An isoxazoline compound and use thereof

Abstract

This invention discloses an isoxazoline compound and its application, belonging to the field of sanitary and agricultural insecticide technology. The isoxazoline compound is shown in Formula I: I; where: R1 represents a substituent on the benzene ring, selected from monosubstituted or polysubstituted groups; when R1 is polysubstituted, the multiple substituents may be the same or different; R1 is selected from one or more of hydrogen, chlorine, fluorine, and trifluoromethyl; R2 is selected from C 1‑6 Straight-chain or branched alkyl groups, C 1‑6 Straight-chain or branched fluoroalkyl, C 3‑6 cycloalkyl, C 3‑6 The isoxazoline compound provided in this application is one of the following: fluorocycloalkyl, N-alkylamide with 1-3 carbon atoms, or N-fluoroalkylamide. It exhibits high insecticidal activity, rapid onset of action, and long duration of action, demonstrating excellent biological activity in killing parasites. It can be used for the prevention and treatment of parasitic infections and invasions, and has broad clinical application prospects and market promotion value.

Description

Technical Field

[0001] This invention relates to the field of sanitary and agricultural pesticides, specifically to an isoxazoline compound and its applications. Background Technology

[0002] Pet parasites are a common problem in pet breeding and raising, with an extremely high overall incidence. If domestic pets are not properly dewormed, the incidence of external parasites can reach over 80%, and the incidence of internal parasites is around 50%. Stray / free-roaming pets have a near 100% parasite infection rate, often with mixed infections. These parasites pose significant threats to both pet health and human public health. The direct harms of parasites to pets include nutrient depletion and growth retardation, tissue and organ damage, immunosuppression and secondary diseases, and neurological and systemic symptoms. In addition to their harm to pets, parasites also pose a significant threat to human public health and safety, such as toxoplasmosis, Lyme disease, and anaplasmosis, which are extremely dangerous for pregnant women.

[0003] Isoxazoline is a new type of broad-spectrum oral and external anthelmintic, and it is currently the core category of external / oral external anthelmintics in pet clinical practice. Common drugs include fipronil (banned), fleranal, salorananal, lentilana, afolanana, fipronilamide, loxadustat, and selamectin (some classifications belong to macrolides, often used in combination with isoxazoline). Its core action is on the nervous system of parasites, and it has the characteristics of high selectivity and irreversible killing.

[0004] Isoxazoline derivatives, with their broad-spectrum, high-efficiency, convenient, and low-toxicity characteristics, have become the mainstream category for external parasite control in pets. They can also be used in combination with other drugs to achieve simultaneous internal and external parasite control. Compared with traditional pyrethroids and imidacloprids, which have led to drug resistance in fleas and ticks in some areas due to long-term use, isoxazoline derivatives have unique targets and no cross-resistance with traditional drugs. They still have a highly effective killing effect on drug-resistant parasites, solving the problem of drug resistance in clinical parasite control.

[0005] However, there is still a clinical need for novel antiparasitic drugs that are highly effective, fast-acting, have a long duration of action, and are suitable for both animals and humans. Summary of the Invention

[0006] In view of the above-mentioned problems in the prior art, this application provides an isoxazoline compound and its application to prevent and treat parasitic infections and invasions.

[0007] To address the above problems, the present invention provides the following technical solution:

[0008] In a first aspect, this application provides an isoxazoline compound, as shown in Formula I:

[0009] ;

[0010] Ⅰ;

[0011] In the formula:

[0012] R1 represents the substituent on the benzene ring, which can be selected from monosubstituted or polysubstituted groups. When R1 is polysubstituted, the multiple substituents may be the same or different.

[0013] R1 is selected from one or more of hydrogen, chlorine, fluorine, and trifluoromethyl;

[0014] R2 is selected from C 1-6 Straight-chain or branched alkyl groups, C 1-6 Straight-chain or branched fluoroalkyl, C 3-6 cycloalkyl, C 3-6 One of fluorocycloalkyl, N-alkylamide with 1-3 carbon atoms, and N-fluoroalkylamide.

[0015] In one embodiment of this application, R2 is selected from C. 1-3 Straight-chain or branched alkyl groups, C 1-3 One of the following: linear or branched fluoroalkyl, N-ethylacetamido, N-ethylpropionamido, N-(2,2,2-trifluoroethyl)acetamido, and N-(2,2,2-trifluoroethyl)propionamido.

[0016] In one embodiment of this application, the isoxazoline compound is a compound selected from the following structures:

[0017] , ,

[0018] , ,

[0019] , ,

[0020] , ,

[0021] , ,

[0022] , ,

[0023] , ,

[0024] , ,

[0025] , ,

[0026] , ,

[0027] , .

