-2-methyl-5-nitro imidazoles-1-ethanol
Prepare α-(morphine quinoline-1-yl) methyl-2-methyl-5-nitro imidazoles-1-ethanol according to embodiment 4 identical methods, different is to replace the 4-hydroxy piperidine with the morphine quinoline, prepares compound 7 of the present invention.Its proton magnetic resonance (PMR) data are:
1HNMR(CD
3Cl)δ2.39～2.73(6H，m)δ2.61(3H，s)δ3.71～3.81(4H，m)δ4.10～4.17(2H，m)δ4.63～4.66(1H，m)δ8.00(1H，s)
Embodiment 8
Preparation α-(3-hydroxyl tetramethyleneimine-1-yl) methyl-2-methyl-5-nitro imidazoles-1-ethanol
Prepare α-(3-hydroxyl tetramethyleneimine-1-yl) methyl-2-methyl-5-nitro imidazoles-1-ethanol according to embodiment 4 identical methods, different is to replace the 4-hydroxy piperidine with the 3-hydroxyl pyrrolidine, prepares compound 8 of the present invention.Its proton magnetic resonance (PMR) data are:
1HNMR(CD
3Cl)δ1.44～1.52(2H，m)δ2.35～2.71(6H，m)δ2.52(3H，s)δ3.70～3.78(1H，m)δ4.11～4.20(2H，m)δ4.65～4.71(1H，m)δ7.99(1H，s)
Embodiment 9
The preparation of compound 1 powder injection
Compound 1 100g
Dextran 40 g
The 100g compound 1 that embodiment is obtained adds an amount of water for injection dissolving, and Dextran 40 g adds an amount of water for injection dissolving, and two solution are mixed, add injection and be diluted with water to 2000ml, with the filtering with microporous membrane of 0.22um, under the aseptic condition, be loaded on respectively in the 10ml cillin bottle, sabot, send in the freeze drying box, after the lyophilize, outlet, roll lid, get final product.
Embodiment 10
The preparation of compound 1 tablet
Compound 1 100g
Starch 100g
Starch slurry (8%) is an amount of
Magnesium Stearate 0.4g
Compound 1, starch uniform mixing with embodiment 1 obtains add 8% starch slurry and make software, granulate with 14 order nylon mesh, and 70-80 ℃ of drying adds Magnesium Stearate, and through the whole grain of 10-12 order iron wire sieve, mixing is with 12mm punch die compressing tablet.
Embodiment 11
The preparation of compound 2 granules
Compound 2 100g
Soluble starch 80g
Icing Sugar 20g
Essence is an amount of
Compound 2 is water-soluble, add starch 80g, Icing Sugar 20g, it is an amount of to add essence again, and mixing is granulated with the 14-16 mesh sieve, and is dry below 60 ℃, packing.
Embodiment 12
The preparation of compound 1 capsule
Compound 3 100g
Microcrystalline Cellulose 40g
Lactose 60g
Sodium Hydroxymethyl Stalcs 4g
Starch slurry is an amount of
Magnesium Stearate 1g
Micropowder silica gel 1g
Compound 3, Microcrystalline Cellulose, lactose, Sodium Hydroxymethyl Stalcs sieves respectively, and mix, add starch slurry and make softwood in right amount, to cross 20 mesh sieves and granulate, wet granular is dry down in 50 ℃, dried particle is crossed the whole grain of 20 mesh sieves, with Magnesium Stearate, micropowder silica gel mixing, can capsule.
Embodiment 13
The preparation of compound 4 oral liquids
Compound 4 100g
Asccharin 0.5g
Essence 0.1g
Water for injection 1000ml
After compound 4, asccharin, essence is dissolved in water for injection respectively, mixed, be diluted to 1000ml, packing, promptly.
Test example 1
Adopt method known to a person of ordinary skill in the art that the test that compound of the present invention carries out anaerobe resistant is shown: compound provided by the invention shown in the following table 2 all has the good in vitro anti-microbial activity to two kinds of anerobes, acts on suitable with ornidazole.
Table 2, to two kinds of anerobe antibacterial activity in vitro
| Compound (embodiment number) | ??????????MIC(μg/ml) | |
| Fragile like bacillus | Peptostreptococcus | |
| 12345678 Ornidazoles | ????2 ????2 ????2 ????2 ????2 ????1 ????1 ????2 ????2 | ????0.5 ????1 ????1 ????1 ????0.5 ????0.5 ????0.25 ????0.5 ????0.5 |
Test example 2
Adopt method known to a person of ordinary skill in the art that the test that compound of the present invention carries out anaerobe resistant is shown: oral or quiet notes all have good antibacterial activity in vivo to two kinds of anerobes to compound provided by the invention shown in the following table 3 to mouse, effect is better than ornidazole, or suitable with ornidazole.
Table 3, to the endogenous protective test-results of two kinds of anaerobic infection mouse
| Compound (embodiment number) | Oral ED 50(mg/kg) | Intravenously administrable ED 50(mg/kg) | ||
| Fragile like bacillus | Peptostreptococcus | Fragile like bacillus | Peptostreptococcus | |
| 12345678 Ornidazoles | ????7 ????18 ????29 ????49 ????40 ????48 ????29 ????10 ????42 | ????16 ????16 ????18 ????30 ????25 ????29 ????12 ????12 ????20 | ????3.6 ????10 ????21 ????20 ????15 ????20 ????21 ????7 ????30 | ????7 ????10 ????15 ????9 ????8 ????10 ????5 ????8 ????10 |
Test example 3
Preliminary toxicity test: give the oral or abdominal injection The compounds of this invention 1 of each group (10 every group, male and female half and half) mouse, dosage is 2000mg/kg, observes for two weeks.The toxicity of The compounds of this invention shown in the table 4 is all less, all less than ornidazole.
