Triazinedione derivatives containing diphenyl ether fragments and applications thereof, agents for preventing and / or treating coccidiosis and applications thereof

Abstract

The present invention relates to the field of veterinary drugs, and discloses a triazinedione derivative containing a diphenyl ether fragment and its application, a medicament for preventing and / or treating coccidiosis and its application, wherein the derivative has a structure shown in formula (I). The compound provided by the present invention has excellent preventive and therapeutic effects on chicken coccidiosis at the test concentration, and has significantly better activity than the currently reported triazine anticoccidial drugs diclazuril, natrazuril and samizuril. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the field of veterinary medicine, and in particular to a triazinedione derivative containing a diphenyl ether fragment and application thereof, and a medicament for preventing and / or treating coccidiosis and application thereof. Background Art

[0002] Chicken coccidiosis is a common, highly contagious intracellular parasitic disease that is very harmful worldwide. After being infected, chickens usually experience symptoms such as weight loss, cecal damage, and blood in the stool, which reduces the growth rate of chickens, reduces the quality of meat and eggs, and even causes death in severe cases.

[0003] According to statistics, the morbidity rate in chicks aged 10 to 30 days or young chickens aged 35 to 60 days can be as high as 80%, and the mortality rate due to outbreaks can reach 30%. The direct and indirect economic losses caused by chicken coccidiosis in my country are more than 3 billion yuan each year.

[0004] The research and development of anticoccidial drugs has played an important role in reducing the harm of coccidiosis and reducing losses in the poultry industry.

[0005] At present, the prevention and treatment of coccidiosis are mainly based on drugs, including polyether ion carriers (such as maduramicin, naramycin, etc.) and chemical synthetic drugs (such as sulfonamide drugs sulfachloropyrazine, sulfaquinoxaline, triazine drugs diclazuril, etc.).

[0006] Triazine anticoccidial drugs are currently the most active chemically synthesized anticoccidial drugs and are therefore widely used.

[0007] Diclazuril and Toltrazuril are the two earliest triazine anticoccidial drugs developed.

[0008] However, after the 1990s, due to the long-term use of anticoccidial drugs, there have been continuous reports of drug-resistant insect strains, resulting in a decrease in the prevention and control effect, but there have been no reports of cross-resistance to triazine anticoccidial drugs.

[0009] Xue Feiqun et al. from the Shanghai Veterinary Research Institute reported in CN102285930A and CN103554046A that the triazine anticoccidial drugs naclofentuzuril and samizuril have good preventive effects on coccidiosis and do not have cross-resistance with diclazuril.

[0010] However, the data showed (Fei Chenzhong et al. Efficacy test of a new triazine compound, Nachuanzhuli, against coccidiosis in chickens. Chinese Journal of Veterinary Drugs, 2020, 44(7):11-12,31) that at a dosage of 1 mg / kg, Nachuanzhuli (oocyst value: 10, lesion value: 6, anticoccidial index: 176.3) was not as effective as diclazuril (oocyst value: 5, lesion value: 0, anticoccidial index: 191.5) in preventing Eimeria tenella in chickens. Furthermore, there are also literature pointing out (Lin Yang. Preliminary study on the toxicology and pharmacodynamics of Nachuanzhuli. Master, Nanjing Agricultural University, 2010.) that Nachuanzhuli was positive in the bacterial reverse mutation test and had mutagenic activity.

[0011] Moreover, the effect of samizuril reported in CN103554046A (oocyst value is 15, lesion value is 10, and anticoccidial index is 158.1 at a dosage of 10 mg / kg) in preventing Eimeria tenella in chickens is not as good as that of diclazuril (oocyst value is 5, lesion value is 5, and anticoccidial index is 182.1 at a dosage of 1 mg / kg).

[0012]

[0013] Therefore, it is of great significance to further study triazine compounds and explore new and highly effective anticoccidial drugs. Summary of the invention

[0014] The object of the present invention is to provide a class of compounds and / or drugs having excellent anticoccidial activity.

[0015] In order to achieve the above object, the first aspect of the present invention provides a triazinedione derivative containing a diphenyl ether segment, wherein the derivative has a structure shown in formula (I):

[0016]

[0017] Wherein, in formula (I),

[0018] R1 is -CH3 or -Cl;

[0019] R2, R3, R4, R5 and R6 are each independently selected from H, -CH3, -Cl, -F and halogen-substituted phenoxy, and R2, R3, R4, R5 and R6 are not H at the same time.

