An external preparation for anti-parasitic infection and its preparation method and application

Abstract

The application provides an external preparation for resisting parasitic infection, a preparation method and application thereof, and the external preparation comprises a first active ingredient and an aldehyde compound, and the first active ingredient is an isoxazoline compound. The effective component, the aldehyde compound, in the preparation has not only insecticidal activity, but also can effectively improve the stability of the preparation; and the transdermal rate of the external preparation is improved, and the utilization rate of the active ingredient of the medicine is improved.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical preparation technology, and in particular relates to a topical pharmaceutical preparation for treating parasitic infections, its preparation method, and its application. Background Technology

[0002] Controlling parasitic infections in animal populations has always been an important global task. Pathogenic organisms can be classified as endoparasites belonging to the classes Nematodes, Tapeworms, and Trematodes, or the phylum Protozoa, or ectoparasites belonging to the phylum Arthropoda. The former includes infections of the stomach, intestines, lymphatic system, tissues, liver, lungs, heart, and brain. The latter, ectoparasites, include ticks, mites, lice, flies, and fleas. These organisms often serve as vectors and intermediate hosts for the transmission of endoparasites to their animal hosts.

[0003] Isoxazoline insecticides are a class of broad-spectrum insecticides that inhibit L-glutamate and γ-aminobutyric acid ligand-gated chloride ion channels at different sites, exhibiting good insecticidal activity against pests such as ticks, fleas, lice, hemiptera, and dipterans. The four currently marketed isoxazoline insecticides all contain the classic isoxazole ring and are primarily used for external insecticidal purposes in animals such as cats and dogs. Due to the excellent insecticidal activity and relatively high safety of isoxazoline compounds, research on their derivatives has increased in recent years. Besides the four marketed isoxazoline drugs, other isoxazoline drugs are only used in the agricultural field. For example, Fluxametamide and Isocycloseram are used as broad-spectrum insecticides and acaricides for fruit trees and vegetables, grains, rice, corn, soybeans, sugar beets, cotton, and other crops. Therefore, it is necessary to identify specific formulations that allow for their veterinary use, i.e., safe administration for effective control of parasites in animals.

[0004] Currently, the most suitable drug delivery system for treating ectoparasites is the transdermal drug delivery system, which mainly uses transdermal absorption enhancers to promote drug absorption through the skin. Extensive research has focused on dosage forms such as drops, pour-over solutions, and sprays. However, the solvents in existing formulations and conventional topical ectoparasite-killing drugs may lead to problems such as a wetted appearance on fur after administration, insolubility of active ingredients, and skin irritation.

[0005] Natural aldehydes are abundant in nature and possess antibacterial, antiviral, antioxidant, insecticidal, and mosquito-repellent properties. They can also dilate blood vessels, promote blood circulation, and have a certain effect on softening and removing skin scars and fibroids. Adding natural aldehydes to topical formulations can not only improve the solution stability of the active pharmaceutical ingredient, reducing skin irritation for pets and promoting drug penetration through the stratum corneum, but also repel mosquitoes, effectively reducing the risk of infection from mosquitoes carrying internal parasites.

[0006] In summary, there is an urgent need in this field to develop an antiparasitic drug composed of isoxazoline compounds with good solubility of active pharmaceutical ingredients, high insecticidal activity, good safety, and low skin irritation. Summary of the Invention

[0007] In view of this, the present invention aims to overcome the deficiencies in the prior art and proposes a topical drug preparation for anti-parasitic infection, its preparation method and application.

[0008] To achieve the above objectives, the technical solution created by this invention is implemented as follows:

[0009] As a first aspect of the present invention, a topical pharmaceutical preparation for treating parasitic infections is provided, the topical pharmaceutical preparation comprising a first active ingredient and an aldehyde compound, wherein the first active ingredient is an isoxazoline compound.

[0010] Preferably, the general structural formula of the isoxazoline compound is shown in formula (I):

[0011]

[0012] R1 is selected from H, OH, CN, NO2, OCH3, CF3, N(CH3)2, Br or F;

[0013] R2 is selected from NH2, OH、 More preferably, R1 is selected from H or F, and R2 is selected from

[0014] Preferably, the isoxazoline compound is selected from the following compounds 1-30:

[0015]

[0016]

[0017]

[0018] Preferably, the aldehyde compound is a combination of one or more of citronellal, citral, strobilal, cinnamaldehyde, and eugenol; more preferably, the aldehyde compound is cinnamaldehyde.

[0019] Preferably, the topical pharmaceutical preparation further includes a solvent and a co-solvent.

[0020] More preferably, the solvent is one or a combination of several of the following: 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. Even more preferably, the solvent is diethylene glycol monoethyl ether.

[0021] More preferably, the co-solvent is one or a combination of several of dimethyl sulfoxide, dimethylformamide, dimethylacetamide, dimethylpropionamide, diethylformamide, diisopropylformamide, acetone, ethanol, and isopropanol. Even more preferably, the co-solvent is dimethyl sulfoxide.

[0022] Preferably, the topical pharmaceutical preparation comprises the following components in the following proportions:

[0023] The concentration of isoxazoline compounds is 10–300 mg / ml;

[0024] The amount of aldehyde compounds added accounts for 1-5% of the total volume of the topical drug preparation;

[0025] The amount of solvent added accounts for 80-90% of the total volume of the topical drug preparation;

[0026] The amount of co-solvent added accounts for 5-15% of the total volume of the topical drug preparation.

[0027] As a second aspect of the present invention, a method for preparing the above-mentioned topical pharmaceutical preparation for treating parasitic infections is provided, comprising the following steps:

[0028] (1) Take isoxazoline compounds, add aldehyde compounds and solvents at a volume ratio of 50-80%, and mix until homogeneous to obtain a mixture;

[0029] (2) Add a co-solvent to the mixture in step (1), dissolve and clarify, then add the remaining 20-50% by volume of solvent to make up the volume to obtain the external preparation solution;

[0030] (3) The topical preparation solution is put into a container to obtain the topical drug preparation.

[0031] As a third aspect of the present invention, another topical pharmaceutical preparation for treating parasitic infections is provided, wherein the topical pharmaceutical preparation further comprises a second active ingredient in addition to the above-mentioned compounds, the second active ingredient being one or more of the following compounds:

[0032] (a) Pyrethroids;

[0033] (b) Macrocyclic lactones;

[0034] (c) Insect growth regulators;

[0035] (d) Carbamates;

[0036] (e) Formamidins;

[0037] (f) Nicotinamides;

[0038] (g) Imidazothiazoles;

[0039] (h) Benzimidazoles;

[0040] (i) Tetrahydroimidazoles;

[0041] (j) Isoquinolines;

[0042] (k) Salicylate aniline derivatives.

