Parasiticidal oral veterinary compositions comprising systemically-acting active agents, methods and uses thereof
This invention relates to oral veterinary compositions for combating ectoparasites and endoparasites in animals, comprising at least one systemically-acting active agent in combination with a pharmaceutically acceptable carrier. This invention also provides for improved methods for eradicating, controlling, and preventing parasite infections and infestations in an animal comprising administering the compositions of the invention to the animal in need thereof.
1. A soft chewable veterinary composition for treating and/or preventing a parasitic infection or infestation in an animal comprising:
a)
at least one isoxazoline active agent of Formula (I):
wherein:
A 1 , A 2 , A 3 , A 4 , A 5 and A 6 are independently selected from the group consisting of CR 3 and N, provided that at most 3 of A 1 , A 2 , A 3 , A 4 , A 5 and A 6 are N;
B 1 , B 2 and B 3 are independently selected from the group consisting of CR 2 and N;
W is O or S;
R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R 6 ;
each R 2 is independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, C 2 -C 4 alkoxycarbonyl, —CN or —NO 2 ;
each R 3 is independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, —CN or —NO 2 ;
R 4 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl, C 4 -C 7 cycloalkylalkyl, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxycarbonyl;
R 5 is H, OR 10 , NR 11 R 12 or Q 1 ; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R 7 ; or
R 4 and R 5 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 atoms of carbon and optionally one additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 1 -C 2 alkyl, halogen, —CN, —NO 2 and C 1 -C 2 alkoxy;
each R 6 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, —CN or —NO 2 ;
each R 7 is independently halogen; C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylamino, C 2 -C 8 dialkylamino, C 3 -C 6 cycloalkylamino, C 2 -C 7 alkylcarbonyl, C 2 -C 7 alkoxycarbonyl, C 2 -C 7 alkylaminocarbonyl, C 3 -C 9 dialkylaminocarbonyl, C 2 -C 7 haloalkylcarbonyl, C 2 -C 7 haloalkoxycarbonyl, C 2 -C 7 haloalkylaminocarbonyl, C 3 -C 9 dihaloalkylaminocarbonyl, hydroxy, —NH 2 , —CN or —NO 2 ; or Q 2 ;
each R 8 is independently halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, C 2 -C 4 alkoxycarbonyl, —CN or NO 2 ;
each R 9 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, —CN, —NO 2 , phenyl or pyridinyl;
R 10 is H; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each optionally substituted with one of more halogen;
R 11 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl, C 4 -C 7 cycloalkylalkyl, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxycarbonyl;
R 12 is H; Q 3 ; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R 7 ; or
R 11 and R 12 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 atoms of carbon and optionally one additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 1 -C 2 alkyl, halogen, —CN, —NO 2 and C 1 -C 2 alkoxy;
Q 1 is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9- or 10-membered fused bicyclic ring system optionally containing one to three heteroatoms selected from the group consisting of up to 1 O, up to 1 S and up to 3 N, each ring or ring system optionally substituted with one or more substituents independently selected from R 8 ;
each Q 2 is independently a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from R 9 ;
Q 3 is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from R 9 ; and
n is 0, 1 or 2;
and
b) a pharmaceutically acceptable carrier;
wherein the pharmaceutically acceptable carrier comprises:
i) a surfactant selected from the group consisting of polyethylene glycol stearates and polyethylene glycol hydroxystearates;
ii) one or more fillers,
iii) one or more binders; and
iv) at least one humectant, solvent or lubricant, or combination thereof.
2. The soft chewable veterinary composition of claim 1 , wherein:
W is O;
R 4 is H or C 1 -C 6 alkyl;
R 5 is —CH 2 C(O)NHCH 2 CF 3 ;
each of A 1 , A 2 , A 3 , A 4 , A 5 and A 6 is CH;
R 1 is C 1 -C 6 alkyl each optionally substituted with one or more substituents independently selected from R 6 ;
R 6 is halogen or C 1 -C 6 alkyl; and
B 1 , B 2 , and B 3 are independently CH, C-halogen, C—C 1 -C 6 alkyl, C—C 1 -C 6 haloalkyl, or C—C 1 -C 6 alkoxy.
