CN117122594A - External medicinal preparation for resisting parasitic infection and preparation method and application thereof - Google Patents

External medicinal preparation for resisting parasitic infection and preparation method and application thereof Download PDF

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Publication number
CN117122594A
CN117122594A CN202210550493.0A CN202210550493A CN117122594A CN 117122594 A CN117122594 A CN 117122594A CN 202210550493 A CN202210550493 A CN 202210550493A CN 117122594 A CN117122594 A CN 117122594A
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CN
China
Prior art keywords
compound
preparation
reaction
external
pharmaceutical preparation
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Pending
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CN202210550493.0A
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Chinese (zh)
Inventor
张亮
李守军
刘爱玲
李亚玲
张朋丽
李岩
张林奇
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RINGPU (TIANJIN) BIO-PHARMACY CO LTD
Tianjin Ringpu Bio Technology Co Ltd
Original Assignee
RINGPU (TIANJIN) BIO-PHARMACY CO LTD
Tianjin Ringpu Bio Technology Co Ltd
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Application filed by RINGPU (TIANJIN) BIO-PHARMACY CO LTD, Tianjin Ringpu Bio Technology Co Ltd filed Critical RINGPU (TIANJIN) BIO-PHARMACY CO LTD
Priority to CN202210550493.0A priority Critical patent/CN117122594A/en
Priority to PCT/CN2023/093563 priority patent/WO2023221862A1/en
Publication of CN117122594A publication Critical patent/CN117122594A/en
Pending legal-status Critical Current

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    • 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
    • A61K31/11—Aldehydes
    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides an external medicinal preparation for resisting parasitic infection, and a preparation method and application thereof. The aldehyde compound which is an active ingredient in the pharmaceutical preparation has insecticidal activity and can effectively improve the stability of the preparation; and the utilization rate of the active ingredients of the medicine is improved by improving the transdermal rate of the external preparation.

Description

External medicinal preparation for resisting parasitic infection and preparation method and application thereof
Technical Field
The invention belongs to the technical field of chemical pharmaceutical preparations, and particularly relates to an external pharmaceutical preparation for resisting parasite infection, and a preparation method and application thereof.
Background
Controlling parasitic infections of animal groups has been an important global task. Pathogenic organisms can be classified as endoparasitic organisms of the nematoda, cestoda and trematoda or protozoan phylum, or ectoparasitic organisms of the arthropoda phylum. The former include infections of the stomach, intestinal tract, lymphatic system, tissues, liver, lung, heart and brain. The latter ectoparasites include ticks, mites, lice, flies and fleas. These organisms often act as vehicles and intermediate hosts for the transmission of endoparasites to animal hosts.
The isoxazolines are broad-spectrum pesticides, can inhibit the ligand-gated chloride ion channels of L-glutamic acid and gamma-aminobutyric acid at different positions, and have good insecticidal activity on pests such as tick order, flea order, louse order, hemiptera order, diptera order and the like. The four types of isoxazoline pesticides on the market at present all contain classical isoxazole rings and are mainly used for in-vitro disinsection of animals such as cats, dogs and the like. 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 that have been marketed, other isoxazoline drugs are only used in the agricultural field, such as fluxamide and Isocycloseram as broad-spectrum insecticides and acaricides for crops such as fruit trees and vegetables, cereals, rice, maize, soybean, sugar beet, cotton, etc. There is therefore a need to identify specific formulations that allow their veterinary use, i.e. safe administration, to effectively control parasites in animals.
At present, a proper anti-ectoparasite drug delivery system is a transdermal drug delivery system, and transdermal absorption of drugs is promoted mainly by a transdermal absorption promoter, so that a plurality of dosage forms such as drops, pouring agents, spraying agents and the like are researched. The solvents of the prior art formulations and of the conventional topical ectoparasiticide formulations may lead to problems of wet appearance of the pelt after administration, insolubility of the active ingredient, skin irritation, etc.
The natural aldehyde compound exists in a large amount in nature, has the functions of sterilizing, resisting virus, resisting oxidation, killing insects, repelling mosquitoes and the like, can dilate blood vessels, promote blood circulation, and has certain effects on softening and eliminating scars and fibroids of skin. By adding the natural aldehyde compound into the external preparation, the solution stability of the raw material medicine can be improved, the irritation to the skin of the pet is small, the medicine is promoted to pass through the skin cuticle, meanwhile, the mosquito can be repelled and avoided, and the risk of the infection of the pet by mosquitoes carrying endoparasites can be effectively reduced.
In summary, there is an urgent need in the art to develop an antiparasitic agent of isoxazolines with good solubility of active pharmaceutical ingredient, high insecticidal activity, good safety, and little skin irritation.
Disclosure of Invention
In view of the above, the invention aims to overcome the defects in the prior art, and provides an external medicinal preparation for resisting parasite infection, and a preparation method and application thereof.
In order to achieve the above purpose, the technical scheme of the invention is realized as follows:
as a first aspect of the present invention, there is provided an external pharmaceutical preparation for combating parasitic infection, the external pharmaceutical preparation comprising a first active ingredient and an aldehyde compound, the first active ingredient being an isoxazoline compound.
Preferably, the structural general formula of the isoxazoline compound is shown as formula (I):
wherein R is 1 Selected from H, OH, CN, NO 2 、OCH 3 、CF 3 、N(CH 3 ) 2 Br or F;
R 2 selected from the group consisting of NH 2 、/>OH、/> More preferably, R 1 Selected from H or F, R 2 Selected from->
Preferably, the isoxazoline compound is selected from the following compounds 1 to 30:
preferably, the aldehyde compound is one or a combination of more of citronellal, citral, solenopsis invicta, cinnamaldehyde and eugenol; more preferably, the aldehyde compound is cinnamaldehyde.