[0028] The compounds of this application may exist in specific geometric or stereoisomeric forms. This application envisions all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers and diastereomers, all of which are within the scope of this application. All such isomers and mixtures thereof are within the scope of this application.

[0029] Secondly, a composition comprising an active ingredient and an agriculturally, forestryly, or sanitarily acceptable carrier, wherein the active ingredient comprises an isoxazoline compound.

[0030] Thirdly, the application of isoxazoline compounds or compositions in the preparation of formulations for the prevention and treatment of parasites.

[0031] In one embodiment of this application, isoxazoline compounds or compositions are effective in controlling all life stages of parasites, including egg, nymph, larva, juvenile, and adult stages. Ectoplasms include several major categories such as insects, ticks / mites, and arachnids.

[0032] Insects include lice, fleas, Diptera, and Licetoflies, including sucking lice, biting lice, human fleas, rat fleas, and cat fleas, as well as Diptera such as Culex, Anopheles, and Evans; and Licetoflies such as Dermatophytes, Gastrophytes, Yellow Flies, Horseflies, Stable Flies, Black Flies, and Green Flies.

[0033] Ticks and mites are small to medium-sized, wingless, and have indistinct body segments. Most are obligate parasites, while some are facultative parasites. They can transmit a variety of pathogens (viruses, bacteria, protozoa) and are among the most pathogenic and transmissible groups of ectoparasites of warm-blooded animals. Ticks and mites include genera such as *Ixodes*, *Tectus*, *Haemaphysalis*, *Tectus*, *Scabiei*, *Ototrichum*, *Demodex*, and *Pterygium*.

[0034] Fourthly, the use of isoxazoline compounds or compositions in the preparation of drugs for treating diseases in humans and animals caused by parasites.

[0035] In one embodiment of this application, isoxazoline compounds or compositions are commonly used to treat various homeothermic animals, especially mammals. Mammals include animals in agricultural and non-agricultural environments, such as livestock (cattle, sheep, goats, cattle, horses, donkeys, etc.), laboratory animals (rats, mice, guinea pigs, rabbits, monkeys, pigs, etc.), companion animals (pet dogs, cats, etc.), zoo animals, etc. Other possible homeothermic animals include birds such as chickens, ducks, geese, turkeys, and parrots.

[0036] In one embodiment of this application, the related diseases caused by parasites include anemia, allergies, Lyme disease, Erik's disease, dermatitis, mange, encephalitis, canine distemper, and parvovirus infection.

[0037] In one embodiment of this application, the pharmaceutical formulation includes solid dosage forms, semi-solid dosage forms, and liquid dosage forms.

[0038] Solid dosage forms include tablets, pills, capsules, powders, granules, etc. In preparing these solid dosage forms, in addition to the compounds described in this invention or their pharmaceutically acceptable salts or compositions, one or more excipients, fillers or compatibilizers, binders, disintegrants, stabilizers, wetting agents, adsorbents, lubricants, or encapsulating materials conventionally used in the art may be added.

[0039] Semi-solid dosage forms include one or more of ointments, creams, pastes, or gels.

[0040] Liquid dosage forms include solvents, suspensions, emulsifiers, syrups, or tinctures. In addition to the compounds described in this invention or their pharmaceutically acceptable salts or compositions, liquid dosage forms may contain one or more of the following commonly used in the art: diluents, solubilizers, emulsifiers, wetting agents, suspending agents, sweeteners, flavoring agents, aromatizers, or preservatives.

[0041] The routes of administration can be oral, injection, or topical application.

[0042] Dosage forms suitable for topical administration include ointments, powders, patches, drops, or sprays.

[0043] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0044] The isoxazoline compounds provided in this application have high insecticidal activity, rapid onset of action, and long duration of action. They exhibit excellent biological activity in killing parasites and can be used to prevent and treat parasitic infections and invasions. They have broad clinical application prospects and market promotion value. Detailed Implementation

[0045] The technical solutions in the embodiments of this application will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments.

[0046] The "range" disclosed in this application is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of the particular range. The range defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range.

[0047] Unless otherwise stated, when this invention relates to percentages between liquids, the percentage is volume / volume percentage; when this invention relates to percentages between liquids and solids, the percentage is volume / weight percentage; when this invention relates to percentages between solids and liquids, the percentage is weight / volume percentage; and the remainder is weight / weight percentage.

[0048] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0049] Example 1: Synthesis of methyl 3-(4-acetylphenyl)bicyclo[1.1.1]pentane-1-carboxylic acid (C3)

[0050] ;

[0051] Step 1, Synthesis of bicyclic [1.1.1]pentane-1,3-dicarboxylic acid monomethyl ester (C1)

[0052] Bicyclic [1.1.1]pentane-1,3-dicarboxylic acid (SM1) (15.6 g, 0.1 mol) was dissolved in 1 L of methanol. While stirring, TMSCl (12.7 mL, 0.1 mol) was added dropwise to the reaction system. The reaction was continued overnight at room temperature with stirring. The solution was concentrated under reduced pressure to give C1 (17.5 g, 100%).

