CN103787994A - 3-methyl-(P-sodium benzenesulfonate)-2-allyl quinoxaline di-nitrogen oxide and preparation method and application thereof - Google Patents
3-methyl-(P-sodium benzenesulfonate)-2-allyl quinoxaline di-nitrogen oxide and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a preparation method of 3-methyl-(P-sodium benzenesulfonate)-2-allyl quinoxaline di-nitrogen oxide, which comprises the following steps: with o-nitroaniline as a raw material, performing oxidation cyclization to obtain benzofuroxan; reacting with acetylacetone through Beirut to obtain mequindox; performing aldol condensation with sodium o-formylbenzenesulfonate to generate the 3-methyl-(P-sodium benzenesulfonate)-2-allyl quinoxaline di-nitrogen oxide. In the method disclosed by the invention, by introducing a hydrotropic group -SO3H and salifying, the drug polarity is improved, and the solubility is enhanced, so that the bioavailability is increased.
Description
Technical field
The present invention relates to a kind of quinoxaline derivatives, belong to field of veterinary.
Background technology
Along with improving constantly of China's livestock industry industrial scale degree, the demand of the non-nutritive medicated feed additive to efficient, low toxicity, low residue increases severely day by day.Its feeding total amount of China accounts for 1/4 of the total number of animals raised in the world according to incompletely statistics, and the same year China the veterinary drug total output value Jin Zhan world veterinary drug gross output value 1/10, extremely unbecoming with the status of animal husbandry big country of China.The annual veterinary drug through Ministry of Agriculture's import (containing vaccine) more than 68 kinds, indicates that China's medicine development research for animals seriously lags behind.On the other hand, because veterinary drug kind is single, weak curative effect, make the abuse phenomenon of antibacterials in livestock industry production very serious, the resistance of bacterium greatly strengthens, and causes many bacteriosises to be difficult to control, livestock product drug residue severe overweight.Therefore the severe domestic and international market competition facing for Ying Ying China, solve in the research and development of the new veterinary drug of China and fodder additives the problems such as kind is single, Autonomy patented products shortage, research and development have novel veterinary drug and the fodder additives of applications well prospect and domestic and international market competitive power extremely urgent.
Quinocetone is the new veterinary drug of national level one class that China initiates in the world, has the antibacterial growth promoting function of only suffering from diarrhoea.Evaluate to do to assert it is the fodder additives of a kind of safety, environment protection health, new high-efficiency through national veterinary drug.Experimental results show that Quinocetone, to promoting Animal diseases prevention and control ability, improves food conversion ratio, improve livestock and poultry meat quality, promote growth, increase culture benefit, significant.Its structure is 3-methyl-2-cinnamicacyl-quinoxaline-1,4-dioxide, due to its poorly water-soluble, affects its bioavailability.
Summary of the invention
The technical problem to be solved in the present invention is to overcome existing defect, and a kind of quinoxaline derivatives of novel good water solubility is provided--3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide;
Another object of the present invention is to provide the preparation method of 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide.
Object of the present invention is carried out specific implementation by the following technical programs:
3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide, its structural formula is as follows:
The preparation method of above-mentioned 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide, first adopt o-Nitraniline as raw material, obtain after benzofuraxan by oxidative cyclization, react and obtain mequindox by Beirut with methyl ethyl diketone, then generate 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide with adjacent phenyl aldehyde sodium sulfonate aldol condensation condensation.
Further, described mequindox and the condensation reaction of adjacent phenyl aldehyde sodium sulfonate aldol, adopt diethylamine as catalysis alkali, and ethanol is as reaction solvent.The mol ratio of mequindox and diethylamine is 1:2.Described mequindox and adjacent phenyl aldehyde sodium sulfonate aldol setting-up point 20-35 ℃, the reaction times is 2-4 hour.
