U.S. patent application number 15/441297 was filed with the patent office on 2017-08-24 for antiparasitic isoxazoline compounds, long-acting injectable formulations comprising them, methods and uses thereof.
This patent application is currently assigned to MERIAL INC.. The applicant listed for this patent is MERIAL INC.. Invention is credited to Susan Mancini Cady, Peter Cheifetz, Izabela Galeska, Loic Patrick Le Hir de Fallois, Charles Q. Meng.
Application Number | 20170239218 15/441297 |
Document ID | / |
Family ID | 58231773 |
Filed Date | 2017-08-24 |
United States Patent
Application |
20170239218 |
Kind Code |
A1 |
Le Hir de Fallois; Loic Patrick ;
et al. |
August 24, 2017 |
ANTIPARASITIC ISOXAZOLINE COMPOUNDS, LONG-ACTING INJECTABLE
FORMULATIONS COMPRISING THEM, METHODS AND USES THEREOF
Abstract
This invention relates to long-acting injectable compositions
for combating parasites in animals, comprising at least one
isoxazoline active agent, a liquid PEG and/or a neutral oil,
optionally a co-solvent, and optionally a pharmaceutically
acceptable additive or excipient. This invention also provides new
isoxazoline active agents with long-lasting efficacy against
ectoparasites. The invention also provides for improved methods for
eradicating, controlling, and preventing parasite infections and
infestations in an animal comprising administering the novel
isoxazoline compounds and long-acting injectable compositions of
the invention to the animal in need thereof.
Inventors: |
Le Hir de Fallois; Loic
Patrick; (Atlanta, GA) ; Meng; Charles Q.;
(Grayson, GA) ; Cady; Susan Mancini; (Yardley,
PA) ; Cheifetz; Peter; (East Windsor, NJ) ;
Galeska; Izabela; (Newtown, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MERIAL INC. |
DULUTH |
GA |
US |
|
|
Assignee: |
MERIAL INC.
DULUTH
GA
|
Family ID: |
58231773 |
Appl. No.: |
15/441297 |
Filed: |
February 24, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62299333 |
Feb 24, 2016 |
|
|
|
62379348 |
Aug 25, 2016 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/14 20130101;
A61K 9/10 20130101; A61K 9/0095 20130101; A61P 33/14 20180101; C07D
261/04 20130101; C07D 491/107 20130101; C07D 471/04 20130101; C07D
413/04 20130101; A61K 9/107 20130101; A61K 31/42 20130101; A61K
47/10 20130101; A61K 31/415 20130101; A61K 9/0019 20130101; A61K
9/08 20130101; A01N 43/80 20130101; A61K 31/422 20130101; A01N
43/80 20130101; A01N 25/02 20130101; A01N 25/22 20130101 |
International
Class: |
A61K 31/415 20060101
A61K031/415; A61K 9/00 20060101 A61K009/00; A61K 47/10 20060101
A61K047/10; A01N 43/80 20060101 A01N043/80 |
Claims
1. A pesticidal and parasiticidal isoxazoline compound of formula
(Ie): ##STR00045## or a pharmaceutically or agriculturally
acceptable salt thereof.
2. A pesticidal and parasiticidal isoxazoline compound of formula
(S)-Ie: ##STR00046## or a pharmaceutically or agriculturally
acceptable salt thereof.
3. A veterinary parasiticidal composition comprising an effective
amount of the compound of formula (Ie) in claim 1 in combination
with a pharmaceutically acceptable carrier.
4. A pesticidal composition for controlling pests that harm plants,
plant propagation material, crops or material derived from wood,
comprising an effective amount of the compound of formula (Ie) in
claim 1 in combination with an agriculturally acceptable
carrier.
5. A veterinary parasiticidal composition comprising an effective
amount of the compound of formula (S)-Ie in claim 2 in combination
with a pharmaceutically acceptable carrier.
6. A pesticidal composition for controlling pests that harm plants,
plant propagation material, crops or material derived from wood,
comprising an effective amount of the compound of formula (S)-Ie in
claim 2 in combination with an agriculturally acceptable
carrier.
7. A method for the treatment or prevention of a parasitic
infestation in an animal comprising administering to the animal an
effective amount of the compound of formula (Ie) in claim 1.
8. A method for the treatment or prevention of a parasitic
infestation in an animal comprising administering to the animal an
effective amount of the compound of formula (S)-Ie in claim 2.
9. method for controlling pests that harm plants, plant propagation
material, crops or material derived from wood, comprising
administering an effective amount of the compound of formula (Ie)
in claim 1 to the plants, the soil in which the plants grow, plant
propagation material, crops or material derived from wood.
10. method for controlling pests that harm plants, plant
propagation material, crops or material derived from wood,
comprising administering an effective amount of the compound of
formula (S)-Ie in claim 2 to the plants, the soil in which the
plants grow, plant propagation material, crops or material derived
from wood.
11. A long-acting injectable composition for the treatment or
prevention of a parasitic infection or infestation in an animal
comprising an effective amount of at least one parasiticidal
isoxazoline active agent, a liquid PEG and/or a neutral oil and,
optionally, a co-solvent, wherein no other pharmaceutically
acceptable polymers are present.
12. The long-acting injectable composition according to claim 11
comprising: a) an effective amount of at least one parasiticidal
isoxazoline active agent, which is: i) an isoxazoline compound of
formula (I): ##STR00047## wherein: A.sup.1, A.sup.2, A.sup.3,
A.sup.4, A.sup.5 and A.sup.6 are independently selected from the
group consisting of CR.sup.3 and N, provided that at most 3 of
A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5 and A.sup.6 are N;
B.sup.1, B.sup.2 and B.sup.3 are independently selected from the
group consisting of CR.sup.2 and N; W is O or S; R.sup.1 is
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
alkylcycloalkyl or C.sub.4-C.sub.7 cycloalkylalkyl, each optionally
substituted with one or more substituents independently selected
from R.sup.6; each R.sup.2 is independently H, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.1-C.sub.6 haloalkylthio, C.sub.1-C.sub.6 alkylsulfinyl,
C.sub.1-C.sub.6 haloalkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl,
C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.1-C.sub.6 alkylamino,
C.sub.2-C.sub.6 dialkylamino, C.sub.2-C.sub.4 alkoxycarbonyl, --CN
or --NO.sub.2; each R.sup.3 is independently H, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.3-C.sub.6 halocycloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.1-C.sub.6 haloalkylthio, C.sub.1-C.sub.6 alkylsulfinyl,
C.sub.1-C.sub.6 haloalkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl,
C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.1-C.sub.6 alkylamino,
C.sub.2-C.sub.6 dialkylamino, --CN or --NO.sub.2; R.sup.4 is H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
alkylcycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl, C.sub.2-C.sub.7
alkylcarbonyl or C.sub.2-C.sub.7 alkoxycarbonyl; R.sup.5 is H,
OR.sup.10, NR.sup.11R.sup.12 or Q.sup.1; or C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.4-C.sub.7 alkylcycloalkyl or C.sub.4-C.sub.7
cycloalkylalkyl, each optionally substituted with one or more
substituents independently selected from R.sup.7; or R.sup.4 and
R.sup.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.sub.1-C.sub.2 alkyl, halogen, --CN, --NO.sub.2 and
C.sub.1-C.sub.2 alkoxy; each R.sup.6 is independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkylthio, C.sub.1-C.sub.6 alkylsulfinyl, C.sub.1-C.sub.6
alkylsulfonyl, --CN or --NO.sub.2; each R.sup.7 is independently
halogen; C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6
alkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6
alkylamino, C.sub.2-C.sub.8 dialkylamino, C.sub.3-C.sub.6
cycloalkylamino, C.sub.2-C.sub.7 alkylcarbonyl, C.sub.2-C.sub.7
alkoxycarbonyl, C.sub.2-C.sub.7 alkylaminocarbonyl, C.sub.3-C.sub.9
dialkylaminocarbonyl, C.sub.2-C.sub.7 haloalkylcarbonyl,
C.sub.2-C.sub.7 haloalkoxycarbonyl, C.sub.2-C.sub.7
haloalkylaminocarbonyl, C.sub.3-C.sub.9 dihaloalkylaminocarbonyl,
hydroxy, --NH.sub.2, --CN or --NO.sub.2; or Q.sup.2; each R.sup.8
is independently halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkoxy, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6
haloalkylthio, C.sub.1-C.sub.6 alkylsulfinyl, C.sub.1-C.sub.6
haloalkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6
haloalkylsulfonyl, C.sub.1-C.sub.6 alkylamino, C.sub.2-C.sub.6
dialkylamino, C.sub.2-C.sub.4 alkoxycarbonyl, --CN or NO.sub.2;
each R.sup.9 is independently halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.3-C.sub.6 halocycloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.1-C.sub.6 haloalkylthio, C.sub.1-C.sub.6 alkylsulfinyl,
C.sub.1-C.sub.6 haloalkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl,
C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.1-C.sub.6 alkylamino,
C.sub.2-C.sub.6 dialkylamino, --CN, --NO.sub.2, phenyl or
pyridinyl; R.sup.10 is H; or C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.4-C.sub.7 alkylcycloalkyl or C.sub.4-C.sub.7 cycloalkylalkyl,
each optionally substituted with one of more halogen; R.sup.11 is
H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
alkylcycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl, C.sub.2-C.sub.7
alkylcarbonyl or C.sub.2-C.sub.7 alkoxycarbonyl; R.sup.12 is H;
Q.sup.3; or C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.4-C.sub.7 alkylcycloalkyl or C.sub.4-C.sub.7 cycloalkylalkyl,
each optionally substituted with one or more substituents
independently selected from R.sup.7; or R.sup.11 and R.sup.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.sub.1-C.sub.2
alkyl, halogen, --CN, --NO.sub.2 and C.sub.1-C.sub.2 alkoxy;
Q.sup.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.sup.8;
each Q.sup.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.sup.9; Q.sup.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.sup.9; and n is 0, 1 or 2; or a pharmaceutically
acceptable salt thereof; and/or ii) an isoxazoline compound of
formula (II): ##STR00048## wherein: R.sub.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.sub.7S(O)--, R.sub.7S(O).sub.2--,
R.sub.7C(O)--, R.sub.7R.sub.8NC(O)--, R.sub.7OC(O)--,
R.sub.7C(O)O--, R.sub.7C(O)NR.sub.8--, --CN or --NO.sub.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.sub.7S(O)--, R.sub.7S(O).sub.2--, R.sub.7C(O)--,
R.sub.7R.sub.8NC(O)--, R.sub.7OC(O)--, R.sub.7C(O)O--,
R.sub.7C(O)NR.sub.8--, --CN or --NO.sub.2; A.sub.1 is oxygen; and
A.sub.2 is oxygen, NR.sub.2 or CR.sub.7R.sub.8; G is G-1 or G-2;
##STR00049## B.sub.1, B.sub.2, B.sub.3, B.sub.4 and B.sub.5 are
independently N or C--R.sub.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.sub.7S(O)--, R.sub.7S(O).sub.2--, R.sub.7C(O)--,
R.sub.7R.sub.8NC(O)--, R.sub.7OC(O)--, R.sub.7C(O)O--,
R.sub.7C(O)NR.sub.8--, --CN or --NO.sub.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;
##STR00050## ##STR00051## R.sub.2, R.sub.3 are independently
hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl,
hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl,
haloalkynyl, cycloalkyl, R.sub.10S(O)--, R.sub.10S(O).sub.2--,
R.sub.10C(O)--, R.sub.10C(S)--, R.sub.10R.sub.11NC(O)--,
R.sub.10R.sub.11NC(S)-- R.sub.10OC(O)--; R.sub.4, R.sub.5 and
R.sub.6 are independently hydrogen, alkyl, haloalkyl, thioalkyl,
alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl,
alkynyl, haloalkynyl, cycloalkyl, aryl or heteroaryl; R.sub.7 and
R.sub.8 are independently hydrogen, alkyl, haloalkyl, thioalkyl,
alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl,
alkynyl or haloalkynyl; R.sub.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.sub.7S(O)--,
R.sub.7S(O).sub.2--, R.sub.7C(O)--, R.sub.7R.sub.8NC(O)--,
R.sub.7OC(O)--, R.sub.7C(O)O--, R.sub.7C(O)NR.sub.8--, --CN or
--NO.sub.2; R.sub.10, R.sub.11, R.sub.12 and R.sub.13 are each
independently hydrogen, alkyl, haloalkyl, thioalkyl,
alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl,
alkynyl or haloalkynyl; or R.sub.10 together with R.sub.11 form
.dbd.O, .dbd.S or .dbd.NR.sub.2; or R.sub.12 together with R.sub.13
form .dbd.O, .dbd.S or .dbd.NR.sub.2; W is O, S or NR.sub.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 (III)
##STR00052## or a pharmaceutically acceptable salt thereof; and/or
iv) an isoxazoline compound of formula (IV) ##STR00053## or a
pharmaceutically acceptable salt thereof; and/or v) an isoxazoline
compound of formula (V): ##STR00054## wherein R.sup.1, R.sup.2 and
R.sup.3 are independently H, Cl, F or CF.sub.3; Y is the diradical
group ##STR00055## and T is a C.sub.1-C.sub.6-alkyl group which is
unsubstituted or substituted by halogen, cyano, nitro, amino,
hydroxyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy,
C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylthio, carboxy,
carbamoyl or C.sub.2-C.sub.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 (VI): ##STR00056## wherein Y is hydrogen,
fluoro, chloro or bromo; R.sup.1 is phenyl substituted with 2-4
substituents selected from halogen, methyl, difluoromethyl,
trifluoromethyl, methoxy, trifluoromethoxy or trifluoroethoxy;
R.sup.2 is methyl, fluoromethyl, trifluoromethyl or perfluoroethyl;
R.sup.3a and R.sup.3b are independently selected from hydrogen,
methyl, ethyl or fluoromethyl; or R.sup.3a and R.sup.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 which is a liquid PEG and/or a neutral oil; c)
optionally, at least one co-solvent; d) optionally, an antioxidant;
and e) optionally at least one pharmaceutically acceptable
additive, excipient or mixtures thereof wherein no other
pharmaceutically acceptable polymers are present.
13. The long-acting injectable composition according to claim 12,
wherein the at least one isoxazoline compound is a compound of
formula (I), or a pharmaceutically acceptable salt thereof.
14. The long-acting injectable composition according to claim 13,
wherein in the isoxazoline active agent is a compound of the
formula (Ib): ##STR00057## or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 independently is halogen, C.sub.1-C.sub.6
alkyl or C.sub.1-C.sub.6 haloalkyl R.sup.4 is H or C.sub.1-C.sub.6
alkyl; R.sup.5 is C.sub.1-C.sub.4 alkyl optionally substituted with
one or more R.sup.7; and R.sup.7 is C.sub.2-C.sub.7 alkylcarbonyl,
C.sub.2-C.sub.7 alkoxycarbonyl, C.sub.2-C.sub.7 alkylaminocarbonyl,
C.sub.3-C.sub.9 dialkylaminocarbonyl, C.sub.2-C.sub.7
haloalkylcarbonyl, C.sub.2-C.sub.7 haloalkoxycarbonyl,
C.sub.2-C.sub.7 haloalkylaminocarbonyl, C.sub.3-C.sub.9
dihaloalkylaminocarbonyl; and n is 0, 1 or 2.
15. The long-acting injectable composition according to claim 14,
wherein the isoxazoline active agent is a compound of formula (Ia):
##STR00058## or a pharmaceutically acceptable salt thereof.
16. The long-acting injectable composition according to claim 13,
wherein the isoxazoline active agent is a compound of formula (Ic):
##STR00059## or a pharmaceutically acceptable salt thereof; wherein
X.sup.1, X.sup.2 and X.sup.3 are each independently H, halogen,
C.sub.1-C.sub.3alkyl or C.sub.1-C.sub.3haloalkyl.
17. The long-acting injectable composition according to claim 11 or
12, wherein the isoxazoline active agent is enriched in an
enantiomer.
18. The long-acting injectable composition according to claim 17,
wherein the isoxazoline active agent is a compound of formula
(S)-Ia or (S)-Ic: ##STR00060## wherein X.sup.1, X.sup.2 and X.sup.3
are independently chloro, fluoro or CF.sub.3; or a pharmaceutically
acceptable salt thereof.
19. The long-acting injectable composition according to any one of
claims 11 to 18, wherein the liquid PEG is PEG 200, PEG 300 or PEG
400, or a mixture thereof.
20. The long-acting injectable composition according to any one of
claims 11 to 19, wherein the composition comprises a co-solvent,
and wherein said co-solvent is a C.sub.1-C.sub.6alcohol, a glycol
ether, glycerol, propylene glycol, a cyclic carbonate,
2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide,
dimethylacetamide, dimethylsulfoxide or glycerol formal, or a
combination thereof.
21. The long-acting injectable composition according to any one of
claims 11 to 19, wherein the composition comprises a co-solvent,
and wherein said co-solvent is benzyl alcohol, benzyl benzoate,
ethyl acetate, triacetin, a lipid, a C.sub.8-C.sub.10 triglyceride,
a C.sub.8-C.sub.10 triglyceride combined with linoleic acid, a
C.sub.8-C.sub.10 triglyceride combined with succinic acid, a
propylene glycol diester of C.sub.8-C.sub.10 fatty acids, castor
oil, cottonseed oil, sesame oil, soybean oil or safflower oil, or a
combination thereof.
22. The long-acting injectable composition according to any one of
claims 11 to 19, wherein the composition comprises a co-solvent,
and wherein the co-solvent is ethanol, isopropanol or benzyl
alcohol, or a mixture thereof.
23. The long-acting injectable composition according to any one of
claims 11 to 22, wherein the composition comprises a
pharmaceutically acceptable excipient, and wherein the excipient is
a surfactant.
24. The long-acting injectable composition according to claim 23,
wherein the surfactant is selected from the group consisting of
glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters,
sorbitan monooleate, polyvinyl alcohol, polysorbate 20, polysorbate
80, d-a-tocopherol polyethylene glycol 1000 succinate, sodium
lauryl sulfate, co-polymers of ethylene oxide and propylene oxide,
polyethylene glycol castor oil derivatives, propylene glycol
monolaurate, glycerol caprylate/caprate, polyglycolized glycerides,
PEG 300 caprylic/capric glycerides, PEG 400 caprylic/capric
glycerides, PEG 300 oleic glycerides, PEG 300 linoleic glycerides,
polyethylene glycol stearates and polyethylene glycol hydroxy
stearates, or a combination thereof.
25. The long-acting injectable composition according to claim 13
comprising: a) about 0.5 to about 30% (w/v) of the isoxazoline
compounds of formula (I); b) pharmaceutically acceptable polymer
which is a liquid PEG, and/or a neutral oil; c) optionally, about
1% to 15% (w/v) of co-solvent, wherein said co-solvent is ethanol,
isopropanol or benzyl alcohol, or a combination thereof; d)
optionally, about 0.01% to about 2% (w/v) of an antioxidant; and e)
optionally about 0.01% to about 10% (w/v) of a pharmaceutically
acceptable additive, excipient or mixtures thereof wherein the only
pharmaceutically acceptable polymer present in said long-acting
injectable composition is a liquid PEG and wherein the liquid PEG
and/or the neutral oil are present in the overall composition in a
proportion representing the complement to 100% of the
composition.
26. The long-acting injectable composition according to claim 25,
wherein the composition comprises: a) about 5 to 15% (w/v) of an
isoxazoline compound of formula (Ia): ##STR00061## or a
pharmaceutically acceptable salt thereof, b) pharmaceutically
acceptable polymer which is a liquid PEG; c) optionally, about 2%
to 10% (w/v) of co-solvent, wherein said co-solvent is ethanol,
isopropanol or benzyl alcohol, or a combination thereof; d)
optionally, about 0.01% to about 2% (w/v) of an antioxidant; and e)
optionally, about 0.5% to about 10% (w/v) of a pharmaceutically
acceptable additive, excipient or mixtures thereof wherein the only
pharmaceutically acceptable polymer present in said long-acting
injectable composition is a liquid PEG and wherein the liquid PEG
is present in the overall composition in a proportion representing
the complement to 100% of the composition.
27. The long-acting injectable composition according to claim 26,
wherein the isoxazoline compound is: ##STR00062## or a
pharmaceutically acceptable salt thereof.
28. The long-acting injectable composition according to claim 25,
wherein the composition comprises: a) about 5 to 15% (w/v) of an
isoxazoline compound of formula (Ic): ##STR00063## or a
pharmaceutically acceptable salt thereof; wherein X.sup.1X.sup.2
and X.sup.3 are each independently H, halogen, C.sub.1-C.sub.3alkyl
or C.sub.1-C.sub.3haloalkyl; b) pharmaceutically acceptable polymer
which is a liquid PEG; c) optionally, about 2% to 10% (w/v) of
co-solvent, wherein said co-solvent is ethanol, isopropanol or
benzyl alcohol, or a combination thereof; d) optionally, about
0.01% to about 2% (w/v) of an antioxidant; and e) optionally, about
0.5% to about 10% (w/v) of a pharmaceutically acceptable additive,
excipient or mixtures thereof wherein the only pharmaceutically
acceptable polymer present in said long-acting injectable
composition is a liquid PEG and wherein the liquid PEG is present
in the overall composition in a proportion representing the
complement to 100% of the composition.
29. The long-acting injectable composition according to claim 28,
wherein; X.sup.1 is Cl; X.sup.2 is F; and X.sup.3 is
--CF.sub.3.
30. The long-acting injectable composition according to any one of
claims 11 to 29, wherein the parasites are treated or prevented for
about 3 to 6 months.
31. The long-acting injectable composition according to any one of
claims 11 to 29 wherein the parasites are treated or prevented for
about 5 to 6 months.
32. The long-acting injectable composition according to any one of
claims 11 to 29, wherein the parasites are treated or prevented for
about 6 months.
33. The long-acting injectable composition according to any one of
claim 30, 31 or 33 wherein the parasites are fleas or ticks
34. The long-acting composition according to any one of claims 11
to 33, which further comprises an effective amount at least one
additional active agent.
35. The long-acting composition according to claim 34, wherein the
additional pharmaceutically active agent is a macrocyclic lactone,
a neonicotinoid active agent, a 1-N-arylpyrazole active agent, a
cyclic depsipeptide, a benzimidazole, an imidazothiazole, a
tetrahydropyrimidine active agent, an organophosphate active agent,
levamisole, a paraherquamide active agent, a marcfortine active
agent, praziquantel, closantel, pyrantel, morantel, clorsulon, a
spinosyn active agent, a spinosoid active agent, an amino
acetonitrile active agent, an aryloazol-2-yl cyanoethyl active
agent or an insect growth regulator.
36. The long-acting composition according to claim 35, wherein the
macrocyclic lactone is abamectin, dimadectin, doramectin,
emamectin, eprinomectin, ivermectin, latidectin, lepimectin,
selamectin, ML-1,694,554, milbemectin, milbemycin D, moxidectin or
nemadectin.
37. A method for treating or preventing parasites in an animal in
need thereof for a period of 3 to 6 months which comprises
administering the long acting injectable composition according to
claim 1 to said animal.
38. The method according to claim 37 wherein the animal is a dog, a
cat, an ovine or a bovine.
39. The method according to claim 37 wherein the parasites are
treated or prevented for about 5 to 6 months
40. The method according to claim 37 wherein the parasites are
fleas and/or ticks.
41. The use of an isoxazoline in the preparation of a long-acting
injectable composition for the treatment or prevention of a
parasite infestation or infection on or in an animal.
Description
FIELD OF THE INVENTION
[0001] The present invention provides pesticidal and antiparasitic
isoxazoline compounds, and long-acting injectable compositions
comprising at least one isoxazoline active agent, a liquid
polyethylene glycol (PEG) and, optionally, a co-solvent. The
invention also provides for the use of these compounds and
compositions against pests and parasites (including ectoparasites
(e.g., fleas or ticks) and/or endoparasites), and methods for
controlling pests and preventing or treating parasitic infections
and infestations in animals.
CROSS REFERENCE TO RELATED APPLICATIONS
[0002] This application claims the benefit of priority to U.S.
Provisional Application Nos. 62/299,333, filed Feb. 24, 2016, and
62/379,348, filed Aug. 25, 2016, both of which are incorporated
herein by reference.
BACKGROUND OF THE INVENTION
[0003] Animals such as mammals and birds are often susceptible to
parasite infestations/infections. These parasites may be
ectoparasites, such as fleas, ticks and parasitic flies, and
endoparasites such as nematodes and other worms. Domesticated
animals, such as cats and dogs, are often infested with one or more
of the following ectoparasites: [0004] fleas (e.g. Ctenocephalides
spp., such as Ctenocephalides fells and the like); [0005] ticks
(e.g. Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyomma
spp., and the like); [0006] mites (e.g. Demodex spp., Sarcoptes
spp., Otodectes spp., and the like); [0007] lice (e.g. Trichodectes
spp., Cheyletiella spp., Linognathus spp. and the like); [0008]
mosquitoes (Aedes spp., Culex spp., Anopheles spp. and the like);
and [0009] flies (Haematobia spp., Musca spp., Stomoxys spp.,
Dermatobia spp., Cochliomyia spp. and the like).
[0010] Fleas are a particular problem because not only do they
adversely affect the health of the animal or human, but they also
cause a great deal of psychological stress. Moreover, fleas may
also transmit pathogenic agents to animals and humans, such as
tapeworm (Dipylidium caninum).
[0011] Similarly, ticks are also harmful to the physical and
psychological health of the animal or human. However, the most
serious problem associated with ticks is that they are vectors of
pathogenic agents in both humans and animals. Major diseases which
may be transmitted by ticks include borreliosis (Lyme disease
caused by Borrelia burgdorferi), babesiosis (or piroplasmosis
caused by Babesia spp.) and rickettsioses (e.g. Rocky Mountain
spotted fever). Ticks also release toxins which cause inflammation
or paralysis in the host. Occasionally, these toxins are fatal to
the host.
[0012] Likewise, farm animals are also susceptible to parasite
infestations. For example, cattle and other bovines are affected by
a large number of parasites. A parasite which is prevalent among
cattle in some regions are ticks of the genus Rhipicephalus,
especially those of the species microplus (cattle tick),
decoloratus and annulatus. Ticks such as Rhipicephalus microplus
(formerly Boophilus microplus) are difficult to control because
they lay eggs in the pasture where farm animals graze. This species
of ticks is considered a one-host tick and spends immature and
adult stages on one animal before the female engorges and falls off
the host to lay eggs in the environment. The life cycle of the tick
is approximately three to four weeks. In addition to cattle,
Rhipicephalus microplus may infest buffalo, horses, donkeys, goats,
sheep, deer, pigs, and dogs. A heavy tick burden on animals can
decrease production and damage hides as well as transmit diseases
such as babesiosis ("cattle fever") and anaplasmosis.
[0013] Animals and humans also suffer from endoparasitic infections
including, for example, helminthiasis which is caused by of
parasitic worms categorized as cestodes (tapeworm), nematodes
(roundworm) and trematodes (flatworm or flukes). These parasites
adversely affect the nutrition of the animal and cause severe
economic losses in pigs, sheep, horses, and cattle as well as
affecting companion animals and poultry. Other parasites which
occur in the gastrointestinal tract of animals and humans include
those from the genus Ancylostoma, Necator, Ascaris, Strongyloides,
Trichinella, Capillaria, Toxocara, Toxascaris, Trichuris,
Enterobius and parasites which are found in the blood or other
tissues and organs such as filarial worms and the extra intestinal
stages of Strongyloides, Toxocara and Trichinella.
[0014] Recently, isoxazole and isoxazoline-containing compounds
have been demonstrated to be effective against parasites that harm
animals. For example, U.S. Pat. No. 7,964,204 (to DuPont,
incorporated by reference herein in its entirety) discloses
isoxazoline compounds according to formula (I) below, which are
active against ectoparasites and/or endoparasites.
##STR00001##
In addition, published patent application nos. US 2010/0254960 A1,
WO 2007/070606 A2, WO 2007/123855 A2, WO 2010/003923 A1, U.S. Pat.
No. 7,951,828 & U.S. Pat. No. 7,662,972, US 2010/0137372 A1, US
2010/0179194 A2, US 2011/0086886 A2, US 2011/0059988 A1, US
2010/0179195 A1 and WO 2007/075459 A2 and U.S. Pat. Nos. 7,951,828
and 7,662,972 describe various other parasiticidal isoxazoline
compounds. Other published patent applications that describe
various other parasiticidal isoxazoline compounds and compositions
comprising the same include WO 2007/079162 A1, WO 2008/154528 A1,
WO 2009/002809 A2, WO 2011/149749 A1, WO 2014/439475 A1, U.S. Pat.
No. 8,466,115, WO 2012/120399, WO 2014/039484, WO 2014/189837,
(Zoetis) and WO2012 120135A1 (Novartis). WO 2012/089623 describes
topical localized isoxazoline compositions comprising glycofurol.
WO 2013/039948 A1 provides for topical veterinary compositions
comprising at least one isoxazoline active agent and WO 2013/119442
A1 provides for oral veterinary compositions such as a soft chew
which comprising at least one isoxazoline active agent.
[0015] In additional to topical and oral dosage forms, it is
sometimes possible to formulate active agents as long-acting
compositions, depending upon, for example, the physiochemical
properties of the individual active agent; these properties
include, for example, solubility, bioavailability, etc. For
example, U.S. Pat. No. 6,733,767 and U.S. Pat. No. 8,362,086
provide for long acting injectable compositions comprising a
bioactive substance, such as, for example, an avermectin or a
milbemycin and a biological acceptable polymer.
[0016] Notwithstanding the highly active isoxazoline active agents
and compositions comprising isoxazoline active agents alone or in
combination with other active agents described in the documents
above, there is a need for more effective isoxazoline compounds and
veterinary compositions and methods with improved efficacy,
bioavailability, and spectrum of coverage to protect animals
against endoparasites and/or ectoparasites. More specifically,
there is a need to develop a long-acting injectable composition
comprising an isoxazoline compound, which has good bioavailability
and exhibits a reduced irritation at the injection site while still
being effective against parasites (e.g., fleas and ticks) for a
long duration (e.g., from three (3) to six (6) months.
INCORPORATION BY REFERENCE
[0017] Any foregoing applications, and all documents cited therein
or during their prosecution ("application cited documents") and all
documents cited or referenced in the application cited documents,
and all documents cited or referenced herein ("herein cited
documents"), and all documents cited or referenced in herein cited
documents, together with any manufacturer's instructions,
descriptions, product specifications, and product sheets for any
products mentioned herein or in any document incorporated by
reference herein, are hereby incorporated herein by reference, and
may be employed in the practice of the invention.
[0018] Citation or identification of any document in this
application is not an admission that such document is available as
prior art to the present invention.
SUMMARY OF THE INVENTION
[0019] In a first aspect, the present invention provides for novel
and inventive long-acting injectable compositions for the treatment
or prevention of parasite infections or infestations in an animal
comprising an antiparasitic effective amount of at least one
isoxazoline compound, a liquid PEG and/or a pharmaceutically
acceptable neutral oil, optionally, a co-solvent and optionally a
pharmaceutically acceptable additive or excipient.
[0020] In accordance with the first aspect of the present
invention, it has been discovered that the inventive long-acting
compositions generally show desirable bioavailability and duration
of efficacy, while causing minimal irritation at the injection
site. The compositions also provide desirable safety profiles
toward the warm-blooded and bird animal recipients. In addition, it
has been discovered that a single administration of such
compositions generally provides potent activity against one or more
parasites (e.g., ectoparasites), while also tending to provide fast
onset of activity, long duration of activity, and/or desirable
safety profiles.
[0021] The invention encompasses uses or veterinary uses of the
isoxazoline compounds and compositions described herein for the
treatment or prevention of parasitic infections and infestations in
or on animals (either wild or domesticated), including livestock
and companion animals such as cats, dogs, horses, chickens, sheep,
goats, pigs, turkeys and cattle, with the aim of ridding these
hosts of parasites commonly encountered by such animals.
[0022] In addition, the compounds of formula (Id) described herein
are useful for protecting crops, plants, plant propagation
material, or material containing wood or derived from wood, from
harmful pests.
[0023] The invention also provides methods for the treatment or
prevention of parasitic infections and infestations in animals,
comprising administering an effective amount of long-acting
injectable compositions comprising an antiparasitic effective
amount of at least one isoxazoline compound together with at least
one liquid PEG and/or a pharmaceutically acceptable neutral oil and
optionally a co-solvent, a pharmaceutically acceptable additive
and/or excipient, wherein the composition does not contain a
pharmaceutically acceptable biodegradable polymer as defined
herein. Surprisingly, it has been found that the inventive
isoxazoline-containing compositions described herein exhibit
superior broad spectrum efficacy against harmful parasites (e.g.
ectoparasites such as fleas and ticks) more rapidly, and over a
long duration compared to other injectable compositions containing
isoxazoline active agents known in the art while exhibiting minimal
irritation at the injection site.
[0024] This invention also provides for the use of an isoxazoline
in the preparation of a long-acting injectable composition for the
treatment or prevention of an animal against parasites.
[0025] In one embodiment, the invention provides for long-acting
injectable compositions comprising antiparasitic effective amounts
of at least one isoxazoline of formula (I) below, in combination
and a pharmaceutically or veterinary acceptable liquid carrier,
where variables A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5,
A.sup.6, B.sup.1, B.sup.2, B.sup.3, R.sup.1, R.sup.2, R.sup.4,
R.sup.5, W and n are defined herein.
##STR00002##
[0026] In another embodiment, the invention provides long-acting
injectable compositions comprising an isoxazoline compound of
formula (Ic):
##STR00003##
[0027] or a pharmaceutically acceptable salt thereof; wherein
X.sup.1, X.sup.2 and X.sup.3 are each independently H, halogen,
C.sub.1-C.sub.3alkyl or C.sub.1-C.sub.3haloalkyl. Long acting
compositions comprising a compound of formula (Ic) wherein X.sup.1
is chloro, X.sup.2 is fluoro and X.sup.3 is CF.sub.3 have been
shown to have surprisingly long-lasting and excellent efficacy
against Rhipicephalus microplus with a quick onset and a very long
duration of time.
[0028] In another embodiment, the long-acting injectable
compositions and methods comprise
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-naphthalen-
ecarboxamide as the active agent.
[0029] In other embodiments, the long-acting injectable
compositions may further comprise one or more additional active
agents that are systemically active. Systemically-acting active
agents may include, but are not limited to, isoxazoline active
agents of different structure, a systemically-acting neonicotinoid
active agent, a systemically-acting 1-N-arylpyrazole active agent,
macrocyclic lactones such as avermectin and milbemycin compounds, a
cyclic depsipeptide such as emodepside or PF1022A or analogs
thereof, benzimidazoles, imidazothiazoles, a tetrahydropyrimidine
active agent, an organophosphate active agent, levamisole, a
paraherquamide active agent and/or a marcfortine active agent,
praziquantel, closantel, clorsulon, morantel, pyrantel, a spinosyn
or spinosoid active agent, an amino acetonitrile active agent, an
aryloazol-2-yl cyanoethyl active agent, a systemically-acting
insect growth regulator. In one embodiment, the long-acting
injectable compositions comprise at least one macrocyclic lactone
active agent, including, but not limited to, avermectins or
milbemycins. In some embodiments, the avermectin or milbemycin
active agent is eprinomectin, ivermectin, selamectin, milbemectin,
milbemycin D, milbemycin oxime, or moxidectin.
[0030] In other embodiments, the compositions and methods comprise
at least one of thiabendazole, oxibendazole, mebendazole,
fenbendazole, oxfendazole, albendazole, triclabendazole, febantel,
levamisole, pyrantel, morantel, praziquantel, closantel, clorsulon,
an amino acetonitrile active agent, or an aryloazol-2-yl
cyanoethylamino active agent.
[0031] In a second aspect, the invention provides novel and
inventive pesticidal and parasiticidal isoxazoline compounds of
formula (Id) shown:
##STR00004##
wherein X.sup.1 is bromo, chloro, iodo or fluoro; and X.sup.2 is
chloro, fluoro or CF.sub.3; Y is a group Y-1, Y-2, Y-3, Y-4 where Z
is N or CH, Y-5 or Y-6
##STR00005##
and Q is OH, --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3, --C(O)NHCH.sub.2CH.sub.2SCH.sub.3
or (--CH.sub.2--)(--CH.sub.2--)N(CO)CH.sub.2S(O).sub.2CH.sub.3.
[0032] The compounds of formula (Id) are highly active against
arthropod pests and parasites and useful for protecting animals,
including livestock and companion animals such as cats, dogs,
horses, chickens, sheep, goats, pigs, turkeys and cattle, from
parasites that infest or infect such animals. The invention also
provides pesticidal isoxazoline compounds of formula (Id) for
protecting crops, plants, plant propagation material, or material
containing wood or derived from wood, from harmful pests.
[0033] It is an object of the invention to not encompass within the
invention any previously known product, process of making the
product, or method of using the product such that the Applicants
reserve the right and hereby disclose a disclaimer of any
previously known product, process, or method. It is further noted
that the invention does not intend to encompass within the scope of
the invention any product, process, or making of the product or
method of using the product, which does not meet the written
description and enablement requirements of the USPTO (35 U.S.C.
.sctn.112, first paragraph) or the EPO (Article 83 of the EPC),
such that Applicants reserve the right and hereby disclose a
disclaimer of any previously described product, process of making
the product, or method of using the product.
[0034] These and other embodiments are disclosed or are obvious
from and encompassed by, the following Detailed Description.
DETAILED DESCRIPTION
Long-Acting Injectable Compositions
[0035] In a first aspect, the present invention provides for novel
and inventive long-acting injectable compositions for the treatment
or prevention of parasitic infections or infestations in an animal
comprising an antiparasitic effective amount of at least one
isoxazoline compound, a liquid PEG and/or a pharmaceutically
acceptable neutral oil, and optionally a co-solvent, a
pharmaceutically acceptable additive and/or excipient, wherein no
other pharmaceutically acceptable polymers, as defined herein are
present.
[0036] Also provided are methods and uses for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals, comprising administering to an animal in need thereof a
long-acting composition comprising an antiparasitic effective
amount of at least one isoxazoline compound, a liquid PEG and/or a
pharmaceutically acceptable neutral oil, and optionally a
co-solvent, a pharmaceutically acceptable additive and/or
excipient.
[0037] In another embodiment, the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising an antiparasitic effective amount of at least
one isoxazoline compound and an effective amount of at least one
additional active agent, a PEG and/or a pharmaceutically acceptable
neutral oil and, optionally, a co-solvent, a pharmaceutically
acceptable additive and/or excipient.
[0038] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[0039] a) an antiparasitic effective amount of at least one
isoxazoline active agent, which is: [0040] i) an isoxazoline
compound of formula (I):
##STR00006##
[0040] wherein:
[0041] A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5 and A.sup.6 are
independently selected from the group consisting of CR.sup.3 and N,
provided that at most 3 of A.sup.1, A.sup.2, A.sup.3, A.sup.4,
A.sup.5 and A.sup.6 are N;
[0042] B.sup.1, B.sup.2 and B.sup.3 are independently selected from
the group consisting of CR.sup.2 and N;
[0043] W is O or S;
[0044] R.sup.1 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.4-C.sub.7 alkylcycloalkyl or C.sub.4-C.sub.7 cycloalkylalkyl,
each optionally substituted with one or more substituents
independently selected from R.sup.6;
[0045] each R.sup.2 is independently H, halogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.1-C.sub.6 haloalkylthio, C.sub.1-C.sub.6 alkylsulfinyl,
C.sub.1-C.sub.6 haloalkylsulfinyl, C, --C.sub.6 alkylsulfonyl,
C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.1-C.sub.6 alkylamino,
C.sub.2-C.sub.6 dialkylamino, C.sub.2-C.sub.4 alkoxycarbonyl, --CN
or --NO.sub.2;
[0046] each R.sup.3 is independently H, halogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.3-C.sub.6 halocycloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.1-C.sub.6 haloalkylthio, C.sub.1-C.sub.6 alkylsulfinyl,
C.sub.1-C.sub.6 haloalkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl,
C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.1-C.sub.6 alkylamino,
C.sub.2-C.sub.6 dialkylamino, --CN or --NO.sub.2;
[0047] R.sup.4 is H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.4-C.sub.7 alkylcycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl,
C.sub.2-C.sub.7 alkylcarbonyl or C.sub.2-C.sub.7
alkoxycarbonyl;
[0048] R.sup.5 is H, OR.sup.10, NR.sup.11R.sup.12 or Q.sup.1; or
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.4-C.sub.7
alkylcycloalkyl or C.sub.4-C.sub.7 cycloalkylalkyl, each optionally
substituted with one or more substituents independently selected
from R.sup.7; or
[0049] R.sup.4 and R.sup.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.sub.1-C.sub.2 alkyl, halogen, --CN, --NO.sub.2 and
C.sub.1-C.sub.2 alkoxy; each R.sup.6 is independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkylthio, C.sub.1-C.sub.6 alkylsulfinyl, C.sub.1-C.sub.6
alkylsulfonyl, --CN or --NO.sub.2;
[0050] each R.sup.7 is independently halogen; C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 alkylsulfinyl,
C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 alkylamino,
C.sub.2-C.sub.8 dialkylamino, C.sub.3-C.sub.6 cycloalkylamino,
C.sub.2-C.sub.7 alkylcarbonyl, C.sub.2-C.sub.7 alkoxycarbonyl,
C.sub.2-C.sub.7 alkylaminocarbonyl, C.sub.3-C.sub.9
dialkylaminocarbonyl, C.sub.2-C.sub.7 haloalkylcarbonyl,
C.sub.2-C.sub.7 haloalkoxycarbonyl, C.sub.2-C.sub.7
haloalkylaminocarbonyl, C.sub.3-C.sub.9 dihaloalkylaminocarbonyl,
hydroxy, --NH.sub.2, --CN or --NO.sub.2; or Q.sup.2;
[0051] each R.sup.8 is independently halogen, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.1-C.sub.6 haloalkylthio, C.sub.1-C.sub.6 alkylsulfinyl,
C.sub.1-C.sub.6 haloalkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl,
C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.1-C.sub.6 alkylamino,
C.sub.2-C.sub.6 dialkylamino, C.sub.2-C.sub.4 alkoxycarbonyl, --CN
or NO.sub.2;
[0052] each R.sup.9 is independently halogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.3-C.sub.6 halocycloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.1-C.sub.6 haloalkylthio, C.sub.1-C.sub.6 alkylsulfinyl,
C.sub.1-C.sub.6 haloalkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl,
C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.1-C.sub.6 alkylamino,
C.sub.2-C.sub.6 dialkylamino, --CN, --NO.sub.2, phenyl or
pyridinyl;
[0053] R.sup.10 is H; or C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.4-C.sub.7 alkylcycloalkyl or C.sub.4-C.sub.7 cycloalkylalkyl,
each optionally substituted with one of more halogen;
[0054] R.sup.11 is H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.4-C.sub.7 alkylcycloalkyl, C.sub.4-C.sub.7 cycloalkylalkyl,
C.sub.2-C.sub.7 alkylcarbonyl or C.sub.2-C.sub.7
alkoxycarbonyl;
[0055] R.sup.12 is H; Q.sup.3; or C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.4-C.sub.7 alkylcycloalkyl or C.sub.4-C.sub.7
cycloalkylalkyl, each optionally substituted with one or more
substituents independently selected from R.sup.7; or
[0056] R.sup.11 and R.sup.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.sub.1-C.sub.2 alkyl, halogen, --CN, --NO.sub.2 and
C.sub.1-C.sub.2 alkoxy;
[0057] Q.sup.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.sup.8;
[0058] each Q.sup.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.sup.9;
[0059] Q.sup.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.sup.9; and
[0060] n is 0, 1 or 2; or a pharmaceutically acceptable salt
thereof; and/or
[0061] ii) an isoxazoline compound of formula (II):
##STR00007##
[0062] wherein:
[0063] R.sub.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.sub.7S(O)--, R.sub.7S(O).sub.2--, R.sub.7C(O)--,
R.sub.7R.sub.8NC(O)--, R.sub.7OC(O)--, R.sub.7C(O)O--,
R.sub.7C(O)NR.sub.8--, --CN or --NO.sub.2;
[0064] 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.sub.7S(O)--, R.sub.7S(O).sub.2--, R.sub.7C(O)--,
R.sub.7R.sub.8NC(O)--, R.sub.7OC(O)--, R.sub.7C(O)O--,
R.sub.7C(O)NR.sub.8--, --CN or --NO.sub.2;
[0065] A.sub.1 is oxygen; and
[0066] A.sub.2 is oxygen, NR.sub.2 or CR.sub.7R.sub.8;
[0067] G is G-1 or G-2;
##STR00008##
[0068] B.sub.1, B.sub.2, B.sub.3, B.sub.4 and B.sub.5 are
independently N or C--R.sub.9;
[0069] 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.sub.7S(O)--, R.sub.7S(O).sub.2--, R.sub.7C(O)--,
R.sub.7R.sub.8NC(O)--, R.sub.7OC(O)--, R.sub.7C(O)O--,
R.sub.7C(O)NR.sub.8--, --CN or --NO.sub.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;
##STR00009## ##STR00010##
[0070] R.sub.2, R.sub.3 are independently hydrogen, alkyl,
haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl,
alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl,
R.sub.10S(O)--, R.sub.10S(O).sub.2--, R.sub.10C(O)--,
R.sub.10C(S)--, R.sub.10R.sub.11NC(O)--,
R.sub.10R.sub.11NC(S)--R.sub.10OC(O)--;
[0071] R.sub.4, R.sub.5 and R.sub.6 are independently hydrogen,
alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl,
alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,
cycloalkyl, aryl or heteroaryl;
[0072] R.sub.7 and R.sub.8 are independently hydrogen, alkyl,
haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl,
alkenyl, haloalkenyl, alkynyl or haloalkynyl;
[0073] R.sub.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.sub.7S(O)--, R.sub.7S(O).sub.2--,
R.sub.7C(O)--, R.sub.7R.sub.8NC(O)--, R.sub.7OC(O)--,
R.sub.7C(O)O--, R.sub.7C(O)NR.sub.8--, --CN or --NO.sub.2;
[0074] R.sub.10, R.sub.11, R.sub.12 and R.sub.13 are each
independently hydrogen, alkyl, haloalkyl, thioalkyl,
alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl,
alkynyl or haloalkynyl; or
[0075] R.sub.10 together with R.sub.11 form .dbd.O, .dbd.S or
.dbd.NR.sub.2; or
[0076] R.sub.12 together with R.sub.13 form .dbd.O, .dbd.S or
.dbd.NR.sub.2;
[0077] W is O, S or NR.sub.2;
[0078] n is 1-4; and
[0079] m is 0, 1 or 2; or a pharmaceutically acceptable salt
thereof; and/or [0080] iii) an isoxazoline compound of formula
(III)
##STR00011##
[0081] or a pharmaceutically acceptable salt thereof; and/or [0082]
iv) an isoxazoline compound of formula (IV)
##STR00012##
[0083] or a pharmaceutically acceptable salt thereof; and/or [0084]
v) an isoxazoline compound of formula (V):
##STR00013##
[0085] wherein R.sup.1, R.sup.2 and R.sup.3 are independently H,
Cl, F or CF.sub.3;
[0086] Y is the diradical group
##STR00014##
and
[0087] T is a C.sub.1-C.sub.6-alkyl group which is unsubstituted or
substituted by halogen, cyano, nitro, amino, hydroxyl,
C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy,
C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylthio, carboxy,
carbamoyl or C.sub.2-C.sub.6-alkanoyl group which may be
unsubstituted or substituted in the alkyl portion by halogen or a
pharmaceutical acceptable salt thereof; and/or [0088] vi) an
isoxazoline compound of formula (VI):
##STR00015##
[0089] wherein Y is hydrogen, fluoro, chloro or bromo; [0090]
R.sup.1 is phenyl substituted with 2-4 substituents selected from
halogen, methyl, difluoromethyl, trifluoromethyl, methoxy,
trifluoromethoxy or trifluoroethoxy; [0091] R.sup.2 is methyl,
fluoromethyl, trifluoromethyl or perfluoroethyl;
[0092] R.sup.3a and R.sup.3b are independently selected from
hydrogen, methyl, ethyl or fluoromethyl; or R.sup.3a and R.sup.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;
[0093] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0094] c) optionally, at least one co-solvent;
[0095] d) optionally, an antioxidant; and
[0096] e) optionally at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0097] wherein no other pharmaceutically acceptable polymers are
present.
[0098] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[0099] a) an antiparasitic effective amount of at least one
isoxazoline active agent, which is: [0100] i) an isoxazoline
compound of formula (I) as described above, or a pharmaceutically
acceptable salt thereof; and/or [0101] ii) an isoxazoline compound
of formula (II) as described above, or a pharmaceutically
acceptable salt thereof; and/or [0102] iii) an isoxazoline compound
of formula (III) as described above, or a pharmaceutically
acceptable salt thereof; and/or [0103] iv) an isoxazoline compound
of formula (IV) as described above, or a pharmaceutically
acceptable salt thereof; and/or [0104] v) an isoxazoline compound
of formula (V) as described above, or a pharmaceutically acceptable
salt thereof; and/or [0105] vi) an isoxazoline compound of formula
(VI) as described above, or a pharmaceutically acceptable salt
thereof;
[0106] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0107] c) optionally, at least one co-solvent wherein said
co-solvent is a polar solvent miscible with water;
[0108] d) optionally, an antioxidant; and
[0109] e) optionally at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0110] wherein no other pharmaceutically acceptable polymers are
present.
[0111] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[0112] a) an antiparasitic effective amount of at least one
isoxazoline active agent, which is: [0113] i) an isoxazoline
compound of formula (I) as described above, or a pharmaceutically
acceptable salt thereof; and/or [0114] ii) an isoxazoline compound
of formula (II) as described above, or a pharmaceutically
acceptable salt thereof; and/or [0115] iii) an isoxazoline compound
of formula (III) as described above, or a pharmaceutically
acceptable salt thereof; and/or [0116] iv) an isoxazoline compound
of formula (IV) as described above, or a pharmaceutically
acceptable salt thereof; and/or [0117] v) an isoxazoline compound
of formula (V) as described above, or a pharmaceutically acceptable
salt thereof; and/or [0118] vi) an isoxazoline compound of formula
(VI) as described above, or a pharmaceutically acceptable salt
thereof;
[0119] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0120] c) optionally, at least one co-solvent wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[0121] d) optionally, an antioxidant; and
[0122] e) optionally at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0123] wherein no other pharmaceutically acceptable polymers are
present.
[0124] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0125] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (I) as described above, or a
pharmaceutically acceptable salt thereof;
[0126] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0127] c) optionally, at least one co-solvent;
[0128] d) optionally, an antioxidant; and
[0129] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0130] wherein no other pharmaceutically acceptable polymers are
present.
[0131] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0132] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (I) as described above, or a
pharmaceutically acceptable salt thereof;
[0133] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0134] c) optionally, at least one co-solvent, wherein said
co-solvent is a polar solvent miscible with water;
[0135] d) optionally, an antioxidant; and
[0136] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0137] wherein no other pharmaceutically acceptable polymers are
present.
[0138] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[0139] a) an antiparasitic effective amount of at least one
isoxazoline active agent of formula (I) described above, or a
pharmaceutically acceptable salt thereof;
[0140] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0141] c) optionally, at least one co-solvent wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[0142] d) optionally, an antioxidant; and
[0143] e) optionally at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0144] wherein no other pharmaceutically acceptable polymers are
present.
[0145] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0146] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ia):
##STR00016## [0147] or a pharmaceutically acceptable salt
thereof
[0148] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0149] c) optionally, at least one co-solvent;
[0150] d) optionally, an antioxidant; and
[0151] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0152] wherein no other pharmaceutically acceptable polymers are
present.
[0153] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0154] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ia) as described above, or a
pharmaceutically acceptable salt thereof;
[0155] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0156] c) optionally, at least one co-solvent, wherein said
co-solvent is a polar solvent miscible with water;
[0157] d) optionally, an antioxidant; and
[0158] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0159] wherein no other pharmaceutically acceptable polymers are
present.
[0160] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising: [0161] a) an antiparasitic effective
amount of at least one isoxazoline compound of formula (Ia) as
described above, or a pharmaceutically acceptable salt thereof;
[0162] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0163] c) optionally, at least one co-solvent wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[0164] d) optionally, an antioxidant; and
[0165] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0166] wherein no other pharmaceutically acceptable polymers are
present.