[0053] 1 H NMR, (400 MHz, CDCl3), δ (ppm): 3.75 (3H, s), 2.34 (6H, s).

[0054] Step 2, Synthesis of bicyclic [1.1.1]pentane-1,3-dicarboxylic acid 1-(1,3-dioxoisoindoline-2-yl) 3-methyl ester (C2)

[0055] C1 (17.5 g, 0.1 mol) was added to 50 mL of dichloromethane, followed by N-hydroxyphthalamide (SM2) (17.93 g, 0.11 mol), DCC (22.73 g, 0.11 mol), and DMAP (1.34 g, 0.011 mol). The reaction mixture was stirred at room temperature for 12 hours. The mixture was filtered and concentrated to dryness. The crude product was extracted with dichloromethane after adding water. The combined organic phases were dried, distilled under reduced pressure, and separated by column chromatography to give C2 (26.46 g, 84%).

[0056] 1HNMR, (400 MHz, CDCl3) δ ppm 7.91 (dd, 2H), 7.78 (dd, 2H), 3.69 (s,3H), 2.54 (s, 6H).

[0057] Step 3, Synthesis of methyl 3-(4-acetylphenyl)bicyclo[1.1.1]pentane-1-carboxylic acid (C3)

[0058] p-Bromoacetophenone (SM3) (1.98 g, 10 mmol), C2 (4.73 g, 15 mmol), Hantzsch ester (5.06 g, 20 mmol), NiBr2 (dtbbpy) (0.98 g, 0.2 mmol), and sodium bicarbonate (4.24 g, 40 mmol) were added to a reaction flask, along with 30 mL of anhydrous DMA, and the mixture was protected under nitrogen. The reaction was carried out for 12 hours under 390 nm light. 100 mL of dilute hydrochloric acid (2N) was added to the reactants, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography using 200-300 mesh silica gel as the stationary phase and ethyl acetate / n-heptane (1:100–1:5) as the mobile phase. The product was collected to give C3 (1.36 g, 56%), colorless crystals.

[0059] 1 H NMR, (400 MHz, CDCl3) δ ppm 7.92 (d, 2H), 7.33 (d, 2H), 3.70 (s, 3H), 2.56 (s, 3H), 2.34 (s, 6H). MS (ESI), [M+H]+, 245.1.

[0060] Example 2: Synthesis of 3-(4-(5-phenyl-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxylic acid (C6)

[0061] ;

[0062] Step 1, Synthesis of methyl 3-(4-(5-phenyl-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxylic acid (C5)

[0063] C3 (24.4 g, 0.1 mol) and trifluoroacetophenone (SM4) (17.4 g, 0.1 mol) were added to toluene (120 mL), followed by triethylamine (30.3 g, 0.3 mol) under nitrogen protection. The mixture was then stirred at 50-60°C to dissolve the precipitate and reacted for 8 hours. DMAP (12.1 g, 0.1 mol) was added, followed by dropwise addition of acetic anhydride (20.5 g, 0.2 mol), and the reaction was continued at 50-60°C for 3 hours. The reaction system was then cooled to 10°C, and an aqueous solution of sodium hydroxide (16 g sodium hydroxide dissolved in 150 mL of water) was added. The mixture was stirred vigorously, maintaining the temperature below 10°C. Hydroxylamine hydrochloride (14 g, 0.2 mol) was then added, and stirring continued for 3-4 hours. After the reaction was complete, the pH of the system was adjusted to neutral with 10% hydrochloric acid. The mixture was separated, and the toluene phase was washed once with water and once with saturated brine, then dried over anhydrous sodium sulfate. The solution was filtered and concentrated to obtain the crude product. The residue was purified by column chromatography with 200-300 mesh silica gel as the stationary phase and ethyl acetate / n-heptane (1:20 – 1:5) as the mobile phase. The product was collected as a C5 solid (32.8 g, 79%), pale yellow in color.

[0064] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.18 (d, 2H), 7.43 (d, 2H), 7.33 (d, 2H), 7.17 (m, 3H), 3.65 (s, 3H), 3.20 (dd, 1H), 2.44 (s, 6H).

[0065] MS (ESI+), [M+H]+, 416.2.

