WO2014039422A1 - Spirocyclic isoxazoline derivatives for treatment of sea lice - Google Patents
Spirocyclic isoxazoline derivatives for treatment of sea lice Download PDFInfo
- Publication number
- WO2014039422A1 WO2014039422A1 PCT/US2013/057787 US2013057787W WO2014039422A1 WO 2014039422 A1 WO2014039422 A1 WO 2014039422A1 US 2013057787 W US2013057787 W US 2013057787W WO 2014039422 A1 WO2014039422 A1 WO 2014039422A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- fish
- compound
- trifluoromethyl
- azetidine
- dihydroisoxazol
- Prior art date
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- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- SNQQPOLDUKLAAF-UHFFFAOYSA-N nonylphenol Chemical compound CCCCCCCCCC1=CC=CC=C1O SNQQPOLDUKLAAF-UHFFFAOYSA-N 0.000 description 1
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- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- PAQZWJGSJMLPMG-UHFFFAOYSA-N propylphosphonic anhydride Substances CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
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- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- GDQBPBMIAFIRIU-UHFFFAOYSA-N thieno[2,3-c]pyridine Chemical compound C1=NC=C2SC=CC2=C1 GDQBPBMIAFIRIU-UHFFFAOYSA-N 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
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- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
Definitions
- This invention relates to spirocyclic isoxazoline derivatives having activity against sea lice in fish.
- SLICE® has been widely used and as a result, significant resistance amongst sea lice populations has arisen. Additionally, macrocyclic lactones are observed to have high toxicity and deleterious environmental effects due to their non-selective activity against other benign microorganisms.
- Isoxazoline derivatives have been disclosed in the art as having insecticidal and acaricidal activity.
- WO2007/105814, WO2008/122375, and WO2009/035004 recite certain alkylene linked amides.
- WO2007/075459, WO2010/084067 and WO2010/025998 disclose phenyl isoxazolines substituted with a 5- to 6-membered heterocycle, and/or 10- to 1 1 -membered fused aryl and heteroaryl substitutions.
- none of these citations exemplify spirocyclic substituted isoxazolines, or processes of manufacturing the spirocyclic
- the present invention overcomes one or more of the various aspects of the various aspects of the various aspects
- the present invention develops new spirocyclic isoxazoline substituted azetidine compounds which demonstrate potent activity against sea lice.
- the present invention provides a method for the treatment of a parasitic infection or infestation in a fish comprising administering to said fish an effective amount of a compound of Formula 1
- X and W are each independently -0-, -S-, -NR 6 -, -CH 2 -, -C(O)-, -C(NR 7 )-, or -C(S)-, when X is -0-, -S-, or -NR 6 -, then W is -CH 2 -, -C(0)-, -C(NR 7 )-, or -C(S)-, and when W is -0-, -S-, or -NR 6 -, then X is -CH 2 -, -C(0)-, -C(NR 7 )-, or -C(S)-;
- R a , R b , and R c are each independently hydrogen, halo, hydroxyl, cyano, nitro, Ci-C6alkyl, C-i-Cehaloalkyl, C-i-Cealkoxy, Co-C3alkylC3-C6 cycloalkyi,
- R 2 is fluoro, chloro, or Ci-C6alkyl
- R 3 is cyano, d-C 6 alkyl, Ci-C 6 haloalkyl, -C(0)NR a R b , C 2 -C 6 alkenyl,
- R 4 is hydrogen, Ci-C 6 alkyl, Co-C 6 alkylC3-C 6 cycloalkyl, -C(0)R 5 , -C(S)R 5 , -C(0)NR a R 5 , -C(0)C(0)NR a R 5 , -S(0) p R c , -S(0) 2 NR a R 5 , -C(NR 7 )R 5 ,
- R 5 is hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Co-C 6 alkylC 3 -C6cycloalkyl,
- R 6 is hydrogen, CrC 6 alkyl, hydroxyl, or C-i-C 6 alkoxy
- R 7 is hydrogen, Ci-C6alkyl, hydroxyl, cyano, nitro, -S(0) p R c , or Ci-C6alkoxy;
- R is Ci-C6alkyl or C 3 -C6cycloalkyl optionally substituted with at least one halo substituent;
- R a is hydrogen, Ci-C6alkyl, or Co-C3alkylC3-C6cycloalkyl; wherein the alkyl and alkylcycloalkyl is optionally substituted by cyano or at least one halo substituent;
- R b is hydrogen, Ci-C6alkyl, C3-C6cycloalkyl, Co-C3alkylphenyl,
- R c is Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 haloalkylC 3 -C 6 cycloalkyl,
- Co-C3alkylC3-C6cycloalkyl Co-C3alkylphenyl, Co-C3alkylheteroaryl, or
- Co-C3alkylheterocycle each optionally substituted with at least one substituent selected from cyano, halo, hydroxyl, oxo, d-Cealkoxy, C-i-Cehaloalkoxy,
- Ci-C 6 haloalkyl -S(0) p R, -SH, -S(0) p NR a R b , -NR a R b , -NR a C(0)R b , -SC(0)R, -SCN, or -C(0)NR a R b ;
- each of R 4 and R 5 Ci-C6alkyl or Co-C6alkylC3-C6cycloalkyl moiety can be optionally and independently substituted by at least one substituent selected from cyano, halo, hydroxyl, oxo, C-i-C 6 alkoxy, C-i-C 6 haloalkoxy, C-i-C 6 haloalkyl, Ci-C 6 alkyl, hydroxylCi-C 6 alkyl-, -S(0) p R c , -SH, -S(0) p NR a R b , -NR a R b ,
- n is the integer 0, 1 , or 2, and when n is 2, each R 2 may be identical or different from each other;
- p is the integer 0, 1 , or 2;
- a method for the treatment of a parasitic infection or infestation in a fish comprising administering to said fish an effective amount of a compound of Formula 1 , selected from: 1 -(cyclopropanecarbonyl)-5'-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-3'H-spiro ⁇ azetidine-3, 1 '-isobenzofuran ⁇ -3'-one;
- a method for the treatment of a parasitic infection or infestation in a fish comprising administering to said fish an effective amount of a compound of Formula 1 that is 1-(5'-(5-(3,5-dichloro-4- fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'H-spiro[azetidine-3,1 '- isobenzofuran]-1 -yl)-2-(methylsulfonyl)ethanone, having the structure:
- a method for the treatment of a parasitic infection or infestation in a fish comprising administering to said fish an effective amount of a compound of Formula 1 that is the S-enantiomer of 1 -(5'-(5- (3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'H- spiro[azetidine-3,1 '-isobenzofuran]-1 -yl)-2-(methylsulfonyl)ethanone).
