WO2009003075A1 - Animal pest control method - Google Patents

Animal pest control method Download PDF

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Publication number
WO2009003075A1
WO2009003075A1 PCT/US2008/068268 US2008068268W WO2009003075A1 WO 2009003075 A1 WO2009003075 A1 WO 2009003075A1 US 2008068268 W US2008068268 W US 2008068268W WO 2009003075 A1 WO2009003075 A1 WO 2009003075A1
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WO
WIPO (PCT)
Prior art keywords
nhch
sme
alkyl
haloalkyl
formula
Prior art date
Application number
PCT/US2008/068268
Other languages
French (fr)
Inventor
George Philip Lahm
Jeffrey Keith Long
Ming Xu
Original Assignee
E.I. Du Pont De Nemours And Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=40003056&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2009003075(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to CN200880019716A priority Critical patent/CN101743000A/en
Priority to EP08771978.7A priority patent/EP2182945B1/en
Priority to KR1020107001744A priority patent/KR101714059B1/en
Priority to KR1020157020688A priority patent/KR101714291B1/en
Priority to SI200831504T priority patent/SI2182945T1/en
Priority to JP2010515096A priority patent/JP6006471B2/en
Priority to MX2015011173A priority patent/MX361762B/en
Priority to MX2014010553A priority patent/MX368680B/en
Priority to CA2685072A priority patent/CA2685072C/en
Priority to ES08771978.7T priority patent/ES2549731T3/en
Priority to MX2009013748A priority patent/MX2009013748A/en
Priority to AU2008268321A priority patent/AU2008268321C1/en
Priority to US12/663,848 priority patent/US11278533B2/en
Priority to DK08771978.7T priority patent/DK2182945T3/en
Application filed by E.I. Du Pont De Nemours And Company filed Critical E.I. Du Pont De Nemours And Company
Priority to EP17206287.9A priority patent/EP3351243A1/en
Priority to RU2010102529/15A priority patent/RU2508102C2/en
Priority to KR1020167030535A priority patent/KR101769728B1/en
Priority to BRPI0810929A priority patent/BRPI0810929B8/en
Publication of WO2009003075A1 publication Critical patent/WO2009003075A1/en
Priority to AU2014259503A priority patent/AU2014259503C1/en
Priority to HRP20150978TT priority patent/HRP20150978T1/en
Priority to US15/207,999 priority patent/US20160317520A1/en
Priority to AU2017203941A priority patent/AU2017203941A1/en
Priority to AU2017204816A priority patent/AU2017204816A1/en
Priority to US16/103,836 priority patent/US20180353494A1/en
Priority to AU2018220081A priority patent/AU2018220081A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0029—Parenteral nutrition; Parenteral nutrition compositions as drug carriers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides

Definitions

  • This invention relates to a method for protecting an animal from a parasitic pest and parasitic pest infestation.
  • PCT Patent Publication WO 05/085216 discloses isoxazoline derivatives of Formula i as insecticides
  • each of A 1 , A 2 and A 3 are independently C or N; G is a benzene ring; W is O or S; and X is halogen or C ⁇ -Cg haloalkyl.
  • This invention pertains to a method for protecting animals from a parasitic invertebrate pest comprising orally or parenterally administering to the animal a pesticidally effective amount of a compound of Formula 1 (including all geometric and steroisomers), an JV-oxide or a salt thereof
  • R 1 is halogen, C 1 -C 3 haloalkyl or C 1 -C 3 haloalkoxy
  • R 2 is H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or cyano
  • R 3 is H, halogen, Q-C 3 haloalkyl or C 1 -C 3 haloalkoxy
  • R 4 is halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 haloalkoxy;
  • R 5 is H, CH 3 , C 2 -C 4 alkylcarbonyl, C 2 -C 4 haloalkylcarbonyl, C 2 -C 5 alkoxycarbonyl or CH 2 O(C 1 -C 3 alkyl);
  • R 6 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl or C 3 -C 6 halocycloalkyl, each group substituted with one R 7 ; or R 6 is (CH 2 ) J11 Q;
  • Q is a 4- to 6-membered saturated ring containing carbon atoms and one O or S(O) n as ring members and optionally substituted with 1 or 2 R 8a and one R 8 * 5 ;
  • R 7 is OR 9 , S(O) n R 10 or C(O)NR 11 R 12 ; or R 7 is pyridine or thiazole, each optionally substituted with 1 or 2 R 15 ;
  • each R 8a is independently halogen, cyano or C 1 -C 2 alkyl;
  • R 8b is OR 9 , S(O) n R 10 or C(O)NR 11 R 12 ;
  • R 9 is H, CHO, C 2 -C 4 alkylcarbonyl, C 2 -C 4 haloalkylcarbonyl or C 2 -C 5 alkoxycarbonyl; or
  • R 9 is C 1 -C 4 alkyl or C 1 -C 4 haloalkyl, each optionally substituted with one R 13 ; or
  • R 9 is pyridine or thiazole, each optionally substituted with 1 or 2 R 15 ;
  • R 10 is C 1 -C 4 alkyl or C 1 -C 4 haloalkyl, each optionally substituted with one R 13 ; or
  • R 10 is pyridine or thiazole, each optionally substituted with 1 or 2 R 15 ;
  • R 11 is H, CHO, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, CH 2 O(C 1 -C 3 alkyl), C 2 -C 4 alkylcarbonyl, C 2 -C 4 haloalkylcarbonyl or C 2 -C 5 alkoxycarbonyl;
  • R 12 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 3 -C 6 cycloalkyl, each optionally substituted with one R 13 ; or
  • R 12 is H, C 3 -C 6 alkenyl, C 3 -C 6 haloalkenyl, C 3 -C 6 alkynyl or OR 14 ;
  • R 13 is cyano, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, OH
  • This invention also relates to such method wherein the parasitic invertebrate pest or its environment is contacted with a composition comprising a biologically effective amount of a compound of Formula 1, an JV-oxide or a salt thereof, and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, said composition optionally further comprising a biologically effective amount of at least one additional biologically active compound or agent.
  • This invention further provides a method for treating, preventing, inhibiting and/or killing ecto- and/or endoparasites comprising administering to and/or on the animal a pesticidally effective amount of a compound of Formula 1, an JV-oxide or a salt thereof, (e.g., as a composition described herein).
  • This invention also relates to such method wherein a pesticidally effective amount of a compound of Formula 1, an JV-oxide or a salt thereof, (e.g., as a composition described herein) is administered to the environment (e.g., a stall or blanket) in which an animal resides.
  • compositions, a mixture, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus.
  • “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 the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
  • the terms “pest”, “invertebrate pest” and “parasitic invertebrate pest” include arthropods, gastropods and nematodes of economic importance as pests.
  • arthropod includes insects, mites, spiders, scorpions, centipedes, millipedes, pill bugs and symphylans.
  • gastropod includes snails, slugs and other Stylommatophora.
  • nematode includes all of the helminths, such as roundworms, heartworms, and phytophagous nematodes (Nematoda), flukes (Tematoda), Acanthocephala, and tapeworms (Cestoda).
  • invertebrate pest control means inhibition of invertebrate pest development (including mortality, feeding reduction, and/or mating disruption), and related expressions are defined analogously.
  • the terms “pesticidal” and “pesticidally” refer to observable effects on a pest to provide protection of an animal from the pest. Pesticidal effects typically relate to diminishing the occurrence or activity of the target parasitic invertebrate pest.
  • Such effects on the pest include necrosis, death, retarded growth, diminished mobility or lessened ability to remain on or in the host animal, reduced feeding and inhibition of reproduction.
  • These effects on parasitic invertebrate pests provide control (including prevention, reduction or elimination) of parasitic infestation or infection of the animal.
  • a parasite "infestation” refers to the presence of parasites in numbers that pose a risk to humans or animals.
  • the infestation can be in the environment (e.g., in human or animal housing, bedding, and surrounding property or structures), on agricultural crops or other types of plants, or on the skin or fur of an animal.
  • the term infestation is also intended to be synonymous with the term “infection” as that term is generally understood in the art, unless otherwise stated.
  • alkyl used either alone or in compound words such as “haloalkyl” includes straight-chain or branched alkyls, such as methyl, ethyl, n-propyl, /-propyl, or the different butyl, pentyl or hexyl isomers.
  • alkenyl includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers.
  • Alkenyl also includes polyenes such as 1 ,2-propadienyl and 2,4-hexadienyl.
  • Alkynyl includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. "Alkynyl” can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
  • Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • cyclopropylmethyl denotes cyclopropyl substitution on a methyl moiety.
  • halogen either alone or in compound words such as “haloalkyl”, or when used in descriptions such as “alkyl substituted with halogen” includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, or when used in descriptions such as “alkyl substituted with halogen” said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” or “alkyl substituted with halogen” include CF 3 , CH 2 Cl, CH 2 CF 3 and CCl 2 CF 3 .
  • halocycloalkyl haloalkoxy
  • haloalkenyl and the like, are defined analogously to the term “haloalkyl”.
  • haloalkoxy include OCF 3 , OCH 2 CCl 3 , OCH 2 CH 2 CHF 2 and OCH 2 CF 3 .
  • Alkylcarbonyl denotes a straight-chain or branched alkyl moiety bonded to a C(O) moiety.
  • the chemical abbreviation C(O) as used herein represents a carbonyl moiety.
  • alkylcarbonyl include C(O)CH 3 , C(O)CH 2 CH 2 CH 3 and C(O)CH(CH 3 ) 2 .
  • Cj-C j The total number of carbon atoms in a substituent group is indicated by the "Cj-C j " prefix where i and j are numbers from 1 to 6.
  • C ⁇ -C 3 alkyl designates methyl through propyl.
  • ring member refers to an atom or other moiety (e.g., O or S(O) n ) forming the backbone of a ring.
  • Q include
  • Compounds of Formula 1 can exist as one or more stereoisomers.
  • the various stereoisomers include enantiomers, diastereomers and atropisomers.
  • one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers.
  • the compounds Formula 1 may be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form.
  • the method of this invention comprises racemic mixtures, for example, equal amounts of the enantiomers of Formulae Ia and Ib.
  • the method of this invention includes compounds that are enriched compared to the racemic mixture in an enantiomer of Formula 1. Also included are the essentially pure enantiomers of compounds of Formula 1, for example, Formula Ia and Formula Ib.
  • enantiomeric excess which is defined as (2x-l)-100 %, where x is the mole fraction of the dominant enantiomer in the mixture (e.g., an ee of 20 % corresponds to a 60:40 ratio of enantiomers).
  • compositions of Formula 1 have at least a 50 % enantiomeric excess; more preferably at least a 75 % enantiomeric excess; still more preferably at least a 90 % enantiomeric excess; and the most preferably at least a 94 % enantiomeric excess of the more active isomer.
  • enantiomerically pure embodiments of the more active isomer are enantiomerically pure embodiments of the more active isomer.
  • Compounds of Formula 1 can comprise additional chiral centers.
  • the method of this invention comprises racemic mixtures as well as enriched and essentially pure stereoconfigurations at these additional chiral centers.
  • Compounds of Formula 1 can exist as one or more conformational isomers due to restricted rotation about the amide bond in Formula 1.
  • the method of this invention comprises mixtures of conformational isomers.
  • the method of this invention includes compounds that are enriched in one conformer relative to others.
  • Embodiments of the present invention as described in the Summary of the Invention include those described below.
  • reference to "a compound of Formula 1" includes the definitions of substituents specified in the Summary of the Invention unless further defined in the Embodiments.