[0043] Preferably, the pyrethroid compounds are selected from one or more of dichlorvos, cypermethrin, deltamethrin, deltamethrin, flufenoxuron, fenvalerate, deltamethrin, methamidophos, and allethrin; the macrolide compounds are selected from one or more of ivermectin, selamectin, moxibustion, spinosad, milbemycin, abamectin, and amoxicillin; the insect growth regulators are selected from one or more of pyriproxyfen, lufenuron, desfenyl, s-tebufenozide, chlorfenapyr, diflubenzuron, flufenoxuron, flufenoxuron, flufenoxuron, difenoconazole, thiamethoxam, and cypermethrin; the carbamate compounds are selected from one or more of indoxacarb, propoxur, isoprocarb, aldicarb, methomyl, and carbofuran; the formamidin compounds are selected from amitraz; and the chloronicotinamide compounds are selected from one or more of dinotefuran, acetamiprid, and thiamethoxam.

[0044] Preferably, the topical pharmaceutical preparation comprises the following components in the following proportions:

[0045] The concentration of isoxazoline compounds is 10–300 mg / ml;

[0046] The concentration of the second active ingredient is 10–300 mg / ml;

[0047] The amount of aldehyde compounds added accounts for 1-5% of the total volume of the topical drug preparation;

[0048] The amount of solvent added accounts for 80-90% of the total volume of the topical drug preparation;

[0049] The amount of co-solvent added accounts for 5-15% of the total volume of the topical drug preparation.

[0050] Preferably, the topical pharmaceutical preparation comprises the following components in the following proportions:

[0051] The concentration of isoxazoline compounds is 10–100 mg / ml;

[0052] The concentration of the second active ingredient is 10–100 mg / ml;

[0053] The amount of aldehyde compounds added accounts for 2-3% of the total volume of the topical drug preparation;

[0054] The amount of solvent added accounts for 85-90% of the total volume of the topical drug preparation;

[0055] The amount of co-solvent added accounts for 5-10% of the total volume of the topical drug preparation.

[0056] As a fourth aspect of the present invention, a method for preparing the above-mentioned topical pharmaceutical preparation for treating parasitic infections is provided, comprising the following steps:

[0057] (1) Take the first active component and the second active component, add aldehyde compound and solvent with a volume ratio of 50-80%, mix until uniform to obtain a mixture;

[0058] (2) Add co-solvent to the mixture in step (1), dissolve and clarify, then add the remaining 20-50% volume ratio of solvent to make up the volume to obtain the external preparation solution;

[0059] (3) The topical preparation solution is put into a container to obtain the topical drug preparation.

[0060] As a fourth aspect of the invention, the use of the above-described topical pharmaceutical preparation in the preparation of a drug for treating or preventing parasites in non-human animals is provided.

[0061] Compared with existing technologies, the present invention has the following advantages:

[0062] (1) The active ingredient in the antiparasitic topical drug preparation of the present invention is an aldehyde compound. This compound not only has insecticidal activity, but can also effectively improve the stability of the preparation of the present invention; and improves the utilization rate of the active ingredient by increasing the transdermal rate of the topical preparation.

[0063] (2) Compared with fluranal, the active ingredient in the antiparasitic topical drug preparation of the present invention can achieve an effective insecticidal effect at a lower dosage.

[0064] (3) The present invention uses isoxazoline compounds that can be combined with one or more of the following: pyrethroids, macrolides, insect growth regulators, carbamates, formamidins, nicotinamides, imidazothiazoles, benzimidazoles, tetrahydroimidazolium, isoquinolines, and salicylaniline to achieve simultaneous treatment of internal and external parasites. Detailed Implementation

[0065] Unless otherwise defined, the technical terms used in the following embodiments have the same meanings as commonly understood by those skilled in the art to which this invention pertains. Unless otherwise specified, the experimental reagents used in the following embodiments are conventional biochemical reagents; and the experimental methods described are conventional methods.

[0066] The invention will be described in detail below with reference to specific embodiments.

[0067] Example 1: A topical pharmaceutical preparation for treating parasitic infections

[0068] Active ingredient: Fluxametamide (compound 1) 500mg;

[0069] Solvent: 9 ml of diethylene glycol monoethyl ether;

[0070] Aldehydes: Cinnamaldehyde 0.1 ml;

[0071] Co-solvent: 1 ml of dimethyl sulfoxide.

[0072] Preparation method: Take the prescribed amount of Fluxametamide and cinnamaldehyde, add 7.2 ml of diethylene glycol monoethyl ether for dispersion, control the temperature at 30-40℃, add 1 ml of dimethyl sulfoxide, clarify, add the remaining 1.8 ml of diethylene glycol monoethyl ether, and fill into a low molecular weight polyethylene sealed container to obtain the product.

[0073] Preparation method of compound 1:

[0074]

[0075] Starting material 1 and oxalyl chloride (1.5 eq) were added to a reaction flask and reacted in dichloromethane at 20–30 °C for 12 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained to obtain an acyl chloride intermediate, which was added to ammonia water. After the reaction was complete, 1 M hydrochloric acid was added to terminate the reaction. The aqueous phase was extracted with dichloromethane, and the organic phase was concentrated and recrystallized to obtain intermediate 1.

[0076] Intermediate 1, triethyl orthoformate (15.0 eq), and methoxyamine hydrochloride (1.5 eq) were added to a reaction flask and reacted at 50–60 °C. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the organic phase was filtered, concentrated, and recrystallized to obtain compound 1.

[0077] Example 2

[0078] The active ingredient is compound 2. The other components in the formulation, their dosages, and the preparation methods are the same as in Example 1.

[0079] Preparation method of compound 2:

[0080]

[0081] Starting material 1 and oxalyl chloride (1.5 eq) were added to a reaction flask and reacted in dichloromethane at 20–30 °C for 12 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained to obtain an acyl chloride intermediate, which was added to ammonia water. After the reaction was complete, 1 M hydrochloric acid was added to terminate the reaction. The aqueous phase was extracted with dichloromethane, and the organic phase was concentrated and recrystallized to obtain intermediate 1.

[0082] Intermediate 1, triethyl orthoformate (15.0 eq), and methylamine hydrochloride (1.5 eq) were added to a reaction flask and reacted at 50–60 °C. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the organic phase was filtered, concentrated, and recrystallized to obtain compound 2.

[0083] Example 3

[0084] The active ingredient is compound 3. The other components in the formulation, their dosages, and the preparation methods are the same as in Example 1.

