WO2015067193A1 - 一种具有抗鸡球虫病的三嗪化合物 - Google Patents

一种具有抗鸡球虫病的三嗪化合物 Download PDF

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WO2015067193A1
WO2015067193A1 PCT/CN2014/090460 CN2014090460W WO2015067193A1 WO 2015067193 A1 WO2015067193 A1 WO 2015067193A1 CN 2014090460 W CN2014090460 W CN 2014090460W WO 2015067193 A1 WO2015067193 A1 WO 2015067193A1
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compound
formula
group
coccidiosis
drugs
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PCT/CN2014/090460
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French (fr)
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张丽芳
薛飞群
费陈忠
张可煜
郑文丽
王霄旸
张德鹏
范超
肖文龙
王米
李涛
王春梅
肖遂
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中国农业科学院上海兽医研究所
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Priority to JP2016504483A priority Critical patent/JP6106798B2/ja
Priority to US14/775,636 priority patent/US20160022689A1/en
Priority to GB1514894.3A priority patent/GB2528793B/en
Publication of WO2015067193A1 publication Critical patent/WO2015067193A1/zh

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/111—Aromatic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/137—Heterocyclic compounds containing two hetero atoms, of which at least one is nitrogen
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/70—Feeding-stuffs specially adapted for particular animals for birds
    • A23K50/75—Feeding-stuffs specially adapted for particular animals for birds for poultry
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D253/075—Two hetero atoms, in positions 3 and 5

Definitions

  • the present invention relates to the synthesis of compounds and compounds, and in particular to a novel triazine-based compound having anticoccidial activity, a process for the preparation thereof and use thereof.
  • Chicken coccidiosis is common in all parts of the world and is an important disease that harms intensive chicken farms. It is a disease caused by parasites of Eimeria coccidia in intestinal epithelial cells.
  • Triazine anticoccidial drugs are currently the most active chemical synthetic antiparasitic drugs, which have been widely used all over the world. The good anticoccidial effect of triazines is worthy of further study. Among the triazine anticoccidial drugs, the most representative drugs are Diclazuril and Toltrazuril. However, after nearly 20 years of use as a feed additive, these drugs have generally developed resistance. At present, a variety of chicken coccidia against triazine anticoccidial drugs Keqili (Zhao Qiping. Resistance test of two chicken fields in Anhui province. Anhui Agricultural Sciences, 2010, 38 (21): 11142-11432 And tortuozhuli (Wang Huizhen et al. The effect of four commonly used anticoccidial drugs on the treatment of chicken coccidiosis. Chinese poultry, 31 (24): 55-56) produced certain resistance, thus limiting its In clinical application.
  • the Chinese patent application “New triazine compound having anticoccidial activity, preparation method and application thereof” (Application No.: 200710040920.6) discloses a novel triazine compound having anticoccidial activity, a preparation method and application thereof.
  • the compound is represented by the formula (VI) and forms a pharmaceutically acceptable acid or base salt thereof, wherein R 1 , R 2 represent hydrogen, a halogen atom, an alkyl group, an alkoxy group, a nitro group, a trifluoromethyl group.
  • R 1 and R 2 may be the same or different, R 3 represents COR 7 , a cycloalkyl group, a heterocyclic ring; R 4 represents a hydrogen atom, an alkyl group;
  • Pharmaceutically acceptable acids include hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, carbonic acid, formic acid, acetic acid, citric acid, lactic acid, fumaric acid, tartaric acid, gluconic acid;
  • the pharmaceutically acceptable bases include sodium hydroxide, Potassium hydroxide, triethylamine, tert-butylamine.
  • R 1 , R 2 represent the same or different groups
  • R 3 represents a hydrogen atom, an alkyl group or a cycloalkyl group
  • R 4 represents hydrogen Atoms, CO 2 R 5 or CONHR 6 ; such compounds have excellent inhibitory effects on coccidiosis in animals.
  • the Chinese invention patent "a triazine compound and its use in controlling chicken coccidiosis” discloses a compound of the formula (IV) and the use of the compound in the prevention and treatment of chicken coccidiosis,
  • the structure of the nitro group exists in the chemical structure of the compound, which has potential toxicity.
