CN104434912A - Application of 5-hydroxy-1-methyl hydantoin - Google Patents
Application of 5-hydroxy-1-methyl hydantoin Download PDFInfo
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- CN104434912A CN104434912A CN201410620600.8A CN201410620600A CN104434912A CN 104434912 A CN104434912 A CN 104434912A CN 201410620600 A CN201410620600 A CN 201410620600A CN 104434912 A CN104434912 A CN 104434912A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
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Abstract
The invention belongs to the field of new applications of medicines, and discloses application of 5-hydroxy-1-methyl hydantoin as well as a pharmaceutical salt and stereisomer thereof in preparing medicines for treating cough. According to the application disclosed by the invention, the influence of 5-hydroxy-1-methyl hydantoin on citric acid induced cough in guinea pigs is determined by virtue of a citric acid cough inducing method, and a result shows that 5-hydroxy-1-methyl hydantoin has a significant inhibitory effect on the citric acid induced cough in the guinea pigs, is capable of remarkably prolonging the incubation period of the cough and is good in bioavailability in the guinea pigs. Therefore, the invention provides the application of 5-hydroxy-1-methyl hydantoin as well as the pharmaceutical salt and stereisomer thereof in preparing medicines for treating cough.
Description
Technical field
The invention belongs to new medicine use field, be specifically related to the application in the medicine of preparation treatment cough of 5-hydroxyl-1-methyl-2,4-imidazolidinedione, its pharmaceutical salts and stereoisomer thereof.The invention still further relates to the pharmaceutical preparation containing 5-hydroxyl-1-methyl-2,4-imidazolidinedione, its pharmaceutical salts and stereoisomer thereof, and the application of the pharmaceutical composition of itself and one or more other medicinal active ingredients composition.
Background technology
Cough is a kind of common disease, but coughs for a long time, trachea pathological changes can be diffused into contiguous bronchia, aggravate disease.In addition, long-term, violent cough not only can affect work and rest, consumes one's strength, even can cause laryngalgia, hoarseness, and breathe myalgia, respiratory tract hemorrhage, brings out emphysema etc., though therefore cough is commonly encountered diseases, can not be ignored, need cause highly vigilant of.
All medicines of any one link in coughre flex arc that can suppress all have antitussive action.Differently with mechanism two large classes are divided into: (1) central antitussive: can optionally suppress oblongata coughing centre and produce the medicine of antitussive action by its effect, be used for cancer, acute lung infraction, the cough that causes of left heart failure, common drug has codeine, carbetapentane citrate, Ethanedisulfonate, cloperastine; (2) peripheral antitussive: be also called peripheral antitussive, the medicine of antitussive action is played by any one link in sensor, nervus centripetalis, nervus centrifugalis in suppression coughre flex arc, better to zest dry cough or apasm of coughing effect, conventional as coughed peaceful, Radix Glycyrrhizae tabellae.Also some drugs is had to have central and periphery property two kinds effect concurrently, the lung-vagus reflex that coughing centre can be suppressed also to suppress lung and pleura stretch receptor cause, as: Benproperine, Pirexyl, just primary and secondary is different.But said medicine, if long-term taking, what have is easily addicted as codeine, and some cough suppressing effects are not obvious.So it is remarkable to develop a kind of cough suppressing effect, the medicine that toxic and side effects is low is extremely urgent.
Hydantoin-based compound refers to containing various substituent penta azacyclo compound, also known as making hydantoin compounds.Owing to there is multiple functional group in its structure, and have larger reactivity, the glycolylurea that various difference replaces and derivant thereof have been widely used in the fields such as medicine, pesticide, chemical industry and weaving.Wherein the pharmacological action of hydantoin-based compound is mainly manifested in the generation etc. of antibacterial, antiinflammatory, epilepsy, reduction blood glucose, sodium ion channel blocker, suppression uremic toxins.