- a method for the treatment of a parasitic infection or infestation in a fish comprising administering to said fish an effective amount of a compound of Formula 1 that is the crystalline Form A of (S)- 1 -(5'-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- 3'H-spiro[azetidine-3,1 '-isobenzofuran]-1 -yl)-2-(methylsulfonyl)ethanone).
- a method for the treatment of a parasitic infection or infestation in a fish comprising administering to said fish an effective amount of a compound of Formula 1 that is the amorphous S-enantiomer of (S)-1 -(5'-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol- 3-yl)-3'H-spiro[azetidine-3, 1 '-isobenzofuran]-1 -yl)-2-(methylsulfonyl)ethanone) prepared from the crystalline Form A of (S)-1 -(5'-(5-(3,5-dichloro-4-fluorophenyl)- 5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'H-spiro[azetidine-3,1 '- isobenzofuran]-1 -yl)
- Compounds of the present invention alone, or in combination with an additional veterinary agent(s) may be administered to a fish as (a) a single veterinary composition which comprises a compound of Formula (1 ), stereoisomer thereof, veterinarily acceptable salt thereof, and optionally, at least one additional veterinary agent and a veterinarily acceptable excipient, diluent, or carrier; or (b) two separate veterinary compositions comprising (i) a first composition comprising a compound of the present invention, stereoisomer thereof, veterinarily acceptable salt thereof, and a veterinarily acceptable excipient, diluent, or carrier, and (ii) a second composition comprising at least one additional veterinary agent and a veterinarily acceptable excipient, diluent, or carrier.
- the veterinary compositions may be administered simultaneously or sequentially and in any order.
- the present invention provides a method of treating a parasitic infestation in a fish comprising administering an effective amount of any one of the foregoing compounds (hereinafter "the compound") to said fish.
- the parasitic infestation is an ectoparasite infestation.
- the ectoparasite is a crustacean; specifically the crustacean is sea lice.
- the sea lice is at least one of Lepeophtheirus or Caligus species, specifically Lepeophtheirus salmonis, Caligus celmensi, Caligus curtus, Caligus dussumieri, Caligus elongates, Caligus longicaudatus, Caligus
- the fish is a farmed fish.
- the fish is selected from the group consisting of carp, tuna, tilapia, cod, halibut, trout or salmon. More particularly, the fish is salmon.
- the compound is administered to the fish orally through a feed composition.
- the feed composition is a pellet comprising fat, nutrients, protein and the compound.
- the compound is injected into the fish. More particularly, the compound is injected into the fish intraperitoneally (IP) or intramuscularly (IM).
- IP intraperitoneally
- IM intramuscularly
- the compound is co-administered with at least one of: another small molecule, an antigen, inactivated or killed virus or bacteria, or adjuvant.
- the compound is administered to the fish by immersing the fish in a solution comprising the compound.
- the compound is administered to the fish in a dose of at least 100 parts per billion (ppb).
- the compound is co-administered to the fish with an additional antiparasitic agent.
- the compound is administered to a plurality of fish.
- compositions for oral administration to a fish comprising the compound and fish food. More particularly, the composition comprises fat, nutrients, protein and the compound.
- fish food comprises at least one of corn starch or oil. More particularly, the oil is vegetable oil or herring oil.
- composition aforementioned composition and instructions for admnistration of the composition to fish.
- the present invention is directed to the use of the compound in treating a sea lice infestation in a fish. In another aspect of the invention, the invention is directed to use of the compound in the
- Additional veterinary agent(s) refers to other veterinary or pharmaceutical compounds or products that provide a therapeutically effective amount of said agents that are useful for the treatment of a parasitic infection in a fish.
- Alkoxy refers to an oxygen moiety having a further alkyl substituent.
- the alkyl portion (i.e., alkyl moiety) of an alkoxy group has the same definition as below. Non-limiting examples include: -OCH3, -OCH2CH3, and the like.
- Alkyl refers to saturated monovalent hydrocarbon alkane radicals of the general formula C n H2n+i -
- the alkane radical may be straight or branched and may be unsubstituted or substituted.
- (Ci-C6)alkyl refers to a monovalent, straight or branched aliphatic group containing 1 to 6 carbon atoms.
- Non-exclusive examples of (C-i-Ce) alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, sec-butyl, t-butyl, n-propyl, n-butyl, i-butyl, s-butyl, n-pentyl,
- alkyl moiety may be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain.