Preferably, the external pharmaceutical preparation further comprises a solvent and a cosolvent.
More preferably, the solvent is one or more of diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monopropyl ether, diethylene glycol butyl methyl ether, dipropylene glycol monoethyl ether, dipropylene glycol monopropyl ether, dipropylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether, and propylene glycol monobutyl ether. Further preferably, the solvent is diethylene glycol monoethyl ether.
More preferably, the cosolvent is one or more of dimethyl sulfoxide, dimethylformamide, dimethylacetamide, dimethylpropionamide, diethylformamide, diisopropylformamide, acetone, ethanol and isopropanol. Further preferably, the co-solvent is dimethyl sulfoxide.
Preferably, the external pharmaceutical preparation comprises the following components in proportion:
the concentration of the isoxazoline compound is 10-300 mg/ml;
the addition amount of the aldehyde compound accounts for 1-5% of the total volume of the external pharmaceutical preparation;
the addition amount of the solvent accounts for 80-90% of the total volume of the external pharmaceutical preparation;
the addition amount of the cosolvent accounts for 5-15% of the total volume of the external pharmaceutical preparation.
As a second aspect of the present invention, there is provided a method for preparing the above-mentioned external pharmaceutical preparation for combating parasitic infection, comprising the steps of:
(1) Adding an isoxazoline compound into an aldehyde compound and a solvent with the volume ratio of 50-80%, and uniformly mixing to obtain a mixture;
(2) Adding a cosolvent into the mixture obtained in the step (1), dissolving and clarifying, and then adding the rest solvent with the volume ratio of 20-50% to fix the volume to obtain an external preparation solution;
(3) And (5) filling the external preparation solution into a container to obtain the external preparation.
As a third aspect of the present invention, there is provided another external pharmaceutical preparation for combating parasitic infection, which further comprises a second active ingredient on the basis of the above-mentioned compounds, the second active ingredient being one or more of the following compounds:
(a) Pyrethroids;
(b) A macrolide compound;
(c) Insect growth regulators;
(d) Carbamates;
(e) Formamidines;
(f) A nicotinoyl chloride;
(g) Imidazothiazoles;
(h) Benzimidazoles;
(i) Tetrahydroimidazoles;
(j) Isoquinolines;
(k) Salicylanilides.
Preferably, the pyrethroid compound is selected from one or more of permethrin, cypermethrin, deltamethrin, fenpropathrin, flumethrin, fenvalerate, phenothrin, tetramethrin and allethrin; the macrolide compound is one or more selected from ivermectin, siramectin, moxidectin, spinosad, milbemycin, avermectin and Ai Mode s; the insect growth regulator is selected from one or more of pyriproxyfen, lufenuron, desiccanil, s-methoprene, antifebrile, tebufenozide, diflubenzuron, chlorfluazuron, hexaflumuron, diafenthiuron, buprofezin and cyromazine; the carbamate compound is selected from one or more of indoxacarb, propoxur, isoprocarb, aldicarb, methomyl and carbofuran; the formamidine compound is selected from amitraz; the nicotinoyl chloride compound is one or more selected from dinotefuran, nitenpyram and thiamethoxam.
Preferably, the external pharmaceutical preparation comprises the following components in proportion:
the concentration of the isoxazoline compound is 10-300 mg/ml;
the concentration of the second active ingredient is 10-300 mg/ml;
the addition amount of the aldehyde compound accounts for 1-5% of the total volume of the external pharmaceutical preparation;
the addition amount of the solvent accounts for 80-90% of the total volume of the external pharmaceutical preparation;
the addition amount of the cosolvent accounts for 5-15% of the total volume of the external pharmaceutical preparation.
Preferably, the external pharmaceutical preparation comprises the following components in parts by weight:
the concentration of the isoxazoline compound is 10-100 mg/ml;
the concentration of the second active ingredient is 10-100 mg/ml;
the addition amount of the aldehyde compound accounts for 2-3% of the total volume of the external pharmaceutical preparation;
the addition amount of the solvent accounts for 85-90% of the total volume of the external pharmaceutical preparation;
the addition amount of the cosolvent accounts for 5-10% of the total volume of the external pharmaceutical preparation.
As a fourth aspect of the present invention, there is provided a method for preparing the above-mentioned external pharmaceutical preparation for combating parasitic infection, comprising the steps of:
(1) Taking a first active component and a second active component, adding an aldehyde compound and a solvent with the volume ratio of 50-80%, and mixing until uniformity is achieved, thus obtaining a mixture;
(2) Adding a cosolvent into the mixture obtained in the step (1), dissolving and clarifying, and then adding the rest solvent with the volume ratio of 20-50% to fix the volume to obtain an external preparation solution;
(3) And (5) filling the external preparation solution into a container to obtain the external preparation.
As a fourth aspect of the present invention, there is provided the use of the above-described topical pharmaceutical formulation in the manufacture of a medicament for the treatment or prophylaxis of parasites in non-human animals.
Compared with the prior art, the invention has the following advantages:
(1) The aldehyde compound which is an effective component in the antiparasitic external pharmaceutical preparation has insecticidal activity and can effectively improve the stability of the preparation; and the utilization rate of the active ingredients of the medicine is improved by improving the transdermal rate of the external preparation.
(2) Compared with fluorine Lei Lana, the active ingredients in the antiparasitic external pharmaceutical preparation can achieve effective insecticidal effect under the condition of lower dosage.
