US2017020848A1PendingUtilityA1
Extended release injectable formulations comprising an isoxazoline active agent, methods and uses thereof
Est. expiryApr 8, 2035(~8.7 yrs left)· nominal 20-yr term from priority
A61K 31/422A61K 47/30A61K 9/0019A61K 31/42A61K 47/22A61K 47/10A61P 33/00A61K 9/00A61K 2300/00A61P 33/14
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Claims
Abstract
This invention relates to extended release injectable formulations for combating parasites in animals, comprising at least one isoxazoline active agent, a pharmaceutically acceptable polymer, and a solvent. This invention also provides for improved methods for eradicating, controlling, and preventing parasite infections and infestations in an animal comprising administering the extended release injectable formulations of the invention to the animal in need thereof.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . An extended release injectable composition for the treatment or prevention of parasite infections or infestations in an animal comprising an antiparasitic effective amount of at least one isoxazoline active agent, a pharmaceutically acceptable polymer and a solvent or mixture of solvents.
2 . An extended release injectable composition for the treatment or prevention of parasite infections or infestations in an animal comprising an antiparasitic effective amount of at least one isoxazoline active agent, a pharmaceutically acceptable polymer which is a copolymer of a polylactides and polyglycolides,—a solvent or mixture of solvents, and optionally a surfactant.
3 . The extended release injectable composition according to claim 2 comprising:
a) an antiparasitic effective amount of at least one isoxazoline active agent, which is:
i) an isoxazoline compound of formula (I):
wherein:
B 1 , B 2 and B 3 are each independently C—R or N;
each R is independently H, halogen, cyano, —NO 2 , alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino or alkoxycarbonyl;
R 1 is C 1 -C 3 alkyl or C 1 -C 3 haloalkyl;
Y is an optionally substituted phenylene, naphthylene, indanylene, a 5- or 6-membered heteroarylene or an 8-10-membered fused heterobicyclylene, wherein the optional substituents are selected from the group consisting of halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, —CN or —NO 2 and NH 2 —C(═S)—;
Q is X—NR 2 R 3 , the group (—CH 2 —)(—CH 2 —)N—R 3 , OH, NH 2 , alkoxy, haloalkoxy, alkylamino, haloalkylamino, dialkylamino, halodialkylamino, thiol, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, or an optionally substituted 5- or 6-membered carbocyclyl, heterocyclyl or heteroaryl ring;
X is (CH 2 ) n , CH(CH 3 ), CH(CN), C(═O) or C(═S);
R 2 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl;
R 3 is H, OR 7 , NR 8 R 9 or Q 1 ; or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl, each optionally substituted with one or more substituents independently selected from R 4 ; or
R 2 and R 3 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 alkyl, halogen, —CN, —NO 2 and alkoxy;
each R 4 is independently halogen; alkyl, cycloalkyl, alkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, haloalkylamino, dialkylamino, dihaloalkylamino, cycloalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylaminocarbonyl, dihaloalkylaminocarbonyl, hydroxy, —NH 2 , —CN or —NO 2 ; or Q 2 ;
each R 5 is independently halogen, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, alkoxycarbonyl, —CN or —NO 2 ;
each R 6 is independently halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, —CN, —NO 2 , phenyl or pyridinyl;
R 7 is H; or alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each optionally substituted with one of more halogen;
R 8 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl;
R 9 is H; Q 3 ; or alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R 4 ; or
R 8 and R 9 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 alkyl, halogen, —CN, —NO 2 and 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 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 5 ;
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 6 ;
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 6 ; and
n is 0, 1 or 2; and/or
ii) an isoxazoline compound of formula (II):
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 1 , 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 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; or a pharmaceutically acceptable salt thereof; and/or
iii) an isoxazoline compound of formula (III):
wherein:
R 1 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each which is unsubstituted or substituted with one or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R 7 S(O)—, R 7 S(O) 2 —, R 7 C(O)—, R 7 R 8 NC(O)—, R 7 OC(O)—, R 7 C(O)O—, R 7 C(O)NR 8 —, —CN or —NO 2 ;
X is aryl or heteroaryl, which may be unsubstituted or substituted by one or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R 7 S(O)—, R 7 S(O) 2 —, R 7 C(O)—, R 7 R 8 NC(O)—, R 7 OC(O)—, R 7 C(O)O—, R 7 C(O)NR 8 —, —CN or —NO 2 ;
A 1 is oxygen; and
A 2 is oxygen, NR 2 or CR 7 R 8 ;
G is G-1 or G-2;
B 1 , B 2 , B 3 , B 4 and B 5 are independently N or C—R 9 ;
Y is hydrogen, halogen, —CN; or Y is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, or heterocyclyl or heteroaryl each of which is unsubstituted or substituted with one or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R 7 S(O)—, R 7 S(O) 2 —, R 7 C(O)—, R 7 R 8 NC(O)—, R 7 OC(O)—, R 7 C(O)O—, R 7 C(O)NR 8 —, —CN or —NO 2 ; or Y is Y-1, Y-2, Y-3, Y-4, Y-5, Y-6, Y-7, Y-8, Y-9, Y-10, Y-11, Y-12 or Y-13;
R 2 , R 3 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, R 10 S(O)—, R 10 S(O) 2 —, R 10 C(O)—, R 10 C(S)—, R 10 R 11 NC(O)—, R 10 R 11 NC(S)—R 10 OC(O)—;
R 4 , R 5 and R 6 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, aryl or heteroaryl;
R 7 and R 8 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl;
R 9 is hydrogen, halogen, —CN, or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each which is unsubstituted or substituted with one or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R 7 S(O)—, R 7 S(O) 2 —, R 7 C(O)—, R 7 R 8 NC(O)—, R 7 OC(O)—, R 7 C(O)O—, R 7 C(O)NR 8 —, —CN or —NO 2 ;
R 10 , R 11 , R 12 and R 13 are each independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl; or
R 10 together with R 11 form ═O, ═S or ═NR 2 ; or
R 12 together with R 13 form ═O, ═S or ═NR 2 ;
W is O, S or NR 2 ,
n is 1-4; and
m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; and/or
iv) an isoxazoline compound of formula (IV)
wherein X 1 , X 2 and X 3 are independently H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, or a pharmaceutically acceptable salt thereof; and/or
iv) an isoxazoline compound of formula (V)
wherein X 1 , X 2 and X 3 are independently H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, or a pharmaceutically acceptable salt thereof; and/or
v) an isoxazoline compound of formula (VI):
wherein R 1 , R 2 and R 3 are independently H, Cl, F or CF 3 ;
Y is the diradical group
T is a C 1 -C 6 -alkyl group which is unsubstituted or substituted by halogen, cyano, nitro, amino, hydroxyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylthio, carboxy, carbamoyl or C 2 -C 6 -alkanoyl group which may be unsubstituted or substituted in the alkyl portion by halogen or a pharmaceutical acceptable salt thereof; and/or
vi) an isoxazoline compound of formula (VII):
wherein Y is hydrogen, fluoro, chloro or bromo;
R 1 is phenyl substituted with 2-4 substituents selected from halogen, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy or trifluoroethoxy;
R 2 is methyl, fluoromethyl, trifluoromethyl or perfluoroethyl;
R 3a and R 3b are independently selected from hydrogen, methyl, ethyl or fluoromethyl; or R 3a and R 3b together combine with the carbon to which they are attached to form a cyclopentyl ring or a cyclohexyl ring; or a pharmaceutically acceptable salt thereof;
b) at least one pharmaceutically acceptable polymer;
c) at least one solvent or a mixture of solvents;
d) optionally, an antioxidant; and
e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof.
4 . The extended release injectable composition according to claim 3 , wherein the isoxazoline active agent is a compound of formula (II).
5 . The extended release injectable composition according to claim 4 , wherein in the isoxazoline active agent is a compound of the formula (IIa):
or a pharmaceutically acceptable salt thereof,
wherein:
R 2 independently is halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl
R 4 is H or C 1 -C 6 alkyl;
R 5 is C 1 -C 4 alkyl optionally substituted with one or more R 7 ; and R 7 is 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; and
n is 0, 1 or 2.
6 . The extended release injectable composition according to claim 5 , wherein in the isoxazoline active agent is a compound of formula (IIc), (IId), (IIe) or (IIf):
or a pharmaceutically acceptable salt thereof.
7 . The extended release injectable composition according to claim 3 , wherein the isoxazoline active agent is enriched in an enantiomer.
8 . The extended release injectable composition according to claim 7 , wherein in the isoxazoline active agent is a compound of formula (S)-IIc, (S)-IId, (S)-IIe or (S)-IIf:
or a pharmaceutically acceptable salt thereof.
