USOO8932613B2

(12) United States Patent (10) Patent No.: US 8,932,613 B2 Taylor (45) Date of Patent: Jan. 13, 2015

(54) ECTOPARASITE CONTROL METHOD WO 98.07423 A1 2/1998 WO O 170671 A2 9, 2001 (75) Inventor: Wendy Sue Taylor, Landenberg, PA W. 89.3 A. 33: (US) (Continued) (73) Assignee: E I du Pont de Nemours and Company, Wilmington, DE (US) OTHER PUBLICATIONS c Londershaunsen Michael: "Approaches to new parasiticides' Pesti (*) Notice: Subject to any disclaimer, the term of this cide science, vol. 48, No. 4, 1996, p. 269-292, XP002561859 ISSN: patent is extendedb) b or dadjusted under 35 OO31-613X. U.S.C. 154(b) by 595 days. S.K. Meegalla et al. Bioorg. & Med. Chem. Lett. (2006), 1702-1706. PN.R.Usherwoodet al., “Towards the development of ryanoid insec (21) Appl. No.: 12/670,494 ticides with low mammalian toxicity' retreived from STN Interna 1-1. tional Database accession No. 9725325 & Toxicology Letters, vol. (22) PCT Filed: Jul. 28, 2008 82/83 No. COM 1995 pp. 247-254. G.P. Lahm et al: “Insecticidal antirhanilic diamides: A new class of (86). PCT No.: PCT/US2008/071287 potent receptor activators' Bioorganic & Medical Chem S371 (c)(1), istry Letters, vol. 15, Sep. 13, 2005 pp. 4898-4906. (2), (4) Date: Jan. 25, 2010 PCT/US2008/071288 International Search Report, Mar. 4, 2010. PCT/US/2008/071288 International Preliminary Report on Patent (87) PCT Pub. No.: WO2009/018185 ability, Mar. 9, 2010. PCT Pub. Date: Feb. 5, 2009 (Continued) (65) Prior Publication Data Primary Examiner — Audrea Buckley US 2010/0204281 A1 Aug. 12, 2010 (57) ABSTRACT O O This invention relates to a method of controlling or preventing Related U.S. Application Data infestations of ectoparasites, preferably hematophageous (60) Provisional application No. 60/962,568, filed on Jul. ectoparasites, on an animal by administering to the animal a 30, 2007. composition comprising an parasiticidally effective amount of a compound of Formula 1, oran N-oxide, or a pharmaceu (51) Int. Cl. ( ) tically or veterinarily acceptable salt thereof, AOIN 25/02 2006.O1 A6 IK3I/4I55 (2006.01) (52) setts (2006.01) R2 1 CPC ...... A0IN 43/56 (2013.01); A61 K31/4155 (2013.01) \ USPC ...... 424/405; 514/183 O M 3 (58) Field of Classification Search R1 N R USPC ...... 424/405 R NH See application file for complete search history. / \

(56) References Cited O o NC R7 U.S. PATENT DOCUMENTS 6,001,384 A 12/1999 Jeannin R41 ns 2004/O198984 A1 10, 2004 Lahm et al. 2007/O161037 A1 7/2007 Gutteridge 2009.0036407 A1 2/2009 Taylor wherein 2009.0036497 A1 2/2009 Taylor R" is Me, Cl, Br or F: 2009.0036498 A1 2/2009 Taylor R’ is F, Cl, Br, C-C haloalkyl or C-C haloalkoxy; 2009.0036499 A1 2/2009 Taylor 2009, O104145 A1 4/2009 Hughes et al. R is F, C1 or Br; 2009/0275471 A1* 11/2009 Funke et al...... 504,100 R" is H; C1-C4 alkyl, C-C alkenyl, C-C alkynyl, Cs-Cs 2010/0056469 A1* 3/2010 Langewald et al...... 514/53 cycloalkyl, or C-C cycloalkylalkyl, each optionally 2010/0120616 A1* 5/2010 Breuninger et al...... 504,100 substituted with one substituent selected from the group 2010/O197738 A1 8/2010 Taylor consisting of halogen, CN, SMe, S(O)Me, S(O).Me, 2010/0210601 A1* 8/2010 Taylor ...... 514,143 and OMe: 2011 OO15153 A1 1/2011 Taylor R is H or Me: FOREIGN PATENT DOCUMENTS R is H. For Cl; and R7 is H, For C1. EP 1717237 A1 2, 2005 GB 2321012 A1 7, 1998 5 Claims, No Drawings US 8,932,613 B2 Page 2

(56) References Cited OTHER PUBLICATIONS PCT/US2008/071287 International Search Report (International Phase of this Application), Feb. 11, 2010. FOREIGN PATENT DOCUMENTS PCT/US2008/071287 International Preliminary Report on Patent ability (International Phase of this Application), Feb. 2, 2010. W. 29.3 A. 39 Ohkawa et al., Pesticide Chemistry, Wiley Verlag Chapters 11 and 12 WO 2006007595 A2 1/2006 Jul 17, 2007. WO 2006/068669 A1 6, 2006 Office Actions and Responses in U.S. Appl. No. 12/182,566, Jul. 2, WO WO 2006,108552 * 10, 2006 2012. WO 2006128867 A1 12/2006 Office Actions and Responses in U.S. Appl. No. 12/670.663, Jun. 14. WO 2007O 17433 A2 2, 2007 2012. WO 2007020877 A1 2, 2007 Office Actions and Responses in U.S. Appl. No. 12/182,551, Feb. 1. WO WO2007/020877 A1 2, 2007 2012. WO 2008104503 A1 9, 2008 WO 2008125410 A2 10, 2008 * cited by examiner US 8,932,613 B2 1. 2 ECTOPARASITE CONTROL METHOD The invention also comprises a compound of Formula 1 for use as a medicament. The invention also relates to the use of a compound of FIELD OF THE INVENTION Formula 1 in the manufacture of a medicament for the treat 5 ment of an infestation of an ectoparasitic insect on a animal This invention relates to certain methods for controlling ectoparasitic insects on homeothermic animals DETAILS OF THE INVENTION As used herein, the terms “comprises.” “comprising.” BACKGROUND OF THE INVENTION “includes.” “including.” “has.” “having.” “contains” or “con 10 taining.” or any other variation thereof, are intended to cover Ectoparasitic insects are particularly bothersome for ani a non-exclusive inclusion. For example, a composition, a mals including humans. They are annoying as well as possi mixture, process, method, article, or apparatus that comprises bly harmful due to the potential transmission of diseases. a list of elements is not necessarily limited to only those Although substantial need has existed in the industry for elements but may include other elements not expressly listed products which control or eradicate Such ectoparasites, prior 15 or inherent to Such composition, mixture, process, method, art attempts have failed to provide effective formulations article, or apparatus. Further, unless expressly stated to the which are capable of fully eradicating or controlling them contrary, “or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of while also being non-toxic to humans and animals. the following: A is true (or present) and B is false (or not In an attempt to meet the consumer demand for products of present), A is false (or not present) and B is true (or present), this nature, various pesticides, and insect repel and both A and B are true (or present). lant formulations have been developed. These products often Also, the indefinite articles “a” and “an preceding an suffer from drawbacks relating to their toxicity or lack of element or component of the invention are intended to be efficacy due to evolved resistance of the parasites. There is a nonrestrictive regarding the number of instances (i.e. occur pressing need therefore for new chemical compounds effica 25 rences) of the element or component. Therefore “a” or “an cious against Such pests which are relatively non-toxic to the should be read to include one or at least one, and the singular animal species they are used to protect. word form of the element or component also includes the plural unless the number is obviously meant to be singular. SUMMARY OF THE INVENTION In the above recitations, the term “alkyl, used either alone 30 or in compound words such as “alkylthio’ or “haloalkyl This invention relates to a method of controlling or pre includes straight-chain or branched alkyl, such as, methyl, venting infestations of an ectoparasitic insect, preferably a ethyl, n-propyl, i-propyl, or the different butyl isomers. The hematophageous ectoparasitic insect, on an animal by admin term "halogen', either alone or in compound words such as istering to the animal a composition comprising an parasiti “haloalkoxy’, includes fluorine, chlorine, bromine or iodine. cidally effective amount of a compound of Formula 1, or an 35 Further, when used in compound words such as “haloalkyl, N-oxide, or a salt thereof, or “haloalkoxy”, said alkyl oralkoxy may be partially or fully Substituted with halogen atoms which may be the same or different. Examples of “haloalkyl include FC, CICH, CFCH and CFCC1. Examples of “haloalkoxy' include R2 40 CFO, HCFO, CC1-CHO, HCFCHCHO and CFCH.O. One skilled in the art will appreciate that not all nitrogen containing heterocycles can form N-oxides since the nitrogen O | MN 3 requires an available lone pair for oxidation to the oxide; one RI N R skilled in the art will recognize those nitrogen-containing 45 heterocycles which can form N-oxides. One skilled in the art R NH / will also recognize that tertiary amines can form N-oxides. N \ Synthetic methods for the preparation of N-oxides of hetero O cycles and tertiary amines are very well known by one skilled NC R7 in the art including the oxidation of heterocycles and tertiary 50 amines with peroxy acids such as peracetic and m-chlorop R41 N NR5 erbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydrop eroxides Such as t-butyl hydroperoxide, Sodium perborate, and dioxiranes such as dimethydroxirane. These methods for wherein the preparation of N-oxides have been extensively described 55 and reviewed in the literature, see for example: T. L. Gilchrist R is Me, Cl, Br or F: in Comprehensive Organic Synthesis, vol. 7, pp 748-750, S. R’ is F, Cl, Br, C-C haloalkyl or C-Chaloalkoxy: V. Ley, Ed., Pergamon Press: M. Tisler and B. Stanovnik in R is F, C1 or Br; Comprehensive Heterocyclic Chemistry, vol. 3, pp 18-20, A. R" is H; C-C alkyl, C-C alkenyl, C-C alkynyl, C-Cs J. Boulton and A. McKillop, Eds. Pergamon Press; M. R. cycloalkyl, or C-C cycloalkylalkyl, each optionally 60 Grimmett and B. R. T. Keene in Advances in Heterocyclic substituted with one substituent selected from the group Chemistry, Vol. 43, pp 149-161, A. R. Katritzky, Ed., Aca consisting of halogen, CN, SMe, S(O)Me, S(O) Me, demic Press: M. Tisler and B. Stanovnik in Advances in and OMe. Heterocyclic Chemistry, vol. 9, pp. 285-291, A. R. Katritzky R is Hor Me: and A. J. Boulton, Eds. Academic Press; and G. W. H. 65 Cheeseman and E. S. G. Werstiuk in Advances in Heterocy R is H. For Cl; and clic Chemistry, Vol. 22, pp.390-392, A. R. Katritzky and A. J. R" is H, For C1. Boulton, Eds., Academic Press. US 8,932,613 B2 3 4 Compounds of this invention can exist as one or more "Ectoparasitic insect’ means insect ectoparasites of warm Stereoisomers. The various Stereoisomers include enanti blooded animals omers, diastereomers, atropisomers and geometric isomers. Hematophagous insect ectoparasites are ectoparasitic One skilled in the art will appreciate that one stereoisomer insects which attack their hosts by ingesting blood. By may be more active and/or may exhibit beneficial effects 5 "ingesting is meant not only piercing the animal integument when enriched relative to the other stereoisomer(s) or when and Sucking the blood from the circulatory system, but also separated from the other stereoisomer(s). Additionally, the consuming tissue or tissue fluids of the host and thereby skilled artisan knows how to separate, enrich, and/or to selec tively prepare said stereoisomers. Accordingly, the present inevitably consume blood or blood constituents. Included invention comprises compounds selected from Formula 1, within the definition of hematophageous ectoparasitic insects N-oxides and salts thereof. Pharmaceutically or veterinarily 10 are fleas, ticks, biting flies, mites, lice, and true bugs. acceptable salts, Suitable to the mode of administration, are “Homeothermic Animals' means warm blooded animals. contemplated. The compounds of the invention may be The term is meant to include all such animals including present as a mixture of stereoisomers, individual stereoiso humans and particularly important agronomic or companion mers, or as an optically active form. animals such cattle, sheep, horses, goats, pigs, llamas, cam The salts of the compounds of the invention include acid 15 els, water buffalo, donkeys, rabbits, fallow deer, reindeer, addition salts with inorganic or organic acids such as hydro minks, chinchillas, ferrets, raccoons, chickens, geese, tur bromic, hydrochloric, nitric, phosphoric, Sulfuric, acetic, keys, ducks, dogs, cats, mice rats, or the like. butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, For the purposes of the present invention, the term flea is salicylic, tartaric, 4-toluenesulfonic or Valeric acids. In the understood to refer to all the usual or accidental species of compositions and methods of this invention, the salts of the parasitic flea of the order Siphonaptera. One of the Sipho compounds of the invention are preferably acceptable for the naptera families known to infest companion animals is Puli Veterinary/pharmaceutical uses described herein. cidae Such as Archaeopsyllinae (cat and dog fleas), Spillop Of note are compounds of Formula 1 wherein syllinae (rabbit fleas), or the like. R" is H or C-C alkyl optionally substituted with one Of particular interest are the species Ctenocephalides, in Substituent selected from the group consisting of CN, 25 particular C. felis and C. canis, rat fleas (Xenopsylla cheopis) SMe and OMe. and human fleas (Pulex irritans). R is H or Me: For the purposes of this invention the terms ticks and mites R is H; and are meant to refer the blood-feeding arthropod parasites that R7 is H. belong to the order Acarina. From the Order Acarina, some of Of further note are: 30 the ticks and mites known to infest production and companion a) Compounds of Formula 1 wherein animals are, Argas spp., Ornithodoros spp., Dermanyssus R" is Me or Cl; gallinae, Boophilus spp., Rhipicephalus spp., Amblyomma R’ is C1, Br, CF. OCF. H. OCF, or OCHCF; and spp., Dermacentor spp., Hyalomma spp., Ixodes spp., Pso R is H, Me, Et, i-Pr, t-Bu, CHCN, CH(Me)CHSMe or roptes spp., Chorioptes spp., Sarcoptes spp., Cheyletiella C(Me),CHSMe. 