CN117126116A - Derivative of isoxazoline compound and application thereof - Google Patents

Derivative of isoxazoline compound and application thereof Download PDF

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Publication number
CN117126116A
CN117126116A CN202210554242.XA CN202210554242A CN117126116A CN 117126116 A CN117126116 A CN 117126116A CN 202210554242 A CN202210554242 A CN 202210554242A CN 117126116 A CN117126116 A CN 117126116A
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reaction
compound
derivative
added
completed
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张亮
李守军
刘爱玲
李亚玲
张冰
张林奇
张鑫鑫
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RINGPU (TIANJIN) BIO-PHARMACY CO LTD
Tianjin Ringpu Bio Technology Co Ltd
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RINGPU (TIANJIN) BIO-PHARMACY CO LTD
Tianjin Ringpu Bio Technology Co Ltd
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Priority to CN202210554242.XA priority Critical patent/CN117126116A/en
Priority to PCT/CN2023/093609 priority patent/WO2023221868A1/en
Publication of CN117126116A publication Critical patent/CN117126116A/en
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P7/00—Arthropodicides
    • A01P7/02—Acaricides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P7/00—Arthropodicides
    • A01P7/04—Insecticides
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
    • C07C25/24—Halogenated aromatic hydrocarbons with unsaturated side chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/48—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention provides a derivative of an isoxazoline compound and application thereof in preventing and treating parasitic infection, wherein the structural general formula of the derivative of the isoxazoline compound is as follows:

Description

Derivative of isoxazoline compound and application thereof
Technical Field
The invention belongs to the technical field of medical compounds, and particularly relates to a derivative of an isoxazoline compound and application thereof.
Background
Animals such as mammals, domestic animals and the like are often susceptible to parasite infestations. Domestic animals such as cats and dogs are typically infested with one or more of the following ectoparasites: cats and dog fleas (Chlamydia, etc.), ticks (Rhipicephalus, hard ticks, leather ticks, etc.), and mites (Demodex, sarcoptic, otoacarus, etc.), lice (Demodex, blazed mites, etc.), mosquitoes (Aedes, culex, anopheles, etc.), and flies (Musca, chrysomya, periomyza, etc.). Parasites which are prevalent in livestock animals are ticks of the genus Bolus, in particular the species Bolus parvus (Bolus) and Bolus looses, etc. Ticks, such as micropin ticks, are particularly difficult to control because they live in pastures where livestock are grazing. Other important parasites of cattle and sheep are listed as follows, with decreasing importance: fly causing myiasis such as bot and trypanosoma philippinensis; flies causing myiasis in sheep such as lucilia sericata and Aerugo. These are flies whose larvae constitute animal parasites; diptera, i.e. those whose adults constitute parasites, such as blood-flies; lice such as sheep jaw lice and the like; and mites such as and sheep pruritus.
Thus, controlling parasitic infections of animal groups has been an important global task. Isoxazolines are a broad spectrum class of pesticides that inhibit L-glutamate and gamma-aminobutyric acid ligand-gated chloride channels at different locations, which are ubiquitous in the central nervous system of vertebrates and invertebrates; and the insecticidal composition also exists at the peripheral nerve muscle part of invertebrates, so that the invertebrate can become an excellent target of insecticide, and has good insecticidal activity on pests such as ticks, fleas, lice, hemiptera, diptera and the like. Four types of isoxazolines of pesticides currently on the market are: fluralaner (fluorine Lei Lana), sarollaner (Sha Luola na), afoxololaner (aforana) and Lotillan (rotilana) all contain classical isoxazole rings in their structures and are mainly used for in vitro disinsection of animals such as cats and dogs.
Due to the excellent insecticidal activity and high safety of isoxazolines, research on derivatives thereof has been increasing in recent years. Besides the four isoxazoline drugs in the following table, other isoxazoline drugs are only applied to the agricultural field, such as Fluxametamide and Isocycloseram as broad-spectrum insecticides and acaricides for crops such as fruit trees and vegetables, grains, rice, corn, soybean, beet, cotton and the like. Therefore, there is a need to develop their use in veterinary medicine, i.e. safe administration, to effectively control parasites in animals.
According to the related patent and literature reports, the LD50 values of fluorine Lei Lana and rotigotine are higher, and the safety of fluorine Lei Lana and rotigotine is higher. However, the higher the safety of the drug, the larger the dosage of the drug to be used. Fluorine Lei Lana and lotirana require significant amounts to maintain effective insecticidal concentrations in skin and blood as shown in the following table:
name of the name LD50(Rat) Dosage(Dog)
Fluorine Lei Lana >2000mg/kg 25mg/kg
Sha Luola nm 783mg/kg 2mg/kg
Alkana (Affara) >1000mg/kg 2.5mg/kg
Rotirana (Lotirana) >2000mg/kg 20mg/kg
In summary, there is an urgent need in the art to develop an isoxazoline antiparasitic drug with high insecticidal activity and good safety.