5-hydroxyl-1-methyl-2,4-imidazolidinedione is an important derivant in hydantoin-based compound, structure as shown in formula I,
Research shows that the disease that 5-hydroxyl-1-methyl-2,4-imidazolidinedione is suitable for has intractable vascular inflammation, low serum albumin mass formed by blood stasis, renal failure, and is used for eliminating the pharmacologically active such as free radical and active oxygen.But it is not yet seen that 5-hydroxyl-1-methyl-2,4-imidazolidinedione can be used for the report of the medicine preparing treatment cough.
Summary of the invention
In view of this, one object of the present invention is to provide the 5-new opplication of hydroxyl-1-methyl-2,4-imidazolidinedione, i.e. 5-hydroxyl-1-methyl-2,4-imidazolidinedione, its pharmaceutical salts and stereoisomer thereof the application in the medicine of preparation treatment cough.
Present invention also offers the application of pharmaceutical preparation in the medicine of preparation treatment cough comprising 5-hydroxyl-1-methyl-2,4-imidazolidinedione, its pharmaceutical salts and stereoisomer thereof.
Further, present invention also offers the pharmaceutical composition that 5-hydroxyl-1-methyl-2,4-imidazolidinedione, its pharmaceutical salts and stereoisomer thereof and one or more medicinal active ingredients form and prepare the application in the medicine for the treatment of and coughing.
In some embodiments, described medicinal active ingredient is anti-infectives.Specifically can be selected from penicillin, amoxicillin, ciprofloxacin, erythromycin, amikacin, miconazole, zidovudine, amantadine, acyclovir, ribavirin, isoniazid or rifampicin one or more;
In some embodiments, described medicinal active ingredient is cough medicine.Specifically can be selected from Benproperine phosphate or lysionotin one or both.
In some embodiments, described medicinal active ingredient is anti-asthmatic.Specifically can be selected from salbutamol sulfate, ipratropium bromide, aminophylline, diprophylline, sodium chromoglicate, dipropionic acid beclometasone, epinephrine, isoproterenol, ephedrine, salbutamol or clenbuterol hydrochloride one or more.
In some embodiments, described medicinal active ingredient is expectorant.Specifically can be selected from ammonium chloride, guaifenesin, eucalyptus oil, benzoin tincture, acetylcysteine or Bisolvon one or more.
In some embodiments, described medicinal active ingredient is antihistaminic.Specifically can be selected from diphenhydramine, chlorphenamine, promethazine, fexofenadine fourth, LEVO CITRAZINE, Desloratadine, cetirizine or Azeptin one or more.
5-hydroxyl-1-methyl-2,4-imidazolidinedione has obvious inhibitory action to the guinea pig cough that citric acid causes, can significant prolongation cough latent period, and bioavailability is good in rat body, can be used for the medicine preparing treatment cough.
Detailed description of the invention
Below in conjunction with the embodiment of the present invention, be clearly and completely described the technical scheme in the embodiment of the present invention, obviously, described embodiment is only the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making the every other embodiment obtained under creative work prerequisite, belong to the scope of protection of the invention.
The pharmaceutical salts of 5-hydroxyl-1-methyl-2,4-imidazolidinedione of the present invention refers to by pharmaceutically acceptable, non-toxic alkali or the standby salt of processed with acid, comprises acylate, inorganic acid salt, organic alkali salt, inorganic base salts.
Wherein, described acylate comprises the salt of formic acid, acetic acid, benzenesulfonic acid, benzoic acid, p-methyl benzenesulfonic acid, camphorsulfonic acid, citric acid, methanesulfonic acid, ethyl sulfonic acid, propane sulfonic acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, glactaric acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid etc.
Described inorganic acid salt comprises the salt of hydrobromic acid, hydrochloric acid, nitric acid, sulphuric acid, phosphoric acid etc.
Described organic alkali salt comprises primary, secondary and tertiary amine salt, is substituted amine salt, native amino hydrochlorate etc.Wherein, the described amine salt that is substituted comprises naturally occurring replacement amine salt, cyclammonium salt and basic ion-exchange resins, specifically can be selected from betanin, caffeine, choline, N, N ' salt of-dibenzyl-ethylenediamin, diethylamine, 2-Diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, meglumine, glucosamine, Hai Baming, isopropylamine, methylglucosamine, morpholine, piperazine, piperidines, procaine, purine, theobromine, triethylamine, trimethylamine, tripropyl amine (TPA), trometamol etc.Described native amino hydrochlorate is as the salt of glycine, alanine, valine, leucine, isoleucine, nor-leucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine etc.
