CN102408413B - Anticoccidial compound, and preparation method and use thereof - Google Patents
Anticoccidial compound, and preparation method and use thereof Download PDFInfo
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Abstract
The invention relates to an anticoccidial compound shown as a formula (I) and a preparation method therefore, wherein R is selected from Me, H or Cbz. The anticoccidial compound provided by the invention can effectively solve the problem of drug resistance of the existing coccidiostat and can exert an important function on the treatment of livestock and poultry, particularly in the aspect of coccidial infection of chicken; furthermore, the main raw materials used in the preparation method are very easy to get on the market and are cheap, further, the technological operation is simple, no risk exists, and meanwhile, the method has the characteristics of low cost, high yield and the like, so that the method is applicable to enlargement and industrial production and has an industrialization value.
Description
Technical field
The present invention relates to field of veterinary, the particularly control of livestock and poultry parasite more specifically, relates to anticoccidial compound and its preparation method and application.
Background technology
Coccidiosis is to cause one of livestock and poultry morbidity main causes of death, can not control coccidiosis effectively and will bring tremendous loss to livestock and poultry breeding industry.From the eighties, livestock and poultry produce very big resistance gradually to existing anticoccidial drug, and it is very urgent that the demand of the broad-spectrum medicinal of new low price becomes.
Coccidiosis is a kind of parasitosis, can cause poultry meat and egg production heavy losses to occur.Parasite in small intestine at double propagation cause tissue injury, reduce nutrient absorbing rate in food consumption and the feed, cause body dehydration and chicken death.Chicken searches for food behind the egg capsule, and coccidia is implantation in enteron aisle, is entrenched between the intestinal cells after several breedings at double damaging tissue.Coccidiosis of chicken is the strongest with the virulence of Eimeria tenella, and this kind coccidia main parasitic is diseases induced in caecum, is commonly called as cecal coccidiosis.Multiple with 21～50 Japanese instar chicklings.Disease just feather is erect, necking down, slow-witted upright, and the later stage, it is heavy that the state of an illness is changeed, and ataxia occurs owing to considerable damage and the body of intestinal epithelial cells are poisoned, and diarrhoea is with symptoms such as blood, the mortality ratio height, even full group is annihilated.
In decades, it mainly is chemicals that the research of the anti-zooparasite medicine of China is used, and mainly based on imitation medicine, for example two clean, the diclazurils of hydrochloric acid awl, three nitrogen amidines, ivermectin, monensin and toltrazuril etc., these medicines all are main product of China's animal parasitosis control at present.But the life-time service of these medicines, cause parasitic resistance easily, therefore having pressed for novel medicament occurs, development need along with animal husbandry and fishery industry and public health security, market will increase new anti-parasite medicine demand, in the world some viral and bacterium causes pathogenetic whiles of infection, parasitosis will be the problem that the next one must draw attention and solve.
Summary of the invention
The purpose of this invention is to provide a kind of novel against-coccidia compound, to treat particularly chickens infected with eimeria of livestock and poultry.
Another object of the present invention provides the method for the described anticoccidial compound of preparation.
The invention provides the anticoccidial compound shown in the following formula (I):
Wherein, R is selected from Me, H or Cbz.
Particularly, described compound is:
1) 2-(4-pyridyl)-3-(4-fluorophenyl)-5-(N-methyl-4-piperidyl) imidazoles;
2) 2-(4-pyridyl)-3-(4-fluorophenyl)-5-(4-piperidyl) imidazoles;
3) 2-(4-pyridyl)-3-(4-fluorophenyl)-5-(N-carbobenzoxy-(Cbz)-4-piperidyl) imidazoles.
