Anthelmintic depsipeptide compounds
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.
1. A method for the treatment or prevention of a parasitic infection or infestation in an animal comprising administering a parasiticidally effective amount of an anthelmintic cyclic depsipeptide of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, to the animal:
wherein:
Cy 1 and Cy 2 are independently aryl, carbocyclic, heteroaryl or heterocyclic optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino, alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF 5 , R 5 S(O)—, R 5 S(O) 2 —, R 5 C(O)—, R 5 R 6 NC(O)—, R 5 R 6 NC(O)NR 5 —, R 5 OC(O)—, R 5 C(O)O—, R 5 C(O)NR 6 —, —CN, —NO 2 , cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl, —O— heterocyclyl and —S-heterocyclyl, wherein each cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino, alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF 5 , R 5 S(O)—, R 5 S(O) 2 —, R 5 C(O)—, R 5 R 6 NC(O)—, R 5 OC(O)—, R 5 C(O)O—, R 5 C(O)NR 6 —, —CN and —NO 2 ;
R 5 and R 6 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, or the group —CH 2 C(O)NHCH 2 CF 3 ; or R 5 and R 6 together with the atom(s) to which they are bonded form a C 3 -C 6 cyclic group;
R′, R″, R′″ and R″″ are each independently hydrogen or C 1 -C 3 alkyl;
R a and R b are independently hydrogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; and
(a) R 1 is C 1 -C 8 alkyl substituted by one or more halogen; and
R 2 , R 3 and R 4 are each independently C 1 -C 8 alkyl; or
(b) R 2 is C 1 -C 8 alkyl substituted by one or more halogen; and
R 1 , R 3 and R 4 are each independently C 1 -C 8 alkyl; or
(c) R 3 is C 1 -C 8 alkyl substituted by one or more halogen; and
R 1 , R 2 and R 4 are each independently C 1 -C 8 alkyl; or
(d) R 4 is C 1 -C 8 alkyl substituted by one or more halogen; and
R 1 , R 2 and R 3 are each independently C 1 -C 8 alkyl; or
(e) R 1 and R 2 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 3 and R 4 are each independently C 1 -C 8 alkyl; or
(f) R 1 and R 3 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 2 and R 4 are each independently C 1 -C 8 alkyl; or
(g) R 1 and R 4 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 2 and R 3 are each independently C 1 -C 8 alkyl; or
(h) R 2 and R 4 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 1 and R 3 are each independently C 1 -C 8 alkyl; or
(i) R 2 and R 3 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 1 and R 4 are each independently C 1 -C 8 alkyl; or
(j) R 3 and R 4 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 1 and R 2 are each independently C 1 -C 8 alkyl; or
(k) R 1 , R 2 and R 3 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 4 is C 1 -C 8 alkyl; or
(l) R 2 , R 3 and R 4 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 1 is C 1 -C 8 alkyl; or
(m) R 1 , R 3 and R 4 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 2 is C 1 -C 8 alkyl; or
(n) R 1 , R 2 and R 4 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 3 is C 1 -C 8 alkyl; or
(o) R 1 , R 2 , R 3 and R 4 are each independently C 1 -C 8 alkyl substituted by one or more halogen.
2. The method of claim 1 , wherein:
(f) R 1 and R 3 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 2 and R 4 are each independently C 1 -C 8 alkyl; or
(h) R 2 and R 4 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 1 and R 3 are each independently C 1 -C 8 alkyl; or
(e) R 1 and R 2 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 3 and R 4 are each independently C 1 -C 8 alkyl; or
(g) R 1 and R 4 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 2 and R 3 are each independently C 1 -C 8 alkyl; or
(i) R 2 and R 3 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 1 and R 4 are each independently C 1 -C 8 alkyl; or
(j) R 3 and R 4 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 1 and R 2 are each independently C 1 -C 8 alkyl.
