Spirocyclic isoxazoline derivatives as antiparasitic agents

A kind of technology of compound and composition, applied in the field of preparing described spirocyclic isoxazoline derivatives

Active Publication Date: 2014-01-15
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 spiro-substituted isoxazolines or methods of preparing such spiro compounds, nor does the prior art indicate that s

Method used

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  • Spirocyclic isoxazoline derivatives as antiparasitic agents
  • Spirocyclic isoxazoline derivatives as antiparasitic agents
  • Spirocyclic isoxazoline derivatives as antiparasitic agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0537] Example 1: 1-(cyclopropanecarbonyl)-5'-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl )-3'H-spiro{azetidine-3,1'-isobenzofuran}-3'-one

[0538]

[0539] 5'-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'H-spiro{ Azetidine-3,1'-isobenzofuran}-3'-one (140 mg, 0.3 mmol) was dissolved in CH 2 Cl 2 (5 mL), and TEA (0.15 mL, 1.1 mmol) was added. The reaction was stirred at room temperature for 5 minutes, and cyclopropanecarbonyl chloride (35 mg, 0.3 mmol) was added. The resulting solution was stirred at room temperature for 15 minutes. Next, a few drops of MeOH were added, and the reaction was concentrated in vacuo to ~3 mL and injected directly onto a 24 g Redi Sep cartridge. The crude material was chromatographed eluting with 100% heptane to 60:40 EtOAc:heptane to afford the final product (68 mg, 46%) as a solid. 1 HNMR (CDCl 3 )δppm: 8.29(1H), 8.04(1H), 7.85(1H), 7.67(2H), 4.94-4.83(1H), 4.86-4.58(2H), 4.49-4.37(1H), ...

Embodiment 2

[0540] Example 2: 5'-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1 -Propyl-3'H-spiro[azetidine-3,1'-isobenzofuran]-3'-one

[0541]

[0542] This compound was prepared similarly to Example 1, except that cyclopropanecarbonyl chloride was replaced with propyl chloride (10 mg, 0.1 mmol), and the alkene (1AB) was 1,3-dichloro-2-fluoro-5-( 1-trifluoromethyl-vinyl)-benzene instead of 1,2,3-trichloro-(1-trifluoromethyl-vinyl)-benzene.

[0543] The reaction was injected directly onto a 24g Redi Sep column. The crude material was chromatographed eluting with 100% heptane to 50:50 EtOAc:heptane to afford the final product (25 mg, 48%) as a solid. m / z(CI)531[M+H] + .

[0544] Preparation 9: 1-Benzhydryl-3-(2-bromo-4-(5-(3,5-dichlorophenyl-4-fluoro)-5-(trifluoromethyl)-4,5- Dihydroisoxazol-3-yl)phenyl)azetidin-3-ol

[0545]

[0546] This compound was prepared from the compound of Preparation 4 according to the method of Preparations 5 and 6 u...

Embodiment 3

[0559] Example 3: 1-(5'-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl )-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-yl)-2-((trifluoromethyl)thio)ethanone

[0560]

[0561] 5'-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]- 3'H-spiro[azetidine-3,1'-[2]benzofuran] (0.05mmol) was dissolved in DMF (0.5ml); it was added to [(trifluoromethyl)sulfane base] acetic acid (0.1 mmol), followed by addition of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium hexafluorophosphate in DMF ( 0.5ml) and triethylamine (0.5mmol) in solution. The resulting mixture was shaken at ambient temperature for 16 hours. The solvent was distilled off in vacuo, and the crude product was purified by preparative HPLC to obtain 3.2 mg of the title compound. m / z[M+H] + 603; retention time 4.21 minutes.

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Abstract

The invention recites spirocyclic isoxazoline derivatives of Formula (V.1), Formula (V.2), Formula (V.1.1), and Formula (1) stereoisomers thereof, veterinarily acceptable salts thereof, compositions thereof, processes for making, and their use as a parasiticide in an animal. The variables A, V, Z, W1, W2, W3, W, Y, X, R1a, R1b, R1c, R2, R3, R4, n, and --- are as described herein.

Description

[0001] cross reference [0002] The present invention claims U.S. Provisional Patent Application No. 61 / 490,804, filed May 27, 2011, now pending, U.S. Provisional Patent Application No. 61 / 489,913, filed May 25, 2011, and now pending Priority to now-pending U.S. Provisional Patent Application No. 61 / 451,256, filed March 10, 2011. field of invention [0003] The present invention relates to spirocyclic isoxazoline derivatives having antiparasitic activity. The compounds of interest are spiroisoxazoline derivatives with an azetidine moiety. The present invention also relates to processes for the preparation of said spirocyclic isoxazoline derivatives, compositions thereof and methods of use thereof. Background technique [0004] There is a need for improved antiparasitic agents for animals, in particular improved insecticides and acaricides. There is also a need for convenient administration comprising one or more of such antiparasitic agents that are useful in the effectiv...

Claims

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Application Information

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IPC IPC(8): C07D491/10A01N43/80
CPCA01N43/90A01N53/00C07D487/10C07D491/107C07D491/10A61P33/00A61P33/02A61P33/14A61K31/422
Inventor D.比伦N.A.L.查布M.柯蒂斯S.D.格林伍德S.梅农T.斯塔克V.A.韦兰柯特
Owner ZOETIS SERVICE LLC
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