[0066] Step 2, Synthesis of 3-(4-(5-phenyl-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxylic acid (C6)

[0067] C5 (20.75 g, 0.05 mol) was added to a mixture of methanol and water (1:1, 100 mL), followed by the addition of LiOH (1.32 g, 0.055 mol). The mixture was stirred at room temperature for 3 hours. The methanol was evaporated to dryness under reduced pressure, and the pH of the remaining liquid was adjusted to 2.0 with 1N HCl. The solid precipitated, was filtered, the filter cake was washed with water, and dried under reduced pressure to obtain C6 (17.6 g, 88%).

[0068] MS (ESI+), [M+H]+, 402.1.

[0069] Example 3: Synthesis of N-ethyl-3-(4-(5-phenyl-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)bicyclo[1.1.1]pentan-1-amide (PCA-01)

[0070] ;

[0071] C6 (800 mg, 2 mmol) was added to dichloromethane (20 mL), along with 1 drop of DMF (catalyst). Oxaloyl chloride (504 mg, 4 mmol) was added at 0–5°C, and the reaction was carried out at 0–5°C for 1 hour. The reaction solvent was evaporated to dryness, and dichloromethane (10 mL) was added. The mixture was distilled under reduced pressure twice to remove residual oxalyl chloride. Dichloromethane (20 mL), triethylamine (404 mg, 4 mmol), and ethylamine hydrochloride (100 mg, 1.25 mmol) were added to the remaining oily liquid, and the mixture was stirred at room temperature for 30 minutes. Water was added, and the mixture was separated. The aqueous layer was washed twice with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by column chromatography using 200–300 mesh silica gel as the stationary phase and ethyl acetate / n-heptane (1:20–1:5) as the mobile phase. The product was collected to give PCA-01 (601 mg, 70%). A light yellow solid.

[0072] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.06 (d, 2H), 7.31 (d, 2H), 7.28 (d, 2H), 7.11 (d, 2H), 7.05 (m, 1H), 3.31 (m, 2H), 3.20 (dd, 1H), 2.34 (s, 6H), 1.01(t, 3H).

[0073] MS (ESI+), [M+H]+, 429.2.

[0074] Example 4: Synthesis of N-isopropyl-3-(4-(5-phenyl-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)bicyclo[1.1.1]pentane-1-amide (PCA-02)

[0075] ;

[0076] The procedure was the same as in Example 3, except that isopropylamine hydrochloride was used instead of ethylamine hydrochloride. PCA-02 (414 mg, 47%) was obtained.

[0077] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.08 (d, 2H), 7.38 (d, 2H), 7.32 (d, 2H), 7.15 (m, 3H), 3.10 (dd, 1H), 3.00 (m, 1H), 2.24 (s, 6H), 0.98 (d, 6H).

[0078] MS (ESI+), [M+H]+, 443.2.

[0079] Example 5: Synthesis of N-propyl-3-(4-(5-phenyl-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)bicyclo[1.1.1]pentan-1-amide (PCA-03)

[0080] ;

[0081] The procedure was the same as in Example 3, except that isopropylamine hydrochloride was used instead of ethylamine hydrochloride. PCA-03 (570 mg, 64%) was obtained.

[0082] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.07 (d, 2H), 7.41 (d, 2H), 7.35 (d, 2H), 7.18 (m, 3H), 3.16 (dd, 1H), 3.00 (m, 2H), 2.20 (s, 6H), 1.55 (m, 2H), 0.88(t, 3H).

[0083] MS (ESI+), [M+H]+, 443.2.

[0084] Example 6: Synthesis of N-(2,2,2,-trifluoroethyl)-3-(4-(5-phenyl-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)bicyclo[1.1.1]pentan-1-amide (PCA-04)

[0085] ;

[0086] The procedure was the same as in Example 3, except that trifluoroethylamine hydrochloride was used instead of ethylamine hydrochloride. This yielded PCA-04 (570 mg, 71%).

[0087] 1H NMR, (400 MHz, CDCl3) δ ppm 8.10 (d, 2H), 7.50 (d, 2H), 7.38 (d, 2H), 7.19 (m, 3H), 3.20 (dd, 1H), 3.70 (m, 2H), 2.28 (s, 6H).

[0088] MS (ESI+), [M+H]+, 482.2.

[0089] Example 7: Synthesis of 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxylic acid (C9)

[0090] ;

[0091] The procedure was the same as in Example 2, except that 3,5-dichloro-trifluoromethylbenzophenone (SM5) was used instead of trifluoromethylacetophenone (SM4). C9 (20.7 g, 88%) was obtained.

[0092] MS (ESI+), [M+H]+, 470.0, 472.0 (3:2, chlorine isotope signal).

[0093] Example 8: Synthesis of N-ethyl-3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)bicyclo[1.1.1]pentan-1-amide (PCA-05)

[0094] ;

[0095] The procedure was the same as in Example 3, except that C9 was used instead of C6. PCA-05 (616 mg, 62%) was obtained.