Disclosure of Invention
Based on the above, the invention aims to solve the technical problems in the prior art and provides a derivative of an isoxazoline compound, and a preparation method and application thereof. The technical scheme of the invention is as follows:
in a first aspect of the invention, there is provided a derivative of an isoxazoline compound, wherein the structural general formula of the derivative of the isoxazoline compound is shown in formula (I):
wherein R1 is selected from H, OH, CN, NO2, OCH3, CF3, N (CH 3) 2, br or F;
r2 is selected from
Preferably, the derivative of the isoxazoline compound is selected from the following compounds 1 to 23:
the preparation method of the derivative of the isoxazoline compound comprises the following steps:
method 1: preparation of Compounds 1-10
Adding a reaction initiator A and a chloro reagent (oxalyl chloride or thionyl chloride, 1.1-1.5 eq) (eq is molar ratio) into a reaction bottle, reacting in a solvent (selected from tetrahydrofuran, dichloromethane, toluene, 5-15V, V is volume mass ratio), detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding into ammonia water to obtain an intermediate state of acyl chloride, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, adding the solvent (selected from tetrahydrofuran, dichloromethane, ethyl acetate, 5-15V) to extract an aqueous phase, concentrating an organic phase, and recrystallizing to obtain an intermediate A.
Adding an intermediate A, an orthoformate reagent (selected from trimethyl orthoformate, triethyl orthoformate and triisopropyl orthoformate, 10.0-15.0 eq) and a nucleophile (selected from methylamine hydrochloride, S-methylthiohydroxylamine hydrochloride, O-cyclopropylhydroxylamine hydrochloride and methoxyamine hydrochloride, 1.0-1.5 eq) into a reaction bottle for reaction, detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, and filtering, concentrating and recrystallizing an organic phase after the reaction is completed to obtain the compound 1-10.
Method 2: preparation of Compounds 11-12
Intermediate B, N, N-dimethylformamide (5.0-10.0V), N-bromosuccinimide (1.0-1.5 eq) and purified water (1.0-2.0V) are added into a reaction bottle and stirred for reaction, the reaction progress is detected by Thin Layer Chromatography (TLC), water is added for dilution after the reaction is completed, liquid separation and water washing are carried out, and an organic phase is concentrated and recrystallized to obtain the compound 11-12.
Method 3: preparation of Compound 13
Adding the reaction initiator 10 and oxalyl chloride (1.1-1.5 eq) into a reaction bottle, performing reaction in a solvent (selected from tetrahydrofuran, dichloromethane, toluene and 5.0-15.0V), detecting the reaction progress by Thin Layer Chromatography (TLC) during the reaction, concentrating until no fraction is obtained after the reaction is completed, adding the acid chloride intermediate into ammonia water, adding 1M hydrochloric acid after the reaction is completed, stopping the reaction, concentrating an organic phase, and recrystallizing to obtain the compound 13.
Method 4: preparation of Compounds 14-23
The reaction initiator B and oxalyl chloride (1.1-1.5 eq) are added into a reaction bottle, the reaction is carried out in a solvent (selected from tetrahydrofuran, dichloromethane, toluene and 5.0-15.0V), the reaction progress is detected by Thin Layer Chromatography (TLC) during the reaction, and the reaction is concentrated until no fraction is obtained after the reaction is completed, thus obtaining the intermediate state of the acyl chloride.
The reaction initiator C (1.2-1.5 eq), triethylamine (3.0-5.0 eq) and solvent (selected from tetrahydrofuran, methylene dichloride, ethyl acetate, 5.0-15.0V) are added into a reaction bottle, the progress of the reaction is detected by Thin Layer Chromatography (TLC) in the reaction process, 1M hydrochloric acid is added to terminate the reaction after the reaction is completed, and the organic phase is concentrated and recrystallized to obtain the compound 14-23.
In a second aspect, the invention provides application of the derivative of the isoxazoline compound in preparing a medicament for preventing and treating parasitic infection.
Preferably, the parasite is an animal ectoparasite; the ectoparasites are selected from fleas, ticks, demodex mites, scabies, ear mites, lice, mosquitoes, flies.
Preferably, the parasite is a parasite in the locus or environment in which the animal is located.
In a third aspect, the invention provides application of the derivative of the isoxazoline compound in preparing a medicament for controlling agricultural pests.
Preferably, the agricultural pest is selected from the group consisting of plutella xylostella, armyworm, spodoptera frugiperda, cotton bollworm, corn borer, mosquito larvae, aphid, and tetranychus cinnabarinus.