35 spp., and the like. b) Compounds of a) above wherein There are two well-established families of ticks, the Ixo R’ is C1, Br, CF, or OCHCF: didae (hard ticks), and Argasidae (soft ticks). Ticks often R" is H, Me, Et or i-Pr; and produce injury after infestation of animals in three respects: R is H. direct damage caused by parasitism Such as local injury and c) Compounds ofb) wherein: 40 blood loss; by toxins injected by the parasites and by the R is Me: R is Br; R is Cl; R is Me. transmission of diseases. Especially in companion animals, Of further note are compounds of a, b, c above wherein R is ticks may be the Source of Zoonotic diseases. H; and R7 is H. For the purpose of this invention “lice' (singular: louse), A compound of special interest is: are ectoparasites of the order Phthiraptera. Among the 45 Phthiraptera families known to be parasites of animals are: Trichodectidae such as Bovicola bovis (important cattle-bit Br ing louse), B. ovis (sheep-biting louse) or B. equi (horsebiting louse): Haematopimidae such as Haematopinus suis (hog louse), or H. asini (horse Sucking louse); Linognathidae Such 50 as Linognathus Stenopsis (goat Sucking louse) or L. vituli O Y.M Me N C (long-nosed cattle louse); or the like. "Flies' are insects in the order Diptera, meaning “two NH winged’. True flies have one pair of wings used for flying. / \ Posterior to the wings is a pair of stalked knob-like structures O o 55 (called halteres), which are organs of balance. Flies undergo NC complete metamorphosis, i.e. the life cycle consists of the following stages: egg, larva (called a maggot), pupa, and N adult. Each stage of the life cycle may be a target for control H1 YMe and intervention. 60 Flies may be categorized into two functional categories or 3-bromo-1-(3-chloro-2-pyridinyl)-N-4-cyano-2-methyl “biting and “non-biting of which biting flies are the primary 6-(methylamino)carbonyl-phenyl)-1H-pyrazole-5-car focus here. boxamide. “Biting flies have specially adapted mouthparts well suited The preferred compositions of the present invention are for piercing the host animal integument. The stable fly Sto those, which comprise the above preferred compounds. The 65 moxys calcitrans is a good example of a biting fly. The stable preferred methods of use are those involving the above-pre fly has a proboscis which is used to pierce the skin and imbibe ferred compounds. blood. Both the males and the females are bloodfeeders. The US 8,932,613 B2 5 6 stable fly is often the only biting, blood-sucking fly breeding Embodiment 6 in any appreciable numbers in and around confined-animal production facilities. Another example of a biting fly is the The method or use of Embodiment 5 wherein the horn fly, Haematobia irritans irritans, which like the stable hematophageous ectoparasite is selected from the group con fly is a bloodsucker and has great economic impact. Like the sisting of fleas, ticks, lice, mites, and biting flies. stable fly the horn fly has piercing/Sucking mouthparts. A“parasiticidally effective amount' is the amount of active Embodiment 7 ingredient needed to achieve an observable effect diminish ing the occurrence or activity of the target parasite pest. One The method or use of any of the previous embodiments skilled in the art will appreciate that the parasitically effective 10 wherein the administering is oral. dose can vary for the various compounds and compositions of the present invention, the desired parasitical effect and dura Embodiment 8 tion, the target invertebrate pest species, the animal to be protected, the mode of application and the like, and the The method or of any of the previous embodiments amount needed to achieve a particular result can be deter 15 wherein the administering is parenteral. mined through simple experimentation “Treating or “Treatment as it applies to infestation refers Embodiment 9 to both the prevention and control of the infestation. “Parenteral as a mode of application means taken into the The method or use of any of the previous embodiments body or administered in a manner other than through the wherein the administering is topical. digestive tract, as by injection. “Enteral” as a mode of application means take into the Embodiment 10 body or administered through the digestive tract as by oral administration. 25 The method or use of any of the previous embodiments Embodiments of the present invention include: wherein the animal is a homeothermic animal.

Embodiment 1 Embodiment 10a The method or use described in the Summary of the Inven 30 The method or use of Embodiment 10 wherein the animal tion wherein the ectoparasitic insect is a hematophageous is a cat or dog. ectoparasitic insect Embodiment 11

Embodiment 2 35 The methodoruse of embodiment 10 wherein the animal is a herd animal. The method or use of as described in the Summary of the Invention wherein Embodiment 12 R" is Me or Cl; R’ is C1, Br, CF, OCFH, OCF, or OCHCF; and 40 The method or use of any of the previous embodiments R is H, Me, Et, i-Pr, t-Bu, CHCN, CH(Me)CHSMe or wherein the composition comprises at least one additional C(Me) CHSMe. component selected from the group consisting of solvents and/or carriers, emulsifiers and/or dispersing agents. Embodiment 3 45 Embodiment 13 The method or use of as described in the Summary of the The method or use of Embodiment 12 wherein the compo Invention wherein sition comprises at least one additional biologically active R’ is C1, Br, CF, or OCHCF; compound or agent. R is H, Me, Et or i-Pr; and 50 R is H. Embodiment 14

Embodiment 4 The method or use of Embodiment 13 wherein the addi 55 tional biologically active compound or agent is selected from The method or use of as described in the Summary of the the group consisting of macrocyclic lactones, acetyl cho Invention wherein the Compound is linesterase inhibitors, arthropod growth regulators, GABA 3-bromo-1-(3-chloro-2-pyridinyl)-N-4-cyano-2-methyl-6- gated chloride channel antagonists, mitochondrial electron (methylamino)carbonylphenyl)-1H-pyrazole-5-car transport inhibitors, nicotinic acetylcholine agonists/antago 60 nists/activator, oxidative phosphorylation inhibitors, anthel boxamide minthics, Sodium channel modulators or other antiparasitic compounds. Embodiment 5 Embodiment 15 The method or use of as described in the Summary of the 65 Invention or in any of the previous embodiments wherein the The method or use of Embodiment 14 wherein said bio ectoparasite is a hematophageous ectoparasite logically active compound is a macrocyclic lactone. US 8,932,613 B2 7 8 Embodiment 16 the manufacture of medicaments for the protection of an animal from aan invertebrate parasitic pest. The animals to be The method or use of Embodiment 14 wherein said bio protected include those delineated in any of Embodiments 10, logically active compound is an acetylcholinesterase inhibi 10a, or 11. The ectoparasitic insect pests include those delin tor selected from the group of and carbam eated in Embodiments 5 or 6. The medicament may be in oral, ates. topical or parenteral dosage forms. The invention is also understood to include compounds of Embodiment 17 Formula 1 or any of Embodiments 2, 3, or 4 for use in the manufacture of medicaments for the protection of an animal The method or use of Embodiment 14 wherein said bio 10 from an invertebrate parasitic pest. The animals to be pro logically active compound is an arthropod growth regulator tected include those delineated in any of Embodiments 10, selected from the group of chitin Synthesis inhibitors, ecdys 10a, or 11. The ectoparasitic insect pests include those delin one agonists/disruptors, lipid biosynthesis inhibitor and juve eated in Embodiments 5 or 6. The medicament may be in oral, nile hormone mimics. 15 topical or parenteral dosage forms. The invention is also understood to include compounds of Embodiment 18 Formula 1 or any of Embodiments 2, 3, or 4 packaged and presented for the protection of an animal from an invertebrate The method or use of Embodiment 14 wherein said bio parasitic pest. The animals to be protected include those logically active compound is a GABA-gated chloride channel delineated in any of Embodiments 10, 10a, or 11. The ecto antagonist. parasitic insect pests include those delineated in Embodi ments 5 or 6. The compounds of the invention may be pack Embodiment 19 aged and presented as oral, topical or parenteral dosage The method or use of Embodiment 14 wherein said bio forms. 25 The invention is also understood to include a process for logically active compound is a mitochondrial electron trans manufacturing a composition for protecting an animal from port inhibitor. an invertebrate parasitic pest characterized in that a com Embodiment 20 pound of Formula 1 is admixed with at least one pharmaceu tically or veterinarily acceptable carrier. The animals to be The method or use of Embodiment 14 wherein said bio 30 protected include those delineated in any of Embodiments 10, logically active compound is a nicotinic acetylcholine ago 10a, or 11. The ectoparasitic insect pests include those delin nist/antagonist/activator. eated in Embodiments 5 or 6. The compositions of the inven tion may be packaged and presented as oral, topical or Embodiment 21 parenteral dosage forms. 