CN101077868A - Thiadiazole-substituted imidazole anti-anaerobe compound - Google Patents
Thiadiazole-substituted imidazole anti-anaerobe compound Download PDFInfo
- Publication number
- CN101077868A CN101077868A CN 200610011972 CN200610011972A CN101077868A CN 101077868 A CN101077868 A CN 101077868A CN 200610011972 CN200610011972 CN 200610011972 CN 200610011972 A CN200610011972 A CN 200610011972A CN 101077868 A CN101077868 A CN 101077868A
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- acid
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- methyl
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- FFYTTYVSDVWNMY-UHFFFAOYSA-N 2-Methyl-5-nitroimidazole Chemical class CC1=NC=C([N+]([O-])=O)N1 FFYTTYVSDVWNMY-UHFFFAOYSA-N 0.000 claims description 6
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- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a thiadiazole-substituted imidazole anaerobic bacterium resistant compound and a preparation method thereof, in particular to a compound 5- [ 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl ] -1, 3, 4-thiadiazole-2-amine and pharmaceutically acceptable salts thereof; the invention also relates to a preparation method thereof and a pharmaceutical composition taking the compound as an active ingredient; the invention also comprises the application of the compound and the medicinal composition in preparing anti-anaerobe drugs, anti-trichomonad drugs and anti-amebiasis drugs.
Description
Technical field:
The present invention relates to a kind of new medical compounds and pharmacy acceptable salt and/or hydrate, definite saying so relates to compound 5-(2-(2-methyl-5-nitro-1H-imidazoles-1-yl) ethyl)-1,3,4-thiadiazoles-2-amine and pharmacy acceptable salt thereof.The invention still further relates to its preparation method and be the pharmaceutical composition of activeconstituents with this compound.The present invention also comprises this compound and the application of medicinal compositions in preparation anti-anaerobic agent, anti-trichomonal medicine and anti-ameba medicine.
Background technology:
Anerobe is the bacterium that could survive and breed in oxygen-free environment, under the situation that Abwehrkraft des Koepers descends, can cause severe infections, and wherein, autogenous infection is in the majority, and normal and aerophil formation polyinfection.Parasitizing the intravital anerobe of people exists or accepts pharmacological agent such as cell toxicant, steroid hormone, immunosuppression or prolonged application Broad spectrum antibiotics and when causing flora imbalance, can cause the endogenous anaerobic infection when Abwehrkraft des Koepers descends, has aerophil or facultative anaerobe to infect.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 (I), its chemical structural formula is as follows:
The present invention includes compound in structural formula I, also comprise its pharmacy acceptable salt and/or hydrate.Compound of the present invention, its chemical name are 5-[2-(2-methyl-5-nitro-1H-imidazoles-1-yl) ethyl]-1,3,4-thiadiazoles-2-amine.
The invention still further relates to the preparation method of formula I compound, react the step that obtains formula I compound comprising intermediate 2-methyl-5-nitro-1-(2-cyano ethyl)-1H-imidazoles and thiosemicarbazide.
The invention still further relates to the preparation method of intermediate 2-methyl-5-nitro-1-(2-cyano ethyl)-1H-imidazoles, it prepares by 2-methyl-5-nitro-1H-imidazoles and acrylonitrile reactor.In this reaction, catalyzer is preferably neutralized verdigris.
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.Mesylate preferably.
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, 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 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 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.With 2-methyl-5-nitro imidazoles (III) is starting raw material, carries out addition reaction with vinyl cyanide, obtains 2-methyl-5-nitro-1-(2-cyano ethyl)-1H-imidazoles (II), Compound I I and thiosemicarbazide condensation then, and cyclization becomes target compound I.In this route, all raw materials all are the method preparation known by the method for describing in these reaction formula, by the organic chemistry filed those of ordinary skill or commercially available.