In a fourth aspect of the present invention, there is provided a pharmaceutical composition for the control of parasitic infections, the pharmaceutical composition comprising a derivative of an isoxazoline compound of the present invention, and optionally one or more pharmaceutically acceptable carriers and/or excipients.
In a fifth aspect of the present invention there is provided a pharmaceutical formulation for use in the control of parasitic infections, said pharmaceutical formulation comprising a pharmaceutical composition as described above.
Preferably, the pharmaceutical formulation is an external pharmaceutical formulation including, but not limited to, drops, pour-on, spray, spread, topical solution, lotion, liniment, ointment, plaster, paste, patch.
Preferably, the pharmaceutical formulation is an oral pharmaceutical formulation including, but not limited to, tablets, granules, capsules, solutions, suspensions, emulsions.
Preferably, the pharmaceutical formulation is an injectable pharmaceutical formulation including, but not limited to, an injectable formulation, a lyophilized powder.
The beneficial effects are that:
(1) Compared with fluorine Lei Lana and rotirasodium, the derivatives of the 23 isoxazolines can achieve effective insecticidal effect under the condition of low dosage.
(2) Compared with fluorine Lei Lana and lotirana, the derivative of the isoxazoline compound has higher safety.
(3) The derivative of the isoxazoline compound has remarkable effects in resisting parasites and agricultural pests in animal bodies, outside environments and places.
Detailed Description
The foregoing will be described in further detail by way of the following detailed description of the embodiments. It should not be construed that the scope of the above subject matter is limited to the following examples. All techniques implemented based on this disclosure are within the scope.
The instruments, reagents, materials, etc. used in the following examples are, unless otherwise specified, conventional instruments, reagents, materials, etc. known in the prior art, and are commercially available, and the experimental methods, detection methods, etc. used in the following examples are, unless otherwise specified, conventional experimental methods, detection methods, etc. known in the prior art.
Example 1 preparation of Compound 1
The starting material 1 and oxalyl chloride (1.5 eq) (eq in the following examples are all expressed as molar ratio) are added into a reaction bottle, the reaction is carried out for 12 hours at 20-30 ℃ in a solvent dichloromethane (10.0V relative to the starting material 1, the volume mass ratio is 10ml:1g, V in the following examples is the volume mass ratio), the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, the reaction is concentrated to a fraction-free intermediate state after the reaction is completed, the acyl chloride is added into ammonia water, 1M hydrochloric acid is added to terminate the reaction after the reaction is completed, the dichloromethane (10.0V) is used for extracting an aqueous phase, and the organic phase is concentrated and recrystallized to obtain the intermediate 1.
Intermediate 1, triethyl orthoformate (15.0 eq) and methylamine hydrochloride (1.5 eq) are added into a reaction bottle to react at 50-60 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and after the reaction is completed, an organic phase is filtered, concentrated and recrystallized to obtain the compound 1.
Example 2 preparation of Compound 2
Adding the initial material 1 and oxalyl chloride (1.5 eq) into a reaction bottle, reacting for 12 hours at 20-30 ℃ in dichloromethane (10.0V), detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the acyl chloride intermediate into ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by using dichloromethane (10.0V), concentrating and recrystallizing the organic phase to obtain the intermediate 1.
Intermediate 1, trimethyl orthoformate (15.0 eq) and S-methyl thiohydroxylamine hydrochloride (1.2 eq) are added into a reaction bottle to react at 30-40 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and after the reaction is completed, an organic phase is filtered, concentrated and recrystallized to obtain a compound 2.
EXAMPLE 3 preparation of Compound 3
Adding the initial material 1 and oxalyl chloride (1.5 eq) into a reaction bottle, reacting for 12 hours at 20-30 ℃ in a solvent dichloromethane (10.0V), detecting the reaction progress by using Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the acyl chloride intermediate into ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by using dichloromethane (10.0V), concentrating and recrystallizing the organic phase to obtain the intermediate 1.
Intermediate 1, triethyl orthoformate (13.0 eq) and O-cyclopropyl hydroxylamine hydrochloride (1.5 eq) are added into a reaction bottle to react at 50-60 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and after the reaction is completed, an organic phase is filtered, concentrated and recrystallized to obtain the compound 3.
Example 4 preparation of Compound 4
Adding the initial material 4 and thionyl chloride (1.5 eq) into a reaction bottle, reacting for 8 hours at 60-70 ℃ in toluene (15.0V), detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the obtained acid chloride intermediate into ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting an aqueous phase by ethyl acetate (10.0V), concentrating an organic phase, and recrystallizing to obtain the intermediate 4.
Intermediate 4, trimethyl orthoformate (13.0 eq) and methoxyamine hydrochloride (1.3 eq) are added into a reaction bottle to react at 30-40 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and after the reaction is completed, an organic phase is filtered, concentrated and recrystallized to obtain the compound 4.
