Novel compound, synthetic method thereof and application of novel compound in preparation of anticoccidial drugs

Abstract

The invention discloses a novel compound, a synthesis method thereof and application of the novel compound in preparation of anticoccidial drugs. The compound provided by the invention is a new substance which is designed and synthesized by applying a splicing principle based on anticoccidial drugs, namely halofuginone hydrobromide and orfluminol. The synthesis method of the substance is a one-pot synthesis method with 7-bromo-6-chloro-4 (3H)-quinazolinone and 2-chloro-6-fluorobenzyl chloride as raw materials. The synthesis process is simple, the used materials are easy to obtain, and the obtained product is high in purity and controllable in quality. The anticoccidial index (ACI) of the anticoccidial drug prepared from the novel compound provided by the invention can reach 180, and the anticoccidial drug has a good anticoccidial effect.

Description

Technical Field

[0001] The present invention relates to the field of veterinary drugs and drug synthesis, and in particular to a new compound and a synthesis method thereof, as well as the use of the new compound in the preparation of anti- Application in insecticides. Technical Background

[0002] Chicken coccidiosis is an intestinal parasitic disease of chickens caused by Eimeria. The high morbidity and mortality of the disease have caused great losses to my country's poultry industry. With the popularization of intensive farming and the strong environmental adaptability of oocysts, the prevention and control of the disease has become increasingly difficult. The main clinical prevention and control methods are drug prevention and control and vaccine immunization. In recent years, vaccine research and application have achieved certain results, with the advantages of safety, high efficiency, no drug resistance, and no drug residues, but also face the risk of high cost and vaccine re-strengthening. Drug prevention and control is low-cost and widely favored by farmers, mainly including polyether ion carrier anticoccidial drugs and chemical synthetic anticoccidial drugs. However, most anticoccidial drugs are easy to remain in poultry meat or eggs, threatening human health, and there are certain limitations; and the currently available coccidial drugs are limited, and coccidia have developed certain drug resistance and cross-resistance to most drugs, which puts drug prevention and control in a dilemma. Therefore, the creation of new green and safe anticoccidial drugs is of great significance in the field of veterinary medicine and plays an important role in ensuring the healthy development of the poultry farming industry. At present, my country has successfully developed two new Class I veterinary drugs: the polyether hainanmycin and the triazine samizulil. In 2020, the applicant also successfully developed a new process for safflowerone and obtained the national Class II new veterinary drug certificate.

[0003] Halofuginone is a halogenated derivative of the natural compound "halofuginine". The synthesis process was developed by Cyanamid Corporation in the United States. It was later transferred to the French company Roussel Uclaf for formulation and marketing for the prevention of Eimeria in broiler chickens. The chemical name of halofuginone is 7-bromo-6-chloro-3-[3-(3-hydroxy-2-piperidinyl)-2-oxypropyl(acetonyl)]-4(3H)-quinazolinone, and its molecular formula is C 16 H 17 BrClN3O3, molecular weight is 414.68, CAS number is 55837-20-2.

[0004] Arprinocid is a highly effective, broad-spectrum anticoccidial drug developed by Merck, USA. Fluoropurinol, fluoroadenine or fluoroadenine, is currently the only type of nucleoside compound used as anticoccidial drug. The drug was originally developed in the UK and widely used in the prevention and treatment of chicken Eimeria. It was approved for marketing in the European Community in 1983. The chemical name of Erpurinol is 9-(2-chloro-6-fluorobenzyl)-9H-purine-6-amine, and its molecular formula is C 12 H9CIFN5, molecular weight is 277.68, CAS number is 55779-18-5.

[0005] The chemical structure of halofugone is: It can be cleaved into two fragments: quinazolinone and 2-propanone piperidine.