[0096] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.16 (d, 2H), 7.60 (s, 1H), 7.43 (d, 2H), 7.29 (s, 2H), 3.28 (m, 2H), 3.29 (dd, 1H), 2.40 (s, 6H), 1.00 (t, 3H).

[0097] MS (ESI+), [M+H]+, 497.2, 499.2 (3:2, chlorine isotope signal).

[0098] Example 9: Synthesis of N-(2,2,2,-trifluoroethyl)-3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)bicyclo[1.1.1]pentan-1-amide (PCA-06)

[0099] ;

[0100] The procedure was the same as in Example 3, except that C9 was used instead of C6, and trifluoroethylamine hydrochloride was used instead of ethylamine hydrochloride. This yielded PCA-06 (550 mg, 50%).

[0101] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.23 ​​(d, 2H), 7.55 (s, 1H), 7.48 (d, 2H), 7.39 (s, 2H), 3.20 (dd, 1H), 3.75 (m, 2H), 2.28 (s, 6H).

[0102] MS (ESI+), [M+H]+, 551.1, 552.1 (3:2, chlorine isotope signal).

[0103] Example 10: Synthesis of 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)-N-(2-(ethylamino)-2-oxoethyl)bicyclo[1.1.1]pentan-1-amide (PCA-07)

[0104] ;

[0105] C9 (940 mg, 2 mmol) was added to tetrahydrofuran (25 mL), followed by EDCI (420 mg, 2.2 mmol), HOBt (300 mg, 2.2 mmol), N-methylmorpholine (600 mg, 6 mmol), and finally glycyl ethylamine hydrochloride (SM6) (224 mg, 2.2 mmol). The mixture was stirred overnight at room temperature. Water was added to the mixture, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by column chromatography using 200-300 mesh silica gel as the stationary phase and ethyl acetate / n-heptane (1:20-1:5) as the mobile phase. The product was collected to give PCA-07 (803 mg, 73%).

[0106] 1H NMR, (400 MHz, CDCl3) δ ppm 8.15 (d, 2H), 7.55 (s, 1H), 7.47 (d, 2H), 7.15 (s, 2H), 4.14 (s, 2H), 3.31 (m, 2H), 3.24 (dd, 1H), 2.41 (s, 6H), 0.91(t, 3H).

[0107] MS (ESI+), [M+H]+, 554.1, 556.1 (3:2, chlorine isotope signal).

[0108] Example 11: Synthesis of 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)-N-(2-((2,2,2-trifluoroethyl)-amino)-2-oxoethyl)bicyclo[1.1.1]pentan-1-amide (PCA-08)

[0109] ;

[0110] The procedure was the same as in Example 10, except that glycyltrifluoroethylamine hydrochloride (SM7) was used instead of SM6 to obtain PCA-08 (817 mg, 67%).

[0111] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.25 (d, 2H), 7.60 (s, 1H), 7.40 (d, 2H), 7.33 (s, 2H), 4.22 (s, 2H), 3.20 (dd, 1H), 3.72 (m, 2H), 2.28 (s, 6H).

[0112] MS (ESI+), [M+H]+, 608.1, 610.1 (3:2, chlorine isotope signal).

[0113] Example 12: Synthesis of 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)-N-((S)-1-(ethylamino)-1-oxopropyl-2-yl)bicyclo[1.1.1]pentan-1-amide (PCA-09)

[0114] ;

[0115] The procedure was the same as in Example 10, except that S-alanyl ethylamine hydrochloride (SM8) was used instead of SM6 to obtain PCA-09 (757 mg, 66%).

[0116] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.13 (d, 2H), 7.51 (s, 1H), 7.45 (d, 2H), 7.09 (s, 2H), 4.54 (m, 1H), 3.29 (m, 2H), 3.21 (dd, 1H), 2.44 (s, 6H), 1.51(d, 3H), 0.91(t, 3H).

[0117] MS (ESI+), [M+H]+, 568.1, 570.1 (3:2, chlorine isotope signal).

[0118] Example 13: Synthesis of 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)-N-((S)-1-oxo-1-((2,2,2-trifluoromethyl)amino)propyl-2-yl)bicyclo[1.1.1]pentan-1-amide (PCA-10)

[0119] ;

[0120] The procedure was the same as in Example 10, except that S-alanyltrifluoroethylamine hydrochloride (SM9) was used instead of SM6 to obtain PCA-10 (630 mg, 51%).

[0121] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.21 (d, 2H), 7.55 (s, 1H), 7.41 (d, 2H), 7.31 (s, 2H), 4.62 (m, 1H), 3.88 (m, 2H), 3.24 (dd, 1H), 2.25 (s, 6H), 1.51(d, 3H).