Described inorganic base salts comprises the salt of ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminum, ferrum, ketone, ferrous iron, manganese, bivalent manganese etc.
When " stereoisomer " of 5-hydroxyl-1-methyl-2,4-imidazolidinedione of the present invention refers to that formula (I) compound exists chiral centre, double bond etc., the all stereoisomers produced, comprise enantiomer, diastereomer, racemization isomer, cis-trans-isomer, tautomer, geometric isomer, epimer and composition thereof, include in the scope of the invention.
As 5-hydroxyl-1-methyl-2,4-imidazolidinedione has a chiral carbon atom at 5, define 2 isomers, namely
above-mentioned two kinds of isomers include in scope.
5-hydroxyl-1-methyl-2,4-imidazolidinedione also can tautomer form exist, instantiation includes but are not limited to:
above-mentioned isomer also includes in scope.
The present invention adopts citric acid to draw the method for coughing and have detected 5-hydroxyl-1-methyl-2,4-imidazolidinedione to the therapeutic effect of the cough that citric acid causes, result display is compared with solvent control group, 5-hydroxyl-1-methyl-2,4-imidazolidinedione group has significant inhibitory action to the cough that citric acid causes, and can significant prolongation animal cough latent period.Compared with the 1-methyl-2,4-imidazolidinedione 2 groups of 5-hydroxyl-1-methyl-2,4-imidazolidinedione group and identical dosage and natural law, to the cough that citric acid causes, there is obvious inhibitory action, and can significant prolongation animal cough latent period, there is significant advantage.Show that 5-hydroxyl-1-methyl-2,4-imidazolidinedione has the effect of significantly treatment cough.
Further, the present invention analyzes at rat drug disposition metabolic condition 5-hydroxyl-1-methyl-2,4-imidazolidinedione.Result shows, and during oral administration, the Pharmacokinetic Characteristics of 1-methyl-2,4-imidazolidinedione and 5-hydroxyl-1-methyl-2,4-imidazolidinedione is all good and effect is suitable.During drug administration by injection, the AUC of 1-methyl-2,4-imidazolidinedione and 5-hydroxyl-1-methyl-2,4-imidazolidinedione
last, Cl and Vss is suitable, but the T of 5-hydroxyl-1-methyl-2,4-imidazolidinedione
1/2but be 4.4 times of 1-methyl-2,4-imidazolidinedione, illustrate that the action time of 5-hydroxyl-1-methyl-2,4-imidazolidinedione is more lasting, there is obvious advantage.
Therefore the invention provides the application in the medicine of preparation treatment cough of 5-hydroxyl-1-methyl-2,4-imidazolidinedione, its pharmaceutical salts and stereoisomer thereof.
5-hydroxyl-1-methyl-2,4-imidazolidinedione of the present invention, its pharmaceutical salts and stereoisomer thereof are for the preparation of when treating the medicine of coughing, can be used alone, make any pharmaceutically acceptable pharmaceutical preparation, comprise through gastrointestinal administration dosage form and non-through gastrointestinal administration dosage form, through gastrointestinal administration dosage form as tablet, capsule, granule, powder, pill, solution, syrup, suspensoid, Emulsion etc.; Non-through gastrointestinal administration dosage form as injection, aerosol, patch etc.Injection comprises injection and injectable sterile powder, and injection can be used for intramuscular injection, intravenous injection, intravenous drip etc.Injectable sterile powder comprises injection freeze-dried product and Injectable sterile subpackage product.
When making pharmaceutical preparation, the conventional method in existing pharmaceutical field can be adopted to produce.