[0167] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0168] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ia) as described above, or a
pharmaceutically acceptable salt thereof;
[0169] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0170] c) optionally, a co-solvent, wherein the co-solvent is a
C.sub.1-C.sub.6alcohol, a glycol ether (e.g., including, but
limited to, diethyleneglycol monoethyl ether, butyl diglycol,
dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether,
ethyleneglycol monomethyl ether, dipropylene glycol monomethyl
ether, propylene glycol monomethyl ether, propylene glycol
monoethyl ether, and the like), glycerol, propylene glycol, cyclic
carbonates (e.g., propylene carbonate), 2-pyrrolidone,
N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,
dimethylsulfoxide or glycerol formal, or a combination thereof;
[0171] d) optionally, an antioxidant; and
[0172] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0173] wherein no other pharmaceutically acceptable polymers are
present.
[0174] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0175] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ia) as described above, or a
pharmaceutically acceptable salt thereof;
[0176] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0177] c) optionally, a co-solvent, wherein the co-solvent is
benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids,
C.sub.8-C.sub.10 triglycerides (e.g. MIGLYOL.RTM. 810 and
MIGLYOL.RTM. 812), C.sub.8-C.sub.10 triglycerides combined with
linoleic acid (e.g. MIGLYOL.RTM. 818), C.sub.8-C.sub.10
triglycerides combined with succinic acid (e.g. MIGLYOL.RTM. 829),
propylene glycol diester of C.sub.8-C.sub.10 fatty acids (e.g.
MIGLYOL.RTM. 840), castor oil, cottonseed oil, sesame oil, soybean
oil and safflower oil, or a combination thereof;
[0178] d) optionally, an antioxidant; and
[0179] e) optionally, a surfactant, and optionally at least one
other pharmaceutically acceptable additive, excipient or mixtures
thereof;
[0180] wherein no other pharmaceutically acceptable polymers are
present.
[0181] In still another embodiment, the present invention provides
for a long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0182] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ia) as described above, or a
pharmaceutically acceptable salt thereof;
[0183] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0184] c) optionally, a co-solvent, wherein the co-solvent is a
C.sub.1-C.sub.6alcohol, benzyl alcohol, or a combination
thereof;
[0185] d) optionally, an antioxidant; and
[0186] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0187] wherein no other pharmaceutically acceptable polymers are
present.
[0188] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0189] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ia) as described above, or a
pharmaceutically acceptable salt thereof;
[0190] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0191] c) optionally, a co-solvent, wherein the co-solvent is
ethanol, isopropanol, benzyl alcohol, or a combination thereof;
[0192] d) optionally, an antioxidant; and
[0193] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0194] wherein no other pharmaceutically acceptable polymers are
present.
[0195] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0196] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ia) as described above, or a
pharmaceutically acceptable salt thereof;
[0197] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0198] c) optionally, at least one co-solvent wherein said
co-solvent is a C.sub.8-C.sub.10 triglyceride, benzyl alcohol, or a
combination thereof;
[0199] d) optionally, an antioxidant; and
[0200] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0201] wherein no other pharmaceutically acceptable polymers are
present.
[0202] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0203] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ia) as described above, or a
pharmaceutically acceptable salt thereof;
[0204] b) at least one neutral oil, wherein said neutral oil is a
C.sub.8-C.sub.10 triglyceride;
[0205] c) optionally, at least one co-solvent wherein said
co-solvent is ethanol, isopropanol, benzyl alcohol, or a
combination thereof;
[0206] d) optionally, an antioxidant; and
[0207] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0208] wherein no other pharmaceutically acceptable polymers are
present.
[0209] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0210] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ib):
##STR00017##
[0211] or a pharmaceutically acceptable salt thereof wherein
[0212] R.sup.2 independently is halogen, C.sub.1-C.sub.6 alkyl or
C.sub.1-C.sub.6 haloalkyl
[0213] R.sup.4 is H or C.sub.1-C.sub.6 alkyl;
[0214] R.sup.5 is C.sub.1-C.sub.4 alkyl optionally substituted with
one or more R.sup.7; and R.sup.7 is C.sub.2-C.sub.7 alkylcarbonyl,
C.sub.2-C.sub.7 alkoxycarbonyl, C.sub.2-C.sub.7 alkylaminocarbonyl,
C.sub.3-C.sub.9 dialkylaminocarbonyl, C.sub.2-C.sub.7
haloalkylcarbonyl, C.sub.2-C.sub.7 haloalkoxycarbonyl,
C.sub.2-C.sub.7 haloalkylaminocarbonyl, C.sub.3-C.sub.9
dihaloalkylaminocarbonyl (e.g., --CH.sub.2C(O)NHCH.sub.2CF.sub.3);
and
[0215] n is 0, 1 or 2;
[0216] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0217] c) optionally, at least one co-solvent;
[0218] d) optionally, an antioxidant; and
[0219] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0220] wherein no other pharmaceutically acceptable polymers are
present.
[0221] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0222] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ib) as described above, or a
pharmaceutically acceptable salt thereof;
[0223] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0224] c) optionally, at least one co-solvent, wherein said
co-solvent is a polar solvent miscible with water;
[0225] d) optionally, an antioxidant; and
[0226] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0227] wherein no other pharmaceutically acceptable polymers are
present.
[0228] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0229] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ib) as described above, or a
pharmaceutically acceptable salt thereof;
[0230] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0231] c) optionally, at least one co-solvent, wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[0232] d) optionally, an antioxidant; and
[0233] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0234] wherein no other pharmaceutically acceptable polymers are
present.
[0235] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0236] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ib) as described above, or a
pharmaceutically acceptable salt thereof;
[0237] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0238] c) optionally, a co-solvent, wherein the co-solvent is a
C.sub.1-C.sub.6alcohol, a glycol ether (e.g., including, but
limited to, diethyleneglycol monoethyl ether, butyl diglycol,
dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether,
ethyleneglycol monomethyl ether, dipropylene glycol monomethyl
ether, propylene glycol monomethyl ether, propylene glycol
monoethyl ether, and the like), glycerol, propylene glycol, cyclic
carbonates (e.g., propylene carbonate), 2-pyrrolidone,
N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,
dimethylsulfoxide or glycerol formal, or a combination thereof;
[0239] d) optionally, an antioxidant; and
[0240] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0241] wherein no other pharmaceutically acceptable polymers are
present.
[0242] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0243] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (lb) as described above, or a
pharmaceutically acceptable salt thereof;
[0244] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0245] c) optionally, a co-solvent, wherein the co-solvent is
benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids,
C.sub.8-C.sub.10 triglycerides (e.g. MIGLYOL.RTM. 810 and
MIGLYOL.RTM. 812), C.sub.8-C.sub.10 triglycerides combined with
linoleic acid (e.g. MIGLYOL.RTM. 818), C.sub.8-C.sub.10
triglycerides combined with succinic acid (e.g. MIGLYOL.RTM. 829),
propylene glycol diester of C.sub.8-C.sub.10 fatty acids (e.g.
MIGLYOL.RTM. 840), castor oil, cottonseed oil, sesame oil, soybean
oil and safflower oil, or a combination thereof;
[0246] d) optionally, an antioxidant; and
[0247] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0248] wherein no other pharmaceutically acceptable polymers are
present.
[0249] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0250] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (lb) as described above, or a
pharmaceutically acceptable salt thereof;
[0251] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0252] c) optionally, a co-solvent, wherein the co-solvent is a
C.sub.1-C.sub.6alcohol, benzyl alcohol, or a combination
thereof;
[0253] d) optionally, an antioxidant; and
[0254] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0255] wherein no other pharmaceutically acceptable polymers are
present.
[0256] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0257] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (lb) as described above, or a
pharmaceutically acceptable salt thereof;
[0258] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0259] c) optionally, a co-solvent, wherein the co-solvent is
ethanol, isopropanol, benzyl alcohol, or a combination thereof;
[0260] d) optionally, an antioxidant; and
[0261] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0262] wherein no other pharmaceutically acceptable polymers are
present.
[0263] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0264] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ib) as described above, or a
pharmaceutically acceptable salt thereof;
[0265] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0266] c) optionally, at least one co-solvent wherein said
co-solvent is a C.sub.8-C.sub.10 triglyceride, benzyl alcohol, or a
combination thereof;
[0267] d) optionally, an antioxidant; and
[0268] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0269] wherein no other pharmaceutically acceptable polymers are
present.
[0270] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0271] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ib) as described above, or a
pharmaceutically acceptable salt thereof;
[0272] b) at least one neutral oil, wherein said neutral oil is a
C.sub.8-C.sub.10 triglyceride;
[0273] c) optionally, at least one co-solvent wherein said
co-solvent is ethanol, isopropanol, benzyl alcohol, or a
combination thereof;
[0274] d) optionally, an antioxidant; and
[0275] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0276] wherein no other pharmaceutically acceptable polymers are
present.
[0277] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0278] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (II) as described above, or a
pharmaceutically acceptable salt thereof, [0279] b) at least one
pharmaceutically acceptable polymer which is a liquid PEG and/or a
pharmaceutically acceptable neutral oil;
[0280] c) optionally, at least one co-solvent;
[0281] d) optionally, an antioxidant; and
[0282] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0283] wherein no other pharmaceutically acceptable polymers are
present.
[0284] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0285] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (II) as described above, or a
pharmaceutically acceptable salt thereof;
[0286] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0287] c) optionally, at least one co-solvent, wherein said
co-solvent is a polar solvent miscible with water;
[0288] d) optionally, an antioxidant; and
[0289] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0290] wherein no other pharmaceutically acceptable polymers are
present.
[0291] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0292] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (II) as described above, or a
pharmaceutically acceptable salt thereof;
[0293] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0294] c) optionally, at least one co-solvent wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[0295] d) optionally, an antioxidant; and
[0296] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0297] wherein no other pharmaceutically acceptable polymers are
present.
[0298] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0299] a) an antiparasitic effective amount of at least one
isoxazoline compound of formulae II-1.001 to 11-1.025 or
II-2.00-11-2.018:
##STR00018##
TABLE-US-00001 Compounds II-1.001 to II-1.025 Compound No.
(Z).sub.p B.sup.5 B.sup.4 B.sup.3 B.sup.2 B.sup.1 R.sup.15 R.sup.16
1.001 3,5-Cl.sub.2 C--H C--H C--H C--H N H
CH.sub.2C(O)NHCH.sub.2CF.sub.3 1.002 3,5-Cl.sub.2 C--H C--H C--H
C--H N H CH.sub.2CF.sub.3 1.003 3,5-(CF.sub.3).sub.2 C--H C--H C--H
C--H N CH.sub.3 CH.sub.2CO.sub.2CH.sub.3 1.004 3,5-(CF.sub.3).sub.2
C--H C--H C--H C--H N CH.sub.3 CH.sub.2CO.sub.2H 1.005
3,5-(CF.sub.3).sub.2 C--H C--H C--H C--H N CH.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 1.006 3,5-(CF.sub.3).sub.2 C--H C--H
C--H C--H N H CH.sub.2C(O)NHCH.sub.2CF.sub.3 1.007
3,5-(CF.sub.3).sub.2 C--H C--H C--H C--H N H
CH.sub.2CH.sub.2SCH.sub.3 1.008 3,5-(CF.sub.3).sub.2 C--H C--H C--H
C--H C--H H CH.sub.2C(O)NHCH.sub.2CF.sub.3 1.009
3,5-(CF.sub.3).sub.2 C--H C--H C--H C--H C--H H
CH.sub.2CH.sub.2SCH.sub.3 1.010 3,5-(CF.sub.3).sub.2 C--H C--H C--H
C--H C--H H CH.sub.2CF.sub.3 1.011 3,5-Cl.sub.2 C--H C--H C--H C--H
C--H H CH.sub.2C(O)NHCH.sub.2CF.sub.3 1.012 3,5-Cl.sub.2 C--H C--H
C--H C--H C--H H CH.sub.2CF.sub.3 1.013 3,5-Cl.sub.2 C--H C--H C--H
C--H C--H H CH.sub.2CH.sub.2SCH.sub.3 1.014 3-Cl,5-CF.sub.3 C--H
C--H C--H C--H C--H H CH.sub.2C(O)NHCH.sub.2CF.sub.3 1.015
3-Cl,5-CF.sub.3 C--H C--H C--H C--H C--H H CH.sub.2CF.sub.3 1.016
3-Cl,5-CF.sub.3 C--H C--H C--H C--H C--H H
CH.sub.2CH.sub.2SCH.sub.3 1.017 3,5-Cl.sub.2 C--H C--H C--Me C--H
C--Me H CH.sub.2C(O)NHCH.sub.2CF.sub.3 1.018 3,5-Cl.sub.2 C--H C--H
C--Me C--H C--Me H CH.sub.2CF.sub.3 1.019 3,5-Cl.sub.2 C--H C--H
C--Me C--H C--Me H CH.sub.2CH.sub.2SCH.sub.3 1.020
3,5-(CF.sub.3).sub.2 C--H C--H C--Me C--H C--Me H
CH.sub.2C(O)NHCH.sub.2CF.sub.3 1.021 3,5-(CF.sub.3).sub.2 C--H C--H
C--Me C--H C--Me H CH.sub.2CF.sub.3 1.022 3,5-(CF.sub.3).sub.2 C--H
C--H C--Me C--H C--Me H CH.sub.2CH.sub.2SCH.sub.3 1.023
3-Cl,5-CF.sub.3 C--H C--H C--Me C--H C--Me H
CH.sub.2C(O)NHCH.sub.2CF.sub.3 1.024 3-Cl,5-CF.sub.3 C--H C--H
C--Me C--H C--Me H CH.sub.2CF.sub.3 1.025 3-Cl,5-CF.sub.3 C--H C--H
C--Me C--H C--Me H CH.sub.2CH.sub.2SCH.sub.3
##STR00019##
TABLE-US-00002 Compounds II-2.001 to II-2.018 Compound No.
(Z).sub.p B.sup.5 B.sup.4 B.sup.3 B.sup.2 B.sup.1 R.sup.15 R.sup.16
2.001 3,5-Cl.sub.2 C--H C--H N C--H C--H H
CH.sub.2C(O)NHCH.sub.2CF.sub.3 2.002 3,5-Cl.sub.2 C--H C--H N C--H
C--H H CH.sub.2CF.sub.3 2.003 3,5-Cl.sub.2 C--H C--H N C--H C--H H
CH.sub.2CH.sub.2SCH.sub.3 2.004 3,5-(CF.sub.3).sub.2 C--H C--H N
C--H C--H H CH.sub.2C(O)NHCH.sub.2CF.sub.3 2.005
3,5-(CF.sub.3).sub.2 C--H C--H N C--H C--H H CH.sub.2CF.sub.3 2.006
3,5-(CF.sub.3).sub.2 C--H C--H N C--H C--H H
CH.sub.2CH.sub.2SCH.sub.3 2.007 3-Cl,5-CF.sub.3 C--H C--H N C--H
C--H H CH.sub.2C(O)NHCH.sub.2CF.sub.3 2.008 3-Cl,5-CF.sub.3 C--H
C--H N C--H C--H H CH.sub.2CF.sub.3 2.009 3-Cl,5-CF.sub.3 C--H C--H
N C--H C--H H CH.sub.2CH.sub.2SCH.sub.3 2.010 3,5-Cl.sub.2 C--H
C--H C--H C--H C--H H CH.sub.2C(O)NHCH.sub.2CF.sub.3 2.011
3,5-Cl.sub.2 C--H C--H C--H C--H C--H H CH.sub.2CF.sub.3 2.012
3,5-Cl.sub.2 C--H C--H C--H C--H C--H H CH.sub.2CH.sub.2SCH.sub.3
2.013 3,5-(CF.sub.3).sub.2 C--H C--H C--H C--H C--H H
CH.sub.2C(O)NHCH.sub.2CF.sub.3 2.014 3,5-(CF.sub.3).sub.2 C--H C--H
C--H C--H C--H H CH.sub.2CF.sub.3 2.015 3,5-(CF.sub.3).sub.2 C--H
C--H C--H C--H C--H H CH.sub.2CH.sub.2SCH.sub.3 2.016
3-Cl,5-CF.sub.3 C--H C--H C--H C--H C--H H
CH.sub.2C(O)NHCH.sub.2CF.sub.3 2.017 3-Cl,5-CF.sub.3 C--H C--H C--H
C--H C--H H CH.sub.2CF.sub.3 2.018 3-Cl,5-CF.sub.3 C--H C--H C--H
C--H C--H H CH.sub.2CH.sub.2SCH.sub.3
[0300] or a pharmaceutically acceptable salt thereof;
[0301] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0302] c) optionally, at least one co-solvent;
[0303] d) optionally, an antioxidant; and
[0304] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof.
[0305] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0306] a) an antiparasitic effective amount of at least one
isoxazoline compound of formulae II-1.001 to 11-1.025 or
II-2.00-11-2.018 as described above, or a pharmaceutically
acceptable salt thereof;
[0307] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0308] c) optionally, at least one co-solvent, wherein said
co-solvent is a polar solvent miscible with water;
[0309] d) optionally, an antioxidant; and
[0310] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0311] wherein no other pharmaceutically acceptable polymers are
present.
[0312] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising: [0313] a) an antiparasitic effective
amount of at least one isoxazoline compound of formulae II-1.001 to
II-1.025 or II-2.00-II-2.018 as described above, or a
pharmaceutically acceptable salt thereof;
[0314] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0315] c) optionally, at least one co-solvent wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[0316] d) optionally, an antioxidant; and
[0317] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0318] wherein no other pharmaceutically acceptable polymers are
present.
[0319] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0320] a) an antiparasitic effective amount of an isoxazoline
compound of formula (III)
##STR00020##
[0321] or a pharmaceutically acceptable salt thereof;
[0322] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0323] c) optionally at least one co-solvent;
[0324] d) optionally, an antioxidant; and
[0325] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0326] wherein no other pharmaceutically acceptable polymers are
present.
[0327] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0328] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (III) as described above, or a
pharmaceutically acceptable salt thereof;
[0329] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0330] c) optionally, at least one co-solvent, wherein said
co-solvent is a polar solvent miscible with water;
[0331] d) optionally, an antioxidant; and
[0332] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0333] wherein no other pharmaceutically acceptable polymers are
present.
[0334] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0335] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (III) as described above, or a
pharmaceutically acceptable salt thereof;
[0336] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0337] c) optionally, at least one co-solvent wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[0338] d) optionally, an antioxidant; and
[0339] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0340] wherein no other pharmaceutically acceptable polymers are
present.
[0341] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0342] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (III) as described above, or a
pharmaceutically acceptable salt thereof;
[0343] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0344] c) optionally, a co-solvent, wherein the co-solvent is a
C.sub.1-C.sub.6alcohol, a glycol ether (e.g., including, but
limited to, diethyleneglycol monoethyl ether, butyl diglycol,
dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether,
ethyleneglycol monomethyl ether, dipropylene glycol monomethyl
ether, propylene glycol monomethyl ether, propylene glycol
monoethyl ether, and the like), glycerol, propylene glycol, cyclic
carbonates (e.g., propylene carbonate), 2-pyrrolidone,
N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,
dimethylsulfoxide or glycerol formal, or a combination thereof;
[0345] d) optionally, an antioxidant; and
[0346] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0347] wherein no other pharmaceutically acceptable polymers are
present.
[0348] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising: [0349] a) an antiparasitic effective
amount of at least one isoxazoline compound of formula (III) as
described above, or a pharmaceutically acceptable salt thereof;
[0350] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0351] c) optionally, a co-solvent, wherein the co-solvent is
benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids,
C.sub.8-C.sub.10 triglycerides (e.g. MIGLYOL.RTM. 810 and
MIGLYOL.RTM. 812),
[0352] C.sub.8-C.sub.10 triglycerides combined with linoleic acid
(e.g. MIGLYOL.RTM. 818), C.sub.8-C.sub.10 triglycerides combined
with succinic acid (e.g. MIGLYOL.RTM. 829), propylene glycol
diester of C.sub.8-C.sub.10 fatty acids (e.g. MIGLYOL.RTM. 840),
castor oil, cottonseed oil, sesame oil, soybean oil and safflower
oil, or a combination thereof;
[0353] d) optionally, an antioxidant; and
[0354] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0355] wherein no other pharmaceutically acceptable polymers are
present.
[0356] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0357] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (III) as described above, or a
pharmaceutically acceptable salt thereof;
[0358] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0359] c) optionally, at least one co-solvent wherein said
co-solvent is a C.sub.1-C.sub.6alcohol, benzyl alcohol, or a
combination thereof;
[0360] d) optionally, an antioxidant; and
[0361] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0362] wherein no other pharmaceutically acceptable polymers are
present.
[0363] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0364] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (III) as described above, or a
pharmaceutically acceptable salt thereof;
[0365] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0366] c) optionally, at least one co-solvent wherein said
co-solvent is ethanol, isopropanol, benzyl alcohol, or a
combination thereof;
[0367] d) optionally, an antioxidant; and
[0368] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0369] wherein no other pharmaceutically acceptable polymers are
present.
[0370] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0371] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (III) as described above, or a
pharmaceutically acceptable salt thereof;
[0372] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0373] c) optionally, at least one co-solvent wherein said
co-solvent is a C.sub.8-C.sub.10 triglyceride, benzyl alcohol, or a
combination thereof;
[0374] d) optionally, an antioxidant; and
[0375] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0376] wherein no other pharmaceutically acceptable polymers are
present.
[0377] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0378] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (III) as described above, or a
pharmaceutically acceptable salt thereof;
[0379] b) at least one neutral oil, wherein said neutral oil is a
C.sub.8-C.sub.10 triglyceride;
[0380] c) optionally, at least one co-solvent wherein said
co-solvent is ethanol, isopropanol, benzyl alcohol, or a
combination thereof;
[0381] d) optionally, an antioxidant; and
[0382] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0383] wherein no other pharmaceutically acceptable polymers are
present.
[0384] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising: [0385] iv) an antiparasitic effective
amount of an isoxazoline compound of formula (IV) as described
above, or a pharmaceutically acceptable salt thereof;
[0386] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0387] c) optionally at least one co-solvent;
[0388] d) optionally, an antioxidant; and
[0389] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0390] wherein no other pharmaceutically acceptable polymers are
present.
[0391] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0392] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (IV) as described above, or a
pharmaceutically acceptable salt thereof;
[0393] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0394] c) optionally, at least one co-solvent, wherein said
co-solvent is a polar solvent miscible with water;
[0395] d) optionally, an antioxidant; and
[0396] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0397] wherein no other pharmaceutically acceptable polymers are
present.
[0398] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising: [0399] a) an antiparasitic effective
amount of at least one isoxazoline compound of formula (IV) as
described above, or a pharmaceutically acceptable salt thereof;
[0400] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0401] c) optionally, at least one co-solvent wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[0402] d) optionally, an antioxidant; and
[0403] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0404] wherein no other pharmaceutically acceptable polymers are
present.
[0405] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0406] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (IV) as described above, or a
pharmaceutically acceptable salt thereof;
[0407] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0408] c) optionally, a co-solvent, wherein the co-solvent is a
C.sub.1-C.sub.6alcohol, a glycol ether (e.g., including, but
limited to, diethyleneglycol monoethyl ether, butyl diglycol,
dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether,
ethyleneglycol monomethyl ether, dipropylene glycol monomethyl
ether, propylene glycol monomethyl ether, propylene glycol
monoethyl ether, and the like), glycerol, propylene glycol, cyclic
carbonates (e.g., propylene carbonate), 2-pyrrolidone,
N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,
dimethylsulfoxide or glycerol formal, or a combination thereof;
[0409] d) optionally, an antioxidant; and
[0410] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0411] wherein no other pharmaceutically acceptable polymers are
present.
[0412] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0413] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (IV) as described above, or a
pharmaceutically acceptable salt thereof;
[0414] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0415] c) optionally, a co-solvent, wherein the co-solvent is
benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids,
C.sub.8-C.sub.10 triglycerides (e.g. MIGLYOL.RTM. 810 and
MIGLYOL.RTM. 812), C.sub.8-C.sub.10 triglycerides combined with
linoleic acid (e.g. MIGLYOL.RTM. 818), C.sub.8-C.sub.10
triglycerides combined with succinic acid (e.g. MIGLYOL.RTM. 829),
propylene glycol diester of C.sub.8-C.sub.10 fatty acids (e.g.
MIGLYOL.RTM. 840), castor oil, cottonseed oil, sesame oil, soybean
oil and safflower oil, or a combination thereof;
[0416] d) optionally, an antioxidant; and
[0417] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0418] wherein no other pharmaceutically acceptable polymers are
present.
[0419] In still another embodiment, the present invention provides
for a long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0420] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (IV) as described above, or a
pharmaceutically acceptable salt thereof;
[0421] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0422] c) optionally, a co-solvent, wherein the co-solvent is a
C.sub.1-C.sub.6alcohol, benzyl alcohol, or a combination
thereof;
[0423] d) optionally, an antioxidant; and
[0424] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0425] wherein no other pharmaceutically acceptable polymers are
present.
[0426] In still another embodiment, the present invention provides
for a long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0427] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (IV) as described above, or a
pharmaceutically acceptable salt thereof;
[0428] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0429] c) optionally, a co-solvent, wherein the co-solvent is
ethanol, isopropanol, benzyl alcohol, or a combination thereof;
[0430] d) optionally, an antioxidant; and
[0431] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0432] wherein no other pharmaceutically acceptable polymers are
present.
[0433] In still another embodiment, the present invention provides
for a long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0434] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (IV) as described above, or a
pharmaceutically acceptable salt thereof;
[0435] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0436] c) optionally, at least one co-solvent wherein said
co-solvent is a C.sub.8-C.sub.10 triglyceride, benzyl alcohol, or a
combination thereof;
[0437] d) optionally, an antioxidant; and
[0438] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0439] wherein no other pharmaceutically acceptable polymers are
present.
[0440] In still another embodiment, the present invention provides
for a long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0441] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (IV) as described above, or a
pharmaceutically acceptable salt thereof;
[0442] b) at least one neutral oil, wherein said neutral oil is a
C.sub.8-C.sub.10 triglyceride;
[0443] c) optionally, at least one co-solvent wherein said
co-solvent is ethanol, isopropanol, benzyl alcohol, or a
combination thereof;
[0444] d) optionally, an antioxidant; and
[0445] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0446] wherein no other pharmaceutically acceptable polymers are
present.
[0447] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising: [0448] a) an antiparasitic effective
amount of at least one isoxazoline compound of formula (V) as
described above, or a pharmaceutically acceptable salt thereof;
[0449] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0450] c) optionally, at least one co-solvent;
[0451] d) optionally, an antioxidant; and
[0452] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0453] wherein no other pharmaceutically acceptable polymers are
present.
[0454] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0455] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (V) as described above, or a
pharmaceutically acceptable salt thereof;
[0456] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0457] c) optionally, at least one co-solvent, wherein said
co-solvent is a polar solvent miscible with water;
[0458] d) optionally, an antioxidant; and
[0459] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0460] wherein no other pharmaceutically acceptable polymers are
present.
[0461] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0462] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (V) as described above, or a
pharmaceutically acceptable salt thereof;
[0463] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0464] c) optionally, at least one co-solvent, wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[0465] d) optionally, an antioxidant; and
[0466] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0467] wherein no other pharmaceutically acceptable polymers are
present.
[0468] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising
[0469] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Va):
##STR00021##
[0470] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0471] c) optionally, at least one co-solvent;
[0472] d) optionally, an antioxidant; and
[0473] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
wherein no other pharmaceutically acceptable polymers are
present.
[0474] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising: [0475] a) an antiparasitic effective
amount of at least one isoxazoline compound of formula (Va) as
described above, or a pharmaceutically acceptable salt thereof;
[0476] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0477] c) optionally, at least one co-solvent, wherein said
co-solvent is a polar solvent miscible with water;
[0478] d) optionally, an antioxidant; and
[0479] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
wherein no other pharmaceutically acceptable polymers are
present.
[0480] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0481] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Va) as described above, or a
pharmaceutically acceptable salt thereof;
[0482] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0483] c) optionally, at least one co-solvent wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[0484] d) optionally, an antioxidant; and
[0485] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
wherein no other pharmaceutically acceptable polymers are
present.
[0486] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0487] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Va) as described above, or a
pharmaceutically acceptable salt thereof;
[0488] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0489] c) optionally, a co-solvent, wherein the co-solvent is a
C.sub.1-C.sub.6alcohol, a glycol ether (e.g., including, but
limited to, diethyleneglycol monoethyl ether, butyl diglycol,
dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether,
ethyleneglycol monomethyl ether, dipropylene glycol monomethyl
ether, propylene glycol monomethyl ether, propylene glycol
monoethyl ether, and the like), glycerol, propylene glycol, cyclic
carbonates (e.g., propylene carbonate), 2-pyrrolidone,
N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,
dimethylsulfoxide or glycerol formal, or a combination thereof;
[0490] d) optionally, an antioxidant; and [0491] e) optionally, at
least one pharmaceutically acceptable additive, excipient or
mixtures thereof; wherein no other pharmaceutically acceptable
polymers are present.
[0492] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0493] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Va) as described above, or a
pharmaceutically acceptable salt thereof;
[0494] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0495] c) optionally, a co-solvent, wherein the co-solvent is
benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids,
C.sub.8-C.sub.10 triglycerides (e.g. MIGLYOL.RTM. 810 and
MIGLYOL.RTM. 812), C.sub.8-C.sub.10 triglycerides combined with
linoleic acid (e.g. MIGLYOL.RTM. 818), C.sub.8-C.sub.10
triglycerides combined with succinic acid (e.g. MIGLYOL.RTM. 829),
propylene glycol diester of C.sub.8-C.sub.10 fatty acids (e.g.
MIGLYOL.RTM. 840), castor oil, cottonseed oil, sesame oil, soybean
oil and safflower oil, or a combination thereof;
[0496] d) optionally, an antioxidant; and
[0497] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
wherein no other pharmaceutically acceptable polymers are
present.
[0498] In still another embodiment, the present invention provides
for a long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0499] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Va) as described above, or a
pharmaceutically acceptable salt thereof;
[0500] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0501] c) optionally, a co-solvent, wherein the co-solvent is a
C.sub.1-C.sub.6alcohol, benzyl alcohol, or a combination
thereof;
[0502] d) optionally, an antioxidant; and
[0503] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
wherein no other pharmaceutically acceptable polymers are
present.
[0504] In still another embodiment, the present invention provides
for a long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0505] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Va) as described above, or a
pharmaceutically acceptable salt thereof;
[0506] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0507] c) optionally, a co-solvent, wherein the co-solvent is
ethanol, isopropanol, benzyl alcohol, or a combination thereof;
[0508] d) optionally, an antioxidant; and
[0509] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
wherein no other pharmaceutically acceptable polymers are
present.
[0510] In still another embodiment, the present invention provides
for a long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0511] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Va) as described above, or a
pharmaceutically acceptable salt thereof;
[0512] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0513] c) optionally, at least one co-solvent wherein said
co-solvent is a C.sub.8-C.sub.10 triglyceride, benzyl alcohol, or a
combination thereof;
[0514] d) optionally, an antioxidant; and
[0515] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
wherein no other pharmaceutically acceptable polymers are
present.
[0516] In still another embodiment, the present invention provides
for a long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0517] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Va) as described above, or a
pharmaceutically acceptable salt thereof;
[0518] b) at least one neutral oil, wherein said neutral oil is a
C.sub.8-C.sub.10 triglyceride;
[0519] c) optionally, at least one co-solvent wherein said
co-solvent is ethanol, isopropanol, benzyl alcohol, or a
combination thereof;
[0520] d) optionally, an antioxidant; and
[0521] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
wherein no other pharmaceutically acceptable polymers are
present.
[0522] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising
[0523] a) an antiparasitic effective amount of at least one
compound of formula (VI) as described above, or a pharmaceutically
acceptable salt thereof;
[0524] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0525] c) optionally, at least one co-solvent;
[0526] d) optionally, an antioxidant; and
[0527] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
wherein no other pharmaceutically acceptable polymers are
present.
[0528] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0529] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (VI) as described above, or a
pharmaceutically acceptable salt thereof;
[0530] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0531] c) optionally, at least one co-solvent, wherein said
co-solvent is a polar solvent miscible with water;
[0532] d) optionally, an antioxidant; and
[0533] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
wherein no other pharmaceutically acceptable polymers are
present.
[0534] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0535] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (VI) as described above, or a
pharmaceutically acceptable salt thereof;
[0536] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0537] c) optionally, at least one co-solvent wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[0538] d) optionally, an antioxidant; and
[0539] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
wherein no other pharmaceutically acceptable polymers are
present.
[0540] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0541] a) an antiparasitic effective amount of at least one
compound of formula (VIa):
##STR00022##
[0542] or a pharmaceutically acceptable salt thereof;
[0543] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0544] c) optionally, at least one co-solvent;
[0545] d) optionally, an antioxidant; and
[0546] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
wherein no other pharmaceutically acceptable polymers are
present.
[0547] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0548] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (VIa) as described above, or a
pharmaceutically acceptable salt thereof;
[0549] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0550] c) optionally, at least one co-solvent, wherein said
co-solvent is a polar solvent miscible with water;
[0551] d) optionally, an antioxidant; and
[0552] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
wherein no other pharmaceutically acceptable polymers are
present.
[0553] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0554] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (VIa) as described above, or a
pharmaceutically acceptable salt thereof;
[0555] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0556] c) optionally, at least one co-solvent wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[0557] d) optionally, an antioxidant; and
[0558] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
wherein no other pharmaceutically acceptable polymers are
present.
[0559] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0560] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (VIa) as described above, or a
pharmaceutically acceptable salt thereof;
[0561] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0562] c) optionally, a co-solvent, wherein the co-solvent is a
C.sub.1-C.sub.6alcohol, a glycol ether (e.g., including, but
limited to, diethyleneglycol monoethyl ether, butyl diglycol,
dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether,
ethyleneglycol monomethyl ether, dipropylene glycol monomethyl
ether, propylene glycol monomethyl ether, propylene glycol
monoethyl ether, and the like), glycerol, propylene glycol, cyclic
carbonates (e.g., propylene carbonate), 2-pyrrolidone,
N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,
dimethylsulfoxide or glycerol formal, or a combination thereof;
[0563] d) optionally, an antioxidant; and
[0564] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
wherein no other pharmaceutically acceptable polymers are
present.
[0565] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0566] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (VIa) as described above, or a
pharmaceutically acceptable salt thereof;
[0567] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0568] c) optionally, a co-solvent, wherein the co-solvent is
benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids,
C.sub.8-C.sub.10 triglycerides (e.g. MIGLYOL.RTM. 810 and
MIGLYOL.RTM. 812), C.sub.8-C.sub.10 triglycerides combined with
linoleic acid (e.g. MIGLYOL.RTM. 818), C.sub.8-C.sub.10
triglycerides combined with succinic acid (e.g. MIGLYOL.RTM. 829),
propylene glycol diester of C.sub.8-C.sub.10 fatty acids (e.g.
MIGLYOL.RTM. 840), castor oil, cottonseed oil, sesame oil, soybean
oil and safflower oil, or a combination thereof;
[0569] d) optionally, an antioxidant; and
[0570] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0571] wherein no other pharmaceutically acceptable polymers are
present.
[0572] In still another embodiment, the present invention provides
for a long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0573] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (VIa) as described above, or a
pharmaceutically acceptable salt thereof;
[0574] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0575] c) optionally, a co-solvent, wherein the co-solvent is a
C.sub.1-C.sub.6alcohol, benzyl alcohol, or a combination
thereof;
[0576] d) optionally, an antioxidant; and
[0577] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
wherein no other pharmaceutically acceptable polymers are
present.
[0578] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0579] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (VIa) as described above, or a
pharmaceutically acceptable salt thereof;
[0580] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0581] c) optionally, at least one co-solvent wherein said
co-solvent is ethanol, isopropanol, benzyl alcohol, or a
combination thereof;
[0582] d) optionally, an antioxidant; and
[0583] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
wherein no other pharmaceutically acceptable polymers are
present.
[0584] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0585] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (VIa) as described above, or a
pharmaceutically acceptable salt thereof;
[0586] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0587] c) optionally, at least one co-solvent wherein said
co-solvent is a C.sub.8-C.sub.10 triglyceride, benzyl alcohol, or a
combination thereof;
[0588] d) optionally, an antioxidant; and
[0589] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
wherein no other pharmaceutically acceptable polymers are
present.
[0590] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0591] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (VIa) as described above, or a
pharmaceutically acceptable salt thereof;
[0592] b) at least one neutral oil, wherein said neutral oil is a
C.sub.8-C.sub.10 triglyceride;
[0593] c) optionally, at least one co-solvent wherein said
co-solvent is ethanol, isopropanol, benzyl alcohol, or a
combination thereof;
[0594] d) optionally, an antioxidant; and
[0595] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
wherein no other pharmaceutically acceptable polymers are
present.
[0596] In another embodiment, the long-acting injectable
compositions of present invention comprise an antiparasitic
effective amount of at least one isoxazoline of formula (Ib), which
has the formula:
##STR00023##
[0597] or a pharmaceutically acceptable salt thereof
[0598] wherein
[0599] R.sup.2 independently is halogen, C.sub.1-C.sub.6 alkyl or
C.sub.1-C.sub.6 haloalkyl
[0600] R.sup.4 is H or C.sub.1-C.sub.6 alkyl;
[0601] R.sup.5 is C.sub.1-C.sub.4 alkyl optionally substituted with
one or more R.sup.7; and R.sup.7 is C.sub.2-C.sub.7 alkylcarbonyl,
C.sub.2-C.sub.7 alkoxycarbonyl, C.sub.2-C.sub.7 alkylaminocarbonyl,
C.sub.3-C.sub.9 dialkylaminocarbonyl, C.sub.2-C.sub.7
haloalkylcarbonyl, C.sub.2-C.sub.7 haloalkoxycarbonyl,
C.sub.2-C.sub.7 haloalkylaminocarbonyl, C.sub.3-C.sub.9
dihaloalkylaminocarbonyl (e.g., --CH.sub.2C(O)NHCH.sub.2CF.sub.3);
and
[0602] n is 0, 1 or 2.
[0603] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0604] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic):
##STR00024##
[0605] or a pharmaceutically acceptable salt thereof
[0606] wherein
[0607] X.sup.1, X.sup.2 and X.sup.3 are each independently H,
halogen, C.sub.1-C.sub.3alkyl or C.sub.1-C.sub.3haloalkyl;
[0608] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0609] c) optionally, at least one co-solvent;
[0610] d) optionally, an antioxidant; and
[0611] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0612] wherein no other pharmaceutically acceptable polymers are
present.
[0613] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0614] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ic) as described above, or a
pharmaceutically acceptable salt thereof;
[0615] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0616] c) optionally, at least one co-solvent, wherein said
co-solvent is a polar solvent miscible with water;
[0617] d) optionally, an antioxidant; and
[0618] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0619] wherein no other pharmaceutically acceptable polymers are
present.
[0620] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0621] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ic) as described above, or a
pharmaceutically acceptable salt thereof;
[0622] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0623] c) optionally, at least one co-solvent wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[0624] d) optionally, an antioxidant; and
[0625] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0626] wherein no other pharmaceutically acceptable polymers are
present.
[0627] In one embodiment, the long-acting injectable compositions
of the invention comprise a compound of formula (Ic) wherein
X.sup.1 and X.sup.3 are independently halogen and X.sup.2 is
hydrogen.
[0628] In another embodiment, the long-acting injectable
compositions of the invention comprise a compound of formula (Ic),
wherein X.sup.1, X.sup.2 and X.sup.3 are each independently
halogen.
[0629] In another embodiment of the invention, the long-acting
injectable compositions comprise a compound of formula (Ic),
wherein X.sup.1 and X.sup.3 are each independently halogen and
X.sup.2 is C.sub.1-C.sub.3haloalkyl.
[0630] In still another embodiment, the invention provides a
long-acting injectable composition comprising a compound of formula
(Ic), wherein X.sup.1 and X.sup.2 are independently halogen and
X.sup.3 is C.sub.1-C.sub.3haloalkyl.
[0631] In another embodiment, the invention provides a long-acting
injectable composition comprising a compound of formula (Ic),
wherein X.sup.1 and X.sup.2 are independently halogen and X.sup.3
is
[0632] CF.sub.3.
[0633] In another embodiment, the invention provides a long-acting
injectable composition comprising a compound of formula (Ic),
wherein X.sup.1 and X.sup.3 are chloro and X.sup.2 is hydrogen.
[0634] In yet another embodiment, the invention provides a
long-acting injectable composition comprising a compound of formula
(Ic), wherein X.sup.1 is chloro, X.sup.2 is fluoro and X.sup.3 is
CF.sub.3.
[0635] In another embodiment, the invention provides a long-acting
injectable composition comprising a compound of formula (Ic),
wherein X.sup.1 and X.sup.3 are chloro and X.sup.2 is fluoro.
[0636] In another embodiment, the long-acting injectable
compositions of present invention comprise an antiparasitic
effective amount of
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-naphthalan-
ecarboxamide (Compound of formula Ia).
[0637] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0638] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic):
##STR00025##
[0639] or a pharmaceutically acceptable salt thereof
[0640] wherein
[0641] X.sup.1 and X.sup.3 are each independently halogen or
C.sub.1-C.sub.3haloalkyl; and
[0642] X.sup.2 is halogen or hydrogen; [0643] b) at least one
pharmaceutically acceptable polymer which is a liquid PEG and/or a
pharmaceutically acceptable neutral oil;
[0644] c) optionally, at least one co-solvent;
[0645] d) optionally, an antioxidant; and
[0646] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0647] wherein no other pharmaceutically acceptable polymers are
present.
[0648] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0649] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) shown above, or a pharmaceutically
acceptable salt thereof,
[0650] wherein
[0651] X.sup.1 and X.sup.3 are each independently halogen or
C.sub.1-C.sub.3haloalkyl; and
[0652] X.sup.2 is halogen or hydrogen;
[0653] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0654] c) optionally, at least one co-solvent, wherein said
co-solvent is a polar solvent miscible with water;
[0655] d) optionally, an antioxidant; and
[0656] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0657] wherein no other pharmaceutically acceptable polymers are
present.
[0658] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0659] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ic) as described above, or a
pharmaceutically acceptable salt thereof;
[0660] wherein
[0661] X.sup.1 and X.sup.3 are each independently halogen or
C.sub.1-C.sub.3haloalkyl; and
[0662] X.sup.2 is halogen or hydrogen;
[0663] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0664] c) optionally, at least one co-solvent wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[0665] d) optionally, an antioxidant; and
[0666] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0667] wherein no other pharmaceutically acceptable polymers are
present.
[0668] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0669] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as shown above, or a pharmaceutically
acceptable salt thereof,
[0670] wherein
[0671] X.sup.1 and X.sup.2 are each independently chloro or fluoro;
and
[0672] X.sup.3 is chloro or CF.sub.3;
[0673] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0674] c) optionally, at least one co-solvent;
[0675] d) optionally, an antioxidant; and
[0676] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0677] wherein no other pharmaceutically acceptable polymers are
present.
[0678] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising: [0679] a) an antiparasitic effective
amount of an isoxazoline compound of formula (Ic) as shown above,
or a pharmaceutically acceptable salt thereof,
[0680] wherein
[0681] X.sup.1 and X.sup.2 are each independently chloro or fluoro;
and
[0682] X.sup.3 is chloro or CF.sub.3;
[0683] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0684] c) optionally, at least one co-solvent, wherein said
co-solvent is a polar solvent that is miscible with water;
[0685] d) optionally, an antioxidant; and
[0686] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0687] wherein no other pharmaceutically acceptable polymers are
present.
[0688] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0689] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ic) as described above, or a
pharmaceutically acceptable salt thereof;
[0690] wherein
[0691] X.sup.1 and X.sup.2 are each independently chloro or fluoro;
and
[0692] X.sup.3 is chloro or CF.sub.3;
[0693] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0694] c) optionally, at least one co-solvent wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[0695] d) optionally, an antioxidant; and
[0696] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0697] wherein no other pharmaceutically acceptable polymers are
present.
[0698] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0699] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ic) as described above, or a
pharmaceutically acceptable salt thereof;
[0700] wherein
[0701] X.sup.1 and X.sup.2 are each independently chloro or fluoro;
and
[0702] X.sup.3 is chloro or CF.sub.3;
[0703] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0704] c) optionally, a co-solvent, wherein the co-solvent is a
C.sub.1-C.sub.6alcohol, a glycol ether (e.g., including, but
limited to, diethyleneglycol monoethyl ether, butyl diglycol,
dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether,
ethyleneglycol monomethyl ether, dipropylene glycol monomethyl
ether, propylene glycol monomethyl ether, propylene glycol
monoethyl ether, and the like), glycerol, propylene glycol, cyclic
carbonates (e.g., propylene carbonate), 2-pyrrolidone,
N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,
dimethylsulfoxide or glycerol formal, or a combination thereof;
[0705] d) optionally, an antioxidant; and
[0706] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0707] wherein no other pharmaceutically acceptable polymers are
present.
[0708] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0709] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ic) as described above, or a
pharmaceutically acceptable salt thereof;
[0710] wherein
[0711] X.sup.1 and X.sup.2 are each independently chloro or fluoro;
and
[0712] X.sup.3 is chloro or CF.sub.3;
[0713] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0714] c) optionally, a co-solvent, wherein the co-solvent is
benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids,
C.sub.8-C.sub.10 triglycerides (e.g. MIGLYOL.RTM. 810 and
MIGLYOL.RTM. 812), C.sub.8-C.sub.10 triglycerides combined with
linoleic acid (e.g. MIGLYOL.RTM. 818), C.sub.8-C.sub.10
triglycerides combined with succinic acid (e.g. MIGLYOL.RTM. 829),
propylene glycol diester of C.sub.8-C.sub.10 fatty acids (e.g.
MIGLYOL.RTM. 840), castor oil, cottonseed oil, sesame oil, soybean
oil and safflower oil, or a combination thereof;
[0715] d) optionally, an antioxidant; and
[0716] e) optionally, at least one surfactant and/or at least one
additional pharmaceutically acceptable additive, excipient or
mixtures thereof;
[0717] wherein no other pharmaceutically acceptable polymers are
present.
[0718] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0719] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ic) as described above, or a
pharmaceutically acceptable salt thereof;
[0720] wherein
[0721] X.sup.1 and X.sup.2 are each independently chloro or fluoro;
and
[0722] X.sup.3 is chloro or CF.sub.3;
[0723] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0724] c) optionally, at least one co-solvent wherein said
co-solvent is a C.sub.8-C.sub.10 triglyceride, benzyl alcohol, or a
combination thereof;
[0725] d) optionally, an antioxidant; and
[0726] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0727] wherein no other pharmaceutically acceptable polymers are
present.
[0728] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0729] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ic) as described above, or a
pharmaceutically acceptable salt thereof;
[0730] wherein
[0731] X.sup.1 and X.sup.2 are each independently chloro or fluoro;
and X.sup.3 is chloro or CF.sub.3; [0732] b) at least one neutral
oil, wherein said neutral oil is a C.sub.8-C.sub.10 triglyceride;
c) optionally, at least one co-solvent wherein said co-solvent is
ethanol, isopropanol, benzyl alcohol, or a combination thereof;
[0733] d) optionally, an antioxidant; and
[0734] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0735] wherein no other pharmaceutically acceptable polymers are
present.
[0736] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0737] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as shown above, or a pharmaceutically
acceptable salt thereof
[0738] wherein
[0739] X.sup.1 and X.sup.3 are each chloro; and
[0740] X.sup.2 is fluoro or hydrogen; [0741] b) at least one
pharmaceutically acceptable polymer which is a liquid PEG and/or a
pharmaceutically acceptable neutral oil;
[0742] c) optionally, at least one co-solvent;
[0743] d) optionally, an antioxidant; and
[0744] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0745] wherein no other pharmaceutically acceptable polymers are
present.
[0746] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0747] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as shown above, or a pharmaceutically
acceptable salt thereof,
[0748] wherein
[0749] X.sup.1 and X.sup.3 are each chloro; and
[0750] X.sup.2 is fluoro or hydrogen;
[0751] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0752] c) optionally, at least one co-solvent, wherein said
co-solvent is a polar solvent that is miscible with water;
[0753] d) optionally, an antioxidant; and
[0754] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0755] wherein no other pharmaceutically acceptable polymers are
present.
[0756] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0757] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ic) as described above, or a
pharmaceutically acceptable salt thereof;
[0758] wherein
[0759] X.sup.1 and X.sup.3 are each chloro; and
[0760] X.sup.2 is fluoro or hydrogen;
[0761] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0762] c) optionally, at least one co-solvent wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[0763] d) optionally, an antioxidant; and
[0764] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0765] wherein no other pharmaceutically acceptable polymers are
present.
[0766] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0767] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as shown above,
[0768] or a pharmaceutically acceptable salt thereof,
[0769] wherein
[0770] X.sup.1 is chloro;
[0771] X.sup.2 is fluoro; and
[0772] X.sup.3 is CF.sub.3;
[0773] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0774] c) optionally, at least one co-solvent;
[0775] d) optionally, an antioxidant; and
[0776] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0777] wherein no other pharmaceutically acceptable polymers are
present.
[0778] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0779] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as described above, or a pharmaceutically
acceptable salt thereof,
[0780] wherein
[0781] X.sup.1 is chloro;
[0782] X.sup.2 is fluoro; and
[0783] X.sup.3 is CF.sub.3;
[0784] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0785] c) optionally, at least one co-solvent, wherein said
co-solvent is a polar solvent that is miscible with water;
[0786] d) optionally, an antioxidant; and
[0787] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0788] wherein no other pharmaceutically acceptable polymers are
present.
[0789] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0790] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ic) as described above, or a
pharmaceutically acceptable salt thereof;
[0791] wherein
[0792] X.sup.1 is chloro;
[0793] X.sup.2 is fluoro; and
[0794] X.sup.3 is CF.sub.3;
[0795] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0796] c) optionally, at least one co-solvent wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[0797] d) optionally, an antioxidant; and
[0798] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0799] wherein no other pharmaceutically acceptable polymers are
present.
[0800] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0801] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ic) as described above, or a
pharmaceutically acceptable salt thereof;
[0802] wherein
[0803] X.sup.1 is chloro;
[0804] X.sup.2 is fluoro; and
[0805] X.sup.3 is CF.sub.3;
[0806] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0807] c) optionally, a co-solvent, wherein the co-solvent is a
C.sub.1-C.sub.6alcohol, a glycol ether (e.g., including, but
limited to, diethyleneglycol monoethyl ether, butyl diglycol,
dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether,
ethyleneglycol monomethyl ether, dipropylene glycol monomethyl
ether, propylene glycol monomethyl ether, propylene glycol
monoethyl ether, and the like), glycerol, propylene glycol, cyclic
carbonates (e.g., propylene carbonate), 2-pyrrolidone,
N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,
dimethylsulfoxide or glycerol formal, or a combination thereof;
[0808] d) optionally, an antioxidant; and
[0809] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0810] wherein no other pharmaceutically acceptable polymers are
present.
[0811] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0812] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ic) as described above, or a
pharmaceutically acceptable salt thereof;
[0813] wherein
[0814] X.sup.1 is chloro;
[0815] X.sup.2 is fluoro; and
[0816] X.sup.3 is CF.sub.3;
[0817] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0818] c) optionally, a co-solvent, wherein the co-solvent is
benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids,
C.sub.8-C.sub.10 triglycerides (e.g. MIGLYOL.RTM. 810 and
MIGLYOL.RTM. 812), C.sub.8-C.sub.10 triglycerides combined with
linoleic acid (e.g. MIGLYOL.RTM. 818), C.sub.8-C.sub.10
triglycerides combined with succinic acid (e.g. MIGLYOL.RTM. 829),
propylene glycol diester of C.sub.8-C.sub.10 fatty acids (e.g.
MIGLYOL.RTM. 840), castor oil, cottonseed oil, sesame oil, soybean
oil and safflower oil, or a combination thereof;
[0819] d) optionally, an antioxidant; and
[0820] e) optionally, at least one surfactant and optionally at
least one additional pharmaceutically acceptable additive,
excipient or mixtures thereof;
[0821] wherein no other pharmaceutically acceptable polymers are
present.
[0822] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0823] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ic) as described above, or a
pharmaceutically acceptable salt thereof;
[0824] wherein
[0825] X.sup.1 is chloro;
[0826] X.sup.2 is fluoro; and
[0827] X.sup.3 is CF.sub.3;
[0828] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0829] c) optionally, at least one co-solvent wherein said
co-solvent is a C.sub.1-C.sub.6alcohol, benzyl alcohol, or a
combination thereof;
[0830] d) optionally, an antioxidant; and
[0831] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0832] wherein no other pharmaceutically acceptable polymers are
present.
[0833] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0834] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ic) as described above, or a
pharmaceutically acceptable salt thereof;
[0835] wherein
[0836] X.sup.1 is chloro;
[0837] X.sup.2 is fluoro; and
[0838] X.sup.3 is CF.sub.3;
[0839] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0840] c) optionally, at least one co-solvent wherein said
co-solvent is ethanol, isopropanol, benzyl alcohol, or a
combination thereof;
[0841] d) optionally, an antioxidant; and
[0842] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0843] wherein no other pharmaceutically acceptable polymers are
present.