  • the LD 50 of the compound was calculated by the modified method of ⁇ , which was 768 mg/kg, and the 95% confidence limit was 644-916 mg/kg;
  • the preparation method of the compound comprises the following steps:
  • a compound of formula (IV) is prepared by condensation of a compound of formula (II) or a phenolic sodium salt thereof with a compound of formula (III) by Williamson synthesis.
  • the substituent x in the compound of formula (III) is a halogen.
  • Williamson synthesis Sawilliamson synthesis
  • This reaction was discovered as early as 1852, it is still asymmetry today.
  • the best general method of ethers (Edited by Yu Lingwei, Name Reaction in Organic Chemistry, Science Press, 1984: 345)
  • the compound of the formula (V) is obtained by the acylation of an amino group in the presence of acetyl chloride in the presence of acetyl chloride to give a compound of the formula (I);
  • the compound of the formula (II) in the present invention can be obtained by the method disclosed in US4968795A (paragraph 22, lines 35-66).
  • An anti-coccidiosis pharmaceutical composition comprising an effective amount of a compound of the formula (I) as an active ingredient or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which is added to the feed for application at a concentration of 10 mg/kg Its anti-coccidial index can reach 189.
  • AZL is a metabolite of formula (IV), its toxicity is further reduced.
  • the LD 50 of compound AZL is calculated by the modified oral toxicity test in rats to be 4743 mg/kg, with a 95% confidence limit. 3754 ⁇ 5993mg / kg.
  • Drug metabolism refers to a series of chemical reactions, also known as biotransformation, that occur after the drug molecules are absorbed by the body and under the action of the body's enzymes. In the long-term evolution process, the body develops a certain self-protection ability, which can chemically treat exogenous substances, including drugs and poisons, so that they can be easily excreted to avoid damage to the body.
  • the reactions involved in drug metabolism are divided into two types: one is a functional group reaction, also called an I phase biotransformation reaction; the other is a binding reaction, also known as a phase II biotransformation reaction.
  • a polar group such as a hydroxyl group or an amino group in a metabolite of a drug molecule or a functionalized group which is metabolized in vivo may be catalyzed by an enzyme and activated endogenous small molecules such as glucuronic acid, sulfuric acid, amino acid, etc. Combine. This process is called a combined reaction.
  • Amphetamine drugs are mostly acetylated when they are metabolized.
  • the amino groups formed by the reduction of the aryl nitro drugs may undergo acetylation. After N-acetylation of drugs, most of them produce inactive or less active products, so it is an effective detoxification pathway (Edited by You Qidong, Medicinal Chemistry (Second Edition), Chemical Industry Press, 2008, 59-66 ).
  • the compound AZL of the present application did not have a decrease in activity, and also had a good anti-coccidial effect, and was added to the feed for application, and its anticoccidial index was added at a concentration of 10 mg/kg. Up to 189. As a result of the new compounds produced in the metabolic process, its toxicity studies have shown that its toxicity is further reduced.
  • the LD 50 of the compound AZL is calculated by the modified oral toxicity test in rats to be 4743 mg/kg, 95%. The limit of confidence is 3754 ⁇ 5993mg / kg.
  • AZL50g Take AZL50g, add 10,000g of soybean meal, and mix well to get AZL premix. Before use, take appropriate amount, add chicken and mix the appropriate amount of feed to prepare the AZL containing the desired concentration.
  • AZL content: 99.10%, self-made by the Shanghai Veterinary Research Institute of the Chinese Academy of Agricultural Sciences.
  • the diclazuril drug substance is added to the chicken compound feed containing no other drugs before use, and is uniformly mixed to prepare a drug-containing feed containing diclazuril concentration of 1 mg/kg.
  • the AZL feed addition group, the compound feed compound of the formula (IV), the compound feed group of the formula (V), and the diclazuril drug control group immediately began feeding the feed with the specified drug, the infected control group and the healthy control.
  • test daily observations were recorded on the feed intake, mental state, morbidity, bloody stools, etc. of the feed and drinking water of the test chicken.
  • fifth, sixth and seventh days after infection the feces of each group of chickens were collected for fecal oocyst count, and the highest value was recorded in the calculation of ACI.
  • death of the test chicken was observed every day, and the necropsy was verified.