(3) The invention adopts isoxazoline compound to be used by being compounded with one or more of pyrethroid, macrolide compound, insect growth regulator, carbamate, formamidine, nicotinyl chloride, imidazothiazole, benzimidazole, tetrahydroimidazole, isoquinoline and salicylanilide, and can realize the simultaneous driving of internal and external parasites.
Detailed Description
Unless defined otherwise, technical terms used in the following examples have the same meaning as commonly understood by one of ordinary skill in the art to which the inventive concepts pertain. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods are conventional methods unless otherwise specified.
The invention will be described in detail with reference to examples.
Example 1A topical pharmaceutical formulation for combating parasitic infections
Active ingredients: fluxametamide (Compound 1) 500mg;
solvent: 9ml of diethylene glycol monoethyl ether;
aldehyde compounds: 0.1ml of cinnamaldehyde;
cosolvent: dimethyl sulfoxide 1ml.
The preparation method comprises the following steps: taking Fluximamide and cinnamaldehyde with the prescription amount, adding 7.2ml of diethylene glycol monoethyl ether for dispersion, controlling the temperature to be 30-40 ℃, adding 1ml of dimethyl sulfoxide, clarifying, adding the rest 1.8ml of diethylene glycol monoethyl ether, and filling into a low molecular weight polyethylene sealed tank to obtain the final product.
The preparation method of the compound 1 comprises the following steps:
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, 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 intermediate state of the acyl chloride into ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by using dichloromethane, concentrating and recrystallizing the organic phase to obtain the intermediate 1.
Intermediate 1, 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 1.
Example 2
The active ingredient is compound 2, and the amounts and preparation methods of other components and components in the preparation are the same as those of example 1.
The preparation method of the compound 2 comprises the following steps:
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, 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 intermediate state of the acyl chloride into ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by using dichloromethane, concentrating and recrystallizing the organic phase 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 a compound 2.
Example 3
The active ingredient is compound 3, and the amounts and preparation methods of other components and components in the preparation are the same as those of example 1.
The preparation method of the compound 3 comprises the following steps:
adding the initial material 1 and oxalyl chloride (1.5 eq) into a reaction bottle, reacting for 12 hours at 20-30 ℃ in dichloromethane, 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 state of the acyl chloride into ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by using dichloromethane, 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 3.
Example 4
The active ingredient is compound 4, and the amounts and preparation methods of other components and components in the preparation are the same as those of example 1.
The preparation method of the compound 4 comprises the following steps:
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, 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 intermediate state of the acyl chloride into ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by using dichloromethane, 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 4.
Example 5
The active ingredient is compound 5, and the amounts and preparation methods of other components and components in the preparation are the same as those of example 1.
The preparation method of the compound 5 comprises the following steps:
adding the initial material 5 and thionyl chloride (1.5 eq) into a reaction bottle, reacting for 8 hours at 60-70 ℃ in toluene, 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 to ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by ethyl acetate, concentrating and recrystallizing the organic phase to obtain the intermediate 5.
Intermediate 5, 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 5.
Example 6
The active ingredient is compound 6, and the amounts and preparation methods of other components and components in the preparation are the same as those of example 1.
The preparation method of the compound 6 comprises the following steps:
adding the initial material 6 and thionyl chloride (1.5 eq) into a reaction bottle, reacting for 8 hours at 60-70 ℃ in toluene, 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 to ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by ethyl acetate, concentrating and recrystallizing the organic phase to obtain the intermediate 6.
Intermediate 6, 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 6.
Example 7
The active ingredient is compound 7, and the amounts and preparation methods of other components and components in the preparation are the same as those of example 1.
The preparation method of the compound 7 comprises the following steps:
adding the initiator 7 and oxalyl chloride (1.3 eq) into a reaction bottle, reacting for 8 hours at 20-30 ℃ in tetrahydrofuran, 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 to ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by tetrahydrofuran, concentrating and recrystallizing the organic phase to obtain the intermediate 7.
Intermediate 7, 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 7.
Example 8
The active ingredient is compound 8, and the amounts and preparation methods of other components and components in the preparation are the same as those of example 1.
The preparation method of the compound 8 comprises the following steps:
adding an initiator 8 and thionyl chloride (1.5 eq) into a reaction bottle, reacting for 8 hours at 60-70 ℃ in toluene, 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 to ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by ethyl acetate, concentrating the organic phase, and recrystallizing to obtain an intermediate 8.
Adding the intermediate 8, 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 8.
Example 9
The active ingredient is compound 9, and the amounts and preparation methods of other components and components in the preparation are the same as those of example 1.
The preparation method of the compound 9 comprises the following steps:
adding the initiator 9 and oxalyl chloride (1.5 eq) into a reaction bottle, reacting for 8 hours at 20-30 ℃ in tetrahydrofuran, 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 to ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by tetrahydrofuran, concentrating and recrystallizing the organic phase to obtain the intermediate 9.
Intermediate 9, 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 9.
Example 10
The active ingredient is compound 10, and the amounts and preparation methods of other components and components in the preparation are the same as those of example 1.
The preparation method of the compound 10 comprises the following steps:
adding the initial material 10 and oxalyl chloride (1.3 eq) into a reaction bottle, reacting for 12 hours at 20-30 ℃ in dichloromethane, 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 state of the acyl chloride into ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by using dichloromethane, concentrating and recrystallizing the organic phase to obtain the intermediate 10.
Intermediate 10, 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 10.
Example 11
The active ingredient is compound 11, and the amounts and preparation methods of other components and components in the preparation are the same as those of example 1.