3. The soft chewable veterinary composition of claim 1 , wherein:
W is O;
R 1 is CF 3 ;
B 2 is CH;
B 1 is C—Cl;
B 3 is C—CF 3 ;
each of A 1 , A 2 , A 3 , A 4 , A 5 and A 6 is CH;
R 4 is H; and
R 5 is —CH 2 C(O)NHCH 2 CF 3 .
4. The soft chewable veterinary composition of claim 1 , wherein the carrier further comprises at least one flavoring agent, optionally an antioxidant, and optionally a preservative.
5. The soft chewable veterinary composition of claim 1 , wherein the one or more fillers are soy protein fines, corn starch, or a mixture thereof.
6. The soft chewable veterinary composition of claim 1 , wherein the binder is polyvinylpyrrolidone, a co-polymer of vinyl acetate and vinyl pyrrolidone or a polyethylene glycol, or a combination thereof.
7. The soft chewable veterinary composition of claim 1 , wherein the composition comprises a solvent and the solvent is a liquid polyethylene glycol or a caprylic/capric triglyceride, or a combination thereof.
8. The soft chewable veterinary composition of claim 1 , wherein the surfactant is a polyethylene glycol hydroxystearate.
9. The soft chewable veterinary composition of claim 1 , wherein composition comprises a humectant and the humectant is glycerin or propylene glycol.
10. The soft chewable veterinary composition of claim 4 , wherein the flavoring agent is an artificial meat or beef flavor.
11. The soft chewable veterinary composition of claim 4 , wherein the composition comprises:
a) a filler selected from the group consisting of corn starch, pre-gelatinized corn starch, corn gluten meal, soy protein fines, and a combination thereof;
b) a solvent selected from the group consisting of liquid polyethylene glycols, propylene glycol, propylene carbonate, caprylic/capric triglycerides, caprylic/capric/linoleic triglycerides, caprylic/capric/succinic triglycerides, propylene glycol dicaprylate/dicaprate, glycerol caprylate/caprate, polyglycolized glycerides, and a combination thereof;
c) a binder selected from the group consisting of polyvinylpyrrolidone, polyethylene glycols, co-polymers of vinyl acetate and vinylpyrrolidone, potato starch, corn starch, and a combination thereof;
d) a humectant selected from the group consisting of glycerol, propylene glycol, cetyl alcohol, glycerin monostearate, polyethylene glycols, and a combination thereof;
and
e) a natural or artificial beef or meat flavor.
12. The soft chewable veterinary composition of claim 11 , wherein the composition comprises a compound of formula (I) at a concentration of about 1% to about 20% by weight.
13. The soft chewable veterinary composition of claim 12 , wherein:
a) the filler is a combination of corn starch and soy protein fines and is present at a concentration of about 30% to about 60% (w/w);
b) the solvent is a mixture of liquid polyethylene glycol and caprylic/capric triglycerides and is present at a concentration of about 5% to about 20% (w/w);
c) the binder is polyethylene glycol or polyvinylpyrrolidone, or a combination thereof, and is present at a concentration of about 5% to about 15% (w/w);
d) the humectant is glycerin and is present at a concentration of about 5% to about 20%;
e) the surfactant is a polyethylene glycol 12-hydroxystearate and is present at a concentration of about 1% to about 5% (w/w).
14. The soft chewable veterinary composition of claim 12 , wherein the compound of Formula (I) is present at a concentration of about 1% to about 5% by weight.
15. The soft chewable veterinary composition of claim 12 , wherein the compound of Formula (I) is present at a concentration of about 10% to about 20% by weight.
16. The composition of claim 1 , wherein the isoxazoline active agent of formula (I) is 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide.
17. The composition of claim 1 , wherein the surfactant is a polyethylene glycol 12-hydroxystearate.
18. The composition of claim 1 , wherein the surfactant is polyethylene glycol 15 12-hydroxystearate.
19. The composition of claim 13 , wherein the surfactant is polyethylene glycol 15 12-hydroxystearate.
20. The composition of claim 13 , wherein the isoxazoline active agent of formula (I) is 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide.