  • eighth day each group was weighed and killed, and the weight gain and cecal lesions of the test chickens were recorded.
  • Relative weight gain rate The average weight gain of the test chickens in each infected group and the average weight gain of the healthy control group.
  • the oocyst ratio is 0-1%, the oocyst value is 0; the oocyst ratio is 2%-25%, the oocyst value is 5; the oocyst ratio is 26%-50%, and the oocyst value is 10
  • the oocyst ratio is 51%-75%, the oocyst value is 20; the oocyst ratio is 6%-100%, and the oocyst value is 40.
  • ACI (relative weight gain rate + survival rate) - (pathological value + oocyst value).
  • AZL content: 99.10%, self-made by the Shanghai Veterinary Research Institute of the Chinese Academy of Agricultural Sciences.
  • Drug solvent 0.5% sodium carboxymethylcellulose.
  • AZL was added to 0.5% sodium carboxymethylcellulose to prepare suspensions of various concentrations.
  • the interval range of LD 0 to LD 100 was determined by repeated pre-tests, and the group-to-group ratio was determined according to the grouping.
  • 80 rats of 180-220 g were randomly divided into 8 groups, 10 in each group, half male and half female, and the doses of each group were 2358, 3000, 3817, 4856, 6178, 7860, 10000 mg/ Kg body weight, rats were orally administered once, and group 1 was used as a negative control group to administer drug vehicle.
  • group 1 was used as a negative control group to administer drug vehicle.
  • statistical mortality, LD 50 value and 95% can be calculated by modified ⁇ method The confidence interval.
  • the specific experimental results are shown in Table 2.
  • the LD 50 value calculated by the modified ⁇ method is 4743 mg/kg, and the 95% confidence interval is 3754 to 5993 mg/kg.

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Abstract