The preparation method of above-mentioned 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide, concrete operation step is as follows:
1) benzofuraxan is synthetic
O-Nitraniline is dissolved in methanol solution, adds NaOH, is stirred to completely and dissolves, the NaClO solution that slowly drips 1mol/L under ice-water bath, add about half an hour, and room temperature continues to stir 2h, TLC follows the tracks of detection, constantly has light yellow solid to separate out, and adds water, suction filtration goes out solid, and washing and drying obtains orange-yellow crude product, 70% ethyl alcohol recrystallization, obtain yellow plate crystal, i.e. benzofuraxan
Wherein, the NaClO of described o-Nitraniline: NaOH:1mol/L is 40g:21g:250mL;
2) mequindox is synthetic
The benzofuraxan that step 1) is obtained, adds excessive methyl ethyl diketone, and water-bath is warmed to molten, under jolting, add triethylamine, more warm 1-10 minute, cooling under room temperature, place, crystallization gradually, separates out a large amount of yellow crystals after 10 hours, suction filtration, collects crystallization, after the dry bath of washing, use dehydrated alcohol recrystallization, obtain aureus needle crystal, i.e. mequindox
Wherein, described benzofuraxan: methyl ethyl diketone: triethylamine is 10g:18g:40mL;
3) synthesizing of end product 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide
By step 2) mequindox of gained is dissolved in ethanol, add adjacent phenyl aldehyde sodium sulfonate, after stirring, control temperature is 20-35 ℃, slowly add diethylamine, constant temperature stirs 3 hours, after reaction finishes, is extracted with ethyl acetate, filter, with washing with acetone, after oven dry, obtain 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide
Wherein, described acetyl second quinoline: adjacent phenyl aldehyde sodium sulfonate: the mol ratio of diethylamine is 1:1:2.
3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide, as the application method in the antibacterial growth promotion medicine of preparation, adopts the aqueous solution of 50mg/kg.
Preferably, 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide is as the application of the medicine of the preparation antagonism medicine of colibacillosis and the prevention of white dysentery.
Beneficial effect of the present invention:
The present invention is by introducing hydrotropy group-SO
3h also makes its salify, has improved the polarity of medicine, and then has increased its solubleness, thereby improved its bioavailability.
Through evidence, product 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide is pale yellow powder, and easily appearance is very easily dissolved in methyl alcohol, ethanol, soluble in water, methyl-sulphoxide, be slightly soluble in chloroform, is insoluble to acetone, ethyl acetate, solvability is largely increased.The bacteriostatic activity of 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide is better than Quinocetone.
The present invention has the following advantages:
1, raw material is easy to get, and o-Nitraniline used in the present invention, methyl ethyl diketone, adjacent phenyl aldehyde sodium sulfonate, diethylamine, ethanol etc. are all conventional raw materials, be easy to obtain, and cost-saving.
2, reactions steps is few, and route is simple, and aftertreatment is simple to operation, is conducive to produce.
3, new compound 3-methyl-(P-phenylbenzimidazole sulfonic acid the sodium)-2-propenyl quinoxaline dinitrogen oxide obtaining with compared with there is better water solubility, better bacteriostatic activity, advantage that toxicity is low.
Embodiment
Below the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein, only for description and interpretation the present invention, is not intended to limit the present invention.
Embodiment 1:
The preparation method of 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide
(1) benzofuraxan is synthetic
Reaction formula is as follows:
O-Nitraniline (40g, 0.29mol) is dissolved in 225ml methanol solution, adds 21gNaOH, be stirred to completely and dissolve, slowly drip the NaClO 250ml of 1mol/L under ice-water bath, add about half an hour, room temperature continues to stir 2h, and TLC follows the tracks of detection, constantly has light yellow solid to separate out, add 300ml water, suction filtration goes out solid, washing and drying, obtain orange-yellow crude product, 70% ethyl alcohol recrystallization, obtains yellow plate crystal, i.e. benzofuraxan.Output 33g, productive rate 83%.
1HNMR(CDCl3)δppm:7.81-7.90(m,2H),8.55-8,58(d,1H),8.62-8.64(d,1H);13CNMR(CDCl3)δppm:113.3,114.7,118.2,132.4,133.8,153.4.
(2) 2-ethanoyl-3-methyl-quinoxaline dinitrogen oxide (being mequindox) is synthetic
Reaction formula is as follows:
Benzofuraxan (10g, 73.5mmol), adds excessive methyl ethyl diketone 18g, and water-bath is warmed to molten, adds triethylamine 40ml under jolting, more warm several minutes, cooling under room temperature, to place, crystallization gradually, separates out a large amount of yellow crystals after 10 hours.Suction filtration, collects crystallization, and a small amount of water washing is dry, output 11g, and dehydrated alcohol recrystallization, obtains aureus needle crystal, productive rate 68%.