- Alkyl groups are optionally substituted as described herein. Further when used in compound words such as alkylphenyl, said alkyl moiety has the same meaning as herein defined and may be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain.
- alkylphenyl include: dalkylphenyl is -CH 2 phenyl, C 2 alkylphenyl is
- Cophenyl is phenyl, and the like.
- alkenyl include: ethenyl, 1 -propenyl, 2-propenyl, isopropenyl, 1 -butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, and the like.
- Alkynyl refers to straight or branched aliphatic hydrocarbon chain having 2- to 6-carbon atoms and containing at least one carbon-carbon triple bond (for example, -C ⁇ C- or -C ⁇ CH).
- alkynyl include: ethynyl, 2-propynyl, 1 -methyl-2-propynyl, 2- butynyl, 3-butynyl, 2-methyl-3-butynyl, and the like.
- Carbocyclic refers to a partially saturated or saturated 5- to 7-membered ring containing only carbon atoms and can be monocyclic or part of a fused ring or spiro ring moiety.
- carbocyclic rings examples include cyclopentane, cyclohexane, and
- cycloheptane The carbocyclic ring is optionally substituted as described herein.
- Chiral refers to the structural characteristic of a molecule that makes it impossible to superimpose it on its mirror image, (e.g., "R” and “S” enantiomers).
- the term is also depicted as an asterisk (i.e.,*) in the Eamples and preparations and refers to a chiral center which includes both the S and R enantiomers.
- Cycloalkyi as used herein, unless otherwise indicated, includes fully saturated or partially saturated carbocyclic alkyl moieties.
- Non-limiting examples of partially saturated cycloalkyls include: cyclopropene, cyclobutene,
- cycloheptene cyclooctene
- cyclohepta-1 ,3-diene and the like.
- Preferred cycloalkyls are 3- to 6-membered saturated monocyclic rings including
- cyclopropyl cyclobutyl, cyclopentyl, and cyclohexyl.
- the cycloalkyi group may be attached to the chemical moiety by any one of the carbon atoms within the carbocyclic ring.
- Cycloalkyl groups are optionally substituted with at least one substituent. Further when used in compound words such as alkylcycloalkyl, said alkyl and cycloalkyl moiety has the same meaning as herein defined and may be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain.
- Co-C6alkylC3-C6cycloalkyl examples include, methylcyclopropane (CialkylCscycloalkyl or -CH 2 cyclopropane), ethylcyclopropane (C2alkylC3cycloalkyl or -CH 2 CH 2 cyclopropane), methylcyclobutane (CialkylCscycloalkyl or
- CoalkylC3-C6cycloalkyl is C3-C6cycloalkyl. Cycloalkyl moieties are optionally substituted as described herein.
- Osteichthyes which live in water, have gills or mucus-covered skin for respiration, fins, and may have scales.
- Non-exclusive examples of fish include food fish, breeding fish and aquarium or pond fish of all ages occurring in freshwater, sea water and brackish water.
- the food fish and breeding fish include, for example, carp, eel, trout, whitefish, salmon, bream, roach, rudd, chub, sole, plaice, halibut, Japanese yellowtail (Serbia quinqueradiata), Japanese eel (Anguilla japonica), tuna, red sea bream (Pagurus major), sea bass
- the fish are kept in sea water tanks or cages.
- the cages are moored in sea inlets such that a constant flow of water passes through them in order to ensure a sufficient supply of oxygen.
- a constant flow of salt water in the sea water tanks is also maintained along with a supply of oxygen.
- the fish are fed and, if necessary, provided with medication until they mature sufficiently for marketing as edible fish or are selected for further breeding.
- Halogen or "halo”, as used herein, unless otherwise indicated, refers to fluorine, chlorine, bromine and iodine. Further, when used in compound words such as “haloalkyl”, “haloalkoxy”, “haloalkenyl”, or “haloalkynyl”, said alkyl, alkoxy, alkenyl, and alkynyl may be partially or fully substituted with halogen atoms which may be the same or different and said alkyl, alkoxy, alkenyl, and alkynyl moiety has the same meaning as above and may be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain.
- haloalkyl examples include F 3 C-, CICH 2 -, CF 3 CH 2 - and CF 3 CCI 2 -, and the like.
- haloalkoxy is defined analogously to the term “haloalkyl”. Examples of “haloalkoxy” include CF 3 O-, CCI 3 CH 2 O-, HCF 2 CH 2 CH 2 O- and CF 3 CH 2 O-, and the like.
- haloalkenyl is defined analogously to the term “haloalkyl” except that the aliphatic chain contains at least one carbon-carbon double bond. Examples of
- haloalkynyl is defined analogously to the term “haloalkyl” except that the aliphatic chain contains at least one carbon-carbon triple bond. Examples of “haloalkynyl” include CF 3 C ⁇ C-, CI 3 CC ⁇ C-, HCF 2 C ⁇ C- and CF 3 C ⁇ CC-, and the like.
- Heteroaryl or “Het”, as used herein, unless otherwise indicated, refers to a 5- to 6-membered aromatic monocyclic ring or an 8- to 10-membered fused aromatic ring where said monocyclic- and fused-ring moiety contains one or more heteroatoms each independently selected from N, O, or S, preferably from one to four heteroatoms.
- Non-exclusive examples of monocyclic heteroaryls include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and the like.
- fused heteroaryls include: benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, benzo[1 ,2,5]thiadiazole, and the like.