[0085] Preparation method of compound 3:

[0086]

[0087] Starting material 1 and oxalyl chloride (1.5 eq) were added to a reaction flask and reacted in dichloromethane at 20–30 °C for 12 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained to obtain an acyl chloride intermediate, which was added to ammonia water. After the reaction was complete, 1 M hydrochloric acid was added to terminate the reaction. The aqueous phase was extracted with dichloromethane, and the organic phase was concentrated and recrystallized to obtain intermediate 1.

[0088] Intermediate 1, trimethyl orthoformate (15.0 eq), and S-methylthiohydroxylamine hydrochloride (1.2 eq) were added to a reaction flask and reacted at 30–40 °C. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the organic phase was filtered, concentrated, and recrystallized to obtain compound 3.

[0089] Example 4

[0090] The active ingredient is compound 4. The other components in the formulation, their dosages, and the preparation methods are the same as in Example 1.

[0091] Preparation method of compound 4:

[0092]

[0093] Starting material 1 and oxalyl chloride (1.5 eq) were added to a reaction flask and reacted in dichloromethane at 20–30 °C for 12 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained to obtain an acyl chloride intermediate, which was added to ammonia water. After the reaction was complete, 1 M hydrochloric acid was added to terminate the reaction. The aqueous phase was extracted with dichloromethane, and the organic phase was concentrated and recrystallized to obtain intermediate 1.

[0094] Intermediate 1, triethyl orthoformate (13.0 eq), and O-cyclopropylhydroxylamine hydrochloride (1.5 eq) were added to a reaction flask and reacted at 50–60 °C. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the organic phase was filtered, concentrated, and recrystallized to obtain compound 4.

[0095] Example 5

[0096] The active ingredient is compound 5. The other components in the formulation, their dosages, and the preparation methods are the same as in Example 1.

[0097] Preparation method of compound 5:

[0098]

[0099] Starting material 5 and thionyl chloride (1.5 eq) were added to a reaction flask and reacted in toluene at 60–70 °C for 8 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained to obtain an acyl chloride intermediate, which was added to ammonia water. After the reaction was complete, 1 M hydrochloric acid was added to terminate the reaction. The aqueous phase was extracted with ethyl acetate, and the organic phase was concentrated and recrystallized to obtain intermediate 5.

[0100] Intermediate 5, trimethyl orthoformate (13.0 eq), and methoxyamine hydrochloride (1.3 eq) were added to a reaction flask and reacted at 30–40 °C. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the organic phase was filtered, concentrated, and recrystallized to obtain compound 5.

[0101] Example 6

[0102] The active ingredient is compound 6. The other components in the formulation, their dosages, and the preparation methods are the same as in Example 1.

[0103] Preparation method of compound 6:

[0104]

[0105] Starting material 6 and thionyl chloride (1.5 eq) were added to a reaction flask and reacted in toluene at 60–70 °C for 8 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained to obtain an acyl chloride intermediate, which was added to ammonia water. After the reaction was complete, 1 M hydrochloric acid was added to terminate the reaction. The aqueous phase was extracted with ethyl acetate, and the organic phase was concentrated and recrystallized to obtain intermediate 6.

[0106] Intermediate 6, triethyl orthoformate (14.0 eq), and methoxyamine hydrochloride (1.3 eq) were added to a reaction flask and reacted at 50–60 °C. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the organic phase was filtered, concentrated, and recrystallized to obtain compound 6.

[0107] Example 7

[0108] The active ingredient is compound 7. The other components in the formulation, their dosages, and the preparation methods are the same as in Example 1.

[0109] Preparation method of compound 7:

[0110]

[0111] Starting material 7 and oxalyl chloride (1.3 eq) were added to a reaction flask and reacted in tetrahydrofuran at 20–30 °C for 8 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained to obtain an acyl chloride intermediate, which was added to ammonia water. After the reaction was complete, 1 M hydrochloric acid was added to terminate the reaction. The aqueous phase was extracted with tetrahydrofuran, and the organic phase was concentrated and recrystallized to obtain intermediate 7.

[0112] Intermediate 7, trimethyl orthoformate (10.0 eq), and methoxyamine hydrochloride (1.1 eq) were added to a reaction flask and reacted at 30–40 °C. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the organic phase was filtered, concentrated, and recrystallized to obtain compound 7.

[0113] Example 8

[0114] The active ingredient is compound 8. The other components in the formulation, their dosages, and the preparation methods are the same as in Example 1.

[0115] Preparation method of compound 8:

[0116]

[0117] Starting material 8 and thionyl chloride (1.5 eq) were added to a reaction flask and reacted in toluene at 60–70 °C for 8 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained to obtain an acyl chloride intermediate, which was added to ammonia water. After the reaction was complete, 1 M hydrochloric acid was added to terminate the reaction. The aqueous phase was extracted with ethyl acetate, and the organic phase was concentrated and recrystallized to obtain intermediate 8.

[0118] Intermediate 8, triisopropyl orthoformate (13.0 eq), and methoxyamine hydrochloride (1.2 eq) were added to a reaction flask and reacted at 60–70 °C. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the organic phase was filtered, concentrated, and recrystallized to obtain compound 8.

[0119] Example 9

[0120] The active ingredient is compound 9. The other components in the formulation, their dosages, and the preparation methods are the same as in Example 1.

[0121] Preparation method of compound 9:

[0122]

[0123] Starting material 9 and oxalyl chloride (1.5 eq) were added to a reaction flask and reacted in tetrahydrofuran at 20-30 °C for 8 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained to obtain the intermediate acyl chloride, which was then added to ammonia water. After the reaction was complete, 1M hydrochloric acid was added to terminate the reaction. The aqueous phase was extracted with tetrahydrofuran, and the organic phase was concentrated and recrystallized to obtain intermediate 9.

[0124] Intermediate 9, triethyl orthoformate (15.0 eq), and methoxyamine hydrochloride (1.5 eq) were added to a reaction flask and reacted at 50–60 °C. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the organic phase was filtered, concentrated, and recrystallized to obtain compound 9.

[0125] Example 10

[0126] The active ingredient is compound 10, and the other components in the formulation, their dosages, and preparation methods are the same as in Example 1.

[0127] Preparation method of compound 10:

[0128]

[0129] Starting material 10 and oxalyl chloride (1.3 eq) were added to a reaction flask and reacted in dichloromethane at 20–30 °C for 12 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained to obtain an intermediate acyl chloride, which was then added to ammonia water. After the reaction was complete, 1 M hydrochloric acid was added to terminate the reaction. The aqueous phase was extracted with dichloromethane, and the organic phase was concentrated and recrystallized to obtain intermediate 10.