21. The composition of claim 11 , wherein the filler is corn starch or soy protein fines, or a combination thereof.
22. The composition of claim 11 , wherein the solvent is liquid polyethylene glycols or caprylic/capric triglycerides, or a combination thereof.
23. The composition of claim 11 , wherein the binder is polyvinylpyrrolidone, a co-polymer of vinyl acetate and vinylpyrrolidone or a polyethylene glycol, or a combination thereof.
24. The composition of claim 11 , wherein the humectant is glycerol, propylene glycol, or a combination thereof.
25. The composition of claim 11 , wherein:
a) the filler is corn starch or soy protein fines, or a combination thereof;
b) the binder is polyvinylpyrrolidone, a co-polymer of vinyl acetate and vinylpyrrolidone or polyethylene glycol, or a combination thereof; and
c) humectant is glycerol, propylene glycol, or a combination thereof.
26. The composition of claim 25 , wherein:
a) the filler is a combination of corn starch and soy protein fines;
b) the solvent is liquid polyethylene glycols or caprylic/capric triglycerides, or a combination thereof;
c) the binder is polyvinylpyrrolidone or polyethylene glycol; and
d) the humectant is glycerol.
27. The composition of claim 25 or 26 , wherein the isoxazoline active agent of formula (I) is 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide.
28. The composition of claim 13 , wherein:
a) the filler is present at a concentration of about 35% to about 55% (w/w);
b) the solvent is present at a concentration of about 5% to about 15% (w/w);
c) the binder is present at a concentration of about 5% to about 10% (w/w); and
d) the humectant is present at a concentration of about 5% to about 15% (w/w).
29. The composition of claim 28 , wherein the isoxazoline active agent of formula (I) is 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide.
30. The composition of claim 4 , wherein the composition is selected from the group consisting of:
Ingredients
Function
% (w/w)
Cmpd. A
Active
2.2
Soy Protein Fines
Filler
26.5 (QS)
Corn Starch
Filler
31.0
artificial meat flavor
Flavoring
5.1
artificial beef flavor
Flavoring
7.1
Povidone K-30
Binder
2.8
PEG 400
Solvent
7.1
PEG 4000
Binder
6.4
polyethylene glycol 12-hydroxystearate
Surfactant
3.0
Glycerin
Humectant
5.1
Potassium Sorbate
Preservative
0.3
Caprylic/capric triglyceride
Solvent/Lubricant
3.2;
Ingredients
Function
% (w/w)
Cmpd. A
Active
1.5
Soy Protein Fines
Filler
46.5 (QS)
beef flavor
Flavoring
20.0
Povidone K-30
Binder
7.0
PEG 400
Solvent
15
polyethylene glycol 12-hydroxystearate
Surfactant
3.0
Caprylic/capric triglyceride
Solvent/lubricant
7.0;
Ingredients
Function
% (w/w)
Cmpd. A
Active
1.875
Soy Protein Fines
Filler
46.1 (QS)
beef flavor
Flavoring
20.0
Povidone K-30
Binder
8.5
PEG 400
Solvent
15.5
polyethylene glycol
Surfactant
3.0
12-hydroxystearate
Caprylic/capric triglyceride
Solvent/lubricant
5.0;
Ingredients
Function
% (w/w)
Cmpd. A
Active
1.875
Soy Protein Fines
Filler
36.1 (QS)
beef flavor
Flavoring
20.0
Povidone K-30
Binder
8.5
PEG 400
Solvent
15.5
polyethylene glycol
Surfactant
3.0
12-hydroxystearate
Caprylic/capric triglyceride
Solvent/lubricant
5.0
Croscarmellose sodium
disintegrant
10.0;
Ingredients
Function
% (w/w)
Cmpd. A
Active
2.3
Soy Protein Fines
Filler
20.6 (QS)
Corn Starch
Filler
25.0
beef flavor
Flavoring