35 The compounds of Formula 1 which can be used according to The method or use of Embodiment 14 wherein said bio the invention, have an excellent action on ectoparasitic logically active compound is an oxidative phosphorylation insects, particularly hematophageous ectoparasitic insects. inhibitor. The compounds are uniquely adapted to enter and spread through the circulatory of the host whilst being very well Embodiment 22 40 tolerated by the animal. The invention thus represents a genu ine enrichment of the art. The method or use of Embodiment 14 wherein said bio The compounds according to the invention possess a good logically active compound is an anthelminthic. ectoparasiticidal activity, whilst being of low toxicity to ani mals. The compounds of Formula 1 can be prepared by the Embodiment 23 45 methods as described in US Patent Publication 2006/ 011 1403A1 (herein incorporated by reference to the extent The method or use of Embodiment 14 wherein said bio not inconsistent with the disclosure herein) and variations logically active compound is a sodium channel modulator. readily apparent to the skilled artisan. This invention relates to a method of controlling or preven Synthetic methods for the preparation of N-oxides of hetero tion infestations of an ectoparasite, preferably a hematoph 50 cycles and tertiary amines are very well known by one skilled ageous ectoparasite, on an animal by administering to the in the art including the oxidation of heterocycles and tertiary animal a composition comprising an parasiticidally effective amines with peroxy acids such as peracetic and m-chlorop amount of a compound of Formula 1, or an N-oxide, or a erbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydrop pharmaceutically or veterinarily acceptable salt thereof, eroxides Such as t-butyl hydroperoxide, Sodium perborate, The compounds of Formula 1 can be used for the protection 55 and dioxiranes such as dimethydroxirane. These methods for of an animal from an ectoparasitic insect by oral, topical or the preparation of N-oxides have been extensively described parenteral administration of the compound. and reviewed in the literature, see for example: T. L. Gilchrist Therefore, the invention is understood to include the com in Comprehensive Organic Synthesis, vol. 7, pp 748-750, S. pounds of Formula 1 (and compositions containing them) for V. Ley, Ed., Pergamon Press: M. Tisler and B. Stanovnik in use as an animal medicament, or more particularly a ecto 60 Comprehensive Heterocyclic Chemistry, vol. 3, pp 18-20, A. parasiticidal animal medicament. The animals to be protected J. Boulton and A. McKillop, Eds. Pergamon Press; M. R. include those delineated in any of Embodiments 10, 10a, or Grimmett and B. R. T. Keene in Advances in Heterocyclic 11. The ectoparasitic insect pests include those delineated in Chemistry, Vol. 43, pp 149-161, A. R. Katritzky, Ed., Aca Embodiments 5 or 6. The medicament may be in oral, topical demic Press: M. Tisler and B. Stanovnik in Advances in or parenteral dosage forms. 65 Heterocyclic Chemistry, vol. 9, pp. 285-291, A. R. Katritzky The invention is also understood to include the use of and A. J. Boulton, Eds. Academic Press; and G. W. H. compounds of Formula 1 or any of Embodiments 2, 3, or 4 in Cheeseman and E. S. G. Werstiuk in Advances in Heterocy

US 8,932,613 B2 16 TABLE 2-continued TABLE 3-continued R2 R2

O | MN O Y.M RI N R3 RI N R3 R6 NH / \ N NH N/ \ 10 O O o NC NC R7 R41NFN R41 N NH 15 RI R2 R3 R4 R6 RI R2 R3 R4 R7

Br C C Me F Me Br F Me F Me Br C Me F C Br F Me F C Br C Me F Br Br F Me F Br Br C Me F Me CF F i-Pir F Me CF C i-Pir F C CF F i-Pir F C CF C i-Pir F Br CF F i-Pir F Br CF C i-Pir F Me C F i-Pir F Me C C i-Pir F C C F i-Pir F C C C i-Pir F Br C F i-Pir F Br C C i-Pir F 25 Me Br F i-Pir F Me Br C i-Pir F C Br F i-Pir F C Br C i-Pir F Br Br F i-Pir F Br Br C i-Pir F Me CF C Me C Me CF C Me C C CF C Me C C CF C Me C Br CF C Me C Br CF C Me C Me C C Me C Me C C Me C 30 C C C Me C C C C Me C Br C C Me C Br C C Me C Me Br C Me C Me Br C Me C C Br C Me C C Br C Me C Br Br C Me C Br Br C Me C Me CF C i-Pir C Me CF C i-Pir C 35 C CF C i-Pir C C CF C i-Pir C Br CF C i-Pir C Br CF C i-Pir C Me C C i-Pir C C C C i-Pir C Me C C i-Pir C Br C C i-Pir C C C C i-Pir C Me Br C i-Pir C Br C C i-Pir C 40 C Br C i-Pir C Me Br C i-Pir C Br Br C i-Pir C C Br C i-Pir C Br Br C i-Pir C The invention described herein relates to a method of con

45 trolling or prevention of infestations of flies on an animal by TABLE 3 administering to the animalan insecticidally effective amount of a compound of Formula 1. R2 Administration of Compounds of the Invention The compounds of Formula 1 of this invention can be 50 O | MN applied to homeothermic animals in need of treatment or RI N R3 prevention of ectoparasitic infestation. Particularly contem plated are important agronomic or companion animals such cattle, sheep, horses, goats, pigs, llamas, camels, water buf NH N/ \ 55 falo, donkeys, rabbits, fallow deer, reindeer, minks, chinchil O las, ferrets, raccoons, chickens, geese, turkeys, ducks, dogs, NC R7 cats, mice rats, or the like. Herd animals such as cattle, sheep, N goats, horses, donkeys, camels, pigs, reindeer, caribou and R41NF buffalo may be treated. Humans may also be treated. 60 Any of the compounds of the present invention, or a Suit R R2 R3 R? R7 able combination of Such compounds, may be administered Me CF F Me F directly to the animal Subject and/or indirectly by applying it C CF F Me F Br CF F Me F to the local environment in which the animal dwells (such as Me C F Me F bedding, enclosures, or the like). Direct administration C C F Me F 65 includes contacting the skin, fur or feathers of a subject ani Br C F Me F mal with the compounds, or by feeding or injecting the com pounds into the animal. US 8,932,613 B2 17 18 Topical Administration advantageous for use on herd animals such as cattle, horses, When topical administration is required, the administra sheep or pigs, in which it is difficult or time-consuming to tion to the animal or the environment can be accomplished by treat all the animals by more labor intensive methods of way of non limiting example, by sprays, dusts, pour on treat administration. ments and controlled-release devices, such as ear tags and Oral Administration tapes, neck collars, ear tags, tail bands, limb bands or halters Compounds of the present invention can be delivered by which comprise compounds or compositions comprising ingestion to the animal to be protected After ingestion by the compounds of Formula 1. In addition to sprays and pour on animal to be protected, parasiticidally effective concentra treatments, application may be by other forms of topical tions of compounds of the invention in the bloodstream pro administration, for example, in the form of immersion or 10 tect the treated animal from blood-sucking pests such as fleas, dipping, washing, coating with powder, or application to a ticks and lice. Small area of the animal. Parenteral Administration Application of the compositions according to the invention The compound of Formula 1 may be administered by to the animals to be treated is done topically via Solutions, parenterally including by injection. Injections may be intra emulsions, Suspensions, (drenches), powders, and pour-on 15 venous, intramuscular or Subcutaneous. formulations. Compositions of the Invention The pour-on or spot-on method consists in applying the The compounds of the invention may be applied or admin compound of Formula 1 to a specific location of the skin or istered alone but are typically formulated into a veterinary or coat, advantageously to the neck or backbone of the animal. pharmaceutical composition. The compounds are prepared or This takes place e.g. by applying a Swab or spray of the formulated into compositions in a known manner, for pour-on or spot-on formulation to a relatively small area of example by extending the active compounds with solvents the coat, from where the active Substance is dispersed almost and/or carriers, if appropriate using emulsifiers and/or dis automatically over wide areas of the fur owing to the spread persing agents; if, for example, water is used as the diluent, ing nature of the components in the formulation and assisted organic solvents can, if appropriate, be used as auxiliary by the animal's movements. 25 Solvents. Importantly the compounds of Formula 1 may be indirectly Typically a parasiticidal composition according to the applied to an animal by applying it to the local environment in present invention comprises a mixture of a compound of which the animal dwells (such as bedding, enclosures, or the Formula 1 with one or more pharmaceutically or veterinarily like). Effective use rates will range from about 1.0 to 50 acceptable carriers comprising excipients and auxiliaries mg/square meter but as little as 0.1 mg/square meter may be 30 selected with regard to the intended route of administration Sufficient or as much as 150 mg/square meter may be (e.g., oral, topical or parenteral administration Such as injec required. One skilled in the art can easily determine the bio tion) and in accordance with standard practice. In addition, a logically effective amount necessary for the desired level of suitable carrier is selected on the basis of compatibility with . the one or more active ingredients in the composition, includ The invention notably provides a process for controlling 35 ing Such considerations as stability relative to pH and mois the hematophageous ectoparasites of Small mammals, and in ture content. Therefore of note is a composition for protecting particular cats and dogs, is treated by locally depositing on the an animal from an ectoparasitic pest comprising a parasiti skin, preferably localized over a Small Surface area (spot-on cally effective amount of a compound of the invention and at application) It is preferable for the treatment according to the least one carrier. invention to be carried out every one, two or, three months on 40 Formulations for topical administration are typically in the cats and dogs. form of a powder, cream, Suspension, spray, emulsion, foam, The compounds of the present invention may be adminis paste, aerosol, ointment, salve or gel. A topical formulation tered in a controlled release form, e.g., in a subcutaneous slow may be a water-soluble solution, which can be in the form of release formulation, or in the form of a controlled release a concentrate that is diluted before use. Parasiticidal compo device affixed to an animal such as a fleacollar. Collars for the 45 sitions Suitable for topical administration typically comprise controlled release of an agent for long term pro a compound of the present invention and one or more topi tection against flea infestation in a companion animal are cally suitable carriers. art-known, and are described, for example, by U.S. Pat. No. In applications of a parasiticidal composition topically to 3,852,416, U.S. Pat. No. 4,224,901, U.S. Pat. No. 5,555,848 the exterior of an animal as a line or spot (i.e. 'spot-on' and U.S. Pat. No. 5,184,573. 