[0130] Intermediate 10, triethyl orthoformate (12.0 eq), and methoxyamine hydrochloride (1.1 eq) were added to a reaction flask and reacted at 50–60 °C. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the organic phase was filtered, concentrated, and recrystallized to obtain compound 10.

[0131] Example 11

[0132] The active ingredient is compound 11. The other components in the formulation, their dosages, and the preparation methods are the same as in Example 1.

[0133] Preparation method of compound 11:

[0134]

[0135] Starting material 11 and oxalyl chloride (1.1 eq) were added to a reaction flask and reacted in dichloromethane at 0-10 °C. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the reaction solution of the oxalyl chloride intermediate was added to ammonia water. After the reaction was complete, 1M hydrochloric acid was added to terminate the reaction. The aqueous phase was extracted with dichloromethane, and the organic phase was concentrated and recrystallized to obtain intermediate 11.

[0136] Intermediate 11, triisopropyl orthoformate (15.0 eq), and methoxyamine hydrochloride (1.5 eq) were added to a reaction flask and reacted at 60–70 °C. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the organic phase was filtered, concentrated, and recrystallized to obtain compound 11.

[0137] Example 12

[0138] The active ingredient is compound 12. The other components in the formulation, their dosages, and the preparation methods are the same as in Example 1.

[0139] Preparation method of compound 12:

[0140]

[0141] Intermediate 1, N,N-dimethylformamide (10.0 V), N-bromosuccinimide (1.5 eq), and purified water (2.0 V) were added to a reaction flask and reacted at 60–70 °C. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, water was added for dilution, the aqueous phase was extracted with ethyl acetate, separated, washed with water, and the organic phase was concentrated and recrystallized to obtain compound 12.

[0142] Example 13

[0143] The active ingredient is compound 13. The other components in the formulation, their dosages, and the preparation methods are the same as in Example 1.

[0144] Preparation method of compound 13:

[0145]

[0146] Intermediate 11, N,N-dimethylformamide (8.0 V), N-bromosuccinimide (1.3 eq), and purified water (1.0 V) were added to a reaction flask and reacted at 60–70 °C. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, water was added for dilution, the aqueous phase was extracted with ethyl acetate, separated, washed with water, and the organic phase was concentrated and recrystallized to obtain compound 13.

[0147] Example 14

[0148] The active ingredient is compound 14. The other components in the formulation, their dosages, and the preparation methods are the same as in Example 1.

[0149] Preparation method of compound 14:

[0150]

[0151] Starting material 11 and oxalyl chloride (1.1 eq) were added to a reaction flask and reacted in dichloromethane at 0-10 °C. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the reaction solution of the acyl chloride intermediate was added to ammonia water. After the reaction was complete, 1M hydrochloric acid was added to terminate the reaction. The aqueous phase was extracted with dichloromethane, and the organic phase was concentrated and recrystallized to obtain intermediate 14.

[0152] Example 15

[0153] The active ingredient is compound 15. The other components in the formulation, their dosages, and the preparation methods are the same as in Example 1.

[0154] The preparation method of compound 15 is as follows:

[0155]

[0156] Starting material 1 and oxalyl chloride (1.5 eq) were added to a reaction flask and reacted in dichloromethane at 20–30 °C for 12 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained to obtain an intermediate acyl chloride, which was then added to methoxyamine. After the reaction was complete, 1 M hydrochloric acid was added to terminate the reaction. The aqueous phase was extracted with dichloromethane, and the organic phase was concentrated and recrystallized to obtain compound 15.

[0157] Example 16

[0158] The active ingredient is compound 16, and the other components in the formulation, their dosages, and preparation methods are the same as in Example 1.

[0159] The preparation method of compound 16 is as follows:

[0160]

[0161] Starting material 1 and oxalyl chloride (1.5 eq) were added to a reaction flask and reacted in dichloromethane at 20–30 °C for 12 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained and the intermediate acyl chloride was added to methanol. After the reaction was complete, 1 M hydrochloric acid was added to terminate the reaction. The aqueous phase was extracted with dichloromethane, and the organic phase was concentrated and recrystallized to obtain compound 16.

[0162] Example 17

[0163] The active ingredient is compound 17. The other components in the formulation, their dosages, and the preparation methods are the same as in Example 1.

[0164] The preparation method of compound 17 is as follows:

[0165]

[0166] Intermediate 1, triethyl orthoformate (15.0 eq), and hydroxylamine hydrochloride (1.5 eq) were added to a reaction flask and reacted at 50–60 °C. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the organic phase was filtered, concentrated, and recrystallized to obtain compound 17.

[0167] Examples 18-19

[0168] The active ingredient is compound 18-19. The other components in the formulation, the dosage of each component, and the preparation method are the same as in Example 1.

[0169] The preparation methods of compounds 18 and 19 are as follows:

[0170]

[0171] Compound 18 was prepared according to the method in the literature: “Sun Hongyang, Yang Xu, Zhang Jing, et al. Synthesis of Flureranar and determination of its insecticidal activity [J]. Fine Chemicals, 2020, 37(5):6.”; Compound 19 was prepared from compound 18 and is an intermediate for the preparation of Fluxametamide.

[0172] Example 20: A topical pharmaceutical preparation for treating parasitic infections

[0173] Active ingredient: Isocycloseram (compound 20) 500mg;

[0174] Solvent: 9 ml of diethylene glycol monoethyl ether;

[0175] Aldehydes: Cinnamaldehyde 0.1 ml;

[0176] Co-solvent: 1 ml of dimethyl sulfoxide.

[0177] Preparation method: Take the prescribed amount of Isocycloseram and cinnamaldehyde, add 7.2 ml of diethylene glycol monoethyl ether for dispersion, control the temperature at 30-40℃, add 1 ml of dimethyl sulfoxide, clarify, add the remaining 1.8 ml of diethylene glycol monoethyl ether, and fill into a low molecular weight polyethylene sealed container to obtain the product.

[0178] Preparation method of compound 20:

[0179]

[0180] The starting material 20-1 and oxalyl chloride (2.0 eq) were added to a reaction flask and reacted in dichloromethane at 20-30 °C for 12 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained to obtain the acyl chloride intermediate.

[0181] The starting material 20-2 (1.5 eq), triethylamine (5.0 eq), and ethyl acetate were added to a reaction flask and stirred until homogeneous. The intermediate acyl chloride was then added to the reaction flask. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, 1M hydrochloric acid was added to terminate the reaction. The organic phase was concentrated and recrystallized to obtain compound 20.

[0182] Example 21

[0183] The active ingredient is compound 21. The other components in the formulation, the dosage of each component, and the preparation method are the same as in Example 20.