  • Embodiment 1. The method described in the Summary of the Invention wherein the pesticidally effective compound is selected from an isoxazoline of Formula 1 (including all geometric and steroisomers), an JV-oxide or a salt thereof
  • R 1 is halogen, C 1 -C 3 haloalkyl or C 1 -C 3 haloalkoxy
  • R 2 is H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or cyano
  • R 3 is H, halogen, C 1 -C 3 haloalkyl or C 1 -C 3 haloalkoxy
  • R 4 is halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 haloalkoxy
  • R 5 is H, CH 3 , C 2 -C 4 alkylcarbonyl, C 2 -C 4 haloalkylcarbonyl, C 2 -C 5 alkoxycarbonyl or CH 2 O(C 1 -C 3 alkyl);
  • R 6 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl or C 3 -C 6 halocycloalkyl, each group substituted with one R 7 ; or R 6 is (CH 2 ) J11 Q;
  • Q is a 4- to 6-membered saturated ring containing carbon atoms and one O or S(O) n as ring members and optionally substituted with 1 or 2 R 8a and one R 8 * 5 ;
  • R 7 is OR 9 , S(O) n R 10 or C(O)NR 11 R 12 ; or
  • R 7 is pyridine or thiazole, each optionally substituted with 1 or 2 R 15
  • R 9 is H, CHO, C 2 -C 4 alkylcarbonyl, C 2 -C 4 haloalkylcarbonyl or C 2 -C 5 alkoxycarbonyl; or R 9 is C 1 -C 4 alkyl or C 1 -C 4 haloalkyl, each optionally substituted with one R 13 ; or R 9 is pyridine or thiazole, each optionally substituted with 1 or 2 R 15 ; R 10 is C 1 -C 4 alkyl or C 1 -C 4 haloalkyl, each optionally substituted with one R 13 ; or
  • R 10 is pyridine or thiazole, each optionally substituted with 1 or 2 R 15 ;
  • R 11 is H, CHO, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, CH 2 O(C 1 -C 3 alkyl), C 2 -C 4 alkylcarbonyl, C 2 -C 4 haloalkylcarbonyl or C 2 -C 5 alkoxycarbonyl;
  • R 12 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 3 -C 6 cycloalkyl, each optionally substituted with one R 13 ; or
  • R 12 is H, C 3 -C 6 alkenyl, C 3 -C 6 haloalkenyl, C 3 -C 6 alkynyl or
  • R 13 is cyano, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, OH, OR 14 or S(O) n R 16 ; or R 13 is pyridine or thiazole, each optionally substituted with 1 or 2 R 15 ;
  • R 14 is C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; each R 15 is independently halogen, cyano, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 haloalkoxy;
  • R 16 is C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; m is 0 or 1 ; and n is 0, 1 or 2.
  • Embodiment 2 The method of Embodiment 1 wherein R 1 is Cl, Br, CF 3 , OCF 3 or OCH 2 CF 3 .
  • Embodiment 3 The method of Embodiment 2 wherein R 1 is Cl, Br or CF 3 .
  • Embodiment 4. The method of Embodiment 3 wherein R 1 is Cl.
  • Embodiment 5. The method of Embodiment 3 wherein R 1 is Br.
  • Embodiment 6. The method of Embodiment 3 wherein R 1 is CF 3 .
  • Embodiment 7. The method of Embodiment 1 wherein R 2 is H, F or Cl.
  • Embodiment 8 The method of Embodiment 7 wherein R 2 is H. Embodiment 9. The method of Embodiment 7 wherein R 2 is F. Embodiment 10. The method of Embodiment 7 wherein R 2 is Cl. Embodiment 11. The method of Embodiment 1 wherein R 3 is H, F, Cl, Br or CF 3 . Embodiment 12. The method of Embodiment 11 wherein R 3 is H, Cl, Br or CF 3 .
  • Embodiment 13 The method of Embodiment 12 wherein R 3 is Cl, Br or CF 3 .
  • Embodiment 14 The method of Embodiment 11 wherein R 3 is H.
  • Embodiment 15 The method of Embodiment 11 wherein R 3 is Cl.
  • Embodiment 16 The method of Embodiment 11 wherein R 3 is Br.
  • Embodiment 17 The method of Embodiment 11 wherein R 3 is CF 3 .
  • Embodiment 18 The method of Embodiment 1 wherein R 4 is halogen or C 1 -C 3 alkyl. Embodiment 19. The method of Embodiment 18 wherein R 4 is halogen or methyl. Embodiment 20. The method of Embodiment 19 wherein R 4 is halogen. Embodiment 21. The method of Embodiment 20 wherein R 4 is Cl. Embodiment 22. The method of Embodiment 19 wherein R 4 is methyl.
  • Embodiment 23 The method of Embodiment 1 wherein R 5 is H.
  • Embodiment 24 The method of Embodiment 1 wherein R 6 is halogen or C 1 -C 6 alkyl.
  • Embodiment 25 The method of Embodiment 1 wherein R 6 is C 1 -C 6 alkyl substituted with one R 7 ;
  • Embodiment 26 The method of Embodiment 1 wherein R 7 is OR 9 , S(O) n R 10 or
  • Embodiment 27 The method of Embodiment 26 wherein R 7 is OR 9 .
  • Embodiment 28 The method of Embodiment 26 wherein R 7 is S(O) n R 10 .
  • Embodiment 29 The method of Embodiment 26 wherein R 7 is C(O)NR 11 R 12 .
  • Embodiment 30 The method of Embodiment 1 wherein R 9 is H or C 1 -C 4 alkyl.
  • Embodiment 31 The method of Embodiment 30 wherein R 9 is H or methyl.
  • Embodiment 32 The method of Embodiment 31 wherein R 9 is H.
  • Embodiment 33 The method of Embodiment 31 wherein R 9 is methyl.
  • Embodiment 34 The method of Embodiment 1 wherein R 10 is C 1 -C 4 alkyl.
  • Embodiment 35 The method of Embodiment 1 wherein R 11 is H.
  • Embodiment 36 The method of Embodiment 1 wherein R 12 is C 1 -C 4 alkyl or C 1 -C 4 haloalkyl, each optionally substituted with one R 13 .
  • Embodiment 37 The method of Embodiment 1 wherein R 12 is C 1 -C 4 alkyl or C 1 -C 4 haloalkyl.
  • Embodiment 38 The method of Embodiment 37 wherein R 12 is C 1 -C 4 haloalkyl.
  • Embodiment 38a The method of Embodiment 1 wherein R 12 is cyclopropyl or cyclopropylmethyl.
  • Embodiment 39 The method of Embodiment 1 wherein R 13 is cyano, OH, OR 14 or
  • Embodiment 40 The method of Embodiment 39 wherein R 13 is cyano.
  • Embodiment 41 The method of Embodiment 39 wherein R 13 is OH.
  • Embodiment 42 The method of Embodiment 39 wherein R 13 is OR 14 .
  • Embodiment 43 The method of Embodiment 39 wherein R 13 is S(O) n R 16 .
  • Embodiment 44 The method of Embodiment 1 wherein the pesticidally effective amount of a compound of Formula 1 is administered orally.
  • Embodiment 45 The method of Embodiment 1 wherein the pesticidally effective amount of a compound of Formula 1 is administered parenterally.
  • Embodiment 46 The method of Embodiment 45 wherein the pesticidally effective amount of a compound of Formula 1 is administered by injection.
  • Embodiment 47 The method of Embodiment 1 wherein the animal to be protected is a vertebrate.
  • Embodiment 48 The method of Embodiment 47 wherein the vertebrate to be protected is a mammal, avian or fish.
  • Embodiment 49 The method of Embodiment 48 wherein the vertebrate to be protected is a mammal.
  • Embodiment 51 The method of Embodiment 48 wherein the vertebrate to be protected is a fish.
  • Embodiment 52. The method of Embodiment 49 wherein the mammal to be protected is a human.
  • Embodiment 53 The method of Embodiment 49 wherein the mammal to be protected is livestock.
  • Embodiment 54. The method of Embodiment 49 wherein the mammal to be protected is a canine.
  • the method of Embodiment 49 wherein the mammal to be protected is a feline.
  • Embodiment 56. The method of Embodiment 1 wherein the parasitic invertebrate pest is an ectoparasite.
  • Embodiment 57 The method of Embodiment 1 wherein the parasitic invertebrate pest is an endoparasite.
  • Embodiment 58 The method of Embodiment 1 wherein the parasitic invertebrate pest is an helminth.
  • Embodiment 59 The method of Embodiment 1 wherein the parasitic invertebrate pest is an arthropod.
  • Embodiment 60 The method of Embodiment 1 wherein the parasitic invertebrate pest is a fly, mosquito, mite, tick, louse, flea, true bug or maggot.
  • Embodiment 61 The method of Embodiment 1 wherein the parasitic invertebrate pest is a fly, mosquito, mite, tick, louse, flea, bed bug, kissing bug or maggot.
  • Embodiment 62 The method of Embodiment 61 wherein the parasitic invertebrate pest is a fly or maggot.
  • Embodiment 63 The method of Embodiment 61 wherein the parasitic invertebrate pest is a mosquito.
  • Embodiment 64 The method of Embodiment 61 wherein the parasitic invertebrate pest is a tick or mite.
  • Embodiment 65 The method of Embodiment 61 wherein the parasitic invertebrate pest is a louse.
  • Embodiment 66 The method of Embodiment 61 wherein the parasitic invertebrate pest is a flea.
  • Embodiment 67 The method of Embodiment 61 wherein the parasitic invertebrate pest is a true bug.
  • Embodiment 68 The method of Embodiment 61 wherein the parasitic invertebrate pest is a bed bug or kissing bug.
  • Embodiment 69 The method of Embodiment 61 wherein the animal to be protected is a cat or dog and the parasitic invertebrate pest is a flea, tick or mite.
  • Embodiment 70 The method of Embodiment 44 wherein the parasiticidally effective amount of a compound of Formula 1 is administered orally two times a year.
  • Embodiment 71 The method of Embodiment 44 wherein the parasiticidally effective amount of a compound of Formula 1 is administered orally once a month.
  • Embodiment 72 The method of Embodiment 61 wherein the parasitic invertebrate pest is a bed bug or kissing bug.
  • Embodiment 69 The method of Embodiment 61 wherein the animal to be protected is a cat or dog and the parasitic invertebrate pest is a flea, tick or
  • Embodiment 44 wherein the parasiticidally effective amount of a compound of Formula 1 is administered orally two times a month.
  • Embodiments of this invention including Embodiments 1-72 above as well as any other embodiments described herein, can be combined in any manner. Combinations of Embodiments 1-43 are illustrated by:
  • Embodiment A The method of Embodiment 1 wherein RMs Cl 5 Br Or CF 3 ; R 2 is H, F or Cl; and R 3 is H, Cl, Br or CF 3 .
  • Embodiment B A method of Embodiment A wherein
  • Embodiment C A method of Embodiment A wherein
  • R 1 and R 3 are Br; and R 2 is H.
  • Embodiment D A method of Embodiment A wherein R 1 and R 3 are CF 3 ; and R 2 is H.
  • Embodiment E A method of Embodiment A wherein R 1 , R 2 and R 3 are Cl.
  • Embodiment F A method of Embodiment A wherein R 1 and R 3 are Cl; and R 2 is F.
  • Embodiment G A method of Embodiment A wherein R 1 is CF 3 ;
  • R 2 and R 3 are H.
  • Embodiment H A method of Embodiment A wherein R 4 is methyl; and R 5 is H.
  • Embodiment I A method of Embodiment A wherein
  • R 5 is H
  • R 6 is C ⁇ -Cg alkyl substituted with one R 7 ; and R 7 is OR 9 , S(O) n R 10 or C(O)NR 11 R 12 .
  • Embodiment J A method of Embodiment A wherein R 7 is C(O)NR 11 R 12 ; and
  • R 12 is C 1 -C 4 alkyl or C 1 -C 4 haloalkyl, each optionally substituted with one R 13 .
  • Embodiment K A method of Embodiment A wherein R 4 is Cl or CH 3 ; R 5 is H;
  • R 6 is C 1 -Cg alkyl substituted with one R 7 ; and R 7 is OR 9 , S(O) n R 10 or C(O)NR 11 R 12 .
  • Embodiment L A method of Embodiment K wherein R 1 is Cl, Br, CF 3 , OCF 3 or OCH 2 CF 3 ;
  • R 2 is H
  • Embodiment M is H, F, Cl, Br or CF 3 .
  • Embodiment M A method of Embodiment L wherein
  • R 4 is CH 3 ; and R 7 is C(O)NR 11 R 12 .
  • Embodiment N A method of Embodiment M wherein R 1 is CF 3 ; and R 3 is Cl, Br or CF 3 .
  • Embodiment O A method of Embodiment M wherein R 11 is H;
  • R 12 is C 1 -C 4 alkyl or C 1 -C 4 haloalkyl.
  • Embodiment P A method of Embodiment M wherein R 11 is H; and
  • R 12 is cyclopropyl or cyclopropylmethyl. Specific embodiments include the method of Embodiment 1 wherein compounds of
  • Formula 1 are selected from the group consisting of: 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2- methyl- ⁇ /-(2-pyridinylmethyl)benzamide,
  • the compounds of Formula 1 or any of Embodiments 1-43 or Embodiments A-P can be used for the protection of an animal from an invertebrate parasitic pest by oral or parenteral administration of the compound. Therefore, the invention is understood to include the compounds of Formula 1 or any of Embodiments 1-43 or Embodiments A-P (and compositions containing them) for use as an animal medicament, or more particularly a parasiticidal animal medicament.
  • the animals to be protected are as defined in any of Embodiments 47-55.
  • the invertebrate parasitic pests are as defined in any of Embodiments 56-68.
  • the medicament may be in oral or parenteral dosage forms.
  • the invention is also understood to include the use of compounds of Formula 1 or any of Embodiments 1-43 or Embodiments A-P in the manufacture of medicaments for the protection of an animal from a an invertebrate parasitic pest.