50 treatment), the active ingredient migrates over the Surface of Large animals particularly herd animals are efficiently the animal to cover most or all of its external Surface area. As treated by a variety of methods well known in the art. a result, the treated animal is particularly protected from Whole-animal sprays provide rapid relief from fly pres invertebrate pests that feed off the epidermis of the animal Sure. Animal sprays are applied either as a dilute coarse spray, such as ticks, fleas and lice. Therefore formulations for topi often applied under high pressure to Soak the skin, or as a fine 55 cal localized administration often comprise at least one low-volume, more concentrated mist. organic solvent to facilitate transport of the active ingredient Self-applicating devices include back rubber covered with over the skin and/or penetration into the epidermis of the an absorbent material treated with an insecticide-oil solution, animal. Pour-on or spot-on formulations Suitably contain car or dust bags filled with an insecticidal dust. Back rubbers and riers, which promote rapid dispersement over the skin Surface dustbags should be placed in gateways, near water and feed 60 or in the coat of the host animal, and are generally regarded as Source, and in other areas where animals will make frequent spreading oils. Suitable carriers are e.g. oily solutions; alco contact with them. holic and isopropanolic Solutions such as solutions of 2-oc Controlled-release ear tags and tapes are generally very tyldodecanol or oleyl alcohol; Solutions in esters of monocar effective for fly control in certain farm areas. boxylic acids, such as isopropyl myristate, isopropyl Pour-on treatments involves the application of an insecti 65 palmitate, lauric acid oxalate, oleic acid oleyl ester, oleic acid cide along the backline of the animalata prescribed dosage of decyl ester, hexyl laurate, oleyl oleate, decyl oleate, capric topical products. The pour-on or spot-on method is especially acid esters of Saturated fatalcohols of chain length C-Cs; US 8,932,613 B2 19 20 solutions of esters of dicarboxylic acids, such as dibutyl able additional ingredients are stabilizers such as antioxi phthalate, diisopropyl isophthalate, adipic acid diisopropyl dants, spreading agents, preservatives, adhesion promoters, ester, di-n-butyladipate or also solutions of esters of aliphatic active solubilisers such as oleic acid, viscosity modifiers, UV acids, e.g. glycols. It may be advantageous for a dispersing blockers or absorbers, and colourants. Surface active agents, agent to be additionally present, such as one known from the including anionic, cationic, non-ionic and ampholytic Surface pharmaceutical or cosmetic industry. Examples are 2-pyrroli active agents, can also be included in these formulations. done, 2-(N-alkyl)pyrrolidone, acetone, polyethylene glycol The formulations of this invention often include an antioxi and the ethers and esters thereof, propylene glycol or Syn dant, such as BHT (butylated hydroxytoluene). The antioxi thetic triglycerides. dant is generally present in amounts of at 0.005-5% (w/v) a The oily Solutions include e.g. Vegetable oils such as olive 10 oil, groundnut oil, Sesame oil, pine oil, linseed oil or castor proportion of from 0.005 to 1% (w/v) is often used, with 0.01 oil. The vegetable oils may also be present in epoxidised to 0.05% often preferred. form. Paraffins and silicone oils may also be used. The compositions according to the invention intended for It may be advantageous for a crystallization inhibitor or a pets, in particular cats and dogs, are generally applied by dispersant known from the pharmaceutical or cosmetic indus 15 being deposited onto the skin (“spot-on' or "pour-on' appli try also to be present. cation); this is generally a localized application overa Surface A pour-on or spot-on formulation generally contains 1 to 20% area of less than 10 cm, especially of between 5 and 10cm, by weight of a compound of Formula 1, 0.1 to 50% by weight in particular at two points and preferably localized between of dispersing agent and 45 to 98.9% by weight of solvent. the animals shoulders. Once deposited, the composition dif The compositions for spot-on application can advanta fuses, in particular over the animal's entire body, and then geously comprise: (a) a crystallization inhibitor, in particular dries without crystallizing or modifying the appearance (in one which is present in a proportion of from 1 to 20% (w/v), particular absence of any whitish deposit or dusty appear preferably from 5 to 15%, this inhibitor satisfying the test ance) or the feel of the fur. The compositions for spot-on according to which: 0.3 ml of 10% (w/v) of a compound of application according to the invention are particularly advan Formula 1 in the solvent defined in (c) below, along with 10% 25 tageous owing to their efficacy, their speed of action and the of this inhibitor, are deposited on a glass slide at 20°C. for 24 pleasant appearance of the animal’s fur after application and hours, after which it is observed with the naked eye that there drying. are few or no crystals, in particular fewer than 10 crystals, AS organic solvent (b) which can be used in the invention, preferably 0 crystals on the glass slide, (b) an organic Solvent mention may be made in particular of acetone, acetonitrile, having a dielectric constant of between 10 and 35, preferably 30 benzyl alcohol, butyl diglycol, dimethylacetamide, dimeth of between 20 and 30, the content of this solvent (b) in the ylformamide, dipropylene glycol n-butyl ether, ethanol, iso overall composition preferably representing the difference to propanol, methanol, ethylene glycol monoethyl ether, ethyl make the composition up to 100%, ene glycol monomethyl ether, monomethylacetamide, (c) an organic cosolvent having a boiling point of below 100'. dipropylene glycol monomethyl ether, liquid polyoxyethyl C., preferably of below 80°C., and having a dielectric con 35 stant of between 10 and 40, preferably of between 20 and 30; ene glycols, propylene glycol, 2-pyrrolidone, in particular this cosolvent may advantageously be present in the compo N-methylpyrrolidone, diethylene glycol monoethyl ether, sition in a (c)/b) weight/weight (w/w) ratio of between 1/15 ethylene glycol and diethyl phthalate, or a mixture of at least and 1/2. The solvent is volatile, so as to serve in particular as two of these solvents. As crystallization inhibitor (a) which a drying promoter, and is miscible with water and/or with the 40 can be used in the invention, mention may be made in par solvent (b). ticular of polyvinylpyrrolidone, polyvinyl alcohols, copoly A pour-on formulation may also be prepared for control of mers of vinyl acetate and vinylpyrrolidone, polyethylene gly parasites in an animal of agricultural worth. The pour-on cols, benzyl alcohol, mannitol, glycerol, Sorbitol, formulations of this invention can be in the form of a liquid, polyoxyethylenated Sorbitan esters; lecithin, Sodium car powder, emulsion, foam, paste, aerosol, ointment, Salve or 45 boxymethylcellulose, acrylic derivatives such as methacry gel. Typically, the pour-on formulation is liquid. These pour lates and the like, anionic Surfactants such as alkaline Stear on formulations can be effectively applied to sheep, cattle, ates, in particular sodium, potassium or ammonium Stearate; goats, other ruminants, camelids, pigs and horses. The pour calcium Stearate; triethanolamine Stearate; sodium abietate; on formulation is typically applied by pouring in one or alkyl Sulphates, in particular Sodium lauryl Sulphate and several lines or in a spot-on the dorsal midline (back) or 50 Sodium cetyl Sulphate; sodium dodecylbenzenesulphonate, shoulder of an animal. More typically, the formulation is Sodium dioctylsulphosuccinate; fatty acids, in particular applied by pouring it along the back of the animal, following those derived from coconut oil, cationic Surfactants such as the spine. The formulation can also be applied to the animal water-soluble quaternary ammonium salts of formula by other conventional methods, including wiping an impreg NR'R"R"R",Y in which the radicals R are optionally nated material over at least a small area of the animal, or 55 hydroxylated hydrocarbon radicals and Y is an anion of a applying it using a commercially available applicator, by strong acid Such as the halide, Sulphate and Sulphonate means of a syringe, by spraying or by using a spray race. The anions; cetyltrimethylammonium bromide is among the cat pour-on formulations include a carrier and can also include ionic Surfactants which can be used, amine salts of formula one or more additional ingredients. Examples of Suitable NR'R"R" in which the radicals R are optionally hydroxy additional ingredients are stabilizers such as antioxidants, 60 lated hydrocarbon radicals; octadecylamine hydrochloride is spreading agents, preservatives, adhesion promoters, active among the cationic Surfactants which can be used, nonionic solubilisers such as oleic acid, viscosity modifiers, UV block Surfactants such as optionally polyoxyethylenated Sorbitan ers or absorbers, and colourants. Surface active agents, esters, in particular polysorbate 80, polyoxyethylenated alkyl including anionic, cationic, non-ionic and ampholytic Surface ethers; polyethylene glycol Stearate, polyoxyethylenated active agents, can also be included in these formulations. 65 derivatives of castor oil, polyglycerol esters, polyoxyethyl The pour-on formulations include a carrier and can also enated fatty alcohols, polyoxyethylenated fatty acids, copoly include one or more additional ingredients. Examples of Suit mers of ethylene oxide and propylene oxide, amphoteric Sur US 8,932,613 B2 21 22 factants such as Substituted lauryl compounds of betaine, or to administer to the animala dose of from 0.1 to 40 mg/kg and preferably a mixture of at least two of these crystallization in particular from 1 to 30 mg/kg. Administration may be given inhibitors. as a single dose or intermittent in time and may be adminis In a particularly preferred manner, a crystallization inhibi tered daily, weekly, monthly, bimonthly or quarterly in order tor couple, namely the combination of a film-forming agent of 5 to achieve effective results in order to achieve effective polymeric type and a Surfactant, will be used. These agents results. will be chosen in particular from the compounds mentioned Nevertheless it can at times be necessary to deviate from as crystallization inhibitor b). the amounts mentioned, and in particular to do so in accor Among the film-forming agents of polymeric type which dance with the body weight of the test animal and/or the are particularly advantageous, mention may be made of the 10 method of application, but also because of the species of various grades of polyvinylpyrrolidone, polyvinyl alcohols, animal and its individual behavior towards the medicament, and copolymers of vinyl acetate and vinylpyrrolidone. As or the nature of the formulation of the latter and the time or regards the Surfactants, mention will be made most particu interval at which it is administered. Thus it can suffice in some larly of nonionic Surfactants, preferably polyoxyethylenated cases to manage with less than the above mentioned mini Sorbitan esters and in particular the various grades of polysor 15 mum amount while in other cases the upper limit mentioned bate, for example polysorbate 80. must be exceeded. Where substantial amounts are applied, it The film-forming agent and the Surfactant may be incor can be advisable to divide these into several individual admin porated, in particular, in similar or identical amounts within istrations over the course of the day. The general sense of the the limit of the total amounts of crystallization inhibitor men other statements made above also applies. tioned elsewhere. For parenteral administration including intravenous, intra The couple thus produced ensures the objectives of muscular and Subcutaneous injection, a compound of the absence of crystallization on the hairs and maintenance of the present invention can beformulated in Suspension, Solution or cosmetic appearance of the coatina note-worthy manner, that emulsion in oily or aqueous vehicles, and may contain is to say without any tendency towards stickiness or to a sticky adjuncts Such as Suspending, stabilizing and/or dispersing appearance, despite the high concentration of active material. 