CN106727576A - Quinoxaline -1,4- dioxide derivatives as colistine sulfate synergist application - Google Patents
Quinoxaline -1,4- dioxide derivatives as colistine sulfate synergist application Download PDFInfo
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Abstract
The invention discloses quinoxaline -1,4- dioxide derivatives as colistine sulfate synergist application.Quinoxaline -1,4- dioxide derivatives are used as colistine sulfate synergetic effect additive, and the compound is combined into a kind for the treatment of method of animal bacterial infection diarrhoea for the treatment of offer for Animal diseases with colistine sulfate.The colistine sulfate synergetic effect additive that the present invention is provided can significantly improve the therapeutic effect of colistine sulfate, it is new, efficient and the non-antibiotic class colistine sulfate synergetic effect additive of safety, it is suitable for the disease prevention and cure of animal-breeding, improves the economic benefit of aquaculture.
Description
Technical field
The invention belongs to livestock and poultry drug field, and in particular to quinoxaline -1,4- dioxide derivatives glue bar as sulfuric acid
The application of rhzomorph synergist and the treatment and prevention medicine of animal bacterial infection diarrhoea.
Background technology
Colistin is produced by poly-viscosity bacillus, there is stronger antibacterial action to Gram-negative bacteria.Colistine sulfate
Sensitive flora has Pseudomonas aeruginosa, Escherichia coli, Enterobacter, Klebsiella, Salmonella, Shigella, Bath
Moral Salmonella and vibrios etc., can be used to treating the intestines problem that causes of Gram-negative bacteria and be used as feed addictive have it is obvious
Growth promoting function, is widely used in being used as feed addictive in feed industry, prevents livestock and poultry, improves the new old of livestock and poultry
Metabolism improves survival rate and feed conversion rate.Colistine sulfate can play drug effect enhancing with the reasonable compatibility of other antibiotic
Effect than be used alone colistine sulfate can more play disease-resistant growth-promoting effect, conventional compatibility reagent have Bacitracin Zinc,
The antibiotic such as kitasamycin, flavomycoin.However, because these antibiotic toxicity in itself and use in conjunction cause antibody-resistant bacterium
Generation, some species gradually European Union etc. area be phased out.Therefore, in order to effectively improve the health status of livestock and poultry with
And the speed of growth, improve food conversion ratio so as to improve the economic benefit of raising, develop the viscous bar of new, safe and effective sulfuric acid
Rhzomorph compatibility reagent is the key factor for improving colistine sulfate in the using effect of livestock and poultry breeding industry.
The content of the invention
It is an object of the invention to provide new, the safe and effective colistine sulfate synergetic effect additive of one kind, replacement has
Conventional compatibility antibiotic Bacitracin Zinc, kitasamycin, flavomycoin of certain toxicity and initiation antibody-resistant bacterium etc. and sulfuric acid Bacillus adhaerens
Plain compatibility is applied to the preventing and treating of livestock and poultry, that is, provide quinoxaline -1, and 4- dioxide derivatives increase as colistine sulfate
Imitate the application of agent.
Colistine sulfate has antibacterial or bactericidal action to Gram-negative bacteria, is treating or is controlling animal by bacterium sense
Diarrhoea aspect caused by dye has good effect, be difficult to be absorbed in alimentary canal, drain rapidly, and compatibility synergetic effect additive makes
With the usage amount that will reduce colistine sulfate so as to reduce burden and pollution on the environment to livestock and poultry alimentary tract.
The colistine sulfate synergetic effect additive Shi quinoxaline -1s that the present invention is provided, 4- dioxide derivatives.
United States Patent (USP) US3344022,3371090,3344022,3644360,4128642,4100284,4303657,
4317824th, the patents such as 4343942,4684649 disclose a series of quinoxaline -1, and 4- dioxide derivatives are used as animal
Medicine for treatment and growth promoter.Part quinoxaline derivative is used for animal-breeding in the U.S. and Discussion on Chinese Listed, but exists
General toxicity or three causing toxicity and activity problems.