- the heteroaryl group may be attached to the chemical moiety by any one of the carbon atoms or nitrogen heteroatoms within the monocyclic or fused ring.
- alkyl and heteroaryl moiety have the same meaning as herein defined and may be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain.
- Coalkylheteroaryl is heteroaryl
- dalkylheteroaryl is -Ch ⁇ heteroaryl
- C ⁇ alkylheteroaryl is -CH 2 CH 2 heteroaryl, and the like.
- Heteroaryls are optionally substituted as described herein.
- Heterocycle refers to a partially saturated or saturated 3- to 7-membered monocyclic ring containing one or more heteroatoms each independently selected from N, O, or S, preferably from one to four heteroatoms.
- the heterocyclic ring can be part of a fused ring or spiro-ring moiety.
- Non-exclusive examples of heterocycle include oxirane, thiarane, aziridine, oxetane, azetidine, thiatane, tetrahydrofuran,
- heterocycle group may be attached to the chemical moiety by any one of the carbon atoms or nitrogen heteroatoms within the ring. Further when used in compound words such as alkylheterocycle, said alkyl and heterocycle moiety have the same meaning as herein defined and may be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain. For example,
- Coalkylheterocycle is heterocycle
- C-ialkylheterocycle is -CH 2 heterocycle
- C 2 alkylheterocycle is -CH 2 CH 2 heterocycle, and the like. Heterocycles are optionally substituted as described herein.
- Optionally substituted is used herein interchangeably with the phrase substituted or unsubstituted. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other. An optionally substituted group also may have no substituents. Therefore, the phrase "optionally substituted with at least one substituent" means that the number of substituents may vary from zero up to a number of available positions for substitution.
- Parasite(s) refers to endoparasites and ectoparasites.
- Endoparasites are parasites that live within the body of its host and include helminths (e.g., trematodes, cestodes, and nematodes) and protozoa.
- Ectoparasites are organisms of the Arthropoda phylum (e.g., arachnids, insects, and crustaceans (e.g., copepods-sea lice) which feed through or upon the skin of its host.
- Preferred arachnids are of the order Acarina, e.g., ticks and mites.
- Preferred insects are midges, fleas, mosquitos, biting flies (stable fly, horn fly, blow fly, horse fly, and the like), bed bugs, and lice.
- Preferred compounds of the present invention can be used for the treatment of parasites, i.e., treatment of a parasitic infection or infestation.
- Sea lice as used herein are parasitic crustaceans within the order Siphonostomatoida, family Caligidae. Two representatives of the class cause substantial losses in yield: Lepeophtheirus and Caligus. Lepeophtheirus has a brown, horseshoe-shaped carapace and Caligus is also brown, but smaller.
- Species within Lepeophtheirus include Lepeophtheirus salmonis and within Caligus include Caligus celmensi, Caligus curtus, Caligus dussumieri, Caligus elongates, Caligus longicaudatus, Caligus rogercresseyi and Caligus stromii.
- Treatment refers to reversing, alleviating, preventing or inhibiting the parasitic infection, infestation, or condition. As used herein, these terms also encompass, depending on the condition of the fish, preventing the onset of a disorder or condition, or of symptoms associated with a disorder or condition, including reducing the severity of a disorder or condition or symptoms associated therewith prior to affliction with said infection or infestation.
- treatment can refer to administration of the compounds of the present invention to a fish that is not at the time of administration afflicted with the infection or infestation. Treating also encompasses preventing the recurrence of an infection or infestation or of symptoms associated therewith as well as references to "control” (e.g., kill, repel, expel, incapacitate, deter, eliminate, alleviate, minimize, and eradicate).
- Reference to treating a parasitic infestation "in” a fish is understood to constitute treatment of an external parasite, such an ectoparasite, which feeds "on” a fish and not necessarily exist inside the fish.
- Veterinary acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, composition, and/or the fish being treated therewith.
- pharmaceutically acceptable has the same meaning as that recited for “veterinarily” acceptable.
- compositions disclosed can be administered in a variety of ways. It should be noted that the composition can be administered alone or in combination with one or more pharmaceutically acceptable carriers, stabilizers, preservatives, colorants, flavorants, and excipients.
- Reference to "fish food” indicates substances specially adapted for administration to fish. Particularly, at least one of fats, nutrients, protein, vitamins or carbohydrates in flake or pellet form, which is capable of adsorbing or mixing with the active compound(s) of the present invention.
- the fish food includes corn starch, vegetable oil and/or fish oil, such as herring oil.
- compositions disclosed can be formulated with conventional carriers and excipients, which are selected in accord with ordinary practice.
- Aqueous formulations are preferably prepared in sterile form, and when intended for delivery by routes other than oral administration, generally are isotonic.
- Excipients include ascorbic acid and other antioxidants, chelating agents (e.g. , EGTA and EDTA), carbohydrates (e.g. , dextrin), hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like.
- the pH of the formulations ranges from about 3 to about 1 1 .
- physiologically acceptable carriers for routes of administration other than oral administration include but are not limited to saline solutions (e.g. , normal saline, Ringer's solution, PBS (phosphate-buffered saline); polysorbate 80; L-arginine; polyvinylpyrrolidone; a-D-glucopyranosyl; a-D-glucopyranoside
- trehalose can be present in the composition in an amount from about 2 to about 10% weight/volume of the composition.