20.5
Povidone K-30
Binder
2.8
PEG 400
Solvent
7.2
PEG 4000
Binder
6.4
polyethylene glycol
Surfactant
3.1
12-hydroxystearate
Glycerin
Humectant
8.6
Potassium Sorbate
Preservative
0.3
Caprylic/capric triglyceride
Solvent/Lubricant
3.1;
Ingredients
Function
% (w/w)
Cmpd. A
Active
2.3
Soy Protein Fines
Filler
20.0 (QS)
Corn Starch
Filler
25.0
beef flavor
Flavoring
20.0
Povidone K-30
Binder
2.8
PEG 400
Solvent
7.1
PEG 4000
Binder
6.4
polyethylene glycol
Surfactant
3.1
12-hydroxystearate
Glycerin
Humectant
10.0
Potassium Sorbate
Preservative
0.3
Caprylic/capric triglyceride
Solvent/Lubricant
3.2 ;
Ingredients
Function
% (w/w)
Cmpd. A
Active
0.5
Soy Protein Fines
Filler
16.6
Corn Starch
Filler
32.5 (QS)
beef flavor
Flavoring
19.4
Povidone K-30
Binder
2.6
PEG 400
Solvent
7.8
PEG 4000
Binder
6.1
polyethylene glycol
Surfactant
4.7
12-hydroxystearate
Lauroyl polyoxyl-32 glycerides
Surfactant
4.7
Potassium Sorbate
Preservative
0.3
Caprylic/capric triglyceride
Solvent/Lubricant
4.9;
Ingredients
Function
% (w/w)
Cmpd. A
Active
0.5
Soy Protein Fines
Filler
26.9 (QS)
Corn Starch
Filler
23.4
beef flavor
Flavoring
20.0
PEG 400
Solvent
6.8
PEG 4000
Binder
5.8
polyethylene glycol
Surfactant
4.8
12-hydroxystearate
Lauroyl polyoxyl-32 glycerides
Surfactant
6.3
Potassium Sorbate
Preservative
0.3
Caprylic/capric triglyceride
Solvent/Lubricant
5.2;
Ingredients
Function
% (w/w)
Cmpd. A
Active
0.5
Soy Protein Fines
Filler
41.6 (QS)
beef flavor
Flavoring
19.9
Povidone K-30
Binder
4.6
PEG 400
Solvent
15.1
PEG 4000
Binder
8.1
polyethylene glycol
Surfactant
4.6
12-hydroxystearate
Potassium Sorbate
Preservative
0.3
Caprylic/capric triglyceride
Solvent/Lubricant
4.6;
Ingredients
Function
% (w/w)
Cmpd. A
Active
0.5
Corn Starch
Filler
40.8 (QS)
beef flavor
Flavoring
19.9
Povidone K-30
Binder
5.7
PEG 400
Solvent
11.4
PEG 4000
Binder
5.7
polyethylene glycol
Surfactant
2.7
12-hydroxystearate
Lauroyl polyoxyl-32 glycerides
Surfactant
2.7
Potassium Sorbate
Preservative
0.3
Caprylic/capric triglyceride
Solvent/Lubricant
5.4
Sodium Starch glycolate
Disintegrate
5.0;
Ingredients
Function
% (w/w)
Cmpd. A
Active
0.5
Soy Protein Fines
Filler
19.4
Corn Starch
Filler
24.0 (QS)
beef flavor
Flavoring
19.2
Povidone K-30
Binder
2.6
PEG 400
Solvent
8.6
PEG 4000
Binder
6.0
polyethylene glycol
Surfactant
4.6
12-hydroxystearate
Lauroyl polyoxyl-32 glycerides
Surfactant
4.6
Potassium Sorbate
Preservative
0.3
Caprylic/capric triglyceride
Solvent/Lubricant
5.3
Glycerin
Humectant
4.8;
Ingredients
Function
% (w/w)
Cmpd. A
Active
2.3
Soy Protein Fines
Filler
22.0 (QS)
Corn Starch
Filler
26.4
beef flavor
Flavoring
10.0
Artificial Powdered Meat Flavor
Flavoring
10.0
Povidone K-30
Binder
2.7
PEG 400
Solvent
7.0
PEG 4000
Binder
6.25
polyethylene glycol
Surfactant
3.0
12-hydroxystearate
Glycerin
Humectant
7.0
Potassium Sorbate
Preservative
0.3
Caprylic/capric triglyceride
Solvent/Lubricant
3.0;
Ingredients
Function
% (w/w)
Cmpd. A
Active
13.6
Soy Protein Fines
Filler
15-25 (QS)
Corn Starch
Filler
15-25
beef flavor
Flavoring
20
PEG 400
Solvent
11.9
PEG 4000
Binder
5
polyethylene glycol
Surfactant
3-5
12-hydroxystearate
Glycerin
Humectant
2-5
Potassium Sorbate
Preservative
0.3;
Ingredients
Function
% (w/w)
Cmpd. A
Active
13.6
Soy Protein Fines
Filler
12.6
Corn Starch
Filler
25 (QS)
beef flavor
Flavoring
20
Povidone K-30
Binder
2.75