3. The method of claim 1 , wherein:
(a) R 1 is C 1 -C 8 alkyl substituted by one or more halogen; and
R 2 , R 3 and R 4 are each independently C 1 -C 8 alkyl; or
(b) R 2 is C 1 -C 8 alkyl substituted by one or more halogen; and
R 1 , R 3 and R 4 are each independently C 1 -C 8 alkyl; or
(c) R 3 is C 1 -C 8 alkyl substituted by one or more halogen; and
R 1 , R 2 and R 4 are each independently C 1 -C 8 alkyl; or
(d) R 4 is C 1 -C 8 alkyl substituted by one or more halogen; and
R 1 , R 2 and R 3 are each independently C 1 -C 8 alkyl.
4. The method of claim 1 , wherein:
(k) R 1 , R 2 and R 3 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 4 is C 1 -C 8 alkyl; or
(l) R 2 , R 3 and R 4 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 1 is C 1 -C 8 alkyl; or
(m) R 1 , R 3 and R 4 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 2 is C 1 -C 8 alkyl; or
(n) R 1 , R 2 and R 4 are each independently C 1 -C 8 alkyl substituted by one or more halogen; and
R 3 is C 1 -C 8 alkyl.
5. The method of claim 1 , wherein:
(o) R 1 , R 2 , R 3 and R 4 are each independently C 1 -C 8 alkyl substituted by one or more halogen.
6. The method of claim 1 , wherein at least one of R 1 , R 2 , R 3 and R 4 is C 1 -C 8 alkyl substituted by halogen.
7. The method of claim 6 , wherein one of R 1 , R 2 , R 3 and R 4 is C 1 -C 8 alkyl substituted by halogen.
8. The method of claim 6 , wherein three of R 1 , R 2 , R 3 and R 4 is C 1 -C 8 alkyl substituted by halogen.
9. The method of claim 6 , wherein each of R 1 , R 2 , R 3 and R 4 are C 1 -C 8 alkyl substituted by halogen.
10. The method of claim 6 , wherein two of R 1 , R 2 , R 3 and R 4 is C 1 -C 8 alkyl substituted by halogen.
11. The method of claim 10 , wherein R 1 and R 3 are C 1 -C 8 alkyl substituted by halogen.
12. The method of claim 11 , wherein halogen is fluoro.
13. The method of claim 10 , wherein R 2 and R 4 are C 1 -C 8 alkyl substituted by halogen.
14. The method of claim 13 , wherein halogen is fluoro.
15. The method of claim 1 , wherein Cy 1 and Cy 2 are independently phenyl, a 5-membered heteroaryl or a 6-membered heteroaryl, wherein said phenyl, 5-membered heteroaryl or 6-membered heteroaryl is optionally substituted with halogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino, alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF 5 , R 5 S(O)—, R 5 S(O) 2 —, R 5 C(O)—, R 5 R 6 NC(O)—, R 5 R 6 NC(O)NR 5 —, R 5 OC(O)—, R 5 C(O)O—, R 5 C(O)NR 6 —, —CN, —NO 2 , cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl, —O— heterocyclyl or —S-heterocyclyl, and wherein each cycloalkyl, heteroalkyl, aryl or heteroaryl substituent is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino, alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF 5 , R 5 S(O)—, R 5 S(O) 2 —, R 5 C(O)—, R 5 R 6 NC(O)—, R 5 R 6 NC(O)NR 5 —, R 5 OC(O)—, R 5 C(O)O—, R 5 C(O)NR 6 —, —CN and —NO 2 .
16. The method of claim 15 , wherein Cy 1 and Cy 2 are independently phenyl, a 5-membered heteroaryl or a 6-membered heteroaryl; wherein said phenyl, 5-membered heteroaryl or 6-membered heteroaryl is independently substituted with halogen, —CN, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R 5 R 6 NC(O)— or heterocyclyl.