[0184] Preparation method of compound 21:

[0185]

[0186] The starting material 20-1 and oxalyl chloride (2.0 eq) were added to a reaction flask and reacted in dichloromethane at 20-30 °C for 12 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained to obtain the acyl chloride intermediate.

[0187] The starting material 21-2 (1.3 eq), triethylamine (4.0 eq), and ethyl acetate were added to a reaction flask and stirred until homogeneous. The intermediate acyl chloride was then added to the reaction flask. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, 1M hydrochloric acid was added to terminate the reaction. The organic phase was concentrated and recrystallized to obtain compound 21.

[0188] Example 22

[0189] The active ingredient is compound 22. The other components in the formulation, the dosage of each component, and the preparation method are the same as in Example 20.

[0190] Preparation method of compound 22:

[0191]

[0192] The starting material 20-1 and oxalyl chloride (2.0 eq) were added to a reaction flask and reacted in dichloromethane at 20-30 °C for 12 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained to obtain the acyl chloride intermediate.

[0193] The starting material 16-2 (1.3 eq), triethylamine (5.0 eq), and tetrahydrofuran were added to a reaction flask and stirred until homogeneous. The acyl chloride intermediate was then added to the reaction flask. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, 1M hydrochloric acid was added to terminate the reaction. The organic phase was concentrated and recrystallized to obtain compound 22.

[0194] Example 23

[0195] The active ingredient is compound 23. The other components in the formulation, the dosage of each component, and the preparation method are the same as in Example 20.

[0196] Preparation method of compound 23:

[0197]

[0198] The starting material 20-1 and oxalyl chloride (2.0 eq) were added to a reaction flask and reacted in dichloromethane at 20-30 °C for 12 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained to obtain the acyl chloride intermediate.

[0199] The starting material 23-2 (1.3 eq), triethylamine (3.0 eq), and tetrahydrofuran were added to a reaction flask and stirred until homogeneous. The acyl chloride intermediate was then added to the reaction flask. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, 1M hydrochloric acid was added to terminate the reaction. The organic phase was concentrated and recrystallized to obtain compound 23.

[0200] Example 24

[0201] The active ingredient is compound 24. The other components in the formulation, the dosage of each component, and the preparation method are the same as in Example 20.

[0202] Preparation method of compound 24:

[0203]

[0204] The starting material 20-1 and oxalyl chloride (2.0 eq) were added to a reaction flask and reacted in dichloromethane at 20-30 °C for 12 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained to obtain the acyl chloride intermediate.

[0205] The starting material 24-2 (1.5 eq), triethylamine (5.0 eq), and tetrahydrofuran were added to a reaction flask and stirred until homogeneous. The intermediate acyl chloride was then added to the reaction flask. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, 1M hydrochloric acid was added to terminate the reaction. The organic phase was concentrated and recrystallized to obtain compound 24.

[0206] Example 25

[0207] The active ingredient is compound 25. The other components in the formulation, the dosage of each component, and the preparation method are the same as in Example 20.

[0208] Preparation method of compound 25:

[0209]

[0210] The starting material 20-1 and oxalyl chloride (2.0 eq) were added to a reaction flask and reacted in dichloromethane at 20-30 °C for 12 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained to obtain the acyl chloride intermediate.

[0211] The starting material 25-2 (1.2 eq), triethylamine (5.0 eq), and tetrahydrofuran were added to a reaction flask and stirred until homogeneous. The acyl chloride intermediate was then added to the reaction flask. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, 1M hydrochloric acid was added to terminate the reaction. The organic phase was concentrated and recrystallized to obtain compound 25.

[0212] Example 26

[0213] The active ingredient is compound 26. The other components in the formulation, the dosage of each component, and the preparation method are the same as in Example 20.

[0214] Preparation method of compound 26:

[0215]

[0216] The starting material 26-1 and thionyl chloride (1.5 eq) were added to a reaction flask and reacted in toluene at 60–70 °C for 8 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was completed, the mixture was concentrated until no fraction was distilled to obtain the acyl chloride intermediate.

[0217] The starting material 20-2 (1.2 eq), triethylamine (5.0 eq), and dichloromethane were added to a reaction flask and stirred until homogeneous. The intermediate acyl chloride was then added to the reaction flask. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, 1M hydrochloric acid was added to terminate the reaction. The organic phase was concentrated and recrystallized to obtain compound 26.

[0218] Example 27

[0219] The active ingredient is compound 27. The other components in the formulation, the dosage of each component, and the preparation method are the same as in Example 20.

[0220] Preparation method of compound 27:

[0221]

[0222] Starting material 8 and thionyl chloride (1.5 eq) were added to a reaction flask and reacted in toluene at 60–70 °C for 8 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained to obtain the acyl chloride intermediate.

[0223] The starting material 20-2 (1.2 eq), triethylamine (4.0 eq), and tetrahydrofuran were added to the reaction flask and stirred until homogeneous. The acyl chloride intermediate was then added to the reaction flask. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, 1M hydrochloric acid was added to terminate the reaction. The organic phase was concentrated and recrystallized to obtain compound 27.

[0224] Example 28

[0225] The active ingredient is compound 28. The other components in the formulation, the dosage of each component, and the preparation method are the same as in Example 20.

[0226] Preparation method of compound 28:

[0227]

[0228] Starting material 6 and thionyl chloride (1.5 eq) were added to a reaction flask and reacted in toluene at 60–70 °C for 8 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, the mixture was concentrated until no fraction was obtained to obtain the acyl chloride intermediate.

[0229] The starting material 20-2 (1.3 eq), triethylamine (5.0 eq), and tetrahydrofuran were added to a reaction flask and stirred until homogeneous. The intermediate acyl chloride was then added to the reaction flask. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, 1M hydrochloric acid was added to terminate the reaction. The organic phase was concentrated and recrystallized to obtain compound 28.

[0230] Example 29

[0231] The active ingredient is compound 29. The other components in the formulation, the dosage of each component, and the preparation method are the same as in Example 20.

[0232] Preparation method of compound 29:

[0233]

[0234] Starting material 9 and oxalyl chloride (1.5 eq) were added to a reaction flask and reacted in tetrahydrofuran at 20-30°C for 8 hours. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was completed, the mixture was concentrated until no fraction was obtained to obtain the acyl chloride intermediate.

[0235] The starting material 20-2 (1.2 eq), triethylamine (3.0 eq), and tetrahydrofuran were added to the reaction flask and stirred until homogeneous. The acyl chloride intermediate was then added to the reaction flask. The reaction progress was monitored by thin-layer chromatography (TLC) during the reaction. After the reaction was complete, 1M hydrochloric acid was added to terminate the reaction. The organic phase was concentrated and recrystallized to obtain compound 29.