The present invention also provides the method for the above-mentioned anticoccidial compound of preparation, comprises the steps:
1) by the synthetic 4-dimethoxy-methyl pyridine of 4-aldehyde radical pyridine with by the synthetic 4-(2-(4-fluorophenyl)-1 that obtains of the synthetic 1-brooethyl of 1-methyl-4-fluorobenzene-4-fluorobenzene reaction, the 1-dimethoxy-ethyl) pyridine, and then synthetic 2-(4-fluorophenyl)-1-(4-pyridyl)-1 oxo ethane that obtains;
2) reaction of the 2-that step 1 is obtained (4-fluorophenyl)-1-(4-pyridyl)-1 oxo ethane and tin anhydride obtains 2-(4-fluorophenyl)-1-(4-pyridyl)-1,2-dioxo ethane, and then synthesize 2-(4-pyridyl)-3-(4-fluorophenyl)-5-(N-carbobenzoxy-(Cbz)-4-piperidyl) imidazoles, 2-(4-pyridyl)-3-(4-fluorophenyl)-5-(4-piperidyl) imidazoles, 2-(4-pyridyl)-3-(4-fluorophenyl)-5-(N-methyl-4-piperidyl) imidazoles.
The synthetic route of anticoccidial compound of the present invention is as follows:
The present invention also provides the medicine that contains above-mentioned anticoccidial compound, for example composition and various pharmaceutical preparation.
The present invention further provides the application in the medicine of above-mentioned anticoccidial compound coccidia in for the preparation of anti-livestock and poultry.
Preferably, described domestic animal is rabbit.
Preferably, described poultry is chicken.
Described livestock and poultry include but not limited to rabbit and chicken, also comprise other fowl poultry kind susceptible animal.
Anticoccidial compound of the present invention and preparation method thereof has following beneficial effect:
1) the invention provides novel anticoccidial drug, can effectively solve the resistance problem of existing anticoccidial drug, particularly can play a significant role aspect the chickens infected with eimeria the treatment livestock and poultry.
2) main raw material that uses of the present invention all is easy to get on market very much, and is inexpensive, and technological operation is simple, does not have danger, and it is low to have cost simultaneously, and characteristics such as yield height are suitable for amplifying, and industrial production has industrial value.
Embodiment
Following examples are used for explanation the present invention, but are not used for limiting the scope of the invention.
All used raw materials of following embodiment are all purchased in domestic, and solvent is purchased in Beijing chemical reagent company.
Embodiment 1
The first step: synthetic 4-dimethoxy-methyl pyridine
Operation:
The 250mL three-necked bottle, the configuration dropping funnel, prolong, (11g 0.1mol) is dissolved in the 100mL methyl alcohol, slowly drips trimethyl orthoformate (30mL), gained mixture heating up backflow 3h with the 4-pyridylaldehyde in the bottle.
Aftertreatment:
Add water 200mL behind the reaction solution evaporate to dryness, use ethyl acetate extraction, organic phase drying, evaporate to dryness.Add a little ether, have solid to separate out, filter, the filtrate evaporate to dryness is product, gets product 11.3g, yield 72%.
1HNMR(CDCl
3)：8.58-8.60(m，2H)，7.36(m，2H)，5.26(d，1H)，3.30(d，6H)。
Second step: synthetic 1-brooethyl-4-fluorobenzene
Operation:
The 250mL three-necked bottle, the configuration dropping funnel, reflux condensing tube, (22g 0.2mol) is dissolved in CCl to compound 8
4(100mL), (46.5g 0.26mol), and then adds the 1g benzoyl peroxide, and the reaction mixture reflux is spent the night to add NBS.
Aftertreatment:
Wash once with aqueous sodium carbonate, wash once with saturated sodium-chloride again, after the dried over sodium sulfate, filter evaporate to dryness.Get product 31g, yield 82.4%.
1HNMR(CDCl
3)：7.06(m，2H)，7.37(m，2H)，4.49(s，2H)。
The 3rd step: synthetic 4-(2-(4-fluorophenyl)-1,1-dimethoxy-ethyl) pyridine
Operation:
The 250mL three-necked bottle, configuration dropping funnel, low-reading thermometer.(9.6g 0.063mol) is dissolved among the anhydrous THF of 120mL compound 1, cools to-80 ℃, and (40mL, reacting liquid temperature remains on-78 ℃ in 0.1mol) the dropping process, after dripping off, stirs half an hour at-78 ℃ slowly to drip n-Butyl Lithium then.(13g 0.069mol) is dissolved among the anhydrous THF of 20mL, enters in the above-mentioned reaction solution in-76 ℃ of droppings, adds the afterreaction liquid that finishes and rises to stirred overnight at room temperature with compound 2 then.