mp153-154℃。
1HNMR(CDCl3)δppm:2.52(s,3H),2.71(s,3H),7.81-7.89(m,2H),8.53-8.55(d,1H),8.60-8.62(d,1H);
13CNMR(CDCl3)δppm:13.8,29.9,78.6,77.0,77.3,120.0,120.2,131.5,132.6。
(3) synthesizing of 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide
Reaction formula is as follows:
In the three-necked bottle of 250 milliliters that thermometer, agitator and prolong are housed, add mequindox 2.182g (10mmol) in 40ml dissolve with ethanol, add phenyl aldehyde-4-sodium sulfonate 2.082g (10mmol), after stirring, temperature control 20-35 ℃, slowly add diethylamine 2ml (20mmol), constant temperature stirs 3 hours.After reaction finishes, be extracted with ethyl acetate, filter, with washing with acetone, dry product and obtain 0.287 gram, yield 59%.
1HNMR(D2O)δppm:2.566(s,3H),7.113(d,J=16,1H),7.515～7.537(m,2H),7.800～7.853(m,2H),7.927～8.020(m,2H),8.363～8.456(m,3H);
13CNMR(D2O)δppm:13.88,119.09,119.16,126.76,127.16,128.27,130.59,131.60,131.66,132.87,134.04,136.14,137.35,138.88,141.26,142.06,147.96,187.41。
Product 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide is pale yellow powder, and easily appearance is very easily dissolved in methyl alcohol, ethanol, and soluble in water, methyl-sulphoxide, is slightly soluble in chloroform, is insoluble to acetone, ethyl acetate, and solvability is largely increased.
Embodiment 2:
The impact test of 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) fodder additives on growth of meat chicken
Novel fodder additive 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone), belong to the derivative compound of the different side-chain structures of quinoxaline together from carbadox (Carbadox), olaquindox (Olaquindox), methlacetylquinoxalinediode (MAQO) and Quinocetone etc., this medical instrument has anti-microbial activity and the growth promoting function of quinoxaline compound, and its toxicity is well below similar drugs Olaquindox as Feed Additive etc.Show according to this medicine toxicity test and the test of pesticide effectiveness, small white mouse LD50 is 9g/kg, and broiler chicken LD50 is 4949.94mg/kg.It has obvious fungistatic effect to colon bacillus, Salmonellas etc., higher than olaquindox 15%～20%, can obviously improve weight gain of piglets and efficiency of feed utilization to the preventive effect of the white scour of chicken, yellow scour of piglet simultaneously, reduces the generation of dysentery.Utilize CPBS method to predict the potential carinogenicity of 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone), result shows, H=0.238<0.30, can tentatively determine that 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) is non-carcinogenic thing.Therefore the author chooses different concns 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone), broiler chicken growth promoting function mechanism is studied, to select best feeding concentration.
1 materials and methods
1.1 experimental animals and test materials test are bought with chicken effluent north Zhao County China ridge chicken house; The development of 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) effluent North America lotus pharmaceutcal corporation, Ltd provides, purity 98.8%.
1.2 test design adopts single-factor random packet test design.0,50,75,100mg/kg if the difference of 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) is added level 4 processing:.1 160 of age in days peace carminum plumage broiler chicken, fed after 1 week, and mean body weight is (133.91 ± 7.62) g, is divided at random 4 groups, every group of 4 repetitions, and 10 of every repetitions, male and female half and half, through variance test, after grouping, body weight difference is not remarkable.
1.3 mensuration project and method
1.3.1 feeding experiment.Trial period is 56d, is divided into for 3 phases, 1～3 week age, 4～6 week age, 7～8 week age.Test diet is prepared each stage corn-soybean meal Screening Experiment of Diet according to 5 peace carminum plumage feeding of broiler administrative manual 6 nutrition recommended amounts, chicken is raised after 6d in advance through blank diet in examination, feed and add antibiotic feed since 7 ages in days, measure day weight gain, daily ingestion amount and feed efficiency.
1.3.2 metabolic test.In the time of 28 age in days, carry out 6d digest supersession test, record charging capacity and the residue material amount of every day; And when take diet to each group of examination chicken every day, gather every group of diet sample, 6d is gathered to diet sample and mix in order to analyzing; Before the digest supersession test phase, fed every morning, collect ight soil, 10% sampling of the ight soil of collection is packed in aluminium box, in 65e baking oven, dry constant weight after moisture regain 24h.