[0006] The parent nucleus of quinazolinone is benzopyrimidone. Compounds containing this structure usually exhibit a broad spectrum of physiological activities such as antibacterial, anti-inflammatory, antifungal, anti-acne, antimalarial, antiplatelet aggregation, antispasmodic, antidepressant, hypoglycemic, vasodilation, insecticide, antioxidant and antiviral. Therefore, quinazolinone molecules are widely used in the fields of medicine and agriculture. On the other hand, the introduction of piperidine ring has multiple effects, namely improving the interaction between drug molecules and their targets, improving the metabolic stability of compounds, and increasing the water solubility of drug molecules. However, the secondary nitrogen group on the piperidine ring is highly toxic, which may be one of the reasons why halofuginone has a narrow safety range when used and is more toxic after exceeding the limit.

[0007] The chemical structure of Erpulinol is: It can be cleaved into two fragments: adenine and a fluorine-substituted benzyl group.

[0008] Adenine is one of the main pharmacodynamic structures of nucleoside drugs, which play an important role in tumor-specific treatment and broad-spectrum antiviral therapy. On the other hand, the introduction of fluorine atoms or fluorine-containing groups can adjust the physical and chemical properties of drugs, change pharmacokinetic properties, and improve the bioavailability of drugs; it can also enhance the binding ability and selectivity of ligands and target proteins by affecting the conformation of compounds; and improve the metabolic stability of drugs by blocking metabolic sites.

[0009] The main task of new drug research and development is the discovery of drug lead compounds and the structural optimization of lead compounds, and structural splicing is becoming more and more important. It is one of the important methods to design and develop new drug lead compounds. The so-called splicing is to splice the structures of two drugs into one molecule, or to make the pharmacophores of the two drugs compatible in one molecule, so that the formed drug has the properties of both drugs, strengthens the pharmacological effects, reduces the corresponding toxic side effects, or makes the two drugs complement each other, exert their respective pharmacological activities, and synergistically complete the treatment.

[0010] Based on the results of literature research, a comprehensive analysis of the structural characteristics of halofuginone and erpurinol can preliminarily infer the anticoccidial efficacy of the two The greatest effect may come from the structural fragments on the left, while the fragments on the right are mostly functional modifications. Therefore, according to the principle of splicing, considering the pharmacological and toxicological characteristics of each structure, it is planned to splice the pharmacological structure of halofuginone - quinazolinone fragment and the functional modification fragment of erpurinol - fluorine-containing group. The compound was searched and determined to be a new compound, and its application or research in the field of anticoccidial has not been reported. Summary of the invention

[0011] The present invention proposes a new compound and its synthesis method and its application in the preparation of anticoccidial drugs. The key is to use the splicing principle to design Design and synthesize new compounds, and apply them to the creation of anticoccidial drugs to solve the eternal problem of lack of new drugs in the anticoccidial drug market.

[0012] The purpose of the present invention is achieved through the following technical means:

[0013] A new compound, a synthesis method thereof and its application in the preparation of anticoccidial drugs, the key points are:

[0014] The structural formula of the new compound is: The molecular formula is C 15 H8OBrCl2FN2, molecular weight is 402.04.

[0015] Furthermore, the synthetic route of the new compound is:

[0016] Further, the synthesis method of the new compound is: 7-bromo-6-chloro-4(3H)-quinazolinone and 2-chloro-6-fluorobenzyl chloride are reacted in an inorganic Alkylation reaction occurs under the action of base to obtain the target product. The mass ratio of 7-bromo-6-chloro-4(3H)-quinazolinone, 2-chloro-6-fluorobenzyl chloride, solvent and inorganic base is 1:(0.7-1.2):(6-15):(0.55-1), preferably 1:1:7.5:0.85; the solvent is acetonitrile, propionitrile, methyltetrahydrofuran, 1,4-dioxane, DMF, N-methylpyrrolidone, preferably DMF; the inorganic base refers to sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, preferably potassium carbonate.

[0017] Furthermore, the new compound is mixed with suitable auxiliary materials to prepare a premix, which is then added to commercial feed for use.