Example 5 preparation of Compound 5
Adding the initial material 5 and thionyl chloride (1.5 eq) into a reaction bottle, reacting for 8 hours at 60-70 ℃ in toluene (10.0V), detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the obtained acid chloride intermediate into ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting an aqueous phase by ethyl acetate (10.0V), concentrating an organic phase, and recrystallizing to obtain the intermediate 5.
Intermediate 5, triethyl orthoformate (14.0 eq) and methoxyamine hydrochloride (1.3 eq) are added into a reaction bottle to react at 50-60 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and after the reaction is completed, an organic phase is filtered, concentrated and recrystallized to obtain the compound 5.
EXAMPLE 6 preparation of Compound 6
Adding the initiator 6 and oxalyl chloride (1.3 eq) into a reaction bottle, reacting for 8 hours at 20-30 ℃ in tetrahydrofuran (5.0V), detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the acyl chloride intermediate into ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the aqueous phase by tetrahydrofuran (10.0V), concentrating and recrystallizing the organic phase to obtain the intermediate 6.
Intermediate 6, trimethyl orthoformate (10.0 eq) and methoxyamine hydrochloride (1.1 eq) are added into a reaction bottle to react at 30-40 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and after the reaction is completed, an organic phase is filtered, concentrated and recrystallized to obtain the compound 6.
EXAMPLE 7 preparation of Compound 7
Adding the initial material 7 and thionyl chloride (1.5 eq) into a reaction bottle, reacting for 8 hours at 60-70 ℃ in toluene (15.0V), detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the obtained acid chloride intermediate into ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting an aqueous phase by ethyl acetate (10.0V), concentrating an organic phase, and recrystallizing to obtain the intermediate 7.
Adding the intermediate 7, triisopropyl orthoformate (13.0 eq) and methoxyamine hydrochloride (1.2 eq) into a reaction bottle to react at 60-70 ℃, detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, and filtering, concentrating and recrystallizing an organic phase after the reaction is completed to obtain the compound 7.
EXAMPLE 8 preparation of Compound 8
Adding the initiator 8 and oxalyl chloride (1.5 eq) into a reaction bottle, reacting for 8 hours at 20-30 ℃ in tetrahydrofuran (5.0V), detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the acyl chloride intermediate into ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the aqueous phase by tetrahydrofuran (15.0V), concentrating and recrystallizing the organic phase to obtain the intermediate 8.
Intermediate 8, triethyl orthoformate (15.0 eq) and methoxyamine hydrochloride (1.5 eq) are added into a reaction bottle to react at 50-60 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and after the reaction is completed, an organic phase is filtered, concentrated and recrystallized to obtain the compound 8.
EXAMPLE 9 preparation of Compound 9
Adding the initiator 9 and oxalyl chloride (1.3 eq) into a reaction bottle, reacting for 12 hours at 20-30 ℃ in dichloromethane (10.0V), detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the acyl chloride intermediate into ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by using dichloromethane (10.0V), concentrating the organic phase, and recrystallizing to obtain the intermediate 9.
Intermediate 9, triethyl orthoformate (12.0 eq) and methoxyamine hydrochloride (1.1 eq) are added into a reaction bottle to react at 50-60 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and after the reaction is completed, an organic phase is filtered, concentrated and recrystallized to obtain the compound 9.
Example 10 preparation of Compound 10
The starting material 10 and oxalyl chloride (1.1 eq) are added into a reaction bottle, the reaction is carried out in methylene dichloride (5.0V) at the temperature of 0-10 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, after the reaction is completed, the reaction liquid in the intermediate state of the acyl chloride is added into ammonia water, after the reaction is completed, 1M hydrochloric acid is added to terminate the reaction, the methylene dichloride (5.0V) is used for extracting the water phase, and the organic phase is concentrated and recrystallized to obtain the intermediate 10.
Adding the intermediate 10, triisopropyl orthoformate (15.0 eq) and methoxyamine hydrochloride (1.5 eq) into a reaction bottle to react at 60-70 ℃, detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, and filtering, concentrating and recrystallizing an organic phase after the reaction is completed to obtain the compound 10.
EXAMPLE 11 preparation of Compound 11
The intermediate 1, N-dimethylformamide (10.0V), N-bromosuccinimide (1.5 eq) and purified water (2.0V) described in example 1 were added into a reaction flask to carry out a reaction at 60-70 ℃, the progress of the reaction was detected by Thin Layer Chromatography (TLC) during the reaction, water was added after the completion of the reaction to dilute, ethyl acetate (10.0V) was used to extract the aqueous phase, the solution was separated, washed with water, and the organic phase was concentrated and recrystallized to give compound 11.