1.3.3 slaughter experiment.Respectively 21,42, each processing is every when 56 age in days repeats to randomly draw 2 chickens, jugular vein blood sampling 5ml, the centrifugal 15min of 3000r/min, separated plasma ,-20e preserves to be measured; Then slaughter examination chicken, sample, gather chest muscle 1g simultaneously ,-70e preserves to be measured.
The preparation of 1.4 samples and analysis
1.4.1 the crude protein in feed and fecaluria is measured.Adopt conventional Micro-kjoldahl method analysis.
1.4.2 blood plasma total protein, albuminous mensuration.Total protein adopts biuret method to measure, and albumin adopts the green colorimetric method for determining of bromo-cresols, and test kit builds up biochemical corp by Nanjing and provides.
1.4.3 the mensuration of DNA and RNA in muscle.In examination chicken muscle tissue, the extraction of DNA and RNA adopts Schmidt-Sa Haze-former times moral method (being called for short STS method), then measures absorbance value with ultraviolet spectrophotometer.
The processing of 1.5 data and statistical study are carried out the one-factor analysis of variance by all data by the OneWay method in SPSS10.0 software, when significant difference, carry out multiple comparisons by LSD method.
2 results and analysis
2.1 different concns 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) on the impact of meat chicken production performance from table 1; feed after 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone); 50 and the day weight gain of 75mg/kg dosage group apparently higher than control group (P<0.05), all not significantly (P>0.05) of 100mg/kg dosage group and other 3 groups of differences; The feed conversion rate of 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) 50mg/kg dosage group is apparently higher than control group and 100mg/kg dosage group (P<0.05); And the average daily ingestion amount utmost point of 50mg/kg dosage group is significantly higher than control group (P<0.01); and be significantly higher than 100mg/kg dosage group (P<0.05), but organize not remarkable (P>0.05) of difference with 75mg/kg; The average daily ingestion amount of 75mg/kg dosage group is significantly higher than 100mg/kg and control group (P<0.05); 100mg/kg group is average daily ingestion amount significant difference (P<0.05) compared with control group in the time of 0～6 week age, but in raising in the later stage with not significantly (P>0.05) of control group difference, and the full phase also show not significantly (P>0.05) of difference.Can be found out by test, 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) 50 and 75mg/kg dosage group can improve day weight gain, food consumption and feed conversion rate, compared with disliking quinoline additive with other quinoline mouths, toxicity is little, without teratogenesis, carcinogenic, mutagenicity and phototoxicity.But along with additive capacity increases, indices declines to some extent.Add 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) and still will note Dose Problem.Broiler diets can be brought into play the energy for growth of livestock and poultry on the one hand to greatest extent, also can reduce on the other hand the drug residue of animal food.
2.2 different concns 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) can be seen by table 2 impact of nitrogen equilibrium, in 4 groups of examination chickens, 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) 50 and eat crude protein 75mg/kg dosage group day and be significantly higher than control group and 100mg/kg dosage group (P<0.05), but 50mg/kg dosage group is than 75mg/kg dosage group slightly high (P>0.05), 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) 100mg/kg group is slightly higher than control group, but difference is remarkable (P>0.05) not, that feeds 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) discharges 3 groups of days albumen significantly lower than control group (P<0.05), and not significantly (P<0.05) of difference between 3 groups.In 4 groups, the crude protein Apparent Availability that adds 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) group is all significantly better than not interpolation group (P<0.05).Because 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) can change enteric microorganism kind, suppress harmful bacteria and produce poisonous substance stimulation enteron aisle, reducing intestines parietal cell upgrades, make the attenuation of intestines wall, be conducive to nutritive substance (particularly protein) to absorb.The report such as Yen and Jensen adds after the carbadox of 55mg/kg in pig feed, and the apparent digestibility and the nitrogen that significantly increase nitrogen retain, and apparent digestive energy is without considerable change.They think, diet carbadox effectively activate digestion enzyme activity and strengthen the absorption of small intestine to nutritive substance (particularly nitrogen).Therefore in research in the future, also can inquire into some enzymes relevant with Proteometabolism.Concrete data are in table 1,2,3.
Table 2 nitrogen balance test result
Note: the different large and small English alphabets of writing of same column of figure shoulder motes represent P<0.01, P<0.05.
The affect mg/ml of table 3 different concns 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) on broiler chicken plasma albumin, total protein
2.3 different concns 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) on the impact of broiler chicken plasma proteins from table 3; add 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) 50,75 and blood plasma total protein in 100mg/kg group with albuminous content compared with control group; although slightly increase, difference is not remarkable; Between each group, there is no significant difference yet.The weanling pig of this and Nousiainen and Suoma report is added after olaquindox, and total protein in blood plasma, albumin are more consistent than the inapparent result of difference with control group.