[0236] Example 30

[0237] The active ingredient is compound 30. The other components in the formulation, the dosage of each component, and the preparation method are the same as in Example 20.

[0238] Compound 30 was prepared according to the method in the literature: “Sun Hongyang, Yang Xu, Zhang Jing, et al. Synthesis of Freranar and determination of its insecticidal activity [J]. Fine Chemicals, 2020, 37(5):6.”

[0239] Example 31: A topical pharmaceutical preparation for treating parasitic infections

[0240] First active ingredient: Fluxametamide (compound 1) 500mg;

[0241] Second active ingredient: Selamectin 600mg;

[0242] Solvent: 9 ml of diethylene glycol monoethyl ether;

[0243] Aldehydes: Cinnamaldehyde 0.1 ml;

[0244] Co-solvent: 1 ml of dimethyl sulfoxide.

[0245] Preparation method: Take the prescribed amounts of Fluxametamide, Selamectin and Cinnamaldehyde, add 7.2 ml of diethylene glycol monoethyl ether for dispersion, control the temperature at 30-40℃, add 1 ml of dimethyl sulfoxide, clarify, add the remaining 1.8 ml of diethylene glycol monoethyl ether, and fill into a low molecular weight polyethylene sealed container to obtain the product.

[0246] Example 32: A topical pharmaceutical preparation for treating parasitic infections

[0247] First active ingredient: Isocycloseram (compound 20) 500mg;

[0248] Second active ingredient: Selamectin 600mg;

[0249] Solvent: 9 ml of diethylene glycol monoethyl ether;

[0250] Aldehydes: Cinnamaldehyde 0.1 ml;

[0251] Co-solvent: 1 ml of dimethyl sulfoxide.

[0252] Preparation method: Take the prescribed amounts of Isocycloseram, selamectin and cinnamaldehyde, add 7.2 ml of diethylene glycol monoethyl ether for dispersion, control the temperature at 30-40℃, add 1 ml of dimethyl sulfoxide, clarify, add the remaining 1.8 ml of diethylene glycol monoethyl ether, and fill into a low molecular weight polyethylene sealed container to obtain the product.

[0253] Example 33: A topical pharmaceutical preparation for treating parasitic infections

[0254] Active ingredient: Fluxametamide (compound 1) 1000mg;

[0255] Solvent: 8.5 ml of diethylene glycol monoethyl ether;

[0256] Aldehydes: Cinnamaldehyde 0.1 ml;

[0257] Co-solvent: 1.5 ml of dimethyl sulfoxide.

[0258] Preparation method: Take the prescribed amount of Fluxametamide and cinnamaldehyde, add 6.8 ml of diethylene glycol monoethyl ether for dispersion, control the temperature at 30-40℃, add 1.5 ml of dimethyl sulfoxide, clarify, add the remaining 1.7 ml of diethylene glycol monoethyl ether, and fill into a low molecular weight polyethylene sealed container to obtain the product.

[0259] Example 34: A topical pharmaceutical preparation for treating parasitic infections

[0260] First active ingredient: Isocycloseram (compound 20) 1000mg;

[0261] Second active ingredient: Selamectin 100mg;

[0262] Solvent: 8.5 ml of diethylene glycol monoethyl ether;

[0263] Aldehydes: Cinnamaldehyde 0.1 ml;

[0264] Co-solvent: 1.5 ml of dimethyl sulfoxide.

[0265] Preparation method: Take the prescribed amounts of Isocycloseram, selamectin and cinnamaldehyde, add 6.8 ml of diethylene glycol monoethyl ether for dispersion, control the temperature at 30-40℃, add 1.5 ml of dimethyl sulfoxide, clarify, add the remaining 1.7 ml of diethylene glycol monoethyl ether, and fill into a low molecular weight polyethylene sealed container to obtain the product.

[0266] Example 35: A topical pharmaceutical preparation for treating parasitic infections

[0267] Active ingredient: Fluxametamide (compound 1) 3000mg;

[0268] Solvent: 8.0 ml of diethylene glycol monoethyl ether;

[0269] Aldehydes: Cinnamaldehyde 0.5 ml;

[0270] Co-solvent: 1.5 ml of dimethyl sulfoxide.

[0271] Preparation method: Take the prescribed amount of compound 1 and cinnamaldehyde, add 6.4 ml of diethylene glycol monoethyl ether for dispersion, control the temperature at 30-40℃, add 1.5 ml of dimethyl sulfoxide, clarify, add the remaining 1.6 ml of diethylene glycol monoethyl ether, and fill into a low molecular weight polyethylene sealed container to obtain the product.

[0272] Example 36: A topical pharmaceutical preparation for treating parasitic infections

[0273] First active ingredient: Isocycloseram (compound 20) 3000mg;

[0274] Second active ingredient: Selamectin 3000mg;

[0275] Solvent: 8.0 ml of diethylene glycol monoethyl ether;

[0276] Aldehydes: Cinnamaldehyde 0.5 ml;

[0277] Co-solvent: 1.5 ml of dimethyl sulfoxide.

[0278] Preparation method: Take the prescribed amount of compound 20, selamectin and cinnamaldehyde, add 6.4 ml of diethylene glycol monoethyl ether for dispersion, control the temperature at 30-40℃, add 1.5 ml of dimethyl sulfoxide, clarify, add the remaining 1.6 ml of diethylene glycol monoethyl ether, and fill into a low molecular weight polyethylene sealed container to obtain the product.

[0279] The 1H NMR and mass spectrometry data of compounds 1-30 are shown in the table below:

[0280] Table 1. 1H NMR and mass spectrometry data for compounds 1-30

[0281]

[0282]

[0283]

[0284]

[0285] Comparative Example 1: A topical pharmaceutical preparation for treating parasitic infections

[0286] Active ingredient: Fluxametamide (compound 1) 500mg;

[0287] Solvent: 9 ml of diethylene glycol monoethyl ether;

[0288] Co-solvent: 1 ml of dimethyl sulfoxide.

[0289] Preparation method: Take the prescribed amount of Fluxametamide, add 7.2 ml of diethylene glycol monoethyl ether for dispersion, control the temperature at 30-40℃, add 1 ml of dimethyl sulfoxide, clarify, add the remaining 1.8 ml of diethylene glycol monoethyl ether, and fill into a low molecular weight polyethylene sealed container to obtain the product.

[0290] Comparative Example 2: A topical pharmaceutical preparation for treating parasitic infections

[0291] Active ingredient: Isocycloseram (compound 20) 500mg;

[0292] Solvent: 9 ml of dipropylene glycol monoethyl ether;

[0293] Co-solvent: 1 ml of dimethyl sulfoxide.