PEG 400
Solvent
5.5
PEG 4000
Binder
6.2
polyethylene glycol
Surfactant
5.0
12-hydroxystearate
Glycerin
Humectant
7-8
Potassium Sorbate
Preservative
0.3
Caprylic/capric triglyceride
Solvent/Lubricant
2.0;
Ingredients
Function
% (w/w)
Cmpd. A
Active
13.6
Soy protein fines
Filler
15.2 (QS)
Corn Starch
Filler
25
beef flavor
Flavoring
20
PEG 400
Solvent
11.9
PEG 4000
Binder
5.0
polyethylene glycol
Surfactant
5.0
12-hydroxystearate
Caprylic/capric triglyceride
Solvent/lubricant
1.0
Glycerin
Humectant
3.0
Potassium Sorbate
Preservative
0.3;
Ingredients
Function
% (w/w)
Cmpd. A
Active
13.6
Soy protein fines
Filler
19.2 (QS)
Corn Starch
Filler
20
beef flavor
Flavoring
20
PEG 400
Solvent
11.9
PEG 4000
Binder
5.0
polyethylene glycol
Surfactant
5.0
12-hydroxystearate
Caprylic/capric triglyceride
Solvent/lubricant
1.0
Glycerin
Humectant
4.0
Potassium Sorbate
Preservative
0.3;
and
Ingredients
Function
% (w/w)
Cmpd. A
Active
13.6
Soy protein fines
Filler
24.2 (QS)
Corn Starch
Filler
15
beef flavor
Flavoring
20
PEG 400
Solvent
11.9
PEG 4000
Binder
5.0
polyethylene glycol
Surfactant
5.0
12-hydroxystearate
Caprylic/capric triglyceride
Solvent/lubricant
1.0
Glycerin
Humectant
4.0
Potassium Sorbate
Preservative
0.3.
31. A soft chewable veterinary composition for treating and/or preventing a parasitic infection or infestation in an animal comprising:
a)
at least one isoxazoline active agent of Formula (I):
wherein:
A 1 , A 2 , A 3 , A 4 , A 5 and A 6 are independently selected from the group consisting of CR 3 and N, provided that at most 3 of A 1 , A 2 , A 3 , A 4 , A 5 and A 6 are N;
B 1 , B 2 and B 3 are independently selected from the group consisting of CR 2 and N;
W is O or S;
R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R 6 ;
each R 2 is independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, C 2 -C 4 alkoxycarbonyl, —CN or —NO 2 ;
each R 3 is independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, —CN or —NO 2 ;
R 4 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl, C 4 -C 7 cycloalkylalkyl, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxycarbonyl;
R 5 is H, OR 10 , NR 11 R 12 or Q 1 ; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R 7 ; or
R 4 and R 5 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 atoms of carbon and optionally one additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 1 -C 2 alkyl, halogen, —CN, —NO 2 and C 1 -C 2 alkoxy;
each R 6 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, —CN or —NO 2 ;
each R 7 is independently halogen; C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylamino, C 2 -C 8 dialkylamino, C 3 -C 6 cycloalkylamino, C 2 -C 7 alkylcarbonyl, C 2 -C 7 alkoxycarbonyl, C 2 -C 7 alkylaminocarbonyl, C 3 -C 9 dialkylaminocarbonyl, C 2 -C 7 haloalkylcarbonyl, C 2 -C 7 haloalkoxycarbonyl, C 2 -C 7 haloalkylaminocarbonyl, C 3 -C 9 dihaloalkylaminocarbonyl, hydroxy, —NH 2 , —CN or —NO 2 ; or Q 2 ;
each R 8 is independently halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, C 2 -C 4 alkoxycarbonyl, —CN or NO 2 ;
each R 9 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, —CN, —NO 2 , phenyl or pyridinyl;
R 10 is H; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each optionally substituted with one of more halogen;