25 agents. The compounds of the present invention may also be As cosolvent (c), mention may be made in particular of formulated for bolus injection or continuous infusion. Phar absolute ethanol, isopropanol, methanol. maceutical compositions for injection include aqueous solu As antioxidant, standard agents are used in particular, Such tions preferably in physiologically compatible buffers con as: butylhydroxyanisole, butylhydroxytoluene, ascorbic acid, taining other excipients or auxiliaries as are known in the art Sodium metabisulphite, propyl gallate and sodium thiosul 30 of pharmaceutical formulation. Additionally, Suspensions of phate, or a mixture of not more than two of these agents. the active compounds may be prepared in a lipophilic vehicle. The compositions for spot-on application according to the Suitable lipophilic vehicles include fatty oils such as sesame invention are usually prepared by simple mixing of the con oil, synthetic fatty acid esters such as ethyl oleate and trig stituents as defined earlier, advantageously, to begin with, the lycerides, or materials such as liposomes. Aqueous injection active material is mixed in the main solvent and the other 35 Suspensions may contain Substances that increase the viscos ingredients or adjuvants are then added. ity of the Suspension, such as sodium carboxymethyl cellu The volume applied may be from about 0.3 to 5 ml, pref lose, sorbitol, or dextran. Formulations for injection may be erably about 0.5 ml for cats, and from about 0.3 to 3 ml for presented in unit dosage form, e.g., in ampoules or in multi dogs, according to the weight of the animal. dose containers. Alternatively, the active ingredient may be in The composition according to the invention may be in the 40 powder form for constitution with a suitable vehicle, e.g., form of a concentrated emulsion, Suspension or solution for sterile, pyrogen-free water, before use. spot-on application to a small area of the animal's skin, gen In addition to the formulations described supra, the com erally between the two shoulders (spot-on type solution). In a pounds of the present invention may also be formulated as a another aspect of the invention forms of Solution or Suspen depot preparation. Such long acting formulations may be sion to be sprayed, forms of solution, Suspension or emulsion 45 administered by implantation (for example, Subcutaneously to be poured or spread onto the animal (pour-on type solution) or intramuscularly) or by intramuscular or Subcutaneous an oil, a cream, an ointment or any other fluid formulation for injection. The compounds of the present invention may be topical administration may be provided. formulated for this route of administration with suitable poly Other delivery systems for relatively hydrophobic pharma meric or hydrophobic materials (for instance, in an emulsion ceutical compounds may be employed. Liposomes and emul 50 with a pharmacologically acceptable oil), with ion exchange sions are well-known examples of delivery vehicles or carri resins, or as a sparingly soluble derivative such as, without ers for hydrophobic drugs. In addition, organic Solvents such limitation, a sparingly soluble salt. as dimethylsulfoxide may be used. For administration by inhalation, the compounds of the The compounds of Formula 1 are generally present in the present invention can be delivered in the form of an aerosol compositions in concentrations of 0.1 to 95 percent by 55 spray using a pressurized pack or a nebulizer and a Suitable weight, preferably 0.5 to 90 percent by weight. Preparations propellant, e.g., without limitation, dichlorodifluoromethane, which are intended for direct application contain the active trichlorofluoromethane, dichlorotetrafluoroethane or carbon compound according to the invention in concentrations of dioxide. In the case of a pressurized aerosol, the dosage unit between 0.001 and 5 percent by weight, preferably 0.005 to 3 may be controlled by providing a valve to deliver a metered percent by weight. 60 amount. Capsules and cartridges of for example, gelatin for Dosages may range from 0.0001 mg/kg of animal body use in an inhaler or insufflator may be formulated containing weight to about 1000 mg/kg. of the compound of Formula 1. a powder mix of the compound and a suitable powder base Sometimes dosages may be from 0.1 mg/kg of animal body Such as lactose or starch. weight to about 200 mg/kg. Often times it would be advan Compounds of the present invention can be delivered by tageous to administer amounts of about 0.01 to about 100 mg 65 ingestion to the animal to be protected. After ingestion by the or between 0.02 to about 50 mg/kg. and frequently between animal to be protected, parasiticidally effective concentra 0.1 and 75 mg/kg. Preferably, the treatment is carried out so as tions of compounds of the invention in the bloodstream pro US 8,932,613 B2 23 24 tect the treated animal from blood-sucking pests such as fleas, can be advisable to divide these into several individual admin ticks and lice. Therefore of note is a composition for protect istrations over the course of the day. The general sense of the ing an animal from an invertebrate parasite pest in a form for other statements made above also applies. oral administration (i.e. comprising, in addition to a parasiti The Compositions of the Invention May Comprise Additional cidally effective amount of a compound of the invention, one 5 Active Compounds: or more carriers selected from binders and fillers suitable for It is contemplated that additional biologically active com oral administration and feed concentrate carriers). pounds may be administered at the same time or separately For oral administration in the form of solutions (the most over time to obtain broader spectrum of parasitic control. readily available form for absorption), emulsions, Suspen Such additional biologically active compounds may be pack sions, pastes, gels, capsules, tablets, boluses, powders, gran- 10 aged together with the compound of Formula 1 as a kit. For ules, rumen-retention and feed/water/lick blocks, a com convenience sake such additional biologically active com pound of the present invention can be formulated with pounds may be formulated into the same composition con binders/fillers known in the art to be suitable for oral admin taining the compound of Formula 1 and are selected both with istration compositions, such as Sugars and Sugar derivatives respect to the parasites needing control as well as the Suitabil (e.g., lactose, Sucrose, mannitol, Sorbitol), starch (e.g., maize 15 ity of the compound in the mode of administration (oral, starch, wheat starch, rice starch, potato starch), cellulose and parenteral, topical etc.) Therefore the present invention con derivatives (e.g., methylcellulose, carboxymethylcellulose, templates the use of compositions characterised in that they ethylhydroxycellulose), protein derivatives (e.g., Zein, gela contain, in addition to a compound of Formula 1, further tin), and synthetic polymers (e.g., polyvinyl alcohol, polyvi auxiliaries and/or active compounds. Such as additional bio nylpyrrolidone). If desired, lubricants (e.g., magnesium Stear- 20 logically active compounds, disinfectants (I the case of topi ate), disintegrating agents (e.g., cross-linked cal application) or antibiotics may be admixed to the formu polyvinylpyrrolidinone, agar, alginic acid) and dyes or pig lations, or the ready-to-use solutions, in addition to the ments can be added. Pastes and gels often also contain adhe customary Solid or liquid extenders, diluents and/or surface sives (e.g., acacia, alginic acid, bentonite, cellulose, Xanthan active agents. gum, colloidal magnesium aluminum silicate) to aid in keep- 25 Of note are additional biologically active compounds or ing the composition in contact with the oral cavity and not agents selected from art-known anthelmintics, such as, for being easily ejected. example, avermectins (e.g. ivermectin, moxidectin, milbe If the parasiticidal compositions are in the form of feed mycin), benzimidazoles (e.g. albendazole, triclabendazole), concentrates, the carrier is typically selected from high-per salicylanilides (e.g. closantel, oxyclozanide), Substituted formance feed, feed cereals or protein concentrates. Such 30 phenols (e.g. nitroxynil), pyrimidines (e.g. pyrantel), imida feed concentrate-containing compositions can, in addition to Zothiazoles (e.g. levamisole) and praziquantel. the parasiticidal active ingredients, comprise additives pro Other biologically active compounds or agents useful in moting animal health or growth, improving quality of meat the compositions of the present invention can be selected from animals for slaughter or otherwise useful to animal from Insect Growth Regulators (IGRs) and Juvenile Hor husbandry. These additives can include, for example, vita- 35 mone Analogues (JHAS) Such as , triflumuron, mins, antibiotics, chemotherapeutics, bacteriostats, fung fluaZuron, cyromazine, , etc., thereby providing istats, coccidiostats and hormones. both initial and Sustained control of parasites (at all stages of The compounds of Formula 1 are generally present in the insect development, including eggs) on the animal Subject, as compositions in concentrations of 0.1 to 95 percent by well as within the environment of the animal subject. weight, preferably 0.5 to 90 percent by weight. Preparations 40 The compounds of Formula 1 according to the invention which are intended for direct application contain the active may be used alone or in combination with other biocides. compound according to the invention in concentrations of They may be combined with pesticides having the same between 0.001 and 5 percent by weight, preferably 0.005 to 3 sphere of activity e.g. to increase activity, or with Substances percent by weight. having another sphere of activity e.g. to broaden the range of Dosages may range from 0.0001 mg/kg of animal body 45 activity. It can also be sensible to add so-called repellents. If weight to about 1000 mg/kg. of the compound of Formula 1. the range of activity is to be extended to endoparasites, e.g. Sometimes dosages may be from 0.1 mg/kg of animal body wormers, the compounds of Formula 1 are suitably combined weight to about 200 mg/kg. Often times it would be advan with Substances having endoparasitic properties. Of course, tageous to administer amounts of about 0.01 to about 100 mg they can also be used in combination with antibacterial com or between 0.02 to about 50 mg/kg. and frequently between 50 positions. 0.1 and 75 mg/kg. Preferably, the treatment is carried out so as Preferred groups of combination partners and especially to administer to the animala dose of from 0.1 to 40 mg/kg and preferred combination partners are named in the following, in particular from 1 to 30 mg/kg. Administration may be given whereby combinations may contain one or more of these as a single dose or intermittent in time and may be adminis partners in addition to a compound of Formula 1. tered daily, weekly, monthly, bimonthly or quarterly in order 55 Suitable partners in the mixture may be biocides, e.g. the to achieve effective results in order to achieve effective insecticides and acaricides with a varying mechanism of results. activity, which are named in the following and have been Nevertheless it can at times be necessary to deviate from known to the person skilled in the art for a long time, e.g. the amounts mentioned, and in particular to do so in accor chitin synthesis inhibitors, growth regulators; active ingredi dance with the body weight of the test animal and/or the 60 ents which act as juvenile hormones; active ingredients which method of application, but also because of the species of act as adulticides; broad-band insecticides, broad-band aca animal and its individual behavior towards the medicament, ricides and nematicides; and also the well known anthelmin or the nature of the formulation of the latter and the time or thics and insect- and/or acarid-deterring Substances, and also interval at which it is administered. Thus it can suffice in some repellents or detachers. cases to manage with less than the above mentioned mini- 65 Examples of Such biologically active compounds include but mum amount while in other cases the upper limit mentioned are not restricted to the following: Organophosphates, a class must be exceeded. Where substantial amounts are applied, it which are generally know to be inhibitors of acetylcholinest US 8,932,613 B2 25 26 erase: , , azinphos-ethyl, azinphos-me benomyl, bialaphos, blasticidin-S, Bordeaux mixture, bro thyl, bromophos, bromophos-ethyl, cadusafos, chlorethoxy muconazole, bupirimate, carpropamid, captafol, captan, car phos, , , chlormephos, demeton, bendazim, chlorfenazole, chloroneb, chloropicrin, chlorotha demeton-S-methyl, demeton-S-methyl