Inventor once disclosed a kind of to livestock and poultry in patent CN103145631A (China, the applying date 2013 year 03 month 18)
Low toxicity is nontoxic with stronger antibacterial activity quinoxaline -1s, 4- dioxide derivatives, treatment for Animal diseases and anti-
Control and be used to promote growth of animal as feed addictive.Understood described in antibacterial experiment in vitro from the test data of patent
Quinoxaline -1, the derivative of 4- dioxide derivatives is to Escherichia coli, salmonella without antibacterial ability to golden yellow
Staphylococcus and C.perfringens have very strong inhibitory action.
Therefore, this numb offer quinoxaline -1,4- dioxide derivatives or its cis-trans-isomer or its pharmaceutically may be used
The salt and its solvate of receiving as colistine sulfate synergetic effect additive application, the quinoxaline -1s, 4- titanium dioxides
Shown in the structure of thing derivative such as formula (I)：
Wherein,
R1-R5It is H, OH, NO2、O-CH3、C1-6Straight or branched alkane, Ph, CH2- Ph or halogen；
R6And R7It is H, halogen or-O-CH3；
Described halogen is F, Cl, Br or I；
Described CH2Phenyl in-Ph and Ph refers to not by the phenyl ring of any substitution base substitution.
In another embodiment, the quinoxaline -1s, 4- dioxide derivatives preferably its structural formula such as formula (II)
It is shown：
Inventor has investigated the quinoxaline -1s, 4- titanium dioxides in antibacterial tests by test tube doubling dilution in vitro
Colistine sulfate is to the minimal inhibitory concentration of Gram-negative bacteria, quinoxaline -1s, 4- dioxide in the presence of thing derivative
Colistine sulfate enhances 2-4 to the Gram-negative bacteria bacteriostasis of sensitiveness or drug resistance in the presence of the collaboration of derivative
Times.Described Gram-negative bacteria includes Escherichia coli, salmonella, Pseudomonas aeruginosa, Shigella, Klebsiella, Bath
Moral Salmonella, proteus, brucella, Serratieae etc..
, quinoxaline -1s as can be seen here, 4- dioxide derivatives have association to the vitro antibacterial activity of colistine sulfate
With the ability of synergy, minimal inhibitory concentration of the colistine sulfate to Gram-negative bacteria is reduced, can be used as colistine sulfate
In the synergetic effect additive of antibiosis service efficiency is improved so as to reduce the dosage of colistine sulfate.
Colistine sulfate is applied in feed processing industry as feed addictive, can not only prevent and treat livestock and poultry, and
The metabolism of livestock and poultry can be improved, survival rate and feed conversion rate is improved, promote the growth of livestock and poultry.Diarrhoea be in livestock and poultry most
For common, often caused by bacterium infection, colistine sulfate has in terms of control livestock and poultry are because of the diarrhoea caused by bacterium infection
There is good curative effect to come from itself to the antibacterial or sterilizing ability of flora so as to improve animal and bird intestines flora environment.
In the in vivo studies scheme of animal, different quinoxaline -1s, 4- dioxide derivatives and colistine sulfate
Use in conjunction in weanling pig, broiler chicken and boiler duck feeding, by feeding mode to the diarrhea rate of piglet, broiler chicken and meat duck,
Weightening and the price of deed are studied, and as a result show significantly to control the effect of animal diarrhea.
It is preferred that, the quinoxaline -1s, 4- dioxide derivatives as colistine sulfate synergetic effect additive application
It is the medicine for preparing sulfuric-resisting colistin sensitive bacteria or drug-fast bacteria.
It is preferred that, the quinoxaline -1s, 4- dioxide derivatives as colistine sulfate synergetic effect additive application
It is for preparing animal feed additive.Further preferably, described animal feed additive is animal growth promoting agent.