本发明属于医药技术领域，涉及一种具有抗鸡球虫病的三嗪化合物及其制备方法和用途，其化合物具有式（I）结构；本发明药效好，毒性低，可用于抗动物球虫病。

Description

一种具有抗鸡球虫病的三嗪化合物 技术领域
本发明涉及化合物及化合物的合成，具体而言，本发明涉及一种具有抗球虫活性的三嗪类新化合物及其制备方法和用途。
背景技术
鸡球虫病在世界各地普遍发生，是危害集约化养鸡场的一种重要疾病。是由艾美尔球虫寄生于肠上皮细胞引起的疾病。
目前,对鸡球虫病防治的手段主要有两种：疫苗和球虫药。球虫活疫苗、亚单位疫苗及重组疫苗的开发与应用虽取得了一定效果,但球虫病的预防和治疗仍以药物为主。抗球虫药物的开发对于减轻鸡球虫病的危害、减少和挽回养鸡业的损失，确保养鸡业的发展起到了至关重要的作用。
然而，一种抗球虫药物的长期使用而导致的耐药性一直困扰着兽医临床。特别是在养鸡业，球虫产生的耐药性更普遍，对使用时间长的药物问题更突出，球虫耐药性问题已成为养鸡业抗球虫的头号大敌。研究表明，在中国广东地区，58％的虫株仅对一种抗球虫药物敏感，有14％的虫株对所有药物都不敏感。由此可见球虫的耐药性的确已非常普遍，能够选择的有效治疗药物的余地已经越来越小，这也是很多地区球虫病难以控制的主要原因。由于缺乏新型抗球虫药物，临床上不得不采用穿梭用药、轮换用药等方法避免耐药性的进一步加剧。这也严重制约养鸡业的发展，兽医临床上急需更新换代、高效、低毒的抗球虫药物出现。
三嗪类抗球虫药物，是目前活性最高的化学合成抗寄生虫药物，已在全世界被广泛应用，三嗪类的良好抗球虫效果值得继续深入研究。在三嗪类抗球虫药物中，最具有代表性的药物是地克珠利(Diclazuril)和妥曲珠利(Toltrazuril)。但是，经过近20年作为饲料添加剂的使用，这类药物普遍都产生了耐药性。目前，多种鸡球虫对三嗪类抗球虫药地克珠利(赵其平等.安徽两个鸡场球虫的抗药性试验.安徽农业科学，2010，38(21)：11142-11432)和妥曲珠利(王慧珍等.四种常用抗球虫药对鸡球虫病的治疗效果观察.中国家禽,31(24):55-56)产生了一定的耐药，因此限制了其在临床上的应用。
可喜的是，这类化合物的高抗球虫活性以及药物间无交叉耐药性(如地克珠利和妥曲珠利并无交叉耐药性)，为进一步利用这类化合物开发新药提供了空间。
中国专利申请“具有抗球虫活性的新型三嗪类化合物、制备方法及其应用”(申请号：200710040920.6)公开了一种具有抗球虫活性的新型三嗪类化合物、制备方法及其应用。该化合物由结构式(Ⅵ)表示以及以该结构式形成在药学上可接受的酸或碱的盐：其中R1、R2代表氢、卤原子、烷基、烷氧基、硝基、三氟甲基的一种或几种基团，R1、R2代表的基团可以 相同的也可以不同，R3代表COR7、环烷基、杂环；R4代表氢原子、烷基；所述药学上可接受的酸包括盐酸、硫酸、氢溴酸、磷酸、碳酸、甲酸、乙酸、柠檬酸、乳酸、富马酸、酒石酸、葡萄糖酸；所述药学上可接受的碱包括氢氧化钠、氢氧化钾、三乙胺、叔丁胺。这些化合物对动物的球虫病有优良的抑制效果。
中国专利申请“具有抗球虫活性的三嗪类化合物及其制备方法”(申请号：200810202470.0)中，公开了一种具有抗球虫活性的三嗪类式(Ⅶ)化合物，以及它们所形成的在药学上可接受的酸或碱的盐：其中，A代表氧或硫，R1、R2代表氢、卤原子、烷基、环烷基、烷氧基、硝基、三氟甲基、三氯甲基、COR5、杂环的一种或几种基团；R1、R2代表的基团相同或不同；R3代表氢原子、烷基或环烷基；R4代表氢原子、CO2R5或CONHR6；这类化合物对动物的球虫病有优良的抑制效果。
中国发明专利“一种三嗪化合物及其在控制鸡球虫病中的应用”(专利号：201110230812.1)中公开了式(Ⅳ)化合物及该化合物在防治鸡球虫病中的应用，由于该化合物的化学结构中存在有硝基的结构，具有潜在的毒性可能。通过小鼠的经口急性毒性试验，采用寇氏改良法计算得到该化合物的LD50为768mg/kg，95％可信限为644～916mg/kg；
Figure PCTCN2014090460-appb-000001
发明内容
本发明的目的是提供一种具有抗球虫活性的新三嗪类化合物和该化合物的制备方法及其应用。
本发明的目的是这样实现的：
一种三嗪化合物，该化合物具有下式结构：
Figure PCTCN2014090460-appb-000002
所述化合物的制备方法，包括以下步骤：