Aftertreatment:
Pour 300mL yellow soda ash into, organic layer separates, and water is with ethyl acetate extraction twice then, and organic layer merges, and use dried over sodium sulfate, filtration, and evaporate to dryness gets product 12.6g, yield 76.8%.
1HNMR(CDCl
3)：8.48-8.50(dd，2H)，7.04-7.10(dd，2H)，6.72-6.81(m，4H)，3.30(s，6H)。
The 4th step: synthetic 2-(4-fluorophenyl)-1-(4-pyridyl)-1-oxo ethane
Operation:
The 250mL three-necked bottle, configuration dropping funnel, reflux condensing tube.With compound 3 (10.6g 0.04mol) is dissolved in the 130mL formic acid, and 90 ℃ were refluxed 2 hours, the reaction solution cooling, solvent evaporated, the gained crude product is crossed the chromatography column purifying and is got product 4.5g, yield 51.7%.
1HNMR(CDCl
3)：8.81-8.91(dd，2H)，7.76-7.77(dd，2H)，7.22(m，2H)，7.64(t，2H)，7.21(s，2H)。
The 5th step: synthetic 2-(4-fluorophenyl)-1-(4-pyridyl)-1,2-dioxo ethane
Operation:
The 250mL three-necked bottle, the configuration dropping funnel, reflux condensing tube, (21.5g 0.1mol) is dissolved among the HCOOH (100mL) compound 4, adds SeO
2(11.1g, 0.1mol), reaction mixture reflux 2h.The reaction solution cooling, solvent evaporated, the gained crude product is crossed the chromatography column purifying and is got product 18g, yield 78.6%.
1HNMR(CDCl
3)：8.89-8.91(dd，2H)，8.04-8.08(m，2H)，7.79(dd，2H)，7.22-7.28(m，2H)。
The 6th step: synthetic 2-(4-pyridyl)-3-(4-fluorophenyl)-5-(4-piperidyl) imidazoles
Operation:
The 50mL three-necked bottle, the configuration dropping funnel, reflux condensing tube, compound 5 (22.9g 0.1mol) is dissolved among the HCOOH (100mL), add 4-N-Boc-piperazine formaldehyde (42.6g, 0.2mol), ammonium acetate 77g (1mol), reaction mixture reflux 10h.The reaction solution cooling, solvent evaporated, the gained crude product is crossed the chromatography column purifying and is got product 12g, yield 37.3%.
1HNMR(CDCl
3)：9.7(brs，1H)，8.48(d，2H)，7.46-7.51(m，4H)，7.08-7.12(t，2H)，3.50(m，2H)，3.19-3.25(m，1H)，2.89-2.95(t，2H)，2.38-2.46(m，2H)，2.17(m，1H)。
The 7th step: synthetic 2-(4-pyridyl)-3-(4-fluorophenyl)-5-(N-carbobenzoxy-(Cbz)-4-piperidyl) imidazoles
The 250mL three-necked bottle, configuration dropping funnel, compd B
1-2 (32.2g 0.1mol) is dissolved in THF (300mL), H
2Among the O (300mL), add CbzCl (18.8g, 0.12mol), NaOH (8g, 0.2mol), reaction mixture reflux 10h.The reaction solution cooling, solvent evaporated, the gained crude product is crossed the chromatography column purifying and is got product 12g, yield 37.3%.
1HNMR(CDCl
3)：8.42(d，2H)，7.28-7.43(m，9H)，7.07(t，3H)，5.07(d，2H)，4.26(d，2H)，2.93-2.99(m，4H)，2.01-2.04(d，2H)，1.75-1.82(m，2H)。
The 8th step: synthetic 2-(4-pyridyl)-3-(4-fluorophenyl)-5-(N-methyl-4-piperidyl) imidazoles
Operation:
The 250mL three-necked bottle, configuration dropping funnel, reflux condensing tube, compd B
1-3 (0.912g 0.001mol) is dissolved among the anhydrous THF (60mL), and slow adding Lithium Aluminium Hydride under the ice bath (1g, 0.027mol), reaction mixture stirring at room 12h.