2.4 different concns 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) shows the table 4 that affects of RNA in Muscle of chicken and DNA, and adds in the Muscle of chicken of 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) group RNA concentration apparently higher than control group (P<0.05); And not significantly (P>0.05) of difference between each group of DNA concentration; In the examination chicken muscle of interpolation 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone), RNA/DNA value is significantly higher than control group (P<0.05), not remarkable (P>0.05) of difference between each group of interpolation 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone).
Therefore think, 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) can affect metabolism, increase RNA concentration and RNA/DNA value in muscle, thereby cause the formation of protein, cell and composition to increase, promote the synthetic enhancing of mytolin, and then reach increase the weight of animals, promote to produce.Moser etc. have studied the carbadox impact synthetic on protein in body, and result show the to feed myocyte of carbadox group increases, and the biosynthesis ability of mytolin strengthens.Concrete data are in table 4.
The impact of table 4 different concns 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) on DNA and RNA in Muscle of chicken tissue
3 conclusions
The evidence of different concns 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone); interpolation 50 and 75mg/kg3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) mainly contain following several respects effect: improve day weight gain; increase food consumption, improve food conversion ratio; Improve the utilization ratio of feed nitrogen, increase nitrogen retention; Promote myocyte's hypertrophy hyperplasia, the bioprotein synthesis capability of strengthen muscle.
This 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) effect of testing to add 50mg/kg is the most obvious, and high dosage 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) is not remarkable on the production performance impact of examination chicken, therefore suitable addition can guarantee that livestock and poultry bring into play production performance to greatest extent in practice, also can reduce production costs, obtain the highest economic benefit simultaneously.
Embodiment 3:
3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) bacteriostatic test
3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) is a kind of newtype drug fodder additives that the development of effluent North America lotus pharmaceutcal corporation, Ltd is synthesized on the basis of olaquindox, and its structure female ring is identical with olaquindox structure female ring (quinoline is favored with piperazine).
1 materials and methods
1.1 test drug 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) Haizheng Pharmaceutical Co is entrusted development; Olaquindox is produced by Ruicheng, Shanxi pharmaceutical factory, and purity is more than 980g/kg.
1.2 test strain test strains comprise Pseudomonas aeruginosa (1024), colon bacillus (C83-1), white dysentery Salmonellas (C79-6), streptococcus aureus (84184), klebsiella and erysipelothrix ruhsiopathiae, provide by China Veterinary Drugs Supervisory Inst..
1.3 test method
1.3.1 test liquid preparation and accurately take 3-methyl-No. 1, (P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) and No. 3 each 75mg of 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone), add respectively 5mL dioxane and methyl-sulphoxide, heating for dissolving, respectively add again 25mL meat soup, make the content of two kinds of liquids be 215mg/mL.Above-mentioned liquid is become to 1250100,625100 with meat soup two-fold dilution, 312150,156120,78110,39100,19150 and the liquid substratum of 9175Lg/mL.Control group take 1250100 and the contained organic solvent of 78110Lg/mL concentration liquid as benchmark, measure the bacteriostatic action of organic solvent, to get rid of the interference of organic solvent in thinner.The contrast of wherein 3-methyl-No. 1, (P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone)
for 1125mL dioxane+13175mL meat soup (the dioxane content in 1250100Lg/mL liquid), contrast
for 0108mL dioxane+14192mL meat soup (with dioxane content in 78110mg/mL liquid); The contrast of 3-methyl-No. 3, (P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone)
for 1125mL methyl-sulphoxide+13175mL meat soup, contrast
for 0108mL methyl-sulphoxide+14192mL meat soup.Olaquindox liquid dilutes with meat soup, does not add organic solvent, does not establish contrast.Control group is not all containing any medicine.
1.3.2 the preparation of bacterium liquid is selected single bacterium colony from standard bacterium test tube slant, is inoculated in 2mL broth culture, and 37e cultivates 24h, makes 10-3 dilute with meat soup.
1.3.3 minimal inhibitory concentration is measured 3-methyl-No. 1, (P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) and No. 3 and the contrast of getting different concns
in test tube (each bacterial strain needs a set of above liquid test tube), every pipe adds corresponding bacterium liquid 0102mL with the each 2mL of olaquindox liquid substratum, observations after 37e cultivation 24h.