- trehalose and polysorbate 80 are both present in the composition, trehalose can be present in the amount of about 4 to about 6% wt./vol. and the polysorbate 80 can be present in the amount of about 0.001 to 0.01 % (wt./vol.) and generally mixtures of various physiologically compatible salts including potassium and phosphate salts with or without sugar additives (e.g. , glucose).
- Suitable excipients for use in the immunogenic formulations are, for example, water, saline, dextrose, glycerol, and ethanol.
- Non-toxic auxiliary substances, such as wetting agents, buffers, stabilizers, or emulsifiers can also be added to the composition.
- Parenteral administration if used, is generally characterized by injection.
- Sterile injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
- the total amount of the composition necessary for administration can be derived by routine practice of those skilled in the art.
- the exact amount of such compositions required may vary from fish to fish or stock to stock.
- the formulations include those suitable for the foregoing administration routes.
- the formulations can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the art of veterinary science. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
- the oil phase of the emulsions of this invention can be constituted from known ingredients in a known manner. While the phase can comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include both an oil and a fat.
- Veterinary carriers are materials useful for the purpose of administering the composition and can be solid, liquid or gaseous materials, which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally, or by any other desired route.
- the present disclosure provides compositions and methods that employ the compound administered orally.
- the compound is used in the form of a pure powder, though other formulations may be appropriate.
- the oral feed compositions and formulations which follow are all contemplated in the fish food of the present invention.
- Exemplary oral non-toxic inert suitable excipients include, for example, fillers and extenders, binders, humectants, solution retarders, absorption accelerators, wetting agents, adsorbents or lubricants, which may have a solid, semisolid or liquid consistency. Such excipients are known to those of skill in the art.
- the compound may be added to the feed by customary methods, by simply mixing as a pure substance, such as a powder, or in a formulated form mixed with edible, nontoxic excipients in the form of a premix.
- the compound may be formulated together with pharmaceutically active compounds, minerals, salts, elements, vitamins, proteins, fats, colorants and/or flavorings.
- the amount of the compound that is administered to a fish to achieve the desired effect can be substantially varied because of the favorable non-toxic properties of the compound.
- the compound is administered orally at about 0.005 to 5000 mg/kg, in particular 0.01 to 500 mg/kg (i.e. mg compound per kg fish body weight per day).
- the compound can be administered at relatively high doses, such as exceeding (i.e. greater than) 0.01 mg/kg, 0.1 mg/kg, 1 mg/kg, 10 mg/kg or even greater than 100 mg/kg.
- the duration of administration can be from a few hours or days up to several years.
- the compound When applied topically in water baths or orally, the compound can be present, for example, in a concentration by weight of about 0.0005 to 50, in particular 0.001 to 10 ppm, thus greater than 100 parts per billion in one embodiment.
- feed compositions can be used, and these preferably contain the customary balance of energy carriers and builders, which are necessary for a balanced diet, including vitamins and minerals.
- the feed can be composed of vegetable materials, for example, hay, roots, cereals, cereals by-products, kelp, lettuce, animal materials, for example meat, fats, bone meal, fish products, vitamins, for example vitamin A, D complex and B complex, proteins, amino acids, for example DL-methionine and inorganic substances, for example lime and sodium chloride.
- Feed concentrates contain the active compound in addition to edible substances, for example rye meal, corn meal, corn starch, soy bean meal or lime, where appropriate with other nutrients and builders, and proteins, mineral salts and vitamins. They can be produced by the customary mixing methods.
- the compound When formulated as a feed, the compound may be admixed with one or more fish-appropriate feedstuff.
- the premix may comprise other nontoxic material(s), which are typically though not exclusively carbohydrate-based, and are of sufficient granularity to facilitate thorough mixing when added to larger quantities of feedstuff. Other nutrients, proteins, mineral salts, and vitamins may be included in the compound premix.
- the feed mixtures indicated are adjusted to be appropriate preferably for the rearing, fattening and harvesting of fish.
- a pre-mix of concentrated compound it is generally then added to additional stores of untreated food.
- the optimum final concentration of the compound will depend upon the amount of food to be consumed by the fish and can be readily determined by those of skill in the art.
- the type of food and its composition will be determined by the skilled artisan based upon the particular requirements of the species of fish and location or size
- fish food can be combined with the compound to form of a pellet for oral administration to the fish.
- the pellet may include ingredients such as corn starch, oil, such as herring oil or vegetable oil, and the compound.
- the compound can be added by surface coating of fish feed pellets or coextrusion with fish meal ingredients to form pellets.
- a premix is typically suspended in fish oil and the suspension is poured onto the feed under mixing in a suitable mixer (ribbon or cementtype mixer).
- a premix comprising the compound also be dusted onto feed pellets followed by the oil coat, which is referred to as the double-coating procedure.
- a premix of the compound is blended with feed ingredients in a mixer. The blend is then conditioned and passed through an extruder under high heat and humidity conditions. The extruded pellets are then dried and coated with oil, if desired.
- Emulsifiable Concentrates Active compound: 1 to 90%, preferably 5 to 20%, surfactant: 1 to 30%, preferably 10 to 20% solvent: 5 to 98%, preferably 70 to 85%
- Active compound 5 to 75%, preferably 10 to 50%, water: 94 to 24%, preferably 88 to 30%, surfactant: 1 to 40%, preferably 2 to 30%
- Active compound 0.5 to 90%, preferably 1 to 80% surfactant: 0.5 to 20%, preferably 1 to 15% solid carrier: 5 to 99%, preferably 15 to 98%
- Active compound 0.5 to 30%, preferably 3 to 15%, solid carrier: 99.5 to 70%, preferably 97 to 85%
- Active compound 25%-50%; calcium dodecylbenzene sulfonate 5% -8%; castor oil polyethylene glycol ether 5%; tributylphenol polyethylene glycol 4%-12%; ether cyclohexanone; 15%-20%; and xylene mixture 20% -65%
- Active compound 10%, sodium ligninsulfonate 2%, carboxymethyl cellulose 1 %, kaolin 87% . Active compound is mixed with the adjuvants and the mixture is ground and moistened with water. This mixture is extruded, granulated and then dried in a stream of air.
