Anthelmintic depsipeptide compounds

Abstract

The present invention provides cyclic depsipeptide compounds of formula (I) and compositions comprising the compounds that are effective against parasites that harm animals. The compounds and compositions may be used for combating parasites in or on mammals and birds. The invention also provides for an improved method for eradicating, controlling and preventing parasite infestation in birds and mammals.

Description

[0001] Cross references to related applications

[0002] This application claims the benefits of U.S. Provisional Application No. 62 / 163,997 filed on May 20, 2015, which is incorporated herein by reference. Invention field

[0003] The present invention relates to a new anthelmintic depsipeptide compound with improved activity against endoparasites and ectoparasites. The present invention also relates to a composition comprising the compound, a method and use of the compound for eradicating, controlling and preventing parasite infestation and / or infection in animals. The compounds of the present invention can be administered to animals, particularly mammals, fish and birds, to prevent or treat parasitic infections. Background of the invention

[0004] Animals, such as mammals and birds, are usually susceptible to parasitic infections. These parasites can be ectoparasites, such as fleas and ticks. Animals and humans can also suffer from ectoparasitic infections, including, for exa...

Examples

preparation Embodiment 1

[1054] Preparation Example 1: Preparation of monomer M1.

[1055] The monomer M1 was prepared by the method shown in Scheme 2 below.

[1056] Scenario 2

[1057]

[1058] Experimental details

[1059]

[1060] (2S)-2-[[(tert-butoxy)carbonyl]amino]succinic acid 1-benzyl 4-methyl ester (butanedioate): To a 20-L 3-neck circle that is purged and maintained with an inert nitrogen atmosphere Put (2S)-2-[[(tert-butoxy)carbonyl]amino]-4-methoxy-4-oxobutanoic acid (150g, 606.69mmol, 1.00 equivalent) in the bottom flask in N, N- Solution in dimethylformamide (5L), Cs 2 CO 3 (396g, 1.22mol, 2.00 equivalents), BnBr (124g, 725.02mmol, 1.20 equivalents). The resulting solution was stirred at room temperature for 2 hours. The resulting solution was diluted with 10 L of EA. Use 3×5L of H 2 O wash. The resulting mixture was washed with 3×5 L brine. The mixture was dried over anhydrous sodium sulfate. The solid is filtered out. The resulting mixture was concentrated under vacuum. This gave 170...

preparation Embodiment 2

[1073] Preparation Example 2: Preparation of monomer M2.

[1074] The monomer M2 was prepared by the method shown in Scheme 3 below.

[1075] Scheme 3

[1076]

[1077] Experimental details

[1078]

[1079] (R)-2-Hydroxy-3-[4-(trifluoromethyl)phenyl]propionic acid: Put (R)-2-amino-3-[4 in a 500-mL 3-neck round bottom flask -(Trifluoromethyl)phenyl]propionic acid (20g, 85.77mmol, 1.00 equivalent), sulfuric acid (0.5M) (340mL). Next, add NaNO dropwise at 0°C 2 (35.5 g, 514.49 mmol, 6.00 equivalents) in water (80 mL) while stirring. The resulting solution was stirred for 1 hour at 0°C. The resulting solution was allowed to react, while stirring, overnight at room temperature. The solid was collected by filtration. This gave 17.5 g (87%) of (R)-2-hydroxy-3-[4-(trifluoromethyl)phenyl]propionic acid as a white solid. MS(ES,m / z):233(M-H); 1 H NMR (DMSO, 300MHz) δ: 7.63 (d, J = 3.9 Hz, 2H), 7.46 (d, J = 4.0 Hz, 2H), 4.21-4.17 (m, 1H), 3.09-3.03 (m, 1H) ,2.91-2.84(m,1H).

[1080]

[108...

preparation Embodiment 3

[1082] Preparation Example 3: Preparation of monomer M3.

[1083] Monomer M3 was prepared by the method shown in Scheme 4 below.

[1084] Scheme 4

[1085]

[1086] Experimental details

[1087]

[1088] (2R)-3-(4-Fluorophenyl)-2-hydroxypropionic acid: Put (2R)-2-amino-3-(4-fluorophenyl) into a 500-mL 4-neck round bottom flask Propionic acid (10 g, 54.59 mmol, 1.00 equivalent), sulfuric acid (218.6 mL, 2.00 equivalent). Next, add NaNO dropwise at 0°C 2 (23 g, 333.33 mmol, 6.00 equivalents) in water (15 mL) while stirring. The resulting solution was stirred at 5°C for 3 hours. The resulting solution was extracted with 3×30 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 5×40 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate, and concentrated under vacuum. This gave 12 g (crude material) of (2R)-3-(4-fluorophenyl)-2-hydroxypropionic acid as a white solid. MS (ES, m / z): 183 (M-H).