sulphone, dialifos, lonil, chloZolinate, copper oxychloride, copper salts, , , , , , cyflufenamid, cymoxanil, cyproconazole, cyprodinil, cypro , ethoprophos, etrimfos, famphur, , feni furam, RH-7281, diclocymet, diclobutrazole, diclomezine, trothion, fensulfothion, , flupyrazofos, , for dicloran, difenoconazole, RP-407213, dimethomorph, mothion, fosthiazate, heptenophos, isaZophos, isothioate, domoxystrobin, diniconazole, diniconazole-M, dodine, , , methacriphos, , edifenphos, epoxiconazole, famoxadone, fenamidone, fena , methyl-, , monocroto 10 rimol, fenbuconazole, fencaramid, fenpiclonil, fenpropidin, phos, , , oxydemeton-methyl, , par fenpropimorph, fentin acetate, fluazinam, fludioxonil, flume athion, parathion-methyl, , , , tover, flumorf7flumorlin, fentin hydroxide, fluoxastrobin, flu phosphocarb, , , , , pir quinconazole, flusilazole, flutolanil, flutriafol, folpet, fosetyl imiphos, pirimiphos-methyl, , propaphos, proet aluminium, furalaxyl, furametapyr, hexaconazole, amphos, prothiofos, pyraclofos, pyridapenthion, , 15 ipconazole, iprobenfos, iprodione, isoprothiolane, kasuga Sulprophos, temephos, , , tetrachlorvin mycin, krSoxim-methyl, mancoZeb, maneb, mefenoxam, phos, thimeton, triaZophos, trichlorfon, Vamidothion. mepronil, metalaxyl, metconazole, metominostrobin/fe , a class which are generally known to be inhibi nominostrobin, metrafenone, myclobutanil, neo-asozin, tors of acetylcholinesterase: alanycarb, , 2-sec-bu nicobifen, orysastrobin, oxadixyl, penconazole, pencycuron, tylphenyl methylcarbamate, benfuracarb, , carbofu probenazole, prochloraz, propamocarb, propioconazole, pro ran, , cloethocarb, ethiofencarb, , quinazid, prothioconazole, pyrifenox, pyraclostrobin, fenthiocarb, furathiocarb, HCN-801, isoprocarb, indoxacarb, pyrimethanil, pyroquilon, quinoxyfen, Spiroxamine, Sulfur, , , 5 methyl-m-cumenylbutyryl(methyl) tebuconazole, tetrconazole, thiabendazole, thifluZamide, , oxamyi, , , thiodicarb, thio thiophanate-methyl, thiram, tiadinil, triadimefon, triadime fanox, triazamate, UC-51717 , a class which are 25 nol, tricyclazole, trifioxystrobin, triticonazole, validamycin, generally known to be modulators of Sodium channels: acri Vinclozin Biological agents: Bacillus thuringiensis ssp alza nathin, allethrin, alphametrin, 5-benzyl-3-furylmethyl (E)- wai, kurstaki, Bacillus thuringiensis delta endotoxin, bacu (1R)-cis-2,2-dimethyl-3-(2-oxothiolan-3-ylidenemethyl)cy lovirus, entomopathogenic bacteria, virus and fungi Bacteri clopropanecarboxylate, , 8 , cyfluthrin, cides: chlortetracycline, oxytetracycline, Streptomycin, oc-, 8-cypermethrin, , bioallethrin 30 Additional more specific examples of partnerinsecticides and ((S)—I cyclopentylisomer), bioresmethrin, bifenthrin, NCI acaricides are listed below: 85193, cycloprothrin, , cythithrin, , , , , ethofenproX, fen fluthrin, fempropathrin, , flucythrinate, , Compound Class fluvalinate (D isomer), , cyhalothrin, \-cyhalo 35 Compound Class thrin, , , , (natural Abamectin macrocyclic lactones products), , , , theta AC3O3 630 energy production modulator cypermethrin, , T-fluvalinate, , tralom Acephate acetylcholinesterase inhibitor ethrin, Zeta-cypermethrin. sodium channel modulator Alanycarb acetylcholinesterase inhibitor Arthropod growth regulators including: a) chitin synthesis 40 Aldicarb acetylcholinesterase inhibitor inhibitors: : chlorfluaZuron, diflubenzuron, alpha.-Cypermethrin sodium channel modulator fluaZuron, flucycloXuron, , hexaflumuron, Alphamethrin sodium channel modulator Amitraz octopamine receptor ligand lufenuron, novaluron, teflubenZuron, triflumuron, bupro Avermectin macrocyclic lactones fezin, diofenolan, hexythiazox, etoxazole, chlorfentazine; b) AZinphos A acetylcholinesterase inhibitor ecdysone agonists/disruptors: halofenozide, methoxy 45 Azinphos M acetylcholinesterase inhibitor fenozide, ; c) juvenoid hormone mimcs: AZinphos-methyl acetylcholinesterase inhibitor , methoprene, fenoxycarb; d) lipid biosynthesis AZOcyclotin oxidative phosphorylation inhibitor Bacilius Subiii. toxin inhibitors: Spirodiclofen. Other antiparasitics: acequinocyl. acetylcholinesterase inhibitor amitraz, AKD-1022, ANS-118, azadirachtin, Bacillus thur Benfuracarb acetylcholinesterase inhibitor ingiensis, benSultap, bifenazate, binapacryl, bromopropylate, 50 Bensultap nicotinic acetylcholine agonistantagonist beta.-Cyfluthrin sodium channel modulator BTG-504, IBTG-505, camphechlor, cartap, chlorobenzilate, Bifenthrin sodium channel modulator , chlorfenapyr, chromafenozide, clothiani Brofenprox sodium channel modulator dine, cyromazine, diacloden, diafenthiuron, DBI-3204, Bromophos A acetylcholinesterase inhibitor dinactin, dihydroxymethyldihydroxypyrrolidine, dinobuton, Bufencarb acetylcholinesterase inhibitor dinocap, , ethiprole, ethofenproX, fenaZaquin, flu 55 chitin synthesis inhibitor Butocarboxin acetylcholinesterase inhibitor mite, MTI-800, fenpyroximate, fluacrypyrim, flubenzimine, Cadusafos acetylcholinesterase inhibitor flubrocythrinate, flufenzine, flufenprox, fluproxyfen, Carbaryl acetylcholinesterase inhibitor halofenprox, , IKI-220, kanemite, NC-196, acetylcholinesterase inhibitor Carbophenthion acetylcholinesterase inhibitor neem guard, nidinorterfuran, nitenpyram, SD-35651, Cartap nicotinic acetylcholine agonistantagonist WL-108477, pirydaryl, propargite, protrifenbute, 60 Chloethocarb acetylcholinesterase inhibitor pymethrozine, pyridaben, pyrimidifen, NC-11 11, R-195, acetylcholinesterase inhibitor RH-0345, RH-2485, RYI-210, S-1283, S-1833, S1-8601, Chlorfeinapyr oxidative phosphorylation inhibitor Chlorfluazuron chitin synthesis inhibitor Silafluofen, silomadine, spinosad, tebufenpyrad, , Chlormephos acetylcholinesterase inhibitor tetranactin, , thiocyclam, , tolfen Chlorpyrifos acetylcholinesterase inhibitor pyrad, triaZamate, triethoxyspinosyn, trinactin, Verbutin, Ver 65 Cis-Resmethrin sodium channel modulator talec, Y1-5301 Fungicides: acilbenzolar, aldimorph, ampropy Clofentezine lfos, andoprim, azaconazole, azoxystrobin, benalaxyl, US 8,932,613 B2 27 28 -continued -continued

Compound Class Compound Class Compound Class Compound Class acetylcholinesterase inhibitor Milbemectin macrocyclic lactones Cycloprothrin sodium channel modulator Moxidectin macrocyclic lactones Cyfluthrin sodium channel modulator Naled acetylcholinesterase inhibitor Cyhexatin oxidative phosphorylation inhibitor NI-25, nicotinic acetylcholine agonistantagonist D 2341 (bifenazate) Nitenpyram nicotinic acetylcholine agonistantagonist Deltamethrin sodium channel modulator Nodulisporic acid derivatives macrocyclic lactones Demeton M acetylcholinesterase inhibitor 10 Omethoat acetylcholinesterase inhibitor Demeton S acetylcholinesterase inhibitor acetylcholinesterase inhibitor Demeton-S-methyl acetylcholinesterase inhibitor Oxydemethon M acetylcholinesterase inhibitor Dichlofenthion acetylcholinesterase inhibitor Oxydeprofos acetylcholinesterase inhibitor Dicliphos acetylcholinesterase inhibitor Parathion acetylcholinesterase inhibitor Diethion acetylcholinesterase inhibitor Parathion-methyl acetylcholinesterase inhibitor Diflubenzuron chitin synthesis inhibitor 15 Permethrin sodium channel modulator Dimethoate acetylcholinesterase inhibitor Phenthoate acetylcholinesterase inhibitor Dimethylvinphos acetylcholinesterase inhibitor Phorat acetylcholinesterase inhibitor acetylcholinesterase inhibitor Phosalone acetylcholinesterase inhibitor Doramectin macrocyclic lactones Phosmet acetylcholinesterase inhibitor DPX-MP062 (indoxacarb) sodium channel modulator Phoxim acetylcholinesterase inhibitor Edifenphos acetylcholinesterase inhibitor Pirimicarb acetylcholinesterase inhibitor Emamectin macrocyclic lactones Pirimiphos A acetylcholinesterase inhibitor Endosulfan gaba-gated chloride channel antagonist Pirimiphos M acetylcholinesterase inhibitor Eprinomectin macrocyclic lactones Promecarb acetylcholinesterase inhibitor Esfenvalerate sodium channel modulator Propaphos acetylcholinesterase inhibitor Ethiofencarb acetylcholinesterase inhibitor Propoxur acetylcholinesterase inhibitor Ethion acetylcholinesterase inhibitor Prothiofos acetylcholinesterase inhibitor Ethofenprox sodium channel modulator 25 Prothoat acetylcholinesterase inhibitor Ethoprophos acetylcholinesterase inhibitor Pyrachlophos acetylcholinesterase inhibitor Etrimphos acetylcholinesterase inhibitor Pyradaphenthion acetylcholinesterase inhibitor Fenamiphos acetylcholinesterase inhibitor Pyresmethrin sodium channel modulator Fenazaquin mitochondrial electron transport inhibitor Pyrethrim sodium channel modulator Fenbutatin oxide oxidative phosphorylation inhibitor acetylcholinesterase inhibitor 30 Pyridaben mitochondrial electron transport inhibitor (BPMC) acetylcholinesterase inhibitor Pyrimidifen mitochondrial electron transport inhibitor Fenothiocarb acetylcholinesterase inhibitor Pyriproxyfen juvenile hormone mimic Fenoxycarb juvenile hormone mimic RH 5992 ecclysone agonist sodium channel modulator RH-2485 ecclysone agonist Fenpyrad mitochondrial electron transport inhibitor Salithion acetylcholinesterase inhibitor Fenpyroximate mitochondrial electron transport inhibitor 35 Selamectin macrocyclic lactones Fenthion acetylcholinesterase inhibitor Silafluofen sodium channel modulator Fenvalerate sodium channel modulator Spinosad nicotinic acetylcholine activator gaba-gated chloride channel antagonist Sulfotep acetylcholinesterase inhibitor Fluazinam oxidative phosphorylation uncoupler Sulprofos acetylcholinesterase inhibitor Fuazuron chitin synthesis inhibitor Tebufenozide ecclysone agonist Flucycloxuron chitin synthesis inhibitor 40 Tebufenpyrad mitochondrial electron transport inhibitor Flucythrinate sodium channel modulator Tebupirimphos acetylcholinesterase inhibitor Fufenoxuron chitin synthesis inhibitor Teflubenzuron chitin synthesis inhibitor Flufenprox sodium channel modulator Tefluthrin sodium channel modulator Fonophos acetylcholinesterase inhibitor Temephos acetylcholinesterase inhibitor acetylcholinesterase inhibitor Fosthiazate acetylcholinesterase inhibitor Terbufos acetylcholinesterase inhibitor HCH gaba-gated chloride channel antagonist 45 acetylcholinesterase inhibitor Heptenophos acetylcholinesterase inhibitor Thiafenox Hexaflumuron chitin synthesis inhibitor Thiodicarb acetylcholinesterase inhibitor Hexythiazox acetylcholinesterase inhibitor juvenile hormone mimic Thionazin acetylcholinesterase inhibitor midacloprid nicotinic acetylcholine agonistantagonist Thuringiensin insect-active fungi 50 Trailomethrin sodium channel modulator insect-active nematodes Triarathen insect-active viruses Triazamate acetylcholinesterase inhibitor probenfos acetylcholinesterase inhibitor Triazophos acetylcholinesterase inhibitor Sofenphos acetylcholinesterase inhibitor Trichlorfon acetylcholinesterase inhibitor Soprocarb acetylcholinesterase inhibitor Trifumuron chitin synthesis inhibitor Soxathion acetylcholinesterase inhibitor 55 Trimethacarb acetylcholinesterase inhibitor vermectin chloride channel activator Vamidothion acetylcholinesterase inhibitor ambda.-Cyhalothrin sodium channel modulator XMC (3,5,-Xylyl- acetylcholinesterase inhibitor Lufenuron chitin synthesis inhibitor methylcarbamate) Malathion acetylcholinesterase inhibitor Xylylcarb acetylcholinesterase inhibitor Mecarbam acetylcholinesterase inhibitor YI 5301/53O2 Mesulfenphos acetylcholinesterase inhibitor 60 Zeta.