- Active compound 3% polyethylene glycol 3%, kaolin 94%.
- the finely ground active substance is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol.
- Non-dusty coated granulates are obtained in this manner.
- Active compound 40%, ethylene glycol 10%, nonylphenol polyethylene glycol ether 6%, sodium ligninsulfonate 10%, carboxymethyl cellulose 1 %, 37% aqueous formaldehyde solution 0.2%, silicone oil in the form of a 75%, 0.8% aqueous emulsion water 32%.
- the finely ground active substance is homogeneously mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired concentration can be obtained by dilution with water.
- Ampoule containing active compound Disodium Pamidronat Pentahydrate and Water. After Dissolution (Concentration 3 Mg/MI), the Solution can be Used for Injections. Active compound 15.0 mg, mannitol 250 mg, water for injection 5 ml.
- Derquatel 1 -20% herrring or vegetable oil 1 -5%, corn starch q.s. to reach 100% ( about 75%-98%). Ingredients are mixed into a pellet formulation with the oil acting as an adherent and flavorant.
- the compounds and compositions can also be used in combination with other active ingredients. Such combinations are selected based on the condition to be treated, cross-reactivities of ingredients, and pharmacological properties of the combination. For instance, multifunctional agents, such as polyvalent vaccines are preferable in fish treatment, thus the composition may be administered with antigens targting other diseases. These compounds and compositions can be administered together with, or in the same course of, therapy with the compounds and compositions described herein.
- combination can be administered either sequentially or simultaneously in separate or combined vetrinary formulations.
- Form A has characteristic PXRD peaks expressed in degrees 2 ⁇ ( ⁇ 0.2° ⁇ ) at about one or more of the following positions: 9.39, 14.10, 17.18, 18.83, 19.12, 20.07, 21 .42, 22.54, 23.62, and 28.42, all of which have a relative intensity of at least 33%.
- Form A has a PXRD peak expressed in degrees 2 ⁇ ( ⁇ 0.2° ⁇ ) at about 20.07.
- Form A has a PXRD peak expressed in degrees 2 ⁇ ( ⁇ 0.2° ⁇ ) at about 20.07 and further comprises at least one additional diffraction peak expressed in degrees 2 ⁇ ( ⁇ 0.2° ⁇ ) selected from the group consisting of peaks at about 9.39, 14.10, 17.18, 18.83, 19.12, 20.07, 21 .42, 22.54, 23.62, and 28.42.
- Form A has characteristic PXRD peaks expressed in degrees 2 ⁇ ( ⁇ 0.2° ⁇ ) at about one or more of the following positions: 17.18, 18.83, 20.07, 21 .42, 22.54, and 28.42, all of which have a relative intensity of at least 40%.
- Form A has characteristic PXRD peaks expressed in degrees 2 ⁇ ( ⁇ 0.2° ⁇ ) at about one or more of the following positions: 17.18, 18.83, 20.07, 21 .42, and 28.42, all of which have a relative intensity of at least 50%.
- Form A also exhibits a Fournier- Transform Infrared (FT-IR) spectrum at the 1800 to 600 cm “1 range substantially as shown in Table 2. Characteristic FT-IR peaks of Form A are shown in Table 2 below.
- FT-IR Fournier- Transform Infrared
- Form A exhibits characteristic Fournier-Transform Infrared (FT-IR) peaks at the 1800 to 600 cm “1 spectrum range at one or more of the following: 1662, 1459, 1352, 1304, 1 191 , 1 166, 1 133, 1023, 984, 912, 815, 757, 721 , 659, and 625cm "1 .
- FT-IR Fournier-Transform Infrared
- Form A also exhibits a differential scanning calorimetry (DSC) thermogram substantially characterized by a predominant endotherm peak at about 145.53°C.
- DSC differential scanning calorimetry
- Form A also exhibits a differential scanning calorimetry (DSC) thermogram, which is characterized by a predominant endotherm peak at about 145.53°C with an onset peak at about 135.26°C.
- Form A is characterized by PXRD peaks expressed in degrees 2 ⁇ ( ⁇ 0.2° ⁇ ) at one or more of the following positions: 9.39, 14.10, 17.18, 18.83, 19.12, 20.07, 21 .42, 22.54, 23.62, and 28.42 and with characteristic FT-IR peaks at the 1800 to 600 cm "1 spectrum range at one or more of the following 1662, 1459, 1352, 1304, 1 191 , 1 166, 1 133, 1023, 984, 912, 815, 757, 721 , 659, and 625cm "1 .
- Form A is characterized by PXRD peaks expressed in degrees 2 ⁇ ( ⁇ 0.2° ⁇ ) at one or more of the following positions: 9.39, 14.10, 17.18, 18.83, 19.12, 20.07, 21 .42, 22.54, 23.62, and 28.42 and with a predominant DSC endotherm peak at about 145.53°C.