A、由式(Ⅱ)化合物或其酚钠盐与式(Ⅲ)化合物通过威廉森合成法缩合制备成式(Ⅳ)化合物。式(Ⅲ)化合物中取代基x为卤素。威廉森合成法(Williamson合成法)，即卤代烷用醇盐或酚盐处理得到醚类，是合成醚键的通法，这个反应虽然早在1852年就发现了，但到今天仍为合成不对称醚类的最好的一般方法(俞凌翀编，有机化学中的人名反应，科学出版社，1984：345)
Figure PCTCN2014090460-appb-000003
B、由式(IV)化合物，用还原硝基制备得到式(V)化合物；
Figure PCTCN2014090460-appb-000004
C、由式(Ⅴ)化合物在乙酰氯存在下，通过氨基的酰基化制备得到式(Ⅰ)化合物；
Figure PCTCN2014090460-appb-000005
本发明中式(Ⅱ)化合物可参照US4968795A(第22段，第35-66行)所公开的方法得到。
含有有效量的式(I)化合物作为活性成分或其可药用盐和可药用载体的一种抗鸡球虫病药物组合物，将其添加到饲料中施用，在添加浓度为10mg/kg下，其抗球虫指数可达189。
背景技术中所述式(Ⅵ)、(Ⅶ)、(Ⅳ)化合物至今均未上市销售，其药效机理及临床应用仍在研究过程中。在研究这些药物的药效机理及药物代谢过程中，研究了多个新结构的代谢产物如式(Ⅳ)化合物在鸡体内的代谢产物式(Ⅰ)化合物和式(Ⅴ)化合物，显示出了 不同于所述式(Ⅵ)、(Ⅶ)、(Ⅳ)化合物，即式(Ⅰ)化合物(代号：AZL)，具有意外的良好抗球虫效果，将其添加到饲料中施用，在添加浓度为10mg/kg下，其抗球虫指数可达189。由于AZL是式(Ⅳ)的代谢产物，其毒性也进一步降低，通过大鼠的经口急性毒性试验，采用寇氏改良法计算得到化合物AZL的LD50为4743mg/kg，95％可信限为3754～5993mg/kg。
药物代谢是指药物分子被机体吸收后，在机体酶的作用下发生的一系列化学反应，又称生物转化。在长期的进化过程中，机体发展出一定的自我保护能力，能把外源性的物质，包括药物和毒物，进行化学处理，使其易于排出体外，以避免机体受到这些物质的伤害。药物代谢所涉及的反应分为两大类型：一类是官能团化反应，也叫Ⅰ相生物转化反应；另一类是结合反应，又称Ⅱ相生物转化反应。药物分子或经体内代谢的官能团化反应后的代谢物中的极性基团如羟基、氨基等，可在酶的催化下与活化的内源性的小分子如葡萄糖醛酸、硫酸、氨基酸等结合。这一过程就叫结合反应。芳伯胺药物在代谢时大都被乙酰化结合。芳硝基类药物在还原后所形成的氨基，都可能进行乙酰化结合。药物经N-乙酰化后，大都生成无活性或活性较小的产物，因此是一条有效的解毒途径(尤启冬主编，药物化学(第二版)，化学工业出版社，2008，59-66)。
令人预想不到的是，本申请化合物AZL并没有发生活性降低的结果，同样具有良好的抗球虫效果，将其添加到饲料中施用，在添加浓度为10mg/kg下，其抗球虫指数可达189。由于是代谢过程中产生的新化合物，其毒性研究表明其毒性也进一步降低，通过大鼠的经口急性毒性试验，采用寇氏改良法计算得到化合物AZL的LD50为4743mg/kg，95％可信限为3754～5993mg/kg。
具体实施方式
以下实施例是为了举例说明本发明，但不足以限制本发明以其他通常的方式得以实现。
实施例1
2-{3-甲基-4-(4’-硝基苯氧基)苯基}-1,2,4-三嗪-3,5(2H,4H)-二酮(式(Ⅳ)化合物)的制备
式(Ⅱ)化合物Ⅱ(15克，0.068mol)，无水碳酸钠(7.9克，0.075mol)，对氯硝基苯(11.8克，0.075mol)和DMF(150ml)，加入四口烧瓶中，加热至120℃反应10小时，降至室温后，反应液倾入1000ml水中，10％稀盐酸调至pH＝3，析出淡黄色固体，过滤，水洗，干燥得到式(I)化合物(16.2克，69.5％)；
mp:169–171.5℃。ESI-MS(m/z):339.2(M-H)-，1HNMR(CDCl3):2.25(s,3H)，7.00(d,2H)，7.09(d，1H)，7.44(d,1H)，7.50(s,1H)，7.60(s,1H)，8.22(d,2H)，9.69(s,1H)。
实施例2
2-{3-甲基-4-(4’-氨基苯氧基)苯基}-1,2,4-三嗪-3,5(2H,4H)-二酮(式(Ⅴ)化合物)的制备