The quinoxaline -1s, 4- dioxide derivatives and colistine sulfate are that form gives treatment of animals by oral administration
The colistine sulfate of dosage or preventive dose is He quinoxaline -1,4- dioxide derivatives.
Described oral form is with clothes with the oral tank clothes of peroral dosage form or through feed.
Described peroral dosage form include tablet, capsule, powder, powder agent, supensoid agent, emulsion, solution, granule,
Pre-mixing agent etc..
Described quinoxaline -1,4- dioxide derivatives can be united and applied in control with separate dosage forms and colistine sulfate
Braking thing diarrhea disease.
The quinoxaline -1s, 4- dioxide derivatives can combine with colistine sulfate and be prepared into combined dosage form application
In control animal diarrhea disease.
Described animal includes poultry and livestock, particularly the chicken of each growth phase, duck, goose, dove or quail and each
The pig of individual growth phase, ox, sheep, horse, rabbit, donkey, deer, dog, cat, fox, ermine or racoon dog.
Described therapeutic dose can be effectively control the animal state of an illness and cure diseases but do not cause influence animal safety
Required dosage.
Described preventive dose is to maintain animal to be enough to resist the normal life shape of paathogenic factor holding in growth course
Dosage needed for state.
Described quinoxaline -1, the therapeutic dose or preventive dose of 4- dioxide derivatives press animal body metering for 1-
500mg/kg, preferably 10-300mg/kg.
Any embodiment of either side of the invention can be combined with other embodiments, as long as between them
Occur without contradiction.Additionally, in any embodiment of either side of the present invention, any technical characteristic goes for other realities
The technical characteristic in scheme is applied, as long as between them being not in contradiction.
As can be seen here, the present invention provides quinoxaline -1s, and 4- dioxide can glue bar as the sulfuric acid of new effective and safe
Rhzomorph synergetic effect additive is used for the treatment of Animal diseases.
Specific embodiment：
Following examples are further illustrated to of the invention, rather than limitation of the present invention.
Following examples are related to quinoxaline -1s, and 4- dioxide is as shown in table 1
The quinoxaline -1 of table 1,4- dioxide derivatives
Embodiment 1：Quinoxaline -1, the preparation of 4- dioxide derivatives
Quinoxaline -1,4- dioxide derivatives, shown in its structural formula such as formula (I)：
Wherein, R1-R5It is H, OH, NO2、O-CH3、C1-6Straight or branched alkane, Ph, CH2- Ph or halogen；R6And R7For
H, halogen or O-CH3。
Described halogen is F, Cl, Br or I；
Described CH2Phenyl in-Ph and Ph refers to not by the phenyl ring of any substitution base substitution.
Above-mentioned quinoxaline -1, preparation method and CN103145631A (China, the patent No. of 4- dioxide derivatives
ZL201310087021.7, the applying date 2013 year 03 month 18) disclosed in it is consistent, therefore may be referred to the patent and prepare quinoline
Evil quinolines-Isosorbide-5-Nitrae-dioxide derivative.The reaction mechanism mechanism of reaction is probably as follows：With 2- acetyl group -3- Jia based quinoxalines-Isosorbide-5-Nitrae-dioxide
Derivative is that initiation material reacts by alkali of NaOH in ice bath in methyl alcohol with benzaldehyde derivative, TLC monitoring reactions
To terminal, with filter operation as post-processing approach, 300 mesh silica gel column chromatographies carry out the positive and negative separation of product.