[0018] Furthermore, the addition amount of the new compound is 6 to 9 grams per ton of feed, and the anticoccidial index of the new compound is confirmed by animal infection tests. The ACI can reach 180, which has a good anticoccidial effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 This is the high-resolution mass spectrum (MS spectrum) of the new compound obtained in the synthesis step of Example 1

[0020] Figure 2 This is the infrared absorption spectrum (IR spectrum) of the new compound obtained in the synthesis step of Example 1

[0021] Figure 3 is the H NMR spectrum of the new compound obtained in the synthesis step of Example 1 ( 1 HNMR spectrum)

[0022] Figure 4 is the carbon NMR spectrum of the new compound obtained in the synthesis step of Example 1 ( 13 CNMR spectrum) DETAILED DESCRIPTION

[0023] Example 1

[0024] Synthesis of new compounds

[0025] 130 g (0.5 mol) of 7-bromo-6-chloro-4(3H)-quinazolinone, 130 g of 2-chloro-6-fluorobenzyl chloride, 110 g of potassium carbonate and 975 g of DMF were added to the reaction flask in sequence; the reaction system was heated to 100-110° C. and the reaction was continued with stirring for 8 hours; after the reaction was completed, the reaction was cooled to room temperature, 2000 ml of water was added, and the reaction was stirred for 1 hour; the reaction was filtered, and the filter cake was transferred to 800 g of ethanol and stirred for 2 hours; the reaction was filtered, and the filter cake was dried at 80-90° C. to obtain 178 g of gray product. Yield: 88.4%.

[0026] Example 2

[0027] Synthesis of new compounds

[0028] 7-bromo-6-chloro-4(3H)-quinazolinone 130 g (0.5 mol), 2-chloro-6-fluorobenzyl chloride 130 g, potassium carbonate 110 g and 1500g of acetonitrile; heat the reaction system to reflux and continue stirring for 15 hours; after the reaction is completed, cool to room temperature; filter with suction, transfer the filter cake to 1000ml of water, stir for 2 hours; filter with suction, dry the filter cake at 100-110℃, and obtain 165g of gray product. The yield is 81.9%.

[0029] Example 3

[0030] The new compound product and starch obtained in Example 1 were crushed and passed through an 80-mesh sieve for later use. Two parts of the new compound and 98 parts of corn starch were weighed. parts (by weight), mixed in equal and increasing amounts to prepare a premix with a specification of 2%.

[0031] Example 4

[0032] The new compound product and starch obtained in Example 1 were crushed and passed through an 80-mesh sieve for later use. 3 parts of the new compound and 97 parts of corn starch were weighed. parts (by weight), mixed in equal and increasing amounts to prepare a premix with a specification of 3%.

[0033] Example 5

[0034] The new compound product and starch obtained in Example 1 were crushed and passed through an 80-mesh sieve for later use. 3 parts of the new compound and 97 parts of corn cob powder were weighed. parts (by weight), mixed in equal and increasing amounts to prepare a premix with a specification of 3%.

[0035] Experimental example

[0036] Experimental study on the anti-Eimeria tenella effect of new compounds

[0037] This experimental example conducted a drug efficacy evaluation test on the premix obtained in Example 3-5, including the following test contents:

[0038] (1) Purchase 200 healthy chicks and raise them to 12 days old. Select 180 chicks with similar weights and divide them into 6 groups, 30 in each group. The grouping and dosing schedule are as follows: Group No. name Dosing cycle Usage and Dosage Active ingredient dosage 1 Blank control group / / 0 2 Infection control group / / 0 3 Halofuginone control group D12-22 1 ton of feed mixed with 500g premix (0.6%) 3mg / kg 4 Example 3 Group D12-22 1 ton of feed mixed with 300g premix (2%) 6mg / kg 5 Example 4 Group D12-22 1 ton of feed mixed with 300g premix (3%) 9mg / kg 6 Example 5 Group D12-22 1 ton of feed mixed with 300g premix (3%) 9mg / kg

[0039] (2) Experimental groups 2 to 6 were orally inoculated with 5×10 4 sporulated Eimeria oocysts, and record daily mental status status, feeding, oocyst excretion, bloody stool, death, etc.