The mortality ratio of the once oral or abdominal injection of table 4, mouse.
| Compound (embodiment) | Oral 2000mg/kg mortality ratio | Abdominal injection 2000mg/kg mortality ratio |
| 12345678 Ornidazoles | ????0 ????0 ????0 ????0 ????1 ????3 ????0 ????0 ????5 | ????3 ????2 ????2 ????0 ????3 ????5 ????0 ????0 ????7 |
Claims (4)
1, hydrate or the solvated compounds or the pharmacy acceptable salt of the compound of general formula (I) representative and general formula (I) compound.
Wherein R is CH
2F,
CHF
2, CF
3,
2, according to the preparation method of the described compound of claim 1, comprising:
With formula II compound with
Reaction;
Or with formula IIIization
Compound with
Reaction,
Obtain as right
Require 1 described compound.
3, 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.
4, the described compound of claim 1 is used to prepare the purposes of anti-anaerobic agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2003101000570A CN100344626C (en) | 2003-10-08 | 2003-10-08 | Application of alpha- (morpholine-1-yl) methyl-2-methyl-5-nitroimidazole-1-ethanol in preparation of anti-anaerobe drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2003101000570A CN100344626C (en) | 2003-10-08 | 2003-10-08 | Application of alpha- (morpholine-1-yl) methyl-2-methyl-5-nitroimidazole-1-ethanol in preparation of anti-anaerobe drugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1605586A true CN1605586A (en) | 2005-04-13 |
| CN100344626C CN100344626C (en) | 2007-10-24 |
Family
ID=34755805
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2003101000570A Expired - Lifetime CN100344626C (en) | 2003-10-08 | 2003-10-08 | Application of alpha- (morpholine-1-yl) methyl-2-methyl-5-nitroimidazole-1-ethanol in preparation of anti-anaerobe drugs |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100344626C (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007079653A1 (en) * | 2006-01-06 | 2007-07-19 | Jiangsu Hansen Pharmaceutical Co., Ltd. | OPTICALLY PURE α-SUBSTITUTED 2-METHYL-5-NITROIMIDAZOLE-1-ETHANOL DERIVATIVES |
| CN100387233C (en) * | 2006-06-09 | 2008-05-14 | 南京圣和药业有限公司 | Use of levo morpholine nidazole for preparing medicine for antiparasitic infection |
| CN100427094C (en) * | 2005-12-13 | 2008-10-22 | 江苏豪森药业股份有限公司 | Application of alpha- (morpholine-1-yl) methyl-2-methyl-5-nitroimidazole-1-ethanol in preparation of anti-trichomonad and anti-amebiasis medicines |
| CN1810815B (en) * | 2006-03-08 | 2011-03-16 | 陕西合成药业有限公司 | Nitroimidazole derivative for treatment |
| CN1903846B (en) * | 2006-08-15 | 2011-07-13 | 杨成 | Ornidazole derivative used for therapy, its preparation method and use |
| CN102199147A (en) * | 2011-03-19 | 2011-09-28 | 陕西合成药业有限公司 | Nitroimidazole derivative in therapy |
| 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 |
| 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 |
| CN114907250A (en) * | 2021-02-06 | 2022-08-16 | 华创合成制药股份有限公司 | Deuterated morpholine ornidazole and application thereof |
-
2003
- 2003-10-08 CN CNB2003101000570A patent/CN100344626C/en not_active Expired - Lifetime
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100427094C (en) * | 2005-12-13 | 2008-10-22 | 江苏豪森药业股份有限公司 | Application of alpha- (morpholine-1-yl) methyl-2-methyl-5-nitroimidazole-1-ethanol in preparation of anti-trichomonad and anti-amebiasis medicines |
| WO2007079653A1 (en) * | 2006-01-06 | 2007-07-19 | Jiangsu Hansen Pharmaceutical Co., Ltd. | OPTICALLY PURE α-SUBSTITUTED 2-METHYL-5-NITROIMIDAZOLE-1-ETHANOL DERIVATIVES |
| CN1810815B (en) * | 2006-03-08 | 2011-03-16 | 陕西合成药业有限公司 | Nitroimidazole derivative for treatment |
| CN100387233C (en) * | 2006-06-09 | 2008-05-14 | 南京圣和药业有限公司 | Use of levo morpholine nidazole for preparing medicine for antiparasitic infection |
| CN1903846B (en) * | 2006-08-15 | 2011-07-13 | 杨成 | Ornidazole derivative used for therapy, its preparation method and use |
| CN102199147A (en) * | 2011-03-19 | 2011-09-28 | 陕西合成药业有限公司 | Nitroimidazole derivative in therapy |
| 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 |
| 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 |
| CN114907250A (en) * | 2021-02-06 | 2022-08-16 | 华创合成制药股份有限公司 | Deuterated morpholine ornidazole and application thereof |
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| Publication number | Publication date |
|---|---|
| CN100344626C (en) | 2007-10-24 |
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