-Cypermethrin sodium channel modulator Metaldehyd Zetamethrin sodium channel modulator Methamidophos acetylcholinesterase inhibitor Methiocarb acetylcholinesterase inhibitor Methomyl acetylcholinesterase inhibitor Methoprene juvenile hormone mimic Non-limitative examples of suitable anthelminthics are acetylcholinesterase inhibitor 65 named in the following, a few representatives have insecti Mevlinphos acetylcholinesterase inhibitor cidal and acaricidal activity in addition to the anthelminthic activity, and are partly already in the above list. US 8,932,613 B2 29 30 (A1) Praziquantel-2-cyclohexylcarbonyl-4-oxo-1,2,3,6,7, (VIII) S.S'-(2-dimethylaminotrimethylene)-bis(thiocarbam 11b-hexahydro-O-4H-pyrazino.2, 1-alpha. isoquinoline ate) (Cartap), from The Pesticide Manual, 11. Sup.thEd. (A2) Closantel-3,5-diiodo-N-5-chloro-2-methyl-4-(a-cy (1997), The British Crop Protection Council, London, page ano-4-chlorob-enzyl)phenyl-Salicylamide 193; (A3) Triclabendazole=5-chloro-6-(2,3-dichlorophenoxy)-2- (IX) 1-3,5-Dichloro-4-(3-chloro-5-trifluoromethyl-2-py methylthio-1H-benzimidazole ridyloxy)phe-nyl-3-(2,6-difluorobenzoyl)-urea (Chlorflua (A4) Levamisol=L-(+2,3,5,6-tetrahydro-6-phenylimidazo[2. Zuron), from The Pesticide Manual, 11. Sup.thEd. (1997), The 1bthiazo-le British Crop Protection Council, London, page 213; (A5) Mebendazole=(5-benzoyl-1H-benzimidazol-2-yl)car (X) O.O-diethyl-O-3,5,6-trichloro-2-pyridyl-phosphorothio baminic acid methylester 10 ate (Chlorpyrifos), from The Pesticide Manual, 11. Sup.thEd. (A6) Omphalotin a macrocyclic fermentation product of the (1997), The British Crop Protection Council, London, page fungus Omphalotus olearius described In WO97/20857 235; (A7) Abamectin–avermectin B1 (XI) (RS)-alpha.-cyano-4-fluoro-3-phenoxybenzyl-(1RS, (A8) Ivermectin-22,23-dihydroavermectin B1 3RS;1RS,3RS)-3-(2,2-dichlorovinyl)-2,2-di-methylcyclo (A9) Moxidectin=5-O-demethyl-28-deoxy-25-(1,3-dim 15 propanecarboxylate (Cyfluthrin), from The Pesticide ethyl-1-butenyl)-6-28-epoxy-23-(methoxyimino)-milbe Manual, 11...sup.thEd. (1997), The British Crop Protection mycin B Council, London, page 293; (A10) Doramectin-25-cyclohexyl-5-O-demethyl-25-de(1- (XII) Mixture of (S)-alpha.-cyano-3-phenoxybenzyl-(Z)- methylpropyl)-a-Vermectin Ala (1R,3R)-3-(2-1-chloro-3,3,3-trifluoropropenyl)-2,2-dimeth (A11) Milbemectin-mixture of milbemycin A3 and milbe ylcyclopropanecarboxylate and (R)-.alpha.-cyano-3-phe mycin A4 noxybenzyl-(Z)-(1R,3)-3-(2-chloro-3,3,3-trifluorop (A12) Milbemycinoxim=5-oxime of milbemectin ropenyl)-2,2-dimethylcyclopropanecarboxylate (Lambda Non-Limitative Examples of Suitable Repellents and Detach Cyhalothrin), from The Pesticide Manual, 11. Sup.thEd. CS a 25 (1997), The British Crop Protection Council, London, page (R1) DEET (N,N-diethyl-m-toluamide) 300; (R2) KBR 3023 N-butyl-2-oxycarbonyl-(2-hydroxy)-piperi (XIII) Racemate consisting of (S)-alpha.-cyano-3-phenoxy dine benzyl-(2)-1-(1R,3R)-3-(2,2-dichlorovinyl)-2,2-dimethyl (R3) Cymiazole=N.-2,3-dihydro-3-methyl-1,3-thiazol-2- cyclopropanecarboxylate and (R)-alpha.-cyano-3-phenoxy ylidene-2,4-Xy-lidene 30 benzyl-(1S,3S)-3-(2,2-dichlorovinyl)-2,2-dimet The aforementioned partners in the mixture are best known hylcyclopropanecarboxylate (Alpha-cypermethrin), from to specialists in this field. Most are described in various edi tions of the Pesticide Manual, The British Crop Protection The Pesticide Manual, 11...sup.thEd. (1997), The British Crop Council, London, and others in the various editions of The Protection Council, London, page 308; Merck Index, Merck & Co., Inc., Rahway, N.J., USA or in 35 (XIV) a mixture of the stereoisomers of (S)-alpha.-cyano-3- patent literature. Therefore, the following listing is restricted phenoxy-benzyl (1RS,3RS.1 RS,3RS)-3-(2,2-dichlorovi to a few places where they may be found by way of example. nyl)-2,2-dimethylcyclopropaneca-rboxylate (Zeta-Cyper (I) 2-Methyl-2-(methylthio)propionaldehyde-O-methylcar methrin), from The Pesticide Manual, 11...sup.thEd. (1997), bamoyloxime (Aldicarb), from The Pesticide Manual, The British Crop Protection Council, London, page 314: 11...sup.th Ed. (1997), The British Crop Protection Council, 40 (XV) (S)-alpha.-cyano-3-phenoxybenzyl-(1R,3R)-3-(2,2- London, page 26: dibromovinyl)-1-2.2-dimethylcyclopropanecarboxylate (II) S-(3,4-dihydro-4-oxobenzod-1,2,3-triazin-3-ylm (Deltamethrin), from The Pesticide Manual, 11. Sup.thEd. ethyl)O.O-di-methyl-phosphorodithioate (AZinphos-me (1997), The British Crop Protection Council, London, page thyl), from The Pesticide Manual, 11...sup.thEd. (1997), The 344; British Crop Protection Council, London, page 67: 45 (XVI) (4-chlorophenyl)-3-(2,6-difluorobenzoyl)urea (Di (III) Ethyl-N-2,3-dihydro-2,2-dimethylbenzofuran-7- flubenzuron), from The Pesticide Manual, 11. Sup.thEd. yloxycarbonyl-(-methyl)aminothio-N-isopropyl-..beta.- (1997), The British Crop Protection Council, London, page alaninate (Benfuracarb), from The Pesticide Manual, 395; 11...sup.thEd. (1997), The British Crop Protection Council, (XVII) (1,4,5,6,7,7-Hexachloro-8,9,10-trinorborn-5-en-2,3- London, page 96: 50 ylenebism-ethylene)-sulphite (Endosulfan), from The Pesti (IV) 2-Methylbiphenyl-3-ylmethyl-(Z)-(1RS)-cis-3-(2- cide Manual, 11...sup.thEd. (1997), The British Crop Protec chloro-3,3,3-tr-ifluoroprop-1-enyl)-2,2-dimethylcyclopro tion Council, London, page 459: panecarboxylate (Bifenthrin), from The Pesticide Manual, (XVIII) ..alpha.-ethylthio-o-tolyl-methylcarbamate 11...sup.thEd. (1997), The British Crop Protection Council, (Ethiofencarb), from The Pesticide Manual, 11. Sup.thEd. London, page 118; 55 (1997), The British Crop Protection Council, London, page (V) 2-tert-butylimino-3-isopropyl-5-phenyl-1,3,5-thiadiaz 479; ian-4-one (Buprofezin), from The Pesticide Manual, (XIX) O,O-dimethyl-O-4-nitro-m-tolyl-phosphorothioate 11...sup.thEd. (1997), The British Crop Protection Council, (Fenitrothion), from The Pesticide Manual, 11. Sup.thEd. London, page 157: (1997), The British Crop Protection Council, London, page (VI) 2.3-Dihydro-2,2-dimethylbenzofuran-7-yl-methylcar 60 514; bamate (Carbofuran), from The Pesticide Manual, (XX) 2-sec-butylphenyl-methylcarbamate (Fenobucarb). 11...sup.thEd. (1997), The British Crop Protection Council, from The Pesticide Manual, 11...sup.thEd. (1997), The British London, page 186: Crop Protection Council, London, page 516; (VII) 2.3-Dihydro-2,2-dimethylbenzofuran-7-yl-(dibuty (XXI) (RS)-alpha.-cyano-3-phenoxybenzyl-(RS)-2-(4- laminothio)met-hylcarbamate (Carbosulfan), from The Pes 65 chlorophenyl)-3-methylbutyrate (Fenvalerate), from The ticide Manual, 11...sup.thEd. (1997), The British Crop Protec Pesticide Manual, 11...sup.thEd. (1997), The British Crop Pro tion Council, London, page 188; tection Council, London, page 539; US 8,932,613 B2 31 32 (XXII) S-formyl(methyl)carbamoylmethyl-O.O-dimethyl drazide (Tebufenozide), from The Pesticide Manual, phosphorodith-ioate (Formothion), from The Pesticide 11...sup.thEd. (1997), The British Crop Protection Council, Manual, 11...sup.thEd. (1997), The British Crop Protection London, page 1147; Council, London, page 625; (XLI) (...+-)-5-amino-1-(2,6-dichloro-alpha...alpha...alpha.- (XXIII) 4-Methylthio-3,5-xylyl-methylcarbamate (Methio triflu-oro-p-tolyl)-4-trifluoromethyl-sulphinylpyrazol-3-car carb), from The Pesticide Manual, 11...sup.thEd. (1997), The bonitrile (Fipronil), from The Pesticide Manual, 11. Sup.thEd. British Crop Protection Council, London, page 813; (1997), The British Crop Protection Council, London, page (XXIV) 7-Chlorobicyclo[3.2.0]hepta-2,6-dien-6-yl-dimeth 545; ylphosphate (Heptenophos), from The Pesticide Manual, (XLII) (RS)-alpha.-cyano-4-fluoro-3-phenoxybenzyl(1RS, 10 3RS:1 RS,3RS)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclo 11...sup.thEd. (1997), The British Crop Protection Council, propanecarboxylate (beta-Cyfluthrin), from The Pesticide London, page 670; Manual, 11...sup.thEd. (1997), The British Crop Protection (XXV) 1-(6-chloro-3-pyridylmethyl)-N-nitroimidazolidin Council, London, page 295; 2-ylidenamin-e (), from The Pesticide Manual, (XLIII) (4-ethoxyphenyl)-3-(4-fluoro-3-phenoxyphenyl) 11...sup.thEd. (1997), The British Crop Protection Council, 15 propyl (dimet-hyl)silane (Silafluofen), from The Pesticide London, page 706; Manual, 11...sup.thEd. (1997), The British Crop Protection (XXVI) 2-isopropylphenyl-methylcarbamate (Isoprocarb). Council, London, page 1105; from The Pesticide Manual, 11...sup.thEd. (1997), The British (XLIV) tert.-butyl (E)-alpha.-(1,3-dimethyl-5-phenoxy Crop Protection Council, London, page 729; pyrazol-4-yl-methylenamino-oxy)-p-toluate (Fenpyroxi (XXVII) O.S.-dimethyl-phosphoramidothioate (Methami mate), from The Pesticide Manual, 11...sup.thEd. (1997), The dophos), from The Pesticide Manual, 11...sup.thEd. (1997), British Crop Protection Council, London, page 530; (XLV) The British Crop Protection Council, London, page 808; 2-tert-butyl-5-(4-tert-butylbenzylthio)-4-chloropyridazin (XXVIII) S-Methyl-N-(methylcarbamoyloxy)thioacetimi 3-(2H)-one (Pyridaben), from The Pesticide Manual, date (Methomyl), from The Pesticide Manual, 11...sup.thEd. 11...sup.thEd. (1997), The British Crop Protection Council, (1997), The British Crop Protection Council, London, page 25 London, page 1161; 815; (XLVI) 4-4-(1,1-dimethylphenyl)phenylethoxy-quinazo (XXIX) Methyl-3-(dimethoxyphosphinoyloxy)but-2-enoate line (Fenazaquin), from The Pesticide Manual, 11. Sup.thEd. (Mevinphos), from The Pesticide Manual, 11...sup.thEd. (1997), The British Crop Protection Council, London, page (1997), The British Crop Protection Council, London, page 507; 844; 30 (XLVII) 4-phenoxyphenyl-(RS)-2-(pyridyloxy)propyl-ether (XXX) O.O-diethyl-O-4-nitrophenyl-phosphorothioate (Par (Pyriproxyfen), from The Pesticide Manual, 11. Sup.thEd. athion), from The Pesticide Manual, 11. Sup.thEd. (1997), (1997), The British Crop Protection Council, London, page The British Crop Protection Council, London, page 926; 1073; (XXXI) O.O-dimethyl-O-4-nitrophenyl-phosphorothioate (XLVIII) 5-chloro-N-(2-4-(2-ethoxyethyl)-2,3-dimeth (Parathion-methyl), from The Pesticide Manual, 35 ylphenoxyethyl-}-6-ethylpyrimidine-4-amine (Pyrimid 11...sup.thEd. (1997), The British Crop Protection Council, ifen), from The Pesticide Manual, 11...sup.thEd. (1997), The London, page 928; British Crop Protection Council, London, page 1070; (XXXII) S-6-chloro-2,3-dihydro-2-oxo-1,3-benzoxazol-3- (XLIX) (E)-N-(6-chloro-3-pyridylmethyl)-N-ethyl-N'-me ylmethyl-O.O-diethyl-phosphordithioate (Phosalone), from thyl-2-nitrovi-nylidenediamine (Nitenpyram), from The Pes The Pesticide Manual, 11...sup.thEd. (1997), The British Crop 40 ticide Manual, 11...sup.thEd. (1997), The British Crop Protec Protection Council, London, page 963: tion Council, London, page 880; (XXXIII) 2-Dimethylamino-5,6-dimethylpyrimidin-4-yl (L) (E)-N.sup. 1-(6-chloro-3-pyridyl)methyl-N. Sup.2-cy dimethylcarbama- to (Pirimicarb), from The Pesticide ano-N. Sup.1-methylacetamidine (NI-25, Acetamiprid), from Manual, 11...sup.thEd. (1997), The British Crop Protection The Pesticide Manual, 11...sup.thEd. (1997), The British Crop Council, London, page 985; 45 Protection Council, London, page 9; (XXXIV) 2-isopropoxyphenyl-methylcarbamate (Pro (LI) Avermectin B. sub.1, from The Pesticide Manual, poxur), from The Pesticide Manual, 11...sup.thEd. (1997), The 11...sup.thEd. (1997), The British Crop Protection Council, British Crop Protection Council, London, page 1036; London, page 3: (XXXV) 1-(3,5-dichloro-2,4-difluorophenyl)-3-(2,6-difluo (LII) an insect-active extract from a plant, especially (2R,6aS, robenzoyl)u-rea (TeflubenZuron), from The Pesticide 50 12aS)-1.2.6.6a, 12.12a-hexhydro-2-isopropenyl-8.9- Manual, 11...sup.thEd. (1997), The British Crop Protection dimethoxy-chrome-no3,4-bfuro2.3-hchromen-6-one Council, London, page 1158; (Rotenone), from The Pesticide Manual, 11...sup.thEd. (1997), (XXXVI) S-tert-butylthiomethyl-O.O-dimethyl-phospho The British Crop Protection Council, London, page 1097; and rodithioate (Terbufos), from The Pesticide Manual, an extract from Azadirachta indica, especially azadirachtin, 11...sup.thEd. (1997), The British Crop Protection Council, 55 from The Pesticide Manual, 11...sup.thEd. (1997), The British London, page 1165; Crop Protection