[0040] (3) On the eighth day after the attack, the animals were killed and the scores of cecal lesions and oocyst counts were calculated. The anticoccidial index (ACI) was further calculated. The formula is ACI = (survival rate + relative weight gain rate) - (lesion value + oocyst value).

[0041] (4) Result A: The weight gain of animals after drug administration is as follows: Group Average initial weight (g) Average final body weight (g) Weight gain rate (%) Relative weight gain rate (%) 1 67.98±8.13 100.18±14.06 47.37 100 2 63.64±7.17 80.61±8.60 26.66 56 3 64.30±7.94 91.40±9.88 42.16 89 4 67.23±8.15 94.94±13.39 41.22 87 5 64.28±8.68 92.05±12.11 43.20 91 6 64.60±6.60 92.26±9.50 42.82 90

[0042] (5) Result B: The comprehensive evaluation of the anticoccidial effect is as follows: Group Relative weight gain rate (%) Survival rate (%) Cecal lesion value Oocyst value Anticoccidial Index (ACI) 1 100 100(30 / 30) 0.0 0 / 2 56 86.67(26 / 30) 63.5 40 / 3 89 100(30 / 30) 1.0 0 188 4 87 96.67(29 / 30) 5.7 5 173 5 91 100(30 / 30) 3.1 5 183 6 90 100(30 / 30) 3.3 5 182

[0043] (6) Conclusion: Adding 6-9 mg of the new compound proposed in the present invention to every 1 kg of feed has a good preventive effect on chicken coccidia infection. Adding 6 mg can exert a moderate anticoccidial effect; adding 9 mg has the same effect as the control drug "halofuginone hydrobromide" in terms of improving survival rate, alleviating cecal lesions, and reducing oocyst excretion, and is a highly effective anticoccidial drug. The new compound designed in the present invention has a significant anticoccidial effect and good safety, can be used to develop new anticoccidial drugs, and has broad application prospects in the field of anticoccidial drugs.

[0044] The present invention has been described in detail above using general descriptions and specific embodiments. However, some modifications or improvements may be made on the basis of the present invention, which are within the scope of protection required by the present invention without departing from the spirit of the present invention.

Claims

1. A new compound and a method for synthesizing the same and use thereof in the preparation of anticoccidial drugs, characterized in that: The structural formula of the new compound is: The molecular formula is C 15 H8OBrCl2FN2, molecular weight is 402.

04.

2. A novel compound and a synthesis method thereof and use thereof in the preparation of anticoccidial drugs according to claim 1, characterized in that: The synthetic route of the new compound is:

3. A novel compound and a synthesis method thereof and use thereof in the preparation of anticoccidial drugs according to claim 1, characterized in that: The synthesis method of the new compound is as follows: 7-bromo-6-chloro-4(3H)-quinazolinone and 2-chloro-6-fluorobenzyl chloride undergo alkylation reaction in a suitable solvent under the action of an inorganic base to obtain the target product. The mass ratio of 7-bromo-6-chloro-4(3H)-quinazolinone, 2-chloro-6-fluorobenzyl chloride, solvent, and inorganic base is 1:(0.7-1.2):(6-15):(0.55-1), preferably 1:1:7.5:0.85; the solvent is acetonitrile, propionitrile, methyltetrahydrofuran, 1,4-dioxane, DMF, N-methylpyrrolidone, preferably DMF; the inorganic base refers to sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, preferably potassium carbonate.

4. A novel compound and a synthesis method thereof and use thereof in the preparation of anticoccidial drugs according to claim 1, characterized in that: The new compound is mixed with suitable auxiliary materials to prepare a premix, which is then added to commercial feed for use, with the added amount being 6 to 9 grams per ton of feed.

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