[0294] Preparation method: Take the prescribed amount of Isocycloseram, add 7.2 ml of diethylene glycol monoethyl ether for dispersion, control the temperature at 30-40℃, add 1 ml of dimethyl sulfoxide, clarify, add the remaining 1.8 ml of diethylene glycol monoethyl ether, and fill into a low molecular weight polyethylene sealed container to obtain the product.

[0295] Comparative Example 3: A topical pharmaceutical preparation for treating parasitic infections

[0296] Active ingredient: Fluxametamide (compound 1) 500mg;

[0297] Solvent: 9 ml of diethylene glycol monoethyl ether;

[0298] Antioxidant: Butylated hydroxytoluene 0.1g;

[0299] Co-solvent: 1 ml of dimethyl sulfoxide.

[0300] Preparation method: Take the prescribed amount of Fluxametamide and Butylated Hydroxytoluene, add 7.2 ml of diethylene glycol monoethyl ether for dispersion, control the temperature at 30-40℃, add 1 ml of dimethyl sulfoxide, clarify, add the remaining 1.8 ml of diethylene glycol monoethyl ether, and fill into a low molecular weight polyethylene sealed container to obtain the product.

[0301] Comparative Example 4: A topical pharmaceutical preparation for treating parasitic infections

[0302] Active ingredient: Isocycloseram (compound 20) 500mg;

[0303] Solvent: 9 ml of diethylene glycol monoethyl ether;

[0304] Antioxidant: Butylated hydroxytoluene 0.1g;

[0305] Co-solvent: 1 ml of dimethyl sulfoxide.

[0306] Preparation method: Take the prescribed amount of Isocycloseram and butylated hydroxytoluene, add 7.2 ml of diethylene glycol monoethyl ether for dispersion, control the temperature at 30-40℃, add 1 ml of dimethyl sulfoxide, clarify, add the remaining 1.8 ml of diethylene glycol monoethyl ether, and fill into a low molecular weight polyethylene sealed container to obtain the product.

[0307] Example 37 Stability Test

[0308] The topical formulation solutions from Examples 1, 20, and Comparative Examples 1, 2, 3, and 4 were placed in a constant temperature and humidity chamber at 40±2℃ and RH 25%±5%. Samples were taken at the end of 3 and 6 months to test their properties, pH, and content. The test results are shown in Table 2.

[0309] Table 2. Results of accelerated testing of topical solutions at 3 and 6 months.

[0310]

[0311] As shown in Table 2, the content of the topical formulation of the present invention remained stable after accelerated testing. By comparing the HPLC purity, it was found that the topical formulation using cinnamaldehyde had better stability. The HPLC purity of Fluxametamide and Isocycloseram remained basically consistent under accelerated conditions of 3 months and 6 months.

[0312] Example 38 Transdermal Test

[0313] A single-chamber permeation diffusion cell was used. 0.5 ml of the topical formulation (Examples 1, 20, Comparative Examples 1, 2, 3, and 4) was evenly placed on a synthetic membrane. The permeation diffusion apparatus was set to a rotation speed of 200 rpm. After stabilization, samples were taken at 0.5, 1, 2, 3, 4, 5, and 6 hours to serve as test solutions at each time point. The content of compound 1 (or compound 20) in the test solution at each time point was calculated using the external standard method based on peak area. The cumulative drug release per membrane was then calculated based on the content of each main component at each time point. The drug release per unit area was calculated based on the permeate membrane area, expressed as the amount of drug released per unit area (mcg / cm²). 2 The slope of the square root of the line relative to time (regression) represents the release rate of the formulation.

[0314] Table 3 Comparison of transdermal penetration rates of topical solutions

[0315]

[0316] Table 3 shows that the cumulative permeation and permeation rate of topical preparations with added cinnamaldehyde are both high, proving that the addition of cinnamaldehyde can effectively promote the skin penetration rate of isoxazoline drugs, thereby improving drug utilization.

[0317] Example 39: Evaluation Test of Deworming Efficacy

[0318] (1) External parasite control (ticks)

[0319] In this evaluation, mixed-sex beagle dogs were used and assigned to a blank control group, a commercially available positive group, and the groups of the present invention examples (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 infested with 50 unfeeded adult ticks (Hypericum erythrophagus).

[0320] Dogs were treated on day 0 with 40 mg / kg of fluranarine, 5 mg / kg of the isoxazoline compounds in the example group of this invention, and 6 mg / kg of selamectin. The formulation was administered externally using a pipette. The dose was applied in a thread along the back of the neck at the base of the skull.

[0321] The average detection rate of ticks in dogs was calculated for each group on days 0, 5, 10, 20 and 30 after drug administration. Any immediate response to treatment was observed on days 1, 2 and 7 after treatment. Adverse reactions, skin irritation and the characteristics of the test preparation were also observed after treatment.

[0322] Table 4. Average detection rate of drugs against ticks in vitro.

[0323]

[0324]

[0325] (2) External parasite control (fleas)

[0326] In this evaluation, mixed-sex beagle dogs were used and assigned to a blank control group, a commercially available positive group, and the groups of the present invention examples (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 infested with 50 unfed adult fleas (Ctenopharynx cateri).

[0327] Dogs were treated on day 0 with 40 mg / kg of fluranarine, 5 mg / kg of the isoxazoline compounds in the example group of this invention, and 6 mg / kg of selamectin. The formulation was administered externally using a pipette. The dose was applied in a thread along the back of the neck at the base of the skull.

[0328] The average detection rate of ticks in dogs was calculated for each group on days 0, 5, 10, 20 and 30 after drug administration. Any immediate response to treatment was observed on days 1, 2 and 7 after treatment. Adverse reactions, skin irritation and the characteristics of the test preparation were also observed after treatment.

[0329] Table 5. Average detection rate of drugs against fleas outside the body.

[0330]

[0331] (3) External parasite (mite) control

[0332] In this evaluation, mixed-sex beagle dogs were used and assigned to the blank control group, the commercially available positive group, and the groups of Examples 31, 32, 34, and 36 of this invention. The experimental dogs were infested with 50 unfed adult mites (ear mites).

[0333] Dogs were treated on day 0 with 5 mg / kg of Fluxametamide, 5 mg / kg of Isocycloseram, and 6 mg / kg of Selamectin. The formulations were administered externally using a pipette. The doses were applied as a thread along the back of the neck at the base of the skull.

[0334] The average detection rate of ticks in dogs was calculated for each group on days 0, 5, 10, 20 and 30 after drug administration. Any immediate response to treatment was observed on days 1, 2 and 7 after treatment. Adverse reactions, skin irritation and the characteristics of the test preparation were also observed after treatment.