[0844] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0845] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ic) as described above, or a
pharmaceutically acceptable salt thereof;
[0846] wherein
[0847] X.sup.1 is chloro;
[0848] X.sup.2 is fluoro; and
[0849] X.sup.3 is CF.sub.3;
[0850] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0851] c) optionally, at least one co-solvent wherein said
co-solvent is a C.sub.8-C.sub.10 triglyceride, benzyl alcohol, or a
combination thereof;
[0852] d) optionally, an antioxidant; and
[0853] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0854] wherein no other pharmaceutically acceptable polymers are
present.
[0855] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0856] a) an antiparasitic effective amount of at least one
isoxazoline compound of formula (Ic) as described above, or a
pharmaceutically acceptable salt thereof;
[0857] wherein
[0858] X.sup.1 is chloro;
[0859] X.sup.2 is fluoro; and
[0860] X.sup.3 is CF.sub.3;
[0861] b) at least one neutral oil, wherein said neutral oil is a
C.sub.8-C.sub.10 triglyceride;
[0862] c) optionally, at least one co-solvent wherein said
co-solvent is ethanol, isopropanol, benzyl alcohol, or a
combination thereof;
[0863] d) optionally, an antioxidant; and
[0864] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0865] wherein no other pharmaceutically acceptable polymers are
present.
[0866] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0867] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as shown above, or a pharmaceutically
acceptable salt thereof,
[0868] wherein
[0869] X.sup.1 and X.sup.3 are chloro; and
[0870] X.sup.2 is fluoro;
[0871] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0872] c) optionally, at least one co-solvent;
[0873] d) optionally, an antioxidant; and
[0874] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0875] wherein no other pharmaceutically acceptable polymers are
present.
[0876] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0877] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as described above, or a pharmaceutically
acceptable salt thereof;
[0878] wherein
[0879] X.sup.1 and X.sup.3 are chloro; and
[0880] X.sup.2 is fluoro;
[0881] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0882] c) optionally, at least one co-solvent, wherein said
co-solvent is a polar solvent that is miscible with water;
[0883] d) optionally, an antioxidant; and
[0884] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0885] wherein no other pharmaceutically acceptable polymers are
present.
[0886] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0887] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as described above, or a pharmaceutically
acceptable salt thereof
[0888] wherein
[0889] X.sup.1 and X.sup.3 are chloro; and
[0890] X.sup.2 is fluoro;
[0891] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0892] c) optionally, at least one co-solvent wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[0893] d) optionally, an antioxidant; and
[0894] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0895] wherein no other pharmaceutically acceptable polymers are
present.
[0896] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0897] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as described above, or a pharmaceutically
acceptable salt thereof
[0898] wherein
[0899] X.sup.1 and X.sup.3 are chloro; and
[0900] X.sup.2 is fluoro;
[0901] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0902] c) optionally, a co-solvent, wherein the co-solvent is a
C.sub.1-C.sub.6alcohol, a glycol ether (e.g., including, but
limited to, diethyleneglycol monoethyl ether, butyl diglycol,
dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether,
ethyleneglycol monomethyl ether, dipropylene glycol monomethyl
ether, propylene glycol monomethyl ether, propylene glycol
monoethyl ether, and the like), glycerol, propylene glycol, cyclic
carbonates (e.g., propylene carbonate), 2-pyrrolidone,
N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,
dimethylsulfoxide or glycerol formal, or a combination thereof;
[0903] d) optionally, an antioxidant; and
[0904] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0905] wherein no other pharmaceutically acceptable polymers are
present.
[0906] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0907] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as described above, or a pharmaceutically
acceptable salt thereof
[0908] wherein
[0909] X.sup.1 and X.sup.3 are chloro; and
[0910] X.sup.2 is fluoro;
[0911] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0912] c) optionally, a co-solvent, wherein the co-solvent is
benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids,
C.sub.8-C.sub.10 triglycerides (e.g. MIGLYOL.RTM. 810 and
MIGLYOL.RTM. 812), C.sub.8-C.sub.10 triglycerides combined with
linoleic acid (e.g. MIGLYOL.RTM. 818), C.sub.8-C.sub.10
triglycerides combined with succinic acid (e.g. MIGLYOL.RTM. 829),
propylene glycol diester of C.sub.8-C.sub.10 fatty acids (e.g.
MIGLYOL.RTM. 840), castor oil, cottonseed oil, sesame oil, soybean
oil and safflower oil, or a combination thereof;
[0913] d) optionally, an antioxidant; and
[0914] e) optionally, at least one surfactant, and optionally at
least one additional pharmaceutically acceptable additive,
excipient or mixtures thereof;
[0915] wherein no other pharmaceutically acceptable polymers are
present.
[0916] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0917] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as described above, or a pharmaceutically
acceptable salt thereof
[0918] wherein
[0919] X.sup.1 and X.sup.3 are chloro; and
[0920] X.sup.2 is fluoro;
[0921] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0922] c) optionally, at least one co-solvent wherein said
co-solvent is a C.sub.8-C.sub.10 triglyceride, benzyl alcohol, or a
combination thereof;
[0923] d) optionally, an antioxidant; and
[0924] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0925] wherein no other pharmaceutically acceptable polymers are
present.
[0926] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0927] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as described above, or a pharmaceutically
acceptable salt thereof
[0928] wherein
[0929] X.sup.1 and X.sup.3 are chloro; and
[0930] X.sup.2 is fluoro; [0931] b) at least one neutral oil,
wherein said neutral oil is a C.sub.8-C.sub.10 triglyceride;
[0932] c) optionally, at least one co-solvent wherein said
co-solvent is ethanol, isopropanol, benzyl alcohol, or a
combination thereof;
[0933] d) optionally, an antioxidant; and
[0934] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0935] wherein no other pharmaceutically acceptable polymers are
present.
[0936] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0937] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as shown above,
[0938] or a pharmaceutically acceptable salt thereof,
[0939] wherein
[0940] X.sup.1, X.sup.2 and X.sup.3 are each chloro;
[0941] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0942] c) optionally, at least one co-solvent;
[0943] d) optionally, an antioxidant; and
[0944] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0945] wherein no other pharmaceutically acceptable polymers are
present.
[0946] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0947] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as described above, or a pharmaceutically
acceptable salt thereof wherein
[0948] X.sup.1, X.sup.2 and X.sup.3 are each chloro;
[0949] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0950] c) optionally, at least one co-solvent, wherein said
co-solvent is a polar solvent that is miscible with water;
[0951] d) optionally, an antioxidant; and
[0952] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0953] wherein no other pharmaceutically acceptable polymers are
present.
[0954] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0955] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as described above, or a pharmaceutically
acceptable salt thereof
[0956] wherein
[0957] X.sup.1, X.sup.2 and X.sup.3 are each chloro;
[0958] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0959] c) optionally, at least one co-solvent wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[0960] d) optionally, an antioxidant; and
[0961] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0962] wherein no other pharmaceutically acceptable polymers are
present.
[0963] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0964] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as described above, or a pharmaceutically
acceptable salt thereof
[0965] wherein
[0966] X.sup.1, X.sup.2 and X.sup.3 are each chloro;
[0967] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0968] c) optionally, a co-solvent, wherein the co-solvent is a
C.sub.1-C.sub.6alcohol, a glycol ether (e.g., including, but
limited to, diethyleneglycol monoethyl ether, butyl diglycol,
dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether,
ethyleneglycol monomethyl ether, dipropylene glycol monomethyl
ether, propylene glycol monomethyl ether, propylene glycol
monoethyl ether, and the like), glycerol, propylene glycol, cyclic
carbonates (e.g., propylene carbonate), 2-pyrrolidone,
N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,
dimethylsulfoxide or glycerol formal, or a combination thereof;
[0969] d) optionally, an antioxidant; and
[0970] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0971] wherein no other pharmaceutically acceptable polymers are
present.
[0972] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0973] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as described above, or a pharmaceutically
acceptable salt thereof
[0974] wherein
[0975] X.sup.1, X.sup.2 and X.sup.3 are each chloro;
[0976] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[0977] c) optionally, a co-solvent, wherein the co-solvent is
benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids,
C.sub.8-C.sub.10 triglycerides (e.g. MIGLYOL.RTM. 810 and
MIGLYOL.RTM. 812), C.sub.8-C.sub.10 triglycerides combined with
linoleic acid (e.g. MIGLYOL.RTM. 818), C.sub.8-C.sub.10
triglycerides combined with succinic acid (e.g. MIGLYOL.RTM. 829),
propylene glycol diester of C.sub.8-C.sub.10 fatty acids (e.g.
MIGLYOL.RTM. 840), castor oil, cottonseed oil, sesame oil, soybean
oil and safflower oil, or a combination thereof;
[0978] d) optionally, an antioxidant; and
[0979] e) optionally, at least one surfactant, and optionally at
least one additional pharmaceutically acceptable additive,
excipient or mixtures thereof;
[0980] wherein no other pharmaceutically acceptable polymers are
present.
[0981] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0982] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as described above, or a pharmaceutically
acceptable salt thereof
[0983] wherein
[0984] X.sup.1, X.sup.2 and X.sup.3 are each chloro; [0985] b) at
least one pharmaceutically acceptable polymer which is a liquid PEG
and/or a neutral oil; [0986] c) optionally, a co-solvent, wherein
the co-solvent is a C.sub.1-C.sub.6alcohol, benzyl alcohol, or a
combination thereof;
[0987] d) optionally, an antioxidant; and
[0988] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0989] wherein no other pharmaceutically acceptable polymers are
present.
[0990] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[0991] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as shown above,
[0992] or a pharmaceutically acceptable salt thereof,
[0993] wherein
[0994] X.sup.1, X.sup.2 and X.sup.3 are each independently chloro
or fluoro;
[0995] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[0996] c) optionally, at least one co-solvent;
[0997] d) optionally, an antioxidant; and
[0998] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[0999] wherein no other pharmaceutically acceptable polymers are
present.
[1000] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[1001] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as described above, or a pharmaceutically
acceptable salt thereof
[1002] wherein
[1003] X.sup.1, X.sup.2 and X.sup.3 are each independently chloro
or fluoro;
[1004] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[1005] c) optionally, at least one co-solvent, wherein said
co-solvent is a polar solvent that is miscible with water;
[1006] d) optionally, an antioxidant; and
[1007] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[1008] wherein no other pharmaceutically acceptable polymers are
present.
[1009] In another embodiment, the present invention provides for a
long-acting injectable composition for the treatment and/or
prevention (prophylaxis) of parasitic infections and infestations
in or on animals comprising:
[1010] a) an antiparasitic effective amount of an isoxazoline
compound of formula (Ic) as described above, or a pharmaceutically
acceptable salt thereof
[1011] wherein
[1012] X.sup.1, X.sup.2 and X.sup.3 are each independently chloro
or fluoro;
[1013] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG and/or a pharmaceutically acceptable neutral oil;
[1014] c) optionally, at least one co-solvent wherein said
co-solvent is not miscible with water or only partially soluble in
water;
[1015] d) optionally, an antioxidant; and
[1016] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof;
[1017] wherein no other pharmaceutically acceptable polymers are
present.
[1018] The compounds of formula (I) through formula (VIa) can exist
as stereoisomers, and each individual stereoisomer present are
encompassed by the structural formulas depicted herein. The various
stereoisomers include enantiomers, diastereomers and atop isomers.
For avoidance of doubt, when an isoxazoline compound (e.g. any of
the isoxazoline active agents as described herein) includes two or
more stereoisomers (e.g. an (S)- and (R)-enantiomers), the formulae
depicted herein that does not explicitly include stereochemical
configurations encompasses each of the possible stereoisomers. One
of skill in the art will understand that one stereoisomer of an
active isoxazoline compound may be more active and/or may exhibit
beneficial properties relative to the other enantiomer. In
addition, the skilled person in the art knows how to separate,
enrich, and/or selectively prepare a stereoisomer of the
isoxazoline compounds described herein. The isoxazoline compounds
described herein contain a chiral quaternary carbon atom in the
five-membered isoxazoline ring (shown by the asterisk (*) in the
structures below); therefore, the compounds will contain at least
two possible stereoisomers. As an example for the compounds of
formula (Ia), the two possible stereoisomers resulting from the
quaternary carbon are shown as formulae (S)-Ia and (R)-Ia:
##STR00026##
[1019] The compound of formula (S)-Ia above has the (S)
configuration at the chiral carbon atom and the compound of formula
(R)-Ia has the (R) configuration. Molecular depictions drawn herein
follow standard conventions for depicting stereochemistry. To
indicate stereo configuration, bonds rising from the plane of the
drawing and towards the viewer are denoted by solid wedges wherein
the broad end of the wedge is attached to the atom rising from the
plane of the drawing towards the viewer. Bonds going below the
plane of the drawing and away from the viewer are denoted by dashed
wedges wherein the narrow end of the wedge is attached to the atom
further away from the viewer. Constant width lines indicate bonds
with a direction opposite or neutral relative to bonds shown with
solid or dashed wedges; constant width lines also depict bonds in
molecules or parts of molecules in which no particular stereo
configuration is intended to be specified.
[1020] In one embodiment of the invention, the more biologically
active enantiomer is believed to be formula (S)-Ia. Similarly, the
more biologically active enantiomers of isoxazoline compounds of
formula (Ib), (Ic) and (II) to (VIa) are believed to have the (S)
configuration at the chiral carbon of the isoxazoline ring. In
certain embodiments, an isoxazoline compound of the invention, or
compositions comprising the compound, are enriched in an enantiomer
that displays significant in vitro and in vivo activity (the
eutomer) with a favorable toxicity profile relative to a compound
or a composition enriched with the other corresponding enantiomer
that displays significantly less in vitro and in vivo activity (the
distomer).
[1021] When enantiomerically enriched, one enantiomer is present in
greater amounts than the other, and the extent of enrichment may be
defined by an expression of enantiomeric excess ("ee"), which is
defined as (2.times.-1). 100%, where x is the mole fraction of the
dominant enantiomer in the mixture (e.g., an ee of 20% corresponds
to a 60:40 ratio of enantiomers). In some embodiments, the
compositions of the invention comprise compounds that have at least
a 50% enantiomeric excess. In other embodiments, the compositions
of the invention comprise compounds that have at least a 75%
enantiomeric excess, at least a 90% enantiomeric excess, or at
least a 94% enantiomeric excess of the more active isomer. Of
particular note are enantiomerically pure embodiments of the more
active isomer (the eutomer).
[1022] Compounds of this invention may also exist as one or more
conformational isomers due to restricted rotation about the amide
bond bonded to the aryl or heteroaryl ring (e.g. the amide bonded
to the naphthyl group in formula (I)). This invention comprises
mixtures of conformational isomers. In addition, this invention
includes compounds that are enriched in one conformer relative to
others.
[1023] It will be appreciated that in addition to the compounds of
formula (Ia), the other isoxazoline compounds of formula (I),
formula (Ib), formula (Ic), formula (II), formula (II-1.1001) to
formula (II-1.025), formula (II-2.001) to formula (II-018), formula
(III), formula (IV), formula (V), formula (Va), formula (VI) and
formula (VIa) will also have at least two possible enantiomers as a
result of the quaternary carbon atom on the isoxazoline ring. In
addition, certain compounds may include other chiral centers in one
or more sub stituents.
[1024] This invention comprises racemic mixtures, for example,
equal amounts of the enantiomers of formulae (I) to (VIa). The
invention also includes compounds of formula (I), formula (Ia),
formula (Ib), formula (Ic), formula (II), formula (II-1.1001) to
formula (II-1.025), formula (II-2.001) to formula (II-018), formula
(III), formula (IV), formula (V), formula (Va), formula (VI) or
formula (VIa), that are enriched in one enantiomer compared to the
racemic mixture. Also included are the essentially pure enantiomers
of the compounds of formula (I), formula (Ia), formula (Ib),
formula (Ic), formula (II), formula (II-1.1001) to formula
(II-1.025), formula (II-2.001) to formula (II-018), formula (III),
formula (IV), formula (V), formula (Va), formula (VI) or formula
(VIa).
[1025] Hence, in one embodiment, the long-acting injectable
compositions of present invention comprise an antiparasitic
effective amount of at least one isoxazoline of formula (I),
formula (Ia), formula (Ib), formula (Ic), formula (II), formula
(II-1.1001) to formula (II-1.025), formula (II-2.001) to formula
(II-018), formula (III), formula (IV), formula (V), formula (Va),
formula (VI) or formula (VIa), which is substantially enriched in
one enantiomer, or a pharmaceutically acceptable salt thereof. The
term "substantially enriched" means that the compound is enriched
in a weight:weight ratio of at least about 1.5 or higher in favor
of the desired enantiomer. In another embodiment, the long-acting
compositions of the invention comprise at least one isoxazoline
compound of formula (I), formula (Ia), formula (Ib), formula (Ic),
formula (II), formula (II-1.1001) to formula (II-1.025), formula
(II-2.001) to formula (II-018), formula (III), formula (IV),
formula (V), formula (Va), formula (VI) or formula (VIa) that are
enriched in one enantiomer in a weight:weight ratio of at least
2:1, at least 5:1 or at least 10:1. In another embodiment, the
compositions comprise at least one compound of formula (I), formula
(Ia), formula (Ib), formula (Ic), formula (II), formula (II-1.1001)
to formula (II-1.025), formula (II-2.001) to formula (II-018),
formula (III), formula (IV), formula (V), formula (Va), formula
(VI) or formula (VIa), which is enriched in one enantiomer in a
weight:weight ratio of at least 15:1 or at least 20:1, or a
pharmaceutically acceptable salt thereof. In an embodiment, the
isoxazoline compounds of formula (I), formula (Ia), formula (Ib),
formula (Ic), formula (II), formula (II-1.1001) to formula
(II-1.025), formula (II-2.001) to formula (II-018), formula (III),
formula (IV), formula (V), formula (Va), formula (VI) or formula
(VIa) present in the compositions of the invention are essentially
pure enantiomers.
[1026] In another embodiment of the invention, the compositions
comprise a compound of formula (I), formula (Ia), formula (Ib),
formula (Ic), formula (II), formula (II-1.1001) to formula
(II-1.025), formula (II-2.001) to formula (II-018), formula (III),
formula (IV), formula (V), formula (Va), formula (VI) or formula
(VIa), that is enriched in the (S)-enantiomer in a weight:weight
ratio is at least approximately 1.5:1 or 2:1. In yet another
embodiment, the compositions of the invention comprise a compound
of formula (I), formula (Ia), formula (Ib), formula (Ic), formula
(II), formula (II-1.1001) to formula (II-1.025), formula (II-2.001)
to formula (II-018), formula (III), formula (IV), formula (V),
formula (Va), formula (VI) or formula (VIa), that is enriched in
the (S)-enantiomer in a weight:weight ratio of at least about 5:1
or greater. In still another embodiment, the compositions of the
invention comprise a compound of formula (I), formula (Ia), formula
(Ib), formula (Ic), formula (II), formula (II-1.1001) to formula
(II-1.025), formula (II-2.001) to formula (II-018), formula (III),
formula (IV), formula (V), formula (Va), formula (VI) or formula
(VIa), that is enriched in the (S)-enantiomer in a weight:weight
ratio of at least approximately 10:1, 20:1, or greater. In still
another embodiment, the compositions of the invention comprise a
compound of formula (I), formula (Ia), formula (Ib), formula (Ic),
formula (II), formula (II-1.1001) to formula (II-1.025), formula
(II-2.001) to formula (II-018), formula (III), formula (IV),
formula (V), formula (Va), formula (VI) or formula (VIa), that is
essentially the pure (S)-enantiomer.
[1027] In one embodiment, the compositions of the invention
comprise a compound of formula (I), (Ia), (Ib) or (Ic) that is
substantially enriched in an enantiomer. In another embodiment, the
long-acting injectable compositions of the invention comprise a
compound of formula (I), (Ia), (Ib) or (Ic) that is substantially
enriched in the (S)-enantiomer. In another embodiment, the
long-acting injectable compositions of the invention comprise a
compound of formula (I), (Ia), (Ib) or (Ic) that is substantially
enriched in the (R)-enantiomer.
[1028] In another embodiment of the invention, the compositions
comprise a compound of formula (I), (Ia), (Ib) or (Ic) that is
enriched in the (S)-enantiomer in a weight:weight ratio is at least
approximately 1.5:1 or 2:1 or greater. In yet another embodiment,
the compositions of the invention comprise a compound of formula
(I), (Ia), (Ib) or (Ic) that is enriched in the (5)-enantiomer in a
weight:weight ratio of at least about 5:1 or greater. In still
another embodiment, the compositions of the invention comprise a
compound of formula (I), (Ia), (Ib) or (Ic) that is enriched in the
(S)-enantiomer in a weight:weight ratio of at least approximately
10:1, 20:1, or greater. In still another embodiment, the
compositions of the invention comprise a compound of formula (I),
(Ia), (Ib) or (Ic) that is essentially the pure (S)-enantiomer.
[1029] In another embodiment of the invention, the compositions
comprise a compound of formula (I), (Ia), (Ib) or (Ic) that is
enriched in the (R)-enantiomer in a weight:weight ratio is at least
approximately 2:1 or greater. In yet another embodiment, the
compositions of the invention comprise a compound of formula (I),
(Ia), (Ib) or (Ic) that is enriched in the (R)-enantiomer in a
weight:weight ratio of at least about 5:1 or greater. In still
another embodiment, the compositions of the invention comprise a
compound of formula (I), (Ia), (Ib) or (Ic) that is enriched in the
(R)-enantiomer in a weight:weight ratio of at least about 10:1,
20:1, or greater. In still another embodiment, the compositions of
the invention comprise a compound of formula (I), (Ia), (Ib) or
(Ic) that is essentially the pure (R)-enantiomer.
[1030] In another embodiment of the invention, the compositions
comprise a compound of formula (II), formula (II-1.1001) to formula
(II-1.025), formula (II-2.001) to formula (II-018), formula (III),
formula (IV), formula (V), formula (Va), formula (VI) or formula
(VIa), that is enriched in the (R)-enantiomer in a weight:weight
ratio is at least approximately 2:1 or greater. In yet another
embodiment, the compositions of the invention comprise a compound
of formula (II), formula (II-1.1001) to formula (II-1.025), formula
(II-2.001) to formula (II-018), formula (III), formula (IV),
formula (V), formula (Va), formula (VI) or formula (VIa), that is
enriched in the (R)-enantiomer in a weight:weight ratio of at least
about 5:1 or greater. In still another embodiment, the compositions
of the invention comprise a compound of formula (II), formula
(II-1.1001) to formula (II-1.025), formula (II-2.001) to formula
(II-018), formula (III), formula (IV), formula (V), formula (Va),
formula (VI) or formula (VIa), that is enriched in the
(R)-enantiomer in a weight:weight ratio of at least approximately
10:1, 20:1, or greater. In still another embodiment, the
compositions of the invention comprise a compound of formula (II),
formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to
formula (II-018), formula (III), formula (IV), formula (V), formula
(Va), formula (VI) or formula (VIa), that is essentially the pure
(R)-enantiomer.
[1031] In another embodiment, the long-acting injectable
compositions of present invention comprise an antiparasitic
effective amount of at least one isoxazoline disclosed in WO
2007/079162, WO 2007/075459 and US 2009/0133319, WO 2007/070606 and
US 2009/0143410, WO 2009/003075, WO 2009/002809, WO 2009/024541, WO
2005/085216 and US 2007/0066617 WO 2008/122375, WO 2014/439475 A1
and WO2012 120135A1, all of which are incorporated herein by
reference in their entirety.
[1032] In yet another embodiment, the long-acting injectable
compositions of present invention comprise an antiparasitic
effective amount of at least one isoxazoline compound described in
WO 2009/02451A2 and WO 2011/075591A1, both incorporated herein by
reference in their entirety.
[1033] In yet another embodiment, the long-acting injectable
compositions of present invention comprise an antiparasitic
effective amount of at least one isoxazoline which is compound 11-1
described in WO 2009/02451A2, which has the structure:
##STR00027##
[1034] In one embodiment, the compositions of the invention may
comprise about 0.5 to about 50% (w/v) of an isoxazoline active
agent of any of formulae (I), (Ia), (Ic), (II), (III), (IV), (V),
(Va), (VI) or (VIa), or a pharmaceutically acceptable salt thereof,
either as a racemic mixture or enriched in an enantiomer as
described above. In another embodiment, the compositions of the
invention may comprise about 1 to about 40% (w/v) of an isoxazoline
active agent of any of formulae (I), (Ia), (Ib), (Ic), (II), (III),
(IV), (V), (Va), (VI) or (VIa), or a pharmaceutically acceptable
salt thereof. In yet another embodiment, the compositions of the
invention may comprise about 1 to about 30% (w/v), about 1 to about
20% (w/v) or about 1 to about 15% (w/v) of an isoxazoline active
agent of any of formulae (I), (Ia), (Ib), (Ic), (II), (III), (IV),
(V), (Va), (VI) or (VIa), or a pharmaceutically acceptable salt
thereof. In another embodiment, the compositions of the invention
may comprise about 0.5 to about 10% (w/v) or about 0.5% to about 5%
(w/v) of an isoxazoline active agent of any of formulae (I), (Ia),
(Ib), (Ic), (II), (III), (IV), (V), (Va), (VI) or (VIa), or a
pharmaceutically acceptable salt thereof.
[1035] In another embodiment, the compositions of the invention may
comprise about 5 to about 40% (w/v) or about 5 to about 30% (w/v)
of an isoxazoline active agent, or a pharmaceutically acceptable
salt thereof. In another embodiment, the compositions may comprise
about 10% to about 40% (w/v) of an isoxazoline active agent, or a
pharmaceutically acceptable salt thereof. In yet another
embodiment, the compositions of the invention may comprise about
15% to about 40% (w/v), about 15% to about 35% (w/v) or about 15%
to about 30% (w/v) of an isoxazoline compound, or a
pharmaceutically acceptable salt thereof.
[1036] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prevention of parasitic infections and infestations in or on
animals comprising:
[1037] a) about 0.5 to 30% (w/v) of an isoxazoline active agent,
such as, for example, any of the isoxazoline compounds provided for
in the embodiments above (e.g., a compound of any of formula I to
VIa described above), or a pharmaceutically acceptable salt
thereof;
[1038] b) a pharmaceutically acceptable polymer which is a liquid
PEG and/or a pharmaceutically acceptable neutral oil;
[1039] c) optionally, about 1% to 40% (w/v) of co-solvent;
[1040] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1041] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1042] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1043] In another embodiment the present invention provides for
long-acting injectable compositions for the treatment and/or
prevention of parasitic infections and infestations in or on
animals comprising:
[1044] a) about 0.5 to 20% (w/v) of an isoxazoline active agent,
such as, for example, any of the isoxazoline compounds provided for
in the embodiments above (e.g., a compound of any of formula Ito
VIa described above), or a pharmaceutically acceptable salt
thereof;
[1045] b) pharmaceutically acceptable polymer which is a liquid PEG
and/or a pharmaceutically acceptable neutral oil;
[1046] c) optionally, about 1% to 40% (w/v) of co-solvent;
[1047] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1048] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1049] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1050] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prevention of parasitic infections and infestations in or on
animals comprising:
[1051] a) about 5 to 30% (w/v) of an isoxazoline active agent, such
as, for example, any of the isoxazoline compounds provided for in
the embodiments above (e.g., a compound of any of formula Ito VIa
described above), or a pharmaceutically acceptable salt
thereof;
[1052] b) pharmaceutically acceptable polymer which is a liquid PEG
and/or a pharmaceutically acceptable neutral oil;
[1053] c) optionally, about 1% to 40% (w/v) of co-solvent;
[1054] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1055] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1056] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1057] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prevention of parasitic infections and infestations in or on
animals comprising:
[1058] a) about 0.5 to 30% (w/v) of an isoxazoline active agent,
such as, for example, any of the isoxazoline compounds provided for
in the embodiments above (e.g., a compound of any of formula Ito
VIa described above), or a pharmaceutically acceptable salt
thereof;
[1059] b) a pharmaceutically acceptable polymer which is a liquid
PEG and/or a pharmaceutically acceptable neutral oil;
[1060] c) optionally, about 1% to 40% (w/v) of co-solvent, wherein
said co-solvent is a polar solvent that is miscible with water;
[1061] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1062] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1063] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1064] In another embodiment the present invention provides for
long-acting injectable compositions for the treatment and/or
prevention of parasitic infections and infestations in or on
animals comprising:
[1065] a) about 0.5 to 20% (w/v) of an isoxazoline active agent,
such as, for example, any of the isoxazoline compounds provided for
in the embodiments above (e.g., a compound of any of formula Ito
VIa described above), or a pharmaceutically acceptable salt
thereof;
[1066] b) pharmaceutically acceptable polymer which is a liquid PEG
and/or a pharmaceutically acceptable neutral oil;
[1067] c) optionally, about 1% to 40% (w/v) of co-solvent, wherein
said co-solvent is a polar solvent that is miscible with water;
[1068] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1069] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1070] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1071] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prevention of parasitic infections and infestations in or on
animals comprising:
[1072] a) about 5 to 30% (w/v) of an isoxazoline active agent, such
as, for example, any of the isoxazoline compounds provided for in
the embodiments above (e.g., a compound of any of formula Ito VIa
described above), or a pharmaceutically acceptable salt
thereof;
[1073] b) pharmaceutically acceptable polymer which is a liquid PEG
and/or a pharmaceutically acceptable neutral oil;
[1074] c) optionally, about 1% to 40% (w/v) of co-solvent, wherein
said co-solvent is a polar solvent that is miscible with water;
[1075] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1076] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1077] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1078] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1079] a) about 0.5 to 30% (w/v) of an isoxazoline active agent of
the formula (Ia), (e.g., a compound of formulae I-VIa), such as, a
compound of the formula:
##STR00028##
[1080] wherein X.sup.1, X.sup.2 and X.sup.3 are independently
chloro, fluoro or CF.sub.3;
##STR00029##
[1081] wherein X.sup.1, X.sup.2 and X.sup.3 are independently
chloro, fluoro or CF.sub.3;
##STR00030##
[1082] wherein X.sup.1, X.sup.2 and X.sup.3 are independently
chloro, fluoro or CF.sub.3;
##STR00031##
[1083] or a pharmaceutically acceptable salt thereof,
[1084] b) pharmaceutically acceptable polymer which is a liquid PEG
and/or a pharmaceutically acceptable neutral oil;
[1085] c) optionally, about 1% to 40% (w/v) of a co-solvent,
wherein the co-solvent is a C.sub.1-C.sub.6alcohol, a glycol ether
(e.g., including, but limited to, diethyleneglycol monoethyl ether,
butyl diglycol, dipropylene glycol n-butyl ether, ethyleneglycol
monoethyl ether, ethyleneglycol monomethyl ether, dipropylene
glycol monomethyl ether, propylene glycol monomethyl ether,
propylene glycol monoethyl ether, and the like), glycerol,
propylene glycol, cyclic carbonates (e.g., propylene carbonate),
2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI),
dimethylacetamide, dimethylsulfoxide or glycerol formal, or a
combination thereof;
[1086] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1087] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1088] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1089] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1090] a) about 0.5 to 20% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (R)-Ia, (Ic), wherein X.sup.1, X.sup.2
and X.sup.3 are independently chloro, fluoro or CF.sub.3; (S)-Ic,
wherein X.sup.1, X.sup.2 and X.sup.3 are independently chloro,
fluoro or CF.sub.3; (R)-Ic wherein X.sup.1, X.sup.2 and X.sup.3 are
independently chloro, fluoro or CF.sub.3; (III), (S)-III, (IV),
(Va), (S)-Va, (VIa) or (S)-VIa as shown above;
[1091] or a pharmaceutically acceptable salt thereof,
[1092] b) pharmaceutically acceptable polymer which is a liquid PEG
and/or a pharmaceutically acceptable neutral oil;
[1093] c) optionally, about 1% to 40% (w/v) of co-solvent, wherein
the co-solvent is a C.sub.1-C.sub.6alcohol, a glycol ether (e.g.,
including, but limited to, diethyleneglycol monoethyl ether, butyl
diglycol, dipropylene glycol n-butyl ether, ethyleneglycol
monoethyl ether, ethyleneglycol monomethyl ether, dipropylene
glycol monomethyl ether, propylene glycol monomethyl ether,
propylene glycol monoethyl ether, and the like), glycerol,
propylene glycol, cyclic carbonates (e.g., propylene carbonate),
2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI),
dimethylacetamide, dimethylsulfoxide or glycerol formal, or a
combination thereof;
[1094] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1095] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1096] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1097] In other embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1098] a) about 1 to 20% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (R)-Ia, (Ic), wherein X.sup.1, X.sup.2
and X.sup.3 are independently chloro, fluoro or CF.sub.3; (S)-Ic,
wherein X.sup.1, X.sup.2 and X.sup.3 are independently chloro,
fluoro or CF.sub.3; (R)-Ic wherein X.sup.1, X.sup.2 and X.sup.3 are
independently chloro, fluoro or CF.sub.3; (III), (S)-III, (IV),
(Va), (S)-Va, (Va) or (S)-VIa as shown above;
[1099] or a pharmaceutically acceptable salt thereof,
[1100] b) pharmaceutically acceptable polymer which is a liquid PEG
and/or a pharmaceutically acceptable neutral oil;
[1101] c) optionally, about 1% to 40% (w/v) of co-solvent, wherein
the co-solvent is a C.sub.1-C.sub.6alcohol, a glycol ether (e.g.,
including, but limited to, diethyleneglycol monoethyl ether, butyl
diglycol, dipropylene glycol n-butyl ether, ethyleneglycol
monoethyl ether, ethyleneglycol monomethyl ether, dipropylene
glycol monomethyl ether, propylene glycol monomethyl ether,
propylene glycol monoethyl ether, and the like), glycerol,
propylene glycol, cyclic carbonates (e.g., propylene carbonate),
2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI),
dimethylacetamide, dimethylsulfoxide or glycerol formal, or a
combination thereof;
[1102] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1103] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1104] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1105] In other embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1106] a) about 1 to 15% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (R)-Ia, (Ic), wherein X.sup.1, X.sup.2
and X.sup.3 are independently chloro, fluoro or CF.sub.3; (S)-Ic,
wherein X.sup.1, X.sup.2 and X.sup.3 are independently chloro,
fluoro or CF.sub.3; (R)-Ic wherein X.sup.1, X.sup.2 and X.sup.3 are
independently chloro, fluoro or CF.sub.3; (III), (S)-III, (IV),
(S)-IV, (Va), (S)-Va, (Va) or (S)-VIa as shown above; or a
pharmaceutically acceptable salt thereof,
[1107] b) pharmaceutically acceptable polymer which is a liquid PEG
and/or a pharmaceutically acceptable neutral oil;
[1108] c) optionally, about 1% to 40% (w/v) of co-solvent, wherein
the co-solvent is a C.sub.1-C.sub.6alcohol, a glycol ether (e.g.,
including, but limited to, diethyleneglycol monoethyl ether, butyl
diglycol, dipropylene glycol n-butyl ether, ethyleneglycol
monoethyl ether, ethyleneglycol monomethyl ether, dipropylene
glycol monomethyl ether, propylene glycol monomethyl ether,
propylene glycol monoethyl ether, and the like), glycerol,
propylene glycol, cyclic carbonates (e.g., propylene carbonate),
2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI),
dimethylacetamide, dimethylsulfoxide or glycerol formal, or a
combination thereof;
[1109] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1110] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1111] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1112] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1113] a) about 0.5 to 30% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (R)-Ia, (Ic), wherein X.sup.1, X.sup.2
and X.sup.3 are independently chloro, fluoro or CF.sub.3; (S)-Ic,
wherein X.sup.1, X.sup.2 and X.sup.3 are independently chloro,
fluoro or CF.sub.3; (R)-Ic wherein X.sup.1, X.sup.2 and X.sup.3 are
independently chloro, fluoro or CF.sub.3; (III), (S)-III, (IV),
(S)-IV, (Va), (S)-Va, (Va) or (S)-VIa as shown above, or a
pharmaceutically acceptable salt thereof;
[1114] b) pharmaceutically acceptable polymer which is a liquid
PEG;
[1115] c) optionally, about 1% to 40% (w/v) of a co-solvent,
wherein the co-solvent is benzyl alcohol, benzyl benzoate, ethyl
acetate, triacetin, lipids, C.sub.8-C.sub.10 triglycerides (e.g.
MIGLYOL.RTM. 810 and MIGLYOL.RTM. 812), C.sub.8-C.sub.10
triglycerides combined with linoleic acid (e.g. MIGLYOL.RTM. 818),
C.sub.8-C.sub.10 triglycerides combined with succinic acid (e.g.
MIGLYOL.RTM. 829), propylene glycol diester of C.sub.8-C.sub.10
fatty acids (e.g. MIGLYOL.RTM. 840), castor oil, cottonseed oil,
sesame oil, soybean oil and safflower oil, or a combination
thereof;
[1116] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1117] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1118] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG is present in the overall composition in a
proportion representing the complement to 100% of the
composition.
[1119] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1120] a) about 0.5 to 20% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (R)-Ia, (Ic), wherein X.sup.1, X.sup.2
and X.sup.3 are independently chloro, fluoro or CF.sub.3; (S)-Ic,
wherein X.sup.1, X.sup.2 and X.sup.3 are independently chloro,
fluoro or CF.sub.3; (R)-Ic wherein X.sup.1, X.sup.2 and X.sup.3 are
independently chloro, fluoro or CF.sub.3; (III), (S)-III, (IV),
(S)-IV, (Va), (S)-Va, (Va) or (S)-VIa as shown above;
[1121] or a pharmaceutically acceptable salt thereof,
[1122] b) pharmaceutically acceptable polymer which is a liquid
PEG;
[1123] c) optionally, about 5% to 40% (w/v) of co-solvent, wherein
the co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate,
triacetin, lipids, C.sub.8-C.sub.10 triglycerides (e.g.
MIGLYOL.RTM. 810 and MIGLYOL.RTM. 812), C.sub.8-C.sub.10
triglycerides combined with linoleic acid (e.g. MIGLYOL.RTM. 818),
C.sub.8-C.sub.10 triglycerides combined with succinic acid (e.g.
MIGLYOL.RTM. 829), propylene glycol diester of C.sub.8-C.sub.10
fatty acids (e.g. MIGLYOL.RTM. 840), castor oil, cottonseed oil,
sesame oil, soybean oil and safflower oil, or a combination
thereof;
[1124] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1125] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1126] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG is present in the overall composition in a
proportion representing the complement to 100% of the
composition.
[1127] In other embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1128] a) about 1 to 20% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (R)-Ia, (Ic), wherein X.sup.1, X.sup.2
and X.sup.3 are independently chloro, fluoro or CF.sub.3; (S)-Ic,
wherein X.sup.1, X.sup.2 and X.sup.3 are independently chloro,
fluoro or CF.sub.3; (R)-Ic wherein X.sup.1, X.sup.2 and X.sup.3 are
independently chloro, fluoro or CF.sub.3; (III), (S)-III, (IV),
(S)-IV, (Va), (S)-Va, (Va) or (S)-VIa as shown above;
[1129] or a pharmaceutically acceptable salt thereof,
[1130] b) pharmaceutically acceptable polymer which is a liquid
PEG;
[1131] c) optionally, about 1% to 40% (w/v) of co-solvent, wherein
the co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate,
triacetin, lipids, C.sub.8-C.sub.10 triglycerides (e.g.
MIGLYOL.RTM. 810 and MIGLYOL.RTM. 812), C.sub.8-C.sub.10
triglycerides combined with linoleic acid (e.g. MIGLYOL.RTM. 818),
C.sub.8-C.sub.10 triglycerides combined with succinic acid (e.g.
MIGLYOL.RTM. 829), propylene glycol diester of C.sub.8-C.sub.10
fatty acids (e.g. MIGLYOL.RTM. 840), castor oil, cottonseed oil,
sesame oil, soybean oil and safflower oil, or a combination
thereof;
[1132] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1133] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1134] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG is present in the overall composition in a
proportion representing the complement to 100% of the
composition.
[1135] In other embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1136] a) about 1 to 15% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (R)-Ia, (Ic), wherein X.sup.1, X.sup.2
and X.sup.3 are independently chloro, fluoro or CF.sub.3; (S)-Ic,
wherein X.sup.1, X.sup.2 and X.sup.3 are independently chloro,
fluoro or CF.sub.3; (R)-Ic wherein X.sup.1, X.sup.2 and X.sup.3 are
independently chloro, fluoro or CF.sub.3; (III), (S)-III, (IV),
(S)-IV, (Va), (S)-Va, (VIa) or (S)-VIa as shown above;
[1137] or a pharmaceutically acceptable salt thereof,
[1138] b) pharmaceutically acceptable polymer which is a liquid
PEG;
[1139] c) optionally, about 1% to 40% (w/v) of co-solvent, wherein
the co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate,
triacetin, lipids, C.sub.8-C.sub.10 triglycerides (e.g.
MIGLYOL.RTM. 810 and MIGLYOL.RTM. 812), C.sub.8-C.sub.10
triglycerides combined with linoleic acid (e.g. MIGLYOL.RTM. 818),
C.sub.8-C.sub.10 triglycerides combined with succinic acid (e.g.
MIGLYOL.RTM. 829), propylene glycol diester of C.sub.8-C.sub.10
fatty acids (e.g. MIGLYOL.RTM. 840), castor oil, cottonseed oil,
sesame oil, soybean oil and safflower oil, or a combination
thereof;
[1140] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1141] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1142] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG is present in the overall composition in a
proportion representing the complement to 100% of the composition.
In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1143] a) about 0.5 to 30% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (Ic), wherein X.sup.1, X.sup.2 and
X.sup.3 are independently chloro, fluoro or CF.sub.3; (S)-Ic,
wherein X.sup.1, X.sup.2 and X.sup.3 are independently chloro,
fluoro or CF.sub.3; (III), (S)-III, (IV), (S)-IV, (S)-Va, (VIa) or
(S)-VIa as shown above, or a pharmaceutically acceptable salt
thereof;
[1144] b) pharmaceutically acceptable polymer which is a liquid PEG
and/or a pharmaceutically acceptable neutral oil;
[1145] c) optionally, about 1% to 40% (w/v) of a co-solvent,
wherein the co-solvent is a C.sub.1-C.sub.6alcohol, benzyl alcohol,
or a combination thereof;
[1146] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1147] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1148] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1149] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1150] a) about 0.5 to 20% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (Ic), wherein X.sup.1, X.sup.2 and
X.sup.3 are independently chloro, fluoro or CF.sub.3; (S)-Ic,
wherein X.sup.1, X.sup.2 and X.sup.3 are independently chloro,
fluoro or CF.sub.3; (III), (S)-III, (IV), (S)-IV, (S)-Va, (VIa) or
(S)-VIa as shown above, or a pharmaceutically acceptable salt
thereof;
[1151] b) pharmaceutically acceptable polymer which is a liquid PEG
and/or a pharmaceutically acceptable neutral oil;
[1152] c) optionally, about 1% to 40% (w/v) of co-solvent, wherein
the co-solvent is a C.sub.1-C.sub.6alcohol, benzyl alcohol, or a
combination thereof;
[1153] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1154] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1155] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1156] In other embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1157] a) about 1 to 20% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (Ic), wherein X.sup.1, X.sup.2 and
X.sup.3 are independently chloro, fluoro or CF.sub.3; (S)-Ic,
wherein X.sup.1, X.sup.2 and X.sup.3 are independently chloro,
fluoro or CF.sub.3; (III), (S)-III, (IV), (S)-IV, (S)-Va, (VIa) or
(S)-VIa as shown above, or a pharmaceutically acceptable salt
thereof;
[1158] or a pharmaceutically acceptable salt thereof,
[1159] b) pharmaceutically acceptable polymer which is a liquid PEG
and/or a pharmaceutically acceptable neutral oil;
[1160] c) optionally, about 1% to 40% (w/v) of co-solvent, wherein
the co-solvent is a C.sub.1-C.sub.6alcohol, benzyl alcohol, or a
combination thereof;
[1161] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1162] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1163] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1164] In other embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1165] a) about 1 to 15% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (Ic), wherein X.sup.1, X.sup.2 and
X.sup.3 are independently chloro, fluoro or CF.sub.3; (S)-Ic,
wherein X.sup.1, X.sup.2 and X.sup.3 are independently chloro,
fluoro or CF.sub.3; (III), (S)-III, (IV), (S)-IV, (S)-Va, (VIa) or
(S)-VIa as shown above, or a pharmaceutically acceptable salt
thereof;
[1166] or a pharmaceutically acceptable salt thereof,
[1167] b) pharmaceutically acceptable polymer which is a liquid PEG
and/or a pharmaceutically acceptable neutral oil;
[1168] c) optionally, about 1% to 40% (w/v) of co-solvent, wherein
the co-solvent is a C.sub.1-C.sub.6alcohol, benzyl alcohol, or a
combination thereof;
[1169] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1170] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1171] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1172] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1173] a) about 0.5 to 30% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (Ic), wherein X.sup.1 is chloro, X.sup.2
is fluoro and X.sup.3 is CF.sub.3; or (S)-Ic, wherein X.sup.1 is
chloro, X.sup.2 is fluoro and X.sup.3 is CF.sub.3, as shown above,
or a pharmaceutically acceptable salt thereof;
[1174] b) pharmaceutically acceptable polymer which is a liquid
PEG;
[1175] c) optionally, about 1% to 40% (w/v) of a co-solvent,
wherein the co-solvent is ethanol, isopropanol or benzyl alcohol,
or a combination thereof;
[1176] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1177] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1178] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1179] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1180] a) about 0.5 to 30% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (Ic), wherein X.sup.1 is chloro, X.sup.2
is fluoro and X.sup.3 is CF.sub.3; or (S)-Ic, wherein X.sup.1 is
chloro, X.sup.2 is fluoro and X.sup.3 is CF.sub.3, as shown above,
or a pharmaceutically acceptable salt thereof;
[1181] b) at least one pharmaceutically acceptable polymer which is
a liquid PEG;
[1182] c) optionally, about 1% to 40% (w/v) of a co-solvent,
wherein said co-solvent is a C.sub.8-C.sub.10 triglyceride, benzyl
alcohol, or a combination thereof;
[1183] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1184] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1185] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1186] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1187] a) about 0.5 to 30% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (Ic), wherein X.sup.1 is chloro, X.sup.2
is fluoro and X.sup.3 is CF.sub.3; or (S)-Ic, wherein X.sup.1 is
chloro, X.sup.2 is fluoro and X.sup.3 is CF.sub.3, as shown above,
or a pharmaceutically acceptable salt thereof;
[1188] b) at least one neutral oil, wherein said neutral oil is a
C.sub.8-C.sub.10 triglyceride;
[1189] c) optionally, about 1% to 40% (w/v) of a co-solvent,
wherein said co-solvent is ethanol, isopropanol, benzyl alcohol, or
a combination thereof;
[1190] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1191] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1192] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1193] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1194] a) about 0.5 to 20% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (Ic), wherein X.sup.1 is chloro, X.sup.2
is fluoro and X.sup.3 is CF.sub.3; or (S)-Ic, wherein X.sup.1 is
chloro, X.sup.2 is fluoro and X.sup.3 is CF.sub.3, as shown above,
or a pharmaceutically acceptable salt thereof;
[1195] b) pharmaceutically acceptable polymer which is a liquid
PEG;
[1196] c) optionally, about 1% to 40% (w/v) of co-solvent, wherein
the co-solvent is ethanol, isopropanol or benzyl alcohol, or a
combination thereof;
[1197] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1198] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1199] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1200] In other embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1201] a) about 1 to 20% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (Ic), wherein X.sup.1 is chloro, X.sup.2
is fluoro and X.sup.3 is CF.sub.3; or (S)-Ic, wherein X.sup.1 is
chloro, X.sup.2 is fluoro and X.sup.3 is CF.sub.3, as shown above,
or a pharmaceutically acceptable salt thereof;
[1202] or a pharmaceutically acceptable salt thereof,
[1203] b) pharmaceutically acceptable polymer which is a liquid
PEG;
[1204] c) optionally, about 1% to 40% (w/v) of co-solvent, wherein
the co-solvent is ethanol, isopropanol or benzyl alcohol, or a
combination thereof;
[1205] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1206] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1207] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1208] In other embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1209] a) about 1 to 15% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (Ic), wherein X.sup.1 is chloro, X.sup.2
is fluoro and X.sup.3 is CF.sub.3; or (S)-Ic, wherein X.sup.1 is
chloro, X.sup.2 is fluoro and X.sup.3 is CF.sub.3, as shown above,
or a pharmaceutically acceptable salt thereof;
[1210] or a pharmaceutically acceptable salt thereof,
[1211] b) pharmaceutically acceptable polymer which is a liquid
PEG;
[1212] c) optionally, about 1% to 40% (w/v) of co-solvent, wherein
the co-solvent is ethanol, isopropanol or benzyl alcohol, or a
combination thereof;
[1213] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1214] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1215] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1216] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1217] a) about 0.5 to 30% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (Ic), wherein X.sup.1 is chloro, X.sup.2
is fluoro and X.sup.3 is CF.sub.3; or (S)-Ic, wherein X.sup.1 is
chloro, X.sup.2 is fluoro and X.sup.3 is CF.sub.3, as shown above,
or a pharmaceutically acceptable salt thereof;
[1218] b) pharmaceutically acceptable polymer which is a liquid PEG
and/or a neutral oil;
[1219] c) optionally, about 1% to 20% (w/v) of a co-solvent,
wherein the co-solvent is ethanol, isopropanol or benzyl alcohol,
or a combination thereof;
[1220] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1221] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1222] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1223] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1224] a) about 0.5 to 20% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (Ic), wherein X.sup.1 is chloro, X.sup.2
is fluoro and X.sup.3 is CF.sub.3; or (S)-Ic, wherein X.sup.1 is
chloro, X.sup.2 is fluoro and X.sup.3 is CF.sub.3, as shown above,
or a pharmaceutically acceptable salt thereof;
[1225] b) pharmaceutically acceptable polymer which is a liquid PEG
and/or a neutral oil;
[1226] c) optionally, about 1% to 20% (w/v) of co-solvent, wherein
the co-solvent is ethanol, isopropanol or benzyl alcohol, or a
combination thereof;
[1227] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1228] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1229] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1230] In other embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1231] a) about 1 to 20% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (Ic), wherein X.sup.1 is chloro, X.sup.2
is fluoro and X.sup.3 is CF.sub.3; or (S)-Ic, wherein X.sup.1 is
chloro, X.sup.2 is fluoro and X.sup.3 is CF.sub.3, as shown above,
or a pharmaceutically acceptable salt thereof;
[1232] or a pharmaceutically acceptable salt thereof,
[1233] b) pharmaceutically acceptable polymer which is a liquid PEG
and/or a neutral oil;
[1234] c) optionally, about 1% to 20% (w/v) of co-solvent, wherein
the co-solvent is ethanol, isopropanol or benzyl alcohol, or a
combination thereof;
[1235] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1236] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1237] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1238] In other embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1239] a) about 1 to 15% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (Ic), wherein X.sup.1 is chloro, X.sup.2
is fluoro and X.sup.3 is CF.sub.3; or (S)-Ic, wherein X.sup.1 is
chloro, X.sup.2 is fluoro and X.sup.3 is CF.sub.3, as shown above,
or a pharmaceutically acceptable salt thereof;
[1240] or a pharmaceutically acceptable salt thereof,
[1241] b) pharmaceutically acceptable polymer which is a liquid PEG
and/or a neutral oil;
[1242] c) optionally, about 1% to 20% (w/v) of co-solvent, wherein
the co-solvent is ethanol, isopropanol or benzyl alcohol, or a
combination thereof;
[1243] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1244] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1245] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1246] In other embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising: [1247] a) about 1 to 15% (w/v) of an
isoxazoline active agent of the formula (Ia), (S)-Ia, (Ic), wherein
X.sup.1 is chloro, X.sup.2 is fluoro and X.sup.3 is CF.sub.3; or
(S)-Ic, wherein X.sup.1 is chloro, X.sup.2 is fluoro and X.sup.3 is
CF.sub.3, as shown above, or a pharmaceutically acceptable salt
thereof;
[1248] or a pharmaceutically acceptable salt thereof,
[1249] b) pharmaceutically acceptable polymer which is a liquid
PEG;
[1250] c) optionally, about 1% to 20% (w/v) of a co-solvent wherein
said co-solvent is a C.sub.8-C.sub.10 triglyceride, benzyl alcohol,
or a combination thereof;
[1251] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1252] e) optionally about 0.01% to about 5.0% (w/v) of at least
one pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1253] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1254] In other embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1255] a) about 1 to 15% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (Ic), wherein X.sup.1 is chloro, X.sup.2
is fluoro and X.sup.3 is CF.sub.3; or (S)-Ic, wherein X.sup.1 is
chloro, X.sup.2 is fluoro and X.sup.3 is CF.sub.3, as shown above,
or a pharmaceutically acceptable salt thereof;
[1256] or a pharmaceutically acceptable salt thereof,
[1257] b) at least one neutral oil, wherein said neutral oil is a
C.sub.8-C.sub.10 triglyceride;
[1258] c) optionally, about 1% to 20% (w/v) at least one
co-solvent, wherein said co-solvent is ethanol, isopropanol, benzyl
alcohol, or a combination thereof;
[1259] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1260] e) optionally about 0.01% to about 5.0% (w/v) of at least
one pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1261] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1262] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1263] a) about 0.5 to 30% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (Ic), wherein X.sup.1 is chloro, X.sup.2
is fluoro and X.sup.3 is CF.sub.3; or (S)-Ic, wherein X.sup.1 is
chloro, X.sup.2 is fluoro and X.sup.3 is CF.sub.3, as shown above,
or a pharmaceutically acceptable salt thereof;
[1264] b) pharmaceutically acceptable polymer which is a liquid
PEG;
[1265] c) optionally, about 2% to 15% (w/v) of a co-solvent,
wherein the co-solvent is ethanol, isopropanol or benzyl alcohol,
or a combination thereof;
[1266] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1267] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1268] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG is present in the overall composition in a
proportion representing the complement to 100% of the
composition.