2 results and discussion
3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) and the extracorporeal bacteria inhibitor test of olaquindox the results are shown in Table 5.
Table 53-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) and olaquindox extracorporeal bacteria inhibitor test
As can be seen from Table 5,3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) has stronger restraining effect to white dysentery Salmonellas, and minimal inhibitory concentration is 9175Lg/ mL; And olaquindox is low to the bacteriostatic activity of white dysentery Salmonellas, minimal inhibitory concentration is greater than 1250100Lg/mL.3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) is to the fungistatic effect of colon bacillus apparently higher than olaquindox, and minimal inhibitory concentration is 9175Lg/mL.3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) is slightly better than olaquindox to the fungistatic effect of Pseudomonas aeruginosa.
3 brief summaries
This test-results shows, 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) has stronger bacteriostatic action to colon bacillus, white dysentery Salmonellas, and these two kinds of common pathogens that bacterium is livestock and poultry alimentary tract, therefore take 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) as fodder additives, the preventive effect of colibacillosis and white dysentery is better than to olaquindox.
Embodiment 4:
The broiler chicken acute toxicity test of feeding of 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone)
3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) is the novel antibacterial fodder additives of Hebei Mei He pharmaceutcal corporation, Ltd development, is the substituent derivative of different side-chain structure configurations of quinoline mouth evil quinoline compounds.It is compared with similar drugs olaquindox, has both kept quinoline mouth to dislike the biological activity of quinoline compounds, has reduced again toxicity, is a kind of high-efficiency low-toxicity chemical feed additive.3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) is 9000m g/kg to mouse LD50, intestinal bacteria, Salmonellas etc. are had to obvious bacteriostatic action, to the preventive effect of the white scour of chicken, yellow scour of piglet higher than olaquindox 15%～20%, in feed, add 150mg/kg the growth rate of weanling pig is improved to 13%, feed conversion rate improves 5%～8%, and histopathologic examination shows no obvious abnormalities.Through verification, find no the report of 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) similar structures, belong to structure innovation.For this reason, be necessary to inquire into the acute toxicity of 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) to chick, for its widespread use aborning provides scientific basis.
1 materials and methods
1.1 for reagent product
3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) (development of Lanzhou Livestock and Animal Drug Inst., Chinese Academy of Agricultural Science's Animal nutrition chamber) purity is more than 98%, yellow powder, water insoluble, be dissolved in methyl-sulphoxide and dioxane organic solvent.Xylo-Mucine is analytical pure.
1.2 experimental animals and test method
3 age in days Ai Wei mattress chicks for meat 150 plumages of selecting the honest chicken house in Hebei to provide, duration of test is not thrown clothes and is injected other any microbiotic.LD50,95% fiducial limit are measured all with simplifying karber's method.Show that by trial test between test dose, common ratio progression is r=1.3.60 test chickens are supported to 20 ages in days, be divided at random 6 groups, 10 every group.1 group is control group, and every plumage only takes 1% Xylo-Mucine suspension liquid 2ml; 2～6 groups is various dose test group, each group 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) gavages dosage and is respectively every kg body weight 3000mg, 3900mg, 5000mg, 6600mg, 8600mg, gavages with the Xylo-Mucine suspension liquid of 10%3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone).Low dose of gavaging for 1 time, heavy dose of point gavages for 2 times, the about 30min of every minor tick.
1.3 clinical observation
After perfusion, carry out 5 clinical observations every day, records food consumption, water uptake, clinical symptom and death condition.
1.4 pathologic finding
Dead chicken is carried out to the ptomatopsia of system.After test 7d, the chicken sacrificed by exsanguination of surviving, cuts open inspection one by one.When being expert at ptomatopsia, gather the organs such as the heart, liver, spleen, lung, kidney, duodenum, glandular stomach, muscular stomach, the fabricius bursa, fix by 10% neutral formalin, paraffin embedding, HE dyeing, cuts into slices (5～6Lm), light microscopy checking.
2 results
2.1 clinical symptom
This test do not occur clinical symptom except 1～2 group, and 3～4 groups occur respectively symptom after perfusion 48h, within the 3rd day, start dead; 5 groups there is symptom after perfusion 24h, within the 2nd day, start dead; 6 groups there is symptom and occur dead in 24h.Initial stage spirit is depressed, drowsiness, anorexia, extends in time, and sick chicken lies prostrate, and drinking-water appetite is absolutely useless, final exhaustion death.From occurring that symptom is 16h to dead maximum duration.