Example 12 preparation of Compound 12
The intermediate 10, N-dimethylformamide (8.0V), N-bromosuccinimide (1.3 eq) and purified water (1.0V) described in example 10 were added into a reaction flask to carry out a reaction at 60-70 ℃, the progress of the reaction was detected by Thin Layer Chromatography (TLC) during the reaction, water was added after the completion of the reaction to dilute, ethyl acetate (10.0V) was used to extract the aqueous phase, the solution was separated, washed with water, and the organic phase was concentrated and recrystallized to give compound 12.
EXAMPLE 13 preparation of Compound 13
The starting material 10 and oxalyl chloride (1.1 eq) are added into a reaction bottle, the reaction is carried out at 0-10 ℃ in methylene dichloride (10.0V), the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, after the reaction is completed, the reaction liquid in the intermediate state of the acyl chloride is added into ammonia water, after the reaction is completed, 1M hydrochloric acid is added to terminate the reaction, the methylene dichloride (10.0V) is used for extracting the water phase, and the organic phase is concentrated and recrystallized to obtain the compound 13 (intermediate 10).
EXAMPLE 14 preparation of Compound 14
Adding the initial material 1 and oxalyl chloride (1.5 eq) into a reaction bottle, reacting for 12 hours at 20-30 ℃ in dichloromethane (10.0V), detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the intermediate acid chloride into methoxyamine, adding 1M hydrochloric acid after the reaction is completed to terminate the reaction, extracting the aqueous phase by using dichloromethane (10.0V), concentrating the organic phase, and recrystallizing to obtain the compound 14.
EXAMPLE 15 preparation of Compound 15
The starting material 15-1 and oxalyl chloride (2.0 eq) are added into a reaction bottle, the reaction is carried out for 12 hours at 20-30 ℃ in methylene dichloride (15.0V), the reaction progress is detected by Thin Layer Chromatography (TLC) during the reaction, and the reaction is concentrated until no fraction is obtained after the reaction is completed, thus obtaining the intermediate state of the acyl chloride.
The starting materials 15-2 (1.3 eq), triethylamine (4.0 eq) and ethyl acetate (15.0V) are added into a reaction bottle, stirred and mixed uniformly, the intermediate state of acyl chloride is added into the reaction bottle, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, 1M hydrochloric acid is added after the reaction is completed to terminate the reaction, and the organic phase is concentrated and recrystallized to obtain the compound 15.
EXAMPLE 16 preparation of Compound 16
The starting material 15-1 and oxalyl chloride (2.0 eq) are added into a reaction bottle, the reaction is carried out for 12 hours at 20-30 ℃ in methylene dichloride (15.0V), the reaction progress is detected by Thin Layer Chromatography (TLC) during the reaction, and the reaction is concentrated until no fraction is obtained after the reaction is completed, thus obtaining the intermediate state of the acyl chloride.
Starting material 16-2 (1.3 eq), triethylamine (5.0 eq) and tetrahydrofuran (5.0V) are added into a reaction bottle, stirred and mixed uniformly, acyl chloride intermediate is added into the reaction bottle, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, 1M hydrochloric acid is added after the reaction is completed to terminate the reaction, and an organic phase is concentrated and recrystallized to obtain the compound 16.
EXAMPLE 17 preparation of Compound 17
The starting material 15-1 and oxalyl chloride (2.0 eq) are added into a reaction bottle, the reaction is carried out for 12 hours at 20-30 ℃ in methylene dichloride (15.0V), the reaction progress is detected by Thin Layer Chromatography (TLC) during the reaction, and the reaction is concentrated until no fraction is obtained after the reaction is completed, thus obtaining the intermediate state of the acyl chloride.
Starting material 17-2 (1.3 eq), triethylamine (3.0 eq) and tetrahydrofuran (10.0V) are added into a reaction bottle, stirred and mixed uniformly, acyl chloride intermediate is added into the reaction bottle, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, 1M hydrochloric acid is added after the reaction is completed to terminate the reaction, and an organic phase is concentrated and recrystallized to obtain the compound 17.
Example 18 preparation of Compound 18
The starting material 15-1 and oxalyl chloride (2.0 eq) are added into a reaction bottle, the reaction is carried out for 12 hours at 20-30 ℃ in methylene dichloride (15.0V), the reaction progress is detected by Thin Layer Chromatography (TLC) during the reaction, and the reaction is concentrated until no fraction is obtained after the reaction is completed, thus obtaining the intermediate state of the acyl chloride.
The starting material 18-2 (1.5 eq), triethylamine (5.0 eq) and tetrahydrofuran (5.0V) are added into a reaction bottle, stirred and mixed uniformly, the intermediate state of acyl chloride is added into the reaction bottle, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, 1M hydrochloric acid is added after the reaction is completed to terminate the reaction, and the organic phase is concentrated and recrystallized to obtain the compound 18.