9 . The extended release injectable composition according to claim 3 , wherein the isoxazoline active agent is a compound of formula (III):
wherein:
R 1 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each which is unsubstituted or substituted with one or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R 7 S(O)—, R 7 S(O) 2 —, R 7 C(O)—, R 7 R 8 NC(O)—, R 7 OC(O)—, R 7 C(O)O—, R 7 C(O)NR 8 —, —CN or —NO 2 ;
X is aryl or heteroaryl, which may be unsubstituted or substituted by one or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R 7 S(O)—, R 7 S(O) 2 —, R 7 C(O)—, R 7 R 8 NC(O)—, R 7 OC(O)—, R 7 C(O)O—, R 7 C(O)NR 8 —, —CN or —NO 2 ;
A 1 is oxygen; and
A 2 is oxygen, NR 2 or CR 7 R 8 ;
G is G-1 or G-2;
B 1 , B 2 , B 3 , B 4 and B 5 are independently N or C—R 9 ;
Y is hydrogen, halogen, —CN; or Y is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, or heterocyclyl or heteroaryl each of which is unsubstituted or substituted with one or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R 7 S(O)—, R 7 S(O) 2 —, R 7 C(O)—, R 7 R 8 NC(O)—, R 7 OC(O)—, R 7 C(O)O—, R 7 C(O)NR 8 —, —CN or —NO 2 ; or Y is Y-1, Y-2, Y-3, Y-4, Y-5, Y-6, Y-7, Y-8, Y-9, Y-10, Y-11, Y-12 or Y-13;
R 2 , R 3 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, R 10 S(O)—, R 10 S(O) 2 —, R 10 C(O)—, R 10 C(S)—, R 10 R 11 NC(O)—, R 10 R 11 NC(S)—R 10 OC(O)—;
R 4 , R 5 and R 6 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, aryl or heteroaryl;
R 7 and R 8 are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl;
R 9 is hydrogen, halogen, —CN, or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each which is unsubstituted or substituted with one or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R 7 S(O)—, R 7 S(O) 2 —, R 7 C(O)—, R 7 R 8 NC(O)—, R 7 OC(O)—, R 7 C(O)O—, R 7 C(O)NR 8 —, —CN or —NO 2 ;
R 10 , R 11 , R 12 and R 13 are each independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl; or
R 10 together with R 11 form ═O, ═S or ═NR 2 ; or
R 12 together with R 13 form ═O, ═S or ═NR 2 ;
W is O, S or NR 2 ;
n is 1-4; and
m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.
10 . The extended release injectable composition according to claim 9 , wherein isoxazoline agent is a compound of formulae III-1.001 to III-1.025 or III-2.00-III-2.018:
Compounds III-1.001 to III-1.025
Compound
No.
(Z) p
B 5
B 4
B 3
B 2
B 1
R 15
R 16
1.001
3,5-Cl 2
C—H
C—H
C—H
C—H
N
H
CH 2 C(O)NHCH 2 CF 3
1.002
3,5-Cl 2
C—H
C—H
C—H
C—H
N
H
CH 2 CF 3
1.003
3,5-(CF 3 ) 2
C—H
C—H
C—H
C—H
N
CH 3
CH 2 CO 2 CH 3
1.004