When making oral formulations, suitable filler, binding agent, disintegrating agent, lubricant etc. can be added.Wherein filler is selected from starch, Icing Sugar, calcium phosphate, calcium sulfate two water thing, dextrin, microcrystalline Cellulose, lactose, pregelatinized Starch, mannitol etc.; Binding agent can be selected from sodium carboxymethyl cellulose, PVP – K30, hydroxypropyl cellulose, starch slurry, methylcellulose, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent can be selected from dried starch, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose etc.; Lubricant can be selected from magnesium stearate, Pulvis Talci, sodium lauryl sulphate, micropowder silica gel etc.
When making injection, suitable solvent and additives can be added according to the character of medicine, also can not add additives.Wherein solvent can be selected from water for injection, ethanol, glycerol, propylene glycol, Polyethylene Glycol, benzyl benzoate, dimethyl acetylamide; Additives can be selected from solubilizing agent, wetting agent, emulsifying agent, buffer agent, suspending agent, antioxidant, antibacterial, local anesthetic, osmotic pressure regulator etc.Solubilizing agent, wetting agent or emulsifying agent can be selected from Tween 80, polyvinylpyrrolidone, lecithin, NaTDC, F68 etc.; Buffer agent can be selected from acetic acid, sodium acetate, citric acid, sodium citrate, lactic acid, tartaric acid, sodium tartrate etc.; Suspending agent can be selected from methylcellulose, sodium carboxymethyl cellulose, gelatin etc.; Antioxidant is selected from sodium sulfite, sodium sulfite, sodium thiosulfate etc.; Antibacterial can be selected from chlorobutanol, benzyl alcohol, phenol etc.; Local anesthetic can be selected from procaine hydrochloride, lignocaine; Osmotic pressure regulator can be selected from sodium chloride and glucose etc.
5-hydroxyl-1-methyl-2,4-imidazolidinedione of the present invention, its pharmaceutical salts and stereoisomer thereof are for the preparation of when treating the medicine of coughing, pharmaceutical composition can also be formed with one or more other medicinal active ingredients, this pharmaceutical composition is clinically or pharmaceutically acceptable arbitrary dosage form, is preferably oral formulations or injection.This pharmaceutical composition can be that 5-hydroxyl-1-methyl-2,4-imidazolidinedione, its pharmaceutical salts and stereoisomer thereof and other active ingredient combinations use, also can be and other medicines conbined usage, such as, with anti-infectives, with the conbined usage such as other relieving cough and asthma expelling phlegm drugs, antihistamine drug or use with active ingredient combinations wherein.Wherein, described anti-infectives includes but are not limited to antibiotic, quinolones, sulfonamides, antifungal agent, antiviral agents, antituberculotic, antileprotic, as penicillin, amoxicillin, ciprofloxacin, erythromycin, amikacin, miconazole, zidovudine, amantadine, acyclovir, ribavirin, isoniazid, rifampicin; Described cough medicine includes but are not limited to Benproperine phosphate, lysionotin; Described anti-asthmatic includes but are not limited to salbutamol sulfate, ipratropium bromide, aminophylline, diprophylline, sodium chromoglicate, dipropionic acid beclometasone, epinephrine, isoproterenol, ephedrine, salbutamol, clenbuterol hydrochloride; Described expectorant includes but are not limited to ammonium chloride, guaifenesin, eucalyptus oil, benzoin tincture, acetylcysteine, Bisolvon; Described antihistaminic includes but are not limited to diphenhydramine, chlorphenamine, promethazine, fexofenadine fourth, LEVO CITRAZINE, Desloratadine, cetirizine, Azeptin.