EXAMPLE 19 preparation of Compound 19
The starting material 15-1 and oxalyl chloride (2.0 eq) are added into a reaction bottle, the reaction is carried out for 12 hours at 20-30 ℃ in methylene dichloride (15.0V), the reaction progress is detected by Thin Layer Chromatography (TLC) during the reaction, and the reaction is concentrated until no fraction is obtained after the reaction is completed, thus obtaining the intermediate state of the acyl chloride.
The starting material 19-2 (1.2 eq), triethylamine (5.0 eq) and tetrahydrofuran (5.0V) are added into a reaction bottle, stirred and mixed uniformly, the intermediate state of acyl chloride is added into the reaction bottle, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, 1M hydrochloric acid is added after the reaction is completed to terminate the reaction, and the organic phase is concentrated and recrystallized to obtain the compound 19.
EXAMPLE 20 preparation of Compound 20
The starting material 4 and thionyl chloride (1.5 eq) are added into a reaction bottle, the reaction is carried out for 8 hours at 60-70 ℃ in toluene (10.0V), the reaction progress is detected by Thin Layer Chromatography (TLC) during the reaction, and the reaction is concentrated until no fraction is obtained after the reaction is completed.
The starting materials 20-2 (1.2 eq), triethylamine (5.0 eq) and methylene dichloride (15.0V) are added into a reaction bottle, stirred and mixed uniformly, the intermediate state of acyl chloride is added into the reaction bottle, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, 1M hydrochloric acid is added after the reaction is completed to terminate the reaction, and the organic phase is concentrated and recrystallized to obtain the compound 20.
Example 21 preparation of Compound 21
The starting material 7 and thionyl chloride (1.5 eq) are added into a reaction bottle, the reaction is carried out for 8 hours at 60-70 ℃ in toluene (15.0V), the reaction progress is detected by Thin Layer Chromatography (TLC) during the reaction, and the reaction is concentrated until no fraction is obtained after the reaction is completed.
The starting materials 20-2 (1.2 eq), triethylamine (4.0 eq) and tetrahydrofuran (5.0V) are added into a reaction bottle, stirred and mixed uniformly, the intermediate state of acyl chloride is added into the reaction bottle, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, 1M hydrochloric acid is added after the reaction is completed to terminate the reaction, and the organic phase is concentrated and recrystallized to obtain the compound 21.
Example 22 preparation of Compound 22
The starting material 5 and thionyl chloride (1.5 eq) are added into a reaction bottle, the reaction is carried out for 8 hours at 60-70 ℃ in toluene (15.0V), the reaction progress is detected by Thin Layer Chromatography (TLC) during the reaction, and the reaction is concentrated until no fraction is obtained after the reaction is completed.
The starting materials 20-2 (1.3 eq), triethylamine (5.0 eq) and tetrahydrofuran (5.0V) are added into a reaction bottle, stirred and mixed uniformly, the intermediate state of acyl chloride is added into the reaction bottle, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, 1M hydrochloric acid is added after the reaction is completed to terminate the reaction, and the organic phase is concentrated and recrystallized to obtain the compound 22.
EXAMPLE 23 preparation of Compound 23
The starting material 8 and oxalyl chloride (1.5 eq) were added into a reaction flask, reacted in tetrahydrofuran (15.0V) at 20-30 ℃ for 8 hours, the progress of the reaction was checked by Thin Layer Chromatography (TLC) during the reaction, and concentrated to no fraction after the reaction was completed to obtain the intermediate acid chloride.
The starting materials 20-2 (1.2 eq), triethylamine (3.0 eq) and tetrahydrofuran (5.0V) are added into a reaction bottle, stirred and mixed uniformly, the intermediate state of acyl chloride is added into the reaction bottle, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, 1M hydrochloric acid is added after the reaction is completed to terminate the reaction, and the organic phase is concentrated and recrystallized to obtain the compound 23.
The nuclear magnetic hydrogen spectrum data and mass spectrum data for compounds 1-23 are shown in the following table:
table 1 Nuclear magnetic Hydrogen Spectrometry and Mass Spectrometry data for Compounds 1-23
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EXAMPLE 24 in vitro insecticidal toxicity test of the isoxazoline drugs of the invention against parasitic infection
In vitro ticks: compounds 1-23 were dissolved in DMSO and aliquots were added to citrated bovine blood in membrane-covered Petri dishes. The petri dish was placed on a warm dish. The fed ticks were removed and placed in a petri dish containing sand. Paralysis and/or death of the fed ticks was observed at about 24, 48 and 72 hours. Endpoint data was recorded as LC90 in μg/mL. The positive control was fluorine Lei Lana and DMSO was used as the negative control.