The preparation method of the compound 11 comprises the following steps:
adding the initial material 11 and oxalyl chloride (1.1 eq) into a reaction bottle, reacting at 0-10 ℃ in dichloromethane, detecting the reaction progress by Thin Layer Chromatography (TLC) during the reaction, adding the reaction liquid of the intermediate state of the acyl chloride into ammonia water after the reaction is completed, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by using dichloromethane, concentrating and recrystallizing the organic phase to obtain the intermediate 11.
Intermediate 11, triisopropyl orthoformate (15.0 eq) and methoxyamine hydrochloride (1.5 eq) are added into a reaction bottle to react at 60-70 ℃, 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 11.
Example 12
The active ingredient is compound 12, and the amounts and preparation methods of other components and components in the preparation are the same as those of example 1.
The preparation method of the compound 12 comprises the following steps:
intermediate 1, N-dimethylformamide (10.0V), N-bromosuccinimide (1.5 eq) and purified water (2.0V) are added into a reaction bottle for reaction at 60-70 ℃, the progress of the reaction is detected by Thin Layer Chromatography (TLC) in the reaction process, water is added for dilution after the reaction is completed, ethyl acetate is used for extracting an aqueous phase, liquid separation and water washing are carried out, and an organic phase is concentrated and recrystallized to obtain the compound 12.
Example 13
The active ingredient is compound 13, and the amounts and preparation methods of other components and components in the preparation are the same as those of example 1.
The preparation method of the compound 13 comprises the following steps:
intermediate 11, N-dimethylformamide (8.0V), N-bromosuccinimide (1.3 eq) and purified water (1.0V) are added into a reaction bottle for reaction at 60-70 ℃, the progress of the reaction is detected by Thin Layer Chromatography (TLC) in the reaction process, water is added for dilution after the reaction is completed, ethyl acetate is used for extracting an aqueous phase, the aqueous phase is separated, water is used for washing, and an organic phase is concentrated and recrystallized to obtain the compound 13.
Example 14
The active ingredient is compound 14, and the amounts and preparation methods of other components and components in the preparation are the same as those of example 1.
The preparation method of the compound 14 comprises the following steps:
the starting material 11 and oxalyl chloride (1.1 eq) are added into a reaction bottle, the reaction is carried out in methylene dichloride at 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 is used for extracting the water phase, and the organic phase is concentrated and recrystallized to obtain an intermediate 14.
Example 15
The active ingredient is compound 15, and the amounts and preparation methods of other components and each component in the preparation are the same as those of example 1.
The preparation method of the compound 15 comprises the following steps:
adding the initial material 1 and oxalyl chloride (1.5 eq) into a reaction bottle, reacting for 12 hours at 20-30 ℃ in dichloromethane, 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 to terminate the reaction after the reaction is completed, extracting the water phase by using dichloromethane, concentrating and recrystallizing the organic phase to obtain the compound 15.
Example 16
The active ingredient is compound 16, and the amounts and preparation methods of other components and each component in the preparation are the same as those of example 1.
The preparation method of the compound 16 comprises the following steps:
adding the initial material 1 and oxalyl chloride (1.5 eq) into a reaction bottle, reacting for 12 hours at 20-30 ℃ in dichloromethane, 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 methanol, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by using dichloromethane, concentrating and recrystallizing the organic phase to obtain the compound 16.
Example 17
The active ingredient is compound 17, and the amounts and preparation methods of other components and components in the preparation are the same as those of example 1.
The preparation method of the compound 17 comprises the following steps:
intermediate 1, triethyl orthoformate (15.0 eq) and 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 a compound 17.
Examples 18 to 19
The active ingredients are compounds 18-19, and the amounts and preparation methods of other components and components in the preparation are the same as those of the example 1.
The preparation method of the compounds 18 and 19 comprises the following steps:
compound 18 is according to literature: the method is characterized in that the method is prepared by the method in 'Sun Hongyang, yang Xu, zhang Jing, etc. fluorine Lei Lana synthesis and insecticidal activity determination [ J ]. Fine chemical engineering, 2020,37 (5): 6'; compound 19 was prepared from compound 18 as an intermediate for the preparation of Fluxametamide.
EXAMPLE 20 an external preparation for combating parasitic infection
Active ingredients: isocycloseram (Compound 20) 500mg;
solvent: 9ml of diethylene glycol monoethyl ether;
aldehyde compounds: 0.1ml of cinnamaldehyde;
cosolvent: dimethyl sulfoxide 1ml.
The preparation method comprises the following steps: adding 7.2ml of diethylene glycol monoethyl ether for dispersion, controlling the temperature to be 30-40 ℃, adding 1ml of dimethyl sulfoxide, clarifying, adding the rest 1.8ml of diethylene glycol monoethyl ether, and filling into a low molecular weight polyethylene sealed tank to obtain the product.
The preparation method of the compound 20 comprises the following steps:
the starting material 20-1 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, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and the reaction is concentrated until no fraction is obtained after the reaction is completed.
Adding the initial material 20-2 (1.5 eq), triethylamine (5.0 eq) and ethyl acetate into a reaction bottle, stirring and mixing uniformly, adding the intermediate state of acyl chloride into the reaction bottle, detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, concentrating an organic phase, and recrystallizing to obtain the compound 20.
Example 21
The active ingredients are respectively compound 21, and the amounts and preparation methods of other components and each component in the preparation are the same as those of example 20.
The preparation method of the compound 21 comprises the following steps:
the starting material 20-1 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, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and the reaction is concentrated until no fraction is obtained after the reaction is completed.
Adding the starting material 21-2 (1.3 eq), triethylamine (4.0 eq) and ethyl acetate into a reaction bottle, stirring and mixing uniformly, adding the intermediate acid chloride into the reaction bottle, detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, concentrating an organic phase, and recrystallizing to obtain the compound 21.