3,5-(CF 3 ) 2
C—H
C—H
C—H
C—H
N
CH 3
CH 2 CO 2 H
1.005
3,5-(CF 3 ) 2
C—H
C—H
C—H
C—H
N
CH 3
CH 2 C(O)NHCH 2 CF 3
1.006
3,5-(CF 3 ) 2
C—H
C—H
C—H
C—H
N
H
CH 2 C(O)NHCH 2 CF 3
1.007
3,5-(CF 3 ) 2
C—H
C—H
C—H
C—H
N
H
CH 2 CH 2 SCH 3
1.008
3,5-(CF 3 ) 2
C—H
C—H
C—H
C—H
C—H
H
CH 2 C(O)NHCH 2 CF 3
1.009
3,5-(CF 3 ) 2
C—H
C—H
C—H
C—H
C—H
H
CH 2 CH 2 SCH 3
1.010
3,5-(CF 3 ) 2
C—H
C—H
C—H
C—H
C—H
H
CH 2 CF 3
1.011
3,5-Cl 2
C—H
C—H
C—H
C—H
C—H
H
CH 2 C(O)NHCH 2 CF 3
1.012
3,5-Cl 2
C—H
C—H
C—H
C—H
C—H
H
CH 2 CF 3
1.013
3,5-Cl 2
C—H
C—H
C—H
C—H
C—H
H
CH 2 CH 2 SCH 3
1.014
3-Cl, 5-CF 3
C—H
C—H
C—H
C—H
C—H
H
CH 2 C(O)NHCH 2 CF 3
1.015
3-Cl, 5-CF 3
C—H
C—H
C—H
C—H
C—H
H
CH 2 CF 3
1.016
3-Cl, 5-CF 3
C—H
C—H
C—H
C—H
C—H
H
CH 2 CH 2 SCH 3
1.017
3,5-Cl 2
C—H
C—H
C—Me
C—H
C—Me
H
CH 2 C(O)NHCH 2 CF 3
1.018
3,5-Cl 2
C—H
C—H
C—Me
C—H
C—Me
H
CH 2 CF 3
1.019
3,5-Cl 2
C—H
C—H
C—Me
C—H
C—Me
H
CH 2 CH 2 SCH 3
1.020
3,5-(CF 3 ) 2
C—H
C—H
C—Me
C—H
C—Me
H
CH 2 C(O)NHCH 2 CF 3
1.021
3,5-(CF 3 ) 2
C—H
C—H
C—Me
C—H
C—Me
H
CH 2 CF 3
1.022
3,5-(CF 3 ) 2
C—H
C—H
C—Me
C—H
C—Me
H
CH 2 CH 2 SCH 3
1.023
3-Cl, 5-CF 3
C—H
C—H
C—Me
C—H
C—Me
H
CH 2 C(O)NHCH 2 CF 3
1.024
3-Cl, 5-CF 3
C—H
C—H
C—Me
C—H
C—Me
H
CH 2 CF 3
1.025
3-Cl, 5-CF 3
C—H
C—H
C—Me
C—H
C—Me
H
CH 2 CH 2 SCH 3
Compounds III-2.001 to III-2.018
Compound
No.
(Z) p
B 5
B 4
B 3
B 2
B 1
R 15
R 16
2.001
3,5-Cl 2
C—H
C—H
N
C—H
C—H
H
CH 2 C(O)NHCH 2 CF 3
2.002
3,5-Cl 2
C—H
C—H
N
C—H
C—H
H
CH 2 CF 3
2.003
3,5-Cl 2
C—H
C—H
N
C—H
C—H
H
CH 2 CH 2 SCH 3
2.004
3,5-(CF 3 ) 2
C—H
C—H
N
C—H
C—H
H
CH 2 C(O)NHCH 2 CF 3
2.005
3,5-(CF 3 ) 2
C—H
C—H
N
C—H
C—H
H
CH 2 CF 3
2.006
3,5-(CF 3 ) 2
C—H
C—H
N
C—H
C—H
H
CH 2 CH 2 SCH 3
2.007
3-Cl, 5-CF 3
C—H
C—H
N
C—H
C—H
H
CH 2 C(O)NHCH 2 CF 3
2.008
3-Cl, 5-CF 3
C—H
C—H
N
C—H
C—H
H
CH 2 CF 3
2.009
3-Cl, 5-CF 3
C—H
C—H
N
C—H
C—H
H
CH 2 CH 2 SCH 3
2.010
3,5-Cl 2
C—H
C—H
C—H
C—H
C—H
H
CH 2 C(O)NHCH 2 CF 3
2.011
3,5-Cl 2
C—H
C—H
C—H
C—H
C—H
H
CH 2 CF 3
2.012
3,5-Cl 2
C—H
C—H
C—H
C—H
C—H
H
CH 2 CH 2 SCH 3
2.013
3,5-(CF 3 ) 2
C—H
C—H
C—H
C—H
C—H
H
CH 2 C(O)NHCH 2 CF 3
2.014
3,5-(CF 3 ) 2
C—H
C—H
C—H
C—H
C—H
H
CH 2 CF 3
2.015
3,5-(CF 3 ) 2
C—H
C—H
C—H
C—H
C—H
H
CH 2 CH 2 SCH 3
2.016
3-Cl, 5-CF 3
C—H
C—H
C—H
C—H
C—H
H
CH 2 C(O)NHCH 2 CF 3
2.017
3-Cl, 5-CF 3
C—H
C—H
C—H
C—H
C—H
H
CH 2 CF 3
2.018
3-Cl, 5-CF 3
C—H
C—H
C—H
C—H
C—H
H
CH 2 CH 2 SCH 3
or a pharmaceutically acceptable salt thereof.
11 . The extended release injectable composition according to claim 3 , wherein isoxazoline active agent is a compound of formula (IVa):
or a pharmaceutically acceptable salt thereof.