17. The method of claim 16 , wherein Cy 1 and Cy 2 are independently phenyl, thienyl, oxazolyl, isothiazolyl, 1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or tetrazinyl, each independently optionally substituted with R 5 R 6 NC(O)—, wherein R 5 and R 6 are independently hydrogen or —CH 2 C(O)NHCH 2 CF 3 , or R 5 and R 6 together with the nitrogen atom to which they are bonded together form a C 3 -C 6 cyclic amine.
18. The method of claim 16 , wherein Cy 1 and Cy 2 are independently phenyl, a 5-membered heteroaryl or a 6-membered heteroaryl substituted with t-butyl, cyclohexyl, heterocyclyl, fluoro, trifluoromethyl, trifluoromethoxy or cyano.
19. The method of claim 18 , wherein Cy L and Cy 2 are independently phenyl, a 5-membered heteroaryl or pyridinyl substituted with pyrrolidinyl, morpholinyl, tetrahydropyranyl, tetrazolyl or —S-tetrazolyl.
20. The method of claim 16 , wherein:
Cy 1 and Cy 2 are independently phenyl substituted with alkyl, cycloalkyl, heterocyclyl, halogen, haloalkyl, haloalkoxy, haloalkylthio or cyano;
R a and R b are independently hydrogen or C 1 -C 3 alkyl;
R′, R″, R′″ and R″″ are independently C 1 -C 3 alkyl; and
(a) R 1 and R 2 are each independently C 1 -C 8 alkyl substituted by one or more fluoro; and
R 3 and R 4 are each independently C 1 -C 8 alkyl; or
(b) R 1 and R 3 are each independently C 1 -C 8 alkyl substituted by one or more fluoro; and
R 2 and R 4 are each independently C 1 -C 8 alkyl; or
(c) R 1 and R 4 are each independently C 1 -C 8 alkyl substituted by one or more fluoro; and
R 2 and R 3 are each independently C 1 -C 8 alkyl; or
(d) R 2 and R 4 are each independently C 1 -C 8 alkyl substituted by one or more fluoro; and
R 1 and R 3 are each independently C 1 -C 8 alkyl; or
(e) R 2 and R 3 are each independently C 1 -C 8 alkyl substituted by one or more fluoro; and
R 1 and R 4 are each independently C 1 -C 8 alkyl; or
(f) R 3 and R 4 are each independently C 1 -C 8 alkyl substituted by one or more fluoro; and
R 1 and R 2 are each independently C 1 -C 8 alkyl.
21. The method of claim 20 , wherein (b) R 1 and R 3 are each independently C 1 -C 8 alkyl substituted by one or more fluoro; and
R 2 and R 4 are each independently C 1 -C 8 alkyl.
22. The method of claim 21 , wherein Cy 1 and Cy 2 are independently phenyl substituted by t-butyl, fluoro, trifluoromethyl, trifluoromethoxy, cyano, morpholinyl or tetrahydropyranyl.
23. The method of claim 22 , wherein:
R a and R b are each methyl; and R′, R″, R′″ and R″″ are methyl.
24. The method of claim 21 , wherein R 1 and R 3 are each —CH 2 CF(CH 3 ) 2 ; and R 2 and R 4 are independently 2-methylpropyl or 2,2-dimethylpropyl.
25. The method of claim 24 , wherein Cy 1 and Cy 2 are independently phenyl substituted by t-butyl, fluoro, trifluoromethyl, trifluoromethoxy, cyano, morpholinyl or tetrahydropyranyl.
26. The method of claim 25 , wherein:
R a and R b are each methyl; and
R′, R″, R′″ and R″″ are methyl.
27. The method of claim 20 , wherein (a) R 2 and R 4 are each independently C 1 -C 8 alkyl substituted by one or more fluoro; and
R 1 and R 3 are each independently C 1 -C 8 alkyl.
28. The method of claim 27 , wherein Cy 1 and Cy 2 are independently phenyl substituted by t-butyl, fluoro, trifluoromethyl, trifluoromethoxy, cyano, morpholinyl or tetrahydropyranyl.