Example 22
The active ingredients are respectively compound 22, and the amounts and preparation methods of other components and each component in the preparation are the same as those of example 20.
The preparation method of the compound 22 comprises the following steps:
the starting material 20-1 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, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and the reaction is concentrated until no fraction is obtained after the reaction is completed.
The starting material 16-2 (1.3 eq), triethylamine (5.0 eq) and tetrahydrofuran 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
The active ingredients are respectively compound 23, and the amounts and preparation methods of other components and each component in the preparation are the same as those of example 20.
The preparation method of the compound 23 comprises the following steps:
the starting material 20-1 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, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and the reaction is concentrated until no fraction is obtained after the reaction is completed.
The starting material 23-2 (1.3 eq), triethylamine (3.0 eq) and tetrahydrofuran 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.
Example 24
The active ingredients are respectively compound 24, and the amounts and preparation methods of other components and each component in the preparation are the same as those of example 20.
The preparation method of the compound 24 comprises the following steps:
the starting material 20-1 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, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and the reaction is concentrated until no fraction is obtained after the reaction is completed.
The initiator 24-2 (1.5 eq), triethylamine (5.0 eq) and tetrahydrofuran 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 24.
Example 25
The active ingredients are respectively compound 25, and the amounts and preparation methods of other components and each component in the preparation are the same as those of example 20.
The preparation method of the compound 25 comprises the following steps:
the starting material 20-1 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, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and the reaction is concentrated until no fraction is obtained after the reaction is completed.
The starting material 25-2 (1.2 eq), triethylamine (5.0 eq) and tetrahydrofuran 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 25.
Example 26
The active ingredients are respectively compound 26, and the amounts and preparation methods of other components and each component in the preparation are the same as those of example 20.
The preparation method of the compound 26 comprises the following steps:
the initiator 26-1 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, 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 are added into a reaction bottle, stirred and mixed uniformly, the intermediate state of the 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 26.
Example 27
The active ingredients are respectively compound 27, and the amounts and preparation methods of other components and each component in the preparation are the same as those of example 20.
The preparation method of the compound 27 comprises the following steps:
the initiator 8 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, 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 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 27.
Example 28
The active ingredients are respectively compound 28, and the amounts and preparation methods of other components and each component in the preparation are the same as those of example 20.
The preparation method of the compound 28 comprises the following steps:
the initiator 6 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, 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 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 28.
Example 29
The active ingredients are respectively compound 29, and the amounts and preparation methods of other components and each component in the preparation are the same as those of example 20.
The preparation method of the compound 29 comprises the following steps:
adding the initial material 9 and oxalyl chloride (1.5 eq) into a reaction bottle, reacting for 8 hours at 20-30 ℃ in tetrahydrofuran, detecting the reaction progress by Thin Layer Chromatography (TLC) during the reaction process, concentrating until no fraction is obtained after the reaction is completed, obtaining the intermediate state of the acyl chloride
The starting materials 20-2 (1.2 eq), triethylamine (3.0 eq) and tetrahydrofuran 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 29.
Example 30
The active ingredients are respectively compound 30, and the amounts and preparation methods of other components and each component in the preparation are the same as those of example 20.
Compound 30 is according to literature: the "Sun Hongyang, yang Xu, zhang Jing, etc. fluorine Lei Lana synthesis and insecticidal activity assay [ J ]. Fine chemical engineering, 2020,37 (5): 6.
Example 31A topical pharmaceutical formulation for combating parasitic infections
A first active ingredient: fluxametamide (Compound 1) 500mg;
A second active ingredient: 600mg of selamectin;
solvent: 9ml of diethylene glycol monoethyl ether;
aldehyde compounds: 0.1ml of cinnamaldehyde;
cosolvent: dimethyl sulfoxide 1ml.
The preparation method comprises the following steps: taking Fluximamide, selamectin and cinnamaldehyde with the prescription amount, adding 7.2ml of diethylene glycol monoethyl ether for dispersion, controlling the temperature to be 30-40 ℃, adding 1ml of dimethyl sulfoxide, clarifying, adding the rest 1.8ml of diethylene glycol monoethyl ether, and filling into a low molecular weight polyethylene sealed tank to obtain the novel compound.
Example 32A topical pharmaceutical preparation for combating parasitic infections
A first active ingredient: isocycloseram (Compound 20) 500mg;
a second active ingredient: 600mg of selamectin;
solvent: 9ml of diethylene glycol monoethyl ether;
aldehyde compounds: 0.1ml of cinnamaldehyde;
cosolvent: dimethyl sulfoxide 1ml.
The preparation method comprises the following steps: taking Isocycloseram, selamectin and cinnamaldehyde with the prescription amount, adding 7.2ml of diethylene glycol monoethyl ether for dispersion, controlling the temperature to be 30-40 ℃, adding 1ml of dimethyl sulfoxide, clarifying, adding the rest 1.8ml of diethylene glycol monoethyl ether, and filling into a low molecular weight polyethylene sealed tank.
Example 33A topical pharmaceutical preparation for combating parasitic infections
Active ingredients: fluxametamide (Compound 1) 1000mg;
Solvent: 8.5ml of diethylene glycol monoethyl ether;
aldehyde compounds: 0.1ml of cinnamaldehyde;
cosolvent: dimethyl sulfoxide 1.5ml.
The preparation method comprises the following steps: taking Fluximamide and cinnamaldehyde with the prescription amount, adding 6.8ml of diethylene glycol monoethyl ether for dispersion, controlling the temperature to be 30-40 ℃, adding 1.5ml of dimethyl sulfoxide, clarifying, adding the rest 1.7ml of diethylene glycol monoethyl ether, and filling into a low molecular weight polyethylene sealed tank to obtain the final product.