5-hydroxyl-1-methyl-2,4-imidazolidinedione of the present invention, its pharmaceutical salts and stereoisomer thereof are for the preparation of when treating the medicine of coughing, oral dose is by wherein containing 5-hydroxyl-1-methyl-2,4-imidazolidinedione, its pharmaceutical salts or its stereoisomer 50mg ~ 500mg, can be 50mg, 75mg, 100mg, 200mg, 300mg, 500mg etc., described compound can be given by the arrangement of 1 ~ 3 time every day.Injection consumption is by wherein containing 5-hydroxyl-1-methyl-2,4-imidazolidinedione, its pharmaceutical salts or its stereoisomer 10mg ~ 100mg, and can be 10mg, 15mg, 20mg, 25mg, 50mg, 75mg, 100mg etc., every day gives described compound 1 ~ 3 time.When 5-hydroxyl-1-methyl-2,4-imidazolidinedione of the present invention, its pharmaceutical salts and stereoisomer thereof and one or more other medicinal active ingredients combinationally use, the weight ratio of 5-hydroxyl-1-methyl-2,4-imidazolidinedione, its pharmaceutical salts or its stereoisomer and other medicinal active ingredients can change, and it depends on the effective dose of various composition.In general, will adopt respective effective dose, such as, the weight ratio of 5-hydroxyl-1-methyl-2,4-imidazolidinedione and other medicinal active ingredients at about 1000:1 to about between 1:1000, can be preferably about 200:1 to about between 1:200.When 5-hydroxyl-1-methyl-2,4-imidazolidinedione of the present invention, its pharmaceutical salts or its stereoisomer and other medicines conbined usage, generally also in above-mentioned scope, but at each occurrence, can should use the effective dose of each active component.
In order to understand the present invention further, below in conjunction with embodiment, the present invention is described in detail.Below the beneficial effect of 5-hydroxyl-1-methyl-2,4-imidazolidinedione is set forth in experiment further, but the present invention does not limit by these experimental examples.
The antitussive test of pesticide effectiveness (citric acid draws the method for coughing) of experimental example 1:5-hydroxyl-1-methyl-2,4-imidazolidinedione
Test sample: 1-methyl-2,4-imidazolidinedione, 5-hydroxyl-1-methyl-2,4-imidazolidinedione: purchased from Jilin Chuangzhi Pharmaceutical Development Co., Ltd.; Normal saline, purchased from traditional Chinese medicines company; Citric acid, available from Sigma.
Experimental technique: accurately take 1-methyl-2,4-imidazolidinedione respectively, 5-hydroxyl-1-methyl-2,4-imidazolidinedione, adds physiological saline solution, is formulated as the solution of 20mg/mL respectively.
Cavia porcellus is put 4L airtight shroud in, and spray into 17.5% citric acid atomization gas 25 seconds with ultrasonic nebulizer, record the cough number of times of Cavia porcellus in 5 minutes, cough number of times is greater than 10 persons and selects.Be divided into 5 groups at random according to cough number of times, only often organize 8-9, grouping situation is in table 1 (note: the same day was thought the 0th day in screening).From after screening the 3rd day, 1-methyl-2,4-imidazolidinedione group 1 gastric infusion, administration volume was 5ml/kg, every day 1 time, successive administration 3 days.Other groups all after screening the 5th day, gastric infusion or solvent, solvent is normal saline, and administration volume is 5ml/kg, every day 1 time, administration 1 day.Within 5th day, administration is after 1 hour, Cavia porcellus is put 4L airtight shroud in, and spray into 17.5% citric acid atomization gas 25 seconds with ultrasonic nebulizer, the cough number of times of Cavia porcellus in record incubation period and 5 minutes, based on solvent control group cough number, value calculates the suppression ratio of each group.With statistical analysis between One-Way ANOVA and Dunnett ' s test group.Test data is in table 2.Wherein the computing formula of suppression ratio is: suppression ratio=(number of times of coughing after solvent control group cough number of times-administration)/solvent control group cough number of times * 100%.
Table 1 divides into groups and dosage
Table 2 test of pesticide effectiveness result
Result shows, and compare with solvent control group, 5-hydroxyl-1-methyl-2,4-imidazolidinedione group has significant inhibitory action to the cough that citric acid causes, and can significant prolongation animal cough latent period.Compared with the 1-methyl-2,4-imidazolidinedione 2 groups of 5-hydroxyl-1-methyl-2,4-imidazolidinedione group and identical dosage and natural law, to the cough that citric acid causes, there is obvious inhibitory action (being respectively 25.8% and 11.8%), and energy significant prolongation animal cough latent period (being respectively 104.6 and 86.8), there is significant advantage.Compared with the identical dosage successive administration 1-methyl-2,4-imidazolidinedione of 3 days 1 group, suppress the effect of animal cough number of times slightly weak, but the effect extending animal cough latent period is suitable.Therefore, in general, compared with 1-methyl-2,4-imidazolidinedione, the antitussive action of 5-hydroxyl-1-methyl-2,4-imidazolidinedione has clear superiority.