2.2 pathology change
Survival chicken is cutd open the each organ of inspection and shows no obvious abnormalities after putting to death.Be poisoned to death in chicken stomach and have a small amount of liquor residue, mucous hyperemia,
Liver enlargement, edge rust, there are khaki color and garnet patch, tangent plane unfairness in surface; Gall-bladder enlargement, bile is full; In muscular stomach, glandular stomach, there is Huang
Look pasty medicament, two stomaches are knot place hyperemia, hemorrhage mutually, increases with dosage, and hemorrhage more serious, muscular stomach stratum corneum is easily peeled off, and under severe patient stratum corneum, has
Blood point; Enteron aisle inanition, duodenal wall hyperemia, intestinal mucosa comes off on a small quantity, has a little yellow mucus in enteric cavity, and indivedual chicken caecums and colonic have secretly
Yellow and brown ight soil; Heart is enlargement slightly, ventricle hematocele, coronary sulcus hyperemia; Spleen enlargement, tangent plane is outstanding, unfairness; Ureter has urate full; The organs such as lungs, spleen, the fabricius bursa are showed no considerable change histopathologic examination and show, low dose group has no considerable change with the each organ-tissue of blank group.The each organ-tissue of the chicken that is poisoned to death has variation in various degree; Alveolus wall hyperemia, hemorrhage, is full of red corpuscle in bronchiole; Liver cell has cloudy swelling in various degree; increase with dosage; hepatic cords is unclear; sinus hepaticus gap diminishes, disappears or obviously broadening; the course of disease is compared with elder; under tunicle, there is hyporrhea, being dispersed in property intiltration of acidophilic leukocyte in sinus hepaticus gap, poisoning myofiber distortion when serious, dyeing are uneven, the visible intiltration of acidophilic leukocyte of interstitial; Glandular stomach, muscular stomach and duodenum cell all have granular degeneration in various degree; Glandular stomach mucomembranous epithelial cell has obvious sex change, muscular stomach mucous epithelium and mucous membrane hypodermal layer cytopathy; Small dose group spleen is without considerable change, and heavy dose of group germinal center is not obvious, and red pulp, white pulp boundary are unclear; Renal cells is granular degeneration and vacuolar degeneration in various degree, and renal glomerulus changes not obvious; The fabricius bursa has no significant change in each test group, but the long middle dosage group visible cell vacuolar degeneration of the course of disease, between cortex and medullary substance, interstitial proliferation is obvious.
The calculating (simplification karber's method) of 2.3LD50
Acute experiment data are in table 6.Data substitution is simplified to karber's method formula, and calculating 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) LD50 is 4949.94mg/kg, and 95% credibility interval is 5553.67～4411.84mg/kg.
3 discuss
Table 6 broiler chicks gavages 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) the acute toxicity tests
This research shows, 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) is oral to 20 age in days Ai Wei mattress broiler chicks, LD50 is 4949.94 (mg/kg), and 95% fiducial interval is 5553.67～4411.84m g/kg.Show to blue (1996) research, olaquindox Ai Wei mattress broiler chicks is oral, and LD50 is 208.4mg/kg.Dong's drench ripple (1993) is measured Shiqiza olaquindox for oral administration, and LD50 is 304.9mg/kg, and under comparing, 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide (water-soluble Quinocetone) toxicity is extremely low.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, although the present invention is had been described in detail with reference to previous embodiment, for a person skilled in the art, its technical scheme that still can record aforementioned each embodiment is modified, or part technical characterictic is wherein equal to replacement.Within the spirit and principles in the present invention all, any modification of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (8)
1.3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide, its structural formula is as follows:
2. the preparation method of 3-methyl according to claim 1-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide, it is characterized in that: first adopt o-Nitraniline as raw material, obtain after benzofuraxan by oxidative cyclization, react and obtain mequindox by Beirut with methyl ethyl diketone, then generate 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide with adjacent phenyl aldehyde sodium sulfonate aldol condensation condensation.
3. the preparation method of 3-methyl according to claim 2-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide, it is characterized in that: described mequindox and the condensation reaction of adjacent phenyl aldehyde sodium sulfonate aldol, adopt diethylamine as catalysis alkali, ethanol is as reaction solvent.