[0020] The second aspect of the present invention provides use of the triazinedione derivative containing a diphenyl ether segment described in the first aspect in preventing and / or treating chicken coccidiosis.

[0021] The third aspect of the present invention provides use of the triazinedione derivative containing a diphenyl ether segment described in the first aspect in the preparation of a medicament for preventing and / or treating coccidiosis.

[0022] The fourth aspect of the present invention provides a medicament for preventing and / or treating coccidiosis, which comprises an active ingredient and excipients, wherein the active ingredient is a therapeutically effective amount of the triazinedione derivative containing a diphenyl ether fragment described in the first aspect.

[0023] The fifth aspect of the present invention provides use of the agent described in the fourth aspect in preventing and / or treating chicken coccidiosis.

[0024] The compound provided by the present invention has excellent preventive and therapeutic effects on chicken coccidiosis at the tested concentration, and compared with the currently reported triazine anticoccidial drugs diclazuril, samizuril and natropizuril, the compound of the present invention has more excellent activity and lower toxicity. DETAILED DESCRIPTION

[0025] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0026] The halogen mentioned in the present invention includes fluorine, chlorine, bromine and iodine.

[0027] The halogen-substituted phenoxy group of the present invention has no special requirements on the substituted position of the halogen, which can be any position that can be substituted. There is no special requirement on the number of substitutions and the type of halogen, which can be any number and type.

[0028] As mentioned above, the first aspect of the present invention provides a triazinedione derivative containing a diphenyl ether segment, wherein the derivative has a structure shown in formula (I):

[0029]

[0030] Wherein, in formula (I),

[0031] R1 is -CH3 or -Cl;

[0032] R2, R3, R4, R5 and R6 are each independently selected from H, -CH3, -Cl, -F and halogen-substituted phenoxy, and R2, R3, R4, R5 and R6 are not H at the same time.

[0033] Preferably, the compound represented by formula (I) is selected from any one of the following:

[0034] Compound 1:

[0035] Compound 2:

[0036] Compound 3:

[0037] Compound 4:

[0038] The present invention does not specifically limit the specific method for preparing the triazinedione derivative containing a diphenyl ether fragment described in the first aspect. Those skilled in the art can determine a suitable synthesis route to prepare the triazinedione derivative containing a diphenyl ether fragment by combining the structural formula disclosed in the present invention with known synthesis methods in the field of organic synthesis.

[0039] However, in order to obtain the aforementioned triazinedione derivative containing a diphenyl ether fragment with a higher yield and higher purity at a lower cost, the present invention preferably provides the following route for preparing the triazinedione derivative containing a diphenyl ether fragment:

[0040]

[0041] (a) first contacting the compound represented by A1 with the compound represented by A2 to obtain the compound represented by A3;

[0042]

[0043] (b) contacting the compound represented by A4 with the compound represented by A5 for a second time to obtain the compound represented by A6;

[0044] (c) subjecting the compound represented by A6 to a reduction reaction to obtain the compound represented by A7;

[0045]

[0046] (d) subjecting the compound represented by A7 to a ring-closing reaction with the compound represented by A3 to obtain the compound represented by A8;

[0047] (e) subjecting the compound represented by A8 to a decarboxylation reaction to obtain a compound represented by formula (I).

[0048] The present invention has no particular requirements for the specific operating parameters in the aforementioned synthetic route, and can be carried out by using operations known in the art, which will not be described in detail in the present invention, and those skilled in the art should not interpret this as a limitation of the present invention.

[0049] As mentioned above, the second aspect of the present invention provides the use of the triazinedione derivative containing a diphenyl ether segment described in the first aspect in preventing and / or treating chicken coccidiosis.

[0050] Preferably, the triazinedione derivative containing a diphenyl ether fragment is added to drinking water and administered in the form of drinking water, and the amount used is such that the content of the triazinedione derivative containing a diphenyl ether fragment in the drinking water is 0.5-100 mg / kg.

[0051] According to another preferred embodiment, the triazinedione derivative containing a diphenyl ether fragment is prepared as a feed additive into a premix and added to the feed, or the triazinedione derivative containing a diphenyl ether fragment is directly added to the feed for administration, and the amount used is such that the content of the triazinedione derivative containing a diphenyl ether fragment in the feed is 0.5-100 mg / kg.

[0052] As mentioned above, the third aspect of the present invention provides the use of the triazinedione derivative containing a diphenyl ether segment described in the first aspect in the preparation of a medicament for preventing and / or treating coccidiosis.