  • the animals to be protected are as defined in any of Embodiments 47-55.
  • the invertebrate parasitic pests are as defined in any of Embodiments 56-68.
  • the medicament may be in oral or parenteral dosage forms.
  • the invention is also understood to include compounds of Formula 1 or any of
  • Embodiments 1-43 or Embodiments A-P for use in the manufacture of medicaments for the protection of an animal from an invertebrate parasitic pest.
  • the animals to be protected are as defined in any of Embodiments 47-55.
  • the invertebrate parasitic pests are as defined in any of Embodiments 56-68.
  • the medicament may be in oral or parenteral dosage forms.
  • the invention is also understood to include compounds of Formula 1 or any of Embodiments 1-43 or Embodiments A-P packaged and presented for the protection of an animal from an invertebrate parasitic pest.
  • the animals to be protected are as defined in any of Embodiments 47-55.
  • the invertebrate parasitic pests are as defined in any of Embodiments 56-68.
  • the compounds of the invention may be packaged and presented as oral or parenteral dosage forms.
  • the invention is also understood to include a process for manufacturing a composition for protecting an animal from an invertebrate parasitic pest characterized in that a compound of Claim 1 is admixed with at least one pharmaceutically or veterinarily acceptable carrier.
  • the animals to be protected are as defined in any of Embodiments 47-55.
  • the invertebrate parasitic pests are as defined in any of Embodiments 56-68.
  • the compositions of the invention may be packaged and presented as oral or parenteral dosage forms.
  • Isoxazolines of Formula 1 can be prepared as described in PCT Patent Publication WO 2005/085216.
  • One skilled in the art will appreciate that not all pyridine heterocycles can form
  • TV-oxides are those pyridine heterocycles which can form TV-oxides.
  • Synthetic methods for the preparation of TV-oxides of pyridine heterocycles are very well known by one skilled in the art including the oxidation of heterocycles with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane.
  • MCPBA peroxy acids
  • alkyl hydroperoxides such as t-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxiranes such as dimethyldioxirane.
  • salts of chemical compounds are in equilibrium with their corresponding nonsalt forms, salts share the biological utility of the nonsalt forms.
  • the salts of the compounds of Formula 1 include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.
  • the method of the present invention comprises compounds selected from Formula 1, TV-oxides and salts thereof.
  • Formula 1 TV-oxides and salts thereof.
  • Me means methyl
  • Et means ethyl
  • n-Pr means CH 2 CH 2 CH 3
  • z-Pr means CH(CH 3 ) 2
  • c-Pr means cyclopropyl
  • z-Bu means CH 2 CH(CH 3 ) 2
  • s-Bu means CH(CH 3 )CH 2 CH 3
  • t-Eu means C(CH 3 ) 3
  • S(O) means sulfinyl
  • S(O) 2 means sulfonyl
  • C(O) means carbonyl.
  • R 1 is Br
  • R 3 is Br
  • R 1 is CF 2 .
  • R 3 is F
  • R 1 is CF 2 .
  • R 3 is Br
  • R 1 is CL
  • R 2 is F
  • R 3 is Cl
  • R 1 is Br.
  • R 2 is H.
  • R 3 is H
  • R 1 is Br.
  • R 2 is F.
  • R 3 is Br
  • R 1 is Br.
  • R 2 is CL
  • R 3 is Br
  • R 1 is CF
  • R 3 is H
  • compositions of Formula 1 compounds may also contain formulation auxiliaries and additives, known to those skilled in the art as formulation aids (some of which may be considered to also function as solid diluents, liquid diluents or surfactants).
  • formulation auxiliaries and additives may control: pH (buffers), foaming during processing (antifoams such polyorganosiloxanes), sedimentation of active ingredients (suspending agents), viscosity (thixotropic thickeners), in-container microbial growth (antimicrobials), product freezing (antifreezes), color (dyes/pigment dispersions), wash-off (film formers or stickers), evaporation (evaporation retardants), and other formulation attributes.
  • Film formers include, for example, polyvinyl acetates, polyvinyl acetate copolymers, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers and waxes.
  • formulation auxiliaries and additives include those listed in McCutcheon 's Volume 2: Functional Materials, annual International and North American editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; and PCT Publication WO 03/024222.
  • a composition comprising a compound of Formula 1 useful in the present method can further comprise a biologically effective amount of at least one additional parasitic invertebrate pest control active ingredient having a similar spectrum of control but a different site of action.
  • the compounds of Formula 1 can be applied without other adjuvants, but most often application will be of a formulation comprising one or more active ingredients with suitable carriers, diluents, and surfactants and possibly in combination with a food depending on the contemplated end use.
  • One method of application involves spraying a water dispersion or refined oil solution of a compound of Formula 1. Combinations with spray oils, spray oil concentrations, spreader stickers, adjuvants, other solvents, and synergists such as piperonyl butoxide often enhance compound efficacy.
  • Such sprays can be applied from spray containers such as a can, a bottle or other container, either by means of a pump or by releasing it from a pressurized container, e.g., a pressurized aerosol spray can.
  • Such spray compositions can take various forms, for example, sprays, mists, foams, fumes or fog.
  • Such spray compositions thus can further comprise propellants, foaming agents, etc. as the case may be.
  • a spray composition comprising a biologically effective amount of a compound or a composition of Formula 1 and a carrier.
  • One embodiment of such a spray composition comprises a biologically effective amount of a compound or a composition of Formula 1 and a propellant.
  • propellants include, but are not limited to, methane, ethane, propane, butane, isobutane, butene, pentane, isopentane, neopentane, pentene, hydrofluorocarbons, chlorofluorocarbons, dimethyl ether, and mixtures of the foregoing.
  • a spray composition (and a method utilizing such a spray composition dispensed from a spray container) used to control at least one parasitic invertebrate pest selected from the group consisting of mosquitoes, black flies, stable flies, deer flies, horse flies, wasps, yellow jackets, hornets, ticks, spiders, ants, gnats, and the like, including individually or in combinations.
  • the controlling of animal parasites includes controlling external parasites that are parasitic to the surface of the body of the host animal (e.g., shoulders, armpits, abdomen, inner part of the thighs) and internal parasites that are parasitic to the inside of the body of the host animal (e.g., stomach, intestine, lung, veins, under the skin, lymphatic tissue).
  • External parasitic or disease transmitting pests include, for example, chiggers, ticks, lice, mosquitoes, flies, mites and fleas.
  • Internal parasites include heartworms, hookworms and helminths.
  • Compounds and compositions of Formula 1 are particularly suitable for combating external parasitic pests.
  • Compounds and compositions of Formula 1 are suitable for systemic and/or non-systemic control of infestation or infection by parasites on animals.
  • Compounds and compositions of Formula 1 are suitable for combating parasitic invertebrate pests that infest animal subjects including those in the wild, livestock and agricultural working animals.
  • Livestock is the term used to refer (singularly or plurally) to a domesticated animal intentionally reared in an agricultural setting to make produce such as food or fiber, or for its labor; examples of livestock include cattle, sheep, goats, horses, pigs, donkeys, camels, buffalo, rabbits, hens, turkeys, ducks and geese (e.g., raised for meat, milk, butter, eggs, fur, leather, feathers and/or wool).
  • fatalities and performance reduction in terms of meat, milk, wool, skins, eggs, etc.
  • applying a composition comprising a compound of Formula 1 allows more economic and simple husbandry of animals.
  • Compounds and compositions of Formula 1 are especially suitable for combating parasitic invertebrate pests that infest companion animals and pets (e.g., dogs, cats, pet birds and aquarium fish), research and experimental animals (e.g., hamsters, guinea pigs, rats and mice), as well as animals raised for/in zoos, wild habitats and/or circuses.
  • companion animals and pets e.g., dogs, cats, pet birds and aquarium fish
  • research and experimental animals e.g., hamsters, guinea pigs, rats and mice
  • animals raised for/in zoos wild habitats and/or circuses.
  • the animal is preferably a vertebrate, and more preferably a mammal, avian or fish.
  • the animal subject is a mammal (including great apes, such as humans).
  • Other mammalian subjects include primates (e.g., monkeys), bovine (e.g., cattle or dairy cows), porcine (e.g., hogs or pigs), ovine (e.g., goats or sheep), equine (e.g., horses), canine (e.g., dogs), feline (e.g., house cats), camels, deer, donkeys, buffalos, antelopes, rabbits, and rodents (e.g., guinea pigs, squirrels, rats, mice, gerbils, and hamsters).
  • primates e.g., monkeys
  • bovine e.g., cattle or dairy cows
  • porcine e.g., hogs or pigs
  • ovine
  • Avians include Anatidae (swans, ducks and geese), Columbidae (e.g., doves and pigeons), Phasianidae (e.g., partridges, grouse and turkeys), Thesienidae (e.g., domestic chickens), Psittacines (e.g., parakeets, macaws, and parrots), game birds, and ratites (e.g., ostriches). Birds treated or protected by the compounds of Formula 1 can be associated with either commercial or noncommercial aviculture.
  • fish shall be understood to include without limitation, the Teleosti grouping of fish, i.e., teleosts.
  • Both the Salmoniformes order (which includes the Salmonidae family) and the Perciformes order (which includes the Centrarchidae family) are contained within the Teleosti grouping.
  • Examples of potential fish recipients include the Salmonidae, Serranidae, Sparidae, Cichlidae, and Centrarchidae, among others.
  • inventions are also contemplated to benefit from the inventive methods, including marsupials (such as kangaroos), reptiles (such as farmed turtles), and other economically important domestic animals for which the inventive methods are safe and effective in treating or preventing parasite infection or infestation.
  • examples of parasitic invertebrate pests controlled by administering a pesticidally effective amount of a compound of Formula 1 to an animal to be protected include ectoparasites (arthropods, acarines, etc.) and endoparasites (helminths, e.g., nematodes, trematodes, cestodes, acanthocephalans, etc.).
  • helminthiasis The disease or group of diseases described generally as helminthiasis is due to infection of an animal host with parasitic worms known as helminths.
  • helminths The term 'helminths' is meant to include nematodes, trematodes, cestodes and acanthocephalans.
  • Helminthiasis is a prevalent and serious economic problem with domesticated animals such as swine, sheep, horses, cattle, goats, dogs, cats and poultry.
  • Nematodes that are contemplated to be treated by the compounds of this invention and by the inventive methods include, without limitation, the following genera: Acanthocheilonema, Aelurostrongylus, Ancylostoma, Angiostrongylus, Ascaridia, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia, Crenosoma, Dictyocaulus, Dioctophyme, Dipetalonema, Diphyllobothrium, Dirofilaria, Dracunculus, Enterobius, Filaroides, Haemonchus, Heterakis, Lagochilascaris, Loa, Mansonella, Muellerius, Necator, Nematodirus, Oesophagostomum, Ostertagia, Oxyuris, Parafilaria, Parascaris
  • Dictyocaulus Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria,
  • Trematodes that are contemplated to be treated by the compounds of this invention and by the inventive methods include, without limitation, the following genera: Alaria, Fasciola,
  • Cestodes that are contemplated to be treated by the compounds of this invention and by the inventive methods include, without limitation, the following genera:
  • Other medically important genera of parasites which are found in the blood or other tissues and organs outside the gastrointestinal tract are the filarial worms such as
  • Insect and acarine pests include, e.g., biting insects such as flies and mosquitoes, mites, ticks, lice, fleas, true bugs, parasitic maggots, and the like.
  • Adult flies include, e.g., the horn fly or Haematobia irritans, the horse fly or Tabanus spp., the stable fly or Stomoxys calcitrans, the black fly or Simulium spp., the deer fly or
  • Chrysops spp. the louse fly or Melophagus ovinus, and the tsetse fly or Glossina spp.
  • Parasitic fly maggots include, e.g., the bot fly (Oestrus ovis and Cuterebra spp.), the blow fly or Phaenicia spp., the screwworm or Cochliomyia hominivorax, the cattle grub or Hypoderma spp., the fleeceworm and the Gastrophilus of horses.
  • Mosquitoes include, for example, Culex spp., Anopheles spp. and Aedes spp.
  • Mites include Mesostigm ⁇ t ⁇ spp. e.g., mesostigmatids such as the chicken mite,
  • Ticks include, e.g., soft-bodied ticks including Argasidae spp. for example Arg ⁇ s spp. and Ornithodoros spp.; hard-bodied ticks including Ixodidae spp., for example Rhipiceph ⁇ lus sanguineus, Dermacentor variabilis, Dermacentor andersoni, Amblyomma americanum, Ixodes scapularis and other Rhipicephalus spp. (including the former
  • Lice include, e.g., sucking lice, e.g., Menopon spp. and Bovicola spp.; biting lice, e.g., Haematopinus spp., Linognathus spp. and Solenopotes spp.