The preparation of compound 003002：
Take NaOH (0.6g, 15mmol, 1eq) and 100mL methyl alcohol is added in the eggplant-shape bottle of 250mL, ice bath cooling
To 0 DEG C.2- acetyl group -3- Jia based quinoxalines-Isosorbide-5-Nitrae-dioxide (3.27g, 15mmol, 1eq) is added thereto, while keeping molten
At 0 DEG C, stirring has solid to analyse in 10~15 minutes to the temperature of liquid under adding 3- fluorobenzaldehyde (2.23g, 18mmol, 1.2eq) ice bath
Go out and TLC display raw material 2- acetyl group -3- Jia based quinoxaline-Isosorbide-5-Nitraes-dioxide reactions are complete.Filtering, filter cake methyl alcohol
(100mL × 3) wash, and obtain the solid of yellow, are spin-dried for solvent and obtain product 2- (3- (3- fluorobenzene) acryloyl group) -3- Jia Ji Kui Evil
Quinoline-Isosorbide-5-Nitrae-dioxide.
Cis-trans-isomer split process：TLC (DCM 100%) shows three points, and product dissolubility in DCM compares
It is good, take 5g product silica gel column chromatography separation (300 mesh silica gel) DCM:MeOH=100:1~10:1 obtains yellow fluffy solid,
(E) -2- (3- (3- fluorophenyls) acryloyl group) -3- Jia based quinoxaline-Isosorbide-5-Nitrae-dioxide 4.5g, yield 90%.
1H(400MHz,CDCl3)δ(ppm):8.7(1H,d),8.57(1H,d),7.86(2H,m),7.58(1H,d),7.37
(2H,m),7.29(1H,m),7.15(2H,m),2.57(3H,s).
1H(400MHz,DMSO-d6)δ(ppm):8.5 (1H, d, Ar-H, J=9.6Hz), 8.4 (1H, d, Ar-H, J=
9.2Hz), 7.99 (2H, m), 7.8 (1H, d, J=16.4Hz), 7.64 (1H, d, Ar-H, J=10Hz), 7.57 (1H, d, Ar-H,
J=8Hz), 7.48 (1H, m), 7.3 (2H, m), 2.35 (3H, s)
The preparation of compound 15042：
Take NaOH (0.6g, 15mmol, 1eq) and 100mL methyl alcohol is added in the eggplant-shape bottle of 250mL, ice bath cooling
To 0 DEG C.2- acetyl group -3- Jia based quinoxalines-Isosorbide-5-Nitrae-dioxide (3.27g, 15mmol, 1eq) is added thereto, while keeping molten
At 0 DEG C, stirring has solid to analyse in 10~15 minutes to the temperature of liquid under tolualdehyde (2.16g, 18mmol, 1.2eq) ice bath between addition
Go out and TLC display raw material 2- acetyl group -3- Jia based quinoxaline-Isosorbide-5-Nitraes-dioxide reactions are complete.Filtering, filter cake methyl alcohol
(100mL × 3) wash, and obtain the solid of yellow, are spin-dried for solvent and obtain product 2- methyl -3- (tolyl acryloyl group) Kui Evil between 3-
Quinoline-Isosorbide-5-Nitrae-dioxide.
Cis-trans-isomer split process such as compound 003002.
1H(400MHz,CDCl3)δ(ppm):8.65(1H,d),8.58(1H,d),7.89(2H,m),7.55(1H,d),
7.37(2H,d),7.27(2H,m),7.1(1H,d),2.56(3H,s),2.35(3H,s).
1H(400MHz,DMSO-d6)δ(ppm):8.65 (1H, d), 8.58 (1H, d), 7.99 (2H, m), 7.8 (1H, d, J=
16.4Hz), 7.55 (2H, s), 7.27 (2H, m), 7.1 (1H, d, J=16.4Hz), 2.36 (3H, s), 2.29 (3H, s)
The preparation of compound 15052：
Take nafoxidine (1g, 15mmol, 1eq) and 100mL dichloromethane is added in the eggplant-shape bottle of 250mL, ice bath drop
Temperature is to 0 DEG C.2- acetyl group -3- Jia based quinoxalines-Isosorbide-5-Nitrae-dioxide (3.27g, 15mmol, 1eq) is added thereto, while keeping
The temperature of solution is stirred 20 minutes, TLC at 0 DEG C under addition 3- trifluoromethylated benzaldehyde (3.13g, 18mmol, 1.2eq) ice bath
The dioxide reaction of display raw material 2- acetyl group -3- Jia based quinoxaline-Isosorbide-5-Nitraes-is complete.Add about 100mL water, extracting and demixing, rotation
Dry organic phase, being subsequently adding methyl alcohol has solid to separate out, and filtering, filter cake is washed with methyl alcohol (100mL × 3), obtains the solid of yellow,
It is spin-dried for solvent and obtains product 2- methyl -3- (3- (3- (trifluoromethyl) phenyl) acryloyl group) quinoxaline -1s, 4- dioxide.