R 11 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl, C 4 -C 7 cycloalkylalkyl, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxycarbonyl;
R 12 is H; Q 3 ; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R 7 ; or
R 11 and R 12 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 atoms of carbon and optionally one additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 1 -C 2 alkyl, halogen, —CN, —NO 2 and C 1 -C 2 alkoxy;
Q 1 is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9- or 10-membered fused bicyclic ring system optionally containing one to three heteroatoms selected from the group consisting of up to 1 O, up to 1 S and up to 3 N, each ring or ring system optionally substituted with one or more substituents independently selected from R 8 ;
each Q 2 is independently a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from R 9 ;
Q 3 is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from R 9 ; and
n is 0, 1 or 2; and
b) a pharmaceutically acceptable carrier;
wherein the pharmaceutically acceptable carrier comprises:
i) a surfactant selected from the group consisting of polyoxyl 8 stearate, polyoxyl 40 stearate and polyethyleneglycol 12-hydroxystearate;
ii) one or more fillers;
iii) one or more binders; and
iv) at least one humectant, solvent or lubricant, or a combination thereof.
32. The soft chewable veterinary composition of claim 31 , wherein:
W is O;
R 1 is CF 3 ;
B 2 is CH;
B 1 is C—Cl;
B 3 is C—CF 3 ;
each of A 1 , A 2 , A 3 , A 4 , A 5 and A 6 is CH;
R 4 is H; and
R 5 is —CH 2 C(O)NHCH 2 CF 3 .
33. The soft chewable veterinary composition of claim 31 , wherein the one or more fillers are soy protein fines, corn starch, or a mixture thereof.
34. The soft chewable veterinary composition of claim 31 , wherein the binder is polyvinylpyrrolidone or a polyethylene glycol.
35. The soft chewable veterinary composition of claim 31 , wherein the composition comprises a solvent and the solvent is a liquid polyethylene glycol or a caprilic/capric triglyceride.
36. The soft chewable veterinary composition of claim 31 , wherein the composition comprises a humectant and the humectant is glycerol.
37. The soft chewable veterinary composition of claim 31 , wherein the composition further comprises a flavoring agent, and wherein the flavoring agent is an artificial meat or beef flavor.
38. The soft chewable veterinary composition of claim 31 , wherein:
a) the surfactant is a polyethyleneglycol 12-hydroxystearate and is present at a concentration of about 1% to about 5% (w/w);
b) the filler is a combination of corn starch and soy protein fines and is present at a concentration of about 30% to about 50% (w/w);
c) the composition comprises a solvent and the solvent is a mixture of liquid polyethylene glycol and caprilic/capric triglycerides and is present at a concentration of about 5% to about 20% (w/w);
d) the binder is a combination of polyethylene glycol and a polyvinylpyrrolidone and is present at a concentration of about 5% to about 15% (w/w); and
e) the composition comprises a humectant and the humectant is glycerol and is present at a concentration of about 5% to about 20% (w/w).
39. The soft chewable veterinary composition of claim 38 , wherein:
W is O;
R 1 is CF 3 ;
B 2 is CH;
B 1 is C—Cl;
B 3 is C—CF 3 ;
each of A 1 , A 2 , A 3 , A 4 , A 5 and A 6 is CH;
R 4 is H; and
R 5 is —CH 2 C(O)NHCH 2 CF 3 .