Spirocyclic isoxazolines as antiparasitic agents

A technology of cycloalkyl and stereoisomers, which is applied in the field of manufacturing the spirocyclic isoxazoline derivatives, and can solve problems such as not indicating the range of life cycle stages

Inactive Publication Date: 2015-05-06
ZOETIS SERVICE LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, none of these citations exemplifies pyridyl spirocyclic substituted isoxazolines or methods for their manufacture, nor does the prior art indicate that such c...

Method used

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  • Spirocyclic isoxazolines as antiparasitic agents
  • Spirocyclic isoxazolines as antiparasitic agents
  • Spirocyclic isoxazolines as antiparasitic agents

Examples

Experimental program
Comparison scheme
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preparation example Construction

[0134] In the preparation of compounds of the present invention, protection of remote functional groups of intermediates from undesired reactions can be accomplished with protecting groups. The term "protecting group" or "Pg" refers to a substituent typically used to block or protect a particular functional group while allowing other functional groups on the compound to react. For example, an amine protecting group is an amine-attached substituent that blocks or protects the amine functionality of a compound or intermediate. Suitable amine protecting groups include: 1-tert-butoxycarbonyl (Boc); acyl groups including: formyl, acetyl, chloroacetyl, trichloro-acetyl, o-nitrophenylacetyl, o-nitrophenoxy Acetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl, acyl isothiocyanate, aminocaproyl, benzoyl, etc.; and acyloxy, including: methoxycarbonyl, 9-fluorenyl-methoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, v...

example

[0193] The following examples can be prepared according to the schemes and preparations as presented herein.

[0194] Intermediate 1. tert-butyl 3'-bromo-1H,5'H-spiro[azetidine-3,7'-furo[3,4,b]pyridine]-1-carboxylate

[0195]

[0196] Step 1. 5-Bromo-2-iodo-3-methyl-pyridine

[0197]

[0198] To a stirred solution of 2,5-dibromo-3-methyl-pyridine (20.0 g, 79.7 mmol, 1 eq) in acetonitrile (120 mL) was added acetyl chloride (8.5 mL, 119.5 mmol, 1.5 eq) at room temperature, Then NaI (47.8 gm, 319 mmol, 4 eq) was added. The resulting reaction mixture was refluxed for 16 hours. After complete consumption of starting material, the reaction mixture was quenched with water (200 mL), and extracted with ethyl acetate (3 x 200 mL). The organic layer was washed with aqueous sodium bicarbonate (2 x 300 mL), brine (300 mL), and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to give a brown oil (35.5 g, crude). The crude material was purified ...

example 1

[0210] Example 1. 3'-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-1-[(methylsulfonyl Acyl)acetyl]-5'H-spiro[azetidine-3,7'-furo[3,4,b]pyridine]

[0211]

[0212] Step 1. tert-butyl 3'-formyl-1H,5'H-spiro[azetidine-3,7'-furo[3,4,b]pyridine]-1-carboxylate

[0213]

[0214] 3'-Bromo-1H,5'H-spiro[azetidine-3,7'-furo[3,4,b]pyridine]-1-carboxylic acid tert-butyl ester (intermediate To a stirred solution of compound 1, 2g, 5.7mmol, 1eq) in anhydrous THF (30mL) was added n-BuLi (1.0M in hexane, 6.4mL, 7.0mmol, 1.2eq), and at -78°C Stir under nitrogen atmosphere for 10 minutes. After 10 minutes, anhydrous DMF (0.68 mL, 8.79 mmol, 1.5 eq) was added at -78 °C. The resulting reaction mixture was stirred at -20°C under nitrogen atmosphere for 3 hours. After complete consumption of the starting material, the reaction mixture was washed with 10% NH 4 The Cl solution (10 mL) was quenched, diluted with water (50 mL), and extracted with ethyl acetate (2 x 50 ...

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PUM

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Abstract

The invention recites spirocyclic isoxazoline derivatives of Formula (1) stereoisomers thereof, veterinary or pharmaceutical acceptable salts thereof, compositions thereof, processes for making, and their use as a parasiticide in an animal. The variables W1, W2, W3, W, X, R1a, R1b, R1c, R2, R3, R4, and n are as described herein.

Description

technical field [0001] The present invention relates to spirocyclic isoxazoline derivatives having parasiticidal activity. The compounds of interest are spiroisoxazoline derivatives with an azetidine moiety. The present invention also relates to methods of making said spirocyclic isoxazoline derivatives, their compositions and methods of use. Background technique [0002] There is a need for improved antiparasitic agents for animals, and in particular improved insecticides and acaricides. Furthermore, there is a need for improved topical and oral products that are easy to administer and that contain one or more of such antiparasitic agents that can be used to effectively treat ectoparasites such as insects (e.g. fleas, lice, etc.) and flies) and acarids (such as mites and ticks). Such products would specifically be useful in the treatment of animals including: poultry (e.g. chickens and turkeys), fish, companion animals (e.g. cats, dogs, camels and horses) and livestock (...

Claims

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Application Information

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IPC IPC(8): C07D491/10A61K31/397A61P33/00C07D491/20C07D495/10
CPCC07D491/20C07D495/10A61P33/00A01N43/90
Inventor S.梅农S.M.K.希恩V.A.瓦利安考特
Owner ZOETIS SERVICE LLC
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