  • Fleas include, e.g., Ctenocephalides spp., such as dog flea (Ctenocephalides canis) and cat flea ⁇ Ctenocephalides felis); Xenopsylla spp. such as oriental rat flea (Xenopsylla cheopis); and Pulex spp. such as human flea (Pulex irritans).
  • True bugs include, e.g., Cimicidae or e.g., the common bed bug (Cimex lectularius); Triatominae spp. including triatomid bugs also known as kissing bugs; for example Rhodnius prolixus and Triatoma spp.
  • flies, fleas, lice, mosquitoes, gnats, mites, ticks and helminths cause tremendous losses to the livestock and companion animal sectors.
  • Arthropod parasites also are a nuisance to humans and can vector disease-causing organisms in humans and animals.
  • the compounds of Formula 1 are especially effective against ectoparasites including Stomoxys calcitrans (stable fly); ticks such as Ixodes spp., Boophilus spp.,
  • Haemaphysalis spp. and fleas such as Ctenocephalides felis (cat flea) and Ctenocephalides canis (dog flea).
  • the compounds of Formula 1 may also be effective against ectoparasites including: flies such as Haematobia (Lyperosia) irritans (horn fly), Simulium spp. (blackfly), Glossina spp. (tsetse flies), Hydrotaea irritans (head fly), Musca autumnalis (face fly), Musca domestica (house fly), Morellia simplex (sweat fly), Tabanus spp. (horse fly), Hypoderma bovis, Hypoderma lineatum, Lucilia sericata, Lucilia cuprina (green blowfly), Calliphora spp.
  • flies such as Haematobia (Lyperosia) irritans (horn fly), Simulium spp. (blackfly), Glossina spp. (tsetse flies), Hydrotaea irritans (head fly), Musca autumnalis (face fly), Musca domestic
  • biologically active compounds or agents may be administered at the same or different times as the compounds of Formula 1. Such compounds, for example, may be useful adjuncts in Formula 1 compositions for the present method. As noted below, such biologically active compounds may be included in the composition of Formula 1.
  • biologically active compounds for use in the present invention include the organophosphate pesticides. This class of pesticides has very broad activity as insecticides and, in certain instances, anthelmintic activity.
  • Organophosphate pesticides include, e.g., dicrotophos, terbufos, dimethoate, diazinon, disulfoton, trichlorfon, azinphos-methyl, chlorpyrifos, malathion, oxydemeton-methyl, methamidophos, acephate, ethyl parathion, methyl parathion, mevinphos, phorate, carbofenthion and phosalone.
  • compositions of Formula 1 compounds for the present method are also comtemplated to include carbamate -type pesticides, including, e.g., carbaryl, carbofuran, aldicarb, molinate, methomyl, carbofuran, etc., as well as combinations with the organochlorine type pesticides.
  • Compositions of Formula 1 compounds are further contemplated to include combinations with biological pesticides, including repellents, the pyrethrins (as well as synthetic variations thereof, e.g., allethrin, resmethrin, permethrin, tralomethrin), and nicotine, that is often employed as an acaricide.
  • miscellaneous pesticides including: Bacillus thuringiensis, chlorobenzilate, formamidines (e.g., amitraz), copper compounds (e.g., copper hydroxide and cupric oxychloride sulfate), cyfluthrin, cypermethrin, dicofol, endosulfan, esfenvalerate, fenvalerate, lambda-cyhalothrin, methoxychlor and sulfur.
  • Bacillus thuringiensis chlorobenzilate
  • formamidines e.g., amitraz
  • copper compounds e.g., copper hydroxide and cupric oxychloride sulfate
  • cyfluthrin e.g., cypermethrin, dicofol
  • endosulfan esfenvalerate, fenvalerate, lambda-cyhalothrin, methoxychlor and
  • avermectins e.g., ivermectin, moxidectin, milbemycin
  • benzimidazoles e.g., albendazole, triclabendazole
  • salicylanilides e.g., closantel, oxyclozanide
  • substituted phenols e.g., nitroxynil
  • pyrimidines e.g., pyrantel
  • imidazothiazoles e.g., levamisole
  • biologically active compounds or agents useful in the Formula 1 compositions for the present method can be selected from Insect Growth Regulators (IGRs) and Juvenile Hormone Analogues (JHAs) such as diflubenzuron, triflumuron, fluazuron, cyromazine, methoprene, etc., thereby providing both initial and sustained control of parasites (at all stages of insect development, including eggs) on the animal subject, as well as within the environment of the animal subject.
  • biologically active compounds or agents useful in the Formula 1 compositions for the present method selected from the avermectin class of antiparasitic compounds.
  • the avermectin family of compounds includes very potent antiparasitic agents known to be useful against a broad spectrum of endoparasites and ectoparasites in mammals.
  • a preferred compound for use within the scope of the present invention is ivermectin.
  • Ivermectin is a semi-synthetic derivative of avermectin and is generally produced as a mixture of at least 80% 22,23-dihydroavermectin B la and less than 20% 22,23- dihydroavermectin B 1 ⁇ .
  • Ivermectin is disclosed in U.S. Patent No. 4,199,569.
  • Abamectin is an avermectin that is disclosed as avermectin B 1 ⁇ B 1 J 5 in U.S. Patent No.
  • Abamectin contains at least 80% of avermectin B la and not more than 20% of avermectin B 1 ⁇ .
  • avermectin is doramectin, also known as 25-cyclohexyl-avermectin B 1 .
  • doramectin also known as 25-cyclohexyl-avermectin B 1 .
  • the structure and preparation of doramectin is disclosed in U.S. Patent No. 5,089,480.
  • Another preferred avermectin is moxidectin.
  • Moxidectin also known as LL-F28249 alpha, is known from U.S. Patent No. 4,916,154.
  • Another preferred avermectin is selamectin.
  • Selamectin is 25-cyclohexyl-25-de(l- methylpropyl)-5 -deoxy-22,23 -dihydro-5 -(hydroxyimino)-avermectin B 1 monosaccharide .
  • Milbemycin or B41
  • Milbemycin is a substance which is isolated from the fermentation broth of a milbemycin-producing strain of Streptomyces.
  • the microorganism, the fermentation conditions and the isolation procedures are described in U.S. Patent Nos. 3,950,360 and 3,984,564.
  • Emamectin (4"-deoxy-4"-epi-methylaminoavermectin B 1 ), which can be prepared as described in U.S. Patent Nos. 5,288,710 and 5,399,717, is a mixture of two homologues, 4"- deoxy-4"-epi-methylaminoavermectin B la and 4"-deoxy-4"-epi-methylaminoavermectin B 1 ⁇ .
  • a salt of emamectin is used.
  • salts of emamectin which may be used in the present invention include the salts described in U.S. Patent No.
  • 5,288,710 e.g., salts derived from benzoic acid, substituted benzoic acid, benzenesulfonic acid, citric acid, phosphoric acid, tartaric acid, maleic acid, and the like.
  • the emamectin salt used in the present invention is emamectin benzoate.
  • Eprinomectin is chemically known as 4"-epi-acetylamino-4"-deoxy-avermectin B 1 .
  • Eprinomectin was specifically developed to be used in all cattle classes and age groups. It was the first avermectin to show broad-spectrum activity against both endo- and ectoparasites while also leaving minimal residues in meat and milk. It has the additional advantage of being highly potent when delivered topically.
  • compositions for the present method optionally comprise combinations of one or more of the following antiparasite compounds: imidazo[l,2-b]pyridazine compounds as described by U.S. Patent Application Publication No. 2005/0182059 Al; l-(4- mono and di-halomethylsulphonylphenyl)-2-acylamino-3-fluoropropanol compounds, as described by U.S. Patent No. 7,361,689; trifluoromethanesulfonanilide oxime ether derivatives, as described by U.S. Patent No.
  • the Formula 1 compositions may also further comprise a flukicide.
  • Suitable flukicides include, for example, triclabendazole, fenbendazole, albendazole, clorsulon and oxibendazole. It will be appreciated that the above combinations may further include combinations of antibiotic, antiparasitic and anti-fluke active compounds.
  • Formula 1 compositions as described herein for the present method, with other animal health remedies such as trace elements, antiinflammatories, anti-infectives, hormones, dermatological preparations, including antiseptics and disinfectants, and immunobiologicals such as vaccines and antisera for the prevention of disease.
  • animal health remedies such as trace elements, antiinflammatories, anti-infectives, hormones, dermatological preparations, including antiseptics and disinfectants, and immunobiologicals such as vaccines and antisera for the prevention of disease.
  • such antinfectives include one or more antibiotics that are optionally coadministered during treatment using the inventive methods, e.g., in a combined composition and/or in separate dosage forms.
  • antibiotics suitable for this purpose include, for example, those listed herein below.
  • One useful antibiotic is florfenicol, also known as D-(threo)-l-(4- methylsulfonylphenyl)-2-dichloroacetamido-3-fluoro- 1 -propanol.
  • Another preferred antibiotic compound is D-(threo)-l-(4-methylsulfonylphenyl)-2-difluoroacetamido-3-fluoro- 1 -propanol.
  • Another useful antibiotic is thiamphenicol.
  • Processes for the manufacture of these antibiotic compounds, and intermediates useful in such processes, are described in U.S. Patent Nos. 4,31,857; 4,582,918; 4,973,750; 4,876,352; 5,227,494; 4,743,700; 5,567,844; 5,105,009; 5,382,673; 5,352,832; and 5,663,361.
  • Other florfenicol analogs and/or prodrugs have been disclosed and such analogs also can be used in the compositions and methods of the present invention (see e.g., U.S. Patent Nos. 7,041,670 and 7,153,842).
  • Tilmicosin is a macrolide antibiotic that is chemically defined as 20-dihydro-20-deoxy-20-(c ⁇ -3,5-dimethylpiperidin-l-yl)- desmycosin and is disclosed in U.S. Patent No. 4,820,695.
  • Another useful antibiotic for use in the present invention is tulathromycin.
  • Tulathromycin may be prepared in accordance with the procedures set forth in U.S. Patent No. 6,825,327.
  • Further antibiotics for use in the present invention include the cephalosporins such as, for example, ceftiofur, cefquinome, etc.
  • the concentration of the cephalosporin in the formulation of the present invention optionally varies between about 1 mg/mL to 500 mg/mL.
  • Another useful antibiotic includes the fluoroquinolones, such as, for example, enrofloxacin, danofloxacin, difloxacin, orbifloxacin and marbofloxacin.
  • enrofloxacin In the case of enrofloxacin, it may be administered in a concentration of about 100 mg/mL. Danofloxacin may be present in a concentration of about 180 mg/mL.
  • Other useful macrolide antibiotics include compounds from the class of ketolides, or, more specifically, the azalides. Such compounds are described in, for example, U.S. Patent Nos. 6,514,945; 6,472,371; 6,270,768; 6,437,151; 6,271,255; 6,239,12; 5,958,888; 6,339,063; and 6,054,434.
  • antibiotics include the tetracyclines, particularly chlortetracycline and oxytetracycline.
  • Other antibiotics may include ⁇ -lactams such as penicillins, e.g., penicillin, ampicillin, amoxicillin, or a combination of amoxicillin with clavulanic acid or other beta lactamase inhibitors.
  • Treatments of the invention are by conventional means such as by enteral administration in the form of, for example, tablets, capsules, drinks, drenching preparations, granulates, pastes, boli, feed-through procedures, or suppositories; or by parenteral administration, such as, for example, by injection (including intramuscular, subcutaneous, intravenous, intraperitoneal) or implants; or by nasal administration.
  • enteral administration in the form of, for example, tablets, capsules, drinks, drenching preparations, granulates, pastes, boli, feed-through procedures, or suppositories
  • parenteral administration such as, for example, by injection (including intramuscular, subcutaneous, intravenous, intraperitoneal) or implants; or by nasal administration.
  • a parasiticidal composition according to the present invention comprises a mixture of a compound of Formula 1, an JV-oxide or a salt thereof, with one or more pharmaceutically or veterinarily acceptable carriers comprising excipients and auxiliaries selected with regard to the intended route of administration (e.g., oral or parenteral administration such as injection) and in accordance with standard practice.
  • a suitable carrier is selected on the basis of compatibility with the one or more active ingredients in the composition, including such considerations as stability relative to pH and moisture content.
  • compositions for protecting an animal from an invertebrate parasitic pest comprising a parasitically effective amount of a compound of Formula 1 and at least one carrier.
  • a compound of Formula 1 can be formulated in suspension, solution or emulsion in oily or aqueous vehicles, and may contain adjuncts such as suspending, stabilizing and/or dispersing agents.
  • the compounds of Formula 1 may also be formulated for bolus injection or continuous infusion.