[0053] As mentioned above, the fourth aspect of the present invention provides a medicament for preventing and / or treating coccidiosis, which is composed of an active ingredient and excipients, wherein the active ingredient is a therapeutically effective amount of the triazinedione derivative containing a diphenyl ether fragment described in the first aspect.

[0054] Preferably, the content of the active ingredient in the medicament is 0.1wt%-99.9wt%. Exemplarily, the content of the active ingredient in the medicament is 1wt%, 5wt%, 10wt%, 15wt%, 20wt%, 25wt%, 30wt%, 35wt%, 40wt%, 45wt%, 50wt%, 55wt%, 60wt%, 65wt%, 70wt%, 75wt%, 80wt%, 85wt%, 90wt%, 95wt%.

[0055] Preferably, the auxiliary material is selected from at least one of fillers, binders, disintegrants, lubricants, glidants, pressurizing agents, effervescent agents, surfactants, film formers, colorants, flavoring agents, preservatives, dispersants, and fragrances.

[0056] Preferably, the dosage form of the medicament is selected from at least one of powder, granules, pills, tablets, pastes, capsules, syrups, mixtures, and solutions.

[0057] As mentioned above, the fifth aspect of the present invention provides use of the agent described in the fourth aspect in preventing and / or treating chicken coccidiosis.

[0058] Preferably, the agent is added to drinking water and administered in the form of drinking water, and the dosage is such that the content of the triazinedione derivative containing a diphenyl ether segment in the drinking water is 0.5-100 mg / kg.

[0059] Alternatively, preferably, the agent is prepared as a feed additive into a premix and added to the feed or directly added to the feed for administration, and the dosage is such that the content of the triazinedione derivative containing the diphenyl ether fragment in the feed is 0.5-100 mg / kg.

[0060] The present invention will be described in detail below by way of examples. In the following examples, unless otherwise specified, the raw materials used are all common commercially available products.

[0061] Preparation Example

[0062]

[0063] Synthesis of intermediate A3

[0064] Malonic acid (0.5 mol) and ethyl carbamate (1 mol) were dissolved in acetic anhydride (100 mL) and reacted at 110°C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and slowly poured into a mixed solution of isopropyl ether and petroleum ether (v / v=10:1) under stirring. A large amount of solid precipitated, which was filtered and the filter cake was washed with isopropyl ether and dried under infrared to obtain intermediate A3 as a white solid with a yield of 46%. 1 HNMR (400MHz, CDCl3) δ7.74 (s, 2H), 4.28 (s, 2H), 4.22 (q, J = 7.2Hz, 4H), 1.30 (t, J = 7.2Hz, 6H).

[0065]

[0066] Synthesis of intermediate A6

[0067] Dissolve substituted 4-fluoronitrobenzene (10 mmol), substituted phenol (11 mol) and potassium carbonate (13 mol) in anhydrous N,N-dimethylformamide (DMF, 80 mL), heat to 100°C and stir to react. After the reaction is completed by TLC monitoring, cool to room temperature, pour into ice water under stirring, and a light yellow to yellow solid precipitates. Filter and wash the filter cake with water, dry under infrared to obtain intermediate A6, which is directly used in the next reaction without purification.

[0068] Synthesis of intermediate A7

[0069] 4 mmol of intermediate A6 and ammonium chloride (4.8 mmol) were added to a 100 mL round-bottom flask, followed by 50 mL of ethanol and 6 mL of water. The mixture was heated to reflux and reduced iron powder (12 mmol) was added. The reaction was stopped after the reaction of the raw materials was completed by TLC monitoring. The filtrate was filtered through celite and concentrated under reduced pressure. Most of the solvent was removed by rotation and then 50 mL of ethyl acetate was added for extraction. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed and the intermediate A7 was obtained by column chromatography.

[0070] Specifically:

[0071]

[0072] Yellow solid; one-step yield: 95%; 1 H NMR (400MHz, DMSO-d6) δ6.69–6.61(m,2H),6.34(s,2H),4.98(s,2H),1.91(s,6H).

[0073]

[0074] Pale yellow solid; one-step yield: 86%; 1 H NMR (400MHz, DMSO-d6) δ7.41(d,J=8.8Hz,2H),7.06–6.96(m,4H),6.82(d,J=8.8Hz,2H),6.72(s,2H),5.68(s,2H).