12 . The extended release injectable composition according to claim 3 , wherein isoxazoline compound is a compound of formula (Va):
or a pharmaceutically acceptable salt thereof.
13 . The extended release injectable composition according to claim 3 , wherein isoxazoline compound is a compound of formula (VIa):
or a pharmaceutically acceptable salt thereof.
14 . The extended release composition according to claim 1 , wherein the pharmaceutically acceptable polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), poly(methyl vinyl ether), poly(maleic anhydride), chitin, chitosan, copolymers thereof or terpolymers thereof, or combinations or mixtures thereof.
15 . The extended release injectable composition according to claim 2 , wherein the solvent is an alcohol, a liquid polyethylene glycol, propylene glycol, glycerol, a glycerol ester, a cyclic carbonate, 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide, dimethylacetamide, glycerol formal, a triglyceride, a propylene glycol diester, a poloxamer, or a mixture of at least two of these solvents.
16 . The extended release injectable composition according to claim 2 , wherein the solvent is a mixture of a water-miscible solvent and a water-immiscible solvent.
17 . The extended release injectable composition according to claim 2 comprising:
a) about 5 to 20% (w/w) of an isoxazoline compound of Formula (II):
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 1 , 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 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 or a pharmaceutically acceptable salt thereof;
b) about 1 to about 30% (w/w) of a pharmaceutically acceptable polymer which is a copolymer of polylactides and polyglycolides that has a lactide to glycolide ratio of 40:60 to 85:15(weight:weight);
c) about 40 to about 85% (w/w) of solvent selected from a cyclic carbonate, dimethylisosorbide, a poloxamer, a glycerol ester, a triglyceride, a liquid polyethylene glycol and an alcohol, or a mixture thereof;
d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;
e) optionally, about 0.1% to about 10% (w/w) of a surfactant and
f) optionally about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient or mixtures thereof.
18 . The extended release injectable formulation according to claim 17 , wherein the compound is a compound of formula (IIc):
or a pharmaceutically acceptable salt thereof.
19 . The extended release injectable formulation according to claim 17 , wherein the isoxazoline compound is:
or a pharmaceutically acceptable salt thereof.
20 . The extended release formulation according to claim 17 , wherein the solvent is a cyclic carbonate.
21 . The extended release formulation according to claim 17 , wherein the solvent is a solvent mixture comprising a cyclic carbonate and a glycerol ester.
22 . The extended release formulation according to claim 18 , wherein the ratio of cyclic carbonate to glycerol ester is about 1.5:1 to about 15:1 (w/w).
23 . The extended release formulation according to claim 17 or 18 , wherein the cyclic carbonate is propylene carbonate.
24 . The extended release formulation of claim 17 or 18 , wherein the glycerol ester is triacetin.
25 . The extended release formulation of claim 17 or claim 18 , wherein the solvent is a mixture comprising propylene carbonate and triacetin.
26 . The extended release formulation according to claim 21 wherein the solvent mixture further comprises a poloxamer.
27 . The extended release formulation according to claim 26 , which comprises about 0.5 to about 20% (w/w) of the poloxamer.
28 . The extended release formulation according to claim 17 , wherein the ratio of the copolymer of polylactides and polyglycolides to the isoxazoline compound of Formula (II) is about 1.5:1 to about 1:1.5 (weight:weight).
29 . The extended release formulation according to claim 28 , wherein the weight average molecular weight of the copolymer of polylactides and polyglycolides is from about 5 to about 20 kDa.
30 . The extended release formulation according to claim 2 , which further comprise an effective amount at least one additional pharmaceutically active agent.
31 . The extended release formulation according to claim 30 , wherein the additional pharmaceutically active agent is a macrocyclic lactone.
32 . The extended release formulation according to claim 31 , wherein the macrocyclic lactone is abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycin D, milbemycin oxime, moxidectin or nemadectin.
33 . A method for treating or preventing parasites in an animal in need thereof for a period of 3 to 12 months which comprises administering the long acting injectable formulation according to claim 2 to said animal.
34 . The method according to claim 33 wherein the animal is a dog, cat, sheep or cattle.
35 . The method according to claim 33 wherein the parasites are treated or prevented for about 5 to 6 months.
36 . The method according to claim 33 wherein the parasites are treated or prevented for about 6 months or longer.
37 . The method according to claim 33 wherein the parasites are fleas and/or ticks.
38 . The use of an isoxazoline in the preparation of an extended release injectable formulation for the treatment or prevention of a parasite infestation or infection on or in an animal.Join the waitlist — get patent alerts
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