- Form A is characterized by FT-IR peaks at the 1000 cm "1 spectrum range at one or more of the following 1662, 1459, 1352, 1304, 1 191 , 1 166, 1 133, 1023, 984, 912, 815, 757, 721 , 659, and 625cm "1 , and with a DSC endotherm peak at about 145.53°C.
- Form A is characterized by PXRD peaks expressed in degrees 2 ⁇ ( ⁇ 0.2° ⁇ ) at one or more of the following positions: 9.39, 14.10, 17.18, 18.83, 19.12, 20.07, 21 .42, 22.54, 23.62, and 28.42, characteristic FT-IR peaks at the 1800 to 600 cm "1 spectrum range at one or more of the following 1662, 1459, 1352, 1304, 1 191 , 1 166, 1 133, 1023, 984, 912, 815, 757, 721 , 659, and 625cm "1 , and with a predominant DSC endotherm peak at about 145.53°C.
- Form A has characteristic PXRD peaks expressed in degrees 2 ⁇ ( ⁇ 0.2° ⁇ ) at about one or more of the following positions: 17.18, 18.83, 20.07, 21 .42, 22.54, and 28.42, and with characteristic FT-IR peaks at the 1800 to 600 cm "1 spectrum range at one or more of the following 1662, 1459, 1352, 1304, 1 191 , 1 166, 1 133, 1023, 984, 912, 815, 757, 721 , 659, and 625cm "1 .
- Form A has characteristic PXRD peaks expressed in degrees 2 ⁇ ( ⁇ 0.2° ⁇ ) at about one or more of the following positions: 17.18, 18.83, 20.07, 21 .42, 22.54, and 28.42, and with a DSC endotherm peak at about 145.53°C.
- Form A has characteristic PXRD peaks expressed in degrees 2 ⁇ ( ⁇ 0.2° ⁇ ) at about one or more of the following positions: 17.18, 18.83, 20.07, 21 .42, 22.54, and 28.42, with characteristic FT-IR peaks at the 1800 to 600 cm "1 spectrum range at one or more of the following 1662, 1459, 1352, 1304, 1 191 , 1 166, 1 133, 1023, 984, 912, 815, 757, 721 , 659, and 625cm "1 , and with a DSC endotherm peak at about 145.53°C.
- Form A has characteristic PXRD peaks expressed in degrees 2 ⁇ ( ⁇ 0.2° ⁇ ) at about one or more of the following positions: 17.18, 18.83, 20.07, 21 .42, and 28.42, and with characteristic FT-IR peaks at the 1800 to 600 cm "1 spectrum range at one or more of the following 1662, 1459, 1352, 1304, 1 191 , 1 166, 1 133, 1023, 984, 912, 815, 757, 721 , 659, and 625cm "1 .
- Form A has characteristic PXRD peaks expressed in degrees 2 ⁇ ( ⁇ 0.2° ⁇ ) at about one or more of the following positions: 17.18, 18.83, 20.07, 21 .42, and 28.42, and with a DSC endotherm peak at about 145.53°C.
- Form A has characteristic PXRD peaks expressed in degrees 2 ⁇ ( ⁇ 0.2° ⁇ ) at about one or more of the following positions: 17.18, 18.83, 20.07, 21 .42, and 28.42, and with characteristic FT-IR peaks at the 1800 to 600 cm "1 spectrum range at one or more of the following 1662, 1459, 1352, 1304, 1 191 , 1 166, 1 133, 1023, 984, 912, 815, 757, 721 , 659, and 625cm "1 , and with a DSC endotherm peak at about 145.53°C.
- Form A also exhibits a differential scanning calorimetry (DSC) thermogram, which displays four different Form A samples, which is characterized by a predominant endotherm peak at about 144.01 , 144.82, 146.32, and 146.92°C with onset peaks at about 133.95, 136.29, 137.54, and 137.96°C.
- DSC thermogram of the four samples is characterized by a predominant endotherm peak at about 145.52°C with an onset peak at about 136.44°C.
- Compounds for use in the compositions and methods of the present invention may be synthesized by synthetic routes that include processes analogous to those well known in the chemical arts, particularly in light of the description contained herein.
- the starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, "Reagents for Organic Synthesis", 1 ; 19, Wiley, New York (1967, 1999 ed.), or Beilsteins Handbuch der orqanischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).
- reaction schemes depicted below demonstrate potential routes for synthesizing compounds of the present invention, and key intermediates.
- Examples section below A skilled artisan will appreciate that other suitable starting materials, reagents, and synthetic routes may be used to synthesize the compounds of the present invention and a variety of derivatives thereof.
- many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to the skilled artisan.
- Enantiomeric mixtures can be separated into their individual enantiomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as chromatography and/or fractional crystallization.
- chromatography and/or fractional crystallization A more detailed description of techniques that can be used to resolve stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley and Sons, Inc. (1981 ).
- Compounds of this invention can exist as one or more stereoisomers.
- the various stereoisomers include enantiomers, diastereomers and atropisomers.
- one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers.
- the compounds of the invention may be present as a mixture of stereoisomers, individual stereo isomers or as an optically active form.
- Example 1 1 -(5'-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-3'H-spiro[azetidine-3,1 '-isobenzofuran]-1 -yl)-2- (methylsulfonyl)ethanone.
- the "*" represents the chiral carbon.
- racemate of the besylate salt of the sulfonamide can be removed by mixing methanesulfonylacetic acid (0.615g, 1 .3eq) with the
- Form A seeds were prepared by dissolving between 100 mg and
- the solvent vapors were allowed to evaporate/diffuse for a period of 5 days, at which time solids were noted. Examination of the solids under light microscopy revealed highly birefringent crystalline particles. Analysis by hot stage microscopy demonstrated a melting point between 130 and 170°C. Further examination confirmed Form A, (e.g., the seed crystals).