[1269] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1270] a) about 0.5 to 20% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (Ic), wherein X.sup.1 is chloro, X.sup.2
is fluoro and X.sup.3 is CF.sub.3; or (S)-Ic, wherein X.sup.1 is
chloro, X.sup.2 is fluoro and X.sup.3 is CF.sub.3, as shown above,
or a pharmaceutically acceptable salt thereof;
[1271] b) pharmaceutically acceptable polymer which is a liquid
PEG;
[1272] c) optionally, about 2% to 15% (w/v) of co-solvent, wherein
the co-solvent is ethanol, isopropanol or benzyl alcohol, or a
combination thereof;
[1273] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1274] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1275] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG is present in the overall composition in a
proportion representing the complement to 100% of the
composition.
[1276] In other embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1277] a) about 1 to 20% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (Ic), wherein X.sup.1 is chloro, X.sup.2
is fluoro and X.sup.3 is CF.sub.3; or (S)-Ic, wherein X.sup.1 is
chloro, X.sup.2 is fluoro and X.sup.3 is CF.sub.3, as shown above,
or a pharmaceutically acceptable salt thereof;
[1278] or a pharmaceutically acceptable salt thereof,
[1279] b) pharmaceutically acceptable polymer which is a liquid
PEG;
[1280] c) optionally, about 2% to 15% (w/v) of co-solvent, wherein
the co-solvent is ethanol, isopropanol or benzyl alcohol, or a
combination thereof;
[1281] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1282] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1283] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG is present in the overall composition in a
proportion representing the complement to 100% of the
composition.
[1284] In other embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1285] a) about 1 to 15% (w/v) of an isoxazoline active agent of
the formula (Ia), (S)-Ia, (Ic), wherein X.sup.1 is chloro, X.sup.2
is fluoro and X.sup.3 is CF.sub.3; or (S)-Ic, wherein X.sup.1 is
chloro, X.sup.2 is fluoro and X.sup.3 is CF.sub.3, as shown above,
or a pharmaceutically acceptable salt thereof;
[1286] or a pharmaceutically acceptable salt thereof,
[1287] b) pharmaceutically acceptable polymer which is a liquid
PEG;
[1288] c) optionally, about 2% to 15% (w/v) of co-solvent, wherein
the co-solvent is ethanol, isopropanol or benzyl alcohol, or a
combination thereof;
[1289] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1290] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1291] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG is present in the overall composition in a
proportion representing the complement to 100% of the
composition.
[1292] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1293] a) about 0.5 to 15% (w/v) of an isoxazoline active agent of
the formula (S)-Ia or (S)-Ic, wherein X.sup.1 is chloro, X.sup.2 is
fluoro and X.sup.3 is CF.sub.3, as shown above, or a
pharmaceutically acceptable salt thereof;
[1294] b) pharmaceutically acceptable polymer which is a liquid
PEG;
[1295] c) optionally, about 2% to 15% (w/v) of a co-solvent,
wherein the co-solvent is ethanol, isopropanol or benzyl alcohol,
or a combination thereof;
[1296] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1297] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1298] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG is present in the overall composition in a
proportion representing the complement to 100% of the
composition.
[1299] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1300] a) about 5 to 20% (w/v) of an isoxazoline active agent of
the formula (S)-Ia or (S)-Ic, wherein X.sup.1 is chloro, X.sup.2 is
fluoro and X.sup.3 is CF.sub.3; as shown above, or a
pharmaceutically acceptable salt thereof;
[1301] b) pharmaceutically acceptable polymer which is a liquid
PEG;
[1302] c) optionally, about 2% to 15% (w/v) of co-solvent, wherein
the co-solvent is ethanol, isopropanol or benzyl alcohol, or a
combination thereof;
[1303] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1304] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1305] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG is present in the overall composition in a
proportion representing the complement to 100% of the
composition.
[1306] In other embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1307] a) about 5 to 15% (w/v) of an isoxazoline active agent of
the formula (S)-Ia or (S)-Ic, wherein X.sup.1 is chloro, X.sup.2 is
fluoro and X.sup.3 is CF.sub.3, as shown above, or a
pharmaceutically acceptable salt thereof;
[1308] or a pharmaceutically acceptable salt thereof,
[1309] b) pharmaceutically acceptable polymer which is a liquid
PEG;
[1310] c) optionally, about 2% to 10% (w/v) of co-solvent, wherein
the co-solvent is ethanol, isopropanol or benzyl alcohol, or a
combination thereof;
[1311] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1312] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1313] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG is present in the overall composition in a
proportion representing the complement to 100% of the
composition.
[1314] In certain embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1315] a) about 0.5 to 30% (w/v) of an isoxazoline active agent,
such as, for example, any of the isoxazoline compounds provided for
in the embodiments above (e.g., a compound of any of formulae I to
VIa described above), such as, a compound of the formula (Ia),
(S)-Ia, (R)-Ia, (Ic), wherein X.sup.1, X.sup.2 and X.sup.3 are
independently chloro, fluoro or CF.sub.3; (S)-Ic, wherein X.sup.1,
X.sup.2 and X.sup.3 are independently chloro, fluoro or CF.sub.3;
(R)-Ic wherein X.sup.1, X.sup.2 and X.sup.3 are independently
chloro, fluoro or CF.sub.3; (III), (S)-III, (IV), (S)-IV, (Va),
(S)-Va, (VIa) or (S)-VIa as shown above;
[1316] or a pharmaceutically acceptable salt thereof:
[1317] b) pharmaceutically acceptable polymer which is a liquid PEG
and/or a pharmaceutically acceptable neutral oil;
[1318] c) optionally, about 5% to 40% (w/v) of co-solvent selected
from the group consisting of ethanol and isopropanol;
[1319] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1320] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1321] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or neutral oil is present in the overall
composition in a proportion representing the complement to 100% of
the composition.
[1322] In other embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1323] a) about 1 to 30% (w/v) of an isoxazoline active agent, such
as, for example, any of the isoxazoline compounds provided for in
the embodiments above (e.g., a compound of any of formulae I to VIa
described above), such as, a compound of the formula (Ia), (S)-Ia,
(R)-Ia, (Ic), wherein X.sup.1, X.sup.2 and X.sup.3 are
independently chloro, fluoro or CF.sub.3; (S)-Ic, wherein X.sup.1,
X.sup.2 and X.sup.3 are independently chloro, fluoro or CF.sub.3;
(R)-Ic wherein X.sup.1, X.sup.2 and X.sup.3 are independently
chloro, fluoro or CF.sub.3; (III), (S)-III, (IV), (S)-IV, (Va),
(S)-Va, (VIa) or (S)-VIa as shown above; or a pharmaceutically
acceptable salt thereof:
[1324] b) pharmaceutically acceptable polymer which is a liquid PEG
and/or a neutral oil;
[1325] c) optionally, about 5% to 40% (w/v) of co-solvent selected
from the group consisting of ethanol and isopropanol;
[1326] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1327] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1328] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or the neutral oil is present in the
overall composition in a proportion representing the complement to
100% of the composition.
[1329] In yet other embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1330] a) about 1 to 20% (w/v) of an isoxazoline active agent, such
as, for example, any of the isoxazoline compounds provided for in
the embodiments above (e.g., a compound of formulae I-VIa), such
as, a compound of the formula (Ia), (S)-Ia, (R)-Ia, (Ic), wherein
X.sup.1, X.sup.2 and X.sup.3 are independently chloro, fluoro or
CF.sub.3; (S)-Ic, wherein X.sup.1, X.sup.2 and X.sup.3 are
independently chloro, fluoro or CF.sub.3; (R)-Ic wherein X.sup.2
and X.sup.3 are independently chloro, fluoro or CF.sub.3; (III),
(S)-III, (IV), (S)-IV, (Va), (S)-Va, (VIa) or (S)-VIa as shown
above; or a pharmaceutically acceptable salt thereof:
[1331] b) pharmaceutically acceptable polymer which is a liquid PEG
and/or a neutral oil;
[1332] c) optionally, about 5% to 40% (w/v) of co-solvent selected
from the group consisting of ethanol and isopropanol;
[1333] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1334] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1335] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG and/or the neutral oil is present in the
overall composition in a proportion representing the complement to
100% of the composition.
[1336] In other embodiments the present invention provides for
long-acting injectable compositions for the treatment and/or
prophylaxis of parasitic infections and infestations in or on
animals comprising:
[1337] a) about 5 to 20% (w/v) or about 5 to about 15% (w/v) of an
isoxazoline active agent, such as, for example, any of the
isoxazoline compounds provided for in the embodiments above (e.g.,
a compound of formulae I-VIa), such as, a compound of the formula
(Ia), (S)-Ia, (R)-Ia,
[1338] (Ic), wherein X.sup.1, X.sup.2 and X.sup.3 are independently
chloro, fluoro or CF.sub.3; (S)-Ic, wherein X.sup.1, X.sup.2 and
X.sup.3 are independently chloro, fluoro or CF.sub.3; (R)-Ic
wherein X.sup.1, X.sup.2 and X.sup.3 are independently chloro,
fluoro or CF.sub.3; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va,
(VIa) or (S)-VIa as shown above; or a pharmaceutically acceptable
salt thereof:
[1339] b) pharmaceutically acceptable polymer which is a liquid
PEG;
[1340] c) optionally, about 5% to 40% (w/v) of co-solvent selected
from the group consisting of ethanol and isopropanol;
[1341] d) optionally, about 0.01% to about 2.0% (w/v) of an
antioxidant; and
[1342] e) optionally about 0.01% to about 5.0% (w/v) of a
pharmaceutically acceptable additive, excipient or mixtures
thereof;
[1343] wherein the only pharmaceutically acceptable polymer present
in said long-acting injectable composition is a liquid PEG and
wherein the liquid PEG is present in the overall composition in a
proportion representing the complement to 100% of the
composition.
[1344] Another embodiment of the present invention is a long-acting
injectable composition for the treatment and/or prevention of
parasitic infections and infestations in or on animals consisting
essentially of:
[1345] a) an antiparasitic effective amount of at least one
isoxazoline active agent, such as, for example, any of the
isoxazoline compounds provided for in the embodiments above (e.g.,
a compound of formulae I-VIa), and optionally at least one
additionally active agent as identified in this application;
[1346] b) a liquid PEG and/or a pharmaceutically acceptable neutral
oil;
[1347] c) optionally, at least one co-solvent wherein said
co-solvent is a polar solvent miscible with water;
[1348] d) optionally, an antioxidant; and
[1349] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof.
[1350] Another embodiment of the present invention is a long-acting
injectable composition for the treatment and/or prevention of
parasitic infections and infestations in or on animals consisting
of:
[1351] a) an antiparasitic effective amount of at least one
isoxazoline active agent, such as, for example, any of the
isoxazoline compounds provided for in the embodiments above (e.g.,
a compound of formulae I-VIa), and optionally at least one
additionally active agent as identified in this application;
[1352] b) a liquid PEG and/or a pharmaceutically acceptable neutral
oil;
[1353] c) at least one co-solvent wherein said co-solvent is not
miscible with water;
[1354] d) optionally, an antioxidant; and
[1355] e) optionally, at least one pharmaceutically acceptable
additive, excipient or mixtures thereof.
[1356] In this disclosure and in the claims, terms such as
"comprises," "comprising," "containing" and "having" and the like
can have the meaning ascribed to them in U.S. patent law and can
mean "includes," "including," and the like; "consisting essentially
of" or "consists essentially" likewise has the meaning ascribed in
U.S. patent law and the term is open-ended, allowing for the
presence of more than that which is recited so long as basic or
novel characteristics of that which is recited is not changed by
the presence of more than that which is recited, but excludes prior
art embodiments. The term "consisting of" excludes any element,
step or ingredient not specified in the claims.
Definitions
[1357] Terms used herein will have their customary meaning in the
art unless specified otherwise. The organic moieties mentioned in
the definitions of the variables of formula (I) are--like the term
halogen--collective terms for individual listings of the individual
group members. The prefix C.sub.n-C.sub.m indicates in each case
the possible number of carbon atoms in the group.
[1358] The term "animal" is used herein to include all mammals,
birds and fish and also include all vertebrate animals. Animals
include, but are not limited to, cats, dogs, cattle, chickens,
cows, deer, goats, horses, llamas, pigs, sheep and yaks. It also
includes an individual animal in all stages of development,
including embryonic and fetal stages. In some embodiments, the
animal will be a non-human animal.
[1359] The term "essentially pure" is used herein to indicate that
a compound or an enantiomer is at least about 90% pure, at least
about 95%, at least about 98% pure, or higher.
[1360] The term "alkyl" refers to saturated straight, branched,
primary, secondary or tertiary hydrocarbons, including those having
1 to 20 atoms. In some embodiments, alkyl groups will include
C.sub.1-C.sub.12, C.sub.1-C.sub.10, C.sub.1-C.sub.8,
C.sub.1-C.sub.6 or C.sub.1-C.sub.4 alkyl groups. Examples of
C.sub.1-C.sub.10 alkyl include, but are not limited to, methyl,
ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,
2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl,
2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl,
hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl,
2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl,
1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,
2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl,
1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,
1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl,
2-ethylhexyl, nonyl and decyl and their isomers.
C.sub.1-C.sub.4-alkyl means for example methyl, ethyl, propyl,
1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or
1,1-dimethyl ethyl.
[1361] Cyclic alkyl groups or "cycloalkyl" include those with 3 to
10 carbon atoms having single or multiple condensed rings. In some
embodiments, cycloalkyl groups include C.sub.4-C.sub.7 or
C.sub.3-C.sub.4 cyclic alkyl groups. Non-limiting examples of
cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
[1362] The alkyl groups described herein can be unsubstituted or
substituted with one or more moieties selected from the group
consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl,
acyloxy, amino, alkyl- or dialkylamino, amido, arylamino, alkoxy,
aryloxy, nitro, cyano, azido, thiol, imino, sulfonic acid, sulfate,
sulfonyl, sulfanyl, sulfinyl, sulfamoyl, ester, phosphonyl,
phosphinyl, phosphoryl, phosphine, thioester, thioether, acid
halide, anhydride, oxime, hydrazine, carbamate, phosphoric acid,
phosphate, phosphonate, or any other viable functional group that
does not inhibit the biological activity of the compounds of the
invention, either unprotected, or protected as necessary, as known
to those skilled in the art, for example, as taught in Greene, et
al., Protective Groups in Organic Synthesis, John Wiley and Sons,
Third Edition, 1999, hereby incorporated by reference.
[1363] Terms including the term "alkyl" such as "alkylcycloalkyl,"
"cycloalkylalkyl," "alkylamino," or "dialkylamino" will be
understood to comprise an alkyl group as defined above linked to
the other functional group, where the group is linked to the
compound through the last group listed, as understood by those of
skill in the art.
[1364] The term "alkenyl" refers to both straight and branched
carbon chains which have at least one carbon-carbon double bond. In
some embodiments, alkenyl groups may include C.sub.2-C.sub.20
alkenyl groups. In other embodiments, alkenyl includes
C.sub.2-C.sub.12, C.sub.2-C.sub.10, C.sub.2-C.sub.8,
C.sub.2-C.sub.6 or C.sub.2-C.sub.4 alkenyl groups. In one
embodiment of alkenyl, the number of double bonds is 1-3, in
another embodiment of alkenyl, the number of double bonds is one or
two. Other ranges of carbon-carbon double bonds and carbon numbers
are also contemplated depending on the location of the alkenyl
moiety on the molecule. "C.sub.2-C.sub.10-alkenyl" groups may
include more than one double bond in the chain. Examples include,
but are not limited to, ethenyl, 1-propenyl, 2-propenyl,
1-methyl-ethenyl, 1-butenyl, 2-butenyl, 3-butenyl,
1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl,
2-methyl-2-propenyl; 1-pentenyl, 2-pentenyl, 3-pentenyl,
4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl,
3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl,
3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl,
3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl,
1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl,
1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl,
3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl,
2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl,
1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl,
4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl,
3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl,
2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl,
1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl,
1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl,
1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl,
1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,
2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl,
2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl,
3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl,
1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl,
2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl,
1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and
1-ethyl-2-methyl-2-propenyl.
[1365] "Alkynyl" refers to both straight and branched carbon chains
which have at least one carbon-carbon triple bond. In one
embodiment of alkynyl, the number of triple bonds is 1-3; in
another embodiment of alkynyl, the number of triple bonds is one or
two. In some embodiments, alkynyl groups include from
C.sub.2-C.sub.20 alkynyl groups. In other embodiments, alkynyl
groups may include C.sub.2-C.sub.12, C.sub.2-C.sub.10,
C.sub.2-C.sub.8, C.sub.2-C.sub.6 or C.sub.2-C.sub.4 alkynyl groups.
Other ranges of carbon-carbon triple bonds and carbon numbers are
also contemplated depending on the location of the alkenyl moiety
on the molecule. For example, the term "C.sub.2-C.sub.10-alkynyl"
as used herein refers to a straight-chain or branched unsaturated
hydrocarbon group having 2 to 10 carbon atoms and containing at
least one triple bond, such as ethynyl, prop-1-yn-1-yl,
prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-1-yn-3-yl, n-but-1-yn-4-yl,
n-but-2-yn-1-yl, n-pent-1-yn-1-yl, n-pent-1-yn-3-yl,
n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent-2-yn-1-yl,
n-pent-2-yn-4-yl, n-pent-2-yn-5-yl, 3-methylbut-1-yn-3-yl,
3-methylbut-1-yn-4-yl, n-hex-1-yn-1-yl, n-hex-1-yn-3-yl,
n-hex-1-yn-4-yl, n-hex-1-yn-5-yl, n-hex-1-yn-6-yl, n-hex-2-yn-1-yl,
n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl, n-hex-3-yn-1-yl,
n-hex-3-yn-2-yl, 3-methylpent-1-yn-1-yl, 3-methylpent-1-yn-3-yl,
3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl,
4-methylpent-1-yn-1-yl, 4-methylpent-2-yn-4-yl or
4-methylpent-2-yn-5-yl and the like.
[1366] The term "haloalkyl" refers to an alkyl group, as defined
herein, which is substituted by one or more halogen atoms. For
example C.sub.1-C.sub.4-haloalkyl includes, but is not limited to,
chloromethyl, bromomethyl, dichloromethyl, trichloromethyl,
fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl,
dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl,
1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl,
2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl,
2,2,2-trichloroethyl, pentafluoroethyl and the like.
[1367] The term "haloalkenyl" refers to an alkenyl group, as
defined herein, which is substituted by one or more halogen
atoms.
[1368] The term "haloalkynyl" refers to an alkynyl group, as
defined herein, which is substituted by one or more halogen
atoms.
[1369] "Alkoxy" refers to alkyl-O--, wherein alkyl is as defined
above. Similarly, the terms "alkenyloxy," "alkynyloxy,"
"haloalkoxy," "haloalkenyloxy," "haloalkynyloxy," "cycloalkoxy,"
"cycloalkenyloxy," "halocycloalkoxy," and "halocycloalkenyloxy"
refer to the groups alkenyl-O--, alkynyl-O--, haloalkyl-O--,
haloalkenyl-O--, haloalkynyl-O--, cycloalkyl-O--, cycloalkenyl-O--,
halocycloalkyl-O--, and halocycloalkenyl-O--, respectively, wherein
alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl,
cycloalkenyl, halocycloalkyl, and halocycloalkenyl are as defined
above. Examples of C.sub.1-C.sub.6-alkoxy include, but are not
limited to, methoxy, ethoxy, C.sub.2H.sub.5--CH.sub.2O--,
(CH.sub.3).sub.2CHO--, n-butoxy, C.sub.2H.sub.5--CH(CH.sub.3)O--,
(CH.sub.3).sub.2CH--CH.sub.2O--, (CH.sub.3).sub.3CO--, n-pentoxy,
1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy,
1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethyl-propoxy,
1-ethylpropoxy, n-hexoxy, 1-methylpentoxy, 2-methylpentoxy,
3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy,
1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy,
2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy,
2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy,
1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxy and the like.
[1370] The term "alkylthio" refers to alkyl-S--, wherein alkyl is
as defined above. Similarly, the terms "haloalkylthio,"
"cycloalkylthio," and the like, refer to haloalkyl-S-- and
cycloalkyl-S--where haloalkyl and cycloalkyl are as defined
above.
[1371] The term "alkylsulfinyl" refers to alkyl-S(O)--, wherein
alkyl is as defined above. Similarly, the term "haloalkylsulfinyl"
refers to haloalkyl-S(O)-- where haloalkyl is as defined above.
[1372] The term "alkylsulfonyl" refers to alkyl-S(O).sub.2--,
wherein alkyl is as defined above.
[1373] Similarly, the term "haloalkylsulfonyl" refers to
haloalkyl-S(O).sub.2-- where haloalkyl is as defined above.
[1374] The term alkylamino and dialkylamino refer to alkyl-NH-- and
(alkyl).sub.2N-where alkyl is as defined above. Similarly, the
terms "haloalkylamino" refers to haloalkyl-NH-- where haloalkyl is
as defined above.
[1375] The terms "alkylcarbonyl," "alkoxycarbonyl,"
"alkylaminocarbonyl," and "dialkylaminocarbonyl" refer to
alkyl-C(O)--, alkoxy-C(O)--, alkylamino-C(O)-- and
dialkylamino-C(O)-- where alkyl, alkoxy, alkylamino and
dialkylamino are as defined above. Similarly, the terms
"haloalkylcarbonyl," "haloalkoxycarbonyl,"
"haloalkylaminocarbonyl," and "dihaloalkylaminocarbonyl" refer to
the groups haloalkyl-C(O)--, haloalkoxy-C(O)--,
haloalkylamino-C(O)-- and dihaloalkylamino-C(O)-- where haloalkyl,
haloalkoxy, haloalkylamino and dihaloalkylamino are as defined
above.
[1376] "Aryl" refers to a monovalent aromatic carbocyclic group of
from 6 to 14 carbon atoms having a single ring or multiple
condensed rings. In some embodiments, aryl groups include
C.sub.6-C.sub.10 aryl groups. Aryl groups include, but are not
limited to, phenyl, biphenyl, naphthyl, tetrahydronaphtyl,
phenylcyclopropyl and indanyl. Aryl groups may be unsubstituted or
substituted by one or more moieties selected from halogen, cyano,
nitro, hydroxy, mercapto, amino, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl,
halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy,
haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkoxy,
cycloalkenyloxy, halocycloalkoxy, halocycloalkenyloxy, alkylthio,
haloalkylthio, cycloalkylthio, halocycloalkylthio, alkylsulfinyl,
alkenylsulfinyl, alkynyl-sulfinyl, haloalkylsulfinyl,
haloalkenylsulfinyl, haloalkynylsulfinyl, alkyl sulfonyl, alkenyl
sulfonyl, alkynylsulfonyl, haloalkyl-sulfonyl, haloalkenyl
sulfonyl, haloalkynyl sulfonyl, alkylamino, alkenylamino,
alkynylamino, di(alkyl)amino, di(alkenyl)-amino, di(alkynyl)amino,
or trialkylsilyl.
[1377] The terms "aralkyl" or "arylalkyl" refers to an aryl group
that is bonded to the parent compound through a diradical alkylene
bridge, (--CH.sub.2--).sub.n, where n is 1-12 and where "aryl" is
as defined above.
[1378] "Heteroaryl" refers to a monovalent aromatic group of from 1
to 15 carbon atoms, preferably from 1 to 10 carbon atoms, having
one or more oxygen, nitrogen, and sulfur heteroatoms within the
ring, preferably 1 to 4 heteroatoms, or 1 to 3 heteroatoms. The
nitrogen and sulfur heteroatoms may optionally be oxidized. Such
heteroaryl groups can have a single ring (e.g., pyridyl or furyl)
or multiple condensed rings provided that the point of attachment
is through a heteroaryl ring atom. Preferred heteroaryls include
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl,
indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinnyl,
furanyl, thiophenyl, furyl, pyrrolyl, imidazolyl, oxazolyl,
isoxazolyl, isothiazolyl, pyrazolyl benzofuranyl, and
benzothiophenyl. Heteroaryl rings may be unsubstituted or
substituted by one or more moieties as described for aryl
above.
[1379] "Heterocyclyl," "heterocyclic" or "heterocyclo" refer to
fully saturated or unsaturated, cyclic groups, for example, 3 to 7
membered monocyclic or 4 to 7 membered monocyclic; 7 to 11 membered
bicyclic, or 10 to 15 membered tricyclic ring systems, which have
one or more oxygen, sulfur or nitrogen heteroatoms in ring,
preferably 1 to 4 or 1 to 3 heteroatoms. The nitrogen and sulfur
heteroatoms may optionally be oxidized and the nitrogen heteroatoms
may optionally be quaternized. The heterocyclic group may be
attached at any heteroatom or carbon atom of the ring or ring
system and may be unsubstituted or substituted by one or more
moieties as described for aryl groups above.
[1380] Exemplary monocyclic heterocyclic groups include, but are
not limited to, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl,
pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl,
oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl,
thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl,
tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,
2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl,
2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl,
pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl,
thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl
sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl,
triazinyl, and the like.
[1381] Exemplary bicyclic heterocyclic groups include, but are not
limited to, indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl,
benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl,
isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl,
benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl,
quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as
furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or
furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such
as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl and the
like.
[1382] Exemplary tricyclic heterocyclic groups include carbazolyl,
benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl,
and the like.
[1383] Halogen means the atoms fluorine, chlorine, bromine and
iodine. The designation of "halo" (e.g. as illustrated in the term
haloalkyl) refers to all degrees of substitutions from a single
substitution to a perhalo substitution (e.g. as illustrated with
methyl as chloromethyl (--CH.sub.2Cl), dichloromethyl
(--CHCl.sub.2), trichloromethyl (--CCl.sub.3)).
[1384] By the term "enriched" is meant when the weight:weight ratio
is at least approximately 1.05 or higher in favor of the enantiomer
that displays significant in vitro and in vivo activity (the
eutomer).
Stereoisomers and Polymorphic Forms
[1385] As noted above, it will be appreciated by those of skill in
the art that certain compounds within the compositions of the
invention may exist and be isolated as optically active and racemic
forms. Compounds having one or more chiral centers, including at a
sulfur atom, may be present as single enantiomers or diastereomers
or as mixtures of enantiomers and/or diastereomers. For example, it
is well known in the art that sulfoxide compounds may be optically
active and may exist as single enantiomers or racemic mixtures. In
addition, compounds within the compositions of the invention may
include one or more chiral centers, which results in a theoretical
number of optically active isomers. Where compounds within the
compositions of the invention include n chiral centers, the
compounds may comprise up to 2.sup.11 optical isomers. The present
invention encompasses compositions comprising the specific
enantiomers or diastereomers of each compound as well as mixtures
of different enantiomers and/or diastereomers of the compounds of
the invention that possess the useful properties described herein.
In addition, the invention encompasses compositions comprising one
or more conformational isomers (e.g. rotamers) as well as mixtures
of conformational isomers. Conformational isomers of the
isoxazoline compounds may be produced by a restriction of rotation
about the amide bond bonded to the aryl or heteroaryl ring (e.g.
the amide bonded to the naphthyl group in formula (I)). The
optically active forms can be prepared by, for example, resolution
of the racemic forms by selective crystallization techniques, by
synthesis from optically active precursors, by chiral synthesis, by
chromatographic separation using a chiral stationary phase or by
enzymatic resolution.
[1386] In addition, the compounds within the compositions of the
invention may exist as hydrates or solvates, in which a certain
stoichiometric amount of water or a solvent is associated with the
molecule in the crystalline form. The compositions of the invention
may include hydrates and solvates of the active agents. In some
embodiments, the compositions of the invention may include up to
15% (w/w), up to 20% (w/w), or up to 30% (w/w) of a particular
solid form.
Salts
[1387] Also contemplated within the scope of the invention are acid
or base salts, where applicable, of the compounds of the invention
provided for herein.
[1388] The term "acid salt" contemplates salts of the compounds
with all pharmaceutically acceptable inorganic or organic acids.
Inorganic acids include mineral acids such as hydrohalic acids such
as hydrobromic acid and hydrochloric acid, sulfuric acid,
phosphoric acids and nitric acid. Organic acids include all
pharmaceutically acceptable aliphatic, alicyclic and aromatic
carboxylic acids, dicarboxylic acids, tricarboxylic acids and fatty
acids. In one embodiment of the acids, the acids are straight chain
or branched, saturated or unsaturated C.sub.1-C.sub.20 aliphatic
carboxylic acids, which are optionally substituted by halogen or by
hydroxyl groups, or C.sub.6-C.sub.12 aromatic carboxylic acids.
Examples of such acids are carbonic acid, formic acid, acetic acid,
propionic acid, isopropionic acid, valeric acid, .alpha.-hydroxy
acids such as glycolic acid and lactic acid, chloroacetic acid,
benzoic acid, methane sulfonic acid, and salicylic acid. Examples
of dicarboxylic acids include oxalic acid, malic acid, succinic
acid, tartaric acid, fumaric acid, and maleic acid. An example of a
tricarboxylic acid is citric acid. Fatty acids include all
pharmaceutically acceptable saturated or unsaturated aliphatic or
aromatic carboxylic acids having 4 to 24 carbon atoms. Examples
include butyric acid, isobutyric acid, sec-butyric acid, lauric
acid, palmitic acid, stearic acid, oleic acid, linoleic acid,
linolenic acid, and phenylsteric acid. Other acids include gluconic
acid, glycoheptonic acid and lactobionic acid.
[1389] The term "base salt" contemplates salts of the compounds
with all pharmaceutically acceptable inorganic or organic bases,
including hydroxides, carbonates or bicarbonates of alkali metal or
alkaline earth metals. Salts formed with such bases include, for
example, the alkali metal and alkaline earth metal salts,
including, but not limited to, as the lithium, sodium, potassium,
magnesium or calcium salts. Salts formed with organic bases include
the common hydrocarbon and heterocyclic amine salts, which include,
for example, ammonium salts (NH4.sup.+), alkyl- and dialkylammonium
salts, and salts of cyclic amines such as the morpholine and
piperidine salts.
[1390] In another embodiment, the long-acting injectable
compositions of present invention comprise an effective amount of
at least one isoxazoline or a pharmaceutically acceptable salt
thereof in combination at least one other active agent. In one
embodiment, the long-acting injectable compositions comprise an
effective amount of at least one isoxazoline compound of formula
(I) to (VI), or a pharmaceutically acceptable salt thereof, in
combination with at least one other active agent that is
systemically-active.
[1391] Additional veterinary/pharmaceutical active ingredients may
be used with the compositions of the invention. In some
embodiments, the additional active agents may include, but are not
limited to, acaricides, anthelmintics, anti-parasitics and
insecticides. Anti-parasitic agents can include both
ectoparasiticidal and/or endoparasiticidal agents.
[1392] Veterinary pharmaceutical agents that may be included in the
compositions of the invention are well-known in the art (see e.g.
Plumb' Veterinary Drug Handbook, 5.sup.th Edition, ed. Donald C.
Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual,
9.sup.th Edition, (January 2005)) and include but are not limited
to acarbose, acepromazine maleate, acetaminophen, acetazolamide,
acetazolamide sodium, acetic acid, acetohydroxamic acid,
acetylcysteine, acitretin, acyclovir, albendazole, albuterol
sulfate, alfentanil, allopurinol, alprazolam, altrenogest,
amantadine, amikacin sulfate, aminocaproic acid, aminopentamide
hydrogen sulfate, aminophylline/theophylline, amiodarone,
amitriptyline, amlodipine besylate, ammonium chloride, ammonium
molybdate, amoxicillin, clavulanate potassium, amphotericin B
desoxycholate, amphotericin B lipid-based, ampicillin, amprolium,
antacids (oral), antivenin, apomorphione, apramycin sulfate,
ascorbic acid, asparaginase, aspiring, atenolol, atipamezole,
atracurium besylate, atropine sulfate, aurnofin, aurothioglucose,
azaperone, azathioprine, azithromycin, baclofen, barbituates,
benazepril, betamethasone, bethanechol chloride, bisacodyl, bismuth
sub salicylate, bleomycin sulfate, boldenone undecylenate,
bromides, bromocriptine mesylate, budenoside, buprenorphine,
buspirone, busulfan, butorphanol tartrate, cabergoline, calcitonin
salmon, calcitrol, calcium salts, captopril, carbenicillin indanyl
sodium, carbimazole, carboplatin, carnitine, carprofen, carvedilol,
cefadroxil, cefazolin sodium, cefixime, clorsulon, cefoperazone
sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium,
cefpodoxime proxetil, ceftazidime, ceftiofur sodium, ceftiofur,
ceftiaxone sodium, cephalexin, cephalosporins, cephapirin, charcoal
(activated), chlorambucil, chloramphenicol, chlordiazepoxide,
chlordiazepoxide+/-clidinium bromide, chlorothiazide,
chlorpheniramine maleate, chlorpromazine, chlorpropamide,
chlortetracycline, chorionic gonadotropin (HCG), chromium,
cimetidine, ciprofloxacin, cisapride, cisplatin, citrate salts,
clarithromycin, clemastine fumarate, clenbuterol, clindamycin,
clofazimine, clomipramine, claonazepam, clonidine, cloprostenol
sodium, clorazepate dipotassium, clorsulon, cloxacillin, codeine
phosphate, colchicine, corticotropin (ACTH), cosyntropin,
cyclophosphamide, cyclosporine, cyproheptadine, cytarabine,
dacarbazine, dactinomycin/actinomycin D, dalteparin sodium,
danazol, dantrolene sodium, dapsone, decoquinate, deferoxamine
mesylate, deracoxib, deslorelin acetate, desmopressin acetate,
desoxycorticosterone pivalate, detomidine, dexamethasone,
dexpanthenol, dexraazoxane, dextran, diazepam, diazoxide (oral),
dichlorphenamide, diclofenac sodium, dicloxacillin,
diethylcarbamazine citrate, diethylstilbestrol (DES), difloxacin,
digoxin, dihydrotachysterol (DHT), diltiazem, dimenhydrinate,
dimercaprol/BAL, dimethyl sulfoxide, dinoprost tromethamine,
diphenylhydramine, disopyramide phosphate, dobutamine,
docusate/DSS, dolasetron mesylate, domperidone, dopamine,
doramectin, doxapram, doxepin, doxorubicin, doxycycline, edetate
calcium disodium.calcium EDTA, edrophonium chloride,
enalapril/enalaprilat, enoxaparin sodium, enrofloxacin, ephedrine
sulfate, epinephrine, epoetin/erythropoietin, eprinomectin,
epsiprantel, erythromycin, esmolol, estradiol cypionate, ethacrynic
acid/ethacrynate sodium, ethanol (alcohol), etidronate sodium,
etodolac, etomidate, euthanasia agents w/pentobarbital, famotidine,
fatty acids (essential/omega), felbamate, fentanyl, ferrous
sulfate, filgrastim, finasteride, fipronil, florfenicol,
fluconazole, flucytosine, fludrocortisone acetate, flumazenil,
flumethasone, flunixin meglumine, fluorouracil (5-FU), fluoxetine,
fluticasone propionate, fluvoxamine maleate, fomepizole (4-MP),
furazolidone, furosemide, gabapentin, gemcitabine, gentamicin
sulfate, glimepiride, glipizide, glucagon, glucocorticoid agents,
glucosamine/chondroitin sulfate, glutamine, glyburide, glycerin
(oral), glycopyrrolate, gonadorelin, grisseofulvin, guaifenesin,
halothane, hemoglobin glutamer-200 (OXYGLOBIN.RTM.), heparin,
hetastarch, hyaluronate sodium, hydrazaline, hydrochlorothiazide,
hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea,
hydroxyzine, ifosfamide, imidacloprid, imidocarb dipropinate,
impenem-cilastatin sodium, imipramine, inamrinone lactate, insulin,
interferon alfa-2a (human recombinant), iodide (sodium/potassium),
ipecac (syrup), ipodate sodium, iron dextran, isoflurane,
isoproterenol, isotretinoin, isoxsuprine, itraconazole, ivermectin,
kaolin/pectin, ketamine, ketoconazole, ketoprofen, ketorolac
tromethamine, lactulose, leuprolide, levamisole, levetiracetam,
levothyroxine sodium, lidocaine, lincomycin, liothyronine sodium,
lisinopril, lomustine (CCNU), lufenuron, lysine, magnesium,
mannitol, marbofloxacin, mechlorethamine, meclizine, meclofenamic
acid, medetomidine, medium chain triglycerides, medroxyprogesterone
acetate, megestrol acetate, melarsomine, melatonin, meloxican,
melphalan, meperidine, mercaptopurine, meropenem, metformin,
methadone, methazolamide, methenamine mandelate/hippurate,
methimazole, methionine, methocarbamol, methohexital sodium,
methotrexate, methoxyflurane, methylene blue, methylphenidate,
methylprednisolone, metoclopramide, metoprolol, metronidaxole,
mexiletine, mibolerlone, midazolam milbemycin oxime, mineral oil,
minocycline, misoprostol, mitotane, mitoxantrone, morphine sulfate,
moxidectin, naloxone, mandrolone decanoate, naproxen, narcotic
(opiate) agonist analgesics, neomycin sulfate, neostigmine,
niacinamide, nitazoxanide, nitenpyram, nitrofurantoin,
nitroglycerin, nitroprusside sodium, nizatidine, novobiocin sodium,
nystatin, octreotide acetate, olsalazine sodium, omeprozole,
ondansetron, opiate antidiarrheals, orbifloxacin, oxacillin sodium,
oxazepam, oxibutynin chloride, oxymorphone, oxytretracycline,
oxytocin, pamidronate disodium, pancreplipase, pancuronium bromide,
paromomycin sulfate, parozetine, pencillamine, general information
penicillins, penicillin G, penicillin V potassium, pentazocine,
pentobarbital sodium, pentosan polysulfate sodium, pentoxifylline,
pergolide mesylate, phenobarbital, phenoxybenzamine, pheylbutazone,
phenylephrine, phenypropanolamine, phenytoin sodium, pheromones,
parenteral phosphate, phytonadione/vitamin K-1, pimobendan,
piperazine, pirlimycin, piroxicam, polysulfated glycosaminoglycan,
ponazuril, potassium chloride, pralidoxime chloride, prazosin,
prednisolone/prednisone, primidone, procainamide, procarbazine,
prochlorperazine, propantheline bromide, propionibacterium acnes
injection, propofol, propranolol, protamine sulfate,
pseudoephedrine, psyllium hydrophilic mucilloid, pyridostigmine
bromide, pyrilamine maleate, pyrimethamine, quinacrine, quinidine,
ranitidine, rifampin, s-adenosyl-methionine (SAMe),
saline/hyperosmotic laxative, selamectin, selegiline/1-deprenyl,
sertraline, sevelamer, sevoflurane, silymarin/milk thistle, sodium
bicarbonate, sodium polystyrene sulfonate, sodium stibogluconate,
sodium sulfate, sodum thiosulfate, somatotropin, sotalol,
spectinomycin, spironolactone, stanozolol, streptokinase,
streptozocin, succimer, succinylcholine chloride, sucralfate,
sufentanil citrate, sulfachlorpyridazine sodium,
sulfadiazine/trimethroprim, sulfamethoxazole/trimethoprim,
sulfadimentoxine, sulfadimethoxine/ormetoprim, sulfasalazine,
taurine, tepoxaline, terbinafline, terbutaline sulfate,
testosterone, tetracycline, thiacetarsamide sodium, thiamine,
thioguanine, thiopental sodium, thiotepa, thyrotropin, tiamulin,
ticarcilin disodium, tiletamine/zolazepam, tilmocsin, tiopronin,
tobramycin sulfate, tocainide, tolazoline, telfenamic acid,
topiramate, tramadol, trimcinolone acetonide, trientine,
trilostane, trimepraxine tartrate w/prednisolone, tripelennamine,
tylosin, urdosiol, valproic acid, vanadium, vancomycin,
vasopressin, vecuronium bromide, verapamil, vinblastine sulfate,
vincristine sulfate, vitamin E/selenium, warfarin sodium, xylazine,
yohimbine, zafirlukast, zidovudine (AZT), zinc acetate/zinc
sulfate, zonisamide and mixtures thereof.
[1393] In one embodiment of the invention, arylpyrazole compounds
such as phenylpyrazoles, known in the art may be combined with the
isoxazoline compounds in the long-acting injectable compositions of
the invention. Examples of such arylpyrazole compounds include but
are not limited to those described in U.S. Pat. Nos. 6,001,384;
6,010,710; 6,083,519; 6,096,329; 6,174,540; 6,685,954 and 6,998,131
(all of which are incorporated herein by reference, each assigned
to Merial, Ltd., Duluth, Ga.).
[1394] In another embodiment of the invention, one or more
macrocyclic lactones or lactams, which act as an acaricide,
anthelmintic agent and/or insecticide, can be added to the
compositions of the invention.
[1395] The macrocyclic lactones include, but are not limited to,
avermectins such as abamectin, dimadectin, doramectin, emamectin,
eprinomectin, ivermectin, latidectin, lepimectin, selamectin and
ML-1,694,554, and milbemycins such as milbemectin, milbemycin D,
milbemycin oxime, moxidectin and nemadectin. Also included are the
5-oxo and 5-oxime derivatives of said avermectins and milbemycins.
Examples of combinations of arylpyrazole compounds with macrocyclic
lactones include but are not limited to those described in U.S.
Pat. Nos. 6,426,333; 6,482,425; 6,962,713 and 6,998,131 (all
incorporated herein by reference--each assigned to Merial, Ltd.,
Duluth, Ga.).
[1396] The macrocyclic lactone compounds are known in the art and
can easily be obtained commercially or through synthesis techniques
known in the art. Reference is made to the widely available
technical and commercial literature. For avermectins, ivermectin
and abamectin, reference may be made, for example, to the work
"Ivermectin and Abamectin", 1989, by M. H. Fischer and H. Mrozik,
William C. Campbell, published by Springer Verlag., or
Albers-Schonberg et al. (1981), "Avermectins Structure
Determination", J. Am. Chem. Soc., 103, 4216-4221. For doramectin,
"Veterinary Parasitology", vol. 49, No. 1, July 1993, 5-15 may be
consulted. For milbemycins, reference may be made, inter alia, to
Davies H. G. et al., 1986, "Avermectins and Milbemycins", Nat.
Prod. Rep., 3, 87-121, Mrozik H. et al., 1983, Synthesis of
Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336,
U.S. Pat. No. 4,134,973 and EP 0 677 054.
[1397] Macrocyclic lactones are either natural products or are
semi-synthetic derivatives thereof. The structure of the
avermectins and milbemycins are closely related, e.g., by sharing a
complex 16-membered macrocyclic lactone ring. The natural product
avermectins are disclosed in U.S. Pat. No. 4,310,519 and the
22,23-dihydro avermectin compounds are disclosed in U.S. Pat. No.
4,199,569. Mention is also made of U.S. Pat. Nos. 4,468,390,
5,824,653, EP 0 007 812 A1, U.K. Patent Specification 1 390 336, EP
0 002 916, and New Zealand Patent No. 237 086, inter alia.
Naturally occurring milbemycins are described in U.S. Pat. No.
3,950,360 as well as in the various references cited in "The Merck
Index" 12.sup.th ed., S. Budavari, Ed., Merck & Co., Inc.
Whitehouse Station, N.J. (1996). Latidectin is described in the
"International Nonproprietary Names for Pharmaceutical Substances
(INN)", WHO Drug Information, vol. 17, no. 4, pp. 263-286, (2003).
Semisynthetic derivatives of these classes of compounds are well
known in the art and are described, for example, in U.S. Pat. Nos.
5,077,308, 4,859,657, 4,963,582, 4,855,317, 4,871,719, 4,874,749,
4,427,663, 4,310,519, 4,199,569, 5,055,596, 4,973,711, 4,978,677,
4,920,148 and EP 0 667 054.
[1398] In another embodiment of the invention, the invention
comprises a long-acting injectable composition comprising an
isoxazoline compound in combination with systemically-acting
compounds from a class of acaricides or insecticides known as
insect growth regulators (IGRs). Compounds belonging to this group
are well known to the practitioner and represent a wide range of
different chemical classes. These compounds all act by interfering
with the development or growth of the insect pests. Insect growth
regulators are described, for example, in U.S. Pat. Nos. 3,748,356,
3,818,047, 4,225,598, 4,798,837, 4,751,225, EP 0 179 022 or U.K. 2
140 010 as well as U.S. Pat. Nos. 6,096,329 and 6,685,954 (all
incorporated herein by reference).
[1399] In one embodiment the IGR is a compound that mimics juvenile
hormone. Examples of juvenile hormone mimics include azadirachtin,
diofenolan, fenoxycarb, hydroprene, kinoprene, methoprene,
pyriproxyfen, tetrahydroazadirachtin and
4-chloro-2(2-chloro-2-methyl-propyl)-5-(6-iodo-3-pyridylmethoxy)pyridazin-
e-3 (2H)-one.
[1400] In an embodiment, the long-acting injectable compositions of
present invention comprise an effective amount of at least one
isoxazoline of formula (I) to (VIa), or a pharmaceutically
acceptable salt thereof, in combination with methoprene or
pyriproxyfen.
[1401] In another embodiment, the IGR compound is a chitin
synthesis inhibitor. Chitin synthesis inhibitors include
chlorofluazuron, cyromazine, diflubenzuron, fluazuron,
flucycloxuron, flufenoxuron, hexaflumoron, lufenuron, tebufenozide,
teflubenzuron, triflumuron, novaluron, 1-(2,
6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea,
1-(2,6-difluoro-benzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)-phenyl-
urea and 1-(2,
6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea.
[1402] In yet another embodiment of the invention, adulticide
insecticides and acaricides can also be added to the long-acting
compositions of the present invention. These include pyrethrins
(which include cinerin I, cinerin II, jasmolin I, jasmolin II,
pyrethrin I, pyrethrin II and mixtures thereof) and pyrethroids,
and carbamates including, but are not limited to, benomyl,
carbanolate, carbaryl, carbofuran, methiocarb, metolcarb, promacyl,
propoxur, aldicarb, butocarboxim, oxamyl, thiocarboxime and
thiofanox. In one embodiment, the compositions can include
permethrin in combination with an isoxazoline active agent.
[1403] In some embodiments, the long-acting injectable compositions
of the present invention may include one or more antinematodal
agents including, but not limited to, active agents in the
benzimidazoles, imidazothiazoles, tetrahydropyrimidines, and
organophosphate class of compounds. In some embodiments,
benzimidazoles including, but not limited to, thiabendazole,
cambendazole, parbendazole, oxibendazole, mebendazole,
flubendazole, fenbendazole, oxfendazole, albendazole,
cyclobendazole, febantel, thiophanate and its o,o-dimethyl analogue
may be included in the compositions.
[1404] In other embodiments, the long-acting injectable
compositions of the present invention may include an
imidazothiazole compounds including, but not limited to,
tetramisole, levamisole and butamisole. In still other embodiments,
the long-acting compositions of the present invention may include
tetrahydropyrimidine active agents including, but not limited to,
pyrantel, oxantel, and morantel. Suitable organophosphate active
agents include, but are not limited to, coumaphos, trichlorfon,
haloxon, naftalofos and dichlorvos, heptenophos, mevinphos,
monocrotophos, TEPP, and tetrachlorvinphos.
[1405] In other embodiments, the long-acting injectable
compositions of the present invention may include the antinematodal
compounds phenothiazine and piperazine as the neutral compound or
in various salt forms, diethylcarbamazine, phenols such as
disophenol, arsenicals such as arsenamide, ethanolamines such as
bephenium, thenium closylate, and methyluridine; cyanine dyes
including pyrvinium chloride, pyrvinium pamoate and dithiazanine
iodide; isothiocyanates including bitoscanate, suramin sodium,
phthalofyne, and various natural products including, but not
limited to, hygromycin B, .alpha.-santonin and kainic acid.
[1406] In other embodiments, the long-acting injectable
compositions of the present invention of the invention may include
anti-trematodal agents. Suitable anti-trematodal agents include,
but are not limited to, the miracils such as miracil D and mirasan;
praziquantel, clonazepam and its 3-methyl derivative, oltipraz,
lucanthone, hycanthone, oxamniquine, amoscanate, niridazole,
nitroxynil, various bisphenol compounds known in the art including
hexachlorophene, bithionol, bithionol sulfoxide and menichlopholan;
various salicylanilide compounds including tribromsalane,
oxyclozanide, diloxanide, rafoxanide, brotianide, bromoxanide and
closantel; triclabendazole, diamfenetide, clorsulon, hetolin and
emetine.
[1407] Anticestodal compounds may also be advantageously used in
the long-acting compositions of the present invention of the
invention including, but not limited to, arecoline in various salt
forms, bunamidine, niclosamide, nitroscanate, paromomycin and
paromomycin II.
[1408] In yet other embodiments, the long-acting injectable
compositions of the present invention may include other active
agents that are effective against arthropod parasites. Suitable
active agents include, but are not limited to, bromocyclen,
chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene,
bromophos, bromophos-ethyl, carbophenothion, chlorfenvinphos,
chlorpyrifos, crotoxyphos, cythioate, diazinon, dichlorenthion,
diemthoate, dioxathion, ethion, famphur, fenitrothion, fenthion,
fospirate, iodofenphos, malathion, naled, phosalone, phosmet,
phoxim, propetamphos, ronnel, stirofos, allethrin, cyhalothrin,
cypermethrin, deltamethrin, fenvalerate, flucythrinate, permethrin,
phenothrin, pyrethrins, resmethrin, benzyl benzoate, carbon
disulfide, crotamiton, diflubenzuron, diphenylamine, disulfiram,
isobornyl thiocyanato acetate, methoprene, monosulfiram,
pirenonylbutoxide, rotenone, triphenyltin acetate, triphenyltin
hydroxide, deet, dimethyl phthalate, and the compounds
1,5a,6,9,9a,9b-hexahydro-4a(4H)-dibenzofurancarboxaldehyde
(MGK-11), 2-(2-ethylhexyl)-3a,4, 7,7a-tetrahydro-4,
7-methano-1H-isoindole-1,3 (2H)dione (MGK-264),
dipropyl-2,5-pyridinedicarboxylate (MGK-326) and
2-(octylthio)ethanol (MGK-874).
[1409] An antiparasitic agent that can be combined with an
isoxazoline compounds in the long-acting compositions of the
present invention can be a biologically active peptide or protein
including, but not limited to, depsipeptides, which act at the
neuromuscular junction by stimulating presynaptic receptors
belonging to the secretin receptor family resulting in the
paralysis and death of parasites. In one embodiment of the
depsipeptide, the depsipeptide is emodepside (see Willson et al.,
Parasitology, January 2003, 126(Pt 1):79-86). In another
embodiment, the depsipeptide is PF1022A or a derivative
thereof.
[1410] In another embodiment, the long-acting injectable
compositions of the present invention may comprise an active agent
from the neonicotinoid class of pesticides. The neonicotinoids bind
and inhibit insect specific nicotinic acetylcholine receptors. In
one embodiment, the neonicotinoid insecticidal agent that can be
combined with an isoxazoline compound to form a long-acting
injectable composition of the invention is imidacloprid.
Imidacloprid is a well-known neonicotinoid active agent and is the
key active ingredient in the topical parasiticide products
Advantage.RTM., Advantage.RTM. II, K9 Advantix.RTM., and K9
Advantix.RTM. II sold by Bayer Animal Health and the oral
soft-chewable composition Advantus.TM. from Piedmont Animal Health.