In vitro mites: compounds 1-23 were dissolved in DMSO and aliquots were added to citrated bovine blood in membrane-covered petri dishes pre-warmed to 37 ℃. The fed mites were placed on petri dishes. Mortality of the fed mites was observed at about 24, 48 and 72 hours. Endpoint data was recorded as LC90 in μg/mL. The positive control was fluorine Lei Lana and DMSO was used as the negative control.
In vitro mosquitoes: compounds 1-23 were dissolved in DMSO and aliquots were added to citrated bovine blood in membrane-covered Petri dishes. About 10 mosquitoes were placed on each petri dish and capped. The mosquitoes were then fed on the treated bovine blood. Mosquitoes were kept at about 80°f and at a minimum of about 50% relative humidity. The knockdown and mortality of mosquitoes were checked at about 2 and 24 hours. Endpoint data was recorded as LC90 in μg/mL. The positive control was fluorine Lei Lana and DMSO was used as the negative control.
Fleas in vitro: compounds 1-23 were dissolved in DMSO and aliquots were added to citrated bovine blood in membrane-covered petri dishes pre-warmed to 37 ℃. The fleas are fed are placed in a container on one side of the artificial membrane and the treated bovine blood is added to the container on the other side of the artificial membrane. Mortality of fleas fed was observed at about 48, 96 and 128 hours. Endpoint data was recorded as LC90 in μg/mL. The positive control was fluorine Lei Lana and DMSO was used as the negative control.
Table 2 in vitro toxicity test of isoxazoline derivatives-drugs
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The results demonstrate that the derivatives of isoxazoline compounds obtained by chemical synthesis in examples 1-23 have lower in vitro lethal concentrations against mosquitoes, ticks, mites, fleas, compared with the marketed isoxazoline drug fluorine Lei Lana, demonstrating higher in vitro insecticidal activity.
EXAMPLE 25 oral toxicity test
Acute toxicity: the mice are subjected to quarantine observation and adaptive feeding, the number of animals is determined according to the grouping number, and the number of test animals (female and male halves) is selected for formal tests, and each group comprises 20 animals (female and male halves).
TABLE 3 acute toxicity test of isoxazoline derivatives in mice
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Sub-chronic toxicity: rats were quarantined and raised adaptively, and the number of animals tested (male and female halves) was selected for formal testing, and 20 animals per group (male and female halves) were dosed daily for 30 days in a mixed diet of 25mg according to the dose conversion of fluorine Lei Lana.
TABLE 4 effects of isoxazoline derivatives on rat body weight, food intake, and Water intake experiments
TABLE 5 experiment of the influence of isoxazoline derivatives on blood routine index
TABLE 6 experiment of the Effect of isoxazoline derivatives on rat organ coefficients
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The results demonstrate that the derivatives of the compounds prepared in examples 1-23 of the present invention are safer and have higher LD 50; meanwhile, the drug administration group in the sub-chronic toxicity test has no adverse reaction, and the blood routine index, the organ coefficient and the non-drug administration group have no obvious change, thus proving that the veterinary drug has higher safety.
EXAMPLE 26 antiparasitic external preparations 1 to 23
Active ingredients: compounds 1-23 500mg, respectively
Solvent: diethylene glycol monoethyl ether 9ml
Cosolvent: dimethyl sulfoxide 1ml
The preparation method comprises the following steps: dispersing the active ingredients with 80% diethylene glycol monoethyl ether, controlling the temperature to be 30-40 ℃, adding 1ml dimethyl sulfoxide, clarifying, adding the rest 20% diethylene glycol monoethyl ether, and filling into a low molecular weight polyethylene sealed tank.
EXAMPLE 27 in vitro insect (tick) repellent effect experiment
According to in vitro experimental data and literature reports, the LD50 of ticks in ectoparasites is the highest and the difficulty of killing ticks is the greatest, so ticks are selected for in vitro experiments of target animals.
In this evaluation, beagle dogs of mixed sex were used and assigned to a blank group control group, a commercially positive group (external preparation with fluororalston as an active ingredient) and a group of example 26 of the present invention (external preparation 1-23 with compounds 1-23 as an active ingredient), and experimental dogs were challenged with 50 adult ticks without eating (rhizus).
Dogs received treatment on day 0 at a dose of 40mg/kg of fluorine Lei Lana, 10mg/kg of compounds 1-23. The formulation was administered using a pipette. The dose is administered in the form of a line at the back neck of the skull base.
Average rates of detection of ticks in dogs at day 0, day 5, day 10, day 20 and day 30 after dosing were counted for each group of drugs, and any immediate response of dogs to treatment was observed at day 1, day 2 and day 7 after dosing, as well as adverse effects, skin irritation and the characteristics of the test formulations after treatment.
Table 7 average detection rate of drug against in vitro ticks
The above experimental data show that the external preparations 1-23 prepared by using the compounds 1-23 have better in vitro insect repellent effect compared with the commercial products.