  • Pharmaceutical compositions for injection include aqueous solutions of water-soluble forms of active ingredients (e.g., a salt of an active compound), preferably in physiologically compatible buffers containing other excipients or auxiliaries as are known in the art of pharmaceutical formulation.
  • suspensions of the active compounds may be prepared in a lipophilic vehicle.
  • Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes.
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • the compounds of Formula 1 may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular or subcutaneous injection.
  • the compounds of Formula 1 may be formulated for this route of administration with suitable polymeric or hydrophobic materials (for instance, in an emulsion with a pharmacologically acceptable oil), with ion exchange resins, or as a sparingly soluble derivative such as, without limitation, a sparingly soluble salt.
  • the compounds of Formula 1 can be delivered in the form of an aerosol spray using a pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide.
  • a suitable propellant e.g., without limitation, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide.
  • the dosage unit may be controlled by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • Compounds of Formula 1 have been discovered to have surprisingly favorable pharmacokinetic and pharmacodynamic properties providing systemic availability from oral administration and ingestion. Therefore after ingestion by the animal to be protected, parasiticidally effective concentrations of compounds of Formula 1 in the bloodstream protect the treated animal from blood-sucking pests such as fleas, ticks and lice. Therefore of note is a composition for protecting an animal from an invertebrate parasite pest in a form for oral administration (i.e. comprising, in addition to a parasiticidally effective amount of a compound of Formula 1, one or more carriers selected from binders and fillers suitable for oral administration and feed concentrate carriers).
  • a compound of Formula 1 can be formulated with binders/fillers known in the art to be suitable for oral administration compositions, such as sugars and sugar derivatives (e.g., lactose, sucrose, mannitol, sorbitol), starch (e.g., maize starch, wheat starch, rice starch, potato starch), cellulose and derivatives (e.g., methylcellulose, carboxymethylcellulose, ethylhydroxycellulose), protein derivatives (e.g., zein, gelatin), and synthetic polymers (e.g., polyvinyl alcohol, polyvinylpyrrolidone).
  • sugars and sugar derivatives e.g., lactose, sucrose, mannitol, sorbitol
  • starch e.g., maize starch, wheat starch, rice starch, potato starch
  • cellulose and derivatives e.g., methylcellulose, carboxymethylcellulose, ethylhydroxycellulose
  • protein derivatives e
  • lubricants e.g., magnesium stearate
  • disintegrating agents e.g., cross-linked polyvinylpyrrolidinone, agar, alginic acid
  • dyes or pigments can be added.
  • Pastes and gels often also contain adhesives (e.g., acacia, alginic acid, bentonite, cellulose, xanthan gum, colloidal magnesium aluminum silicate) to aid in keeping the composition in contact with the oral cavity and not being easily ejected.
  • a preferred embodiment is a composition of the present method formulated into a chewable and/or edible product (e.g., a chewable treat or edible tablet).
  • a chewable and/or edible product e.g., a chewable treat or edible tablet.
  • Such a product would ideally have a taste, texture and/or aroma favored by the animal to be protected so as to facilitate oral administration of the compound of Formula 1.
  • the carrier is typically selected from high-performance feed, feed cereals or protein concentrates.
  • feed concentrate-containing compositions can, in addition to the parasiticidal active ingredients, comprise additives promoting animal health or growth, improving quality of meat from animals for slaughter or otherwise useful to animal husbandry.
  • additives can include, for example, vitamins, antibiotics, chemotherapeutics, bacteriostats, fungistats, coccidiostats and hormones.
  • the compounds of Formula 1 may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
  • rectal compositions such as suppositories or retention enemas
  • conventional suppository bases such as cocoa butter or other glycerides.
  • the formulations for the method of this invention may include an antioxidant, such as
  • BHT butylated hydroxytoluene
  • the antioxidant is generally present in amounts of at 0.1- 5% (wt/vol).
  • Some of the formulations require a solubilizer, such as oleic acid, to dissolve the active agent, particularly if spinosad is included.
  • Common spreading agents used in these pour-on formulations include isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated C 12 -C 18 fatty alcohols, oleic acid, oleyl ester, ethyl oleate, triglycerides, silicone oils and dipropylene glycol methyl ether.
  • the pour-on formulations for the method of this invention are prepared according to known techniques.
  • the parasiticide/insecticide is mixed with the carrier or vehicle, using heat and stirring if required.
  • Auxiliary or additional ingredients can be added to the mixture of active agent and carrier, or they can be mixed with the active agent prior to the addition of the carrier.
  • Pour-on formulations in the form of emulsions or suspensions are similarly prepared using known techniques.
  • Liposomes and emulsions are well-known examples of delivery vehicles or carriers for hydrophobic drugs.
  • organic solvents such as dimethylsulfoxide may be used, if needed.
  • the rate of application required for effective parasitic invertebrate pest control (i.e. "pesticidally effective amount") will depend on such factors as the species of parasitic invertebrate pest to be controlled, the pest's life cycle, life stage, its size, location, time of year, host crop or animal, feeding behavior, mating behavior, ambient moisture, temperature, and the like.
  • pesticidally effective amount necessary for the desired level of parasitic invertebrate pest control.
  • a compound or composition of Formula 1 is administered in a pesticidally effective amount to an animal, particularly a homeothermic animal, to be protected from parasitic invertebrate pests.
  • a pesticidally effective amount is the amount of active ingredient needed to achieve an observable effect diminishing the occurrence or activity of the target parasitic invertebrate pest.
  • the pesticidally effective dose can vary for the various compounds and compositions useful for the method of the present invention, the desired pesticidal effect and duration, the target parasitic invertebrate pest species, the animal to be protected, the mode of application and the like, and the amount needed to achieve a particular result can be determined through simple experimentation.
  • a dose of a compound of the present invention administered at suitable intervals typically ranges from about 0.01 mg/kg to about
  • Suitable intervals for the administration of compounds of the present invention to animals range from about daily to about yearly. Of note are administration intervals ranging from about weekly to about once every 6 months. Of particular note are monthly adminstration intervals (i.e. administering the compound to the animal once every month).
  • Control efficacy represents inhibition of parasitic invertebrate pest development (including mortality) that causes significantly reduced feeding.
  • the pest control protection afforded by the compounds is not limited, however, to these species. See Index Tables A and B for compound descriptions.
  • a ⁇ H NMR data are in ppm downfield from tetramethylsilane. Couplings are designated by (s)-singlet, (d)-doublet, (t)-triplet, (q)-quartet, (dd)-doublet of doublets, (dt)-doublet of triplets, (br)-broad peaks, (m)-multiplet.
  • a CD-I ® mouse (about 30 g, male, obtained from Charles River Laboratories, Wilmington, MA) was orally dosed with a test compound in an amount of 10 mg/kg solubilized in propylene glycol/glycerol formal (60:40). Two hours after oral administration of the test compound, approximately 8 to 16 adult fleas were applied to each mouse. The fleas were then evaluated for mortality 48 hours after flea application to the mouse.
  • a CD-I ® mouse (about 30 g, male, obtained from Charles River Laboratories, Wilmington, MA) was orally dosed with a test compound in an amount of 10 mg/kg solubilized in propylene glycol/glycerol formal (60:40). Twenty four hours after oral administration of the test compound, approximately 8 to 16 adult fleas were applied to each mouse. The fleas were then evaluated for mortality 48 hours after flea application to the mouse.
  • TEST C For evaluating control of the cat flea ⁇ Ctenocephalides felis, a CD-I ® mouse (about 30 g, male, obtained from Charles River Laboratories, Wilmington, MA) was subcutaneously dosed with a test compound in an amount of 10 mg/kg solubilized in propylene glycol/glycerol formal (60:40). Two hours after oral administration of the test compound, approximately 8 to 16 adult fleas were applied to each mouse. The fleas were then evaluated for mortality 48 hours after flea application to the mouse.
  • a test compound was solubilized in propylene glycol/glycerol formal (60:40) and then diluted in bovine blood to a final test rate of 30 ppm.
  • the treated blood was placed in a tube, and the bottom of the tube was covered with a membrane. Approximately 10 adult cat fleas were allowed to feed through the membrane on the treated blood. The adult fleas were then evaluated for mortality 72 hours later.

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Abstract

Disclosed is a method for protecting an animal from a parasitic invertebrate pest comprising treating an animal orally or by injection with a pesticidally effective amount of a compound of Formula: (1), wherein R1 is halogen, C1-C3 haloalkyl or C1-C3 haloalkoxy; R2 is H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or cyano; R3 is H, halogen, C1-C3 haloalkyl or C1-C3 haloalkoxy; R4 is halogen, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 haloalkoxy; R5 is H, CH3, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl, C2-C5 alkoxycarbonyl or CH2O(C1-C3 alkyl); R6 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or C3-C6 halocycloalkyl, each group substituted with one R7; or R6 is (CH2)mQ; and Q, R7, R8a and R8b are as defined in the disclosure.

Description

TITLE ANIMAL PEST CONTROL METHOD
FIELD OF THE INVENTION
This invention relates to a method for protecting an animal from a parasitic pest and parasitic pest infestation.
BACKGROUND OF THE INVENTION
The control of animal parasites in animal health is essential, especially in the areas of food production and companion animals. Existing methods of treatment and parasite control are being compromised due to growing resistance to many current commercial parasiticides. The discovery of more effective ways to control animal parasites is therefore imperative. In addition, it is advantageous to discover ways to apply pesticides to animals orally or parenterally so as to prevent the possible contamination of humans or the surrounding environment.
PCT Patent Publication WO 05/085216 discloses isoxazoline derivatives of Formula i as insecticides
Figure imgf000002_0001
wherein, inter alia, each of A1, A2 and A3 are independently C or N; G is a benzene ring; W is O or S; and X is halogen or C^-Cg haloalkyl.
The method of the present invention is not disclosed in this publication.
SUMMARY OF THE INVENTION
This invention pertains to a method for protecting animals from a parasitic invertebrate pest comprising orally or parenterally administering to the animal a pesticidally effective amount of a compound of Formula 1 (including all geometric and steroisomers), an JV-oxide or a salt thereof
Figure imgf000003_0001
1 wherein
R1 is halogen, C1-C3 haloalkyl or C1-C3 haloalkoxy; R2 is H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or cyano; R3 is H, halogen, Q-C 3 haloalkyl or C1-C3 haloalkoxy;
R4 is halogen, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 haloalkoxy;
R5 is H, CH3, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl, C2-C5 alkoxycarbonyl or CH2O(C1-C3 alkyl);
R6 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or C3-C6 halocycloalkyl, each group substituted with one R7; or R6 is (CH2)J11Q;
Q is a 4- to 6-membered saturated ring containing carbon atoms and one O or S(O)n as ring members and optionally substituted with 1 or 2 R8a and one R8*5; R7 is OR9, S(O)nR10 or C(O)NR11R12; or R7 is pyridine or thiazole, each optionally substituted with 1 or 2 R15; each R8a is independently halogen, cyano or C1-C2 alkyl;
R8b is OR9, S(O)nR10 or C(O)NR11R12; R9 is H, CHO, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl or C2-C5 alkoxycarbonyl; or R9 is C1-C4 alkyl or C1-C4 haloalkyl, each optionally substituted with one R13; or R9 is pyridine or thiazole, each optionally substituted with 1 or 2 R15;
R10 is C1-C4 alkyl or C1-C4 haloalkyl, each optionally substituted with one R13; or
R10 is pyridine or thiazole, each optionally substituted with 1 or 2 R15; R11 is H, CHO, C1-C4 alkyl, C1-C4 haloalkyl, CH2O(C1-C3 alkyl), C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl or C2-C5 alkoxycarbonyl; R12 is C1-C4 alkyl, C1-C4 haloalkyl or C3-C6 cycloalkyl, each optionally substituted with one R13; or R12 is H, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl or OR14; R13 is cyano, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, OH, OR14 or S(O)nR16; or R13 is pyridine or thiazole, each optionally substituted with 1 or 2 R15; R14 is C1-C4 alkyl or C1-C4 haloalkyl; each R15 is independently halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 haloalkoxy; R16 is C1-C4 alkyl or C1-C4 haloalkyl; m is 0 or 1 ; and n is 0, 1 or 2.
This invention also relates to such method wherein the parasitic invertebrate pest or its environment is contacted with a composition comprising a biologically effective amount of a compound of Formula 1, an JV-oxide or a salt thereof, and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, said composition optionally further comprising a biologically effective amount of at least one additional biologically active compound or agent. This invention further provides a method for treating, preventing, inhibiting and/or killing ecto- and/or endoparasites comprising administering to and/or on the animal a pesticidally effective amount of a compound of Formula 1, an JV-oxide or a salt thereof, (e.g., as a composition described herein). This invention also relates to such method wherein a pesticidally effective amount of a compound of Formula 1, an JV-oxide or a salt thereof, (e.g., as a composition described herein) is administered to the environment (e.g., a stall or blanket) in which an animal resides.
