Isoxazoline derivatives as antiparasitic agents

A compound, C1-C6 technology, used in biocides, animal repellents, plant growth regulators, etc., can solve problems such as no compound antiparasitic species lineage

Active Publication Date: 2013-08-28
ZOETIS SERVICE LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, none of these mentioned exemplifies any isoxazoline-substituted phenylazetidines, nor is it shown in the prior art that such compounds are useful in combating parasitic species lineages in animals, regardless of life form. stage

Method used

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  • Isoxazoline derivatives as antiparasitic agents
  • Isoxazoline derivatives as antiparasitic agents
  • Isoxazoline derivatives as antiparasitic agents

Examples

Experimental program
Comparison scheme
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preparation example Construction

[0653] Urea analogs can be prepared as shown in Scheme 16. Reaction of azetidine 70 with isocyanates or preformed carbamoyl chlorides in the presence of tertiary amine bases provides ureas.

[0654] Scheme 17

[0655]

[0656] Thioamide 76 can be prepared by treating amide 71 with Lowe's reagent in refluxing toluene. Methyl triflate can be dissolved in a solvent such as CH 2 Cl 2 is added to thioamide 76 to form the thioimidate intermediate as a solution. Cyanamide and Hunig's base in THF can be added directly to the thioimidate solution in one portion to give cyanamide 77.

[0657] Those skilled in the art will appreciate that in some cases, following the addition of specified reagents depicted in the schemes, other routine synthetic steps not described in detail may have to be performed to complete the synthesis of compounds of formula (1) or formula (XX).

[0658] The present invention includes all veterinarily acceptable isotope-labeled formula (1) in which one o...

Embodiment 1

[0718] Example 1 : 1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3- Base) phenyl) azetidin-1-yl) ethanone

[0719]

[0720] To 3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5 - Dihydroisoxazole (Preparation 9, 94mg) in 2mL CH 2 Cl 2 To the solution in , pyridine (0.05 mL) was added, followed by acetyl chloride (31 mg). The reaction was stirred at room temperature for 1 hour. Water (3 mL) was added. Reaction with 3mL CH 2 Cl 2 Dilute, stir for 30 minutes, and pour through a phase extractor. Collect CH 2 Cl 2 layer and concentrate. The crude product from the reaction was adsorbed onto silica and chromatographed on a 12 g silica column eluting with a gradient of 50% EtOAc / hexanes to 100% EtOAc / hexanes to afford 90 mg of the desired compound as a white Foam. 1 H NMR (CDCl 3 )δ7.76(d,2H), 7.67(s,2H), 7.56(d,2H), 4.71-4.31(m,4H), 4.12(d,1H), 3.72(d,1H), 2.01(s ,3H). LC / MS dwell time = 3....

Embodiment 2

[0721] Example 2 : Cyclopropyl(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3 -yl)phenyl)azetidin-1-yl)methanone

[0722]

[0723] To 3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5 -Dihydroisoxazole (preparation 9,94mg) in 2mL CH 2 Cl 2 To the solution in , pyridine (0.05 mL) was added, followed by cyclopropanecarbonyl chloride (31 mg). The reaction was stirred at room temperature for 1 hour. Water (10 mL) was added. Reaction with additional 10mL CH 2 Cl 2 Dilute, stir at room temperature for 30 minutes, then pass through a phase separation tube. Collect CH 2 Cl 2 layer and concentrate. The crude material was adsorbed on silica and chromatographed on a 12 g silica column eluting with a gradient of 20% EtOAc / hexanes to 80% EtOAc / hexanes. Fractions containing the desired material were combined and concentrated. Will Et 2 O (~1 / 2 mL) was added to the resulting film. The flask was placed...

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Abstract

This invention recites isoxazoline substituted azetidine derivatives of Formula (1), stereoisomers thereof, veterinarily acceptable salts thereof, compositions thereof, and their use as a parasiticide in mammals and birds. R1a, R1b, R1c, R2, R3, R4, R6, and n are as described herein.

Description

technical field [0001] The present invention relates to isoxazoline derivatives having antiparasitic activity. Compounds of interest are isoxazoline derivatives substituted with phenylazetidine, naphthylazetidine or heteroarylazetidine. The invention also relates to compositions and methods of use thereof. Background technique [0002] There is a need for improved antiparasitic agents for mammals, in particular for improved insecticides and acaricides. In addition, there is a need for improved topical and oral formulations that can be conveniently applied and that contain one or more species that are useful in the effective treatment of ectoparasites such as insects (e.g., fleas, lice, and flies) and mites ( For example, such antiparasitic agents of mites and ticks). Such products would be particularly useful in the treatment of companion animals such as cats, dogs, llamas and horses, as well as livestock such as cattle, bison, pigs, sheep and goats. [0003] Compounds c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12C07D413/14A01N43/80
CPCA01N43/80A01N47/38C07D413/12C07D413/14A61K31/422A61K31/4439A61K31/501A61K31/7048A61P33/00A61P33/10A61P33/14A61P43/00C07D413/10
Inventor N.A.L.查布M.P.柯蒂斯W.豪森G.M.凯恩S.R.梅农S.M.K.希恩D.J.斯卡利茨基V.A.韦尔兰库尔特J.A.文德特
Owner ZOETIS SERVICE LLC
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