Aftertreatment:
Slowly add 50mL water under the ice bath, suction filtration, organic layer separates, and water is with ethyl acetate extraction twice then, and organic layer merges, and use dried over sodium sulfate, and filtration removes solvent under reduced pressure, and the gained crude product is crossed the chromatography column purifying and is got product 0.2g, yield 30%.、
1HNMR(CDCl
3)：8.48-8.49(d，2H)，7.44(m，4H)，7.09-7.13(t，2H)，3.01-3.04(d，2H)，2.88(m，1H)，2.35(s，3H)，2.12-2.26(m，6H)，1.91-1.99(m，2H)。
Three kinds of medicines of experimental example are to the preventive effect test of artificial challenge's Eimeria Tenella
One, experiment material
1. trial drug
1) for reagent thing and dosage: three kinds are subjected to the reagent thing, are respectively B
1-1, B
1-2, B
1-3,
Dosage 100mg/Kg (contain 100 milligrams in the per kilogram feed and be subjected to the reagent thing).
The test compounds structural formula
B
1-1 B
1-2 3
1-3
2) test chicken: just gone out 100 of the AA broiler chicken of shell, available from hatching factory of herding institute of the Chinese Academy of Agricultural Sciences and Beijing China broiler chicken field all.Raise in the wire mesh cage of flame disinfection after going out shell, free choice feeding, drinking-water are raised to 10 ages in days.
2. feed: feeding dorking perfect compound feed, feed were eliminated the coccidia that may exist in 2 hours through 80 ℃ of high bakes before use.
3. chicken coop is used in poultry: before the feeding chickling, with industrial spirit chicken coop is roasted sterilization, kill the coccidian oocyst that may exist, prevent from polluting cause of diseases such as coccidia.
4. Animal House: have good ventilation and heating plant, independent tank is arranged, environmental drying with the sterilization of industrial spirit barbecue, prevents from polluting before using.
5. test and use egg capsule: purebred Eimeria tenella egg capsule Houghton strain, available from China Agricultural University.
Two, experimental technique
1. animal grouping: select 50 even, healthy chickens of body weight from raising to the broiler chicken of 10 ages in days and be divided into 5 groups at random, be respectively: be subjected to reagent thing group (B
1-1, B
1-2, B
1-3) and not infect not administration group (white contrast) and infect not administration group (red contrast), every group of 10 chickens.Trial drug adopts the administration of mixed feeding method, and administration concentration is 100ppm (being to contain 100 milligrams in the per kilogram feed to be subjected to the reagent thing), and the medicine of feeding continuously is to off-test.
2. infect the globule amount: be subjected to reagent thing group and infect not administration group chicken at 11 ages in days dropper oral administration Eimeria tenella egg capsule (10.0 * 10
4Individual/only).
3. clinical observation and record: after the infection, observe for 3 times every day chicken healthy state, drink water and the situation of searching for food, morbidity and the death condition of chicken respectively organized in record, the promoting circulation of blood of going forward side by side is just kept the score.All cut open test chicken extremely in back 7 days in infecting, observe and record the caecum lesion of respectively organizing chicken.Calculate egg capsule output and cecal content egg sac number in the ight soil.
4. evaluating drug effect:
1) bloody stool is kept the score: keep the score by Morehouse and Baron (1970) method.
From five angle recordings: bloody stool there are 4 minutes, bloody stool+loose stool 3 minutes, mucus is main 2 minutes, loose stool is main 1 minute, moulding 0 minute (from the 4th day opening entry).
2) cecal lesion score is 0～4 fen five grade, and 0 expression is normal, the most serious pathology of+4 expressions, (tender eimeria tenella) specific as follows:
When a) the both sides caecum lesion is inconsistent, be as the criterion with a serious side.
B) 0 minute, no naked eyes pathology.
Minute c)+1, the petechia that the caecum wall has amount seldom to be dispersed in, intestines wall wall thickening, content is normal.
Minute d)+2, pathology quantity is more, and cecal content obviously is with blood, and the caecum wall thickens slightly, and content is normal.