DETAILS OF THE INVENTION
As used herein, the terms "comprises," "comprising," "includes," "including," "has,"
"having," "contains" or "containing," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, a mixture, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus. Further, unless expressly stated to the 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 the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
Also, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore "a" or "an" should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.
As referred to in this disclosure, the terms "pest", "invertebrate pest" and "parasitic invertebrate pest" include arthropods, gastropods and nematodes of economic importance as pests. The term "arthropod" includes insects, mites, spiders, scorpions, centipedes, millipedes, pill bugs and symphylans. The term "gastropod" includes snails, slugs and other Stylommatophora. The term "nematode" includes all of the helminths, such as roundworms, heartworms, and phytophagous nematodes (Nematoda), flukes (Tematoda), Acanthocephala, and tapeworms (Cestoda). In the context of this disclosure "invertebrate pest control" means inhibition of invertebrate pest development (including mortality, feeding reduction, and/or mating disruption), and related expressions are defined analogously. The terms "pesticidal" and "pesticidally" refer to observable effects on a pest to provide protection of an animal from the pest. Pesticidal effects typically relate to diminishing the occurrence or activity of the target parasitic invertebrate pest. Such effects on the pest include necrosis, death, retarded growth, diminished mobility or lessened ability to remain on or in the host animal, reduced feeding and inhibition of reproduction. These effects on parasitic invertebrate pests provide control (including prevention, reduction or elimination) of parasitic infestation or infection of the animal.
A parasite "infestation" refers to the presence of parasites in numbers that pose a risk to humans or animals. The infestation can be in the environment (e.g., in human or animal housing, bedding, and surrounding property or structures), on agricultural crops or other types of plants, or on the skin or fur of an animal. When the infestation is within an animal (e.g., in the blood or other internal tissues), the term infestation is also intended to be synonymous with the term "infection" as that term is generally understood in the art, unless otherwise stated.
In the above recitations, the term "alkyl", used either alone or in compound words such as "haloalkyl" includes straight-chain or branched alkyls, such as methyl, ethyl, n-propyl, /-propyl, or the different butyl, pentyl or hexyl isomers. "Alkenyl" includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. "Alkenyl" also includes polyenes such as 1 ,2-propadienyl and 2,4-hexadienyl. "Alkynyl" includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. "Alkynyl" can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
"Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "cyclopropylmethyl" denotes cyclopropyl substitution on a methyl moiety.
The term "halogen", either alone or in compound words such as "haloalkyl", or when used in descriptions such as "alkyl substituted with halogen" includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as "haloalkyl", or when used in descriptions such as "alkyl substituted with halogen" said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of "haloalkyl" or "alkyl substituted with halogen" include CF3, CH2Cl, CH2CF3 and CCl2CF3. The terms "halocycloalkyl", "haloalkoxy", "haloalkenyl", and the like, are defined analogously to the term "haloalkyl". Examples of "haloalkoxy" include OCF3, OCH2CCl3, OCH2CH2CHF2 and OCH2CF3. Examples of "haloalkenyl" include CH2CH=C(Cl)2 and CH2CH=CHCH2CF3. "Alkylcarbonyl" denotes a straight-chain or branched alkyl moiety bonded to a C(O) moiety. The chemical abbreviation C(O) as used herein represents a carbonyl moiety. Examples of "alkylcarbonyl" include C(O)CH3, C(O)CH2CH2CH3 and C(O)CH(CH3)2.
The total number of carbon atoms in a substituent group is indicated by the "Cj-Cj" prefix where i and j are numbers from 1 to 6. For example, C^-C3 alkyl designates methyl through propyl.
When a group contains a substituent which can be hydrogen, for example R5 or R11, then when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.
The term "ring member", as used in the definition of the substituent Q in the Summary of the Invention, refers to an atom or other moiety (e.g., O or S(O)n) forming the backbone of a ring. Examples of Q include
Figure imgf000006_0001
Compounds of Formula 1 can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers and atropisomers. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. The compounds Formula 1 may be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form. For example, two possible enantiomers of Formula 1 are depicted as Formula Ia and Formula Ib involving the isoxazoline chiral center identified with an asterisk (*). Analogously, other chiral centers are possible at, for example, R1, R6, R9 and R11.
Figure imgf000006_0002
Ia Ib Molecular depictions drawn herein follow standard conventions for depicting stereochemistry. To indicate stereoconfϊguration, bonds rising from the plane of the drawing and towards the viewer are denoted by solid wedges wherein the broad end of the wedge is attached to the atom rising from the plane of the drawing towards the viewer. Bonds going below the plane of the drawing and away from the viewer are denoted by dashed wedges wherein the narrow end of the wedge is attached to the atom further away from the viewer. Constant width lines indicate bonds with a direction opposite or neutral relative to bonds shown with solid or dashed wedges; constant width lines also depict bonds in molecules or parts of molecules in which no particular stereoconfϊguration is intended to be specified. The more biologically active enantiomer is believed to be Formula Ia. Formula Ia has the (S) configuration at the chiral carbon, and Formula Ib has the (R) configuration at the chiral carbon.
The method of this invention comprises racemic mixtures, for example, equal amounts of the enantiomers of Formulae Ia and Ib. In addition, the method of this invention includes compounds that are enriched compared to the racemic mixture in an enantiomer of Formula 1. Also included are the essentially pure enantiomers of compounds of Formula 1, for example, Formula Ia and Formula Ib.
When enantiomerically enriched, one enantiomer is present in greater amounts than the other, and the extent of enrichment can be defined by an expression of enantiomeric excess ("ee"), which is defined as (2x-l)-100 %, where x is the mole fraction of the dominant enantiomer in the mixture (e.g., an ee of 20 % corresponds to a 60:40 ratio of enantiomers).
Preferably the compositions of Formula 1 have at least a 50 % enantiomeric excess; more preferably at least a 75 % enantiomeric excess; still more preferably at least a 90 % enantiomeric excess; and the most preferably at least a 94 % enantiomeric excess of the more active isomer. Of particular note are enantiomerically pure embodiments of the more active isomer.
Compounds of Formula 1 can comprise additional chiral centers. The method of this invention comprises racemic mixtures as well as enriched and essentially pure stereoconfigurations at these additional chiral centers. Compounds of Formula 1 can exist as one or more conformational isomers due to restricted rotation about the amide bond in Formula 1. The method of this invention comprises mixtures of conformational isomers. In addition, the method of this invention includes compounds that are enriched in one conformer relative to others.
Embodiments of the present invention as described in the Summary of the Invention include those described below. In the following Embodiments, reference to "a compound of Formula 1" includes the definitions of substituents specified in the Summary of the Invention unless further defined in the Embodiments. Embodiment 1. The method described in the Summary of the Invention wherein the pesticidally effective compound is selected from an isoxazoline of Formula 1 (including all geometric and steroisomers), an JV-oxide or a salt thereof
Figure imgf000008_0001
1 wherein
R1 is halogen, C1-C3 haloalkyl or C1-C3 haloalkoxy; R2 is H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or cyano; R3 is H, halogen, C1-C3 haloalkyl or C1-C3 haloalkoxy; R4 is halogen, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 haloalkoxy;
R5 is H, CH3, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl, C2-C5 alkoxycarbonyl or CH2O(C1-C3 alkyl); R6 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or C3-C6 halocycloalkyl, each group substituted with one R7; or R6 is (CH2)J11Q; Q is a 4- to 6-membered saturated ring containing carbon atoms and one O or S(O)n as ring members and optionally substituted with 1 or 2 R8a and one R8*5; R7 is OR9, S(O)nR10 or C(O)NR11R12; or R7 is pyridine or thiazole, each optionally substituted with 1 or 2 R15; each R8a is independently halogen, cyano or C1-C2 alkyl; R8b is OR9, S(O)nR10 or C(O)NR11R12;
R9 is H, CHO, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl or C2-C5 alkoxycarbonyl; or R9 is C1-C4 alkyl or C1-C4 haloalkyl, each optionally substituted with one R13; or R9 is pyridine or thiazole, each optionally substituted with 1 or 2 R15; R10 is C1-C4 alkyl or C1-C4 haloalkyl, each optionally substituted with one R13; or
R10 is pyridine or thiazole, each optionally substituted with 1 or 2 R15; R11 is H, CHO, C1-C4 alkyl, C1-C4 haloalkyl, CH2O(C1-C3 alkyl), C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl or C2-C5 alkoxycarbonyl; R12 is C1-C4 alkyl, C1-C4 haloalkyl or C3-C6 cycloalkyl, each optionally substituted with one R13; or R12 is H, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl or
OR14; R13 is cyano, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, OH, OR14 or S(O)nR16; or R13 is pyridine or thiazole, each optionally substituted with 1 or 2 R15; R14 is C1-C4 alkyl or C1-C4 haloalkyl; each R15 is independently halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 haloalkoxy;
R16 is C1-C4 alkyl or C1-C4 haloalkyl; m is 0 or 1 ; and n is 0, 1 or 2.
Embodiment 2. The method of Embodiment 1 wherein R1 is Cl, Br, CF3, OCF3 or OCH2CF3.
Embodiment 3. The method of Embodiment 2 wherein R1 is Cl, Br or CF3. Embodiment 4. The method of Embodiment 3 wherein R1 is Cl. Embodiment 5. The method of Embodiment 3 wherein R1 is Br. Embodiment 6. The method of Embodiment 3 wherein R1 is CF3. Embodiment 7. The method of Embodiment 1 wherein R2 is H, F or Cl.
Embodiment 8. The method of Embodiment 7 wherein R2 is H. Embodiment 9. The method of Embodiment 7 wherein R2 is F. Embodiment 10. The method of Embodiment 7 wherein R2 is Cl. Embodiment 11. The method of Embodiment 1 wherein R3 is H, F, Cl, Br or CF3. Embodiment 12. The method of Embodiment 11 wherein R3 is H, Cl, Br or CF3.
Embodiment 13. The method of Embodiment 12 wherein R3 is Cl, Br or CF3. Embodiment 14. The method of Embodiment 11 wherein R3 is H. Embodiment 15. The method of Embodiment 11 wherein R3 is Cl. Embodiment 16. The method of Embodiment 11 wherein R3 is Br. Embodiment 17. The method of Embodiment 11 wherein R3 is CF3.
Embodiment 18. The method of Embodiment 1 wherein R4 is halogen or C1-C3 alkyl. Embodiment 19. The method of Embodiment 18 wherein R4 is halogen or methyl. Embodiment 20. The method of Embodiment 19 wherein R4 is halogen. Embodiment 21. The method of Embodiment 20 wherein R4 is Cl. Embodiment 22. The method of Embodiment 19 wherein R4 is methyl.
Embodiment 23. The method of Embodiment 1 wherein R5 is H. Embodiment 24. The method of Embodiment 1 wherein R6 is halogen or C1-C6 alkyl. Embodiment 25. The method of Embodiment 1 wherein R6 is C1-C6 alkyl substituted with one R7; Embodiment 26. The method of Embodiment 1 wherein R7 is OR9, S(O)nR10 or
C(O)NR11R12.
Embodiment 27. The method of Embodiment 26 wherein R7 is OR9. Embodiment 28. The method of Embodiment 26 wherein R7 is S(O)nR10. Embodiment 29. The method of Embodiment 26 wherein R7 is C(O)NR11R12. Embodiment 30. The method of Embodiment 1 wherein R9 is H or C1-C4 alkyl. Embodiment 31. The method of Embodiment 30 wherein R9 is H or methyl. Embodiment 32. The method of Embodiment 31 wherein R9 is H. Embodiment 33. The method of Embodiment 31 wherein R9 is methyl.
Embodiment 34. The method of Embodiment 1 wherein R10 is C1-C4 alkyl.
Embodiment 35. The method of Embodiment 1 wherein R11 is H.
Embodiment 36. The method of Embodiment 1 wherein R12 is C1-C4 alkyl or C1-C4 haloalkyl, each optionally substituted with one R13. Embodiment 37. The method of Embodiment 1 wherein R12 is C1-C4 alkyl or C1-C4 haloalkyl.
Embodiment 38. The method of Embodiment 37 wherein R12 is C1-C4 haloalkyl. Embodiment 38a. The method of Embodiment 1 wherein R12 is cyclopropyl or cyclopropylmethyl. Embodiment 39. The method of Embodiment 1 wherein R13 is cyano, OH, OR14 or
S(O)nR^.
Embodiment 40. The method of Embodiment 39 wherein R13 is cyano. Embodiment 41. The method of Embodiment 39 wherein R13 is OH. Embodiment 42. The method of Embodiment 39 wherein R13 is OR14. Embodiment 43. The method of Embodiment 39 wherein R13 is S(O)nR16.