Council, London, page 59; and (XXXVII) ethyl-(3-tert-butyl-1-dimethylcarbamoyl-1H-1, (LII) a preparation which contains insect-active nematodes, 2,4-triazol-5-yl-thio)-acetate. (Triazamate), from The Pesti preferably Heterorhabditis bactedophora and Heterorhabdi cide Manual, 11...sup.thEd. (1997), The British Crop Protec tismegidis, from The Pesticide Manual, 11...sup.thEd. (1997), tion Council, London, page 1224, 60 The British Crop Protection Council, London, page 671; (XXXVIII) Abamectin, from The Pesticide Manual, Steinemema feltiae, from The Pesticide Manual, 11. Sup.thEd. 11...sup.thEd. (1997), The British Crop Protection Council, (1997), The British Crop Protection Council, London, page London, page 3: 1115 and Steinemema scapted sci, from The Pesticide (XXXIX) 2-sec-butylphenyl-methylcarbamate (Fenobu Manual, 11...sup.thEd. (1997), The British Crop Protection carb), from The Pesticide Manual, 11...sup.thEd. (1997), The 65 Council, London, page 1116; British Crop Protection Council, London, page 516; (XL) (LIV) a preparation obtainable from Bacillus subtilis, from N-tert-butyl-N'-(4-ethylbenzoyl)-3,5-dimethylbenzohy The Pesticide Manual, 11...sup.thEd. (1997), The British Crop US 8,932,613 B2 33 34 Protection Council, London, page 72; or from a strain of cattle. About 100 adults were introduced into a mesh cage Bacillus thuringiensis with the exception of compounds iso (30x30x30 cm) containing one cotton gauze (4x4x1 cm) lated from GC91 or from NCTC 11821; The Pesticide soaked in one blood/insecticide concentration. There were 3 Manual, 11...sup.thEd. (1997), The British Crop Protection replicate cages of each blood/insecticide concentration. Council, London, page 73; 5 Blood gauzes were replaced every 12 hours. The untreated (LV) a preparation which contains insect-active fungi, pref control cages received untreated decoagulated blood. All cages were labelled and stored for 72 hours at 25-27°C. in the erably Verticillium lecanii, from The Pesticide Manual, dark at ambient relative humidity (70-85%). Every 12 hours 11...sup.th Ed. (1997), The British Crop Protection Council, the numbers of dead flies were counted in each cage. At 72-96 London, page 1266, Beauveda broginiartii, from The Pesti hours all flies were counted and percentage mortality was cide Manual, 11...sup.thEd. (1997), The British Crop Protec 10 tion Council, London, page 85 and Beauveda bassiana, from calculated. Data was subjected to log-probitanalysis to deter The Pesticide Manual, 11...sup.thEd. (1997), The British Crop mine the LCso if there is a dose response in the assay. Protection Council, London, page 83: (LVI) a preparation which contains insect-active viruses, Adult H. irritans exigua feeding assay preferably Neodipridon Sertifer NPV, from The Pesticide 15 Manual, 11...sup.thEd. (1997), The British Crop Protection % Adult mortality Council, London, page 1342; Mamestra brassicae NPV. from Exposure time The Pesticide Manual, 11...sup.thEd. (1997), The British Crop Protection Council, London, page 759 and Cydia pomonella Compound Concentration 7r 17 hir 24hr granulosis virus, from The Pesticide Manual, 11...sup.thEd. Test compound 600 ppb 8O.S 94.7 96.5 400 ppb 78.8 89.8 94.9 (1997), The British Crop Protection Council, London, page 200 ppb 77.3 78.8 80.3 291; Ivermectin 600 ppb 86.O 95.5 1OO.O (CLXXXI) 7-chloro-2,3,4a,5-tetrahydro-2-methoxycarbo 400 ppb 80.1 94.2 98.0 nyl(4-trifluor-omethoxyphenyl)-carbamoylindol1.2eox 200 ppb 78.5 91.8 93.1 azoline-4-a-carboxylate (DPX-MP062, Indoxycarb), from 25 Control Mortality 10.8 16.8 21.O The Pesticide Manual, 11...sup.thEd. (1997), The British Crop Protection Council, London, page 453; (CLXXXII) N-tert-butyl-N'-(3,5-dimethylbenzoyl)-3- Test B methoxy-2-methyl-Ibenzohydrazide (RH-2485, Methoxy fenozide), from The Pesticide Manual, 11. Sup.thEd. (1997), 30 Adult A. aegypti Contact Assay The British Crop Protection Council, London, page 1094; and (CLXXXIII) (N'-(4-methoxy-biphenyl-3-yl-hydrazinecar Adult A. aegypti were exposed to six rates of the positive boxylic acid isopropylester (D 2341), from Brighton Crop control compound permethrin and the experimental com Protection Conference, 1996, 487-493: (R2) Book of pounds diluted with acetone. The dilutions of test compound Abstracts, 212th ACS National Meeting Orlando, Fla., Aug. 35 (3-bromo-1-(3-chloro-2-pyridinyl)-N-4-cyano-2-methyl-6- 25-29 (1996), AGRO-020. Publisher: American Chemical (methylamino)carbonylphenyl)-1H-pyrazole-5-carboxam Society, Washington, D.C. CONEN: 63BFAF. ide)used were 0 ppm (acetone only), 0.1 ppm, 1 ppm, 10 ppm, As a rule, the anthelminthic compositions according to the 20 ppm, 50 ppm, 100 ppm, 500 ppm and 1000 ppm. Each rate invention contain 0.1 to 99% by weight, especially 0.1 to 95% was replicated 5 times. The test was conducted in 100 mL by weight of active ingredient of Formula 1 mixtures thereof, 40 conical flasks. The entire inside of the flasks was coated with 99.9 to 1% by weight, especially 99.8 to 5% by weight of a Coatasil the day before the treatments are applied. A 0.5 ml solid or liquid admixture, including 0 to 25% by weight, aliquot of each rate was applied to the bases only of the flasks. especially 0.1 to 25% by weight of a surfactant. At 24 hours after the surfaces had been treated adult A. As noted above, in another embodiment of the process aegypti were anaesthetised using food grade carbon dioxide according to the invention, compounds of Formula 1 and the 45 and 10 mosquitoes were introduced to each conical flask and additional compounds noted hereinbefore may be applied in the mouths of the flasks covered with parafilm. Small holes a distinct and separate manner over time. were made in the parafilm to allow gas exchange. The bioas The following TESTS demonstrate the control efficacy of say was run for 8 hrs at 25+2° C. and relative humidity of compounds of this invention on specific pests. The pest con approximately 70%. trol protection afforded by the compounds is not limited, 50 however, to these species. Mosquito adults A. aegypti contact assay BIOLOGICAL, EXAMPLES OF THE INVENTION Compound LC50 (ug?flask) LC90 (ug?flask) Test A 55 Test compound O.O2S O.O33 Permethrin O.O2S O.046 Adult H. irritans exigua Feeding Assay Untreated control mortality - 6% Ablood meal assay was used to determine the LCso for test compound (3-bromo-1-(3-chloro-2-pyridinyl)-N-4-cyano 60 Test C 2-methyl-6-(methylamino)carbonylphenyl)-1H-pyrazole 5-carboxamide) on adult H. irritans exigua. Six (6) serial In Vivo Evaluation Against Artificial Infestations dilutions of the test compound were prepared in decoagulated with Cat Fleas (C. felis) and Brown Dog Ticks (R. bovine blood that was stored refrigerated. Ivermectin was Sanguineus) on Dogs included as a positive control compound and a negative con 65 trol was included in each assay. Flies were collected with a net Twenty five dogs were used in this study that investigated the immediately before each assay from yarded commercial efficacy of test compound (3-bromo-1-(3-chloro-2-pyridi US 8,932,613 B2 35 36 nyl)-N-4-cyano-2-methyl-6-(methylamino)carbonylphe ing the first 9 days after application, this dropped to below nyl)-1H-pyrazole-5-carboxamide) 90% by day 16 and below 70% by day 30. against fleas and ticks. Two groups (one treated and one untreated) of five dogs were used to evaluate the flea efficacy Test D whilst two groups offive dogs (one treated and one untreated) 5 were used to investigate the tick efficacy. The dogs in the In Vivo Evaluation Against Artificial Infestations respective groups were infested weekly with 40 unfed adult with Cat Fleas (C. felis) on Mice ticks and 100 cat fleas. One group was treated with ADVAN For evaluating control of the cat flea (Ctenocephalides felis TIX and served as a positive control. The dogs in this group Bouche), a CD-1(R) mouse (about 30 g. male, obtained from were infested simultaneously with fleas and ticks. Test com- 10 Charles River Laboratories, Wilmington, Mass.) was orally pound was formulated in NMP. The treatment was applied dosed with test compound in an amount of 10 mg/kg Solubi topically via Syringe on the dorsal line of the animals as a lized in propylene glycol/glycerol formal (60:40). Two hours line-on at 60 mg/kg dose rate. The efficacy of the compound after oral administration of the test compound, approximately was assessed by weekly tick and flea counts. The weekly 8 to 16 adult fleas were applied to each mouse. The fleas were counts generated in the treated groups were compared to the 15 then evaluated for mortality 48 hours after flea application to positive and negative untreated control (UTC) group counts the mouse. to evaluate efficacy of Test compound. 3-bromo-1-(3-chloro-2-pyridinyl)-N-4-cyano-2-methyl-6- (methylamino)carbonylphenyl)-1H-pyrazole-5-carboxam In Vivo Evaluation Against Artificial Infestations ide caused 45% mortality. with C. felis and R. sanguineus on Dogs 2O Although the present invention and its advantages have been described in detail, it should be understood that various changes, Substitutions and alterations can be made herein without departing from the spirit and scope of the invention as Group Treatment Day 2 Day 9 Day 16 Day 23 Day 29 defined by the appended claims. What is claimed is: Flea efficacy (%) compared to the untreated control 25 1. A method of controlling infestation of an ectoparasite 4 Test 99.6 99.7 99.7 98.7 97.3 selected from the group consisting of fleas and ticks on a compound homeothermic animal which is either a dog or cat by topical 5 ADVANTIX 1OO 100 89.0 76.7 69.1 spot on administration to the animal, a composition compris UTC Vehicle 57.0 73.8 78.2 76.4 73.2 ing a parasiticidally effective amount of the compound (Mean # (NMP) 30 of fleas) Tick efficacy (%) compared to the untreated control Br 3 Test 74.O 94.9 95.0 90.6 86.2 compound 5 ADVANTIX 44.0 99.3 89.7 84.2 79.7 35 UTC Vehicle 1O.O 27.6 25.2 27.8 24.6 O Y.M (Mean # (NMP) Me N C of ticks) NH Small numbers of engorged ticks were found on dogs in both a \ \ the experimental and positive control treatment groups at all O o assessment times. Test compound provided a similar level of NC protection against ticks to that of the positive control product ADVANTIX, with slightly lower numbers of live ticks col H1 NYMe lected from the dogs during all but one assessment over the 30 as day period. At 48 hours after treatment, the test compound achieved 74% efficacy compared to the negative control. This or an N-oxide or a pharmaceutically or veterinarily accept result was 30% higher than the ADVANTIX that gave 44% able salt thereof; wherein the parasiticidally effective amount efficacy. Test compound provided over 94.9%, 90.5% and of the compound is between 0.1 mg/kg to 200 mg/kg of 90.6% efficacy at 9, 16 and 23 days post-treatment which was so animal body weight and wherein the control offleas and ticks a level of control similar to the ADVANTIX with 99.3%, persists for at least thirty days. 89.7% and 84.2% respectively. The test compound continued 2. The method of claim 1 wherein the animal is a cat. to provide a high level of protection at 30 days post treatment, 3. The method of claim 1 wherein the animal is a dog. with 86.2% efficacy compared to 79.7% provided by the 4. The method of any of claims 1, 2 or 3 wherein the ADVANTIX. 55 composition comprises an additional component selected Overall, the test compound treatment was more effective from the group consisting of Solvents and/or carriers, emul against fleas than the positive control product, with over sifiers and/or dispersing agents. 99.5% efficacy during the first three assessments at 2, 9 and 16 5. The method of claim 1 wherein the compound is neither days post-treatment and 97.3% efficacy at 30 days post-treat an N-oxide or a salt. ment. Although the ADVANTIX achieved 100% efficacy dur