The Pharmacokinetics in Rat test of experimental example 2:5-hydroxyl-1-methyl-2,4-imidazolidinedione
Animal subject: male SD rat, 3, body weight 190-240g.
Test sample: 1-methyl-2,4-imidazolidinedione, 5-hydroxyl-1-methyl-2,4-imidazolidinedione: purchased from Jilin Chuangzhi Pharmaceutical Development Co., Ltd..
Internal standard substance: APAP, dissolves with acetonitrile, makes the inner mark solution containing APAP15ng/mL, 5-bromouracil, dissolves, make the inner mark solution containing 5-bromouracil 1000ng/mL with acetonitrile.
Prepared by need testing solution: get test sample appropriate, use physiological saline solution.
Experimental technique:
Administration: test sample intravenous injection administration (iv), dosage is 15mg/kg, administration volume 5mL/kg; Test sample gastric infusion (po), dosage is 30mg/kg, administration volume 10mL/kg.
Blood sampling: carry out tail vein blood respectively at 0.083h, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h after 1-methyl-2,4-imidazolidinedione administration, each time point takes 100 μ about L whole bloods, centrifugal 6min separated plasma in the high speed centrifuge of 8000 revs/min, blood plasma is frozen in-80 DEG C of refrigerators.
Tail vein blood is carried out respectively at 0.083h, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 24h after 5-hydroxyl-1-methyl-2,4-imidazolidinedione administration, each time point takes 100 μ about L whole bloods, centrifugal 6min separated plasma in the high speed centrifuge of 8000 revs/min, blood plasma is frozen in-80 DEG C of refrigerators.
Plasma sample analysis: (employing precipitation of protein)
1-methyl-2,4-imidazolidinedione: get 50 μ L blood plasma in 1.5mL centrifuge tube, adds 200 μ L inner mark solutions (containing interior mark APAP15ng/mL), vortex 3min, then 12000 revs/min of centrifugal 5min, get supernatant 100 μ L, then add 100 μ L water, vortex mixes; LC-MS/MS analyzes.
5-hydroxyl-1-methyl-2,4-imidazolidinedione: get 50 μ L blood plasma in 1.5mL centrifuge tube, adds 200 μ L inner mark solutions (containing interior mark 5-bromouracil 1000ng/mL), vortex 3min, then 12000 revs/min of centrifugal 5min, get supernatant 100 μ L, then add 100 μ L water, vortex mixes; LC-MS/MS analyzes.
Table 4 P of Rats K evaluation result (iv:15mg/kg)
| Test sample | T 1/2(h) | AUC last(h*ng/ml) | CL(L/h/kg) | Vss(L/kg) |
| 1-methyl-2,4-imidazolidinedione | 0.67 | 25513 | 0.58 | 0.65 |
| 5-hydroxyl-1-methyl-2,4-imidazolidinedione | 2.95 | 27304 | 0.55 | 1.02 |
Table 5 P of Rats K evaluation result (po:30mg/kg)
| Test sample | T 1/2(h) | AUC last(h*ng/ml) | C max(ng/ml) | T max(h) | F(％) |
| 1-methyl-2,4-imidazolidinedione | 0.67 | 60955 | 29067 | 0.5 | 119 |
| 5-hydroxyl-1-methyl-2,4-imidazolidinedione | 0.84 | 43823 | 24866 | 0.5 | 80 |
Wherein, T
1/2represent the half-life; AUC
lastrepresent area under the drug-time curve 0 → t; CL represents clearance rate; Vss represents apparent volume of distribution; C
maxrepresent blood peak concentration of drug; T
maxrepresent blood medicine peak time; F (%) represents absolute bioavailability.