Cis-trans-isomer split process such as compound 003002.
1H(400MHz,DMSO-d6)δ(ppm):8.56(1H,d),8.4(1H,d),8.1(1H,d),8.0(4H,m),7.8
(1H,d),7.6(1H,m),7.4(1H,d),2.5(3H,s).
Embodiment 2：Quinoxaline -1,4- dioxide derivatives are to colistine sulfate sensitivity Escherichia coli inhibitory activity
Synergistic function.
Colistine sulfate is tested He quinoxaline -1,4- dioxide derivatives are to large intestine bar using test tube doubling dilution
The external MIC (MIC) of bacterium (sensitive to colistine sulfate, MIC value is less than 4.0ppm), while test is in culture
Nutrient solution in respectively contain 50.0ppm quinoxaline -1s, colistine sulfate is to corresponding bacterial strain during 4- dioxide derivatives
(it is Yi quinoxaline -1s to external MIC, and 4- dioxide derivatives and colistine sulfate combination are used as test medicine
Thing, , quinoxaline -1s during test, the concentration of 4- dioxide derivatives is fixed as 50.0ppm, and colistine sulfate carries out gradient
Dilution, the purpose is to test containing 50.0ppm quinoxaline -1s, colistine sulfate is to corresponding bacterium during 4- dioxide derivatives
The external MIC of strain), as a result as shown in table 2.From table 2 it can be seen that all test strains are to colistine sulfate
Sensitive and all experiment quinoxaline -1s, 4- dioxide derivatives are to test strain unrestraint activity.And contain 50.0ppm quinolines
The test group colistine sulfate of Evil quinolines-Isosorbide-5-Nitrae-dioxide derivative has difference to the MIC of corresponding test strain
The reduction of degree, about 2-4 times (table 3).
The quinoxaline -1 of table 2,4- dioxide derivatives suppress to the external minimum of colistine sulfate sensitivity Escherichia coli
Concentration (MIC, ppm)
The quinoxaline -1 of table 3, colistine sulfate is to colistine sulfate sensitivity large intestine in the presence of 4- dioxide derivatives
The external MIC (MIC, ppm) of bacillus
The quinoxaline -1 of embodiment 3,4- dioxide derivatives are to colistine sulfate antibiotic-resistance E. coli inhibitory activity
Synergistic function.
Colistine sulfate is tested He quinoxaline -1 using test tube doubling dilution, and 4- dioxide derivatives are viscous to sulfuric acid
The external MIC of bacillin antibiotic-resistance E. coli (to colistine sulfate resistance, MIC value is more than 4.0ppm)
(MIC), while test contains 50.0ppm quinoxaline -1s, sulfuric acid during 4- dioxide derivatives respectively in culture in nutrient solution
External MIC of the colistin to corresponding bacterial strain.Result shows that all test strains are to colistine sulfate resistance
And all experiment quinoxaline -1s, 4- dioxide derivatives are to antibiotic-resistance E. coli unrestraint activity (table 4)；And containing
50.0ppm quinoxaline -1s, the test group colistine sulfate of 4- dioxide derivatives suppresses to the minimum of corresponding test strain
Concentration has different degrees of reduction, reduces 50-100 times (table 5).