Minute e)+3, volume blood or caecum core (the caseous banana type of blood clot or canescence block) are arranged in the caecum, the caecum wall is obviously plump, and ight soil content is less in the caecum.
Minute f)+4, because being full of a large amount of blood or the enlargement of intestines core caecum, containing the excrement slag in the caecum or do not contain, dead chicken also remembers+4 minutes.
3) gram ight soil egg sac number: get the whole ight soil that infect the 7th day each group in back, pulverize, and stir evenly, take by weighing 2 grams then, add 60 milliliters of saturated brines, after fully stirring evenly, with McMaster method counting.
4) cecal content egg sac number: take out the caecum of each repetition, add quantitative saturated aqueous common salt, after the homogenate, get 1 milliliter, add 200 milliliters of saturated brines, behind abundant mixing, with McMaster method counting.And be converted into the egg capsule value, the egg capsule value converts by the following method:
| Egg capsule 1,000,000 numbers/only | The egg capsule value |
| ＜0.1 | 0 |
| 0.1～1.0 | 1 |
| 2.0～5.0 | 10 |
| 6.0～10.0 | 20 |
| ＞11.0 | 40 |
Three, judging criterion
(ACI) judges that formula is as follows by the anticoccidial index:
ACI=(the relative weight gain rate+surviving rate)-(pathology value+egg capsule value)
The relative weight gain rate (%)=(end weight-initial weight)/blank group weightening finish * 100
ACI＞180 are efficient, and 160-180 is middle effect scope, and 120-160 is poor efficiency.
Four, result and discussion
The test-results statistics is at table 1.By table as seen, B
1-1 and B
1-3 reach middle anticoccidial effect, the B of imitating
1-2 reach the poor efficiency anticoccidial effect.
Bloody stool is kept the score the test-results statistics at table 2.By table 2 as seen, B
1-1 does not all see bloody stool in whole prophylactic tria.
According to this test-results, can think that this type of medicine has potential anticoccidial drug exploitation to be worth.
Table 1 is subjected to the reagent thing to the preventive effect of broiler chicken cecal coccidiosis for three kinds
Table 2 is subjected to reagent thing bloody stool score situation for three kinds
Claims (1)
1. the method for preparing the anticoccidial compound shown in the following formula I:
Wherein, R is selected from Me, H or Cbz;
Described method comprises the steps:
1) by the synthetic 4-dimethoxy-methyl pyridine of 4-aldehyde radical pyridine with by the synthetic 4-(2-(4-fluorophenyl)-1 that obtains of the synthetic 1-brooethyl of 1-methyl-4-fluorobenzene-4-fluorobenzene reaction, the 1-dimethoxy-ethyl) pyridine, and then synthetic 2-(4-fluorophenyl)-1-(4-pyridyl)-1 oxo ethane that obtains;
2) reaction of the 2-that step 1 is obtained (4-fluorophenyl)-1-(4-pyridyl)-1 oxo ethane and tin anhydride obtains 2-(4-fluorophenyl)-1-(4-pyridyl)-1,2-dioxo ethane, and then synthesize 2-(4-pyridyl)-3-(4-fluorophenyl)-5-(N-carbobenzoxy-(Cbz)-4-piperidyl) imidazoles, 2-(4-pyridyl)-3-(4-fluorophenyl)-5-(4-piperidyl) imidazoles, 2-(4-pyridyl)-3-(4-fluorophenyl)-5-(N-methyl-4-piperidyl) imidazoles.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101050202A (en) * | 2007-05-18 | 2007-10-10 | 中国农业科学院上海兽医研究所 | Compound in triazine class for anti activity of coccidian, preparation method and application |
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| CN101050202A (en) * | 2007-05-18 | 2007-10-10 | 中国农业科学院上海兽医研究所 | Compound in triazine class for anti activity of coccidian, preparation method and application |
Non-Patent Citations (3)
| Title |
|---|
| Medicinal Chemistry Letters》.2005,第15卷第3296-3301页. * |
| Tesfaye Biftu, et al.."Synthesis and SAR of 2,3-diarylpyrrole inhibitors of parasite".《Bioorganic & * |
| TesfayeBiftu et al.."Synthesis and SAR of 2 |
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