Agents of this class are described, for example, in U.S. Pat. No.
4,742,060 or in EP 0 892 060.
[1411] In another embodiment, the long-acting injectable
compositions of the present invention may comprise nitenpyram,
another active agent of the neonicotinoid class of pesticides.
Nitenpyram has the following chemical structure and is the active
ingredient in the oral product CAPSTAR.TM. Tablets sold by Novartis
Animal Health.
##STR00032##
[1412] Nitenpyram is active against adult fleas when given daily as
an oral tablet. Nitenpyram works by interfering with normal nerve
transmission and leads to the death of the insect. Nitenpyram has a
very fast onset of action against fleas. For example, CAPSTAR.TM.
Tablets begin to act against fleas in as early as 30 minutes after
administration and is indicated for use as often as once a day.
However, nitenpyram is only known to be effective when administered
orally as a systemic parasiticide, as with CAPSTAR.TM. Tablets.
[1413] In yet another embodiment, the invention provides the
long-acting compositions of the present invention comprising
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-naphthalan-
ecarboxamide (Compound of formula Ia) in combination with
nitenpyram.
[1414] In yet another embodiment, the invention provides the
long-acting compositions of the present invention comprising
4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,
5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroe-
thyl)amino]ethyl]-1-naphthalanecarboxamide (Compound of formula Ia)
in combination with imidacloprid. In certain embodiments, an
insecticidal agent that can be combined with the long-acting
compositions of the present invention is a semicarbazone, such as
metaflumizone.
[1415] In another embodiment, the long-acting injectable
compositions of the present invention may advantageously include a
combination of isoxazoline compounds known in the art. These active
agents are described in WO 2007/079162, WO 2007/075459 and US
2009/0133319, WO 2007/070606 and US 2009/0143410, WO 2009/003075,
WO 2009/002809, WO 2009/024541, WO 2005/085216 and US 2007/0066617
and WO 2008/122375, all of which are incorporated herein by
reference in their entirety.
[1416] In another embodiment of the invention, nodulisporic acid
and its derivatives (a class of known acaricidal, anthelmintic,
anti-parasitic and insecticidal agents) may be added to the
long-acting compositions of the present invention. These compounds
are used to treat or prevent infections in humans and animals and
are described, for example, in U.S. Pat. Nos. 5,399,582, 5,962,499,
6,221,894 and 6,399,786, all of which are hereby incorporated by
reference in their entirety. The compositions may include one or
more of the known nodulisporic acid derivatives in the art,
including all stereoisomers, such as those described in the patents
cited above.
[1417] In another embodiment, anthelmintic compounds of the amino
acetonitrile class (AAD) of compounds such as monepantel (ZOLVIX),
and the like, may be added to the. the long-acting compositions of
the present invention These compounds are described, for example,
in WO 2004/024704 and U.S. Pat. No. 7,084,280 (incorporated by
reference); Sager et al., Veterinary Parasitology, 2009, 159,
49-54; Kaminsky et al., Nature vol. 452, 13 Mar. 2008, 176-181.
[1418] The compositions of the invention may also include
aryloazol-2-yl cyanoethylamino compounds such as those described in
U.S. Pat. No. 8,088,801 to Soll et al., which is incorporated
herein in its entirety, and thioamide derivatives of these
compounds, as described in U.S. Pat. No. 7,964,621, which is
incorporated herein by reference.
[1419] The long-acting injectable compositions of the present
invention may also be combined with paraherquamide compounds and
derivatives of these compounds, including derquantel (see Ostlind
et al., Research in Veterinary Science, 1990, 48, 260-61; and
Ostlind et al., Medical and Veterinary Entomology, 1997, 11,
407-408). The paraherquamide family of compounds is a known class
of compounds that include a spirodioxepino indole core with
activity against certain parasites (see Tet. Lett. 1981, 22, 135;
J. Antibiotics 1990, 43, 1380, and J. Antibiotics 1991, 44, 492).
In addition, the structurally related marcfortine family of
compounds, such as marcfortines A-C, are also known and may be
combined with the compositions of the invention (see J. Chem.
Soc.--Chem. Comm. 1980, 601 and Tet. Lett. 1981, 22, 1977). Further
references to the paraherquamide derivatives can be found, for
example, in WO 91/09961, WO 92/22555, WO 97/03988, WO 01/076370, WO
09/004432, U.S. Pat. No. 5,703,078 and U.S. Pat. No. 5,750,695, all
of which are hereby incorporated by reference in their
entirety.
[1420] In general, the additional active agent is included in the
long-acting compositions of the present invention in an amount of
between about 0.1 .mu.g and about 1000 mg. More typically, the
additional active agent may be included in an amount of about 10
.mu.g to about 500 mg, about 1 mg to about 300 mg, about 10 mg to
about 200 mg or about 10 mg to about 100 mg.
[1421] In other embodiments of the invention, the additional active
agent may be included in the composition to deliver a dose of about
5 .mu.g/kg to about 50 mg/kg per weight of the animal. In other
embodiments, the additional active agent may be present in an
amount sufficient to deliver a dose of about 0.01 mg/kg to about 30
mg/kg, about 0.1 mg/kg to about 20 mg/kg, or about 0.1 mg/kg to
about 10 mg/kg of weight of animal. In other embodiments, the
additional active agent may be present in a dose of about 5
.mu.g/kg to about 200 .mu.g/kg or about 0.1 mg/kg to about 1 mg/kg
of weight of animal. In still another embodiment of the invention,
the additional active agent is included in a dose between about 0.5
mg/kg to about 50 mg/kg.
[1422] The long-acting compositions of the present invention, which
include at least an isoxazoline active agent, at least one liquid
PEG and/or a neutral oil and optionally a co-solvent, have been
surprisingly discovered to be stable and effective against a broad
spectrum of ectoparasites, and possibly also endoparasites if
another active is included, for an extended period of time; e.g., a
period from three (3) to six (6) months while exhibiting favorable
properties with respect to the site of injection.
[1423] Liquid PEGs as provided for herein are those polyethylene
glycols that are liquid at room temperature (20-30.degree. C.).
Polyethylene glycols have the following structural formula:
H--(O--CH.sub.2--CH.sub.2).sub.n--OH.
Non-limiting examples for n in the above formula are those
compounds when n is from 1 to about 10,000 (e.g., from about 4 to
about 25). Liquid PEGs include combinations of different
polyethylene glycols. Non-limiting examples of liquid PEGs include
PEG 200, PEG 300, PEG 400, PEG 600, and PEG 1000 or combinations
thereof.
[1424] Pharmaceutically acceptable polymers other than PEGs are
specifically excluded from the inventive long-acting compositions.
Examples of pharmaceutically acceptable polymers that are
specifically excluded from the inventive long-acting compositions
include polylactides, polyglycolides, polycaprolactones,
polyanhydrides, polyamides, polyurethanes, polyester amides,
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,
and copolymers, terpolymers, or combinations or mixtures therein
including copolymers of polylactides, polycaprolactones,
polyglycolides (e.g., poly(lactide-co-glycolide).
[1425] In some embodiments, poloxamers may be included in the
compositions. For the purpose of the compositions described herein,
poloxamers are not considered pharmaceutically-acceptable polymers
but solvents or surfactants. Poloxamers are a family of synthetic
block copolymers of ethylene oxide and propylene oxide. Poloxamers
may be liquid, a milky white paste or a powder and are represented
by the following structure:
##STR00033##
[1426] where a is an integer between 2 and 130 and b is an integer
between 15 and 67 (see, U.S. Pat. No. 3,740,421, incorporated
herein by reference). Poloxamer are available from commercial
sources such as BASF and Croda. An example of a poloxamer that may
be used in the compositions of the invention is P-124 which is a
solid at room temperature. The viscosity of the long-acting
injectable compositions is an important parameter with respect to
the ability to easily administer the composition to animals.
Typically, viscosities of about less than 150 centipois (cPs) are
acceptable. Thus, in one embodiment, the viscosity of the
compositions of the invention at 25.degree. C. is about less than
150 cPs. In other embodiments, the viscosity of the compositions of
the invention are 25.degree. C. is about less than 140 cPs, less
than about 130 cPs or less than about 120 cPs. In other
embodiments, the viscosity of the compositions of the invention at
25.degree. C. is about less than 110 cPs or less than about 100
cPs.
[1427] The co-solvents used in the long-acting injectable
compositions may be a single or a blend of co-solvents. Co-solvents
may be used in the compositions of the invention to improve the
solubility of the isoxazoline active agent and/or to lower the
viscosity of the compositions. In one embodiment, the co-solvents
used in the long-acting injectable compositions of the present
invention include polar solvents that are miscible in water.
Non-limiting examples of these co-solvents include ethanol,
isopropanol, glycol ethers (e.g., including, but limited to,
diethyleneglycol monoethyl ether (DGME, Transcutol.RTM.), butyl
diglycol, dipropylene glycol n-butyl ether, ethyleneglycol
monoethyl ether, ethyleneglycol monomethyl ether, dipropylene
glycol monomethyl ether, propylene glycol monomethyl ether,
propylene glycol monoethyl ether, and the like), propylene glycol,
glycerin, carbonates (e.g., propylene carbonate or ethylene
carbonate), 2-pyrrolidone, substituted 2-pyrrolidones including
N-methylpyrrolidone, 1-ethylpyrrolidone, 1-octylpyrrolidone,
1-dodecylpyrrolidone, 1-isopropylpyrrolidone, 1-(sec- or t- or
n-butyl)pyrrolidone, 1-hexylpyrrolidone, 1-vinyl-2-pyrrolidone,
1-cyclohexylpyrrolidone, 1-(2-hydroxyethyl)-pyrrolidone,
1-(3-hydroxypropyl)pyrrolidone, 1-(2-methoxyethyl)-pyrrolidone,
1-(3-methoxypropyl)pyrrolidone and 1-benzylpyrrolidone; dimethyl
isosorbide (DMI), dimethylacetamide (DMA), dimethylsulfoxide
(DMSO), glycerol formal or a mixture of at least two of these
solvents.
[1428] In one embodiment, the long-acting compositions of the
invention comprise a polar protic solvent including, but not
limited to, an alcohol such a C.sub.1-C.sub.6alcohol including, but
not limited to, ethanol, isopropanol. In another embodiment, the
polar protic solvent is a glycol, such as glycerol or propylene
glycol, or a glycol ether such as diethylene glycol monoethyl ether
(Transcutol) or other commonly used glycol ethers such as those
described above.
[1429] In another embodiment, the long-acting injectable
compositions of the invention comprise a polar aprotic solvent
including, but not limited to, N-methylpyrrolidone, dimethyl
isosorbide, dimethylacetamide, dimethylsulfoxide or propylene
carbonate.
[1430] In yet another embodiment of the invention, the compositions
of the invention include non-water miscible co-solvents or solvents
with only partial solubility in water. Non-water miscible solvents
include esters of aliphatic carboxylic acids (including fatty
acids) and glycerol (glycerides) or esters of aliphatic carboxylic
acids (including fatty acids) and propylene glycol. Non-water
miscible solvents also include oils that are acceptable for
injectable compositions. Non-limiting examples of these co-solvents
include benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin,
lipids, triglycerides including medium chain triglycerides such
C.sub.8-C.sub.10 triglycerides such as capric/caprilic
triglycerides, propylene glycol derivatives (e.g. propylene glycol
monolaurate), caprylocaproyl polyoxyl-8 glycerides (Labrasol)
(non-ionic water dispersible surfactant, isopropyl myristate, or a
mixture of at least two of these co-solvents.
[1431] In one embodiment, the composition of the invention may
include pharmaceutically acceptable neutral oils as a main
component of the composition or as a co-solvent with the liquid
PEG. When a neutral oil us used in combination with a liquid PEG,
it may be necessary to use a bridging solvent or a surfactant to
ensure miscibility. Some neutral oils are triglycerides of
fractionated plant fatty acids with chain lengths of C.sub.8 to
C.sub.10, including caprylic/capric triglycerides. Two commercially
available products are known as MIGLYOL.RTM. 810 and MIGLYOL.RTM.
812. In another embodiment, the neutral oil is a triglyceride of
fractionated plant fatty acids with chain lengths of C.sub.8 and
C.sub.10 combined with linoleic acid (about 4-5%). A commercially
available product is known as MIGLYOL.RTM. 818. In yet another
embodiment, the neutral oil is a glycerin ester of fractionated
plant fatty acids with chain lengths of C.sub.8 and C.sub.10
combined with succinic acid. A commercially available product is
known as MIGLYOL.RTM. 829. In another embodiment, the neutral oil
may be a propylene glycol diester of saturated plant fatty acids
with chain lengths of C.sub.8 and C.sub.10. A commercially
available product is known as MIGLYOL.RTM. 840 (propylene glycol
dicaprylate/dicaprate). In yet another embodiment, the co-solvent
may be a mixture of two or more neutral oils. Other oils that are
acceptable to include in the long-acting injectable compositions of
the invention include, but are not limited to, castor oil,
cottonseed oil, sesame oil, soybean oil and safflower oil.
[1432] In one embodiment, the compositions of the invention may
comprise about 0.5% to about 70% (w/v) of a co-solvent. In another
embodiment, the compositions of the invention may comprise about
0.5% to about 60% (w/v) or about 1 to about 50% (w/v) of a
co-solvent. In still another embodiment, the compositions may
comprise about 1% to about 40% (w/v), about 5% to about 50% (w/v),
about 5% to about 40% (w/v) or about 5% to about 35% (w/v) of a
co-solvent. In other embodiments, the compositions of the invention
may comprise about 1% to about 20% (w/v), about 2% to about 15%
(w/v) or about 2% to about 10% (w/v) of the co-solvent.
[1433] The long-acting injectable compositions of the invention may
include pharmaceutically acceptable additives or excipients.
Pharmaceutically acceptable additives and excipients include, but
are not limited to, surfactants, antioxidants, preservatives, pH
stabilizing agents (e.g. buffers), and other non-active excipients.
In another embodiment, the compositions of the invention may
comprise about 0.01% to about 20% (w/v) of a pharmaceutically
acceptable additive, excipient or mixtures thereof. In other
embodiments, the compositions may comprise about 0.01% to about 5%
(w/v), about 0.1% to about 10% (w/v) or about 0.1% to about 5%
(w/v) of a pharmaceutically acceptable additive, excipient or
mixtures thereof. In other embodiments the compositions may
comprise about 5 to about 15% (w/v) or about 5 to about 10% (w/v)
of a pharmaceutically acceptable additive, excipient or mixtures
thereof. In yet another embodiment, the compositions may comprise
about 7 to about 10% of a pharmaceutically acceptable additive,
excipient or mixtures thereof.
[1434] Surfactants may be present in the inventive compositions at
concentrations of about 0.1% to about 10% (w/w), about 1% to about
10% (w/w) or about 5% to about 10% (w/w). More typically,
surfactants may be present at concentrations of about 0.1% to about
5% (w/w) or about 1 to about 5% (w/w). Examples of surfactants that
may be used in the compositions include, but are not limited to,
glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters,
sorbitan esters including sorbitan monooleate (Span.RTM. 20),
polyvinyl alcohol, polysorbates including polysorbate 20 and
polysorbate 80, d-a-tocopherol polyethylene glycol 1000 succinate
(TPGS), sodium lauryl sulfate, co-polymers of ethylene oxide and
propylene oxide (e.g. poloxamers such as LUTROL.RTM. F87 and the
like), polyethylene glycol castor oil derivatives including
polyoxyl 35 castor oil (Cremophor.RTM. EL), polyoxyl 40
hydrogenated castor oil (Cremophor.RTM. RH 40), polyoxyl 60
hydrogenated castor oil (Cremophor.RTM. RH60); propylene glycol
monolaurate (LAUROGLYCOL.RTM.); glyceride esters including glycerol
caprylate/caprate (CAPMUL.RTM. MCM), polyglycolized
glycerides)(GELUCIRE.RTM., PEG 300 caprylic/capric glycerides
(Softigen.RTM. 767), PEG 400 caprylic/capric glycerides
(Labrasol.RTM.), PEG 300 oleic glycerides (Labrafil.RTM. M-1944CS),
PEG 300 linoleic glycerides (Labrafil.RTM. M-2125CS); polyethylene
glycol stearates and polyethylene glycol hydroxy stearates
including polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl 40
stearate (PEG 1750 monostearate, and the like). Polyethylene glycol
stearates (synonyms include macrogol stearates, polyoxylstearates,
polyoxyethylene stearates, ethoxylated stearates; CAS No.
9004-99-3, 9005-08-7) are mixtures of mono- and distearate esters
of mixed polyoxyethylene polymers. Polyethylene glycol
hydroxystearate is a mixture of mono- and diesters of
hydroxystearic acid with polyethylene glycols. One polyethylene
glycol hydroxystearate that may be used in the compositions is
polyethylene glycol 12-hydroxystearate. In another embodiment, the
inventive compositions may include the surfactant polyethylene
glycol 15 12-hydroxystearate (Kolliphor.RTM. HS 15 from BASF), a
mixture of mono- and diesters of 12-hydroxystearic acid with 15
moles of ethylene oxide. Again, these compounds, as well as their
amounts are well known in the art. In another embodiment of the
invention, the inventive compositions may include polyoxyl 35
castor oil (Kolliphor.RTM. EL) as a surfactant. In other
embodiments, the inventive compositions may include polyoxyl 40
hydrogenated castor oil (Kolliphor.RTM. RH 40) or polyoxyl 60
hydrogenated castor oil as surfactants. The compositions of the
invention may also include a combination of surfactants.
[1435] The inventive compositions may contain other inert
ingredients such as antioxidants, preservatives, or pH stabilizers.
These compounds are well known in the composition art. Antioxidants
such as vitamin E, alpha tocopherol, ascorbic acid, ascorbyl
palmitate, citric acid, fumaric acid, malic acid, sodium ascorbate,
sodium metabisulfate, sodium metabisulfite, n-propyl gallate, BHA
(butylated hydroxy anisole), BHT (butylated hydroxy toluene), BHA
and citric acid, monothioglycerol, tert-butyl hydroquinone (TBHQ),
and the like, may be added to the present composition. The
antioxidants are generally included in the compositions of the
invention in amounts of about 0.01% to about 3%, or from about 0.01
to about 2% (w/v), based upon total weight of the composition
(w/w). In another embodiment, the compositions contain about 0.05
to about 1.0% (w/w) of one or a mixture of antioxidants.
[1436] Preservatives, such as the parabens (methylparaben and/or
propylparaben), are suitably used in the composition in amounts
ranging from about 0.01 to about 2.0%, with about 0.05 to about
1.0% being especially preferred. Other preservatives include
benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl
alcohol, bronopol, butylparaben, cetrimide, chlorhexidine,
chlorobutanol, chlorocresol, cresol, ethylparaben, imidurea,
methylparaben, phenol, phenoxyethanol, phenylethyl alcohol,
phenylmercuric acetate, phenylmercuric borate, phenylmercuric
nitrate, potassium sorbate, sodium benzoate, sodium propionate,
sorbic acid, thimerosal, and the like. Preferred ranges for these
compounds include from about 0.01 to about 5%.
[1437] Compounds which stabilize the pH of the composition are also
contemplated. Again, such compounds are well known to a
practitioner in the art as well as how to use these compounds.
Buffering systems include, for example, systems selected from the
group consisting of acetic acid/acetate, malic acid/malate, citric
acid/citrate, tartaric acid/tartrate, lactic acid/lactate,
phosphoric acid/phosphate, glycine/glycimate, tris, glutamic
acid/glutamates and sodium carbonate.
[1438] Dosage forms may contain from about 0.5 mg to about 5 g of
an active agent or a combination of active agents. More typically,
the amount of active agent(s) in the compositions of the invention
will be from about 1 mg to about 3 g. In another embodiment, the
amount of active agent(s) in the compositions will be from about 20
mg to about 3 g. In another embodiment, the amount of active
agent(s) present in the compositions will be from about 20 mg to
about 2 g, about 20 mg to about 1.5 g or about 20 mg to about 1 g.
In other embodiments, the amount of active agent(s) in the
compositions will be from about 20 mg to about 500 mg, about 30 mg
to about 200 mg or about 50 mg to about 200 mg. In still another
embodiment, the amount of active agent(s) present in the
compositions will be from about 50 mg to about 2 g, about 50 mg to
about 1 g or about 50 mg to about 500 mg. In yet another embodiment
of the invention, the about of active agent(s) present will be from
about 100 mg to about 2 g, about 100 mg to about 1 g or about 100
mg to about 500 mg.
[1439] In another embodiment, the amount of active agent(s) present
in the compositions of the invention is from about 1 mg to about
500 mg of an active agent, about 1 mg to about 100 mg or about 1 mg
to about 25 mg. In still other embodiments, the amount of the
active agent present in the compositions is about 10 mg about 50 mg
or about 10 mg to about 100 mg. In other embodiments, the amount of
active agent present in the compositions is about 50 mg to about
200 mg, about 100 mg to about 300 mg, about 100 mg to about 400 mg,
about 200 mg to about 500 mg, about 300 mg to about 600 mg, about
400 mg to about 800 mg, or about 500 mg to about 1000 mg.
[1440] The compositions of the invention are made by mixing the
appropriate amount of the active agents, a liquid PEG and/or a
neutral oil, a co-solvent (if present) and, optionally, an
antioxidant, pharmaceutically acceptable additive and/or excipient
to form a composition of the invention. In some embodiments the
compositions of the present invention can be obtained by following
the method of making these forms described above by the description
of making these forms found in general composition text known to
those in the art, e.g. Remington--The Science and Practice of
Pharmacy (21.sup.st Edition) (2005), Goodman & Gilman's The
Pharmacological Basis of Therapeutics (11.sup.th Edition) (2005)
and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems
(8.sup.th Edition), edited by Allen et al., Lippincott Williams
& Wilkins, (2005).
Methods of Treatment
[1441] In another aspect of the invention, a method for preventing
or treating a parasite infestation/infection in an animal is
provided, comprising administering to the animal a long-acting
injectable composition comprising an effective amount of at least
one isoxazoline compound, a liquid PEG and/or a neutral oil,
optionally a co-solvent, and optionally, an antioxidant,
pharmaceutically acceptable additive and/or excipient. The
compositions of the invention have long-lasting efficacy against
ectoparasites (e.g. fleas and ticks) and in certain embodiments may
also be active against endoparasites that harm animals.
[1442] In one embodiment of the invention, methods for the
treatment or prevention of a parasitic infestation or infection in
a livestock animal are provided, which comprise administering a
long-acting injectable composition comprising an effective amount
of at least one isoxazoline active agent to the animal.
Ectoparasites against which the methods and compositions of the
invention are effective include, but are not limited to, fleas,
ticks, mites, mosquitoes, flies and lice. In certain embodiments
wherein the inventive compositions include one or more additional
active agents that are active against internal parasites the
compositions and methods of the invention may also be effective
against endoparasites including, but not limited to, cestodes,
nematodes, hookworms and roundworms of the digestive tract of
animals and humans.
[1443] In an alternative embodiment of the invention, methods for
the treatment or prevention of a parasitic infestation or infection
in a domestic animal are provided, which comprise administering a
long-acting injectable composition comprising an effective amount
of at least one isoxazoline active agent to the animal.
Ectoparasites against which the methods and compositions of the
invention are effective include, but are not limited to, fleas,
ticks, mites, mosquitoes, flies and lice. In certain embodiments
wherein the inventive compositions include one or more additional
active agents that are active against internal parasites the
compositions and methods of the invention may also be effective
against endoparasites including, but not limited to, cestodes,
nematodes, hookworms and roundworms of the digestive tract of
animals and humans.
[1444] In one embodiment for treatment against ectoparasites, the
ectoparasite is one or more insect or arachnid including those of
the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes,
Boophilus, Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes,
Psoroptes, Otodectes, Chorioptes, Hypoderma, Damalinia,
Linognathus, Haematopinus, Solenoptes, Trichodectes, and
Felicola.
[1445] In another embodiment for the treatment against
ectoparasites, the ectoparasite is from the genera Ctenocephalides,
Rhipicephalus, Dermacentor, Ixodes and/or Boophilus. The
ectoparasites treated include but are not limited to fleas, ticks,
mites, mosquitoes, flies, lice, blowfly and combinations thereof.
Specific examples include, but are not limited to, cat and dog
fleas (Ctenocephalides felis, Ctenocephalides sp. and the like),
ticks (Rhipicephalus sp., Ixodes sp., Dermacentor sp., Amblyomma
sp. and the like), and mites (Demodex sp., Sarcoptes sp., Otodectes
sp. and the like), lice (Trichodectes sp., Cheyletiella sp.,
Linognathus sp., and the like), mosquitoes (Aedes sp., Culex sp.,
Anopheles sp., and the like) and flies (Haematobia sp. including
Haematobia irritans, Musca sp., Stomoxys sp. including Stomoxys
calcitrans, Dermatobia sp., Cochliomyia sp., and the like).
[1446] Additional examples of ectoparasites include but are not
limited to the tick genus Boophilus, especially those of the
species microplus (cattle tick), decoloratus and annulatus; myiasis
such as Dermatobia hominis (known as Berne in Brazil) and
Cochliomyia hominivorax (greenbottle); sheep myiasis such as
Lucilia sericata, Lucilia cuprina (known as blowfly strike in
Australia, New Zealand and South Africa). Flies proper, namely
those whose adult constitutes the parasite, such as Haematobia
irritans (horn fly) and Stomoxys calcitrans (stable fly); lice such
as Linognathus vituli, etc.; and mites such as Sarcoptes scabiei
and Psoroptes ovis. The above list is not exhaustive and other
ectoparasites are well known in the art to be harmful to animals
and humans. These include, for example migrating dipterous
larvae.
[1447] In some embodiments of the invention, the composition can
also be used to treat against endoparasites such as those helminths
selected from the group consisting of Anaplocephala, Ancylostoma,
Necator, Ascaris, Capillaria, Cooperia, Dipylidium, Dirofilaria,
Echinococcus, Enterobius, Fasciola, Haemonchus, Oesophagostomum,
Ostertagia, Toxocara, Strongyloides, Toxascaris, Trichinella,
Trichuris, and Trichostrongylus, among others.
[1448] In one embodiment, the invention provides methods for the
treatment and prevention of parasitic infections and infestations
in or on animals (either wild or domesticated), including livestock
and companion animals such as cats, dogs, horses, birds including
chickens, sheep, goats, pigs, deer, turkeys and cattle, with the
aim of ridding these hosts of parasites commonly encountered by
such animals.
[1449] In an embodiment, the invention provides methods and
compositions for the treatment or prevention of parasitic
infections and infestations in livestock animals (e.g., sheep and
cattle) or companion animals including, but not limited to, cats
and dogs. The methods and compositions are particularly effective
for preventing or treating parasitic infestations of cattle and
sheep with fleas and ticks.
[1450] In another embodiment, the methods and compositions of the
invention are used for the treatment or prevention of parasitic
infections and infestations in cattle or sheep. When treating
livestock animals such as cattle or sheep, the methods and
compositions are particularly effective against Rhipicephalus
(Boophilus) microplus, Haematobia irritans (horn fly), Stomoxys
calcitrans (stable fly), and sheep myiasis such as Lucilia
sericata, Lucilia cuprina (known as blowfly strike in Australia,
New Zealand and South Africa).
[1451] The terms "treating" or "treat" or "treatment" are intended
to mean the administration of a long-acting composition of the
present invention to an animal that has a parasitic infestation for
the eradication of the parasite or the reduction of the number of
the parasites infesting the animal undergoing treatment. It is
noted that the compositions of the invention may be used to prevent
such a parasitic infestation.
[1452] The terms "prevent", "prevention" or "prophylaxis" are
intended to mean the administration of the long-acting compositions
of the present invention to the animal before the parasitic
infection or infestation has occurred in order to keep said
infection or infestation from occurring. Administration of the
long-acting compositions at recommended regular intervals
effectively prevents new parasitic infestations or infections in
animals by killing new parasites that attack an animal before they
can multiply to establish an infestation or infection.
[1453] The compositions of the invention are administered in
parasiticidally effective amounts which are which are suitable to
control the parasite in question to the desired extent, as
described below. In each aspect of the invention, the compounds and
compositions of the invention can be applied against a single pest
or combinations thereof.
[1454] By "antiparasitic effective amount" is intended a sufficient
amount of a composition of the invention to eradicate or reduce the
number of parasites infesting the animal. In some embodiments, an
effective amount of the active agent achieves at least 70% efficacy
against the target parasite. In other embodiments, an effective
amount of the active agent achieves at least 80%, or at least 90%
efficacy against the target pests. Preferably, an effective amount
of the active agent will achieve at least 95%, at least 98% or 100%
efficacy against the target parasites.
[1455] Generally, a dose of from about 0.001 to about 100 mg per kg
of body weight given as a single dose or in divided doses for a
period of from 1 to 5 days will be satisfactory but, of course,
there can be instances where higher or lower dosage ranges are
indicated, and such are within the scope of this invention. It is
well within the routine skill of the practitioner to determine a
particular dosing regimen for a specific host and parasite.
[1456] In some embodiments for companion animals, the dose of the
isoxazoline active agent administered from the topical compositions
of the invention is between about 0.1 to about 50 mg per kg of body
weight. More typically the dose of the isoxazoline active agent
administered is about 0.5 to about 30 mg/kg or about 0.5 to about
30 mg/kg body weight. In yet another embodiment, the dose of the
isoxazoline active agent will be from about 0.5 to about 20 mg/kg,
about 0.5 to about 10 mg/kg or about 0.5 to about 5 mg/kg body
weight. In another embodiment, the dose will be from about 0.5 to
about 2.5 mg/kg body weight. In another embodiment, the dose of the
isoxazoline active agent administered is about 10 to about 30
mg/kg, about 15 to about 30 mg/kg or about 20 to about 30 mg/kg of
body weight.
[1457] In other embodiments, the dose administered may be lower
depending on the animal and the isoxazoline administered. For
example, if the composition comprises the more active enantiomer of
the isoxazoline compounds a lower dose may be administered. In some
embodiments, the dose is from about 0.1 to about 30 mg/kg of body
weight. In another embodiment, the dose may be from about 0.1 to
about 20 mg/kg or about 0.1 to about 10 mg/kg of body weight. In
another embodiment, a dose of from about 0.1 to about 5 mg/kg, from
about 0.1 to about 2.5 mg/kg body weight will be used. In other
embodiments, the dose may be from about 1 to about 20 mg/kg of body
weight or about 1 to about 10 mg/kg. In yet another embodiment, the
dose may be from about 5 to about 20 mg/kg or about 10 to about 20
mg/kg of body weight.
[1458] The volume of the dose of the long-acting injectable
compositions is typically less than about 10 mL/50 kg body weight
of the animal being treated. In other embodiments, the injection
volume is about 7 mL/50 kg body weight. In yet other embodiments,
the injection volume is less than about 5 mL/50 kg, less than about
3 mL/50 kg body weight or less than about 2 mL/50 kg of body
weight. In yet other embodiments, the injection volume is from
about 0.1 to about 2 mL/50 kg body weight of the animal. In other
embodiments, the injection volume is about 0.05 to about 1 mL/50 kg
body weight of the animal.
[1459] In other embodiments for the treatment of livestock animals
such as cattle or sheep, doses of the isoxazoline active agent
administered may be about 0.1 to about 40 mg/kg of body weight.
More typically the doses administered will be about 1 to about 30
mg/kg, about 1 to about 20 mg/kg or about 1 to about 10 mg/kg of
bodyweight. In yet another embodiment, the dose may be from about
10 to about 25 mg/kg, about 15 to about 30 mg/kg of body weight or
about 20-30 mg/kg of body weight.
[1460] In one embodiment of the method of use in livestock animals
(e.g., cattle or sheep), the long-acting compositions of the
present invention comprising an isoxazoline compound has an
efficacy against ectoparasites including, but not limited to,
fleas, ticks, mites, and parasitic flies, of at least about 90.0%
or higher for about 3 months, or longer. In another embodiment, the
long-acting compositions of the present invention provide an
efficacy against ectoparasites of at least 95.0% or higher for
about 3 months or longer.
[1461] In another embodiment, the long-acting compositions of the
present invention provide an efficacy against ectoparasites in
livestock animals (e.g., cattle or sheep) of at least about 80% for
two months, or longer. In another embodiment, the long-acting
compositions of the present invention efficacy against
ectoparasites in livestock animals (e.g., cattle or sheep) of about
90% for at least about 2 months. In still another embodiment, the
compositions provide an efficacy of about 95% for about 2 months or
longer. In another embodiment, the long-acting compositions of the
present invention efficacy against ectoparasites in livestock
animals (e.g., cattle or sheep) of about 90% for about 3 months, or
longer. In still another embodiment, the compositions provide an
efficacy of about 95% for about 3 months or longer.
[1462] In another embodiment, the long-acting compositions of the
present invention have an efficacy of at least about 80% against
ectoparasites for about 3 months, or longer. In still another
embodiment, the long-acting compositions of the invention provide
an efficacy of at least about 90% against ectoparasites for 3
months or longer. In yet another embodiment, the long-acting
compositions of the present invention of the invention provide an
efficacy of at least about 95% against ectoparasites for 3 months
or longer. In still another embodiment, the long-acting
compositions of the present invention provide an efficacy against
ectoparasites in livestock animals (e.g., cattle or sheep) of at
least 80% or at least 90% for about 3 months to about 6 months or
longer.
[1463] In other embodiments, the long-acting compositions of the
invention have an efficacy of at least about 90% against
ectoparasites including, but not limited to, fleas, ticks, mites
and parasitic flies, of about 7 months or longer, about 8 months or
longer or about 9 months or longer. In other embodiments, the
long-acting compositions of the invention have an efficacy of at
least about 90% against ectoparasites including, but not limited
to, fleas, ticks, mites and parasitic flies, of about 10 months or
longer, about 118 months or longer or even about 12 months or
longer.
[1464] In another aspect of the invention, a kit for the treatment
or prevention of a parasitic infestation in an animal is provided,
which comprises a long-acting composition of the invention and a
syringe.
Antiparasitic Compounds
[1465] In a second aspect of the invention, novel and inventive
pesticidal and parasiticidal isoxazoline compounds of formula (Id)
are provided:
##STR00034##
[1466] wherein X.sup.1 is bromo, chloro, iodo or fluoro; and
X.sup.2 is chloro, fluoro or CF.sub.3;
[1467] Y is a group Y-1, Y-2, Y-3, Y-4 where Z is N or CH, Y-5 or
Y-6
##STR00035##
and
[1468] Q is OH, --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3, --C(O)NHCH.sub.2CH.sub.2SCH.sub.3
or (--CH.sub.2--)(--CH.sub.2--)N(CO)CH.sub.2S(O).sub.2CH.sub.3.
[1469] The second aspect of the present invention includes at least
the following features:
[1470] (a) In one embodiment, the invention provides novel
compounds of formula (Id), or pharmaceutically or agriculturally
acceptable salts thereof, which are active against arthropod pests
and parasites that harm animals and plants;
[1471] (b) veterinary and pesticidal compositions for combating and
controlling pests and parasites comprising a pesticidally or
parasiticidally effective amount of the compounds of formula (Id),
or pharmaceutically or agriculturally acceptable salts thereof, in
combination with a pharmaceutically or agriculturally acceptable
carrier or diluent;
[1472] (c) plant propagation material (e.g. seed), comprising at
least one compound of formula (Id), or agriculturally acceptable
salts thereof
[1473] (d) veterinary and pesticidal compositions for combating
arthropod pests and parasites comprising a pesticidally or
parasiticidally effective amount of the compounds of the invention,
or pharmaceutically or agriculturally acceptable salts thereof, in
combination with at least one additional active agent and a
pharmaceutically or agriculturally acceptable carrier or
diluent;
[1474] (e) methods for treating a parasitic infestation/infection
in or on an animal are provided, which methods comprise
administering a parasiticidally effective amount of a compound of
formula (Id), or pharmaceutically acceptable salts thereof, to the
animal in need thereof;
[1475] (f) methods for the prevention of a parasitic
infestation/infection of an animal, which comprise administering a
parasiticidally effective amount of a compound of formula (Id), or
pharmaceutically acceptable salts thereof, to the animal in need
thereof
[1476] (g) methods for combating or controlling pests that are
detrimental to crops, plants, plant propagation material, or
material containing wood or derived from wood, comprising
contacting the crop, plants, plant propagation material, or
material containing wood or derived from wood, with a pesticidally
effective amount of a compound of formula (Id), or an
agriculturally acceptable salt thereof, or a composition comprising
the compounds;
[1477] (h) methods for combating or controlling pests at a locus,
comprising administering a pesticidally or parasiticidally
effective amount of a compound of formula (Id), or pharmaceutically
or agriculturally acceptable salts thereof, to the locus;
[1478] (i) use of the compounds of formula (Id), or
pharmaceutically or agriculturally acceptable salts thereof, for
controlling pests, including parasites, in or on an animal or on
crops, plants, plant propagation material, or material containing
wood or derived from wood; and
[1479] (j) use of the compounds of formula (Id), or
pharmaceutically acceptable salts thereof, in the manufacture of a
veterinary medicament for controlling pests, including
parasites.
[1480] An important aspect of the invention is to provide
isoxazoline active agents that exhibit surprising and unexpected
fast-acting and long-lasting efficacy against parasites,
particularly ticks, than isoxazoline active compounds having
different substitution patterns on the phenyl ring bound to the
quaternary carbon of the isoxazoline ring. Thus, it has been found
that the compound of formula (Id) in which Y is Y-2, Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3, X.sup.1 is fluoro and
X.sup.2 is chloro, which is not specifically described in WO
2007/079162 A1 or WO 2009/002890 A2, has been found to have
surprisingly improved duration of activity against the tick
Rhipicephalus microplus (formerly Boophilus microplus) on cattle
compared with known isoxazoline compounds in which Y is Y-2 and Q
is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3 but having different
substitution patterns on the phenyl ring.
[1481] Furthermore, the compound of formula (Id) in which Y is Y-2,
Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3, X.sup.1 is fluoro and
X.sup.2 is chloro, has also been found to have surprisingly
improved fast-acting efficacy against the tick Rhipicephalus
microplus on cattle compared with known isoxazoline compounds in
which Y is Y-2 and Q is Y is Y-2, Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3but having different
substitution patterns on the phenyl ring.
[1482] In one embodiment, the invention provides a compound of
formula (Id) wherein the group Y is Y-1. In another embodiment Y is
Y-2. In another embodiment, Y is Y-3. In another embodiment, Y is
Y-4. In still another embodiment, Y is Y-5. In another embodiment,
Y is Y-6.
[1483] In one embodiment, the invention provides a compound of
formula (Id) wherein Y is Y-1, X.sup.1 is fluoro, and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-2,
X.sup.1 is fluoro, and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-3,
X.sup.1 is fluoro, and Q is
(--CH.sub.2--)(--CH.sub.2--)N(CO)CH.sub.2S(O).sub.2CH.sub.3 where
each terminal CH.sub.2 is bonded to the benzylic carbon of Y-3. In
another embodiment, Y is Y-4, X.sup.1 is fluoro, and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-5,
X.sup.1 is fluoro, and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In yet another embodiment, Y is
Y-6, X.sup.1 is fluoro, and Q is OH.
[1484] In another embodiment, the invention provides a compound of
formula (Id) wherein Y is Y-1, X.sup.1 is chloro, and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-2,
X.sup.1 is chloro, and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-3,
X.sup.1 is chloro, and Q is
(--CH.sub.2--)(--CH.sub.2--)N(CO)CH.sub.2S(O).sub.2CH.sub.3 where
each terminal CH.sub.2 is bonded to the benzylic carbon of Y-3. In
another embodiment, Y is Y-4, X.sup.1 is chloro, and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-5,
X.sup.1 is chloro, and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In yet another embodiment, Y is
Y-6, X.sup.1 is chloro, and Q is OH.
[1485] In one embodiment, Y is Y-1, X.sup.1 is fluoro, X.sup.2 is
chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-1,
X.sup.1 is fluoro, X.sup.2 is fluoro and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-1,
X.sup.1 is fluoro, X.sup.2 is CF.sub.3 and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3.
[1486] In another embodiment, Y is Y-1, X.sup.1 is chloro, X.sup.2
is chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-1,
X.sup.1 is chloro, X.sup.2 is fluoro and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-1,
X.sup.1 is chloro, X.sup.2 is CF.sub.3 and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3.
[1487] In one embodiment, Y is Y-1, X.sup.1 is bromo, X.sup.2 is
chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-1,
X.sup.1 is bromo, X.sup.2 is fluoro and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-1,
X.sup.1 is bromo, X.sup.2 is CF.sub.3 and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3.
[1488] In one embodiment, Y is Y-1, X.sup.1 is iodo, X.sup.2 is
chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-1,
X.sup.1 is iodo, X.sup.2 is fluoro and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-1,
X.sup.1 is iodo, X.sup.2 is CF.sub.3 and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3.
[1489] In one embodiment, Y is Y-2, X.sup.1 is fluoro, X.sup.2 is
chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-2,
X.sup.1 is fluoro, X.sup.2 is fluoro and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-2,
X.sup.1 is fluoro, X.sup.2 is CF.sub.3 and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3.
[1490] In another embodiment, Y is Y-2, X.sup.1 is chloro, X.sup.2
is chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-2,
X.sup.1 is chloro, X.sup.2 is fluoro and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-2,
X.sup.1 is chloro, X.sup.2 is CF.sub.3 and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3.
[1491] In one embodiment, Y is Y-2, X.sup.1 is bromo, X.sup.2 is
chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-2,
X.sup.1 is bromo, X.sup.2 is fluoro and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-2,
X.sup.1 is bromo, X.sup.2 is CF.sub.3 and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3.
[1492] In one embodiment, Y is Y-2, X.sup.1 is iodo, X.sup.2 is
chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-2,
X.sup.1 is iodo, X.sup.2 is fluoro and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-2,
X.sup.1 is iodo, X.sup.2 is CF.sub.3 and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3.
[1493] In one embodiment, Y is Y-3, X.sup.1 is fluoro, X.sup.2 is
chloro and Q is
(--CH.sub.2--)(--CH.sub.2--)N(CO)CH.sub.2S(O).sub.2CH.sub.3 where
each terminal CH.sub.2 is bonded to the benzylic carbon of Y-3. In
another embodiment, Y is Y-3, X.sup.1 is fluoro, X.sup.2 is fluoro
and Q is
(--CH.sub.2--)(--CH.sub.2--)N(CO)CH.sub.2S(O).sub.2CH.sub.3 where
each terminal CH.sub.2 is bonded to the benzylic carbon of Y-3. In
another embodiment, Y is Y-3, X.sup.1 is fluoro, X.sup.2 is
CF.sub.3 and Q is
(--CH.sub.2--)(--CH.sub.2--)N(CO)CH.sub.2S(O).sub.2CH.sub.3 where
each terminal CH.sub.2 is bonded to the benzylic carbon of Y-3.
[1494] In another embodiment, Y is Y-3, X.sup.1 is chloro, X.sup.2
is chloro and Q is
(--CH.sub.2--)(--CH.sub.2--)N(CO)CH.sub.2S(O).sub.2CH.sub.3 where
each terminal CH.sub.2 is bonded to the benzylic carbon of Y-3. In
another embodiment, Y is Y-3, X.sup.1 is chloro, X.sup.2 is fluoro
and Q is
(--CH.sub.2--)(--CH.sub.2--)N(CO)CH.sub.2S(O).sub.2CH.sub.3 where
each terminal CH.sub.2 is bonded to the benzylic carbon of Y-3. In
another embodiment, Y is Y-3, X.sup.1 is chloro, X.sup.2 is
CF.sub.3 and Q is
(--CH.sub.2--)(--CH.sub.2--)N(CO)CH.sub.2S(O).sub.2CH.sub.3 where
each terminal CH.sub.2 is bonded to the benzylic carbon of Y-3.
[1495] In one embodiment, Y is Y-3, X.sup.1 is bromo, X.sup.2 is
chloro and Q is
(--CH.sub.2--)(--CH.sub.2--)N(CO)CH.sub.2S(O).sub.2CH.sub.3 where
each terminal CH.sub.2 is bonded to the benzylic carbon of Y-3. In
another embodiment, Y is Y-3, X.sup.1 is bromo, X.sup.2 is fluoro
and Q is
(--CH.sub.2--)(--CH.sub.2--)N(CO)CH.sub.2S(O).sub.2CH.sub.3 where
each terminal CH.sub.2 is bonded to the benzylic carbon of Y-3. In
another embodiment, Y is Y-3, X.sup.1 is bromo, X.sup.2 is CF.sub.3
and Q is
(--CH.sub.2--)(--CH.sub.2--)N(CO)CH.sub.2S(O).sub.2CH.sub.3 where
each terminal CH.sub.2 is bonded to the benzylic carbon of Y-3.
[1496] In one embodiment, Y is Y-3, X.sup.1 is iodo, X.sup.2 is
chloro and Q is
(--CH.sub.2--)(--CH.sub.2--)N(CO)CH.sub.2S(O).sub.2CH.sub.3 where
each terminal CH.sub.2 is bonded to the benzylic carbon of Y-3. In
another embodiment, Y is Y-3, X.sup.1 is iodo, X.sup.2 is fluoro
and Q is
(--CH.sub.2--)(--CH.sub.2--)N(CO)CH.sub.2S(O).sub.2CH.sub.3 where
each terminal CH.sub.2 is bonded to the benzylic carbon of Y-3. In
another embodiment, Y is Y-3, X.sup.1 is iodo, X.sup.2 is CF.sub.3
and Q is
(--CH.sub.2--)(--CH.sub.2--)N(CO)CH.sub.2S(O).sub.2CH.sub.3 where
each terminal CH.sub.2 is bonded to the benzylic carbon of Y-3.
[1497] In one embodiment, Y is Y-4, X.sup.1 is fluoro, X.sup.2 is
chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-4,
X.sup.1 is fluoro, X.sup.2 is fluoro and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-4,
X.sup.1 is fluoro, X.sup.2 is CF.sub.3 and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3.
[1498] In another embodiment, Y is Y-4, X.sup.1 is chloro, X.sup.2
is chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-4,
X.sup.1 is chloro, X.sup.2 is fluoro and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-4,
X.sup.1 is chloro, X.sup.2 is CF.sub.3 and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3.
[1499] In one embodiment, Y is Y-4, X.sup.1 is bromo, X.sup.2 is
chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-4,
X.sup.1 is bromo, X.sup.2 is fluoro and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-4,
X.sup.1 is bromo, X.sup.2 is CF.sub.3 and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3.
[1500] In one embodiment, Y is Y-4, X.sup.1 is iodo, X.sup.2 is
chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-4,
X.sup.1 is iodo, X.sup.2 is fluoro and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-4,
X.sup.1 is iodo, X.sup.2 is CF.sub.3 and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3.
[1501] In one embodiment, Y is Y-5, X.sup.1 is fluoro, X.sup.2 is
chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-5,
X.sup.1 is fluoro, X.sup.2 is fluoro and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-5,
X.sup.1 is fluoro, X.sup.2 is CF.sub.3 and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3.
[1502] In another embodiment, Y is Y-5, X.sup.1 is chloro, X.sup.2
is chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-5,
X.sup.1 is chloro, X.sup.2 is fluoro and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-5,
X.sup.1 is chloro,
[1503] X.sup.2 is CF.sub.3 and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3.
[1504] In one embodiment, Y is Y-5, X.sup.1 is bromo, X.sup.2 is
chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-5,
X.sup.1 is bromo, X.sup.2 is fluoro and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-5,
X.sup.1 is bromo, X.sup.2 is CF.sub.3 and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3.
[1505] In one embodiment, Y is Y-5, X.sup.1 is iodo, X.sup.2 is
chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-5,
X.sup.1 is iodo, X.sup.2 is fluoro and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3. In another embodiment, Y is Y-5,
X.sup.1 is iodo, X.sup.2 is CF.sub.3 and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3,
--C(O)CH.sub.2S(O).sub.2CH.sub.3 or
--C(O)NHCH.sub.2CH.sub.2SCH.sub.3.
[1506] In one embodiment, Y is Y-6, X.sup.1 is fluoro, X.sup.2 is
chloro and Q is OH. In another embodiment, Y is Y-6, X.sup.1 is
fluoro, X.sup.2 is fluoro and Q is OH. In another embodiment, Y is
Y-6, X.sup.1 is fluoro, X.sup.2 is CF.sub.3 and Q is OH.
[1507] In another embodiment, Y is Y-6, X.sup.1 is chloro, X.sup.2
is chloro and Q is OH. In another embodiment, Y is Y-6, X.sup.1 is
chloro, X.sup.2 is fluoro and Q is OH. In another embodiment, Y is
Y-6, X.sup.1 is chloro, X.sup.2 is CF.sub.3 and Q is OH.
[1508] In one embodiment, Y is Y-6, X.sup.1 is bromo, X.sup.2 is
chloro and Q is OH. In another embodiment, Y is Y-6, X.sup.1 is
bromo, X.sup.2 is fluoro and Q is OH. In another embodiment, Y is
Y-6, X.sup.1 is bromo, X.sup.2 is CF.sub.3 and Q is OH.
[1509] In one embodiment, Y is Y-6, X.sup.1 is iodo, X.sup.2 is
chloro and Q is OH. In another embodiment, Y is Y-6, X.sup.1 is
iodo, X.sup.2 is fluoro and Q is OH. In another embodiment, Y is
Y-6, X.sup.1 is iodo, X.sup.2 is CF.sub.3 and Q is OH.
[1510] In another embodiment, Y is Y-1, X.sup.1 is fluoro, X.sup.2
is CF.sub.3 and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3. In
another embodiment, Y is Y-1, X.sup.1 is chloro, X.sup.2 is fluoro
and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3.
[1511] In one embodiment, Y is Y-2, X.sup.1 is fluoro, X.sup.2 is
chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3. In another
embodiment, Y is Y-1, X.sup.1 is chloro, X.sup.2 is chloro and
[1512] Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3.
[1513] In one embodiment, Y is Y-3, X.sup.1 is fluoro, X.sup.2 is
chloro and Q is
(--CH.sub.2--)(--CH.sub.2--)N(CO)CH.sub.2S(O).sub.2CH.sub.3 where
each terminal CH.sub.2 is bonded to the benzylic carbon of Y-3. In
another embodiment, Y is Y-3, X.sup.1 is fluoro, X.sup.2 is
CF.sub.3 and Q is
(--CH.sub.2--)(--CH.sub.2--)N(CO)CH.sub.2S(O).sub.2CH.sub.3 where
each terminal CH.sub.2 is bonded to the benzylic carbon of Y-3.
[1514] In one embodiment, Y is Y-4 where Z is CH, X.sup.1 is
fluoro, X.sup.2 is chloro and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3. In another embodiment, Y is
Y-4 where Z is CH, X.sup.1 is fluoro, X.sup.2 is fluoro and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3. In yet another embodiment,
Y is Y-4, X.sup.1 is fluoro, X.sup.2 is CF.sub.3 and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3.
[1515] In another embodiment, Y is Y-4, X.sup.1 is chloro, X.sup.2
is chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3. In
another embodiment, Y is Y-4, X.sup.1 is chloro, X.sup.2 is fluoro
and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3. In another
embodiment, Y is Y-4, X.sup.1 is chloro, X.sup.2 is CF.sub.3 and Q
is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3.
[1516] In one embodiment, Y is Y-5, X.sup.1 is fluoro, X.sup.2 is
chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3. In another
embodiment, Y is Y-5, X.sup.1 is fluoro, X.sup.2 is fluoro and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3. In another embodiment, Y is
Y-5, X.sup.1 is fluoro, X.sup.2 is CF.sub.3 and Q is
--C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3.
[1517] In another embodiment, Y is Y-5, X.sup.1 is chloro, X.sup.2
is chloro and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3. In
another embodiment, Y is Y-5, X.sup.1 is chloro, X.sup.2 is fluoro
and Q is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3. In another
embodiment, Y is Y-5, X.sup.1 is chloro, X.sup.2 is CF.sub.3 and Q
is --C(O)NHCH.sub.2C(O)NHCH.sub.2CF.sub.3.
[1518] In a preferred embodiment, the invention provides a compound
of formula (Ie) shown below, or a pharmaceutically or
pharmaceutically acceptable salt thereof:
##STR00036##
[1519] As noted above, the isoxazoline compounds of formula (Id)
can exist as stereoisomers since there is a chiral center in the
molecule. The individual stereoisomers are encompassed by the
structural formulas depicted herein. The various stereoisomers
include enantiomers, diastereomers and atropisomers.
[1520] Hence, in another embodiment, the invention provides
isoxazoline compounds of formula (Id), and compositions comprising
the compounds, which are enriched in one enantiomer, or a
pharmaceutically or agriculturally acceptable salt thereof.