[0075]

[0076] Pale yellow solid; one-step yield: 95%; 1 H NMR (400MHz, DMSO-d6) δ6.88–6.81(m,2H),6.72(s,2H),5.75(s,2H).

[0077]

[0078] Pale yellow solid; one-step yield: 94%; 1 H NMR (400MHz, DMSO-d6) δ7.08 (d, J = 2.0Hz, 1H), 6.96 (s, 2H), 6.90–6.83 (m, 2H), 5.63 (s, 2H).

[0079] Synthesis of intermediate A8

[0080] 3.1mmol of intermediate A7, 10mL of acetic acid and 1mL of concentrated hydrochloric acid were added to a 100mL round-bottom flask. The temperature was controlled at 0-5°C. An aqueous solution of sodium nitrite (3.4mmol, 1mL of water) was slowly added dropwise. After the addition was completed, the mixture was stirred for 30 minutes under heat preservation. NaOAc (7.75mmol) and CH2(CONHCOOEt)2 (3.72mmol) shown in A3 were added. The reaction system was then moved to room temperature. After half an hour of reaction, NaOAc (2.5mmol) was added. The temperature was raised to reflux. After TLC monitoring of the reaction of the raw materials, 5mL of concentrated hydrochloric acid was added. The reaction was continued. After TLC monitoring of the hydrolysis, the reaction was stopped. After most of the solvent was removed under reduced pressure, 50mL of water was added. A large amount of solid was precipitated. The intermediate A8 was filtered and dried to obtain a yellow solid. The next step was directly carried out without purification.

[0081] Synthesis of target compounds

[0082] Add intermediate A8 and 5 mL of thioglycolic acid into a 50 mL round-bottom flask and heat to 160-180 °C. After monitoring by TLC, stop the reaction after the reaction of the raw materials is complete. After cooling, add saturated NaHCO3 aqueous solution to neutralize the excess thioglycolic acid. A large amount of solid precipitates. Filter to obtain the crude product of the target compound. After drying, column chromatography is performed to obtain the target compound.

[0083] Specifically:

[0084]

[0085] Light yellow solid; one-step yield 75%; mp, 223.8-225.4℃; 1 H NMR (400MHz, DMSO-d6) δ12.37(s,1H),7.65(s,1H),7.34(s,2H),6.76(dd,J=9.2,6.0Hz,2H),2.11(s,6H). 13 C NMR(100MHz,DMSO-d6)δ157.06,152.91,152.88,152.79,152.77,152.26,152.20,152.15,152.09,149.80,149 .74,149.70,149.64,148.93,147.77,137.39,136.16,131.18,126.36,100.07,99.84,15.86.HRMS(ESI)calcd for C 17 H 12 F3N3O3[MH] - :362.0753,found:362.0759.

[0086]

[0087] Pale yellow solid; one-step yield: 74%; mp, 167.2-168.2℃; 1 H NMR (400MHz, DMSO-d6) δ12.52(s,1H),7.85(s,2H),7.73(s,1H),7.42(d,J=8. 8Hz,2H),7.07(d,J=8.8Hz,2H),7.00(d,J=9.2Hz,2H),6.92(d,J=9.2Hz,2H). 13 CNMR(100MHz,DMSO-d6)δ156.95,156.22,152.42,151.23,147.65,145.50,138.05, 136.86,129.89,128.40,126.91,126.59,120.82,119.61,116.25.HRMS(ESI)calcd for C 21 H 12 Cl3N3O4[MH] - :473.9815,found:473.9829.

[0088]

[0089] Light yellow solid; one-step yield: 55%; mp, 157.6-158.9℃; 1 H NMR (400MHz, DMSO-d6) δ12.52(s,1H),7.86(s,2H),7.74(s,1H),7.08(dd,J=8.4,5.6Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ159.96,156.87,147.59,144.39,138.59,136.92,129.10,128.80,128.08,126.59,116.25.HRMS(ESI)calcd for C 15 H6Cl2F3N3O3[M] + :402.9738,found:402.9700.

[0090]

[0091] Pale yellow solid; one-step yield: 63%; mp, 89.5-90.4℃; 1H NMR (400MHz, DMSO-d6) δ12.51(s,1H),7.82(s,2H),7.72(s,1H),7.11(s,1H),6.88(d,J=8.0Hz,1H),6.21(d,J=8.4Hz,1H),2.35(s,3H),2.22(s,3H). 13 C NMR(100MHz,DMSO-d6)δ156.97,152.31,147.67,146.17,137.76,136.82,132.06 ,131.68,128.33,127.37,126.54,125.56,111.91,20.12,15.86.HRMS(ESI)calcd for C 17 H 13 Cl2N3O3[M] + :377.0334,found:377.0300.