Example 28 Effect of killing agricultural pests experiment
(1) Plutella xylostella
For evaluation of control of plutella xylostella by the compounds of the present invention, the test unit consisted of a small open container with 12-14 day old radish plants inside. They were pre-infested with about 50 new larvae distributed in the test unit via corn cob cuttings. After distribution into the test unit, the larvae were moved on the test plants.
Test compounds were formulated using a formulation comprising 20% dimethyl sulfoxide and 80% water. All test compounds in this test were sprayed at a concentration of 50ppm and the test was assayed in triplicate. The test units were kept in a growth chamber at 25℃and 70% relative humidity for 6 days. Plant feeding damage was then assessed based on the fed leaf vision, and pest mortality was also counted and calculated for each test unit.
Table 8 average rate of detection of plutella xylostella by drug
Day 0 For 6 days
Blank group 100％ 100％
Compound 1 100％ 1％
Compound 2 100％ 9％
Compound 3 100％ 6％
Compound 4 100％ 8％
Compound 5 100％ 10％
Compound 6 100％ 5％
Compound 7 100％ 14％
Compound 8 100％ 10％
Compound 9 100％ 17％
Compound 10 100％ 4％
Compound 11 100％ 3％
Compound 12 100％ 14％
Compound 13 100％ 9％
Compound 14 100％ 13％
Compound 15 100％ 5％
Compound 16 100％ 6％
Compound 17 100％ 8％
Compound 18 100％ 11％
Compound 19 100％ 4％
Compound 20 100％ 3％
Compound 21 100％ 20％
Compound 22 100％ 17％
Compound 23 100％ 13％
(2) Armyworm
To evaluate the control of armyworm by the compounds of the present invention, the test unit consisted of a small open container with 4-5 day old corn plants inside. It was pre-infested with 10 to 15 1 day old larvae on a piece of insect diet. Test compounds were formulated as described in test (1) and sprayed at a concentration of 50ppm, and the tests were performed in triplicate. After spraying, the test units were kept in the growth chamber and then each test unit was assessed for control efficacy as described in test (1).
Table 9 average rate of drug detection against armyworm
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(3) Aphids
To evaluate the control effect of the compounds of the invention on aphids, the test unit consisted of a small open container with 12 to 15 day old radish plants inside. The plants were pre-infested by placing 30 to 40 aphids (leaf cutting method) on one leaf of the test plant, which are located on one leaf cut from the cultivated plant.
Test compounds were formulated and sprayed as described in test (1). All test compounds in these tests were sprayed at a concentration of 100ppm and the tests were assayed in triplicate. The test units were kept in a growth chamber at 19-21 ℃ and 50% -70% relative humidity for 6 days. The insect mortality of each test unit was then assessed visually.
Table 10 average aphid detection rate of drug
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The experiments show that the compounds 1-23 have good effects of preventing and controlling agricultural pests.
The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily recognize that variations or substitutions are within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (10)

1. The derivative of the isoxazoline compound is characterized in that the structural general formula of the derivative of the isoxazoline compound is shown as formula (I):
wherein R1 is selected from H, OH, CN, NO2, OCH3, CF3, N (CH 3) 2, br or F;
r2 is selected from
2. The derivative of isoxazolines according to claim 1, wherein the derivative is one of compounds 1-23:
3. use of a derivative of an isoxazoline compound as defined in claim 1 or 2 for the preparation of a medicament for the control of parasitic infections.
4. Use of the derivative of isoxazolines as defined in claim 1 or 2 for the preparation of a medicament for controlling agricultural pests.
5. Use according to claim 3, wherein the parasite is an animal ectoparasite.
6. The use according to claim 5, wherein the ectoparasite is one or more of fleas, ticks, demodex mites, scabies, ear mites, lice, mosquitoes, flies.
7. Use according to claim 3, wherein the parasite is a parasite in the locus or environment of the animal.
8. The use according to claim 4, wherein the agricultural pest is one or more of plutella xylostella, armyworm, spodoptera frugiperda, cotton bollworm, corn borer, mosquito larva, aphid, tetranychus cinnabarinus.
9. A pharmaceutical composition for controlling parasitic infections comprising a derivative of an isoxazoline compound as described in claim 1 or 2, further comprising one or more pharmaceutically acceptable carriers and/or excipients.
10. Use of a derivative of a compound as claimed in claim 1 or 2 or a pharmaceutical composition as claimed in claim 9 for the preparation of a pharmaceutical formulation for the control of parasitic infections.
CN202210554242.XA 2022-05-20 2022-05-20 Derivative of isoxazoline compound and application thereof Pending CN117126116A (en)

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JP4883296B2 (en) * 2004-03-05 2012-02-22 日産化学工業株式会社 Isoxazoline-substituted benzamide compounds and pest control agents
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