[1521] In another embodiment, the invention provides isoxazoline
compounds of formula (Id), and compositions comprising the
compounds, which are enriched an enantiomer that displays
significant in vitro and in vivo activity with a favorable toxicity
profile (the eutomer), or a pharmaceutically acceptable salt
thereof.
[1522] In one embodiment of the invention, the more biologically
active enantiomer of the compound of formula (Id) is believed to be
compound of formula (S)-Id shown below. Accordingly, the more
biologically active enantiomers of isoxazoline compounds of
formulae (Id) wherein Y is Y-1, Y-2, Y-3, Y-4, Y-5 and Y-6 have the
(S) configuration at the chiral carbon of the isoxazoline ring.
[1523] In an embodiment, the compounds of formulae formula (Id)
(including (Ie)), or compositions comprising the compounds, are
enriched in one enantiomer over the other enantiomer in a
weight:weight ratio of at least 1.5:1. In another embodiment, the
compounds of formula (Id) and compositions comprising the compounds
are enriched in one enantiomer in a weight:weight ratio of at least
2:1, at least 5:1, at least 10:1 or at least 20:1.
[1524] In another embodiment, the compounds of formula (Id), or
compositions comprising the compounds, are essentially pure
enantiomers. In one embodiment, the compounds and composition of
the invention comprises a compound of formula (Id) that is
substantially enriched in an enantiomer. The term "substantially
enriched" is meant wherein the weight:weight ratio is at least
about 1.5:1 or higher in favor of the desired enantiomer. In
another embodiment, the compounds and compositions of the invention
are substantially enriched in the (S)-enantiomer. In another
embodiment, the compounds and compositions of the invention are
substantially enriched in the (R)-enantiomer.
[1525] In another embodiment of the invention, the compounds of
formula (Id), or compositions comprising the compounds, are
enriched in the (S)-enantiomer in a weight:weight ratio of at least
about 2:1, (S) to (R), or greater. In yet another embodiment, the
compounds or compositions of the invention comprise a compound of
formula (Id) that is enriched in the (S)-enantiomer in a
weight:weight ratio of at least about 5:1, (S) to (R), or greater.
In still another embodiment, the compounds and compositions of the
invention comprise a compound of formula (Id), that is enriched in
the (S)-enantiomer in a weight:weight ratio of at least about 10:1,
(S) to (R), or greater. In another embodiment, the compounds and
compositions of the invention comprise a compound of formula (Id),
that is enriched in the (S)-enantiomer in a weight:weight ratio of
at least about 20:1, (S) to (R), or greater. In still another
embodiment, the compounds and compositions of the invention
comprise a compound of formula (Id), that is essentially the pure
(S)-enantiomer.
[1526] In one embodiment, the invention provides a compound of
formula (S)-Ie, or a pharmaceutically or pharmaceutically
acceptable salt thereof, shown below:
##STR00037##
[1527] In another embodiment, the invention provides a compound of
formula (R)-Ie, or a pharmaceutically or pharmaceutically
acceptable salt thereof, shown below:
##STR00038##
[1528] In another embodiment, the invention provides pesticidal and
parasiticidal compositions comprising a compound of formula (S)-Ie.
In yet another embodiment, the invention provides pesticidal and
parasiticidal compositions comprising a compound of formula (R)-Ie.
For the avoidance of doubt, the compositions of the invention
comprising a compound of formula (S)-Ie or (R)-Ie may be enriched
in the desired enantiomer at the rations discussed above for the
compound of formula (Id).
Processes for the Preparation of the Compounds of formula (Id)
[1529] The compounds of formula (Id) and intermediates used in the
processes to make the compounds may be prepared by processes
adapted from those described in U.S. Pat. No. 7,964,204, U.S. Pat.
No. 8,410,153, U.S. Pat. No. 8,546,618, U.S. Pat. No. 8,217,180,
U.S. Pat. No. 8,546,613, U.S. Pat. No. 7,662,972, U.S. Pat. No.
8,466,115, U.S. Pat. No. 8,383,659, U.S. Pat. No. 8,853,186, U.S.
Pat. No. 8,618,126, US 2014/0371464, US 2015/0291612 and WO
2014/090918, all of which are incorporated herein by reference in
their entirety.
[1530] In one embodiment, the compounds of the invention may be
prepared according to the general process shown in Scheme 1 below,
wherein Y, Q, X.sup.1 and X.sup.2 are as defined for formula (Id)
above, W is Cl, Br or I and R is alkyl.
##STR00039##
[1531] This general process is described, for example, in U.S. Pat.
No. 8,546,618 to prepare compounds in which Y is Y-2. Using
suitably substituted compounds of formula Id-1 and Id-4, a variety
of compounds of formula (Id) may be prepared. Processes for the
preparation intermediates of formula Id-1, Id-3, Id-4 and Id-5 are
described in U.S. Pat. No. 8,546,618 and U.S. Pat. No. 8,217,180,
both incorporated herein by reference. The formation of isoxazoline
compounds of formula (Id) from Id-5 is also described in U.S. Pat.
No. 8,546,618 and U.S. Pat. No. 8,217,180. Additional information
on processes for the preparation of intermediates Id-1, Id-3, Id-4
and Id-5 that may be used for the preparation of compounds of
formula (Id) is found in U.S. Pat. No. 7,662,972, U.S. Pat. No.
8,466,115, U.S. Pat. No. 8,383,659, U.S. Pat. No. 8,853,186, US
2014/0371464, US 2015/0291612 and WO 2014/090918, all incorporated
herein by reference in their entirety.
Animal Health Applications
I. Veterinary Compositions:
[1532] The compounds of formula (Id) and compositions comprising
the compounds are useful for the prevention and treatment of
parasitic infestations/infections in animals. The compositions of
the invention comprise an effective amount of at least one
isoxazoline compound of formula (Id), or a pharmaceutically
acceptable salt thereof, in combination with a pharmaceutically
acceptable carrier or diluent and optionally other non-active
excipients. In a preferred embodiment, the compositions of the
invention comprise an effective amount of an isoxazoline of formula
(Ie) or (S)-Ie, or a pharmaceutically acceptable salt thereof. The
compositions may be in a variety of solid and liquid forms which
are suitable for various forms of application or administration to
an animal. For example, the veterinary compositions comprising the
inventive compounds may be in compositions suitable for oral
administration, injectable administration, including subcutaneous
and parenteral administration, and topical administration (e.g.
spot-on or pour-on). The compositions are intended to be
administered to an animal including, but not limited to, mammals,
birds and fish. Examples of mammals include but are not limited to
humans, cattle, sheep, goats, llamas, alpacas, pigs, horses,
donkeys, dogs, cats and other livestock or domestic mammals.
Examples of birds include turkeys, chickens, ostriches and other
livestock or domestic birds. The use of the compounds of formula
(Id) to protect companion animals, such as dogs and cats, and
livestock animals, such as cattle and sheep, from ectoparasites is
particularly useful.
[1533] As discussed above, the compositions of the invention may be
in a form suitable for oral use (see, e.g., U.S. Pat. No.
4,564,631, which is hereby incorporated by reference in its
entirety), dietary supplements, troches, lozenges, chewables,
tablets, hard or soft capsules, bolus, emulsions, aqueous or oily
suspensions, aqueous or oily solutions, oral drench compositions,
dispersible powders or granules, premixes, syrups or elixirs,
enteric compositions or pastes. Compositions intended for oral use
may be prepared according to any method known in the art for the
manufacture of pharmaceutical compositions and such compositions
may contain one or more sweetening agents, bittering agents,
flavoring agents, coloring agents and preserving agents in order to
provide pharmaceutically elegant and palatable preparations.
[1534] Tablets may contain the active ingredient in admixture with
non-toxic, pharmaceutically acceptable excipients which are
suitable for the manufacture of tablets. These excipients may be,
for example, inert diluents, such as calcium carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example starch, gelatin or
acacia, and lubricating agents, for example, magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monostearate or glyceryl distearate may be
employed. They may also be coated by the technique described in
U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 (all
incorporated herein by reference in their entirety) to form osmotic
therapeutic tablets for controlled release.
[1535] Oral compositions include hard gelatin capsules, wherein the
active ingredient is mixed with an inert solid diluent, for
example, calcium carbonate, calcium phosphate or kaolin. Capsules
may also be soft gelatin capsules, wherein the active ingredient is
mixed with water or miscible solvents such as propylene glycol,
PEGs and ethanol, or an oil medium, for example peanut oil, liquid
paraffin, or olive oil.
[1536] In one embodiment, the compounds of formula (Id) may be
administered in chewable tablet compositions or soft chewable
compositions such as those described in U.S. Pat. No. 9,233,100
B2,
[1537] U.S. Pat. No. 9,259,417, US 2010/0087492, US 2006/0222684,
US 2004/0151759, U.S. Pat. No. 7,955,632, US 2015/0057321, US
2015/0057239 and WO 2016/073347, all incorporated herein by
reference in their entirety.
[1538] The veterinary compositions may be in the form of a soft
chewable composition ("soft chew") which is palatable and
acceptable to the animal. In addition to the active ingredient(S),
the soft chews of the invention may include one or more of the
following components: a solvent or mixture of solvents, one or more
fillers, one or more binders, one or more surfactants, one or more
humectants, one or more lubricants, one or more disintegrants, one
or more colorants, one or more antimicrobial agents, one or more
antioxidants, one or more pH modifiers and one or more flavoring
agents.
[1539] Solvents that may be used in the compositions of the
invention include, but are not limited to, various grades of liquid
polyethylene glycol (PEG) including PEG 200, PEG 300, PEG 400 and
PEG 540; propylene carbonate; propylene glycol; triglycerides
including, but not limited to caprylic/capric triglyceride,
caprylic/capric/linoleic triglyceride (e.g. MIGLYOL.RTM. 810 and
812, caprylic/capric/succinic triglyceride, propylene glycol
dicaprylate/dicaprate, and the like; water, sorbitol solution,
glycerol caprylate/caprate and polyglycolized glycerides
(GELUCIRE.RTM.), or a combination thereof.
[1540] Various fillers known in the art may be used in the soft
chewable compositions of the invention. Fillers include, but are
not limited to, corn starch, pre-gelatinized corn starch, soy
protein fines, corn cob, and corn gluten meal, and the like. In
some embodiments, a combination of two or more fillers may be used
in the compositions.
[1541] Binders that may be used in the compositions of the
invention include, but are not limited to, polyvinylpyrrolidone
(e.g. Povidone), cross-linked polyvinylpyrrolidone (Crospovidone),
polyethylene glycols of various grades including PEG 3350, PEG
4000, PEG 6000, PEG 8000 and even PEG 20,000, and the like;
co-polymers of vinylpyrrolidone and vinyl acetate (e.g. Copovidone)
such as the product sold by BASF by the tradename Kollidon.RTM. VA
64 and the like; starch such as potato starch, tapioca starch or
corn starch; molasses, corn syrup, honey, maple syrup and sugars of
various types; or a combination of two or more binders.
[1542] Humectants that may be used in the compositions include, but
are not limited to, glycerol (also referred to herein as glycerin),
propylene glycol, cetyl alcohol and glycerol monostearate, and the
like. Polyethylene glycols of various grades may also be used as
humectants.
[1543] Surfactants may be present in the chewable composition at
concentrations of about 0.1% to about 10% (w/w), about 1% to about
10% (w/w) or about 5% to about 10% (w/w). More typically,
surfactants may be present at concentrations of about 0.1% to about
5% (w/w) or about 1 to about 5% (w/w). Examples of surfactants that
may be used in the compositions include, but are not limited to,
glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters,
sorbitan esters including sorbitan monooleate (Span.RTM. 20),
polyvinyl alcohol, polysorbates including polysorbate 20 and
polysorbate 80, d-a-tocopherol polyethylene glycol 1000 succinate
(TPGS), sodium lauryl sulfate, co-polymers of ethylene oxide and
propylene oxide (e.g. poloxamers such as LUTROL.RTM. F87 and the
like), polyethylene glycol castor oil derivatives including
polyoxyl 35 castor oil (Cremophor.RTM. EL), polyoxyl 40
hydrogenated castor oil (Cremophor.RTM. RH 40), polyoxyl 60
hydrogenated castor oil (Cremophor.RTM. RH60); propylene glycol
monolaurate) (LAUROGLYCOL.RTM.; glyceride esters including glycerol
caprylate/caprate (CAPMUL.RTM. MCM), polyglycolized
glycerides)(GELUCIRE.RTM., PEG 300 caprylic/capric glycerides
(Softigen.RTM. 767), PEG 400 caprylic/capric glycerides
(Labrasol.RTM.), PEG 300 oleic glycerides (Labrafil.RTM. M-1944CS),
PEG 300 linoleic glycerides (Labrafil.RTM. M-2125CS); polyethylene
glycol stearates and polyethylene glycol hydroxy stearates
including polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl 40
stearate (PEG 1750 monostearate, and the like. Polyethylene glycol
stearates (synonyms include macrogol stearates, polyoxylstearates,
polyoxyethylene stearates, ethoxylated stearates; CAS No.
9004-99-3, 9005-08-7) are mixtures of mono- and distearate esters
of mixed polyoxyethylene polymers. Polyethylene glycol
hydroxystearate is a mixture of mono- and diesters of
hydroxystearic acid with polyethylene glycols. One polyethylene
glycol hydroxystearate that may be used in the compositions is
polyethylene glycol 12-hydroxystearate. In another embodiment, the
compositions may include the surfactant polyethylene glycol 15
12-hydroxystearate (Solutol.RTM. HS 15 from BASF), a mixture of
mono- and diesters of 12-hydroxystearic acid with 15 moles of
ethylene oxide. Again, these compounds, as well as their amounts
are well known in the art. In another embodiment of the invention,
the compositions may include polyoxyl 35 castor oil (Cremophor EL)
as a surfactant. In other embodiments, the chewable compositions
may include polyoxyl 40 hydrogenated castor oil (Cremophor.RTM. RH
40) or polyoxyl 60 hydrogenated castor oil (Cremophor.RTM. RH60) as
surfactants. The compositions of the invention may also include a
combination of surfactants.
[1544] The chewable compositions may contain other inert
ingredients such as antioxidants, preservatives, or pH stabilizers.
These compounds are well known in the composition art. Antioxidants
may be added to the compositions of the invention to inhibit
degradation of the active agents. Suitable antioxidants include,
but are not limited to, alpha tocopherol, ascorbic acid, ascorbyl
palmitate, fumaric acid, malic acid, sodium ascorbate, sodium
metabisulfate, n-propyl gallate, BHA (butylated hydroxy anisole),
BHT (butylated hydroxy toluene) monothioglycerol and the like.
[1545] The chewable compositions of the invention may also include
one or more lubricants and/or processing aids. In some cases, the
lubricant/processing aid may also behave as a solvent, and
accordingly, there some of the components of the inventive
compositions may have dual functions. Lubricants/processing aids
include, but are not limited to polyethylene glycols of various
molecular weight ranges including PEG 3350 (Dow Chemical) and PEG
4000, corn oil, mineral oil, hydrogenated vegetable oils (STEROTEX
or LUBRITAB), peanut oil and/or castor oil.
[1546] Many flavoring agents may be used in the compositions of the
invention to improve the palatability of the oral veterinary
compositions. Preferred flavoring agents are those that are not
derived from animal sources. In various embodiments, flavoring
components derived from fruit, meat (including, but not limited to
pork, beef, chicken, fish, poultry, and the like), vegetable,
cheese, bacon, cheese-bacon and/or artificial flavorings may be
used. A flavoring component is typically chosen based upon
consideration related to the organism that will be ingesting the
soft chew. For example, a horse may prefer an apple flavoring
component, while a dog may prefer a meat flavoring component.
Although flavoring components derived from non-animal sources are
preferred, in some embodiments, natural flavors containing beef or
liver extracts, etc., may be used such as braised beef flavor
artificial powdered beef flavor, roast beef flavor and corned beef
flavor among others.
[1547] In another embodiment of the invention, the active
composition may be administered via an oral drench. Drench
compositions are those in which the liquid-containing compositions
of the invention are administered to the mouth or throat of the
animal.
[1548] The compositions of the invention may also be in the form of
oil-in-water or water-in-oil emulsions. The oily phase maybe a
vegetable oil, for example, olive oil or arachis oil, or a mineral
oil, for example, liquid paraffin or mixtures of these. Suitable
emulsifying agents include naturally-occurring phosphatides, for
example, soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example, sorbitan
monooleate, and condensation products of the said partial esters
with ethylene oxide, for example, polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening agents,
bittering agents, flavoring agents, and/or preservatives.
[1549] In one embodiment, the composition of the invention may be
in the form of a microemulsion. Microemulsions are well suited as
the liquid carrier vehicle. Microemulsions are quaternary systems
comprising an aqueous phase, an oily phase, a surfactant and a
co-surfactant. They are translucent and isotropic liquids.
[1550] Microemulsions are composed of stable dispersions of micro
droplets of the aqueous phase in the oily phase or conversely of
micro droplets of the oily phase in the aqueous phase. The size of
these micro droplets may be less than 200 nm (1000 to 100,000 nm
for emulsions).
[1551] The interfacial film may be composed of an alternation of
surface-active (SA) and co-surface-active (Co-SA) molecules which,
by lowering the interfacial tension, allows the microemulsion to be
formed spontaneously.
[1552] In one embodiment of the oily phase, the oily phase may be
formed from mineral or vegetable oils, from unsaturated
polyglycosylated glycerides or from triglycerides, or alternatively
from mixtures of such compounds. In one embodiment of the oily
phase, the oily phase may be comprised of triglycerides; in another
embodiment of the oily phase, the triglycerides are medium-chain
triglycerides, for example C.sub.8-C.sub.10 caprylic/capric
triglyceride. In another embodiment of the oily phase may represent
a % v/v range of about 2 to about 15%; about 7 to about 10%; and
about 8 to about 9% v/v of the microemulsion.
[1553] The aqueous phase may include, for example water or glycol
derivatives, such as propylene glycol, glycol ethers, polyethylene
glycols or glycerol. In one embodiment, the glycol may be propylene
glycol, diethylene glycol monoethyl ether, dipropylene glycol
monoethyl ether or mixtures thereof. Generally, the aqueous phase
will represent a proportion from about 1 to about 4% v/v in the
microemulsion.
[1554] Surfactants for the microemulsion may include diethylene
glycol monoethyl ether, dipropylene glycol monomethyl ether,
polyglycolide C.sub.8-C.sub.10 glycerides or polyglyceryl-6
dioleate. In addition to these surfactants, the co-surfactants may
include short-chain alcohols, such as ethanol and propanol.
[1555] Some compounds are common to the three components discussed
above, i.e., aqueous phase, surfactant and co-surfactant. However,
it is well within the skill level of the practitioner to use
different compounds for each component of the same composition. In
one embodiment for the amount of surfactant/co-surfactant, the
co-surfactant to surfactant ratio will be from about 1/7 to about
1/2. In another embodiment for the amount of co-surfactant, there
will be from about 25 to about 75% v/v of surfactant and from about
10 to about 55% v/v of co-surfactant in the microemulsion.
[1556] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example, arachis oil, olive oil,
sesame oil or coconut oil, or in mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as sucrose, saccharin or aspartame, bittering agents, and
flavoring agents may be added to provide a palatable oral
preparation. These compositions may be preserved by the addition of
an anti-oxidant such as ascorbic acid, or other known
preservatives.
[1557] Aqueous suspensions may contain the active material in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients include suspending agents, for
example, sodium carboxymethylcellulose, methylcellulose,
hydroxy-propylmethylcellulose, sodium alginate,
polvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents include naturally-occurring phosphatide, for example
lecithin, or condensation products of an alkylene oxide with fatty
acids, for example polyoxyethylene stearate, or condensation
products of ethylene oxide with long chain aliphatic alcohols, for
example, heptadecaethyleneoxycetanol, or condensation products of
ethylene oxide with partial esters derived from fatty acids and a
hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide, with partial esters
derived from fatty acids and hexitol anhydrides, for example
polyethylene sorbitan monooleate. The aqueous suspensions may also
contain one or more preservatives, for example ethyl, or n-propyl,
p-hydroxybenzoate, one or more coloring agents, one or more
flavoring agents, and one or more sweetening agents and/or
bittering agents, such as those set forth above.
[1558] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water may provide the
active ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example,
sweetening, bittering, flavoring and coloring agents, may also be
present.
[1559] Syrups and elixirs may be formulated with sweetening agents,
for example, glycerol, propylene glycol, sorbitol or sucrose. Such
compositions may also contain a demulcent, a preservative,
flavoring agent(S) and/or coloring agent(S).
[1560] In another embodiment of the invention, the composition may
be in paste form. Examples of embodiments in a paste form include,
but are not limited to, those described in U.S. Pat. Nos. 6,787,342
and 7,001,889 (each of which are incorporated herein by reference).
In addition to the compounds of the invention, the paste may
further contain fumed silica; a viscosity modifier; a carrier;
optionally, an absorbent; and optionally, a colorant, stabilizer,
surfactant, or preservative.
[1561] In one embodiment of the composition, the composition may be
a paste containing the compounds of the invention, fumed silica, a
viscosity modifier, an absorbent, a colorant; and a hydrophilic
carrier which is triacetin, a monoglyceride, a diglyceride, or a
triglyceride.
[1562] The paste may also include a viscosity modifier. Suitable
viscosity modifiers include, but are not limited to, polyethylene
glycols (PEG) including, but not limited to, PEG 200, PEG 300, PEG
400, PEG 600; monoethanolamine, triethanolamine, glycerol,
propylene glycol, polyoxyethylene (20) sorbitan mono-oleate
(polysorbate 80 or Tween 80), or poloxamers (e.g., Pluronic L 81);
an absorbent such as magnesium carbonate, calcium carbonate,
starch, and cellulose and its derivatives; and a colorant
including, but not limited to, titanium dioxide iron oxide, or
FD&C Blue #1 Aluminum Lake.
[1563] In some embodiments, the compositions may be in the form of
a sterile injectable composition. The injectable composition may be
a solution in organic solvents or an aqueous or oleaginous
suspension. This suspension may be formulated according to the
known art using those suitable dispersing or wetting agents and
suspending agents which have been mentioned above. The sterile
injectable preparation may also be a sterile injectable solution or
suspension in a non-toxic parenterally-acceptable diluent or
solvent, for example, as a solution in 1,3-butane diol. Among the
acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution.
Co-solvents such as ethanol, propylene glycol, glycerol formal or
polyethylene glycols may also be used. Preservatives, such as
phenol or benzyl alcohol, may be used.
[1564] In addition, sterile, fixed oils may be conventionally
employed as a solvent or suspending medium. For this purpose any
bland fixed oil may be employed including synthetic mono- or
diglycerides. In addition, fatty acids such as oleic acid find use
in the preparation of injectables.
[1565] In another embodiment, the present invention provides for
long-acting injectable compositions comprising an isoxazoline
compound of formula (Id), a poloxamer and, optionally, a
co-solvent. The long-acting compositions comprising an isoxazoline
compound of formula (Id), a poloxamer and a co-solvent, have been
surprisingly discovered to be stable and effective against a broad
spectrum of ectoparasites, and possibly also endoparasites if
another active is included, for an extended period of time; e.g., a
period from three (3) to six (6) months or longer while exhibiting
favorable properties with respect to the site of injection.
[1566] Poloxamers are a family of synthetic block copolymers of
ethylene oxide and propylene oxide. Poloxamers may be liquid, a
milky white paste or a powder and are represented by the following
structure:
##STR00040##
where a is an integer between 2 and 130 and b is an integer between
15 and 67 (see, U.S. Pat. No. 3,740,421). Poloxamer are available
from commercial sources such as BASF and Croda. An example of a
poloxamer is P-124 which is a solid at room temperature. In one
embodiment, poloxamer P-124 has the values a=12 and b=20. Other
poloxamers include P-128 (a=38 and b=29), P-181 (a=3 and b=30)
P-188 (a=80 and b=27), P-237 (a=64 and b=37), P338(a=141 and b=44,)
and P407(a=101 and b=56,).
[1567] The co-solvents used in the long-acting injectable
compositions comprising a compound of formula (Id) and a poloxamer
may be a single or a blend of co-solvents. In one embodiment, the
co-solvents used in the long-acting injectable compositions of the
present invention include polar solvents that are miscible in
water. Non-limiting examples of these co-solvents include ethanol,
isopropanol, benzyl alcohol, glycol ethers (e.g., including, but
limited to, diethyleneglycol monoethyl ether (DGME,
Transcutol.RTM., butyl diglycol, dipropylene glycol n-butyl ether,
ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether,
dipropylene glycol monomethyl ether, propylene glycol monomethyl
ether, propylene glycol monoethyl ether, and the like), liquid
polyethylene glycols (PEGs) (for example, PEG 400), propylene
glycol, carbonates (e.g., propylene carbonate), 2-pyrrolidone,
N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,
dimethylsulfoxide, glycerol formal or a mixture of at least two of
these solvents.
[1568] In one embodiment, the long-acting compositions of the
invention comprise a polar protic solvent including, but not
limited to, an alcohol such as ethanol, isopropanol or a glycol or
glycol ether. In another embodiment, the long-acting injectable
compositions of the invention comprise a polar aprotic solvent such
as N-methylpyrrolidone, dimethyl isosorbide, dimethylacetamide,
dimethylsulfoxide or propylene carbonate.
[1569] In yet another embodiment of the invention, the long-acting
injectable compositions of the invention include non-water miscible
co-solvents. Non-limiting examples of these co-solvents include
benzyl benzoate, ethyl acetate, triacetin, lipids, triglycerides
including medium chain triglycerides such C.sub.8-C.sub.10
triglycerides such as capric/caprilic triglycerides, propylene
glycol derivatives (e.g. propylene glycol monolaurate),
caprylocaproyl polyoxyl-8 glycerides (Labrasol) (non-ionic water
dispersible surfactant, isopropyl myristate, or a mixture of at
least two of these co-solvents. In one embodiment, the compositions
include a protic solvent that is not completely miscible with water
including, but not limited to, benzyl alcohol.
[1570] In another embodiment, the long-acting injectable
composition of the invention may include neutral oils as a
co-solvent. Neutral oils are triglycerides of fractionated plant
fatty acids with chain lengths of C.sub.8 to C.sub.10. Two
commercially available products are known as MIGLYOL.RTM. 810 and
MIGLYOL.RTM. 812. In another embodiment, the neutral oil is a
triglyceride of fractionated plant fatty acids with chain lengths
of C.sub.8 and C.sub.10 combined with linoleic acid (about 4-5%). A
commercially available product is known as MIGLYOL.RTM. 818. In yet
another embodiment, the neutral oil is a glycerin ester of
fractionated plant fatty acids with chain lengths of C.sub.8 and
C.sub.10 combined with succinic acid. A commercially available
product is known as MIGLYOL.RTM. 829. In another embodiment, the
neutral oil may be a propylene glycol diester of saturated plant
fatty acids with chain lengths of C.sub.8 and C.sub.10. A
commercially available product is known as MIGLYOL.RTM. 840
(propylene glycol dicaprylate/dicaprate). In yet another
embodiment, the co-solvent may be a mixture of two or more neutral
oils.
[1571] In another embodiment, the present invention provides
extended release injectable compositions for the treatment or
prevention of parasite infections or infestations in an animal
comprising an antiparasitic effective amount of at least one
isoxazoline compound of formula
[1572] (Id), a pharmaceutically acceptable polymer and optionally a
solvent or mixture of solvents. The pharmaceutically acceptable
polymers in the extended release injectable compositions, include,
but are not limited to, polylactides, polyglycolides,
polycaprolactones, polyanhydrides, polyamides, polyurethanes,
polyester amides, polyorthoesters, polydioxanones, polyacetals,
polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes,
pseudo poly(amides), polyhydroxyalcanoates, polyhydroxybutyrates,
polyhydroxyvalerates, polyalkylene oxalates, polyalkylene
succinates, poly(malic acid), poly(amino acids), poly(methyl vinyl
ether), poly(maleic anhydride), chitin, chitosan, and copolymers,
terpolymers, or combinations or mixtures therein including
copolymers of polylactides, polycaprolactones, polyglycolides
(e.g., poly(lactide-co-glycolide) and copolymers of polyethylene
glycol or methoxy polyethylene glycol with one or more of
polycaprolactone, polylactide or any of the other polymers/polymer
groups mentioned above. Also included are derivatives of
pharmaceutically acceptable polymers such as hydroxylated
derivatives including polycaprolactone diols and the like.
[1573] The solvents used in the extended release injectable
compositions of the invention may be a single or a blend of
solvents. Non-limiting examples of these solvents include alcohols
such as ethanol, 1-propanol, isopropanol, glycol ethers (e.g.,
including, but limited to, diethyleneglycol monoethyl ether (DGME,
Transcutol.RTM., butyl diglycol, dipropylene glycol n-butyl ether,
ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether,
dipropylene glycol monomethyl ether, propylene glycol monomethyl
ether, propylene glycol monoethyl ether, and the like), liquid
polyethylene glycols (PEGs) including, but not limited to, PEG 200,
PEG 300 and PEG 400; propylene glycol, glycerol, glycerol esters
including glycerol triacetate (triacetin), benzyl benzoate, ethyl
acetate, cyclic carbonates (e.g., ethylene carbonate and propylene
carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide
(DMI), dimethylacetamide (DMA), dimethyl formamide (DMF),
caprolactam, glycerol formal, acetone, dimethylsulfoxide (DMSO),
ethyl acetate, ethyl lactate, benzyl benzoate, or a mixture of at
least two of these solvents.
[1574] Topical, dermal and subdermal compositions may include, by
way of non-limiting example, emulsions, creams, ointments, gels,
pastes, powders, shampoos, pour-on compositions, ready-to-use
compositions, spot-on solutions and suspensions, dips and sprays.
Topical application of an inventive compound or of a composition
including at least one inventive compound among active agent(S)
therein, in the form of a spot-on, spray-on or pour-on composition,
may allow for the inventive composition to be absorbed through the
skin to achieve systemic levels, distributed through the sebaceous
glands or on the surface of the skin achieving levels throughout
the coat. When the compound is distributed through the sebaceous
glands, they may act as a reservoir, whereby there may be a
long-lasting effect (up to several months) effect. Spot-on
compositions are typically applied in a localized region which
refers to an area other than the entire animal. In one embodiment,
the location may be between the shoulders. In another embodiment it
may be a stripe, e.g. a stripe from head to tail of the animal.
[1575] Pour-on compositions are described in U.S. Pat. Nos.
6,010,710 and 9,180,121, both incorporated herein by reference.
Pour-on compositions may be advantageously oily, and generally
comprise a diluent or vehicle and also a solvent (e.g. an organic
solvent) for the active ingredient if the latter is not soluble in
the diluent.
[1576] Organic solvents that can be used in the invention include,
but are not limited to, acetyltributyl citrate, fatty acid esters
such as the dimethyl ester, diisobutyl adipate, acetone,
acetonitrile, benzyl alcohol, ethyl alcohol, butyl diglycol,
dimethylacetamide, dimethylformamide, dimethylsulfoxide, dimethyl
isosorbide, dipropylene glycol n-butyl ether, ethanol, isopropanol,
methanol, ethylene glycol monoethyl ether, ethylene glycol
monomethyl ether, monomethylacetamide, dipropylene glycol
monomethyl ether, liquid polyoxyethylene glycols, propylene glycol,
2-pyrrolidone, N-methylpyrrolidone, diethylene glycol monoethyl
ether, ethylene glycol, benzyl benzoate, ethyl acetate, triacetin,
C.sub.1-C.sub.10 esters of carboxylic acids such as butyl or octyl
acetate, glycerol formal, dialkyl esters of dicarboxylic acids
including diethyl sebacate, diisopropyl sebacate, diisopropyl
adipate and the like, and diethyl phthalate, or a mixture of at
least two of these solvents.
[1577] The solvent will be used in proportion with the
concentration of the active agent compound and its solubility in
this solvent. It will be sought to have the lowest possible volume.
The vehicle makes up the difference to 100%.
[1578] A vehicle or diluent for the compositions may include
dimethyl sulfoxide (DMSO), glycol derivatives such as, for example,
propylene glycol, glycol ethers, polyethylene glycols or glycerol.
As vehicle or diluent, mention may also be made of plant oils such
as, but not limited to soybean oil, groundnut oil, castor oil, corn
oil, cotton oil, olive oil, rape seed oil, sunflower oil, etc.;
mineral oils such as, but not limited to, petrolatum, paraffin,
silicone, etc.; aliphatic or cyclic hydrocarbons or alternatively,
for example, medium-chain (such as C.sub.8 to C.sub.12)
triglycerides.
[1579] In another embodiment of the invention, an emollient and/or
spreading and/or film-forming agent may be added. In one
embodiment, the emollient and/or spreading and/or film-forming
agent may be:
[1580] (a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of
vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl
alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan
esters; lecithin, sodium carboxymethylcellulose, silicone oils,
polydiorganosiloxane oils (such as polydimethylsiloxane (PDMS)
oils), for example those containing silanol functionalities, or a
45V2 oil,
[1581] (b) anionic surfactants such as alkaline stearates, sodium,
potassium or ammonium stearates; calcium stearate, triethanolamine
stearate; sodium abietate; alkyl sulfates (e.g. sodium lauryl
sulfate and sodium cetyl sulfate); sodium dodecylbenzenesulfonate,
sodium dioctylsulphosuccinate; fatty acids (e.g. those derived from
coconut oil),
[1582] (c) cationic surfactants include water-soluble quaternary
ammonium salts of formula N.sup.+R'R''R''R'''', Y.sup.- in which
the radicals R are optionally hydroxylated hydrocarbon radicals and
Y.sup.- is an anion of a strong acid such as the halide, sulfate
and sulfonate anions; cetyltrimethylammonium bromide is among the
cationic surfactants which can be used,
[1583] (d) amine salts of formula N.sup.+HR'R''R''' in which the
radicals R are optionally hydroxylated hydrocarbon radicals;
octadecylamine hydrochloride is among the cationic surfactants
which can be used,
[1584] (e) nonionic surfactants such as sorbitan esters, which are
optionally polyoxyethylenated (e.g. polysorbate 80),
polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols
such as polyoxypropylene-styrol ether; polyethylene glycol
stearate, polyoxyethylenated derivatives of castor oil,
polyglycerol esters, polyoxyethylenated fatty alcohols,
polyoxyethylenated fatty acids, copolymers of ethylene oxide and
propylene oxide,
[1585] (f) amphoteric surfactants such as the substituted lauryl
compounds of betaine; or
[1586] (g) a mixture of at least two of these agents.
[1587] In one embodiment of the amount of emollient, the emollient
used may be in a proportion of from about 0.1 to 50% or 0.25 to 5%,
by volume. In another embodiment, the emollient used may be in a
proportion of from about 0.1% to about 30%, about 1% to about 30%,
about 1% to about 20%, or about 5% to about 20% by volume.
[1588] In another embodiment of the invention, the composition may
be in the form of a ready-to-use spot-on solution form as is
described in U.S. Pat. Nos. 6,395,765 and 9,180,121, both
incorporated herein by reference. In addition to the compounds of
the invention, the ready-to-use solution may contain a
crystallization inhibitor and an organic solvent or a mixture of
organic solvents. In some embodiments, water may be included with
the organic solvent.
[1589] In various embodiments of the invention, the compositions
may include a crystallization inhibitor in an amount of about 1 to
about 50% (w/v) or about 5 to about 40% (w/v) based on the total
weight of the composition. In other embodiments, the amount of
crystallization inhibitor in the inventive compositions may be
about 1% to about 30%, about 5% to about 20%, about 1% to about
15%, or about 1% to about 10% (w/w). The type of crystallization
inhibitor used in the inventive compositions is not limited as long
as it functions to inhibit crystallization of the active or
inactive agents from the composition. For example, in certain
embodiments of the invention, a solvent or co-solvent of the
composition may also function as a crystallization inhibitor if it
sufficiently inhibits the formation of crystals from forming over
time when the composition is administered.
[1590] Crystallization inhibitors which are useful for the
invention include, but are not limited to:
[1591] (a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of
vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl
alcohol, dimethylformamide, dimethylacetamide, dimethylsulfoxide,
2-pyrrolidone, N-methylpyrrolidone, mannitol, glycerol, sorbitol or
polyoxyethylenated esters of sorbitan; lecithin or sodium
carboxymethylcellulose; or acrylic derivatives, such as acrylates
or methacrylates or polymers or copolymers thereof,
polyethyleneglycols (PEG) or polymers containing
polyethyleneglycols, such as glycofurol and the like, and
others;
[1592] (b) anionic surfactants, such as alkaline stearates (e.g.
sodium, potassium or ammonium stearate); calcium stearate or
triethanolamine stearate; sodium abietate; alkyl sulfates, which
include but are not limited to sodium lauryl sulfate and sodium
cetyl sulfate; sodium dodecylbenzenesulfonate or sodium dioctyl
sulphosuccinate; or fatty acids (e.g. coconut oil);
[1593] (c) cationic surfactants, such as water-soluble quaternary
ammonium salts of formula N.sup.+R'R''R'''R''''Y.sup.-, in which
the R radicals are identical or different optionally hydroxylated
hydrocarbon radicals and Y is an anion of a strong acid, such as
halide, sulfate and sulfonate anions; cetyltrimethylammonium
bromide is one of the cationic surfactants which can be used;
[1594] (d) amine salts of formula N.sup.+HR'R''R'', in which the R
radicals are identical or different optionally hydroxylated
hydrocarbon radicals; octadecylamine hydrochloride is one of the
cationic surfactants which can be used;
[1595] (e) non-ionic surfactants, such as optionally
polyoxyethylenated esters of sorbitan, e.g. Polysorbate 80, or
polyoxyethylenated alkyl ethers; polyethylene glycol stearate,
polyoxyethylenated derivatives of castor oil, polyglycerol esters,
polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids
or copolymers of ethylene oxide and of propylene oxide;
[1596] (f) amphoteric surfactants, such as substituted lauryl
compounds of betaine;
[1597] (g) a mixture of at least two of the compounds listed in
(a)-(f) above; or
[1598] (h) an organic solvent or mixture of solvents which inhibit
the formation of crystals or amorphous solid after the composition
is administered.
[1599] In one embodiment of the crystallization inhibitor, a
crystallization inhibitor pair will be used. Such pairs include,
for example, the combination of a film-forming agent of polymeric
type and of a surface-active agent. These agents will be selected
from the compounds mentioned above as crystallization
inhibitor.
[1600] In some embodiments, the organic solvent(S) may have a
dielectric constant of between about 10 and about 35 or between
about 20 and about 30. In other embodiments, the organic solvent
may have a dielectric constant of between about 10 and about 40 or
between about 20 and about 30. The content of this organic solvent
or mixture of solvents in the overall composition is not limited
and will be present in an amount sufficient to dissolve the desired
components to a desired concentration. As discussed above, the
organic solvent may also function as a crystallization inhibitor in
the composition.
[1601] In some embodiments, one or more of the organic solvent(S)
may have a boiling point of below about 100.degree. C., or below
about 80.degree. C. In other embodiments, the organic solvent(S)
may have a boiling point of below about 300.degree. C., below about
250.degree. C., below about 230.degree. C., below about 210.degree.
C. or below about 200.degree. C.
[1602] In some embodiments where there is a mixture of solvents,
i.e. a solvent and a co-solvent, the solvents may be present in the
composition in a weight/weight (W/W) ratio of about 1/50 to about
1/1. Typically the solvents will be in a ratio of about 1/30 to
about 1/1, about 1/20 to about 1/1, or about 1/15 to about 1/1 by
weight. Preferably, the two solvents will be present in a
weight/weight ratio of about 1/15 to about 1/2. In some
embodiments, at least one of the solvents present may act as to
improve solubility of the active agent or as a drying promoter. In
particular embodiments, at least one of the solvents will be
miscible with water.
[1603] The composition may also comprise an antioxidizing agent
intended to inhibit oxidation in air, this agent may be present in
a proportion of about 0.005 to about 1% (w/v), about 0.01 to about
0.1%, or about 0.01 to about 0.05%.
[1604] In one embodiment of the film-forming agent, the agents are
of the polymeric type which include but are not limited to the
various grades of polyvinylpyrrolidone, polyvinyl alcohols, and
copolymers of vinyl acetate and of vinylpyrrolidone.
[1605] In one embodiment of the surface-active agents, the agents
include but are not limited to those made of non-ionic surfactants;
in another embodiment of the surface active agents, the agent is a
polyoxyethylenated esters of sorbitan and in yet another embodiment
of the surface-active agent, the agents include the various grades
of polysorbate, for example Polysorbate 80.
[1606] In another embodiment of the invention, the film-forming
agent and the surface-active agent may be incorporated in similar
or identical amounts within the limit of the total amounts of
crystallization inhibitor mentioned elsewhere.
[1607] In another embodiment, the topical compositions include the
compound crotamiton which may inhibit the crystallization of active
agents from solution.
[1608] The crystallization inhibitor inhibits the formation of
crystals on the coat, and improves the maintenance of the cosmetic
appearance of the skin or fur; that is to say without a tendency
towards sticking or towards a sticky appearance, despite the high
concentration of active material. Substances other than those
mentioned herein may be used as crystallization inhibitors in the
present invention. In one embodiment, the effectiveness of the
crystallization inhibitor may be demonstrated by a test according
to which 0.3 mL of a solution comprising 10% (w/v) of the active
agent in an appropriate solvent as defined above, and 10% (w/v) of
the compound acting as a crystallization inhibitor are placed on a
glass slide at 20.degree. C. for 24 hours, after which fewer than
10 crystals, preferably 0 crystals, are seen with the naked eye on
the glass slide.
[1609] In one embodiment of the antioxidizing agents, the agents
are those conventional in the art and include but are not limited
to butylated hydroxyanisole, butylated hydroxytoluene, ascorbic
acid, sodium metabisulfite, propyl gallate, sodium thiosulfate or a
mixture of at least two compounds with antioxidant properties.
[1610] The composition adjuvants discussed above are well known to
the practitioner in this art and may be obtained commercially or
through known techniques. These concentrated compositions are
generally prepared by simple mixing of the constituents as defined
above; advantageously, the starting point is to mix the active
material in the main solvent and then the other ingredients or
adjuvants are added.
[1611] The volume of the composition applied will depend on the
type of animal and the size of the animal as well as the strength
of the composition and the potency of the active agents. In one
embodiment, an amount of about 0.3 to about 20 ml of the
composition may be applied to the animal. In other embodiment for
the volume, the volume may be about 0.1 to about 10 ml, about 0.3
to about 5 ml, about 0.5 ml to about 10 ml, or about 0.3 to about 3
ml.
[1612] In another embodiment of the invention, application of a
spot-on composition according to the present invention may also
provide long-lasting and broad-spectrum efficacy when the solution
is applied to the mammal or bird. The spot-on compositions provide
for topical administration of a concentrated solution, suspension,
microemulsion or emulsion for intermittent application to a spot on
the animal, generally between the two shoulders (solution of
spot-on type).
[1613] For spot-on compositions, the carrier may be a liquid
carrier vehicle as described in U.S. Pat. Nos. 6,426,333; 6,395,765
(incorporated herein by reference), which in may comprise a solvent
or mixture of solvents including, but not limited to, acetone, an
aliphatic alcohol such as methanol, ethanol, propanol, butanol,
isopropanol, pentanol, hexanol, heptanol, octanol, nonanol,
cyclopentanol, cyclohexanol, ethylene glycol, propylene glycol and
the like; an aromatic alcohol such as phenol, cresol, naphthol,
benzyl alcohol and the like; acetonitrile, butyl diglycol, an
organic amide such as dimethylacetamide, dimethylformamide,
monomethylacetamide, 2-pyrrolidone, N-methylpyrrolidone,
vinylpyrrolidone and the like; propylene or ethylene carbonate,
dimethylsulfoxide (DMSO), a glycol polymer or an ether thereof,
such as polyethylene glycol (PEG) of various grades, polypropylene
glycols of various grades, dipropylene glycol n-butyl ether,
ethylene glycol monoethyl ether, ethylene glycol monomethyl ether,
dipropylene glycol monomethyl ether, diethylene glycol monoethyl
ether, ethylene glycol, diethyl phthalate fatty acid esters, such
as the diethyl ester or diisobutyl adipate, or a mixture of at
least two of these solvents.
[1614] In another embodiment, the solvents used for the spot-on or
pour-on compositions of the invention include those described in
U.S. Pat. No. 9,180,121 (incorporated by reference). Solvents for
the spot-on or pour-on compositions may include, but are not
limited to, carboxylic acid esters, diesters of dicarboxylic acids,
fatty acid esters or diesters of fatty diacids, or a combination
thereof, including, but not limited to, isopropyl palmitate,
isostearyl lactate, diisopropyl adipate, dibutyl adipate, diethyl
sebacate, dibutyl sebacate, octyl palmitate, polyethylene glycol
(PEG) stearate and cetearyl octanoate; oils including, but not
limited to, mineral oil, diglycerides, triglycerides, jojoba oil,
lecithin and castor oil, or a combination thereof; long chain
aliphatic alcohols such as isostearyl alcohol and the like; fatty
alcohols and their esters, including for example, cetyl alcohol,
cetearyl alcohol and the like, or a combination thereof;
polyethylene glycols of different molecular weight ranges
including, but not limited to, PEG 300, PEG 400, PEG 600 and PEG
1000, or a combination thereof; and glycol ethers including, but
not limited to, diethyleneglycol monoethyl ether)(Transcutol.RTM.,
butyl diglycol, propylene glycol monomethyl ether, propylene glycol
monoethyl ether, dipropylene glycol n-butyl ether, ethylene glycol
monoethyl ether, ethylene glycol monomethyl ether and dipropylene
glycol monomethyl ether, or a combination thereof; or a combination
of two or more of these solvents.
[1615] Excipients that may promote the containment of the active
agent in the skin for longer periods of time and may be included in
the compositions of the invention include, but are not limited to,
mixed esters of sucrose and carboxylic acids including sucrose
acetate isobutyrate (SAIB) and the like; low temperature melting
waxes, hydrogenated vegetable oils, caprylic/capric glycerides;
glycerol esters, including for example, triacetin, glycerol
monooleate, glycerol monolinoleate, glycerol stearate, glyceryl
distearate and the like; triglycerides, including for example,
caprylic, capric/myristic/stearic triglyceride; thermoreversible
polymers, such as Pluronic and poloxamers, including for example,
Lutrol F127 by itself or in mixture with other poloxamers; or a
combination thereof.
[1616] In another embodiment of the invention the pharmaceutically
acceptable carrier for the topical compositions comprise a mixture
of a diester of a dicarboxylic acid alone or in combination with
one or more of additional solvents listed above, and/or an "oily"
lipophilic substance, including a liquid or low melting lipophilic
active agent such as (S)-methoprene, pyriproxyfen and/or
permethrin; and/or a mixed ester of sucrose and carboxylic acids
including a mixed ester of sucrose and acetic and isobutyric acids
such as sucrose acetate isobutyrate (SAM), and/or low melting waxes
and/or hard fats.
[1617] In one embodiment, the diester of a dicarboxylic acid in the
topical compositions is diethyl sebacate or diisopropyl adipate. In
another embodiment, the blend of solvents comprising a dicarboxylic
acid ester comprises a glycol or polyglycol, or a glycol or
polyglycol ether or ester including, but not limited to, ethylene
glycol (EG), propylene glycol (PG), liquid polyoxyethylene glycols
(PEGs) of various grades including PEG 400, EG or PG monocaprylate,
EG or PG caprylate, EG or PG monolaurate, EG or PG
dicaprylate/dicaprate, diethyleneglycol monoethyl ether (DGME,
Transcutol.RTM., butyl diglycol, dipropylene glycol n-butyl ether,
ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether,
dipropylene glycol monomethyl ether, propylene glycol monomethyl
ether, propylene glycol monoethyl ether, and the like, or a
combination thereof; an ether including, but not limited to,
dimethyl isosorbide; an ester or di-ester including, but not
limited to, triacetin, lauryl lactate; and other solvents including
glycerol formal, or mixtures thereof.
[1618] In preferred embodiments, the carrier for the topical
compositions comprises a dialkyl ester of a dicarboxylic acid such
as diethyl sebacate, diisopropyl sebacate, diisopropyl adipate,
dibutyl adipate, or a combination thereof, alone or in combination
with solvents selected from: [1619] a) a propylene glycol (PG)
ester including PG monocaprylate, PG caprylate, PG monolaurate, PG
dicaprylate/dicaprate, or a combination thereof; [1620] b) an ether
solvent including dimethyl isosorbide, diethylene glycol monoethyl
ether (also known as DGME or Transcutol.RTM., or a combination
thereof; [1621] c) a carboxylic acid ester including, but not
limited to, triacetin, lauryl lactate, isopropyl palmitate,
diisopropyl sebacate, or a combination thereof; and [1622] d) other
"oily" or lipophilic organic solvents including glycerol formal and
the like.
[1623] In some embodiments, the amount the additional solvents
combined with the carboxylic acid ester or diester of a
dicarboxylic acid are present in an amount of at least about 1%
(v/v), at least about 5% (v/v), at least about 9.0% (v/v), at least
about 13% (v/v), at least about 17% (v/v) or at least about 20%
(v/v). Preferably the additional solvents will be in an amount of
at least about 9% (v/v).
[1624] In other embodiments, the additional solvents will be
present in an amount of about 5-70% (v/v), about 10-60% (v/v),
about 10-50% (v/v), about 15-60% (v/v) or about 15-50% (v/v). In
preferred embodiments, the additional solvents will be present in
an amount of about 20-70% (v/v), about 20-60% (v/v), about 20-50%
(v/v) or about 25-50% (v/v).
[1625] In some embodiments, the liquid carrier vehicle may
optionally contain a crystallization inhibitor including, but not
limited to, those described in (a) to (h) above, or a compound that
may act both as a solvent and a crystallization inhibitor (as
defined above), or a mixture of these crystallization
inhibitors.
[1626] Spot-on compositions may be prepared by dissolving the
active ingredients into the pharmaceutically or veterinary
acceptable vehicle. Alternatively, the spot-on composition may be
prepared by encapsulation of the active ingredient to leave a
residue of the therapeutic agent on the surface of the animal.
These compositions will vary with regard to the weight of the
therapeutic agent in the combination depending on the species of
host animal to be treated, the severity and type of infection and
the body weight of the host.
[1627] Dosage forms may typically contain from about 0.1 mg to
about 5 g. In other embodiments, the dosage form may contain about
0.5 mg to about 5 g of an active agent. In one embodiment of the
dosage form, the dosage may contain from about 1 mg to about 500 mg
of an active agent, typically about 25 mg, about 50 mg, about 100
mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about
600 mg, about 800 mg, or about 1000 mg.
[1628] In one embodiment of the invention, the active agent may be
present in the composition at a concentration of about 0.05 to
about 10% weight/volume. In another embodiment of the invention,
the active agent may be present in the composition as a
concentration from about 0.1 to about 2% weight/volume. In yet
another embodiment of the invention, the active agent may be
present in the composition as a concentration from about 0.25 to
about 1.5% weight/volume. In still another embodiment of the
invention, the active agent may be present in the composition as a
concentration about 1% weight/volume.
II. Methods of Treatment:
[1629] As discussed above, the compounds of formula (Id) are
effective against ectoparasites and may be used to treat and
prevent parasitic infestations in or on animals. In one embodiment,
the present invention provides a method of treating or preventing
an ectoparasite infestation in or on an animal (e.g. a mammal or
bird) comprising administering an ectoparasiticidally effective
amount of a compound of formula (Id), or pharmaceutically
acceptable salts thereof, or a composition comprising the compound,
to the animal. In another embodiment, the methods of the invention
comprise administering an effective amount of a compound of formula
(Ie) or (5)-Ie, or a pharmaceutically acceptable salt thereof, to
the animal.
[1630] In another embodiment when the compounds of formula (Id) are
administered in combination with compounds that are active against
endoparasites, the invention provides a method for treating or
preventing an endoparasitic infection and an ectoparasitic
infestation in and on an animal, comprising administering a
composition comprising an effective amount of a compound of formula
(Id) in combination with an effective amount of at least a second
active agent, or pharmaceutically acceptable salts thereof, to the
animal.
[1631] Mammals which can be treated include but are not limited to
humans, cats, dogs, cattle, chickens, cows, bison, deer, goats,
horses, llamas, camels, pigs, sheep and yaks. In one embodiment of
the invention, the mammals treated are humans, cats or dogs.
[1632] In one embodiment of the invention, the compositions of the
invention comprising a compound of formula (Id) in combination with
an additional compound that is active against endoparasites are
effective against endoparasites that are resistant to active agents
of the macrocyclic lactone class. In one embodiment, the compounds
and compositions of the invention are effective for controlling
Haemonchus contortus, Ostertagia circumcincta and Trichostrongylus
colubriformis in mammals or birds.