还原铁粉(9.8g，1.75mol)，水(50mL)，氯化铵(3.75g，70mmol)，加入反应瓶中，加热至60℃。将式(Ⅳ)化合物Ⅳ(11.9g，35mmol)的乙酸乙酯(100mL)溶液，滴加到反应液中。加毕，在回流下反应6-7小时，过滤，滤液分去有机相，水相用乙酸乙酯萃取，合并有机相，水洗中性，无水硫酸钠干燥，过滤，减压蒸除溶剂，得土黄色固体(式(Ⅴ)化合物)(8.68g，收率80％)。
ESI-MS(m/z):309.2[M-H]-；1HNMR(400MHz,DMSO-d6)δ:2.27(s,3H),6.60(d,2H),6.68(d,1H),6.75(d,2H),7.19(d,1H),7.34(s,1H),7.59(s,1H)。
实施例3
2-{3-甲基-4-(4’-乙酰氨基苯氧基)苯基}-1,2,4-三嗪-3,5(2H,4H)-二酮(式(Ⅰ)化合物)的制备
式(Ⅴ)化合物(15.0g，48mmol)，三乙胺(9.1g，90mmol)溶解于DMF(60mL)中，冰浴降温至5℃以下，缓慢加入乙酰氯(6.0g，77mmol)，加毕，冰浴保温5℃以下反应30min，然后升至室温反应3h，反应完毕，加入适量水，搅拌，过滤，滤饼水洗中性，甲醇/水重结晶,干燥，得类白色固体15.0g，收率88.7％。
熔点：215～218℃。ESI-MS(m/z):351.1[M-H]-；1H NMR(400MHz,DMSO-d6)δ:2.03(s,3H),2.24(s,3H),6.86(d,1H),6.94(d,2H),7.28(d,1H),7.41(d,1H),7.58(s,1H),7.61(d,2H),9.94(s,1H),12.31(s,1H)。
实施例4
AZL预混剂的制备
取AZL50g，加豆粕粉10000g，搅拌均匀即得AZL预混剂。临用前，取适量，加鸡配合饲料适量搅拌均匀制备成所需浓度的含AZL饲料使用。
实施例5
AZL在预防鸡柔嫩艾美尔球虫病中的应用
1材料和方法
1.1动物
1日龄浦东黄羽小公鸡。
1.2药物
AZL，含量：99.10％,中国农业科学院上海兽医研究所自制。
临用前，将其加入不含其他药物的鸡配合饲料中，混合均匀，分别制备成含AZL浓度为5mg/kg和10mg/kg的含药饲料。
式(Ⅴ)化合物，含量：99.58％,中国农业科学院上海兽医研究所自制。
临用前，将其加入不含其他药物的鸡配合饲料中，混合均匀，分别制备成含式(Ⅴ)化合物浓度为5mg/kg和10mg/kg的含药饲料。
式(Ⅳ)化合物，含量：99.26％,中国农业科学院上海兽医研究所自制。
临用前，将其加入不含其他药物的鸡配合饲料中，混合均匀，分别制备成含式(Ⅳ)化合物浓度为5mg/kg和10mg/kg的含药饲料。
地克珠利原料药，临用前，将其加入不含其他药物的鸡配合饲料中，混合均匀，制备成含地克珠利浓度为1mg/kg的含药饲料。
1.3实验方法
1.3.1实验分组
测试中使用90只1日龄浦东黄羽小公鸡在健康动物房中饲养至14天后，随机分组分为8组。每组10只。其中一组为健康对照组。AZL饲料添加组设5mg/kg和10mg/kg两个浓度各一组；式(Ⅳ)化合物饲料添加组设5mg/kg和10mg/kg两个浓度各一组；式(Ⅴ)化合物饲料添加组设5mg/kg和10mg/kg两个浓度各一组；药物对照组为地克珠利饲料添加组，浓度为1mg/kg；另设感染对照组一组。
1.3.2给药方法和球虫感染
分组完成后，AZL饲料添加组、式(Ⅳ)化合物饲料添加组、式(Ⅴ)化合物饲料添加组和地克珠利药物对照组立即开始饲喂添加指定药物的饲料，感染对照组和健康对照组喂不添加药物的饲料。各组正常饮水。15日龄，除健康对照组外，各组每只鸡人工感染鸡柔嫩艾美尔球虫孢子化卵囊80000个。
1.4临床观察
试验期间，每日观察记录试验鸡的饲料和饮水的采食情况、精神状态、发病、血便等。感染后第五、六、七天，收集每组鸡的粪便进行粪便卵囊计数，最高值记入ACI的计算中。试验期间每天观察试验鸡的死亡情况，并做好剖检验证。第八天，各组分别称重并全部剖杀，观察记录试验鸡的增重和盲肠病变情况。
1.5药效评价
1.5.1死亡率：因感染球虫而致死的鸡数占试验鸡数的百分比。
1.5.2相对增重率：各感染组试验鸡平均增重与健康对照组平均增重的百分比。
1.5.3盲肠病变值：按Johson和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)的方法进行盲肠病变记分病变值＝全组 平均病变记分×10。