Route 1
When 2-methyl-5-nitro imidazoles (III) and vinyl cyanide carry out addition reaction, can add catalyzer, improve the yield of reaction and the time of shortening reaction, catalyzer can be venus crystals, acetate, acetate-cupric chloride.Preferred venus crystals.
The preparation of above The compounds of this invention, the raw materials used prior art that all derives from can be passed through prior art for preparing, also can buy from Chemical market.
Preparation method and step that the present invention is concrete are seen the embodiment of the invention.
The beneficial effect of The compounds of this invention is described with experimental data below.
Test 1
Adopting 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 measures, select clinical separation anerobe for use, adopt agar dilution to detect the minimal inhibitory concentration (MIC (μ g/ml)) of embodiment 1 compound and contrast medicine metronidazole, the results are shown in Table 1.
The external anti-anaerobic activity of table 1 embodiment 1
| The bacterium name | The bacterial strain number | MIC(μg/ml) | ||
| Example I | Metronidazole | Tinidazole | ||
| Propionibacterium acnes | 20 | 8.0 | ＞32 | ＞32 |
| Peptostreptococcus | 15 | 0.5 | 1.0 | 2.0 |
| Peptostreptococcus asaccharolyticus | 17 | 4.0 | ＞32 | ＞32 |
| Clostridium perfringens | 18 | 0.5 | 1.0 | 2.0 |
| The osculant suis | 11 | 0.25 | 0.5 | 1.0 |
| The aerogenesis Eubacterium | 19 | 0.25 | 0.25 | 0.25 |
| Bacteroides vulgatus | 12 | 0.5 | 1.0 | 1.0 |
| Bacteroides uniformis | 14 | 0.5 | 1.0 | 0.5 |
| The excrement bacterioide | 10 | ＜0.125 | 0.25 | 0.25 |
| The fertile Salmonella of mouth Prey | 10 | ＜0.125 | 0.125 | 0.125 |
| Clostridium perfringens | 17 | 0.125 | 0.25 | 0.125 |
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
With the Kunming mouse is experimental animal, and male and female half and half are irritated stomach and intravenous administration, and embodiment 1 compound has been carried out preliminary studies on acute toxicity, the results are shown in Table 2.
Table 2 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 | 7000 |
| Embodiment 2 | Intravenously administrable | The 30%DMSO sodium chloride injection | 200 |
Compound according to following formula I of the present invention has anti-microbial effect to multiple anerobe, and is better than metronidazole and tinidazole; Acute toxicity test shows that the toxicity of its mouse vein and oral administration is all lower.Therefore, they can be as the medicine of preparation treatment anaerobic infection.
Compound of the present invention, the biologically active height, overcome the resistance of medicine of the prior art, particularly also inhibited to metronidazole of the prior art and the drug-fast anaerobism bacterial strain of tinidazole, it is low to have toxicity simultaneously, the preparation method is simple, and raw material is easy to get, mild condition, is fit to characteristics such as suitability for industrialized production.
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 1100LC/MSD; Agents useful for same is analytical pure or chemical pure.
Embodiment 1 5-[2-(2-methyl-5-nitro-1H-imidazoles-1-yl) ethyl]-1,3, the preparation of 4-thiadiazoles-2-amine
Step 1:
2-methyl-5-nitro imidazoles (III) 50g (0.39mol) is added among the vinyl cyanide 80ml (1.2mol), in reaction solution, adds venus crystals 5g, reflux 6h.Reaction is finished, suction filtration while hot, filtrate evaporate to dryness.Resistates is added ethyl acetate 250ml, reflux 0.5h, suction filtration while hot, solid is separated out in the cooling of filtrate room temperature, suction filtration, drying, 2-methyl-5-nitro-1-(2-cyano ethyl)-1H-imidazoles (II) 41g, yield 58%.