[1633] In another embodiment, the invention provides a method for
treating an parasitic infestation and/or infection in an animal,
comprising administering an effective amount of a compound of
formula (Id) in combination with an effective amount of activators
of invertebrate GABA receptors, including an avermectin or
milbemycin, to the animal in need thereof. Avermectins that may be
used in combination with the compounds of the invention include,
but are not limited to abamectin, dimadectin, doramectin,
emamectin, eprinomectin, ivermectin, latidectin, lepimectin, and
selamectin. Milbemycins compounds that may be used in combination
with the compounds of the invention include, but are not limited
to, milbemectin, milbemycin D, milbemycin oxime, moxidectin and
nemadectin. Also included are the 5-oxo and 5-oxime derivatives of
said avermectins and milbemycins.
[1634] In one embodiment for the treatment against ectoparasites,
the ectoparasite is from the genera Ctenocephalides, Rhipicephalus,
Dermacentor, Ixodes, Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes,
Psoroptes, Otodectes, Chorioptes, Hypoderma, Damalinia,
Linognathus, Haematopinus, Solenoptes, Trichodectes, and Felicola.
The ectoparasites treated include but are not limited to fleas,
ticks, mites, mosquitoes, flies, lice, blowfly and combinations
thereof. Specific examples include but are not limited to cat and
dog fleas (Ctenocephalides felis, Ctenocephalides spp. and the
like), ticks (Rhipicephalus spp., Ixodes spp., Dermacentor spp.,
Amblyomma spp. and the like), and mites (Demodex spp., Sarcoptes
spp., Otodectes spp. and the like), lice (Trichodectes spp.,
Cheyletiella spp., Linognathus spp., and the like), mosquitoes
(Aedes spp., Culex spp., Anopheles spp., and the like) and flies
(Haematobia spp., Musca spp., Stomoxys spp., Dermatobia spp.,
Cochliomyia spp., and the like). In yet another embodiment for the
treatment against ectoparasites, the ectoparasite is a flea and/or
tick.
[1635] Additional examples of ectoparasites that may be controlled
with the compounds of formula (Id) include, but are not limited, to
the tick Rhipicephalus microplus (cattle tick), Rhipicephalus
decoloratus and Rhipicephalus annulates; myiasis such as Dermatobia
hominis (known as Berne in Brazil) and Cochliomyia hominivorax
(greenbottle); sheep myiasis such as Lucilia sericata, Lucilia
cuprina (known as blowfly strike in Australia, New Zealand and
South Africa). Flies proper, namely those whose adult constitutes
the parasite, such as Haematobia irritans (horn fly); lice such as
Linognathus vitulorum, etc.; and mites such as Sarcoptes scabiei
and Psoroptes ovis. The above list is not exhaustive and other
ectoparasites are well known in the art to be harmful to animals
and humans. These include, for example migrating dipterous
larvae.
[1636] In one embodiment, when administered with another compound
that is active against endoparasites, the compounds and
compositions of the invention may be used for treating or
preventing an endoparasitic infection of the following parasite:
Anaplocephala (Anoplocephala), 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, Wuchereria, and
combinations thereof.
[1637] In another embodiment of the invention, the parasite is
Haemonchus contortus, Ostertagia circumcincta, Trichostrongylus
axei, Trichostrongylus colubriformis, Cooperia curticei,
Nematodirus battus, Dirofilaria immitis, and combinations
thereof.
[1638] In another embodiment of the invention, the compounds and
compositions of the invention are suitable for controlling pests
such as insects selected from the group consisting of Blatella
germanica, Heliothis virescens, Leptinotarsa decemlineata,
Tetramorium caespitum and combinations thereof.
[1639] The phytoparasitic nematodes include, for example, Anguina
spp., Aphelenchoides spp., Belonolaimus spp., Bursaphelenchus spp.,
Ditylenchus dipsaci, Globodera spp., Helicotylenchus spp.,
Heterodera spp., Longidorus spp., Meloidogyne spp., Pratylenchus
spp., Radopholus similis, Rotylenchus spp., Trichodorus spp.,
Tylenchorhynchus spp., Tylenchulus spp., Tylenchulus semipenetrans,
Xiphinema spp.
[1640] In addition, with or without the other pesticidal agents
added to the composition, the invention can also be used to treat
other pests which include but are not limited to pests:
[1641] (1) from the order of Isopoda, for example Oniscus asellus,
Armadillidium vulgare and Porcellio scaber;
[1642] (2) from the order of Diplopoda, for example Blaniulus
guttulatus;
[1643] (3) from the order of Chilopoda, for example Geophilus
carpophagus and Scutigera spp.;
[1644] (4) from the order of Symphyla, for example Scutigerella
immaculata;
[1645] (5) from the order of Thysanura, for example Lepisma
saccharina;
[1646] (6) from the order of Collembola, for example Onychiurus
armatus;
[1647] (7) from the order of Blattaria, for example Blatta
orientalis, Periplaneta americana, Leucophaea maderae and Blattella
germanica;
[1648] (8) from the order of Hymenoptera, for example Diprion spp.,
Hoplocampa spp., Lasius spp., Monomorium pharaonis and Vespa
spp.;
[1649] (9) from the order of Siphonaptera, for example Xenopsylla
cheopis and Ceratophyllus spp.;
[1650] (10) from the order of Anoplura (Phthiraptera), for example,
Damalinia spp., Haematopinus spp., Linognathus spp., Pediculus
spp., Trichodectes spp.;
[1651] (11) from the class of Arachnida, for example, Acarus siro,
Aceria sheldoni, Aculops spp., Aculus spp., Amblyomma spp., Argas
spp., Boophilus spp., Brevipalpus spp., Bryobia praetiosa,
Chorioptes spp., Dermanyssus gallinae, Eotetranychus spp.,
Epitrimerus pyri, Eutetranychus spp., Eriophyes spp.,
Hemitarsonemus spp., Hyalomma spp., Ixodes spp., Latrodectus
mactans, Metatetranychus spp., Oligonychus spp., Ornithodoros spp.,
Panonychus spp., Phyllocoptruta oleivora, Polyphagotarsonemus
latus, Psoroptes spp., Rhipicephalus spp., Rhizoglyphus spp.,
Sarcoptes spp., Scorpio maurus, Steneotarsonemus spp., Tarsonemus
spp., Tetranychus spp., Vasates lycopersici.;
[1652] (12) from the class of Bivalva, for example, Dreissena
spp.;
[1653] (13) from the order of Coleoptera, for example,
Acanthoscelides obtectus, Adoretus spp., Agelastica alni, Agriotes
spp., Amphimallon solstitialis, Anobium punctatum, Anoplophora
spp., Anthonomus spp., Anthrenus spp., Apogonia spp., Atomaria
spp., Attagenus spp., Bruchidius obtectus, Bruchus spp.,
Ceuthorhynchus spp., Cleonus mendicus, Conoderus spp., Cosmopolites
spp., Costelytra zealandica, Curculio spp., Cryptorhynchus lapathi,
Dermestes spp., Diabrotica spp., Epilachna spp., Faustinus cubae,
Gibbium psylloides, Heteronychus arator, Hylamorpha elegans,
Hylotrupes bajulus, Hypera postica, Hypothenemus spp., Lachnosterna
consanguinea, Leptinotarsa decemlineata, Lissorhoptrus oryzophilus,
Lixus spp., Lyctus spp., Meligethes aeneus, Melolontha melolontha,
Migdolus spp., Monochamus spp., Naupactus xanthographus, Niptus
hololeucus, Oryctes rhinoceros, Oryzaephilus surinamensis,
Otiorrhynchus sulcatus, Oxycetonia jucunda, Phaedon cochleariae,
Phyllophaga spp., Popillia japonica, Premnotrypes spp., Psylliodes
chrysocephala, Ptinus spp., Rhizobius ventralis, Rhizopertha
dominica, Sitophilus spp., Sphenophorus spp., Sternechus spp.,
Symphyletes spp., Tenebrio molitor, Tribolium spp., Trogoderma
spp., Tychius spp., Xylotrechus spp., Zabrus spp.;
[1654] (14) from the order of Diptera, for example, Aedes spp.,
Anopheles spp., Bibio hortulanus, Calliphora erythrocephala,
Ceratitis capitata, Chrysomyia spp., Cochliomyia spp., Cordylobia
anthropophaga, Culex spp., Cuterebra spp., Dacus oleae, Dermatobia
hominis, Drosophila spp., Fannia spp., Gastrophilus spp., Hylemyia
spp., Hyppobosca spp., Hypoderma spp., Liriomyza spp., Lucilia
spp., Musca spp., Nezara spp., Oestrus spp., Oscinella frit,
Pegomyia hyoscyami, Phorbia spp., Stomoxys spp., Tabanus spp.,
Tannia spp., Tipula paludosa, Wohlfahrtia spp.;
[1655] (15) from the class of Gastropoda, for example, Arion spp.,
Biomphalaria spp., Bulinus spp., Deroceras spp., Galba spp.,
Lymnaea spp., Oncomelania spp., Succinea spp.;
[1656] (16) from the class of helminths, for example, Ancylostoma
duodenale, Ancylostoma ceylanicum, Ancylostoma braziliensis,
Ancylostoma spp., Ascaris lumbricoides, Ascaris spp., Brugia
malayi, Brugia timori, Bunostomum spp., Chabertia spp., Clonorchis
spp., Cooperia spp., Dicrocoelium spp, Dictyocaulus filaria,
Diphyllobothrium latum, Dracunculus medinensis, Echinococcus
granulosus, Echinococcus multilocularis, Enterobius vermicularis,
Faciola spp., Haemonchus spp., Heterakis spp., Hymenolepis nana,
Hyostrongulus spp., Loa Loa, Nematodirus spp., Oesophagostomum
spp., Opisthorchis spp., Onchocerca volvulus, Ostertagia spp.,
Paragonimus spp., Schistosomen spp., Strongyloides fuelleborni,
Strongyloides stercoralis, Strongyloides spp., Taenia saginata,
Taenia solium, Trichinella spiralis, Trichinella nativa,
Trichinella britovi, Trichinella nelsoni, Trichinella
pseudopsiralis, Trichostrongulus spp., Trichuris trichiura,
Wuchereria bancrofti;
[1657] (17) from the order of Heteroptera, for example, Anasa
tristis, Antestiopsis spp., Blissus spp., Calocoris spp.,
Campylomma livida, Cavelerius spp., Cimex spp., Creontiades
dilutus, Dasynus piperis, Dichelops furcatus, Diconocoris hewetti,
Dysdercus spp., Euschistus spp., Eurygaster spp., Heliopeltis spp.,
Horcias nobilellus, Leptocorisa spp., Leptoglossus phyllopus, Lygus
spp., Macropes excavatus, Miridae, Nezara spp., Oebalus spp.,
Pentomidae, Piesma quadrata, Piezodorus spp., Psallus seriatus,
Pseudacysta persea, Rhodnius spp., Sahlbergella singularis,
Scotinophora spp., Stephanitis nashi, Tibraca spp., Triatoma
spp.;
[1658] (18) from the order of Homoptera, for example, Acyrthosipon
spp., Aeneolamia spp., Agonoscena spp., Aleurodes spp., Aleurolobus
barodensis, Aleurothrixus spp., Amrasca spp., Anuraphis cardui,
Aonidiella spp., Aphanostigma piri, Aphis spp., Arboridia apicalis,
Aspidiella spp., Aspidiotus spp., Atanus spp., Aulacorthum solani,
Bemisia spp., Brachycaudus helichrysii, Brachycolus spp.,
Brevicoryne brassicae, Calligypona marginata, Carneocephala
fulgida, Ceratovacuna lanigera, Cercopidae, Ceroplastes spp.,
Chaetosiphon fragaefolii, Chionaspis tegalensis, Chlorita onukii,
Chromaphis juglandicola, Chrysomphalus ficus, Cicadulina mbila,
Coccomytilus halli, Coccus spp., Cryptomyzus ribis, Dalbulus spp.,
Dialeurodes spp., Diaphorina spp., Diaspis spp., Doralis spp.,
Drosicha spp., Dysaphis spp., Dysmicoccus spp., Empoasca spp.,
Eriosoma spp., Erythroneura spp., Euscelis bilobatus, Geococcus
coffeae, Homalodisca coagulata, Hyalopterus arundinis, Icerya spp.,
Idiocerus spp., Idioscopus spp., Laodelphax striatellus, Lecanium
spp., Lepidosaphes spp., Lipaphis erysimi, Macrosiphum spp.,
Mahanarva fimbriolata, Melanaphis sacchari, Metcalfiella spp.,
Metopolophium dirhodum, Monellia costalis, Monelliopsis pecanis,
Myzus spp., Nasonovia ribisnigri, Nephotettix spp., Nilaparvata
lugens, Oncometopia spp., Orthezia praelonga, Parabemisia myricae,
Paratrioza spp., Parlatoria spp., Pemphigus spp., Peregrinus
maidis, Phenacoccus spp., Phloeomyzus passerinii, Phorodon humuli,
Phylloxera spp., Pinnaspis aspidistrae, Planococcus spp.,
Protopulvinaria pyriformis, Pseudaulacaspis pentagona, Pseudococcus
spp., Psylla spp., Pteromalus spp., Pyrilla spp., Quadraspidiotus
spp., Quesada gigas, Rastrococcus spp., Rhopalosiphum spp.,
Saissetia spp., Scaphoides titanus, Schizaphis graminum,
Selenaspidus articulatus, Sogata spp., Sogatella furcifera,
Sogatodes spp., Stictocephala festina, Tenalaphara malayensis,
Tinocallis caryaefoliae, Tomaspis spp., Toxoptera spp.,
Trialeurodes vaporariorum, Trioza spp., Typhlocyba spp., Unaspis
spp., Viteus vitifolii.;
[1659] (19) from the order of Isoptera, for example, Reticulitermes
spp., Odontotermes spp.;
[1660] (20) from the order of Lepidoptera, for example, Acronicta
major, Aedia leucomelas, Agrotis spp., Alabama argillacea,
Anticarsia spp., Barathra brassicae, Bucculatrix thurberiella,
Bupalus piniarius, Cacoecia podana, Capua reticulana, Carpocapsa
pomonella, Cheimatobia brumata, Chilo spp., Choristoneura
fumiferana, Clysia ambiguella, Cnaphalocerus spp., Earias insulana,
Ephestia kuehniella, Euproctis chrysorrhoea, Euxoa spp., Feltia
spp., Galleria mellonella, Helicoverpa spp., Heliothis spp.,
Hofmannophila pseudospretella, Homona magnanima, Hyponomeuta
padella, Laphygma spp., Lithocolletis blancardella, Lithophane
antennata, Loxagrotis albicosta, Lymantria spp., Malacosoma
neustria, Mamestra brassicae, Mods repanda, Mythimna separata, Oria
spp., Oulema oryzae, Panolis flammea, Pectinophora gossypiella,
Phyllocnistis citrella, Pieris spp., Plutella xylostella, Prodenia
spp., Pseudaletia spp., Pseudoplusia includens, Pyrausta nubilalis,
Spodoptera spp., Thermesia gemmatalis, Tinea pellionella, Tineola
bisselliella, Tortrix viridana, Trichoplusia spp.;
[1661] (21) from the order of Orthoptera, for example, Acheta
domesticus, Blatta orientalis, Blattella germanica, Gryllotalpa
spp., Leucophaea maderae, Locusta spp., Melanoplus spp.,
Periplaneta americana, Schistocerca gregaria.;
[1662] (22) from the order of Thysanoptera, for example,
Baliothrips biformis, Enneothrips flavens, Frankliniella spp.,
Heliothrips spp., Hercinothrips femoralis, Kakothrips spp.,
Rhipiphorothrips cruentatus, Scirtothrips spp., Taeniothrips
cardamoni, Thrips spp.;
[1663] (23) from the class of Protozoa, for example, Eimeria
spp.
[1664] In each aspect of the invention, the compounds and
compositions of the invention can be applied against a single pest
or combinations thereof.
Non-Veterinary Applications
[1665] For use in a method for combating pests that damage plants,
plant propagation material and crops, or material derived from
wood, according to the present invention, the compounds of formula
(Id) can be converted into the customary compositions, e.g.
solutions, emulsions, suspensions, dusts, powders, pastes, granules
and directly sprayable solutions. The use form depends on the
particular purpose and application method. Formulations and
application methods are chosen to ensure in each case a fine and
uniform distribution of the compound of the formula (Id) according
to the present invention.
I. Agricultural Compositions
[1666] The compositions are prepared in a known manner (see e.g.
for review U.S. Pat. No. 3,060,084, EP-A 707 445 (for liquid
concentrates), Browning, "Agglomeration", Chemical Engineering,
Dec. 4, 1967, 147-48, Perry's Chemical Engineer's Handbook, 4th
Ed., McGraw-Hill, New York, 1963, pages 8-57 and et seq. WO
91/13546, U.S. Pat. No. 4,172,714, U.S. Pat. No. 4,144,050, U.S.
Pat. No. 3,920,442, U.S. Pat. No. 5,180,587, U.S. Pat. No.
5,232,701, U.S. Pat. No. 5,208,030, GB 2,095,558, U.S. Pat. No.
3,299,566, Klingman, Weed Control as a Science, John Wiley and
Sons, Inc., New York, 1961, Hance et al., Weed Control Handbook,
8th Ed., Blackwell Scientific Publications, Oxford, 1989 and
Mollet, H., Grubemann, A., Formulation technology, Wiley VCH Verlag
GmbH, Weinheim (Germany), 2001, 2. D. A. Knowles, Chemistry and
Technology of Agrochemical Formulations, Kluwer Academic
Publishers, Dordrecht, 1998 (ISBN 0-7514-0443-8, all of which are
hereby incorporated by reference in their entirety), for example by
extending the active compound with auxiliaries suitable for the
composition of agrochemicals, such as solvents and/or carriers, if
desired emulsifiers, surfactants and dispersants, preservatives,
antifoaming agents, anti-freezing agents, for seed treatment
composition also optionally colorants and/or binders and/or gelling
agents. The following solvents/carriers are suitable for
compositions of the invention: [1667] solvents such as water,
aromatic solvents (for example Solvesso products, xylene and the
like), paraffins (for example mineral fractions), alcohols (for
example methanol, butanol, pentanol, benzyl alcohol), ketones (for
example cyclohexanone, gamma-butyrolactone), pyrrolidones
(N-methylpyrrolidone (NMP),N-octylpyrrolidone NOP), acetates
(glycol diacetate), alkyl lactates, lactones such as
g-butyrolactone, glycols, fatty acid dimethylamides, fatty acids
and fatty acid esters, triglycerides, oils of vegetable or animal
origin and modified oils such as alkylated plant oils. In
principle, solvent mixtures may also be used. [1668] carriers such
as ground natural minerals and ground synthetic minerals, such as
silica gels, finely divided silicic acid, silicates, talc, kaolin,
attaclay, limestone, lime, chalk, bole, loess, clay, dolomite,
diatomaceous earth, calcium sulfate and magnesium sulfate,
magnesium oxide, ground synthetic materials, fertilizers, such as,
for example, ammonium sulfate, ammonium phosphate, ammonium
nitrate, ureas and products of vegetable origin, such as cereal
meal, tree bark meal, wood meal and nutshell meal, cellulose
powders and other solid carriers.
[1669] Suitable emulsifiers include non-ionic and anionic
emulsifiers (for example polyoxyethylene fatty alcohol ethers,
alkylsulfonates and arylsulfonates).
[1670] Examples of suitable dispersants include lignin-sulfite
waste liquors and methylcellulose.
[1671] Suitable surfactants include alkali metal, alkaline earth
metal and ammonium salts of lignosulfonic acid, naphthalenesulfonic
acid, phenol sulfoni c acid, dibutylnaphthalenesulfonic acid,
alkylarylsulfonates, alkyl sulfates, alkylsulfonates, fatty alcohol
sulfates, fatty acids and sulfated fatty alcohol glycol ethers,
furthermore condensates of sulfonated naphthalene and naphthalene
derivatives with formaldehyde, condensates of naphthalene or of
naphthalenesulfonic acid with phenol and formaldehyde,
polyoxyethylene octylphenyl ether, ethoxylated isooctylphenol,
octylphenol, nonylphenol, alkylphenyl polyglycol ethers,
tributylphenyl polyglycol ether, tristearylphenyl polyglycol ether,
alkylaryl polyether alcohols, alcohol and fatty alcohol/ethylene
oxide condensates, ethoxylated castor oil, polyoxyethylene alkyl
ethers, ethoxylated polyoxypropylene, lauryl alcohol polyglycol
ether acetal, sorbitol esters,
[1672] In some embodiments, anti-freezing agents such as glycerin,
ethylene glycol, propylene glycol and bactericides such as can be
added to the composition.
[1673] In other embodiments, antifoaming agents may be included in
the compositions. Suitable antifoaming agents include antifoaming
agents based on silicon or magnesium stearate.
[1674] The compositions of the invention may comprise
preservatives. Suitable preservatives include, for example,
dichlorophenyl and benzyl alcohol hemiformal In other embodiments,
the compositions of the invention may include thickeners known in
the art. Suitable thickeners include compounds which confer a
pseudoplastic flow behavior to the composition, i.e. high viscosity
at rest and low viscosity in the agitated stage. These thickeners
include, for example, of commercial thickeners based on
polysaccharides, such as Xanthan Gum.RTM. (Kelzan.RTM. from Kelco),
Rhodopol.RTM. 23 (Rhone Poulenc) or Veegum.RTM. (from R.T.
Vanderbilt), or organic phyllosilicates, such as Attaclay.RTM.
(from Engelhardt). Antifoam agents suitable for the dispersions
according to the invention are, for example, silicone emulsions
(such as, for example, Silikon.RTM. SRE, Wacker or Rhodorsil.RTM.
from Rhodia), long-chain alcohols, fatty acids, organofluorine
compounds and mixtures thereof. Biocides can be added to stabilize
the compositions according to the invention against attack by
microorganisms. Suitable biocides are, for example, based on
isothiazolones such as the compounds marketed under the trademarks
Proxel from Avecia (or Arch) or Acticide RS from Thor Chemie and
Kathon MK from Rohm & Haas. Suitable antifreeze agents are
organic polyols, for example ethylene glycol, propylene glycol or
glycerol. These are usually employed in amounts of not more than
10% by weight, based on the total weight of the active compound
composition. If appropriate, the active compound compositions
according to the invention may comprise 1 to 5% by weight of
buffer, based on the total amount of the composition prepared, to
regulate the pH, the amount and type of the buffer used depending
on the chemical properties of the active compound or the active
compounds. Examples of buffers are alkali metal salts of weak
inorganic or organic acids, such as, for example, phosphoric acid,
boronic acid, acetic acid, propionic acid, citric acid, fumaric
acid, tartaric acid, oxalic acid and succinic acid.
[1675] Substances which are suitable for the preparation of
directly sprayable solutions, emulsions, pastes or oil dispersions
are mineral oil fractions of medium to high boiling point, such as
kerosene or diesel oil, furthermore coal tar oils and oils of
vegetable or animal origin, aliphatic, cyclic and aromatic
hydrocarbons, for example toluene, xylene, paraffin,
tetrahydronaphthalene, alkylated naphthalenes or their derivatives,
methanol, ethanol, propanol, butanol, cyclohexanol, cyclohexanone,
isophorone, strongly polar solvents, for example dimethyl
sulfoxide, N-methylpyrrolidone and water.
[1676] Powders, materials for spreading and dusts can be prepared
by mixing or concomitantly grinding the active substances with a
solid carrier.
[1677] Granules, for example coated granules, impregnated granules
and homogeneous granules, can be prepared by binding the active
ingredients to solid carriers. Examples of solid carriers are
mineral earths such as silica gels, silicates, talc, kaolin,
attaclay, limestone, lime, chalk, bole, loess, clay, dolomite,
diatomaceous earth, calcium sulfate, magnesium sulfate, magnesium
oxide, ground synthetic materials, fertilizers, such as, for
example, ammonium sulfate, ammonium phosphate, ammonium nitrate,
ureas, and products of vegetable origin, such as cereal meal, tree
bark meal, wood meal and nutshell meal, cellulose powders and other
solid carriers. In general, the compositions typically comprise
from about 0.01 to about 95% by weight, preferably from about 0.1
to about 90% by weight, of the active ingredient. The active
ingredients are employed typically have a purity of from about 90%
to about 100%, preferably about 95% to about 100% (according to NMR
spectrum).
[1678] For seed treatment purposes, respective compositions can be
diluted 2-10 fold leading to concentrations in the ready to use
preparations of about 0.01 to about 60% by weight active compound
by weight, preferably about 0.1 to about 40% by weight.
[1679] The compound of formula (Id) can be used as such, in the
form of their compositions or the use forms prepared therefrom, for
example in the form of directly sprayable solutions, powders,
suspensions or dispersions, emulsions, oil dispersions, pastes,
dustable products, materials for spreading, or granules, by means
of spraying, atomizing, dusting, spreading or pouring. The use
forms depend entirely on the intended purposes; they are intended
to ensure in each case the finest possible distribution of the
active compounds according to the invention. The following are
examples of compositions:
1. Products for dilution with water. For seed treatment purposes,
such products may be applied to the seed diluted or undiluted.
A) Water-Soluble Concentrates (SL, LS)
[1680] 10 parts by weight of the active compound is dissolved in 90
parts by weight of water or a water-soluble solvent. As an
alternative, wetters or other auxiliaries are added. The active
compound dissolves upon dilution with water, whereby a composition
with 10% (w/w) of active compound is obtained.
B) Dispersible Concentrates (DC)
[1681] 20 parts by weight of the active compound is dissolved in 70
parts by weight of cyclohexanone with addition of 10 parts by
weight of a dispersant, for example polyvinylpyrrolidone. Dilution
with water gives a dispersion, whereby a composition with 20% (w/w)
of active compounds is obtained.
C) Emulsifiable Concentrates (EC)
[1682] 15 parts by weight of the active compounds is dissolved in 7
parts by weight of xylene with addition of calcium
dodecylbenzenesulfonate and castor oil ethoxylate (in each case 5
parts by weight). Dilution with water gives an emulsion, whereby a
composition with 15% (w/w) of active compounds is obtained.
D) Emulsions (EW, EO, ES)
[1683] 25 parts by weight of the active compound is dissolved in 35
parts by weight of xylene with addition of calcium
dodecylbenzenesulfonate and castor oil ethoxylate (in each case 5
parts by weight). This mixture is introduced into 30 parts by
weight of water by means of an emulsifier machine (e.g.
Ultraturrax) and made into a homogeneous emulsion. Dilution with
water gives an emulsion, whereby a composition with 25% (w/w) of
active compound is obtained.
E) Suspensions (SC, OD, FS)
[1684] In an agitated ball mill, 20 parts by weight of the active
compound is comminuted with addition of 10 parts by weight of
dispersants, wetters and 70 parts by weight of water or of an
organic solvent to give a fine active compound suspension. Dilution
with water gives a stable suspension of the active compound,
whereby a composition with 20% (w/w) of active compound is
obtained.
F) Water-Dispersible Granules and Water-Soluble Granules (WG,
SG)
[1685] 50 parts by weight of the active compound is ground finely
with addition of 50 parts by weight of dispersants and wetters and
made as water-dispersible or water-soluble granules by means of
technical appliances (for example extrusion, spray tower, fluidized
bed). Dilution with water gives a stable dispersion or solution of
the active compound, whereby a composition with 50% (w/w) of active
compound is obtained.
G) Water-Dispersible Powders and Water-Soluble Powders (WP, SP, SS,
WS)
[1686] 75 parts by weight of the active compound are ground in a
rotor-stator mill with addition of 25 parts by weight of
dispersants, wetters and silica gel. Dilution with water gives a
stable dispersion or solution of the active compound, whereby a
composition with 75% (w/w) of active compound is obtained.
H) Gel-Formulation (GF)
[1687] In an agitated ball mill, 20 parts by weight of the active
compound is comminuted with addition of 10 parts by weight of
dispersants, 1 part by weight of a gelling agent wetters and 70
parts by weight of water or of an organic solvent to give a fine
active compound suspension. Dilution with water gives a stable
suspension of the active compound, whereby a composition with 20%
(w/w) of active compound is obtained. 2. Products to be applied
undiluted for foliar applications. For seed treatment purposes,
such products may be applied to the seed diluted or undiluted.
I) Dustable Powders (DP, DS)
[1688] 5 parts by weight of the active compound are ground finely
and mixed intimately with 95 parts by weight of finely divided
kaolin. This gives a dustable product having 5% (w/w) of active
compound.
J) Granules (GR, FG, GG, MG)
[1689] 0.5 part by weight of the active compound is ground finely
and associated with 95.5 parts by weight of carriers, whereby a
composition with 0.5% (w/w) of active compound is obtained. Current
methods are extrusion, spray-drying or the fluidized bed. This
gives granules to be applied undiluted for foliar use.
K) ULV Solutions (UL)
[1690] 10 parts by weight of the active compound is dissolved in 90
parts by weight of an organic solvent, for example xylene. This
gives a product having 10% (w/w) of active compound, which is
applied undiluted for foliar use.
[1691] Aqueous use forms can be prepared from emulsion
concentrates, pastes or wettable powders (sprayable powders, oil
dispersions) by adding water. To prepare emulsions, pastes or oil
dispersions, the substances, as such or dissolved in an oil or
solvent, can be homogenized in water by means of a wetter,
tackifier, dispersant or emulsifier. Alternatively, it is possible
to prepare concentrates composed of active substance, wetter,
tackifier, dispersant or emulsifier and, if appropriate, solvent or
oil, and such concentrates are suitable for dilution with water.
The active ingredient concentrations in the ready-to-use products
can be varied within relatively wide ranges. In general, they are
from about 0.0001 to about 10%, preferably from about 0.01 to about
1%.
[1692] The active ingredients may also be used successfully in the
ultra-low-volume process (ULV), it being possible to apply
compositions comprising over 95% by weight of active ingredient, or
even to apply the active ingredient without additives.
II. Mixtures with Other Actives
[1693] In the method of this invention compounds of formula (Id),
including in particular (Ie) and (S)-Ie, may be applied with other
active ingredients, for example with other pesticides,
insecticides, herbicides, fertilizers such as ammonium nitrate,
urea, potash, and superphosphate, phytotoxicants and plant growth
regulators, safeners and nematicides. These additional ingredients
may be used sequentially or in combination with the above-described
compositions, if appropriate also added only immediately prior to
use (tank mix). For example, the plant(S) may be sprayed with a
composition of this invention either before or after being treated
with other active ingredients.
[1694] The following list M of pesticides together with which the
compounds according to the invention can be used and with which
potential synergistic effects might be produced, is intended to
illustrate the possible combinations, but not to impose any
limitation:
M.1. Organo(thio)phosphate compounds: acephate, azamethiphos,
azinphos-ethyl, azinphos-methyl, chlorethoxyfos, chlorfenvinphos,
chlormephos, chlorpyrifos, chlorpyrifos-methyl, coumaphos,
cyanophos, demeton-S-methyl, diazinon, dichlorvos/DDVP,
dicrotophos, dimethoate, dimethylvinphos, disulfoton, EPN, ethion,
ethoprophos, famphur, fenamiphos, fenitrothion, fenthion,
flupyrazophos, fosthiazate, heptenophos, isoxathion, malathion,
mecarbam, methamidophos, methidathion, mevinphos, monocrotophos,
naled, omethoate, oxydemeton-methyl, parathion, parathion-methyl,
phenthoate, phorate, phosalone, phosmet, phosphamidon, phoxim,
pirimiphos-methyl, profenofos, propetamphos, prothiofos,
pyraclofos, pyridaphenthion, quinalphos, sulfotep, tebupirimfos,
temephos, terbufos, tetrachlorvinphos, thiometon, triazophos,
trichlorfon, vamidothion; M.2. Carbamate compounds: aldicarb,
alanycarb, bendiocarb, benfuracarb, butocarboxim, butoxycarboxim,
carbaryl, carbofuran, carbosulfan, ethiofencarb, fenobucarb,
formetanate, furathiocarb, isoprocarb, methiocarb, methomyl,
metolcarb, oxamyl, pirimicarb, propoxur, thiodicarb, thiofanox,
trimethacarb, XMC, xylylcarb, triazamate; M.3. Pyrethroid
compounds: acrinathrin, allethrin, d-cis-trans allethrin, d-trans
allethrin, bifenthrin, bioallethrin, bioallethrin S-cylclopentenyl,
bioresmethrin, cycloprothrin, cyfluthrin, beta-cyfluthrin,
cyhalothrin, lambda-cyhalothrin, gamma-cyhalothrin, cypermethrin,
alpha-cypermethrin, beta-cypermethrin, theta-cypermethrin,
zeta-cypermethrin, cyphenothrin, deltamethrin, empenthrin,
esfenvalerate, etofenprox, fenpropathrin, fenvalerate,
flucythrinate, flumethrin, tau-fluvalinate, halfenprox,
imiprothrin, metofluthrin, permethrin, phenothrin, prallethrin,
profluthrin, pyrethrin (pyrethrum), resmethrin, silafluofen,
tefluthrin, tetramethrin, tralomethrin, transfluthrin; M.4.
Juvenile hormone mimics: hydroprene, kinoprene, methoprene,
fenoxycarb, pyriproxyfen; M.5. Nicotinic receptor
agonists/antagonists compounds: acetamiprid, bensultap, cartap
hydrochloride, clothianidin, dinotefuran, imidacloprid,
thiamethoxam, nitenpyram, nicotine, spinosad (allosteric agonist),
spinetoram (allosteric agonist), thiacloprid, thiocyclam,
thiosultap-sodium and AKD1022. M.6. GABA gated chloride channel
antagonist compounds: chlordane, endosulfan, gamma-HCH (lindane);
ethiprole, fipronil, pyrafluprole, pyriprole M.7. Chloride channel
activators: abamectin, emamectin benzoate, milbemectin, lepimectin;
M.8. METI I compounds: fenazaquin, fenpyroximate, pyrimidifen,
pyridaben, tebufenpyrad, tolfenpyrad, flufenerim, rotenone; M.9.
METI II and III compounds: acequinocyl, fluacyprim, hydramethylnon;
M.10. Uncouplers of oxidative phosphorylation: chlorfenapyr, DNOC;
M.11. Inhibitors of oxidative phosphorylation: azocyclotin,
cyhexatin, diafenthiuron, fenbutatin oxide, propargite, tetradifon;
M.12. Moulting disruptors: cyromazine, chromafenozi de, hal ofenozi
de, methoxyfenozi de, tebufenozide; M.13. Synergists: piperonyl
butoxide, tribufos; M.14. Sodium channel blocker compounds:
indoxacarb, metaflumizone; M.15. Fumigants: methyl bromide,
chloropicrin sulfuryl fluoride; M.16. Selective feeding blockers:
crylotie, pymetrozine, flonicamid; M.17. Mite growth inhibitors:
clofentezine, hexythiazox, etoxazole; M.18. Chitin synthesis
inhibitors: buprofezin, bistrifluron, chlorfluazuron,
diflubenzuron, flucycloxuron, flufenoxuron, hexaflumuron,
lufenuron, novaluron, noviflumuron, teflubenzuron, triflumuron;
M.19. Lipid biosynthesis inhibitors: spirodiclofen, spiromesifen,
spirotetramat; M.20. Octapaminergic agonsits: amitraz; M.21.
Ryanodine receptor modulators: flubendiamide and the phtalamid
compound (R)-,
(S)-3-Chlor-N1-{2-methyl-4-[1,2,2,2-tetrafluor-1-(trifluormethyl)ethyl]ph-
enyl}-N2-(1-methyl-2-methyl sulfonylethyl)phthalamid (M21.1) M.22.
Isoxazoline compounds:
4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-
-methyl-N-pyridin-2-ylmethyl-benzamide (M22.1),
4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,
5-dihydro-isoxazol-3-yl]-2-methyl-N-(2,2,2-trifluoro-ethyl)-benzamide
(M22.2),
4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-
l-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide
(M22.3), 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,
5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylic acid
[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide (M22.4)
4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,
5-dihydro-isoxazol-3-yl]-N-[(methoxyimino)methyl]-2-methylbenzamide
(M22.5),
4-[5-(3-Chloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,
5-dihydro-isoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-met-
hyl]-benzamide (M22.6),
4-[5-(3-Chloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-is-
oxazol-3-yl]-naphthalene-1-carboxylic acid
[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide (M22.7) and
5-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,
5-dihydro-isoxazol-3-yl]-2-[1,2,4]triazol-1-yl-benzonitrile
(M22.8); M.23. Anthranilamide compounds: chloranthraniliprole,
cyantraniliprole,
5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid
[4-cyano-2-(1-cyclopropyl-ethylcarbamoyl)-6-methyl-phenyl]-amide
(M23.1), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic
acid
[2-chloro-4-cyano-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide
(M23.2), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic
acid
[2-bromo-4-cyano-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide
(M23.3), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic
acid
[2-bromo-4-chloro-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide
(M23.4), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic
acid [2,4-dichloro-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide
(M23.5), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic
acid
[4-chloro-2-(1-cyclopropyl-ethylcarbamoyl)-6-methyl-phenyl]-amide
(M23.6),
N'-(2-{[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl-
]-amino}-5-chloro-3-methyl-benzoyl)-hydrazinecarboxylic acid methyl
ester (M23.7),
N'-(2-{[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl-
]-amino}-5-chloro-3-methyl-benzoyl)-N'-methyl-hydrazinecarboxylic
acid methyl ester (M23.8),
N'-(2-{[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}--
5-chloro-3-methyl-benzoyl)-N,N'-dimethyl-hydrazinecarboxylic acid
methyl ester (M23.9),
N'-(3,5-Dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbo-
nyl]-amino}-benzoyl)-hydrazinecarboxylic acid methyl ester
(M23.10),
N'-(3,5-Dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbo-
nyl]-amino}-benzoyl)-N'-methyl-hydrazinecarboxylic acid methyl
ester (M23.11) and
N'-(3,5-Dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbo-
nyl]-amino}-benzoyl)-N,N'-dimethyl-hydrazinecarboxylic acid methyl
ester (M23.12); M.24. Malononitrile compounds:
2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(3,3,3-trifluoro-propyl)malononitr-
ile
(CF.sub.2H--CF.sub.2--CF.sub.2--CF.sub.2--CH.sub.2--C(CN).sub.2--CH.su-
b.2--CH.sub.2--CF.sub.3) (M24.1) and
2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(3,3,4,4,4-pentafluorobutyl)-malon-
odinitrile
(CF.sub.2H--CF.sub.2--CF.sub.2--CF.sub.2--CH.sub.2--C(CM.sub.2--
CH.sub.2--CH.sub.2--CF.sub.2--CF.sub.3) (M24.2); M.25. Microbial
disruptors: Bacillus thuringiensis subsp. Israelensi, Bacillus
sphaericus, Bacillus thuringiensis subsp. Aizawai, Bacillus
thuringiensis subsp. Kurstaki, Bacillus thuringiensis subsp.
Tenebrionis; M.26. Aminofuranone Compounds:
4-{[(6-Bromopyrid-3-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on
(M26.1),
4-{[(6-Fluoropyrid-3-yl)methyl](2,2-difluoroethyl)amino}furan-2(-
5H)-on (M26.2),
4-{[(2-Chloro1,3-thiazolo-5-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on
(M26.3),
4-{[(6-Chloropyrid-3-yl)methyl](2-fluoroethyl)amino}furan-2(5H)--
on (M26.4),
4-{[(6-Chloropyrid-3-yl)methyl](2,2-difluoroethyl)amino}furan-2(5H)-on
(M26.5),
4-{[(6-Chloro-5-fluoropyrid-3-yl)methyl](methyl)amino}furan-2(5H-
)-on (M26.6),
4-{[(5,6-Dichloropyrid-3-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on
(M26.7),
4-{[(6-Chloro-5-fluoropyrid-3-yl)methyl](cyclopropyl)amino}furan-
-2(5H)-on (M26.8),
4-{[(6-Chloropyrid-3-yl)methyl](cyclopropyl)amino}furan-2(5H)-on
(M26.9) and
4-{[(6-Chloropyrid-3-yl)methyl](methyl)amino}furan-2(5H)-on
(M26.10); M.27. Various compounds: aluminium phosphide,
amidoflumet, benclothiaz, benzoximate, bifenazate, borax,
bromopropylate, cyanide, cyenopyrafen, cyflumetofen,
chinomethionate, dicofol, fluoroacetate, phosphine, pyridalyl,
pyrifluquinazon, sulfur, organic sulfur compounds, tartar emetic,
sulfoxaflor,
N--R'-2,2-dihalo-1-R''cyclo-propanecarboxamide-2-(2,6-dichloro-.alpha.,.a-
lpha.,.alpha.-trifluoro-p-tolyl)hydrazone or
N--R'-2,2-di(R''')propionamide-2-(2,6-dichloro-.alpha.,.alpha.,.alpha.-tr-
ifluoro-p-tolyl)-hydrazone, wherein R' is methyl or ethyl, halo is
chloro or bromo, R'' is hydrogen or methyl and R''' is methyl or
ethyl,
4-But-2-ynyloxy-6-(3,5-dimethyl-piperidin-1-yl)-2-fluoro-pyrimidine
(M27.1), Cyclopropaneacetic acid,
1,1'-[(3S,4R,4aR,6S,6aS,12R,12aS,12bS)-4-[[(2-cyclopropylacetyl)oxy]methy-
l]-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-12-hydroxy-4,6a,12b-trimethyl-11-o-
xo-9-(3-pyridinyl)-2H,11H-naphtho[2,1-b]pyrano[3,4-e]pyran-3,6-diyl]ester
(M27.2) and
8-(2-Cyclopropylmethoxy-4-trifluoromethyl-phenoxy)-3-(6-trifluoromethyl-p-
yridazin-3-yl)-3-aza-bicyclo[3.2.1]octane (M27.3). The commercially
available compounds of the group M may be found in The Pesticide
Manual, 13th Edition, British Crop Protection Council (2003) among
other publications.
[1695] Paraoxon and their preparation have been described in Farm
Chemicals Handbook, Volume 88, Meister Publishing Company, 2001.
Flupyrazofos has been described in Pesticide Science 54, 1988, p.
237-243 and in U.S. Pat. No. 4,822,779. AKD 1022 and its
preparation have been described in U.S. Pat. No. 6,300,348. The
anthranilamides M23.1 to M23.6 have been described in WO 2008/72743
and WO 200872783, those M23.7 to M23.12 in WO2007/043677. The
phthalamide M 21.1 is known from WO 2007/101540.--The alkynylether
compound M27.1 is described e.g. in JP 2006131529. Organic sulfur
compounds have been described in WO 2007060839. The isoxazoline
compounds M 22.1 to M 22.8 have been described in e.g.
WO2005/085216, WO 2007/079162, WO 2007/026965, WO 2009/126668 and
WO2009/051956. The aminofuranone compounds M 26.1 to M 26.10 have
been described eg. in WO 2007/115644. The pyripyropene derivative M
27.2 has been described in WO 2008/66153 and WO 2008/108491. The
pyridazin compound M 27.3 has been described in JP 2008/115155.
Malononitrile compounds as those (M24.1) and (M24.2) have been
described in WO 02/089579, WO 02/090320, WO 02/090321, WO
04/006677, WO 05/068423, WO 05/068432 and WO 05/063694. All of the
documents referred to above are hereby incorporated by reference in
their entirety.
[1696] Fungicides that may be mixed with the compounds of the
invention include, but are not limited to, acylalanines such as
benalaxyl, metalaxyl, ofurace, oxadixyl; amine derivatives such as
aldimorph, dodine, dodemorph, fenpropimorph, fenpropidin,
guazatine, iminoctadine, spiroxamin, tridemorph; anilinopyrimidines
such as pyrimethanil, mepanipyrim or cyrodinyl; antibiotics such as
cycloheximid, griseofulvin, kasugamycin, natamycin, polyoxin or
streptomycin; azoles such as bitertanol, bromoconazole,
cyproconazole, difenoconazole, dinicona-zole, epoxiconazole,
fenbuconazole, fluquiconazole, flusilazole, hexaconazole, imazalil,
metconazole, myclobutanil, penconazole, propiconazole, prochloraz,
prothioconazole, tebuconazole, triadimefon, triadimenol,
triflumizol, triticonazole, flutriafol;
[1697] dicarboximides such as iprodion, myclozolin, procymidon,
vinclozolin; dithiocarbamates such as ferbam, nabam, maneb,
mancozeb, metam, metiram, propineb, polycarbamate, thiram, ziram,
zineb; heterocyclic compounds such as anilazine, benomyl, boscalid,
carbendazim, carboxin, oxycarboxin, cyazofamid, dazomet, dithianon,
famoxadon, fenamidon, fenarimol, fuberidazole, flutolanil,
furametpyr, isoprothiolane, mepronil, nuarimol, probenazole,
proquinazid, pyrifenox, pyroquilon, quinoxyfen, silthiofam,
thiabendazole, thifluzamid, thiophanate-methyl, tiadinil,
tricyclazole, triforine; copper fungicides such as Bordeaux
mixture, copper acetate, copper oxychloride, ba-sic copper sulfate;
nitrophenyl derivatives such as binapacryl, dinocap, dinobuton,
nitrophthalisopropyl; phenylpyrroles such as fenpiclonil or
fludioxonil, Sulfur; other fungicides such as acibenzolar-S-methyl,
benthiavalicarb, carpropamid, chlorothalonil, cyflufenamid,
cymoxanil, diclomezin, diclocymet, diethofencarb, edifen-phos,
ethaboxam, fenhexamid, fentin-acetate, fenoxanil, ferimzone,
fluazinam, fosetyl, fosetyl-aluminum, iprovalicarb,
hexachlorobenzene, metrafenon, pencycuron, propamocarb, phthalide,
toloclofos-methyl, quintozene, zoxamid; strobilurins such as
azoxystrobin, dimoxystrobin, fluoxastrobin, kresoxim-methyl,
me-tominostrobin, orysastrobin, picoxystrobin or trifloxystrobin;
sulfenic acid derivatives such as captafol, captan, dichlofluanid,
folpet, tolylfluanid; cinnemamides and analogs such as
dimethomorph, flumetover or flumorph.
III. Uses and Methods
[1698] Due to their excellent activity, the compounds of formula
(Id), and in particular compounds of formula (Ie) and (S)-Ie, may
be used for controlling pests. Accordingly, the present invention
also provides a method for controlling animal pests, which method
comprises treating the pests, their food supply, their habitat or
their breeding ground or a cultivated plant, plant propagation
materials (such as seed), soil, area, material or environment in
which the pests are growing or may grow, or the materials,
cultivated plants, plant propagation materials (such as seed),
soils, surfaces or spaces to be protected from pest attack or
infestation with a pesticidally effective amount of a compound of
formula (Id), or a salt thereof, or a composition as defined
above.
[1699] In one embodiment, the method of the invention serves for
protecting plant propagation material (such as seed) and the plant
which grows therefrom from animal pest attack or infestation and
comprises treating the plant propagation material (such as seed)
with a pesticidally effective amount of a compound of formula (Id)
or an agriculturally acceptable salt thereof as defined above or
with a pesticidally effective amount of an agricultural composition
as defined above and below. The method of the invention is not
limited to the protection of the "substrate" (plant, plant
propagation materials, soil material etc.) which has been treated
according to the invention, but also has a preventive effect, thus,
for example, according protection to a plant which grows from a
treated plant propagation materials (such as seed), the plant
itself not having been treated.
[1700] In one embodiment of the present invention related to
agricultural applications, "animal pests" are preferably selected
from arthropods and nematodes, more preferably from harmful
insects, arachnids and nematodes, and even more preferably from
insects, acarids and nematodes.
[1701] The invention further provides an agricultural composition
for combating such animal pests, which comprises such an amount of
at least one compound of formula (Id) or at least one
agriculturally useful salt thereof, and at least one inert liquid
and/or solid agriculturally acceptable carrier that has a
pesticidal action and, if desired, at least one surfactant. Such a
composition may contain a single active compound of formula (Id),
or a salt thereof, or a mixture of several active compounds of
formula (Id), or their salts, according to the present invention.
The composition according to the present invention may comprise an
individual isomer or mixtures of isomers as well as individual
tautomers or mixtures of tautomers.
[1702] The animal pest, i.e. the insects, arachnids and nematodes,
the plant, soil or water in which the plant is growing can be
contacted with the present compounds of formula (Id) or
composition(S) containing them by any application method known in
the art. As such, "contacting" includes both direct contact
(applying the compounds/compositions directly on the animal pest or
plant--typically to the foliage, stem or roots of the plant) and
indirect contact (applying the compounds/compositions to the locus
of the animal pest or plant).
[1703] The compounds of formula (Id) or the pesticidal compositions
comprising them may be used to protect growing plants and crops
from attack or infestation by animal pests, especially insects,
acaridae or arachnids by contacting the plant/crop with a
pesticidally effective amount of compounds of formula I. The term
"crop" refers both to growing and harvested crops.
[1704] The compounds of the present invention and the compositions
comprising them are particularly important in the control of a
multitude of insects on various cultivated plants, such as cereal,
root crops, oil crops, vegetables, spices, ornamentals, for example
seed of durum and other wheat, barley, oats, rye, maize (fodder
maize and sugar maize/sweet and field corn), soybeans, oil crops,
crucifers, cotton, sunflowers, bananas, rice, oilseed rape, turnip
rape, sugarbeet, fodder beet, eggplants, potatoes, grass, lawn,
turf, fodder grass, tomatoes, leeks, pumpkin/squash, cabbage,
iceberg lettuce, pepper, cucumbers, melons, Brassica species,
melons, beans, peas, garlic, onions, carrots, tuberous plants such
as potatoes, sugar cane, tobacco, grapes, petunias,
geranium/pelargoniums, pansies and impatiens.
[1705] The compounds of the present invention are employed as such
or in form of compositions by treating the insects or the plants,
plant propagation materials, such as seeds, soil, surfaces,
materials or rooms to be protected from insecticidal attack with an
insecticidally effective amount of the active compounds. The
application can be carried out both before and after the infection
of the plants, plant propagation materials, such as seeds, soil,
surfaces, materials or rooms by the insects.
[1706] The present invention also includes a method of combating
animal pests which comprises contacting the animal pests, their
habitat, breeding ground, food supply, cultivated plants, seed,
soil, area, material or environment in which the animal pests are
growing or may grow, or the materials, plants, seeds, soils,
surfaces or spaces to be protected from animal attack or
infestation with a pesticidally effective amount of a mixture of at
least one active compound of formula (Id). Moreover, animal pests
may be controlled by contacting the target pest, its food supply,
habitat, breeding ground or its locus with a pesticidally effective
amount of compounds of formula I. As such, the application may be
carried out before or after the infection of the locus, growing
crops, or harvested crops by the pest.
[1707] In one embodiment, the compounds of the invention can also
be applied preventively to places at which occurrence of the pests
is expected.
[1708] The compounds of formula (Id) may be also used to protect
growing plants from attack or infestation by pests by contacting
the plant with a pesticidally effective amount of compounds of
formula (Id). As such, "contacting" includes both direct contact
(applying the compounds/compositions directly on the pest and/or
plant--typically to the foliage, stem or roots of the plant) and
indirect contact (applying the compounds/compositions to the locus
of the pest and/or plant).
[1709] "Locus" means a habitat, breeding ground, plant, seed, soil,
area, material or environment in which a pest or parasite is
growing or may grow, excluding the body of an animal.
[1710] The term "plant propagation material" refers to any parts of
a plant which are propagable. In general, a plant propagation
material includes the product of the ripened ovule of gymnosperm
and angiosperm plants which occurs after fertilization and some
growth within the mother plant and includes seed, fruits, spurious
fruits, infructescences and also rhizomes (rootstocks), corms,
tubers, bulbs and scions.
[1711] The term "plant propagation material" is to be understood to
denote all the generative parts of the plant such as seeds and
vegetative plant material such as cuttings and tubers (e. g.
potatoes), which can be used for the multiplication of the plant.
This includes seeds, roots, fruits, tubers, bulbs, rhizomes,
shoots, sprouts and other parts of plants. Seedlings and young
plants, which are to be transplanted after germination or after
emergence from soil, may also be included. These plant propagation
materials may be treated prophylactically with a plant protection
compound either at or before planting or transplanting.
[1712] The term "cultivated plants" is to be understood as
including plants which have been modified by breeding, mutagenesis
or genetic engineering. Genetically modified plants are plants,
which genetic material has been so modified by the use of
recombinant DNA techniques that under natural circumstances cannot
readily be obtained by cross breeding, mutations or natural
recombination. Typically, one or more genes have been integrated
into the genetic material of a genetically modified plant in order
to improve certain properties of the plant. Such genetic
modifications also include but are not limited to targeted
post-transitional modification of protein(S) (oligo- or
polypeptides) poly for example by glycosylation or polymer
additions such as prenylated, acetylated or farnesylated moieties
or PEG moieties (e.g. as disclosed in Biotechnol Prog. 2001
July-August; 17(4):720-8., Protein Eng Des Sel. 2004 January;
17(1):57-66, Nat Protoc. 2007; 2(5):1225-35., Curr Opin Chem Biol.