Example 34 an external preparation for combating parasitic infection
A first active ingredient: isocycloseram (Compound 20) 1000mg;
a second active ingredient: 100mg of selamectin;
solvent: 8.5ml of diethylene glycol monoethyl ether;
aldehyde compounds: 0.1ml of cinnamaldehyde;
cosolvent: dimethyl sulfoxide 1.5ml.
The preparation method comprises the following steps: taking Isocycloseram, selamectin and cinnamaldehyde with the prescription amount, adding 6.8ml of diethylene glycol monoethyl ether for dispersion, controlling the temperature to be 30-40 ℃, adding 1.5ml of dimethyl sulfoxide, clarifying, adding the rest 1.7ml of diethylene glycol monoethyl ether, and filling into a low molecular weight polyethylene sealed tank.
Example 35A topical pharmaceutical preparation for combating parasitic infections
Active ingredients: fluxametamide (Compound 1) 3000mg;
Solvent: 8.0ml of diethylene glycol monoethyl ether;
aldehyde compounds: 0.5ml of cinnamaldehyde;
cosolvent: dimethyl sulfoxide 1.5ml.
The preparation method comprises the following steps: adding 6.4ml of diethylene glycol monoethyl ether to disperse, controlling the temperature to be 30-40 ℃, adding 1.5ml of dimethyl sulfoxide, clarifying, adding the rest 1.6ml of diethylene glycol monoethyl ether, and filling into a low molecular weight polyethylene sealed tank to obtain the compound 1 and cinnamaldehyde.
Example 36 an external preparation for combating parasitic infection
A first active ingredient: isocycloseram (Compound 20) 3000mg;
a second active ingredient: 3000mg of selamectin;
solvent: 8.0ml of diethylene glycol monoethyl ether;
aldehyde compounds: 0.5ml of cinnamaldehyde;
cosolvent: dimethyl sulfoxide 1.5ml.
The preparation method comprises the following steps: taking compound 20, selamectin and cinnamaldehyde with the prescription amount, adding 6.4ml of diethylene glycol monoethyl ether for dispersion, controlling the temperature to be 30-40 ℃, adding 1.5ml of dimethyl sulfoxide, clarifying, adding the rest 1.6ml of diethylene glycol monoethyl ether, and filling into a low molecular weight polyethylene sealed tank to obtain the compound.
The nuclear magnetic hydrogen spectrum data and mass spectrum data for compounds 1-30 are shown in the following table:
table 1 Nuclear magnetic Hydrogen Spectrometry and Mass Spectrometry data for Compounds 1-30
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Comparative example 1A topical pharmaceutical preparation for combating parasitic infections
Active ingredients: fluxametamide (Compound 1) 500mg;
solvent: 9ml of diethylene glycol monoethyl ether;
cosolvent: dimethyl sulfoxide 1ml.
The preparation method comprises the following steps: taking Fluximamide with a prescription amount, adding 7.2ml of diethylene glycol monoethyl ether for dispersion, controlling the temperature to be 30-40 ℃, adding 1ml of dimethyl sulfoxide, clarifying, adding the rest 1.8ml of diethylene glycol monoethyl ether, and filling into a low molecular weight polyethylene sealed tank to obtain the final product.
Comparative example 2 an external preparation for preventing parasitic infection
Active ingredients: isocycloseram (Compound 20) 500mg;
solvent: dipropylene glycol monoethyl ether 9ml;
cosolvent: dimethyl sulfoxide 1ml.
The preparation method comprises the following steps: adding 7.2ml of diethylene glycol monoethyl ether to disperse, controlling the temperature to be 30-40 ℃, adding 1ml of dimethyl sulfoxide, clarifying, adding the rest 1.8ml of diethylene glycol monoethyl ether, and filling into a low molecular weight polyethylene sealed tank to obtain the product.
Comparative example 3A topical pharmaceutical preparation for combating parasitic infections
Active ingredients: fluxametamide (Compound 1) 500mg;
solvent: 9ml of diethylene glycol monoethyl ether;
antioxidant: 0.1g of butylhydroxytoluene;
Cosolvent: dimethyl sulfoxide 1ml.
The preparation method comprises the following steps: taking Fluximamide and butylhydroxytoluene with the prescription amount, adding 7.2ml of diethylene glycol monoethyl ether for dispersion, controlling the temperature to be 30-40 ℃, adding 1ml of dimethyl sulfoxide, clarifying, adding the rest 1.8ml of diethylene glycol monoethyl ether, and filling into a low molecular weight polyethylene sealed tank to obtain the final product.
Comparative example 4 an external preparation for treating parasitic infection
Active ingredients: isocycloseram (Compound 20) 500mg;
solvent: 9ml of diethylene glycol monoethyl ether;
antioxidant: 0.1g of butylhydroxytoluene;
cosolvent: dimethyl sulfoxide 1ml.
The preparation method comprises the following steps: taking Isocycloseram and butylhydroxytoluene with the prescription amount, adding 7.2ml of diethylene glycol monoethyl ether for dispersion, controlling the temperature to be 30-40 ℃, adding 1ml of dimethyl sulfoxide, clarifying, adding the rest 1.8ml of diethylene glycol monoethyl ether, and filling into a low molecular weight polyethylene sealed tank.