29. The method of claim 28 , wherein: R a and R b are reach methyl; and R′, R″, R′″ and R″″ are each methyl.
30. The method of claim 27 , wherein R 2 and R 4 are each —CH 2 CF(CH 3 ) 2 ; and R 1 and R 3 are independently 2-methylpropyl or 2,2-dimethylpropyl.
31. The method of claim 30 , wherein Cy 1 and Cy 2 are independently phenyl substituted by t-butyl, fluoro, trifluoromethyl, trifluoromethoxy, cyano, morpholinyl or tetrahydropyranyl.
32. The method of claim 31 , wherein:
R a and R b are reach methyl; and
R′, R″, R′″ and R″″ are each methyl.
33. The method of claim 1 , wherein R a and R b are independently hydrogen or C 1 -C 3 alkyl.
34. The method of claim 33 , wherein R a and R b are methyl.
35. The method of claim 1 , wherein R′, R″, R′″ and R″″ are independently C 1 -C 3 alkyl.
36. The method of claim 35 , wherein R′, R″, R′″ and R″″ are methyl.
37. The method of claim 1 , wherein the parasite is an endoparasite.
38. The method of claim 37 , wherein the endoparasite is selected from the group consisting of Anaplocephala, Ancylostoma, Necator, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia, Cyathostomum, Cylicocyclus, Cylicodontophorus, Cylicostephanus, Craterostomum, Dictyocaulus, Dipetalonema, Dipylidium, Dirofilaria, Dracunculus, Echinococcus, Enterobius, Fasciola, Filaroides, Habronema, Haemonchus, Metastrongylus, Moniezia, Necator, Nematodirus, Nippostrongylus, Oesophagostomum, Onchocerca, Ostertagia, Oxyuris, Parascaris, Schistosoma, Strongylus, Taenia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris, Trichostrongylus, Triodontophorus, Uncinaria and Wuchereria.
39. The method of claim 38 , wherein the endoparasite is Haemonchus contortus, Ostertagia circumcincta or Trichostrongylus colubriformis.
40. The method of claim 39 , wherein the animal a human, a cat, a dog, cattle, a chicken, a bison, deer, a goat, a horse, a llama, a camel, a pig, sheep or a yak.
41. The method of claim 40 , wherein the animal is a cattle or a horse.
42. A method for the treatment or prevention of a parasitic infection in an animal comprising administering a parasiticidally effective amount of an anthelmintic cyclic depsipeptide formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, to the animal:
wherein:
R 1 and R 3 are each —CH 2 CF(CH 3 ) 2 ; and R 2 and R 4 are independently 2-methylpropyl or 2,2-dimethylpropyl; or
R 2 and R 4 are each —CH 2 CF(CH 3 ) 2 ; and R 1 and R 3 are independently 2-methylpropyl or 2,2-dimethylpropyl;
R a and R b are each methyl;
R′, R″, R′″ and R″″ are each methyl; and
Cy 1 and Cy 2 are independently selected from the group consisting of:
Para-fluorophenyl, para-trifluoromethoxyphenyl, para-trifluoromethylphenyl, 3,4,5-trifluorophenyl, para-iodophenyl, para-bromophenyl, p-nitrophenyl, p-tert-butylphenyl, para-sf 5 -phenyl, para-aminophenyl,
wherein the parasitic infection is caused by a parasite selected from group consisting of Anaplocephala, Ancylostoma, Necator, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia, Cyathostomum, Cylicocyclus, Cylicodontophorus, Cylicostephanus, Craterostomum, Dictyocaulus, Dipetalonema, Dipylidium, Dirofilaria, Dracunculus, Echinococcus, Enterobius, Fasciola, Filaroides, Habronema, Haemonchus, Metastrongylus, Moniezia, Necator, Nematodirus, Nippostrongylus, Oesophagostomum, Onchocerca, Ostertagia, Oxyuris, Parascaris, Schistosoma, Strongylus, Taenia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris, Trichostrongylus, Triodontophorus, Uncinaria and Wuchereria.