2006 October; 10(5):487-91. Epub 2006 Aug. 28., Biomaterials. 2001
March; 22(5):405-17, Bioconjug Chem. 2005 January-February;
16(1):113-21).
[1713] The term "cultivated plants" is to be understood also
including plants that have been rendered tolerant to applications
of specific classes of herbicides, such as hydroxy-phenylpyruvate
dioxygenase (HPPD) inhibitors; acetolactate synthase (ALS)
inhibitors, such as sulfonyl ureas (see e. g. U.S. Pat. No.
6,222,100, WO 01/82685, WO 00/26390, WO 97/41218, WO 98/02526, WO
98/02527, WO 04/106529, WO 05/20673, WO 03/14357, WO 03/13225, WO
03/14356, WO 04/16073) or imidazolinones (see e. g. U.S. Pat. No.
6,222,100, WO 01/82685, WO 00/26390, WO 97/41218, WO 98/02526, WO
98/02527, WO 04/106529, WO 05/20673, WO 03/14357, WO 03/13225, WO
03/14356, WO 04/16073); enolpyruvylshikimate-3-phosphate synthase
(EPSPS) inhibitors, such as glyphosate (see e. g. WO 92/00377);
glutamine synthetase (GS) inhibitors, such as glufosinate (see e.
g. EP-A-0242236, EP-A-242246) or oxynil herbicides (see e. g. U.S.
Pat. No. 5,559,024) as a result of conventional methods of breeding
or genetic engineering. Several cultivated plants have been
rendered tolerant to herbicides by conventional methods of breeding
(mutagenesis), for example Clearfield.RTM. summer rape (Canola)
being tolerant to imidazolinones, e. g. imazamox. Genetic
engineering methods have been used to render cultivated plants,
such as soybean, cotton, corn, beets and rape, tolerant to
herbicides, such as glyphosate and glufosinate, some of which are
commercially available under the trade names RoundupReady.RTM.
(glyphosate) and LibertyLink.RTM. (glufosinate).
[1714] The term "cultivated plants" is to be understood also
including plants that are by the use of recombinant DNA techniques
capable to synthesize one or more insecticidal proteins, especially
those known from the bacterial genus Bacillus, particularly from
Bacillus thuringiensis, such as d-endotoxins, e. g. CryIA(b),
CryIA(c), CryIF, CryIF(a2), CryIIA(b), CryIIIA, CryIIIB(b1) or
Cry9c; vegetative insecticidal proteins (VIP), e. g. VIP1, VIP2,
VIP3 or VIP3A; insecticidal proteins of bacteria colonizing
nematodes, for example Photorhabdus spp. or Xenorhabdus spp.;
toxins produced by animals, such as scorpion toxins, arachnid
toxins, wasp toxins, or other insect-specific neurotoxins; toxins
produced by fungi, such Streptomycetes toxins, plant lectins, such
as pea or barley lectins; agglutinins; proteinase inhibitors, such
as trypsin inhibitors, serine protease inhibitors, patatin,
cystatin or papain inhibitors; ribosome-inactivating proteins
(RIP), such as ricin, maize-RIP, abrin, luffin, saporin or bryodin;
steroid metabolism enzymes, such as 3-hydroxysteroid oxidase,
ecdysteroid-IDP-glycosyl-transferase, cholesterol oxidases,
ecdysone inhibitors or HMG-CoA-reductase; ion channel blockers,
such as blockers of sodium or calcium channels; juvenile hormone
esterase; diuretic hormone receptors (helicokinin receptors);
stilben synthase, bibenzyl synthase, chitinases or glucanases. In
the context of the present invention these insecticidal proteins or
toxins are to be understood expressly also as pre-toxins, hybrid
proteins, truncated or otherwise modified proteins. Hybrid proteins
are characterized by a new combination of protein domains, (see,
for example WO 02/015701). Further examples of such toxins or
genetically-modified plants capable of synthesizing such toxins are
disclosed, for example, in EP-A 374 753, WO 93/007278, WO 95/34656,
EP-A 427 529, EP-A 451 878, WO 03/018810 and WO 03/052073. The
methods for producing such genetically modified plants are
generally known to the person skilled in the art and are described,
for example, in the publications mentioned above. These
insecticidal proteins contained in the genetically modified plants
impart to the plants producing these proteins protection from
harmful pests from certain taxonomic groups of arthropods,
particularly to beetles (Coleoptera), flies (Diptera), and
butterflies and moths (Lepidoptera) and to plant parasitic
nematodes (Nematoda).
[1715] The term "cultivated plants" is to be understood also
including plants that are by the use of recombinant DNA techniques
capable to synthesize one or more proteins to increase the
resistance or tolerance of those plants to bacterial, viral or
fungal pathogens. Examples of such proteins are the so-called
"pathogenesis-related proteins" (PR proteins, see, for example EP-A
0 392 225), plant disease resistance genes (for example potato
cultivars, which express resistance genes acting against
Phytophthora infestans derived from the Mexican wild potato Solanum
bulbocastanum) or T4-lysozym (e. g. potato cultivars capable of
synthesizing these proteins with increased resistance against
bacteria such as Erwinia amylvora). The methods for producing such
genetically modified plants are generally known to the person
skilled in the art and are described, for example, in the
publications mentioned above.
[1716] The term "cultivated plants" is to be understood also
including plants that are by the use of recombinant DNA techniques
capable to synthesize one or more proteins to increase the
productivity (e. g. bio mass production, grain yield, starch
content, oil content or protein content), tolerance to drought,
salinity or other growth-limiting environmental factors or
tolerance to pests and fungal, bacterial or viral pathogens of
those plants.
[1717] The term "cultivated plants" is to be understood also
including plants that contain by the use of recombinant DNA
techniques a modified amount of substances of content or new
substances of content, specifically to improve human or animal
nutrition, for example oil crops that produce health-promoting
long-chain omega-3 fatty acids or unsaturated omega-9 fatty acids
(e. g. Nexera.RTM. rape).
[1718] The term "cultivated plants" is to be understood also
including plants that contain by the use of recombinant DNA
techniques a modified amount of substances of content or new
substances of content, specifically to improve raw material
production, for example potatoes that produce increased amounts of
amylopectin (e. g. Amflorag potato).
[1719] In general, "pesticidally effective amount" means the amount
of active ingredient needed to achieve an observable effect on
growth, including the effects of necrosis, death, retardation,
prevention, and removal, destruction, or otherwise diminishing the
occurrence and activity of the target organism. The pesticidally
effective amount can vary for the various compounds/compositions
used in the invention. A pesticidally effective amount of the
compositions will also vary according to the prevailing conditions
such as desired pesticidal effect and duration, weather, target
species, locus, mode of application, and the like.
[1720] In the case of soil treatment or of application to the pests
dwelling place or nest, the quantity of active ingredient ranges
from about 0.0001 to about 500 g per 100 m.sup.2, preferably from
about 0.001 to about 20 g per 100 m.sup.2.
[1721] Customary application rates in the protection of materials
are, for example, from about 0.01 g to about 1000 g of active
compound per m.sup.2 treated material, desirably from about 0.1 g
to about 50 g per m.sup.2.
[1722] Insecticidal compositions for use in the impregnation of
materials typically contain from about 0.001 to about 95 weight %,
preferably from about 0.1 to about 45 weight %, and more preferably
from about 1 to about 25 weight % of at least one repellent and/or
insecticide.
[1723] For use in treating crop plants, the rate of application of
the active ingredients of this invention may be in the range of
about 0.1 g to about 4000 g per hectare, desirably from about 25 g
to about 600 g per hectare, more desirably from about 50 g to about
500 g per hectare.
[1724] The compounds of formula (Id) are effective through both
contact (via soil, glass, wall, bed net, carpet, plant parts or
animal parts), and ingestion (bait, or plant part).
[1725] The compounds of the invention may also be applied against
non-crop insect pests, such as ants, termites, wasps, flies,
mosquitos, crickets, or cockroaches. For use against said non-crop
pests, compounds of formula (Id) are preferably used in a bait
composition. The bait can be a liquid, a solid or a semisolid
preparation (e.g. a gel). Solid baits can be formed into various
shapes and forms suitable to the respective application e.g.
granules, blocks, sticks, disks. Liquid baits can be filled into
various devices to ensure proper application, e.g. open containers,
spray devices, droplet sources, or evaporation sources. Gels can be
based on aqueous or oily matrices and can be formulated to
particular necessities in terms of stickiness, moisture retention
or aging characteristics.
[1726] The bait employed in the composition is a product, which is
sufficiently attractive to incite insects such as ants, termites,
wasps, flies, mosquitos, crickets etc. or cockroaches to eat
it.
[1727] The attractiveness can be manipulated by using feeding
stimulants or sex pheromones. Food stimulants are chosen, for
example, but not exclusively, from animal and/or plant proteins
(meat-, fish- or blood meal, insect parts, egg yolk), from fats and
oils of animal and/or plant origin, or mono-, oligo- or
polyorganosaccharides, especially from sucrose, lactose, fructose,
dextrose, glucose, starch, pectin or even molasses or honey. Fresh
or decaying parts of fruits, crops, plants, animals, insects or
specific parts thereof can also serve as a feeding stimulant. Sex
pheromones are known to be more insect specific. Specific
pheromones are described in the literature and are known to those
skilled in the art.
[1728] For use in bait compositions, the typical content of active
ingredient is from about 0.001 weight % to about 15 weight %,
desirably from about 0.001 weight % to about 5% weight % of active
compound.
[1729] Formulations of compounds of formula (Id) as aerosols (e.g.
in spray cans), oil sprays or pump sprays are highly suitable for
the non-professional user for controlling pests such as flies,
fleas, ticks, mosquitos or cockroaches. Aerosol recipes are
preferably composed of the active compound, solvents such as lower
alcohols (e.g. methanol, ethanol, propanol, butanol), ketones (e.g.
acetone, methyl ethyl ketone), paraffin hydrocarbons (e.g.
kerosenes) having boiling ranges of approximately 50 to 250.degree.
C., dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide,
aromatic hydrocarbons such as toluene, xylene, water, furthermore
auxiliaries such as emulsifiers such as sorbitol monooleate, oleyl
ethoxylate having 3-7 mol of ethylene oxide (e.g. Labrafil.RTM. M
1944 CS), fatty alcohol ethoxylate, perfume oils such as ethereal
oils, esters of medium fatty acids with lower alcohols, aromatic
carbonyl compounds, if appropriate stabilizers such as sodium
benzoate, amphoteric surfactants, lower epoxides, triethyl
orthoformate and, if required, propellants such as propane, butane,
nitrogen, compressed air, dimethyl ether, carbon dioxide, nitrous
oxide, or mixtures of these gases.
[1730] The oil spray compositions differ from the aerosol recipes
in that no propellants are used. For use in spray compositions, the
content of active ingredient is from about 0.001 to about 80
weights %, preferably from about 0.01 to about 50 weight % and most
preferably from about 0.01 to about 15 weight %.
[1731] The compounds of formula (Id), or salts thereof, and their
respective compositions can also be used in mosquito and fumigating
coils, smoke cartridges, vaporizer plates or long-term vaporizers
and also in moth papers, moth pads or other heat-independent
vaporizer systems.
[1732] Methods to control infectious diseases transmitted by
insects (e.g. malaria, dengue and yellow fever, lymphatic
filiariasis, and leishmaniasis) with compounds of formula (Id), or
salts thereof, and its respective compositions also comprise
treating surfaces of huts and houses, air spraying and impregnation
of curtains, tents, clothing items, bed nets, tsetse-fly trap or
the like. Insecticidal compositions for application to fibers,
fabric, knitgoods, non-wovens, netting material or foils and
tarpaulins preferably comprise a mixture including the insecticide,
optionally a repellent and at least one binder. Suitable repellents
for example are N,N-Diethyl-meta-toluamide (DEET), N,N-di
ethylphenylacetamide (DEPA),
1-(3-cyclohexan-1-yl-carbonyl)-2-methylpiperine,
(2-hydroxymethylcyclohexyl) acetic acid lactone,
2-ethyl-1,3-hexandiol, indalone, Methylneodecanamide (MNDA), a
pyrethroid not used for insect control such as
{(+/-)-3-allyl-2-methyl-4-oxocyclopent-2-(+)-enyl-(+)-trans-chrysantemate
(Esbiothrin), a repellent derived from or identical with plant
extracts like limonene, eugenol, (+)-Eucamalol (1),
(-)-1-epi-eucamalol or crude plant extracts from plants like
Eucalyptus maculata, Vitex rotundifolia, Cymbopogan martinii,
Cymbopogan citratus (lemon grass), Cymopogan nartdus (citronella).
Suitable binders are selected for example from polymers and
copolymers of vinyl esters of aliphatic acids (such as such as
vinyl acetate and vinyl versatate), acrylic and methacrylic esters
of alcohols, such as butyl acrylate, 2-ethylhexylacrylate, and
methyl acrylate, mono- and di-ethylenically unsaturated
hydrocarbons, such as styrene, and aliphatic dienes, such as
butadiene. The impregnation of curtains and bednets is done in
general by dipping the textile material into emulsions or
dispersions of the insecticide or spraying them onto the nets.
[1733] The compounds of formula (Id) and their compositions can
also be used for protecting wooden materials such as trees, board
fences, sleepers, etc. and buildings such as houses, outhouses,
factories, but also construction materials, furniture, leathers,
fibers, vinyl articles, electric wires and cables etc. from ants
and/or termites, and for controlling ants and termites from doing
harm to crops or human being (e.g. when the pests invade into
houses and public facilities). The compounds of formula (Id) are
applied not only to the surrounding soil surface or into the
under-floor soil in order to protect wooden materials but can also
be applied to lumbered articles such as surfaces of the under-floor
concrete, alcove posts, beams, plywoods, furniture, etc., wooden
articles such as particle boards, half boards, etc. and vinyl
articles such as coated electric wires, vinyl sheets, heat
insulating material such as styrene foams, etc. In case of
application against ants doing harm to crops or human beings, the
ant controller of the present invention is applied to the crops or
the surrounding soil, or is directly applied to the nest of ants or
the like.
IV. Seed Treatment
[1734] In some embodiments of the invention, the compounds of
formula (Id) are also suitable for the treatment of seeds in order
to protect the seed from insect pest, in particular from
soil-living insect pests and the resulting plant's roots and shoots
against soil pests and foliar insects.
[1735] The compounds of formula (Id) are particularly useful for
the protection of the seed from soil pests and the resulting
plant's roots and shoots against soil pests and foliar insects. The
protection of the resulting plant's roots and shoots is preferred.
More preferred is the protection of resulting plant's shoots from
piercing and sucking insects, wherein the protection from aphids is
most preferred.
[1736] The present invention therefore comprises a method for the
protection of seeds from insects, in particular from soil insects
and of the seedlings' roots and shoots from insects, in particular
from soil and foliar insects, said method comprising contacting the
seeds before sowing and/or after pregermination with a compound of
the general formula (Id), or a salt thereof. Particularly preferred
is a method, wherein the plant's roots and shoots are protected,
more preferably a method, wherein the plants shoots are protected
from piercing and sucking insects, most preferably a method,
wherein the plants shoots are protected from aphids.
[1737] The term seed embraces seeds and plant propagules of all
kinds including but not limited to true seeds, seed pieces,
suckers, corms, bulbs, fruit, tubers, grains, cuttings, cut shoots
and the like and means in a preferred embodiment true seeds.
[1738] The term seed treatment comprises all suitable seed
treatment techniques known in the art, such as seed dressing, seed
coating, seed dusting, seed soaking and seed pelleting. The present
invention also comprises seeds coated with or containing the active
compound. The term "coated with and/or containing" generally
signifies that the active ingredient is for the most part on the
surface of the propagation product at the time of application,
although a greater or lesser part of the ingredient may penetrate
into the propagation product, depending on the method of
application. When the said propagation product is (re)planted, it
may absorb the active ingredient.
[1739] Suitable seed includes, but is not limited to, seed of
cereals, root crops, oil crops, vegetables, spices, ornamentals,
for example seed of durum and other wheat, barley, oats, rye, maize
(fodder maize and sugar maize/sweet and field corn), soybeans, oil
crops, crucifers, cotton, sunflowers, bananas, rice, oilseed rape,
turnip rape, sugarbeet, fodder beet, eggplants, potatoes, grass,
lawn, turf, fodder grass, tomatoes, leeks, pumpkin/squash, cabbage,
iceberg lettuce, pepper, cucumbers, melons, Brassica species,
melons, beans, peas, garlic, onions, carrots, tuberous plants such
as potatoes, sugar cane, tobacco, grapes, petunias,
geranium/pelargoniums, pansies and impatiens.
[1740] In addition, the active compounds may also be used for the
treatment seeds from plants, which tolerate the action of
herbicides or fungicides or insecticides owing to breeding,
including genetic engineering methods. For example, the active
compounds can be employed in treatment of seeds from plants, which
are resistant to herbicides from the group consisting of the
sulfonylureas, imidazolinones, glufosinate-ammonium or
glyphosate-isopropylammonium and analogous active substances (see
for example, EP-A-0242236, EP-A-242246) (WO 92/00377)
(EP-A-0257993, U.S. Pat. No. 5,013,659) or in transgenic crop
plants, for example cotton, with the capability of producing
Bacillus thuringiensis toxins (Bt toxins) which make the plants
resistant to certain pests (EP-A-0142924, EP-A-0193259).
[1741] Furthermore, the active compounds of the invention can be
used also for the treatment of seeds from plants, which have
modified characteristics in comparison with existing plants
consist, which can be generated for example by traditional breeding
methods and/or the generation of mutants, or by recombinant
procedures). For example, a number of cases have been described of
recombinant modifications of crop plants for the purpose of
modifying the starch synthesized in the plants (e.g. WO 92/11376,
WO 92/14827, WO 91/19806) or of transgenic crop plants having a
modified fatty acid composition (WO 91/13972).
[1742] The seed treatment application of the active compound is
typically carried out by spraying or by dusting the seeds before
sowing of the plants and before emergence of the plants.
Compositions which are especially useful for seed treatment
include:
A Soluble concentrates (SL, LS)
D Emulsions (EW, EO, ES)
E Suspensions (SC, OD, FS)
[1743] F Water-dispersible granules and water-soluble granules (WG,
SG) G Water-dispersible powders and water-soluble powders (WP, SP,
WS)
H Gel-Formulations (GF)
[1744] I Dustable powders (DP, DS)
[1745] Conventional seed treatment compositions include, for
example, flowable concentrates FS, solutions LS, powders for dry
treatment DS, water dispersible powders for slurry treatment WS,
water-soluble powders SS and emulsion ES and EC and gel composition
GF. These compositions can be applied to the seed diluted or
undiluted. Application to the seeds is carried out before sowing,
either directly on the seeds or after having pregerminated the
latter.
[1746] In a preferred embodiment a FS composition is used for seed
treatment. Typically, a FS composition may comprise about 1-800 g/l
of active ingredient, about 1-200 g/l Surfactant, about 0 to 200
g/l antifreezing agent, about 0 to 400 g/l of binder, about 0 to
200 g/l of a pigment and up to about 1 liter of a solvent,
preferably water.
[1747] Especially preferred FS compositions of compounds of formula
I for seed treatment usually comprise from about 0.1 to about 80%
by weight (1 to 800 g/l) of the active ingredient, from about 0.1
to about 20% by weight (1 to 200 g/l) of at least one surfactant,
e.g. about 0.05 to about 5% by weight of a wetter and from about
0.5 to about 15% by weight of a dispersing agent, up to about 20%
by weight, e.g. from about 5 to about 20% of an anti-freeze agent,
from about 0 to about 15% by weight, e.g. about 1 to about 15% by
weight of a pigment and/or a dye, from about 0 to about 40% by
weight, e.g. about 1 to about 40% by weight of a binder
(sticker/adhesion agent), optionally up to about 5% by weight, e.g.
from about 0.1 to about 5% by weight of a thickener, optionally
from about 0.1 to about 2% of an anti-foam agent, and optionally a
preservative such as a biocide, antioxidant or the like, e.g. in an
amount from about 0.01 to about 1% by weight and a filler/vehicle
up to 100% by weight.
[1748] Seed Treatment compositions may additionally also comprise
binders and optionally colorants. Binders can be added to improve
the adhesion of the active materials on the seeds after treatment.
Suitable binders include, but are not limited to, homo- and
copolymers from alkylene oxides like ethylene oxide or propylene
oxide, polyvinylacetate, polyvinylalcohols, polyvinylpyrrolidones,
and copolymers thereof, ethylene-vinyl acetate copolymers, acrylic
homo- and copolymers, polyethyleneamines, polyethylene amides and
polyethyleneimines, polysaccharides like celluloses, tylose and
starch, polyolefin homo- and copolymers like olefin/maleic
anhydride copolymers, polyurethanes, polyesters, polystyrene homo
and copolymers
[1749] Optionally, colorants or dyes may also be included in the
composition. Suitable colorants or dyes for seed treatment
compositions include, but are not limited to, Rhodamin B, C.I.
Pigment Red 112, C.I. Solvent Red 1, pigment blue 15:4, pigment
blue 15:3, pigment blue 15:2, pigment blue 15:1, pigment blue 80,
pigment yellow 1, pigment yellow 13, pigment red 112, pigment red
48:2, pigment red 48:1, pigment red 57:1, pigment red 53:1, pigment
orange 43, pigment orange 34, pigment orange 5, pigment green 36,
pigment green 7, pigment white 6, pigment brown 25, basic violet
10, basic violet 49, acid red 51, acid red 52, acid red 14, acid
blue 9, acid yellow 23, basic red 10, basic red 108.
[1750] A gelling agent may also be used in some compositions of the
invention. One non-limiting example of a gelling agent is carrageen
(Satiagel.RTM.)
[1751] In the treatment of seed, the application rates of the
compounds of formula (Id) are generally from about 0.1 g to about
10 kg per 100 kg of seed, preferably from about 1 g to about 5 kg
per 100 kg of seed, more preferably from about 1 g to about 1000 g
per 100 kg of seed and in particular from about 1 g to about 200 g
per 100 kg of seed.
[1752] The invention therefore also relates to seed comprising a
compound of formula (Id), or an agriculturally useful salt thereof,
as defined herein. The amount of the compound of formula (Id), or
the agriculturally useful salt thereof, will in general vary from
about 0.1 g to about 10 kg per 100 kg of seed, preferably from
about 1 g to about 5 kg per 100 kg of seed, in particular from
about 1 g to about 1000 g per 100 kg of seed. The application rate
will vary depending on the specific crop, as known to those in
skill in the art. For specific crops such as lettuce the rate may
be higher than specified above.
[1753] The invention will now be further described by way of the
following non-limiting examples.
Examples
[1754] The invention is further described by the following
non-limiting examples which further illustrate the invention, and
are not intended, nor should they be interpreted to, limit the
scope of the invention.
Synthesis Examples
Synthesis Example 1: Synthesis of (S)-Ie
[1755] The compound of formula (S)-Ie of the invention was prepared
according to Scheme 2 below. Compound 2-1 is described in U.S. Pat.
No. 7,951,828 B 1, incorported herein by reference. Preparation of
the compound 2-4 is described in U.S. Pat. No. 8,217,180 B2 and
U.S. Pat. No. 8,546,618 B2, both incorporated herein by reference
in their entirety. Cinchona alkaloid-based chiral phase transfer
catalyst similar to 2-6 are prepared according to the procedures
described in, for example, U.S. Pat. No. 9,126,995 B2, WO
2011/104089 and US 2014/0206633, all incorporated herein by
reference. Further, Matoba et al., Angew. Chem. 2010, 122,
5898-5902 describes the use of these catalysts to prepare
enantiomerically pure isoxazoline compounds.
##STR00041##
Step 1
[1756] 1-Chloro-2-fluoro-5-iodo-3-(trifluoromethyl)benzene (2-1,
100 g, 0.31 mol) and tetrahydrofuran (THF, 200 ml, 2 volumes) were
charged into a 500 ml reactor under an atmosphere of nitrogen. The
mixure was cooled to -15 to -20.degree. C. and a solution of
i-PrMgCl in THF (2M, 170 ml, 0.34 mol, 1.1 eq.) was added to the
reactor slowly (over 30 min.) at -20 to -5.degree. C. The resulting
mixture was stirred for an additional 0.5-1 hour and checked for
reaction completion by GCMS, which showed that the starting
material was consumed. Methyl 2,2,2-trifluoroacetate was added to
the reaction mixture over 0.5-1 hour at -20 to -5.degree. C. The
resulting mixture was stirred overnight at -20 to -10.degree. C.
and checked for reaction conversion. When the reaction was
complete, aqueous HCl (1 M, 500 ml) was added and the mixture was
stirred for 1-2 hours at -5 to 5.degree. C.
[1757] The quenched reaction mixture was extracted with cyclohexane
twice (500 ml, 200 ml) and the combined organic layers were
concentrated under vacuum to provide intermediate 2-3 as a crude
product (62.0 g, purity 98.4%, 77.7%).
Step 2
[1758] 2-methyltetrahydrofuran (2-Me-THF, 25 ml, 5 vol.),
intermediate 2-4 (5.0 g, 17 mmol, 1 eq.), molecular sieves (1.0 g,
20% w/w) and potassium carbonate (0.7 g, 5.1 mmol, 0.3 eq.) were
charged into a 100 ml, 3-neck flask. The resulting mixture was
warmed to 75-85.degree. C. and compound 2-3 was added drop-wise to
the mixture at 75-85.degree. C. over 0.5-1 hour. The mixture was
then stirred for an additional 4 hours at the same temperature and
tested by HPLC for reaction progression. Additional K.sub.2CO.sub.3
(0.2 g, 1.7 mmol) and 2-3 (0.1 g, 0.34 mmol, 0.2 eq.) were added
and the mixture was stirred for a further 16 hours. The mixture was
cooled to 30-40.degree. C. and filtered. The filtrate was
concentrated to a brown solid. The product was purified by
chromatography (silica gel, petroleum ether/ethyl acetate) to yield
the product as a yellow solid (6.6 grams, 79.7% purity). The
product was then recrystallized from acetonitrile to yield compound
2-5 in 44.9% yield (4.0 grams) and 91.6% purity.
Step 3
[1759] Dichloromethane (DCM, 150 ml, 30 vol.) and 2-5 (5.0 g, 7.95
mmol, 1.0 eq.) were charged into a 500 ml 3-neck flask. The mixture
was stirred for 10-30 min. until the compound was dissolved and
then cooled to -10 to 15.degree. C. The chiral phase transfer
catalyst 2-6 was added (0.18 g, 0.024 mmol, 0.03 eq.) to the
solution and then a solution of NH.sub.2OH (50% w/w)/NaOH/H.sub.2O
(20 ml, 5 vol.) was added dropwise at -10 to 15.degree. C. over
0.5-1 hour. The resulting mixture was stirred for 16 hours at -10
to 15.degree. C. and sampled for analysis by HPLC to check the
reaction completion, at which time there was less than 3.0% of the
starting material. The organic layer was separated and washed with
a saturated solution of KH.sub.2PO.sub.4 (20 ml, 4 vol.) twice. The
resulting organic layer was further washed with brine (20 ml) twice
and then concentrated under vacuum at 30-40.degree. C. with the
concomitant addition of toluene (20 ml, 4 vol.) and then
concentrated to dryness.
[1760] To 4.9 grams of the isolated crude product was charged 15 ml
of toluene in a 3-neck flask and the mixture was heated to
60-70.degree. C. to dissolve the solid. The resulting solution was
cooled slowly to 45-50.RTM. over 1 hour and seed (0.025 g, 0.05%
w/w) was added. The seeded mixture was stirred for 1 hour at
45-50.degree. C. and then cooled further to 37-42.degree. C. over 1
hour and then stirred for a further 6 hours. During this time the
product was observed to crystallize from solution. The mixture was
cooled to 30-35.degree. C. over 1 hour and stirred for 3 hours. The
solid was filtered and the cake washed with toluene (10 ml, 2
vol.). The cake was then dried in an oven at 40-45.RTM. under
vacuum for 6 hours to yield 2.3 grams (45.1% yield) of (S)-Ie in
99.4% purity and 99.3% chiral purity.
[1761] Using the same approach but an alternative chiral phase
transfer catalyst (e.g. isomer of 2-6), the compound (R)-Ie may be
made. Alternatively, a racemic compound of formula (Ie) may be
prepared without the use of a chiral phase transfer catalyst. The
final step in these processes are described in the examples
below.
Synthesis Example 2: Racemic Compound (Ie)
Step 3
[1762] Into a 5 liter reactor was charged 2 liters (10 volumes) of
DCM and 200.0 grams (0.32 mol, 1.0 eq.) and the mixture was stirred
for 10-30 minutes to dissolve the solid. The solution was cooled to
0-5.degree. C. and NH.sub.2OH (50% w/w)/NaOH/H.sub.2O (104.9 g/76.3
g/1.0 L) was added dropwise at 0-25.degree. C. over 30-60 min. The
resulting mixture was stirred at 10-25.degree. C. for 3 hours and
then sampled to check the reaction conversion by HPLC, which showed
that the starting material was present at less than 3.5%. The
mixture was allowed to settle and the DCM layer was washed with a
saturated solution of KH.sub.2PO.sub.4 (0.8 L, 4 vol.) twice. The
resulting organic layer was further washed with brine (0.8 L, 4
vol.) twice. The combined organic layers were concentrated under
vacuum at 30-40.degree. C. to dryness and to provide the crude
product as a yellow solid (196.0 g, purity: 94%, chiral purity:
49.7%). The crude product was purified by chromatography over
silica gel using DCM:ethanol (100:1 to 20:1) to get 138.0 grams of
the pure product (purity: 99.5%, chiral purity: 49.7%). The product
was further dried to remove toluene to yield 125.0 grams as a light
yellow solid (yield, 61.2%, purity: 99.5%, chiral purity:
49.7%).
Synthesis Example 3: Preparation of Compound (5)-If
[1763] The compound of formula (S)-If was prepared using a process
very similar to that shown above for (S)-Ie with the key difference
that 1-iodo-3,5-dichlorobenzene was used as starting material
instead of 1-Chloro-2-fluoro-5-iodo-3-(trifluoromethyl)benzene. The
process for the preparation of (S)-If is shown in Scheme 3 below
and the detailed procedure for Step 3 is provided.
##STR00042##
Step 3
[1764] Dichloromethane (150 ml, 30 vol.) and intermediate 3-5 (5.0
g, 8.66 mmol, 1.0 eq.) were charged into a 3-neck 500 ml flask and
stirred for 10-30 minutes to dissolve the solid. The solution was
then cooled to 0-5.degree. C. and chiral phase transfer catalyst
2-6 was added (0.20 g, 0.026 mmol, 0.03 eq.). To the resulting
solution was added a solution of NH.sub.2OH (50% w/w)/Na0H/H.sub.2O
(20 ml, 5 vol.) drop-wise at 0 to 5.degree. C. over 0.5-1 hour. The
resulting reaction mixture was stirred for 2 hours at 0-5.degree.
C. and then sampled to check the reaction completion by HPLC, which
showed less than 1% starting material. The layers were allowed to
settle and the DCM layer was washed with saturated KH.sub.2PO.sub.4
(20 ml, 4 vol.) twice. The organic layer was then washed with brine
(20 ml, 4 vol.) twice. The combined organic layers were
concentrated under vacuum at 30-40.degree. C. with concomitant
addition of toluene (20 ml, 4 vol., twice) and then concentrated to
dryness. Toluene (15 ml, 3 vol.) and the crude product (5.0 g) were
charged into a 50 ml, 3-neck flask and the mixture was heated to
60-70.degree. C. to dissolve the solid. The resulting mixture was
cooled slowly to 45-50.degree. C. over 2 hours and filtered. The
filter cake was washed with toluene (10 ml, 2 vol.) and the
filtrate was dried in an oven under vacuum at 40-50.degree. C. for
6 hours to yield the product (2.5 g, yield: 49.0%, purity 99.4%,
chiral purity: 99.3%).
Synthesis Example 4: Preparation of compound (Ic) where X.sup.1 and
X.sup.2.dbd.Cl and X.sup.3.dbd.F
[1765] The compound of formula (Ic), where X.sup.1 and
X.sup.2.dbd.Cl and X.sup.3.dbd.F, was prepared according to a
process very similar to that shown in Schemes 2 and 3 above with
the key difference that 1,3-dichloro-2-fluoro-5-iodobenzene was
used as starting material instead of
1-chloro-2-fluoro-5-iodo-3-(trifluoromethyl)benzene. Step 3 of the
process is described in detail below.
##STR00043##
Compound 4-5 (5, 8.4 mmol, 1.0 eq.) and THF (30 ml, 6 vol.) were
charged into a 100 ml 3-neck flask. The solid was dissolved and
NaOH (1.5 g, 50%, 18.5 mmol, 2.2 eq.) and hydroxylamine sulfate
(0.6 g, 4.62 mmol, 0.55 eq.) were added to the mixture at
0-5.degree. C. The reaction mixture was stirred for 90 minutes and
sampled for analysis by HPLC, which indicated that less than 1.0%
of the starting material was left. To the resulting mixture was
added KH.sub.2PO.sub.4 (1.3 g, 10.9 mmol, 1.3 eq.) and the mixture
was warmed to 20-25.degree. C. The layers were allowed to separate
and the organic layer isolated. The THF was removed by distillation
with concomitant addition of acetonitrile (20 ml, 4 vol.) twice and
then concentrated to dryness. Acetonitrile (20 ml, 4 vol.) was
added to dissolve the residue and the solution was cooled to
25-30.degree. C. slowly and stirred at this temperature for 180
min. The solid was filtered and the cake washed with acetonitrile
(10 ml, 2 vol.). The solid was dried under vacuum at 30-35.degree.
C. for 6 hours to obtain the product (2.1 g, 98.9% purity, yield,
41.2%).
Veterinary Long-Acting Injectable Formulation Examples
[1766] The following long-acting injectable compositions are
prepared by mixing the following ingredients:
Formulation Example 5
TABLE-US-00003 [1767] Compound of formula (Ia) 30% (w/v) Ethanol 9%
(w/v) PEG 400 QS.
Formulation Example 6
TABLE-US-00004 [1768] Compound of formula (Ia) 15% (w/w) PEG 400
85% (w/w)
Formulation Example 7
TABLE-US-00005 [1769] Compound of formula (Ia) 26% (w/w) PEG 400
74% (w/w)
Formulation Example 8
TABLE-US-00006 [1770] Compound of formula (Ia) 26% (w/w) PEG 400
66% (w/w) Ethanol 8% (w/w)
Formulation Example 9
TABLE-US-00007 [1771] Compound of formula (Ia) 26% (w/w) PEG 400
66% (w/w) Isopropanol 8% (w/w)
Formulation Example 10
TABLE-US-00008 [1772] Compound of formula (Ia) 26% (w/w) PEG 400
64% (w/w) Capryol 90 10% (w/w)
Formulation Example 11
TABLE-US-00009 [1773] Compound of formula (Ia) 26% (w/w) PEG 66%
(w/w) Benzyl alcohol 8% (w/w)
Formulation Example 12
TABLE-US-00010 [1774] Compound of formula (S)-Ia 13% (w/w) PEG 400
79% (w/w) Ethanol 8% (w/w)
Formulation Example 13
TABLE-US-00011 [1775] Compound of formula Ic where X.sup.1, X.sup.3
= Cl, X.sup.2 is F 30% (w/v) Ethanol 9% (w/v) PEG 400 QS.
Formulation Example 14
TABLE-US-00012 [1776] Compound of formula (Ic), where X.sup.1 = Cl,
X.sup.2 = F, X.sup.3 = CF.sub.3 30% (w/v) Ethanol 9% (w/v) PEG 400
QS.
Formulation Example 15
TABLE-US-00013 [1777] Compound of formula(S)-Ic, where X.sup.1,
X.sup.3 = Cl, X.sup.2 is F 13% (w/w) PEG 400 79% (w/w) Ethanol 8%
(w/w).
Formulation Example 16
TABLE-US-00014 [1778] Compound of formula(S)-Ic, where 13% (w/w)
X.sup.1 = Cl, X.sup.2 = F, X.sup.3 = CF.sub.3 PEG 400 79% (w/w)
Ethanol 8% (w/w).
Formulation Example 17
TABLE-US-00015 [1779] Compound of formula (S)-Ic, where X.sup.1,
X.sup.3 = Cl, X.sup.2 is H 13% (w/w) PEG 400 79% (w/w) Ethanol 8%
(w/w).
Formulation Example 18
TABLE-US-00016 [1780] Compound of formula (S)-Ic, where X.sup.1,
X.sup.2, X.sup.3 = chloro 13% (w/w) PEG 400 79% (w/w) Ethanol 8%
(w/w).
Formulation Example 19
TABLE-US-00017 [1781] Compound of formula (S)-Ic, X.sup.1 = Cl,
X.sup.2 = F, X.sup.3 = CF.sub.3 10% (w/v) Ethanol 8% (w/w) PEG 400
QS.
Formulation Example 20
TABLE-US-00018 [1782] Compound of formula (S)-Ic, X.sup.1 = Cl,
X.sup.2 = F, X.sup.3 = CF.sub.3 10% (w/v) PEG 400 QS.
Formulation Example 21
TABLE-US-00019 [1783] Compound of formula (S)-Ic, X.sup.1 = Cl,
X.sup.2 = F, X.sup.3 = CF.sub.3 5% (w/v) PEG 400 QS.
Formulation Example 22
TABLE-US-00020 [1784] Compound of formula (S)-Ic, X.sup.1 = Cl,
X.sup.2 = F, X.sup.3 = CF.sub.3 10% (w/v) Ethanol 3% (w/v) PEG 400
QS.
Formulation Example 23
TABLE-US-00021 [1785] Compound of formula (S)-Ic, X.sup.1 = Cl,
X.sup.2 = F, X.sup.3 = CF.sub.3 5% (w/v) Ethanol 8% (w/v) PEG 400
QS.
Formulation Example 24
TABLE-US-00022 [1786] Compound of formula (S)-Ic, X.sup.1 = Cl,
X.sup.2 = F, X.sup.3 = CF.sub.3 2.5% (w/v) PEG 400 QS.
Formulation Example 25
TABLE-US-00023 [1787] Compound of formula (S)-Ic, X.sup.1 = Cl,
X.sup.2 = F, X.sup.3 = CF.sub.3 2.5% (w/v) Ethanol 8% (w/v) PEG 400
QS.
Formulation Example 26
TABLE-US-00024 [1788] Compound of formula (S)-Ie 20% (w/v) Medium
chain triglycerides (e.g. Miglyol .RTM. 812) QS Sorbitan monooleate
0.5% (w/v) Benzyl alcohol 8% (w/v).
Formulation Example 27
TABLE-US-00025 [1789] Compound of formula (S)-Ie 10% (w/v) Medium
chain triglycerides (e.g. Miglyol .RTM. 812) QS Sorbitan monooleate
0.5% (w/v) Benzyl alcohol 8% (w/v).
Formulation Example 28
TABLE-US-00026 [1790] Compound of formula (S)-Ie 5% (w/v) Medium
chain triglycerides (e.g. Miglyol .RTM. 812) QS Sorbitan monooleate
0.5% (w/v) Benzyl alcohol 8% (w/v).
Formulation Example 29
TABLE-US-00027 [1791] Compound of formula (S)-Ie 2.5% (w/v) Medium
chain triglycerides (e.g. Miglyol .RTM. 812) QS Sorbitan monooleate
0.5% (w/v) Benzyl alcohol 8% (w/v).
Formulation Example 30
TABLE-US-00028 [1792] Compound of formula (S)-Ie 20% (w/v) PEG 400
QS Medium chain triglycerides (e.g. Miglyol .RTM. 812) 30% (w/v)
Sorbitan monooleate 0.5% (w/v) Benzyl alcohol 8% (w/v).
Formulation Example 31
TABLE-US-00029 [1793] Compound of formula (S)-Ie 10% (w/v) PEG 400
QS Medium chain triglycerides (e.g. Miglyol .RTM. 812) 30% (w/v)
Sorbitan monooleate 0.5% (w/v) Benzyl alcohol 8% (w/v).
Formulation Example 32
TABLE-US-00030 [1794] Compound of formula (S)-Ie 5% (w/v) PEG 400
QS Medium chain triglycerides (e.g. Miglyol .RTM. 812) 30% (w/v)
Sorbitan monooleate 0.5% (w/v) Benzyl alcohol 8% (w/v).
Formulation Example 33
TABLE-US-00031 [1795] Compound of formula (S)-Ie 2.5% (w/v) PEG 400
QS Medium chain triglycerides (e.g. Miglyol .RTM. 812) 30% (w/v)
Sorbitan monooleate 0.5% (w/v) Benzyl alcohol 8% (w/v).
Formulation Example 34
TABLE-US-00032 [1796] Compound of formula (S)-Ie 20% (w/v)
Propylene glycol dicaprylate/dicaprate QS (e.g. Miglyol .RTM. 840)
Sorbitan monooleate 0.5% (w/v) Benzyl alcohol 8% (w/v).
Formulation Example 35
TABLE-US-00033 [1797] Compound of formula (S)-Ie 10% (w/v)
Propylene glycol dicaprylate/dicaprate QS (e.g. Miglyol .RTM. 840)
Sorbitan monooleate 0.5% (w/v) Benzyl alcohol 8% (w/v).
Formulation Example 36
TABLE-US-00034 [1798] Compound of formula (S)-Ie 5% (w/v) Propylene
glycol dicaprylate/dicaprate QS (e.g. Miglyol .RTM. 840) Sorbitan
monooleate 0.5% (w/v) Benzyl alcohol 8% (w/v).
Formulation Example 37
TABLE-US-00035 [1799] Compound of formula (S)-Ie 2.5% (w/v)
Propylene glycol dicaprylate/dicaprate (e.g. Miglyol .RTM. 840) QS
Sorbitan monooleate 0.5% (w/v) Benzyl alcohol 8% (w/v).
Formulation Example 38
TABLE-US-00036 [1800] Compound of formula (S)-Ie 20% (w/v) PEG 400
QS Propylene glycol dicaprylate/dicaprate (e.g. Miglyol .RTM. 840)
30% (w/v) Sorbitan monooleate 0.5% (w/v) Benzyl alcohol 8%
(w/v).
Formulation Example 39
TABLE-US-00037 [1801] Compound of formula (S)-Ie 10% (w/v) PEG 400
QS Propylene glycol dicaprylate/dicaprate (e.g. Miglyol .RTM. 840)
30% (w/v) Sorbitan monooleate 0.5% (w/v) Benzyl alcohol 8%
(w/v).
Formulation Example 40
TABLE-US-00038 [1802] Compound of formula (S)-Ie 5% (w/v) PEG 400
QS Propylene glycol dicaprylate/dicaprate (e.g. Miglyol .RTM. 840)
30% (w/v) Sorbitan monooleate 0.5% (w/v) Benzyl alcohol 8%
(w/v).
Formulation Example 41
TABLE-US-00039 [1803] Compound of formula (S)-Ie 2.5% (w/v) PEG 400
QS Propylene glycol dicaprylate/dicaprate (e.g. Miglyol .RTM. 840)
30% (w/v) Sorbitan monooleate 0.5% (w/v) Benzyl alcohol 8%
(w/v).
Formulation Example 42
TABLE-US-00040 [1804] Compound of formula (S)-Ie 20% (w/v) PEG 400
QS Propylene glycol dicaprylate/dicaprate (e.g. Miglyol .RTM. 840)
30% (w/v) Sorbitan monooleate 0.5% (w/v).
Formulation Example 43
TABLE-US-00041 [1805] Compound of formula (S)-Ie 10% (w/v) PEG 400
QS Propylene glycol dicaprylate/dicaprate (e.g. Miglyol .RTM. 840)
30% (w/v) Sorbitan monooleate 0.5% (w/v).
Formulation Example 44
TABLE-US-00042 [1806] Compound of formula (S)-Ie 5% (w/v) PEG 400
QS Propylene glycol dicaprylate/dicaprate (e.g. Miglyol .RTM. 840)
30% (w/v) Sorbitan monooleate 0.5% (w/v).
Formulation Example 45
TABLE-US-00043 [1807] Compound of formula (S)-Ie 2.5% (w/v) PEG 400
QS Propylene glycol dicaprylate/dicaprate (e.g. Miglyol .RTM. 840)
30% (w/v) Sorbitan monooleate 0.5% (w/v).
Formulation Example 46
TABLE-US-00044 [1808] Compound of formula (S)-Ie 20% (w/v) PEG 400
QS Medium chain triglycerides (e.g. Miglyol .RTM. 812) 30% (w/v)
Sorbitan monooleate 0.5% (w/v).
Formulation Example 47
TABLE-US-00045 [1809] Compound of formula (S)-Ie 10% (w/v) PEG 400
QS Medium chain triglycerides (e.g. Miglyol .RTM. 812) 30% (w/v)
Sorbitan monooleate 0.5% (w/v).
Formulation Example 48
TABLE-US-00046 [1810] Compound of formula (S)-Ie 5% (w/v) PEG 400
QS Medium chain triglycerides (e.g. Miglyol .RTM. 812) 30% (w/v)
Sorbitan monooleate 0.5% (w/v).
Formulation Example 49
TABLE-US-00047 [1811] Compound of formula (S)-Ie 2.5% (w/v) PEG 400
QS Medium chain triglycerides (e.g. Miglyol .RTM. 812) 30% (w/v)
Sorbitan monooleate 0.5% (w/v).
Example 50: Viscosity of Long-Acting Formulations
[1812] The viscosity of the formulations in Examples 19-25 was
measured to determine their suitability for injection. Polyethylene
glycol 400 (PEG 400) was used as a reference. The conditions below
were used for the measurement:
Instrument: LVDV-E Brookfield viscometer
Spindle: S31
[1813] Speed: 60 revolutions per minute (rpm)
Temperature: 25.degree. C.
[1814] Sample volume: 9.0 mL Measurement time: 2 to 3 minutes
TABLE-US-00048 Measured viscosity Calculated Total Formulation in
cPs Allowable Error Example 19 75.5 .+-.5.75 Example 20 134.5
.+-.6.344 Example 21 109.5 .+-.6.093 Example 22 102.5 .+-.6.023
Example 23 60.0 .+-.5.598 Example 24 95.5 .+-.5.953 Example 25 55.5
.+-.5.553 PEG 400 93.0 .+-.5.929
The viscosity of each of the compositions from Examples 18 to 24
was found to be suitable for administration by injection.
Efficacy Examples
Example 51: Efficacy of Injectable Formulation Against
Rhipicephalus (Boophilus) Microplus Ticks
[1815] The efficacy of long-acting injectable compositions of the
invention comprising the compounds of formula (Ie) and (S)-Ie,
against Rhipicephalus microplus ticks on cattle was determined
against an untreated control group. The efficacy of compositions
comprising the compounds (Ie) and (S)-e were also compared with
injectable compositions comprising afoxolaner (formula Ia,
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-naphthalan-
ecarboxamide), and comparative compounds of formulae (If) and
(S)-If shown below.
##STR00044##
Each compound was formulated in an injectable composition at a
concentration of 10% (w/v) in a carrier comprising 8% (w/v) ethanol
and Q.S. with polyethylene glycol 400. The racemic compounds
afoxolaner and (If) were dosed at 1.0 mg/kg body weight and the
(S)-enantiomers ((S)-Ie and (S)-If) were dosed at 0.5 mg/kg body
weight. Six healthy head of cattle were used in each study group.
Cattle in Group 1 were untreated (control). Cattle in Groups 2, 3,
4, 5 and 6 were treated on Day 0 subcutaneously with injectable
compositions comprising the compounds of formula Ie, (S)-If,
(S)-Ie, afoxolaner (Ia) and (If), respectively. Several weeks
before treatment, cattle were infested three times a week with
approximately 2500 Rhipicephalus microplus larvae to establish
ongoing infestations. Each animal was challenged by infestation
with approximately 5000 R. microplus larvae on Days 7 and 21 and
every 14 days thereafter.
[1816] Ticks dropping from each animal in the previous 24 hours
were collected daily and counted from Day 1 until the end of the
study. The cattle in study Groups 3, 5 and 6 were not infested
further when the efficacy of the treatment dropped
significantly.
[1817] Tables 1A, 1B and 1C below show the total tick count %
efficacy of injectable compositions comprising compounds of the
invention ((Ie) and (S)-Ie) against R. microplus for selected days
through Day 110 post treatment compared with the untreated control
group and the comparison isoxazoline compounds. As evidenced from
the data in Tables 1A, 1B and 1C below, the compositions comprising
the compounds (Ie) and (S)-Ie of the invention dosed at 1.0 mg/kg
and 0.5 mg/kg, respectively, provide surprising and unexpected
efficacy against Rhipicephalus microplus ticks for an extended
period of time compared with compositions comprising afoxolaner,
(If) or (S)-If. Further, the efficacy of compounds (Ie) and (S)-Ie
is also faster-acting than compositions comprising the other
isoxazoline compounds. The superior efficacy of compounds (Ie)
(racemic) and (S)-Ie against R. microplus ticks is unexpected and
unpredictable.
TABLE-US-00049 TABLE 1A Tick Count Efficacy Against Rhipicephalus
microplus Average % Efficacy (Tick Count) Treatment Day Day Day Day
Day Day Day Group 5 10 20 30 40 49 55 Group 2 69 100 100 100 100
100 100 (Ie) Group 3 39 27 33 86 100 36 0 ((S)-If) Group 4 66 93
100 100 100 100 100 ((S)-Ie) Group 5 38 48 77 99 100 94 73
afoxolaner Group 6 70 62 57 84 100 70 14 (If)
TABLE-US-00050 TABLE 1B Tick Count Efficacy Against Rhipicephalus
microplus Average % Efficacy (Tick Count) Treatment Day Day Day Day
Day Day Day Group 60 65 70 75 80 85 88 Group 2 100 100 100 100 100
100 100 (Ie) Group 3 -- -- -- -- -- -- -- ((S)-If) Group 4 100 100
100 100 100 90 88 ((S)-Ie) Group 5 71 48 3 0 -- -- -- afoxolaner
Group 6 -- -- -- -- -- -- -- (If)
TABLE-US-00051 TABLE 1C Tick Count Efficacy against Rhipicephalus
microplus Average % Efficacy (Tick Count) Day Day Day Day Treatment
Group 95 100 105 110 Group 2 (Ie) 100 100 93 82 Group 3 ((S)-If) --
-- -- -- Group 4 ((S)-Ie) 92 88 76 65 Group 5 afoxolaner -- -- --
-- Group 6 (If) -- -- -- --
Example 52: Efficacy of Long-Acting Injectable Compositions Against
Haematobia irritans (Horn Fly) on Cattle
[1818] The efficacy of a long-acting injectable composition
comprising the compound of formula (S)-Ie against horn fly on
cattle was evaluated. Two groups of 15 cattle were selected for the
study and randomly assigned to one of two groups. The cattle in
Group 1 were untreated and the cattle in Group 2 were treated with
a long-acting composition of the invention containing 10% (w/v) of
the compound of formula (S)-Ie in a carrier comprising 8% (w/v)
ethanol in PEG 400 (QS). The composition was administered to the
cattle in Group 2 at a dose of 0.25 mL/50 kg body weight. Each
animal was naturally infested with horn flies, and horn fly counts
were performed on Days -2, 3, 7, 10, 13, 16, 20, 23, 27, 30, 34,
37, 43, 45 and 48. Tables 2A and 2B below provide the horn fly
counts and the % reduction of the treated group relative to the
control.
TABLE-US-00052 TABLE 2A Arithmetic Mean of Horn Fly Counts & %
Reduction Treatment Day Day Day Day Day Day Day Day Group 3 7 10 13
16 20 23 27 Group 1 254.3 136.0 78.3 60.0 104.7 83.0 53.3 59.3
(untreated) Group 2 26.7 35.0 16.0 22.0 44.7 36.0 30.7 22.7
((S)-Ie) % Reduction 89.5 74.3 79.6 63.3 57.3 56.6 42.5 61.8
TABLE-US-00053 TABLE 2B Arithmetic Mean of Horn Fly Counts & %
Reduction Treatment Day Day Day Day Day Day Group 30 34 37 43 45 48
Group 1 71.0 47.7 73.3 43.0 66.7 44.0 (untreated) Group 2 23.0 26.3
28.0 26.0 43.0 30.3 ((S)-Ie) % Reduction 67.6 44.8 61.8 39.5 35.5
31.1
[1819] Having thus described in detail various embodiments of the
present invention, it is to be understood that the invention
defined by the above paragraphs is not to be limited to particular
details set forth in the above description as many apparent
variations thereof are possible without departing from the spirit
or scope of the present invention.
* * * * *