[0122] MS (ESI+), [M+H]+, 622.1, 624.1 (3:2, chlorine isotope signal).

[0123] Example 14: Synthesis of 3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxylic acid (C12)

[0124] ;

[0125] The procedure was the same as in Example 2, except that 3,4,5-trichloro-trifluoromethylbenzophenone (SM10) was used instead of trifluoromethylacetophenone (SM4). C12 (21.3 g, 82%) was obtained.

[0126] MS (ESI+), [M+H]+, 504.1, 506.1 (1:1, chlorine isotope signal).

[0127] Example 15: Synthesis of N-ethyl-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)bicyclo[1.1.1]pentan-1-amide (PCA-11)

[0128] ;

[0129] The procedure was the same as in Example 3, except that C12 was used instead of C6. This yielded PCA-11 (570 mg, 53%).

[0130] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.26 (d, 2H), 7.53 (d, 2H), 7.15 (s, 2H), 3.24 (m, 2H), 3.24 (dd, 1H), 2.44 (s, 6H), 0.91 (t, 3H).

[0131] MS (ESI+), [M+H]+, 531.1, 533.1 (1:1, chlorine isotope signal).

[0132] Example 16: Synthesis of N-(2,2,2,-trifluoroethyl)-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)bicyclo[1.1.1]pentan-1-amide (PCA-12)

[0133] ;

[0134] The procedure was the same as in Example 3, except that C12 was used instead of C6, and trifluoroethylamine hydrochloride was used instead of ethylamine hydrochloride. PCA-12 (632 mg, 54%) was obtained.

[0135] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.31 (d, 2H), 7.53 (d, 2H), 7.20 (s, 2H), 3.21 (dd, 1H), 3.77 (m, 2H), 2.23 (s, 6H).

[0136] MS (ESI+), [M+H]+, 585.1, 587.1 (1:1, chlorine isotope signal).

[0137] Example 17: Synthesis of 3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)-N-(2-(ethylamino)-2-oxoethyl)bicyclo[1.1.1]pentan-1-amide (PCA-13)

[0138] ;

[0139] The procedure was the same as in Example 10, except that C9 was replaced with C12. PCA-13 (932 mg, 79%) was obtained.

[0140] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.19 (d, 2H), 7.45 (d, 2H), 7.23 (s, 2H), 4.14 (s, 2H), 3.33 (m, 2H), 3.28 (dd, 1H), 2.45 (s, 6H), 0.89 (t, 3H).

[0141] MS (ESI+), [M+H]+, 588.1, 590.1 (1:1, chlorine isotope signal).

[0142] Example 18: Synthesis of 3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)-N-(2-((2,2,2-trifluoroethyl)-amino)-2-oxoethyl)bicyclo[1.1.1]pentan-1-amide (PCA-14)

[0143] ;

[0144] The procedure was the same as in Example 10, except that C12 was used instead of C9 and SM7 was used instead of SM6. PCA-14 (1.02 g, 79%) was obtained.

[0145] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.28 (d, 2H), 7.48 (d, 2H), 7.31 (s, 2H), 4.22 (s, 2H), 3.22 (dd, 1H), 3.70 (m, 2H), 2.21 (s, 6H).

[0146] MS (ESI+), [M+H]+, 642.1, 644.1 (1:1, chlorine isotope signal).

[0147] Example 19: Synthesis of 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxylic acid (C15)

[0148] ;

[0149] The procedure was the same as in Example 2, except that 3,5-dichloro-4-fluoro-trifluoromethyl benzophenone (SM11) was used instead of trifluoromethyl acetophenone. C15 (19.8 g, 81%) was obtained.

[0150] MS (ESI+), [M+H]+, 488.0, 490.0 (3:2, chlorine isotope signal).

[0151] Example 20: Synthesis of N-ethyl-3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)bicyclo[1.1.1]pentan-1-amide (PCA-15)

[0152] ;

[0153] The procedure was the same as in Example 3, except that C15 was used instead of C6. This yielded PCA-15 (671 mg, 65%).

[0154] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.05 (d, 2H), 7.29 (d, 2H), 7.28 (s, 2H), 3.35 (m, 2H), 3.24 (dd, 1H), 2.29 (s, 6H), 0.91 (t, 3H).

[0155] MS (ESI+), [M+H]+, 515.2, 517.2 (3:2, chlorine isotope signal).

[0156] Example 21: Synthesis of N-(2,2,2,-trifluoroethyl)-3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)bicyclo[1.1.1]pentan-1-amide (PCA-16)

[0157] ;

[0158] The procedure was the same as in Example 3, except that C15 was used instead of C6, and trifluoroethylamine hydrochloride was used instead of ethylamine hydrochloride. PCA-16 (707 mg, 62%) was obtained.