[0092] Test Example 1:

[0093] The test method is as follows: 1-day-old Pudong yellow chickens are raised in the brooding house until 14 days old, and the feed is a complete formula feed without any drugs. Healthy animals were randomly divided into groups for this test, with 10 in each group, and the test group, drug control group, infection without medication, and non-infection without medication were set up respectively. On the second day after the grouping was completed, except for the healthy control group, each group was artificially infected with 80,000 sporulated oocysts of Eimeria tenella per chicken. The dose of the test compound was uniformly set to 100 mg / kg for mixed feeding, and the drug control selected monensin 100 mg / kg for mixed feeding. During the test, the incidence of the test chickens was observed daily, and the number of bloody stools and deaths was recorded. On the 6th to 8th day after artificial infection, the feces of each group of chickens were collected to count the fecal oocysts. On the 8th day, each group was weighed and all were killed, and the weight gain and cecal lesions of the test chickens were observed and recorded. The test results are shown in Table 1.

[0094] Table 1 Preliminary anticoccidial clinical trial results of test compounds

[0095]

[0096] Relative weight gain rate = average weight gain of experimental chickens in each infection group / average weight gain of healthy control group × 100%.

[0097] Survival rate = number of surviving chickens at the end of the experiment / number of experimental chickens × 100%.

[0098] Oocyst value: Take feces from each group, mix them thoroughly, weigh them, and count the number of oocysts (OPG) per gram of feces by McFarland turbidimetry. Oocyst ratio = number of oocysts in each infected group / number of oocysts in the healthy control group × 100%. The oocyst ratio is 0-1%, and the oocyst value is 0; the oocyst ratio is 2-25%, and the oocyst value is 5; the oocyst ratio is 26-50%, and the oocyst value is 10; the oocyst ratio is 51-75%, and the oocyst value is 20; the oocyst ratio is 76-100%, and the oocyst value is 40.

[0099] Lesion value: The cecal lesions were scored according to the 0-4 point standard of Johnson and Reid (Johnson J, Reid W M. Anticoccidial drugs leision scoring techniques in battery and floor-pan experiments with chickens. Experimental parasitology, 1970, 28(1): 30-36). Lesion value = average cecal score of each group × 10.

[0100] Anticoccidial index (ACI): ACI = (relative weight gain rate + survival rate) - (lesion value + oocyst value).

[0101] ACI below 120 is ineffective, between 120 and 160 is inefficient, between 160 and 180 is moderately efficient, and above 180 is highly efficient.

[0102] The data in the table show that the test compound, when administered in a dose of 100 mg / kg, inhibited the production of coccidial oocysts and lesions, and the anticoccidial index of the test compound ranged from 177 to 184, approaching and reaching the standard of highly effective anticoccidial drugs, showing good anticoccidial activity, which was superior to the control drug monensin. From the oocyst value, relative weight gain and other indicators, the test compound had no visible toxic reactions and adverse effects on the test chickens at an added dose of 100 mg / kg.

[0103] Test Example 2:

[0104] Compounds 1 and 3 were further retested and verified.

[0105] Test method: 1-day-old AA Avian broilers were selected and raised in the brooding house until 12 days old. Healthy animals were randomly divided into groups, with 8 in each group, and the experimental group, drug control group, infection control group without medication, and healthy control group without infection and medication were set up respectively. On the second day after the grouping was completed, except for the healthy control group, each group was artificially infected with 50,000 sporulated oocysts of Eimeria tenella per chicken. Diclazuril was used as the drug control and the drug was administered according to the drug instructions. The calculation methods of relative weight gain, survival rate and other indicators are the same as those in Test Example 1. The test results are shown in Table 2.

[0106] Table 2 Results of anticoccidial clinical trials of test compounds

[0107]

[0108] The results showed that the anticoccidial index of the test compound was between 182 and 187, reaching the standard of highly effective anticoccidial drugs and significantly superior to diclazuril. The repeatability of the test results of test examples 1 and 2 was good, indicating that the test compound had definite anti-Eimeria tenella activity.

[0109] Test Example 3

[0110] Compound 1 was evaluated for its efficacy against diclazuril-resistant strains of Eimeria tenella.