Step 2:
2-methyl-5-nitro-1-(2-cyano ethyl)-1H-imidazoles (II) 41g (0.23mol) and thiosemicarbazide 21g (0.23mol) are added among the trifluoroacetic acid 200ml, heating reflux reaction .5h, reaction is finished, the question response liquid cooling is to temperature, and impouring is stirred to frozen water, reaction solution transfers pH to neutral with saturated sodium bicarbonate solution, separates out solid, suction filtration, washing, drying gets 5-[2-(2-methyl-5-nitro-1H-imidazoles-1-yl) ethyl] 1,3,4-thiadiazoles-2-amine (I) 24.5g, yield 42%.MS[M+H]：255.1；
1H-NMR：2.29(s，3H)，3.34(t，2H，J＝6.9Hz)，4.33(t，2H，J＝6.9Hz)，7.11(s，2H)，8.34(s，1H).
Embodiment 2 5-[2-(2-methyl-5-nitro-1H-imidazoles-1-yl) ethyl]-1,3, the preparation of 4-thiadiazoles-2-amine mesylate
Compound I 10g (0.04mol) is added among the ethanol 50ml, add methylsulfonic acid 3.8g (0.04mol), reflux 30min, cooling, suction filtration, ethanol is washed, drying gets 5-[2-(2-methyl-5-nitro-1H-imidazoles-1-yl) ethyl]-1,3,4-thiadiazoles-2-amine mesylate 13.3g, yield is 95%.
Embodiment 3 5-[2-(2-methyl-5-nitro-1H-imidazoles-1-yl) ethyl]-1,3, the preparation of 4-thiadiazoles-2-amine hydrochlorate
Compound I 10g (0.04mol) is added among the ethanol 30ml, add acidic alcohol (hydrochloric amount is 0.04mol), reflux 30min, cooling, suction filtration, ethanol is washed, drying gets 5-[2-(2-methyl-5-nitro-1H-imidazoles-1-yl) ethyl]-1,3,4-thiadiazoles-2-amine hydrochlorate 11.3g, yield is 97%.
The preparation of embodiment 4 embodiment 1 compound tablet (250mg/ sheet)
Get embodiment 1 compound 250g, starch 30g, 2%HPMC aqueous solution 80ml, sodium starch glycolate 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, 2 compound effervescent tablets (250mg/ sheet)
Get following component:
Embodiment 2 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 2 compounds, 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, 3 compound effervescent tablets (500mg/ piece)
Get following component:
Embodiment 3 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 3 raw materials of compound medicinal powder are 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 3 compound fine powders, 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 2 compound freeze-dried powders (125mg/ props up)
Get following component:
Embodiment 2 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 2 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, compound of formula I structure, and pharmacy acceptable salt and/or hydrate.
According to the compound of claim 1, it is characterized in that 2, described pharmacy acceptable salt is mineral acid or organic acid salt.
3, according to the compound of claim 1, it is characterized in that described mineral acid or organic acid salt are selected from: 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.
According to the compound of claim 1, it is characterized in that 4, described pharmacy acceptable salt is a mesylate.
5, contain in the claim 1 to 4 each compound or its pharmacy acceptable salt and/or hydrate as the active ingredient medicine composition.
6, the pharmaceutical composition of claim 5 is characterized in that, is to be fit to medicinal any dosage form.
7, each compound or its pharmacy acceptable salt and/or the hydrate application in the preparation anti-anaerobic agent in the claim 1 or 3.
8, the preparation method of claim 1 compound is characterized in that, comprises 2-methyl-5-nitro-1-(2-cyano ethyl)-1H-imidazoles and thiosemicarbazide are reacted the step that obtains formula I compound.
9, preparation method according to Claim 8 is characterized in that, wherein compound 2-methyl-5-nitro-1-(2-cyano ethyl)-1H-imidazoles prepares by 2-methyl-5-nitro-1H-imidazoles and acrylonitrile reactor.
According to the preparation method of the described compound of claim 9, it is characterized in that 10, the catalyzer of 2-methyl-5-nitro-1H-imidazoles and acrylonitrile reactor is a venus crystals.
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