[0159] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.25 (d, 2H), 7.48 (d, 2H), 7.01 (s, 2H), 3.18 (dd, 1H), 3.67 (m, 2H), 2.23 (s, 6H).

[0160] MS (ESI+), [M+H]+, 569.1, 571.1 (3:2, chlorine isotope signal).

[0161] Example 22: Synthesis of 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)-N-(2-(ethylamino)-2-oxoethyl)bicyclo[1.1.1]pentan-1-amide (PCA-17)

[0162] ;

[0163] The procedure was the same as in Example 10, except that C9 was replaced with C15. This yielded PCA-17 (799 mg, 70%).

[0164] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.31 (d, 2H), 7.39 (d, 2H), 7.08 (s, 2H), 4.12 (s, 2H), 3.30 (m, 2H), 3.24 (dd, 1H), 2.43 (s, 6H), 0.99 (t, 3H).

[0165] MS (ESI+), [M+H]+, 572.1, 574.1 (3:2, chlorine isotope signal).

[0166] Example 23: Synthesis of 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)-N-(2-((2,2,2-trifluoroethyl)-amino)-2-oxoethyl)bicyclo[1.1.1]pentan-1-amide (PCA-18)

[0167] ;

[0168] The procedure was the same as in Example 10, except that C15 was used instead of C9 and SM7 was used instead of SM6. This yielded PCA-18 (870 mg, 69%).

[0169] 1H NMR, (400 MHz, CDCl3) δ ppm 8.38 (d, 2H), 7.38 (d, 2H), 7.11 (s, 2H), 4.20 (s, 2H), 3.27 (dd, 1H), 3.72 (m, 2H), 2.24 (s, 6H).

[0170] MS (ESI+), [M+H]+, 626.1, 628.1 (3:2, chlorine isotope signal).

[0171] Example 24: Synthesis of 3-(4-(5-(3-chloro-5-trifluoromethylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxylic acid (C18)

[0172] ;

[0173] The procedure was the same as in Example 2, except that 3-chloro-5-trifluoromethylphenyltrifluoromethyl benzophenone (SM12) was used instead of trifluoromethylacetophenone (SM4). C18 (17.1 g, 68%) was obtained.

[0174] MS (ESI+), [M+H]+, 504.1, 506.1 (3:1, chlorine isotope signal).

[0175] Example 25: Synthesis of N-ethyl-3-(4-(5-(3-chloro-5-trifluoromethylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)bicyclo[1.1.1]pentan-1-amide (PCA-19)

[0176] ;

[0177] The procedure was the same as in Example 3, except that C18 was used instead of C6. This yielded PCA-19 (683 mg, 64%).

[0178] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.05 (d, 2H), 7.88 (m, 1H), 7.55 (m, 1H), 7.35 (m, 1H), 7.29 (d, 2H), 3.39 (m, 2H), 3.25 (dd, 1H), 2.23 (s, 6H), 0.98(t, 3H).

[0179] MS (ESI+), [M+H]+, 531.2, 533.2 (3:1, chlorine isotope signal).

[0180] Example 26: Synthesis of N-(2,2,2,-trifluoroethyl)-3-(4-(5-(3-chloro-5-trifluoromethylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)bicyclo[1.1.1]pentan-1-amide (PCA-20)

[0181] ;

[0182] The procedure was the same as in Example 3, except that C18 was used instead of C6, and trifluoroethylamine hydrochloride was used instead of ethylamine hydrochloride. PCA-20 (919 mg, 78%) was obtained.

[0183] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.15 (d, 2H), 7.76 (m, 1H), 7.58 (m, 1H), 7.31 (m, 1H), 7.18 (d, 2H), 3.23 (dd, 1H), 3.71 (m, 2H), 2.28 (s, 6H).

[0184] MS (ESI+), [M+H]+, 585.1, 587.1 (3:1, chlorine isotope signal).

[0185] Example 27: Synthesis of 3-(4-(5-(3-chloro-5-trifluoromethylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)-N-(2-(ethylamino)-2-oxoethyl)bicyclo[1.1.1]pentan-1-amide (PCA-21)

[0186] ;

[0187] The procedure was the same as in Example 10, except that C9 was replaced with C18 to obtain PCA-21 (940 mg, 80%).

[0188] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.09 (d, 2H), 7.71 (m, 1H), 7.62 (m, 1H), 7.22 (m, 1H), 7.08 (d, 2H), 4.15 (s, 2H), 3.35 (m, 2H), 3.19 (dd, 1H), 2.45(s, 6H), 0.89(t, 3H).