[0111] Test method: 30 7-day-old AA broilers were randomly divided into 3 groups (test drug group, control drug group, infection control group), 10 in each group. The infection control group was inoculated with only 50,000 sporulated oocysts of drug-resistant strains of Eimeria tenella, and no anticoccidial drugs were added to feed and drinking water. The test chickens in the test drug group and the control drug group were fed with the recommended dose of 100ppm of compound 1 and diclazuril for 2 days, and then orally inoculated with 50,000 sporulated oocysts of drug-resistant strains of Eimeria tenella, and then continuously fed with compound 1 and diclazuril until 7 days after inoculation, and the death of the chickens was counted. The test results are shown in Table 3.

[0112] Table 3 Results of clinical trials of test compounds against diclazuril-resistant strains of Eimeria tenella

[0113]

[0114] N: No death or obvious abnormal symptoms in chickens

[0115] The results showed that 7 chickens had died on the 5th day in the control drug group using diclazuril, and the total number of chickens that died in 7 days was 8, while no chickens died in the test drug group using compound 1. This shows that compound 1 can effectively control the infection of diclazuril-resistant strains of Eimeria tenella, and compound 1 has no cross-resistance with diclazuril.

[0116] Test Example 4

[0117] Bacterial reverse mutation experiment of compound 1

[0118] Test method: According to GB / T 15670.14-2017 "Toxicological test methods for pesticide registration Part 14: Bacterial reverse mutation test". According to the results of the preliminary test, four test strains of histidine auxotrophic Salmonella typhimurium TA97, TA98, TA100, and TA102 were used. The first test set up five dose groups of 200, 80, 32, 12.8, and 5.12 μg / dish, a solvent control group, and a positive control group, and the plate incorporation method was used for the test; the test dose setting was the same as the first test, and the pre-insulation plate incorporation method was used for the test. The test results are shown in Tables 4 and 5.

[0119] Table 4 Results of the first test

[0120]

[0121] Note: a: The solvent was DMSO; b: Under +S9 conditions, TA97, TA98, and TA100 strain groups all used 200 μg / mL of 2-aminofluorene, and TA102 strain group used 300 μg / mL of 1,8-dihydroxyanthraquinone; under -S9 conditions, TA97, TA98, and TA102 strain groups all used 500 μg / mL of dichlorobenzene, and TA100 strain group used 15 μg / mL of sodium azide.

[0122] Table 5 Confirmation test results

[0123]

[0124] Note: a: The solvent was sterile water; b: Under +S9 conditions, TA97, TA98, and TA100 strain groups all used 200 μg / mL of 2-aminofluorene, and TA102 strain group used 300 μg / mL of 1,8-dihydroxyanthraquinone; under -S9 conditions, TA97, TA98, and TA102 strain groups all used 500 μg / mL of dichlorobenzene, and TA100 strain group used 15 μg / mL of sodium azide.

[0125] The test results showed that under conditions of good background growth, the number of reverse mutation colonies in each dosage group did not exceed twice the number of reverse mutation colonies in the solvent control group, and there was no dose-response relationship, indicating that the bacterial reverse mutation test of compound 1 was negative and had no mutagenic toxicity.

[0126] The compound provided by the present invention has excellent preventive and therapeutic effects on chicken coccidiosis at the tested concentration, and has more excellent activity and lower toxicity than the currently reported triazine anticoccidial drugs diclazuril, natrazuril and samizuril.

[0127] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A triazinedione derivative containing a diphenyl ether fragment, characterized in that: The derivative is selected from any one of the following: Compound 1: Compound 2:

2. Use of the triazinedione derivative containing a diphenyl ether fragment according to claim 1 in the preparation of a medicament for preventing and / or treating coccidiosis.

3. A medicament for preventing and / or treating coccidiosis, characterized in that: The medicament consists of active ingredients and auxiliary materials. The active ingredient is a therapeutically effective amount of the triazinedione derivative containing a diphenyl ether fragment as claimed in claim 1.

4. The agent according to claim 3, wherein The content of the active ingredient in the medicament is 0.1wt%-99.9wt%.

5. The agent according to claim 3 or 4, wherein The auxiliary material is selected from at least one of fillers, binders, disintegrants, lubricants, glidants, pressurizing agents, effervescent agents, surfactants, film formers, colorants, flavoring agents, preservatives, dispersants, and aromatics.

6. The agent according to claim 3 or 4, wherein The dosage form of the medicine is selected from at least one of powder, granules, pills, tablets, pastes, capsules, syrups, mixtures and solutions.

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