- Form A can be prepared by charging 15.4 grams of the amorphous S enantiomer described above, dissolved in 92 mL ethanol and 7.7 mL ethyl acetate, to a preheated 1 -L jacketed reactor equipped with overhead stirring, temperature probe/readout, programmable chiller, nitrogen headspace purge, and water-cooled overhead condenser. Next, 54 mL of n-heptane is added. The resulting system is heated to 60°C and a solution results. The solution is cooled to 45°C over 15 minutes, and a hazy or milky solution results, without any signs of the formation of crystalline solids. 308 mg of polymorphic Form A that was hand ground with a mortar and pestle is then added..
- the seeds persist in the reactor.
- the system is held at 45°C, then the contents of the reactor are cooled to 30°C at 1 .5°C per hour linearly, then cooled to 10°C over three hours linearly, then held at 10°C for 4.5 hours.
- a white, stirrable slurry results.
- the slurry is cooled to 0-1 °C over 20 minutes and held overnight (about 23 hours) at 0-1 °C.
- the contents of the reactor are transferred to a sintered glass filter and vacuum is applied until a solid cake is observed. The cake is washed on the filter with about 40 mL of 60% n-heptane/40% ethanol denatured with 0.5% toluene.
- Form A can be prepared by charging 4 grams of the amorphous S form (isolated by rotavapping to a foam) to a 50-mL MultiMax reactor equipped with jacketed heating/cooling, overhead stirring, thermocouple, and a dispensing box. Add 24 ml. of a solvent mixture consisting of 60 volume% ethanol (denatured with 0.5 volume% toluene), 35% heptane, and 5% ethyl acetate. Heat the mixture to 60°C, and a clear solution results. Cool to 45°C over 20 minutes, then add seeds of polymorphic Form A (approximately 40 mg). The seeds persist in the reactor vessel.
- Form A can be prepared by charging the amorphous S form to a vial containing about 18 mL of diisopropyl ether, 1 .1 mL methanol, and Form A seeds. The reaction mixture was stirred. The reaction mixture was heated and cooled from 40°C to 2°C, with cooling over about 4 hours and heating over about 1 hour, for a duration of six heating and cooling cycles. The reaction mixture was held at about 1 °C for 1 day. The mixture was reheated from 1 °C to 55°C and then cooled to about 25°C over a period of about 3.3 hours (approximately 200 minutes), and then cooled again to about 1 °C over a period of about 1 -hour.
- enantiomeric enrichment can be obtained by stirring in MTBE (for example) and filtering any solids which form.
- Product was identical to the first eluting enantiomer of the racemate under the preparative chiral SFC conditions previously described.
- ACE Excel 2 C18-AR 150 x 4.6mm column. Column temperature of 50°C. Detection at 260 nm. Flow rate is 1 .5 mL per minute.
- Mobile phase A 0.1 % trifluoroacetic acid in water.
- Mobile phase B 0.1 % TFA in acetonitrile. Run at a gradient: initial time 45% B, 4.5 minutes 55% B, 20 minutes 100% B. Elution time of S-isomer is 9.8 minutes.
- the S-enantiomer of Example 1 displayed substantially greater activity against sea lice than emamectin (the active agent in SLICE®), with an EC 5 o against male sea lice of 0.08 ppb and females, 0.13 ppb for generally chemical resistant sea lice. Conversely, emamectin showed substantially decreased potency against the same strain of sea lice, with an EC50 of 202 ppb for adult males and 65 ppb for adult females. These results indicate that the S-enantiomer of Example 1 is significantly more potent against sea lice then the commercially available alternative (SLICE®).
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Abstract
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EP13765836.5A EP2900065A1 (en) | 2012-09-04 | 2013-09-03 | Spirocyclic isoxazoline derivatives for treatment of sea lice |
US14/423,288 US20150223463A1 (en) | 2012-09-04 | 2013-09-03 | Spirocyclic isoxazoline derivatives for treatment of sea lice |
CA2882199A CA2882199A1 (en) | 2012-09-04 | 2013-09-03 | Spirocyclic isoxazoline derivatives for treatment of sea lice |
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Cited By (5)
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AU2013312882B2 (en) * | 2012-09-07 | 2015-11-05 | Zoetis Services Llc | Spirocyclic isoxazoline parasiticidal combinations |
US9221835B2 (en) * | 2012-09-07 | 2015-12-29 | Zoetis Services Llc | Spirocyclic derivatives as antiparasitic agents |
WO2017153218A1 (en) | 2016-03-11 | 2017-09-14 | Basf Se | Method for controlling pests of plants |
WO2018162312A1 (en) | 2017-03-10 | 2018-09-13 | Basf Se | Spirocyclic derivatives |
WO2022226660A1 (en) * | 2021-04-30 | 2022-11-03 | Ohalloran John | Use of isoxazoline for protection against parasitic pests in fish |
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WO2017153218A1 (en) | 2016-03-11 | 2017-09-14 | Basf Se | Method for controlling pests of plants |
WO2018162312A1 (en) | 2017-03-10 | 2018-09-13 | Basf Se | Spirocyclic derivatives |
WO2022226660A1 (en) * | 2021-04-30 | 2022-11-03 | Ohalloran John | Use of isoxazoline for protection against parasitic pests in fish |
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