4. according to the preparation method of the 3-methyl described in 3 of claim-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide, it is characterized in that: the mol ratio of mequindox and diethylamine is 1:2.
5. according to the preparation method of the 3-methyl described in 2 of claim-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide, it is characterized in that: described mequindox and adjacent phenyl aldehyde sodium sulfonate aldol setting-up point 20-35 ℃, the reaction times is 2-4 hour.
6. according to the preparation method of the 3-methyl described in claim 2-5 any one-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide, it is characterized in that: concrete operation step is as follows:
1) benzofuraxan is synthetic
O-Nitraniline is dissolved in methanol solution, adds NaOH, is stirred to completely and dissolves, the NaClO solution that slowly drips 1mol/L under ice-water bath, add about half an hour, and room temperature continues to stir 2h, TLC follows the tracks of detection, constantly has light yellow solid to separate out, and adds water, suction filtration goes out solid, and washing and drying obtains orange-yellow crude product, 70% ethyl alcohol recrystallization, obtain yellow plate crystal, i.e. benzofuraxan
Wherein, the NaClO of described o-Nitraniline: NaOH:1mol/L is 40g:21g:250mL;
2) mequindox is synthetic
The benzofuraxan that step 1) is obtained, adds excessive methyl ethyl diketone, and water-bath is warmed to molten, under jolting, add triethylamine, more warm 1-10 minute, cooling under room temperature, place, crystallization gradually, separates out a large amount of yellow crystals after 10 hours, suction filtration, collects crystallization, after the dry bath of washing, use dehydrated alcohol recrystallization, obtain aureus needle crystal, i.e. mequindox
Wherein, described benzofuraxan: methyl ethyl diketone: triethylamine is 10g:18g:40mL;
3) synthesizing of end product 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide
By step 2) mequindox of gained is dissolved in ethanol, add adjacent phenyl aldehyde sodium sulfonate, after stirring, control temperature is 20-35 ℃, slowly add diethylamine, constant temperature stirs 3 hours, after reaction finishes, is extracted with ethyl acetate, filter, with washing with acetone, after oven dry, obtain 3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide
Wherein, described acetyl second quinoline: adjacent phenyl aldehyde sodium sulfonate: the mol ratio of diethylamine is 1:1:2.
7.3-methyl-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide, as the application method in the antibacterial growth promotion medicine of preparation, is characterized in that: the aqueous solution that adopts 50mg/kg.
8. 3-methyl according to claim 7-(P-phenylbenzimidazole sulfonic acid sodium)-2-propenyl quinoxaline dinitrogen oxide, as the application method in the antibacterial growth promotion medicine of preparation, is characterized in that: as the medicine of the preparation antagonism medicine of colibacillosis and the prevention of white dysentery.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105153050A (en) * | 2015-10-21 | 2015-12-16 | 莱阳市盛华科技有限公司 | Quinocetone derivative and preparation method thereof |
| CN106749051A (en) * | 2016-11-11 | 2017-05-31 | 山东济肽生物科技有限公司 | Water-soluble quinocetone preparation method |
| CN110317178A (en) * | 2019-07-22 | 2019-10-11 | 浙江科泓企业管理咨询有限公司 | A kind of mequindox novel method for synthesizing |
-
2013
- 2013-12-13 CN CN201310683202.6A patent/CN103787994A/en active Pending
Non-Patent Citations (4)
| Title |
|---|
| 张道凌: "喹喔啉类化合物的合成及构效关系研究", 《2008年中国农业科学院硕士学位论文》 * |
| 张铎: "喹烯酮磺酸盐的合成及其生物活性、毒理学研究", 《2013年兰州理工大学硕士学位论文》 * |
| 张铎等: "喹烯酮磺酸盐的制备及生物活性研究", 《中兽医医药杂志》 * |
| 梁剑平等: "新型饲料添加剂喹羟酮对肉鸡生产性能和蛋白质代谢的影响", 《中国兽医科技》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105153050A (en) * | 2015-10-21 | 2015-12-16 | 莱阳市盛华科技有限公司 | Quinocetone derivative and preparation method thereof |
| CN106749051A (en) * | 2016-11-11 | 2017-05-31 | 山东济肽生物科技有限公司 | Water-soluble quinocetone preparation method |
| CN110317178A (en) * | 2019-07-22 | 2019-10-11 | 浙江科泓企业管理咨询有限公司 | A kind of mequindox novel method for synthesizing |
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