Example 37 stability test
The external preparation solutions of example 1, example 20 and comparative examples 1, 2, 3 and 4 were placed in a constant temperature and humidity box at a temperature of 40.+ -. 2 ℃ and a relative humidity of 25.+ -. 5% RH, and sampled at the end of 3 months and 6 months, respectively, to examine the properties, pH and content. The test results are shown in Table 2:
TABLE 2 results of 3 month and 6 month test of topical solutions acceleration
As can be seen from Table 2, the external preparation of the present invention has stable content through an acceleration experiment, and the external preparation using cinnamaldehyde has excellent stability through comparison of HPLC purity, so that the HPLC purity of Fluxamethamide and Isocycloseram under the conditions of 3 months and 6 months is basically consistent.
Example 38 transdermal test
A single-chamber permeation diffusion cell was used, 0.5ml of the external preparation (example 1, example 20, comparative example 1, comparative example 2, comparative example 3, comparative example 4) was uniformly placed on a synthetic membrane, and the parameters of the transdermal diffusion tester were set to a rotation speed of 200 rpm, and after stabilization, samples were taken at 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours and 6 hours, respectively, as test solutions at each time point. The content of compound 1 (or compound 20) in the sample solution at each time point is calculated according to the peak area by an external standard method, and the accumulated drug release amount of each film is calculated according to the content of each main component at each time point. The amount of drug released per unit area was calculated from the area of the permeation membrane, and the amount of drug released per unit area (mcg/cm 2 ) The slope of the line (regression) versus square root of time represents the release rate of the formulation.
TABLE 3 transdermal Rate comparison of topical solutions
From table 3, it can be seen that the external preparation added with cinnamaldehyde has higher cumulative permeation and overpolish rate, which proves that the addition of cinnamaldehyde can effectively promote the skin permeation rate of the isoxazoline drug, thereby improving the drug utilization rate.
EXAMPLE 39 test for evaluating efficacy of insect repellent
(1) In vitro insect repellent (tick)
In this evaluation, beagle dogs of mixed gender were used and assigned to the blank control group, the commercially available positive group, and the inventive example group (examples 1, 3, 4, 6, 7, 9, 10, 11, 16, 18, 20, 23, 24, 27, 28, 29, 31, 32, 33, 34, 35, 36), the experimental dogs were challenged with 50 non-fed adult ticks (rhizus).
Dogs received treatment on day 0 at a dose of 40mg/kg of fluorine Lei Lana, 5mg/kg of isoxazolines and 6mg/kg of selamectin in the example group of the invention. The formulations were administered in vitro 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 4 average detection rate of drug against in vitro ticks
(2) External insect repellent (flea)
In this evaluation, beagle dogs of mixed gender were used and assigned to the blank control group, the commercially available positive group, and the inventive example group (examples 1, 2, 5, 8, 12, 13, 14, 15, 17, 19, 20, 21, 22, 25, 26, 30, 31, 32, 33, 34, 35, 36), the experimental dogs were challenged with 50 non-fed adult fleas (Chlamydia felis).
Dogs received treatment on day 0 at a dose of 40mg/kg of fluorine Lei Lana, 5mg/kg of isoxazolines and 6mg/kg of selamectin in the example group of the invention. The formulations were administered in vitro 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 5 average detection rate of drugs against fleas in vitro
(3) In vitro insect repellent (mite)
In this evaluation, beagle dogs of mixed sex were used and assigned to a blank control group, a commercially available positive group, and the inventive examples 31, 32, 34, 36 groups, and the experimental dogs were challenged with 50 non-feeding adult mites (ear mites).
Dogs received treatment on day 0 at a dose of 5mg/kg Fluxamide, 5mg/kg Isoxycloseram and 6mg/kg selamectin. The formulations were administered in vitro 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 6 average detection rate of drug against in vitro mites
(4) Insect repellent in vivo
In this evaluation, beagle dogs of mixed gender were used and assigned to a blank control group, a commercially available positive group, and a test group (examples 31, 32, 34, 36), and the test dogs were found to be infected with a large number of intestinal parasites (including hookworms, whipworms, roundworms, tapeworms, and the like) by laboratory fecal floatation and direct smear microscopy.
Dogs received treatment on day 0 at a dose of 5mg/kg Fluxamide, 5mg/kg Isoxycloseram and 6mg/kg selamectin. The formulations were administered in vitro using a pipette. The dose is administered in the form of a line at the back neck of the skull base.
Average detection rates of nematodes and tapeworms in dogs were counted for each group of drugs on days 0, 5, 10, 20 and 30 after administration, and any immediate response of dogs to treatment was observed on days 1, 2 and 7 after administration, and adverse reactions, skin irritation and properties of the test preparations after treatment were observed.
TABLE 7 average detection rate of in vivo nematodes by drug
As can be seen from tables 4, 5, 6 and 7, the invention has obvious insecticidal effect on the internal and external parasites of dogs, the detection rate is lower than that of a blank control group and a commercial positive group, the action time is long, and the invention has good in-vitro and in-vivo insecticidal effect at 30 days. The test result shows that the long-acting compound vermifuge liquid preparation prepared by the embodiment of the invention has good vermifuge effect on internal and external parasites of dogs within 30 days.
The above embodiments are merely preferred embodiments of the present invention and are not intended to limit the present invention, and any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. An external pharmaceutical formulation for combating parasitic infections, characterized in that: the external pharmaceutical preparation comprises a first active ingredient and an aldehyde compound, wherein the first active ingredient is an isoxazoline compound.
2. The external pharmaceutical preparation for combating parasitic infection according to claim 1, wherein: the structural general formula of the isoxazoline compound is shown as formula (I):
wherein R is 1 Selected from H, OH, CN, NO 2 、OCH 3 、CF 3 、N(CH 3 ) 2 Br or F;
R 2 selected from the group consisting of More preferably, R 1 Selected from H or F, R 2 Selected from->
3. The external pharmaceutical preparation for combating parasitic infection according to claim 1, wherein: the isoxazoline compound is selected from the following compounds 1-30:
4. the external pharmaceutical preparation for combating parasitic infection according to claim 1, wherein: the aldehyde compound is one or a combination of more of citronellal, citral, solenopsis invicta dialdehyde, cinnamaldehyde and eugenol; more preferably, the aldehyde compound is cinnamaldehyde.