The different quinoxaline -1s of table 4, external minimum of the 4- dioxide derivatives to colistine sulfate antibiotic-resistance E. coli
Inhibition concentration (MIC, ppm)
The quinoxaline -1 of table 5, colistine sulfate is to colistine sulfate resistance large intestine in the presence of 4- dioxide derivatives
The external MIC (MIC, ppm) of bacillus
The various concentrations compound 003042 of embodiment 4 is inverse to the drug resistance of different types of colistine sulfate antibody-resistant bacterium
Transfer to use.
Colistine sulfate and compound 003042 are tested to variety classes sulfuric acid Bacillus adhaerens using test tube doubling dilution
The external MIC of the gramnegative bacterium (to colistine sulfate resistance, MIC value is more than 4.0ppm) of plain resistance,
Test simultaneously in culture respectively containing various concentrations compound 003042 when colistine sulfate to corresponding bacterial strain it is external most
Small inhibition concentration.Result shows that all test strains are to the equal resistance of colistine sulfate；The all test bacterium of compound 003042 pair
Strain unrestraint activity；And the test group colistine sulfate containing compound 003042 is equal to the MIC of corresponding bacterial strain
There is different degrees of reduction, in obvious dosage effect (table 6).
External minimum suppression of the colistine sulfate to variety classes bacterium in the presence of the various concentrations compound 003042 of table 6
Concentration (MIC, ppm) processed
The quinoxaline -1 of example example 5, cooperateing with weaning pigs should with colistine sulfate for 4- dioxide derivatives
Use effect.
The close miscellaneous lean meat species weanling pig of DLY ternary of 150 first 28 age in days body weight is divided into 15 groups, every group 10.Each group
Colistine sulfate and/or different types of quinoxaline -1 are added in the creep feed without antibiotic, 4- dioxide derives
Free choice feeding and drinking-water during thing, experiment, count the weightening of each test group test pig, the price of deed and diarrhea rate in 10 days.Knot
Fruit display (table 7), colistine sulfate is only added in weaning pigs can not effectively reduce the diarrhea rate of test pig, to weightening
Had no with the price of deed and be obviously improved；And quinoxaline -1 is added simultaneously, the survey of 4- dioxide derivatives and colistine sulfate
Examination group can in various degree reduce the diarrhea rate of test group and production performance is improved in varying degrees.
The quinoxaline -1 of table 7, the synergistic application effect of 4- dioxide derivatives and colistine sulfate in weaning pigs
Really
The effect of the compound 003042 of embodiment 6 and the colistine sulfate synergistic application in weaning pigs.
12 groups, every group 10 of the close miscellaneous lean meat species weanling pig of DLY ternary of 120 first 28 age in days body weight point.Each group exists
Colistine sulfate and/or compound 003042 are added in creep feed without antibiotic.Free choice feeding and drinking-water during experiment,
Count the weightening of each test group test pig, the price of deed and diarrhea rate in 10 days.Result is only added in being displayed in weaning pigs
Colistine sulfate or compound 003042 can not effectively reduce the diarrhea rate of test pig, have no bright to weightening and the price of deed
It is aobvious to improve；And the test group (group 10,11 and 12) for adding colistine sulfate and compound 003042 can reduce diarrhea rate, averagely
Daily gain and the price of deed are significantly improved (table 8).
The application effect of the compound 003042 of table 8 and colistine sulfate in weaning pigs
The treatment examination of the various dose compound 003042 of embodiment 7 and colistine sulfate to swine escherichia coli artificial challenge
Test effect.
The close miscellaneous lean meat species weanling pig of DLY ternary such as 6 groups of the table 9 point of 60 first 28 age in days body weight, every group 10, respectively
Group adds the compound 003042 of colistine sulfate and/or various dose in the creep feed without antibiotic, during experiment
Free choice feeding and drinking-water.33 age in days administered by oral gavage enteropathogenic E. Colis, the diarrhoea and death condition of viewing test pig are continuous to see
Examine one week, count each test group test pig morbidity and death condition, compare various dose quinoxaline -1s, 4- dioxide derives
Thing 003042 is with colistine sulfate to enteropathogenic E. Coli artificial challenge property protecting effect.Wherein, the 1st group is not to be administered to attack
Malicious control group 1, second group be only give colistine sulfate attack malicious control group 2 (colistine sulfate), remaining test group is
Attack the 003042 of colistine sulfate that is malicious and giving fixed dosage and various dose.