[0335] Table 6. Average detection rate of drugs against in vitro mites.

[0336]

[0337] (4) Internal deworming

[0338] In this evaluation, mixed-sex beagle dogs were used and assigned to a blank control group, a commercially available positive group, and an experimental group (Examples 31, 32, 34, and 36). Laboratory fecal flotation and direct smear microscopic examination revealed that the experimental dogs were infected with a large number of intestinal parasites (including hookworms, whipworms, roundworms, tapeworms, etc.).

[0339] Dogs were treated on day 0 with 5 mg / kg of Fluxametamide, 5 mg / kg of Isocycloseram, and 6 mg / kg of Selamectin. The formulations were administered externally using a pipette. The doses were applied as a thread along the back of the neck at the base of the skull.

[0340] The average detection rates of nematodes and tapeworms in dogs were counted on days 0, 5, 10, 20 and 30 after drug administration. Any immediate response to treatment was observed on days 1, 2 and 7 after treatment. Adverse reactions, skin irritation and the characteristics of the test preparation were also observed after treatment.

[0341] Table 7. Average detection rate of drugs against nematodes in vivo.

[0342]

[0343]

[0344] As shown in Tables 4, 5, 6, and 7, this invention has a significant insecticidal effect on both internal and external parasites in dogs, with detection rates lower than the blank control group and the commercially available positive group. Furthermore, its effect is long-lasting, maintaining good internal and external parasite control even after 30 days. The experimental results indicate that the long-acting compound anthelmintic liquid preparation of this invention has a good parasite-killing effect on both internal and external parasites in dogs for 30 days.

[0345] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An external pharmaceutical preparation against parasitic infection, characterized by: The external drug preparation comprises a first active ingredient and an aldehyde compound, the first active ingredient is an isoxazoline compound, the aldehyde compound is cinnamyl aldehyde, and the external drug preparation further comprises a solvent and a co-solvent; The isoxazoline compound is selected from compounds 1-30: 。 2. The topical pharmaceutical preparation against parasitic infections according to claim 1, characterized in that: 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.

3. The topical pharmaceutical preparation against parasitic infections according to claim 2, characterized in that: The solvent is diethylene glycol monoethyl ether.

4. The topical pharmaceutical preparation against parasitic infections according to claim 1, characterized in that: The co-solvent is one or a combination of dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, dimethyl propionamide, diethyl formamide, diisopropyl formamide, acetone, ethanol and isopropyl alcohol.

5. The topical pharmaceutical preparation against parasitic infections according to claim 4, characterized in that: The co-solvent is dimethyl sulfoxide.

6. The topical pharmaceutical preparation against parasitic infections according to claim 1, characterized in that: The external drug preparation comprises the following components in the following proportions: The concentration of the isoxazoline compound is 10-300 mg / ml; The aldehyde compound is added in an amount of 1-5% of the total volume of the external drug preparation; The solvent is added in an amount of 80-90% of the total volume of the external drug preparation; The co-solvent is added in an amount of 5-15% of the total volume of the external drug preparation.

7. Process for the preparation of a topical pharmaceutical preparation against parasitic infections according to any one of claims 1 to 6, characterized in that: The method comprises the following steps: (1) Take the isoxazoline compound, add the aldehyde compound and 50-80% of the solvent by volume, mix until uniform, and obtain a mixture; (2) Add the co-solvent to the mixture of step (1), dissolve and clarify, then add the remaining 20-50% of the solvent by volume to obtain an external preparation solution; (3) Fill the external preparation solution into a container to obtain the external drug preparation.

8. The topical pharmaceutical preparation against parasitic infections as claimed in claim 1, characterized in that: The external drug preparation further comprises a second active ingredient, and the second active ingredient is one or a combination of the following compounds: (a) a pyrethroid; (b) a macrolide compound; (c) an insect growth regulator; (d) a carbamate; (e) a formamidine; (f) a chloronicotinyl; (g) an imidazothiazole; (h) a benzimidazole; (i) a tetrahydroimidazole; (j) an isoquinoline; (k) a salicyl amide.

9. The external pharmaceutical preparation against a parasitic infection according to claim 8, characterized by: The pyrethroid compound is selected from one or a combination of dicofol, cypermethrin, deltamethrin, fenpropathrin, flumethrin, fenvalerate, phenothrin, tetramethrin and allethrin; the macrolide compound is selected from one or a combination of ivermectin, selamectin, moxidectin, spinosad, milbemycin, abamectin and emamectin; the insect growth regulator is selected from one or a combination of pyriproxyfen, hydroprene, hexaflumuron, s- methoprene, diflubenzuron, tebufenozide, chlofluazuron, teflubenzuron, flufenoxuron, chlothiofos, buprofezin and diafenthiuron; the carbamate is selected from one or a combination of indoxacarb, propoxur, isoprocarb, aldicarb, methomyl and carbofuran; the formamidine is selected from amitraz; and the chloronicotinyl is selected from one or a combination of dinotefuran, nitenpyram and thiamethoxam.

10. The topical pharmaceutical preparation against a parasitic infection according to claim 8, characterized in that: The external drug preparation comprises the following components in the following proportions: The concentration of the isoxazoline compound is 10-300 mg / ml; The concentration of the second active ingredient is 10-300 mg / ml; The added amount of the aldehyde compound accounts for 1-5% of the total volume of the external drug preparation; The added amount of the solvent accounts for 80-90% of the total volume of the external drug preparation; The added amount of the cosolvent accounts for 5-15% of the total volume of the external drug preparation.

11. The topical pharmaceutical preparation against a parasitic infection according to claim 10, characterized in that: The external drug preparation comprises the following components in the following proportions: The concentration of the isoxazoline compound is 10-100 mg / ml; The concentration of the second active ingredient is 10-100 mg / ml; The added amount of the aldehyde compound accounts for 2-3% of the total volume of the external drug preparation; The added amount of the solvent accounts for 85-90% of the total volume of the external drug preparation; The added amount of the cosolvent accounts for 5-10% of the total volume of the external drug preparation.

12. A method of preparing an external pharmaceutical preparation for combating parasitic infections according to claim 8, characterized in that: The method comprises the following steps: (1) Take the first active component and the second active component, add the aldehyde compound and 50-80% of the solvent by volume, mix until uniform to obtain a mixture; (2) Add the cosolvent to the mixture of step (1), dissolve and clarify, then add the remaining 20-50% of the solvent by volume to make up the volume to obtain an external preparation solution; (3) Fill the external preparation solution into a container to obtain the external drug preparation.

13. Use of the external drug preparation of any one of claims 1-6, 8-11 in the preparation of a drug for resisting parasitic infection.

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