Embodiment 44. The method of Embodiment 1 wherein the pesticidally effective amount of a compound of Formula 1 is administered orally. Embodiment 45. The method of Embodiment 1 wherein the pesticidally effective amount of a compound of Formula 1 is administered parenterally. Embodiment 46. The method of Embodiment 45 wherein the pesticidally effective amount of a compound of Formula 1 is administered by injection. Embodiment 47. The method of Embodiment 1 wherein the animal to be protected is a vertebrate.
Embodiment 48. The method of Embodiment 47 wherein the vertebrate to be protected is a mammal, avian or fish.
Embodiment 49. The method of Embodiment 48 wherein the vertebrate to be protected is a mammal. Embodiment 50. The method of Embodiment 48 wherein the vertebrate to be protected is an avian. Embodiment 51. The method of Embodiment 48 wherein the vertebrate to be protected is a fish. Embodiment 52. The method of Embodiment 49 wherein the mammal to be protected is a human. Embodiment 53. The method of Embodiment 49 wherein the mammal to be protected is livestock. Embodiment 54. The method of Embodiment 49 wherein the mammal to be protected is a canine. Embodiment 55. The method of Embodiment 49 wherein the mammal to be protected is a feline. Embodiment 56. The method of Embodiment 1 wherein the parasitic invertebrate pest is an ectoparasite.
Embodiment 57. The method of Embodiment 1 wherein the parasitic invertebrate pest is an endoparasite.
Embodiment 58. The method of Embodiment 1 wherein the parasitic invertebrate pest is an helminth. Embodiment 59. The method of Embodiment 1 wherein the parasitic invertebrate pest is an arthropod. Embodiment 60. The method of Embodiment 1 wherein the parasitic invertebrate pest is a fly, mosquito, mite, tick, louse, flea, true bug or maggot. Embodiment 61. The method of Embodiment 1 wherein the parasitic invertebrate pest is a fly, mosquito, mite, tick, louse, flea, bed bug, kissing bug or maggot. Embodiment 62. The method of Embodiment 61 wherein the parasitic invertebrate pest is a fly or maggot.
Embodiment 63. The method of Embodiment 61 wherein the parasitic invertebrate pest is a mosquito. Embodiment 64. The method of Embodiment 61 wherein the parasitic invertebrate pest is a tick or mite. Embodiment 65. The method of Embodiment 61 wherein the parasitic invertebrate pest is a louse. Embodiment 66. The method of Embodiment 61 wherein the parasitic invertebrate pest is a flea.
Embodiment 67. The method of Embodiment 61 wherein the parasitic invertebrate pest is a true bug.
Embodiment 68. The method of Embodiment 61 wherein the parasitic invertebrate pest is a bed bug or kissing bug. Embodiment 69. The method of Embodiment 61 wherein the animal to be protected is a cat or dog and the parasitic invertebrate pest is a flea, tick or mite. Embodiment 70. The method of Embodiment 44 wherein the parasiticidally effective amount of a compound of Formula 1 is administered orally two times a year. Embodiment 71. The method of Embodiment 44 wherein the parasiticidally effective amount of a compound of Formula 1 is administered orally once a month. Embodiment 72. The method of Embodiment 44 wherein the parasiticidally effective amount of a compound of Formula 1 is administered orally two times a month. Embodiments of this invention, including Embodiments 1-72 above as well as any other embodiments described herein, can be combined in any manner. Combinations of Embodiments 1-43 are illustrated by:
Embodiment A. The method of Embodiment 1 wherein RMs Cl5 Br Or CF3; R2 is H, F or Cl; and R3 is H, Cl, Br or CF3. Embodiment B . A method of Embodiment A wherein
R1 and R3 are Cl; and R2 is H. Embodiment C. A method of Embodiment A wherein
R1 and R3 are Br; and R2 is H.
Embodiment D. A method of Embodiment A wherein R1 and R3 are CF3; and R2 is H.
Embodiment E. A method of Embodiment A wherein R1, R2 and R3 are Cl.
Embodiment F. A method of Embodiment A wherein R1 and R3 are Cl; and R2 is F.
Embodiment G. A method of Embodiment A wherein R1 is CF3; and
R2 and R3 are H.
Embodiment H. A method of Embodiment A wherein R4 is methyl; and R5 is H. Embodiment I. A method of Embodiment A wherein
R5 is H;
R6 is C^-Cg alkyl substituted with one R7; and R7 is OR9, S(O)nR10 or C(O)NR11R12. Embodiment J. A method of Embodiment A wherein R7 is C(O)NR11R12; and
R12 is C1-C4 alkyl or C1-C4 haloalkyl, each optionally substituted with one R13. Embodiment K. A method of Embodiment A wherein R4 is Cl or CH3; R5 is H;
R6 is C1-Cg alkyl substituted with one R7; and R7 is OR9, S(O)nR10 or C(O)NR11R12. Embodiment L. A method of Embodiment K wherein R1 is Cl, Br, CF3, OCF3 or OCH2CF3;
R2 is H; and
R3 is H, F, Cl, Br or CF3. Embodiment M. A method of Embodiment L wherein
R4 is CH3; and R7 is C(O)NR11R12.
Embodiment N. A method of Embodiment M wherein R1 is CF3; and R3 is Cl, Br or CF3.
Embodiment O. A method of Embodiment M wherein R11 is H; and
R12 is C1-C4 alkyl or C1-C4 haloalkyl. Embodiment P. A method of Embodiment M wherein R11 is H; and
R12 is cyclopropyl or cyclopropylmethyl. Specific embodiments include the method of Embodiment 1 wherein compounds of
Formula 1 are selected from the group consisting of: 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2- methyl-Λ/-(2-pyridinylmethyl)benzamide,
4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2- methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]benzamide, 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2- methyl-Λ/-[2-(methylthio)ethyl]benzamide,
4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2- methyl-Λ/-[2-(methylsulfinyl)ethyl]benzamide,
4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2- methyl-Λ/-[2-(methylsulfonyl)ethyl]benzamide, and
4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2- methyl-JV-[ 1 -methyl-3-(methylthio)propyl]benzamide.
Further specific embodiments include the method of Embodiment 1 wherein compounds of Formula 1 are selected from Table A and B. The following abbreviation is used in Table A: c-Pr means cyclopropyl. TABLE A
Figure imgf000014_0001
CF3 CF3 CH2CF3 CF3 CF3 CH2CF3
CF3 CF3 c-Pr CF3 CF3 c-Pr
CF3 CF3 CH2-C-Pr CF3 CF3 CH2-C-Pr
TABLE B
3 3 3
3 3 3
3 3 3
Figure imgf000015_0001
3 Br CF3 1 CH2CH3 Br CF3 1 CH2CH3
Br CF3 2 CH2CH3 Br CF3 2 CH2CH3
CF3 CF3 0 CH3 CF3 CF3 0 CH3
CF3 CF3 1 CH3 CF3 CF3 1 CH3
CF3 CF3 2 CH3 CF3 CF3 2 CH3
CF3 CF3 0 CH2CH3 CF3 CF3 0 CH2CH3
CF3 CF3 1 CH2CH3 CF3 CF3 1 CH2CH3
CF3 CF3 2 CH2CH3 CF3 CF3 2 CH2CH3
The compounds of Formula 1 or any of Embodiments 1-43 or Embodiments A-P can be used for the protection of an animal from an invertebrate parasitic pest by oral or parenteral administration of the compound. Therefore, the invention is understood to include the compounds of Formula 1 or any of Embodiments 1-43 or Embodiments A-P (and compositions containing them) for use as an animal medicament, or more particularly a parasiticidal animal medicament. The animals to be protected are as defined in any of Embodiments 47-55. The invertebrate parasitic pests are as defined in any of Embodiments 56-68. The medicament may be in oral or parenteral dosage forms.
The invention is also understood to include the use of compounds of Formula 1 or any of Embodiments 1-43 or Embodiments A-P in the manufacture of medicaments for the protection of an animal from a an invertebrate parasitic pest. The animals to be protected are as defined in any of Embodiments 47-55. The invertebrate parasitic pests are as defined in any of Embodiments 56-68. The medicament may be in oral or parenteral dosage forms.
The invention is also understood to include compounds of Formula 1 or any of
Embodiments 1-43 or Embodiments A-P for use in the manufacture of medicaments for the protection of an animal from an invertebrate parasitic pest. The animals to be protected are as defined in any of Embodiments 47-55. The invertebrate parasitic pests are as defined in any of Embodiments 56-68. The medicament may be in oral or parenteral dosage forms.
The invention is also understood to include compounds of Formula 1 or any of Embodiments 1-43 or Embodiments A-P packaged and presented for the protection of an animal from an invertebrate parasitic pest. The animals to be protected are as defined in any of Embodiments 47-55. The invertebrate parasitic pests are as defined in any of Embodiments 56-68. The compounds of the invention may be packaged and presented as oral or parenteral dosage forms.
The invention is also understood to include a process for manufacturing a composition for protecting an animal from an invertebrate parasitic pest characterized in that a compound of Claim 1 is admixed with at least one pharmaceutically or veterinarily acceptable carrier. The animals to be protected are as defined in any of Embodiments 47-55. The invertebrate parasitic pests are as defined in any of Embodiments 56-68. The compositions of the invention may be packaged and presented as oral or parenteral dosage forms.
Isoxazolines of Formula 1 can be prepared as described in PCT Patent Publication WO 2005/085216. One skilled in the art will appreciate that not all pyridine heterocycles can form
TV-oxides; one skilled in the art will recognize those pyridine heterocycles which can form TV-oxides. Synthetic methods for the preparation of TV-oxides of pyridine heterocycles are very well known by one skilled in the art including the oxidation of heterocycles with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for the preparation of TV-oxides have been extensively described and reviewed in the literature, see for example: T. L. Gilchrist in Comprehensive Organic Synthesis, vol. 7, pp 748-750, S. V. Ley, Ed., Pergamon Press; M. Tisler and B. Stanovnik in Comprehensive Heterocyclic Chemistry, vol. 3, pp 18-20, A. J. Boulton and A. McKillop, Eds., Pergamon Press; M. R. Grimmett and B. R. T. Keene in Advances in Heterocyclic Chemistry, vol. 43, pp 149-161, A. R. Katritzky, Ed., Academic Press; M. Tisler and B. Stanovnik in Advances in Heterocyclic Chemistry, vol. 9, pp 285-291, A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk in Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press.