The 003042 of the various dose of table 9 is with colistine sulfate to the coordinating protection effect of Escherichia coli challenge infection
Experiment packet
After SGD plants of artificial challenge's enteropathogenic E. Coli, be not administered attack malicious control group (control group 1) all test pigs it is equal
Performance diarrhoea, wherein there is 6 death during testing.All administration groups have different degrees of to Escherichia coli artificial challenge
Protecting effect (table 10).
Coordinating protection effect of 003042 and the colistine sulfate of the various dose of table 10 to Escherichia coli challenge infection
| Group | Test specimen | Test pig (head) | Attack malicious (Yes/No) | The incidence of disease (%, in terms of suffering from diarrhoea) | The death rate (%) |
| 1 | Control group 1 | 10 | It is | 100 | 10 |
| 2 | Colistine sulfate | 10 | It is | 80 | 0 |
| 3 | Colistine sulfate+003042 | 10 | It is | 50 | 0 |
| 4 | Colistine sulfate+003042 | 10 | It is | 0 | 0 |
| 5 | Colistine sulfate+003042 | 10 | It is | 0 | 0 |
| 6 | Colistine sulfate+003042 | 10 | It is | 0 | 0 |
The quinoxaline -1 of embodiment 8, protecting effect of the 4- dioxide derivatives 003042 to chicken colibacillosis challenge infection
120 fast big yellow-feather broiler such as tables 10 of 1 age in days are randomly divided into 6 test groups, orally give challenge infection chicken large intestine
Bacillus 2 × 107CFU/ chickens, administered by oral gavage administration while attacking poison.Wherein first group is for poison not administration group (control group 1) the
Two groups is to attack poison and give colistine sulfate, and other groups are the compound attacked poison and give colistine sulfate and various concentrations
003042, the then morbidity of viewing test chicken and death condition, dead chicken cut open inspection are confirmed whether it is that chicken escherichia coli infection causes
Death, 7 days observation periods.All test chickens are put to death during off-test, cut open inspection confirms incidence.The statistics such as institute of table 10
Show, the display quinoxaline -1 of table 10,4- dioxide derivatives 003042 can protect chicken colibacillosis to the challenge infection of chicken and be in
Dose relationship.
The quinoxaline -1 of table 10, protecting effect of the 4- dioxide derivatives 003042 to chicken colibacillosis challenge infection
Claims (10)
1. quinoxaline -1,4- dioxide derivatives or its cis-trans-isomer or its pharmaceutically acceptable salt and its solvent are closed
Thing as colistine sulfate synergetic effect additive application, the quinoxaline -1s, the structure such as formula of 4- dioxide derivatives
(I) shown in：
Wherein,
R1-R5It is H, OH, NO2、O-CH3、C1-6Straight or branched alkane, Ph, CH2- Ph or halogen；
R6And R7It is H, halogen or-O-CH3；
Described halogen is F, Cl, Br or I；
Described CH2Phenyl in-Ph and Ph refers to not by the phenyl ring of any substitution base substitution.
2. application according to claim 1, it is characterised in that the quinoxaline -1s, 4- dioxide derivatives have
Structure shown in formula (II)：
3. application according to claim 1 and 2, it is characterised in that the quinoxaline -1s, 4- dioxide derivatives are made
For the application of colistine sulfate synergetic effect additive is the medicine for preparing sulfuric-resisting colistin sensitive bacteria or drug-fast bacteria.