[1089]

[1090] (2R)-3-(4-...

[0001] Cross references to related applications

[0002] This application claims the benefits of U.S. Provisional Application No. 62 / 163,997 filed on May 20, 2015, which is incorporated herein by reference. Invention field

[0003] The present invention relates to a new anthelmintic depsipeptide compound with improved activity against endoparasites and ectoparasites. The present invention also relates to a composition comprising the compound, a method and use of the compound for eradicating, controlling and preventing parasite infestation and / or infection in animals. The compounds of the present invention can be administered to animals, particularly mammals, fish and birds, to prevent or treat parasitic infections. Background of the invention

[0004] Animals, such as mammals and birds, are usually susceptible to parasitic infections. These parasites can be ectoparasites, such as fleas and ticks. Animals and humans can also suffer from ectoparasitic infections, including, for exa...

Examples

preparation Embodiment 1

[1054] Preparation Example 1: Preparation of monomer M1.

[1055] The monomer M1 was prepared by the method shown in Scheme 2 below.

[1056] Scenario 2

[1057]

[1058] Experimental details

[1059]

[1060] (2S)-2-[[(tert-butoxy)carbonyl]amino]succinic acid 1-benzyl 4-methyl ester (butanedioate): To a 20-L 3-neck circle that is purged and maintained with an inert nitrogen atmosphere Put (2S)-2-[[(tert-butoxy)carbonyl]amino]-4-methoxy-4-oxobutanoic acid (150g, 606.69mmol, 1.00 equivalent) in the bottom flask in N, N- Solution in dimethylformamide (5L), Cs 2 CO 3 (396g, 1.22mol, 2.00 equivalents), BnBr (124g, 725.02mmol, 1.20 equivalents). The resulting solution was stirred at room temperature for 2 hours. The resulting solution was diluted with 10 L of EA. Use 3×5L of H 2 O wash. The resulting mixture was washed with 3×5 L brine. The mixture was dried over anhydrous sodium sulfate. The solid is filtered out. The resulting mixture was concentrated under vacuum. This gave 170...

preparation Embodiment 2

[1073] Preparation Example 2: Preparation of monomer M2.

[1074] The monomer M2 was prepared by the method shown in Scheme 3 below.

[1075] Scheme 3

[1076]

[1077] Experimental details

[1078]

[1079] (R)-2-Hydroxy-3-[4-(trifluoromethyl)phenyl]propionic acid: Put (R)-2-amino-3-[4 in a 500-mL 3-neck round bottom flask -(Trifluoromethyl)phenyl]propionic acid (20g, 85.77mmol, 1.00 equivalent), sulfuric acid (0.5M) (340mL). Next, add NaNO dropwise at 0°C 2 (35.5 g, 514.49 mmol, 6.00 equivalents) in water (80 mL) while stirring. The resulting solution was stirred for 1 hour at 0°C. The resulting solution was allowed to react, while stirring, overnight at room temperature. The solid was collected by filtration. This gave 17.5 g (87%) of (R)-2-hydroxy-3-[4-(trifluoromethyl)phenyl]propionic acid as a white solid. MS(ES,m / z):233(M-H); 1 H NMR (DMSO, 300MHz) δ: 7.63 (d, J = 3.9 Hz, 2H), 7.46 (d, J = 4.0 Hz, 2H), 4.21-4.17 (m, 1H), 3.09-3.03 (m, 1H) ,2.91-2.84(m,1H).

[1080]

[108...

preparation Embodiment 3

[1082] Preparation Example 3: Preparation of monomer M3.

[1083] Monomer M3 was prepared by the method shown in Scheme 4 below.

[1084] Scheme 4

[1085]

[1086] Experimental details

[1087]

[1088] (2R)-3-(4-Fluorophenyl)-2-hydroxypropionic acid: Put (2R)-2-amino-3-(4-fluorophenyl) into a 500-mL 4-neck round bottom flask Propionic acid (10 g, 54.59 mmol, 1.00 equivalent), sulfuric acid (218.6 mL, 2.00 equivalent). Next, add NaNO dropwise at 0°C 2 (23 g, 333.33 mmol, 6.00 equivalents) in water (15 mL) while stirring. The resulting solution was stirred at 5°C for 3 hours. The resulting solution was extracted with 3×30 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 5×40 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate, and concentrated under vacuum. This gave 12 g (crude material) of (2R)-3-(4-fluorophenyl)-2-hydroxypropionic acid as a white solid. MS (ES, m / z): 183 (M-H).

[1089]

[1090] (2R)-3-(4-...

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