From table 4 and 5 result, during oral administration, the Pharmacokinetic Characteristics of 1-methyl-2,4-imidazolidinedione and 5-hydroxyl-1-methyl-2,4-imidazolidinedione is all good and effect is suitable.During drug administration by injection, the AUC of 1-methyl-2,4-imidazolidinedione and 5-hydroxyl-1-methyl-2,4-imidazolidinedione
last, Cl and Vss is suitable, but the T of 5-hydroxyl-1-methyl-2,4-imidazolidinedione
1/2but be 4.4 times of 1-methyl-2,4-imidazolidinedione, illustrate that the action time of 5-hydroxyl-1-methyl-2,4-imidazolidinedione is more lasting, there is obvious advantage.
Claims (8)
- The application in the medicine of preparation treatment cough of 1.5-hydroxyl-1-methyl-2,4-imidazolidinedione, its pharmaceutical salts and stereoisomer thereof.
- 2. comprise the application of pharmaceutical preparation in the medicine of preparation treatment cough of 5-hydroxyl-1-methyl-2,4-imidazolidinedione, its pharmaceutical salts and stereoisomer thereof.
- The pharmaceutical composition that 3.5-hydroxyl-1-methyl-2,4-imidazolidinedione, its pharmaceutical salts and stereoisomer thereof and one or more medicinal active ingredients form is preparing the application in the medicine for the treatment of and coughing.
- 4. apply as claimed in claim 3, described medicinal active ingredient is anti-infectives, is selected from one or more in penicillin, amoxicillin, ciprofloxacin, erythromycin, amikacin, miconazole, zidovudine, amantadine, acyclovir, ribavirin, isoniazid or rifampicin.
- 5. apply as claimed in claim 3, described medicinal active ingredient is cough medicine, is selected from one or both in Benproperine phosphate or lysionotin.
- 6. apply as claimed in claim 3, described medicinal active ingredient is anti-asthmatic, is selected from one or more in salbutamol sulfate, ipratropium bromide, aminophylline, diprophylline, sodium chromoglicate, dipropionic acid beclometasone, epinephrine, isoproterenol, ephedrine, salbutamol or clenbuterol hydrochloride.
- 7. apply as claimed in claim 3, described medicinal active ingredient is expectorant, is selected from one or more in ammonium chloride, guaifenesin, eucalyptus oil, benzoin tincture, acetylcysteine or Bisolvon.
- 8. apply as claimed in claim 3, described medicinal active ingredient is antihistaminic, is selected from one or more in diphenhydramine, chlorphenamine, promethazine, fexofenadine fourth, LEVO CITRAZINE, Desloratadine, cetirizine or Azeptin.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6245525A (en) * | 1985-08-22 | 1987-02-27 | Nippon Zoki Pharmaceut Co Ltd | Hypolipemic agent |
| US20040067996A1 (en) * | 2002-10-04 | 2004-04-08 | James Sheppeck | Hydantoin derivatives as inhibitors of matrix metalloproteinases and/or TNF-alpha converting enzyme (TACE) |
| CN1813717A (en) * | 2005-11-04 | 2006-08-09 | 王永生 | Use of 1-methyl hydrantoin for preparing medicine for relieving cough and asthma, and eliminating sputum |
| CN101590041A (en) * | 2008-05-28 | 2009-12-02 | 吉林大学 | A kind of pharmaceutical composition of antitussive |
-
2014
- 2014-11-05 CN CN201410620600.8A patent/CN104434912A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6245525A (en) * | 1985-08-22 | 1987-02-27 | Nippon Zoki Pharmaceut Co Ltd | Hypolipemic agent |
| US20040067996A1 (en) * | 2002-10-04 | 2004-04-08 | James Sheppeck | Hydantoin derivatives as inhibitors of matrix metalloproteinases and/or TNF-alpha converting enzyme (TACE) |
| CN1813717A (en) * | 2005-11-04 | 2006-08-09 | 王永生 | Use of 1-methyl hydrantoin for preparing medicine for relieving cough and asthma, and eliminating sputum |
| CN101590041A (en) * | 2008-05-28 | 2009-12-02 | 吉林大学 | A kind of pharmaceutical composition of antitussive |
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