5. The external pharmaceutical preparation for combating parasitic infection according to claim 1, wherein: the external pharmaceutical preparation further comprises a solvent and a cosolvent; preferably, the solvent is one or a combination of diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monopropyl ether, diethylene glycol butyl methyl ether, dipropylene glycol monoethyl ether, dipropylene glycol monopropyl ether, dipropylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether, and propylene glycol monobutyl ether, and further preferably, the solvent is diethylene glycol monoethyl ether; preferably, the cosolvent is one or a combination of more than one of dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, dimethyl propionamide, diethyl formamide, diisopropyl formamide, acetone, ethanol and isopropanol, and more preferably, the cosolvent is dimethyl sulfoxide.
6. The external pharmaceutical preparation for combating parasitic infection according to claim 1, wherein: the external pharmaceutical preparation comprises the following components in parts by weight:
the concentration of the isoxazoline compound is 10-300 mg/ml;
the addition amount of the aldehyde compound accounts for 1-5% of the total volume of the external pharmaceutical preparation;
the addition amount of the solvent accounts for 80-90% of the total volume of the external pharmaceutical preparation;
the addition amount of the cosolvent accounts for 5-15% of the total volume of the external pharmaceutical preparation.
7. A process for the preparation of an anti-parasitic pharmaceutical preparation for external use according to any one of claims 1 to 6, characterized in that: the method comprises the following steps:
(1) Adding an isoxazoline compound into an aldehyde compound and a solvent with the volume ratio of 50-80%, and uniformly mixing to obtain a mixture;
(2) Adding a cosolvent into the mixture obtained in the step (1), dissolving and clarifying, and then adding the rest solvent with the volume ratio of 20-50% to fix the volume to obtain an external preparation solution;
(3) And (5) filling the external preparation solution into a container to obtain the external preparation.
8. An anti-parasitic pharmaceutical formulation according to any one of claims 1 to 6, characterized in that: the external pharmaceutical preparation further comprises a second active ingredient, wherein the second active ingredient is one or more of the following compounds:
(a) Pyrethroids;
(b) A macrolide compound;
(c) Insect growth regulators;
(d) Carbamates;
(e) Formamidines;
(f) A nicotinoyl chloride;
(g) Imidazothiazoles;
(h) Benzimidazoles;
(i) Tetrahydroimidazoles;
(j) Isoquinolines;
(k) Salicylanilides;
preferably, the pyrethroid compound is selected from one or more of permethrin, cypermethrin, deltamethrin, fenpropathrin, flumethrin, fenvalerate, phenothrin, tetramethrin and allethrin; the macrolide compound is one or more selected from ivermectin, siramectin, moxidectin, spinosad, milbemycin, avermectin and Ai Mode s; the insect growth regulator is selected from one or more of pyriproxyfen, lufenuron, desiccanil, s-methoprene, antifebrile, tebufenozide, diflubenzuron, chlorfluazuron, hexaflumuron, diafenthiuron, buprofezin and cyromazine; the carbamate compound is selected from one or more of indoxacarb, propoxur, isoprocarb, aldicarb, methomyl and carbofuran; the formamidine compound is selected from amitraz; the nicotinoyl chloride compound is one or more selected from dinotefuran, nitenpyram and thiamethoxam;
Preferably, the external pharmaceutical preparation comprises the following components in proportion:
the concentration of the isoxazoline compound is 10-300 mg/ml;
the concentration of the second active ingredient is 10-300 mg/ml;
the addition amount of the aldehyde compound accounts for 1-5% of the total volume of the external pharmaceutical preparation;
the addition amount of the solvent accounts for 80-90% of the total volume of the external pharmaceutical preparation;
the addition amount of the cosolvent accounts for 5-15% of the total volume of the external pharmaceutical preparation;
more preferably, the external pharmaceutical preparation comprises the following components in proportion:
the concentration of the isoxazoline compound is 10-100 mg/ml;
the concentration of the second active ingredient is 10-100 mg/ml;
the addition amount of the aldehyde compound accounts for 2-3% of the total volume of the external pharmaceutical preparation;
the addition amount of the solvent accounts for 85-90% of the total volume of the external pharmaceutical preparation;
the addition amount of the cosolvent accounts for 5-10% of the total volume of the external pharmaceutical preparation.
9. A method for preparing an anti-parasitic pharmaceutical preparation for external use according to claim 8, wherein: the method comprises the following steps:
(1) Taking a first active component and a second active component, adding an aldehyde compound and a solvent with the volume ratio of 50-80%, and mixing until the mixture is uniform to obtain a mixture;
(2) Adding a cosolvent into the mixture obtained in the step (1), dissolving and clarifying, and then adding the rest solvent with the volume ratio of 20-50% to fix the volume to obtain an external preparation solution;
(3) And (5) filling the external preparation solution into a container to obtain the external preparation.
10. Use of a topical pharmaceutical formulation according to any one of claims 1-6, 8 in the manufacture of a medicament for the treatment or prophylaxis of parasites in non-human animals.
CN202210550493.0A 2022-05-20 2022-05-20 External medicinal preparation for resisting parasitic infection and preparation method and application thereof Pending CN117122594A (en)

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WO2007026965A1 (en) * 2005-09-02 2007-03-08 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and harmful organism-controlling agent
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