4. application according to claim 3, it is characterised in that described sulfuric-resisting colistin sensitive bacteria or drug-fast bacteria
Medicine is the treatment and prevention medicine of animal bacterial infection diarrhoea.
5. application according to claim 1 and 2, it is characterised in that the quinoxaline -1s, 4- dioxide derivatives are made
For the application of colistine sulfate synergetic effect additive is for preparing animal feed additive.
6. application according to claim 5, it is characterised in that described animal feed additive promotes for growth of animal
Agent.
7. application according to claim 5, it is characterised in that the quinoxaline -1,4- dioxide derivatives are with oral
The dosage that form gives animal is 10-300mg/kg body weight.
8. application according to claim 5, it is characterised in that described animal is poultry or livestock.
9. application according to claim 8, it is characterised in that described poultry be the chicken of each growth phase, duck, goose,
Dove or quail.
10. application according to claim 8, it is characterised in that described domestic animal be the pig of each growth phase, ox, sheep,
Horse, rabbit, donkey, deer, dog, cat, fox, ermine or racoon dog.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511023319.7A CN106727576B (en) | 2015-12-29 | 2015-12-29 | Use of quinoxaline-1, 4-dioxide derivatives as potentiators of colistin sulphate |
| PCT/CN2016/077920 WO2017113526A1 (en) | 2015-12-29 | 2016-03-30 | Applications of quinoxaline-1,4-dioxide derivative as colistin sulfate synergist |
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| CN201511023319.7A CN106727576B (en) | 2015-12-29 | 2015-12-29 | Use of quinoxaline-1, 4-dioxide derivatives as potentiators of colistin sulphate |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4100284A (en) * | 1977-01-18 | 1978-07-11 | Pfizer Inc. | 1,4-Dioxo- and 4-oxoquinoxaline-2-carboxaldehyde sulfonylhydrazones and certain derivatives thereof |
| CN1197068A (en) * | 1997-04-21 | 1998-10-28 | 中国农业科学院中兽医研究所 | Compound and synthetic process of 3-methyl-2-phenylethylene keto-quinooxaline-1.4-dioxide |
| CN1409638A (en) * | 1999-12-14 | 2003-04-09 | 旭化成株式会社 | Colistin sulfate granules |
| CN103145631A (en) * | 2013-03-18 | 2013-06-12 | 广州英赛特生物技术有限公司 | Antibacterial derivative of quinoxaline-1,4-dioxide and application in animal production thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4343942A (en) * | 1966-11-08 | 1982-08-10 | Research Corporation | Quinoxaline derivatives |
| JPS60176550A (en) * | 1984-02-22 | 1985-09-10 | Asahi Chem Ind Co Ltd | Feed containing immune protein of blood |
| CN101473900A (en) * | 2008-10-27 | 2009-07-08 | 中谷集团农牧科技有限公司 | Complete compound feed for weaning piglet |
-
2015
- 2015-12-29 CN CN201511023319.7A patent/CN106727576B/en active Active
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2016
- 2016-03-30 WO PCT/CN2016/077920 patent/WO2017113526A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4100284A (en) * | 1977-01-18 | 1978-07-11 | Pfizer Inc. | 1,4-Dioxo- and 4-oxoquinoxaline-2-carboxaldehyde sulfonylhydrazones and certain derivatives thereof |
| CN1197068A (en) * | 1997-04-21 | 1998-10-28 | 中国农业科学院中兽医研究所 | Compound and synthetic process of 3-methyl-2-phenylethylene keto-quinooxaline-1.4-dioxide |
| CN1409638A (en) * | 1999-12-14 | 2003-04-09 | 旭化成株式会社 | Colistin sulfate granules |
| CN103145631A (en) * | 2013-03-18 | 2013-06-12 | 广州英赛特生物技术有限公司 | Antibacterial derivative of quinoxaline-1,4-dioxide and application in animal production thereof |
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| WO2017113526A1 (en) | 2017-07-06 |
| CN106727576B (en) | 2020-08-04 |
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