1.5.4卵囊值:将各组盲肠内容物混合匀浆,用Mc-Master′s法计算每克盲肠内容物的卵囊数(OPG)。卵囊比数＝(阴性对照组或投药组卵囊数÷阳性对照组卵囊数)×100％。如果卵囊比数为0-1％，则卵囊值为0；卵囊比数为2％-25％，卵囊值为5；卵囊比数26％-50％，卵囊值为10；卵囊比数51％-75％，卵囊值为20；卵囊比数6％-100％，卵囊值为40。
1.5.5抗球虫指数(ACI)：ACI＝(相对增重率+存活率)-(病变值+卵囊值)。
1.5.6评判标准ACI在120以下为无效，在120-160之间为低效，在160-180为中效，在180以上为高效(农业部兽药审评委员会办公室.兽药试验技术规范汇编.中国农业科学技术出版社，2001，22-23.)。
1.6结果
结果显示，AZL在两个不同添加浓度下，都具有较好的抗球虫效果(表1)。
表1 AZL预防鸡柔嫩艾美尔球虫试验结果
Figure PCTCN2014090460-appb-000006
实施例6
AZL对大鼠的急性毒性试验(LD50)
1.1受试药
AZL，含量：99.10％,中国农业科学院上海兽医研究所自制。
药物溶媒：0.5％羧甲基纤维素钠。
给药前，将AZL加入0.5％羧甲基纤维素钠制备成多个浓度的混悬液。
1.2实验动物：SPF级SD大鼠，雌雄各半，购于西普尔-必凯实验动物有限公司，许可证号 码SCXK(沪)：2008-0016。试验鼠购入后，雌雄动物分笼饲养，正式试验前适应性饲养4天以上。
1.3急性毒性试验
通过反复预试验确定LD0～LD100区间范围，并依之分组，确定组间比。正式试验选用180～220g的大鼠80只，随机分为8组，每组10只，雌雄各半，其中7组各组用药剂量分别为2358、3000、3817、4856、6178、7860、10000mg/kg体重，对大鼠经口1次灌服，1组作为阴性对照组灌服药物溶媒，给药后连续观察14天，统计死亡率，以改良寇氏法计算LD50值及其95％可信限区间。
1.4结果
具体实验结果见表2，以改良寇氏法计算得LD50值为4743mg/kg，95％可信限区间为3754～5993mg/kg。
表2 AZL急性毒性试验结果
Figure PCTCN2014090460-appb-000007

Claims (4)

  1. 一种具有抗鸡球虫病的三嗪化合物，其特征在于该化合物具有下式结构：
    Figure PCTCN2014090460-appb-100001
  2. 一种权利要求1所述化合物的应用，其特征在于该化合物在制备抗鸡球虫病药物中的应用。
  3. 一种抗鸡球虫病药物组合物，其特征在于该组合物含有有效量的作为活性成分的如权利要求1所述式(I)化合物或其可药用盐和可药用载体。
  4. 一种权利要求1所述化合物的的制备方法，其特征在于该方法包括以下步骤：
    A、由式(Ⅱ)化合物或其酚钠盐与式(Ⅲ)化合物通过威廉森合成法缩合制备成式(Ⅳ)化合物；式(Ⅲ)化合物中取代基x为卤素；
    Figure PCTCN2014090460-appb-100002
    B、由式(IV)化合物，还原硝基制备得到式(V)化合物；
    Figure PCTCN2014090460-appb-100003
    C、由式(Ⅴ)化合物在乙酰氯存在下，通过氨基的酰基化制备得到式(Ⅰ)化合物；
    Figure PCTCN2014090460-appb-100004
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CN116606259A (zh) * 2023-07-19 2023-08-18 山东国邦药业有限公司 一种抗虫兽药沙咪珠利关键中间体的制备方法
CN116606259B (zh) * 2023-07-19 2023-09-15 山东国邦药业有限公司 一种抗虫兽药沙咪珠利关键中间体的制备方法

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CN103554046B (zh) 2015-04-01
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