[0189] MS (ESI+), [M+H]+, 587.1, 589.1 (3:1, chlorine isotope signal).

[0190] Example 28: Synthesis of 3-(4-(5-(3-chloro-5-trifluoromethylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoline-3-yl)phenyl)-N-(2-((2,2,2-trifluoroethyl)-amino)-2-oxoethyl)bicyclo[1.1.1]pentan-1-amide (PCA-22)

[0191] ;

[0192] The procedure was the same as in Example 10, except that C18 was used instead of C9 and SM7 was used instead of SM6. PCA-22 (990 mg, 78%) was obtained.

[0193] 1 H NMR, (400 MHz, CDCl3) δ ppm 8.18 (d, 2H), 7.68 (m, 1H), 7.50 (m, 1H), 7.31 (m, 1H), 7.18 (d, 2H), 4.10 (s, 2H), 3.24 (dd, 1H), 3.71 (m, 2H), 2.21(s, 6H).

[0194] MS (ESI+), [M+H]+, 642.1, 644.1 (3:1, chlorine isotope signal).

[0195] Example 29: Preparation of high-concentration concentrate

[0196] As shown in Table 1, add all ingredients to the mixing tank and stir at 10 rpm for 60 minutes to obtain the final product.

[0197] Table 1

[0198] ;

[0199] Example 30: Preparation of tablets

[0200] The prescription information is shown in Table 2. Mix PCA-05 with starch at 30 rpm for 30 minutes, then add 50% of the prescribed amount of lactose and stir at 30 rpm for 15 minutes. Add the remaining 50% of the prescribed amount of lactose and stir at 30 rpm for 5 minutes. Perform dry granulation, add magnesium stearate, mix well, and compress into tablets to obtain the final product.

[0201] Table 2

[0202] ;

[0203] Example 31: Preparation of Powder

[0204] The prescription information is shown in Table 3. Mix all ingredients in a mixing tank and stir at 20 rpm for 30 minutes to obtain the final product.

[0205] Table 3

[0206] ;

[0207] Example 32: Preparation of Emulsion

[0208] The prescription information is shown in Table 4. Add all components to water and mix at 120 rpm for 60 minutes to obtain the final product.

[0209] Table 4

[0210] ;

[0211] Example 33: Efficacy of compounds PCA-01, PCA-04, PCA-05, PCA-06, PCA-07, and PCA-08 against cat fleas.

[0212] Cat fleas were loaded onto artificial membranes and fed with blood containing compounds PCA-01, 04, 05, 06, 07, and 08 at concentrations of 1 ppm, 10 ppm, and 100 ppm, respectively. After 48 hours of continuous feeding, the number of fleas killed and the number of loaded fleas were measured to evaluate the flea-killing ability of the compounds. The results are shown in Table 5.

[0213] Table 5

[0214] ;

[0215] Example 34: Killing efficiency of the compound against fleas on mouse body surface

[0216] Mice were divided into groups of three and administered compounds PCA-11 to PCA-22 orally (10 mg / kg body weight) and topically (100 ppm) to evaluate their flea-killing efficacy against fleas on mouse skin. Caterpillar fleas were used for infection. Mice were observed for 24 hours after administration, and the flea-killing effects of the compounds were evaluated at 1, 4, 8, and 24 hours. The results are shown in Table 6.

[0217] Table 6

[0218] ;

[0219] The present application has been described in detail above with reference to specific embodiments and exemplary examples. However, these descriptions should not be construed as limiting the present application. Those skilled in the art will understand that various equivalent substitutions, modifications, or improvements can be made to the technical solutions and implementation methods of the present application without departing from the spirit and scope of the present application, and all such modifications and improvements fall within the scope of the present application.

Claims

1. An isoxazoline compound, as shown in Formula I: ； In the formula: R1 represents the substituent on the benzene ring, which can be selected from monosubstituted or polysubstituted groups. When R1 is polysubstituted, the multiple substituents may be the same or different. R1 is selected from one or more of hydrogen, chlorine, fluorine, and trifluoromethyl; R2is selected from C 1-3 linear or branched alkyl, C 1-3 one of linear or branched fluoroalkyl.

2. An isoxazoline compound, characterized in that, It is a compound selected from the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 3. A composition characterized in that, The composition contains an active ingredient and an agriculturally, forestryly, or sanitarily acceptable carrier, wherein the active ingredient comprises an isoxazoline compound as described in any one of claims 1-2.

4. The use of the isoxazoline compound of any one of claims 1-2 or the composition of claim 3 in the preparation of an antiparasitic agent.

5. The use of the isoxazoline compound of any one of claims 1-2 or the composition of claim 3 in the preparation of a medicament for treating diseases in humans and animals caused by parasites.

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