One skilled in the art recognizes that because in the environment and under physiological conditions salts of chemical compounds are in equilibrium with their corresponding nonsalt forms, salts share the biological utility of the nonsalt forms. Thus a wide variety of salts of the compounds of Formula 1 are useful for control of invertebrate pests and animal parasites. The salts of the compounds of Formula 1 include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids. Accordingly, the method of the present invention comprises compounds selected from Formula 1, TV-oxides and salts thereof. By the procedures described in PCT Patent Publication WO 2005/085216 together with methods known in the art, the following compounds of Tables 1-4 can be prepared. These tables disclose specific compounds illustrative of compounds of Formula 1 useful in the present method. The following abbreviations are used in the Tables which follow: Me means methyl, Et means ethyl, n-Pr means CH2CH2CH3, z-Pr means CH(CH3)2, c-Pr means cyclopropyl, z-Bu means CH2CH(CH3)2, s-Bu means CH(CH3)CH2CH3, t-Eu means C(CH3)3, S(O) means sulfinyl, S(O)2 means sulfonyl, and C(O) means carbonyl. TABLE 1
Figure imgf000018_0001
3
R1 is Br, R3 is Br
S^ S^ S^
CH2CH2SMe CH2C(O)NH2 CH2C(O)NH(C-Pr)
CH2CH2SEt CH2C(O)NH(Me) CH2C(O)NH(CH2-C-Pr)
CH2CH2S(W-Pr) CH2C(O)NH(Et) CH2C(O)NHCH2CH2Cl
CH2CH2CH2SMe CH2C(O)NH(W-Pr) CH2C(O)NHCH2CHF2
CH2CH2CH2SEt CH2C(O)NH(Z-Pr) CH2C(O)NHCH2CF3
CH2CH2S(O)Me CH2C(O)NH(Z-Bu) CH2C(O)NHCH2CH2CF3
CH2CH2S(O)Et CH2C(O)NH(S-Bu) CH2C(O)NHCH(Me)CF3 CH2CH2S(O)(W-Pr) CH(Me)C(O)NH(Me) CH2C(O)NHCH2CH(Me)CF3
CH2CH2CH2S(O)Me CH(Me)C(O)NH(Et) CH(Me)C(O)NH(C-Pr)
CH2CH2CH2S(O)Et CH(Me)C(O)NH(W-Pr) CH(Me)C(O)NH(CH2-C-Pr)
CH2CH2SO2Me CH(Me)C(O)NH(Z-Pr) CH(Me)C(O)NHCH2CH2Cl
CH2CH2SO2Et CH(Me)C(O)NH(Z-Bu) CH(Me)C(O)NHCH2CHF2
CH2CH2SO2(W-Pr) CH(Me)C(O)NH(S-Bu) CH(Me)C(O)NHCH2CF3
CH2CH2CH2SO2Me CH2(4-thiazolyl) CH(Me)C(O)NHCH2CH2CF3
CH2CH2CH2SO2Et CH2C(O)N(Me)CH2CF3 CH(Me)C(O)NHCH(Me)CF3
CH2(2-pyridinyl) CH(Me)C(O)N(Me)CH2CF3 CH(Me)C(O)NHCH2CH(Me)CF3
Figure imgf000019_0001
3
R1 is CF2. R3 is F
S^ S^
CH2CH2SMe CH2C(O)NH2 CH2C(O)NH(C-Pr)
CH2CH2SEt CH2C(O)NH(Me) CH2C(O)NH(CH2-C-Pr)
CH2CH2S(W-Pr) CH2C(O)NH(Et) CH2C(O)NHCH2CH2Cl
CH2CH2CH2SMe CH2C(O)NH(W-Pr) CH2C(O)NHCH2CHF2
CH2CH2CH2SEt CH2C(O)NH(Z-Pr) CH2C(O)NHCH2CF3
CH2CH2S(O)Me CH2C(O)NH(Z-Bu) CH2C(O)NHCH2CH2CF3
CH2CH2S(O)Et CH2C(O)NH(S-Bu) CH2C(O)NHCH(Me)CF3 CH2CH2S(O)(W-Pr) CH(Me)C(O)NH(Me) CH2C(O)NHCH2CH(Me)CF3
CH2CH2CH2S(O)Me CH(Me)C(O)NH(Et) CH(Me)C(O)NH(C-Pr)
CH2CH2CH2S(O)Et CH(Me)C(O)NH(W-Pr) CH(Me)C(O)NH(CH2-C-Pr)
CH2CH2SO2Me CH(Me)C(O)NH(Z-Pr) CH(Me)C(O)NHCH2CH2Cl
CH2CH2SO2Et CH(Me)C(O)NH(Z-Bu) CH(Me)C(O)NHCH2CHF2
CH2CH2SO2(W-Pr) CH(Me)C(O)NH(S-Bu) CH(Me)C(O)NHCH2CF3
CH2CH2CH2SO2Me CH2(4-thiazolyl) CH(Me)C(O)NHCH2CH2CF3
CH2CH2CH2SO2Et CH2C(O)N(Me)CH2CF3 CH(Me)C(O)NHCH(Me)CF3
CH2(2-pyridinyl) CH(Me)C(O)N(Me)CH2CF3 CH(Me)C(O)NHCH2CH(Me)CF3
Figure imgf000020_0001
3
R1 is CF2. R3 is Br
S^ S^ S^
CH2CH2SMe CH2C(O)NH2 CH2C(O)NH(C-Pr)
CH2CH2SEt CH2C(O)NH(Me) CH2C(O)NH(CH2-C-Pr)
CH2CH2S(W-Pr) CH2C(O)NH(Et) CH2C(O)NHCH2CH2Cl
CH2CH2CH2SMe CH2C(O)NH(W-Pr) CH2C(O)NHCH2CHF2
CH2CH2CH2SEt CH2C(O)NH(Z-Pr) CH2C(O)NHCH2CF3
CH2CH2S(O)Me CH2C(O)NH(Z-Bu) CH2C(O)NHCH2CH2CF3
CH2CH2S(O)Et CH2C(O)NH(S-Bu) CH2C(O)NHCH(Me)CF3 CH2CH2S(O)(W-Pr) CH(Me)C(O)NH(Me) CH2C(O)NHCH2CH(Me)CF3
CH2CH2CH2S(O)Me CH(Me)C(O)NH(Et) CH(Me)C(O)NH(C-Pr)
CH2CH2CH2S(O)Et CH(Me)C(O)NH(W-Pr) CH(Me)C(O)NH(CH2-C-Pr)
CH2CH2SO2Me CH(Me)C(O)NH(Z-Pr) CH(Me)C(O)NHCH2CH2Cl
CH2CH2SO2Et CH(Me)C(O)NH(Z-Bu) CH(Me)C(O)NHCH2CHF2
CH2CH2SO2(W-Pr) CH(Me)C(O)NH(S-Bu) CH(Me)C(O)NHCH2CF3
CH2CH2CH2SO2Me CH2(4-thiazolyl) CH(Me)C(O)NHCH2CH2CF3
CH2CH2CH2SO2Et CH2C(O)N(Me)CH2CF3 CH(Me)C(O)NHCH(Me)CF3
CH2(2-pyridinyl) CH(Me)C(O)N(Me)CH2CF3 CH(Me)C(O)NHCH2CH(Me)CF3
3
Figure imgf000021_0001
CH2CH2S(O)(W-Pr) CH(Me)C(O)NH(Me) CH2C(O)NHCH2CH(Me)CF3
CH2CH2CH2S(O)Me CH(Me)C(O)NH(Et) CH(Me)C(O)NH(C-Pr)
CH2CH2CH2S(O)Et CH(Me)C(O)NH(W-Pr) CH(Me)C(O)NH(CH2-C-Pr)
CH2CH2SO2Me CH(Me)C(O)NH(Z-Pr) CH(Me)C(O)NHCH2CH2Cl
CH2CH2SO2Et CH(Me)C(O)NH(Z-Bu) CH(Me)C(O)NHCH2CHF2
CH2CH2SO2(W-Pr) CH(Me)C(O)NH(S-Bu) CH(Me)C(O)NHCH2CF3
CH2CH2CH2SO2Me CH2(4-thiazolyl) CH(Me)C(O)NHCH2CH2CF3
CH2CH2CH2SO2Et CH2C(O)N(Me)CH2CF3 CH(Me)C(O)NHCH(Me)CF3
CH2(2-pyridinyl) CH(Me)C(O)N(Me)CH2CF3 CH(Me)C(O)NHCH2CH(Me)CF3
3
Figure imgf000022_0001
CH2CH2S(O)(W-Pr) CH(Me)C(O)NH(Me) CH2C(O)NHCH2CH(Me)CF3
CH2CH2CH2S(O)Me CH(Me)C(O)NH(Et) CH(Me)C(O)NH(C-Pr)
CH2CH2CH2S(O)Et CH(Me)C(O)NH(W-Pr) CH(Me)C(O)NH(CH2-C-Pr)
CH2CH2SO2Me CH(Me)C(O)NH(Z-Pr) CH(Me)C(O)NHCH2CH2Cl
CH2CH2SO2Et CH(Me)C(O)NH(Z-Bu) CH(Me)C(O)NHCH2CHF2
CH2CH2SO2(W-Pr) CH(Me)C(O)NH(S-Bu) CH(Me)C(O)NHCH2CF3
CH2CH2CH2SO2Me CH2(4-thiazolyl) CH(Me)C(O)NHCH2CH2CF3
CH2CH2CH2SO2Et CH2C(O)N(Me)CH2CF3 CH(Me)C(O)NHCH(Me)CF3
CH2(2-pyridinyl) CH(Me)C(O)N(Me)CH2CF3 CH(Me)C(O)NHCH2CH(Me)CF3
Figure imgf000023_0001
3
TABLE 2
Figure imgf000024_0001
Figure imgf000024_0002
3
R1 is CL R2 is F. R3 is Cl
S^ S^ S^
CH2CH2SMe CH2C(O)NH2 CH2C(O)NH(C-Pr)
CH2CH2SEt CH2C(O)NH(Me) CH2C(O)NH(CH2-C-Pr)
CH2CH2S(W-Pr) CH2C(O)NH(Et) CH2C(O)NHCH2CH2Cl
CH2CH2CH2SMe CH2C(O)NH(W-Pr) CH2C(O)NHCH2CHF2
CH2CH2CH2SEt CH2C(O)NH(Z-Pr) CH2C(O)NHCH2CF3
CH2CH2S(O)Me CH2C(O)NH(Z-Bu) CH2C(O)NHCH2CH2CF3
CH2CH2S(O)Et CH2C(O)NH(S-Bu) CH2C(O)NHCH(Me)CF3 CH2CH2S(O)(W-Pr) CH(Me)C(O)NH(Me) CH2C(O)NHCH2CH(Me)CF3
CH2CH2CH2S(O)Me CH(Me)C(O)NH(Et) CH(Me)C(O)NH(C-Pr)
CH2CH2CH2S(O)Et CH(Me)C(O)NH(«-Pr) CH(Me)C(O)NH(CH2-C-Pr)
CH2CH2SO2Me CH(Me)C(O)NH(Z-Pr) CH(Me)C(O)NHCH2CH2Cl
CH2CH2SO2Et CH(Me)C(O)NH(Z-Bu) CH(Me)C(O)NHCH2CHF2
CH2CH2SO2(W-Pr) CH(Me)C(O)NH(S-Bu) CH(Me)C(O)NHCH2CF3
CH2CH2CH2SO2Me CH2(4-thiazolyl) CH(Me)C(O)NHCH2CH2CF3
CH2CH2CH2SO2Et CH2C(O)N(Me)CH2CF3 CH(Me)C(O)NHCH(Me)CF3
CH2(2-pyridinyl) CH(Me)C(O)N(Me)CH2CF3 CH(Me)C(O)NHCH2CH(Me)CF3
Figure imgf000025_0001
3
R1 is Br. R2 is H. R3 is H
S^ S^ S^
CH2CH2SMe CH2C(O)NH2 CH2C(O)NH(C-Pr)
CH2CH2SEt CH2C(O)NH(Me) CH2C(O)NH(CH2-C-Pr)
CH2CH2S(W-Pr) CH2C(O)NH(Et) CH2C(O)NHCH2CH2Cl
CH2CH2CH2SMe CH2C(O)NH(W-Pr) CH2C(O)NHCH2CHF2
CH2CH2CH2SEt CH2C(O)NH(Z-Pr) CH2C(O)NHCH2CF3
CH2CH2S(O)Me CH2C(O)NH(Z-Bu) CH2C(O)NHCH2CH2CF3
CH2CH2S(O)Et CH2C(O)NH(S-Bu) CH2C(O)NHCH(Me)CF3 CH2CH2S(O)(W-Pr) CH(Me)C(O)NH(Me) CH2C(O)NHCH2CH(Me)CF3
CH2CH2CH2S(O)Me CH(Me)C(O)NH(Et) CH(Me)C(O)NH(C-Pr)
CH2CH2CH2S(O)Et CH(Me)C(O)NH(«-Pr) CH(Me)C(O)NH(CH2-C-Pr)
CH2CH2SO2Me CH(Me)C(O)NH(Z-Pr) CH(Me)C(O)NHCH2CH2Cl
CH2CH2SO2Et CH(Me)C(O)NH(Z-Bu) CH(Me)C(O)NHCH2CHF2
CH2CH2SO2(W-Pr) CH(Me)C(O)NH(S-Bu) CH(Me)C(O)NHCH2CF3
CH2CH2CH2SO2Me CH2(4-thiazolyl) CH(Me)C(O)NHCH2CH2CF3
CH2CH2CH2SO2Et CH2C(O)N(Me)CH2CF3 CH(Me)C(O)NHCH(Me)CF3
CH2(2-pyridinyl) CH(Me)C(O)N(Me)CH2CF3 CH(Me)C(O)NHCH2CH(Me)CF3
Figure imgf000026_0001
3
R1 is Br. R2 is F. R3 is Br
S^ S^ S^
CH2CH2SMe CH2C(O)NH2 CH2C(O)NH(C-Pr)
CH2CH2SEt CH2C(O)NH(Me) CH2C(O)NH(CH2-C-Pr)
CH2CH2S(W-Pr) CH2C(O)NH(Et) CH2C(O)NHCH2CH2Cl
CH2CH2CH2SMe CH2C(O)NH(W-Pr) CH2C(O)NHCH2CHF2
CH2CH2CH2SEt CH2C(O)NH(Z-Pr) CH2C(O)NHCH2CF3
CH2CH2S(O)Me CH2C(O)NH(Z-Bu) CH2C(O)NHCH2CH2CF3
CH2CH2S(O)Et CH2C(O)NH(S-Bu) CH2C(O)NHCH(Me)CF3 CH2CH2S(O)(W-Pr) CH(Me)C(O)NH(Me) CH2C(O)NHCH2CH(Me)CF3
CH2CH2CH2S(O)Me CH(Me)C(O)NH(Et) CH(Me)C(O)NH(C-Pr)
CH2CH2CH2S(O)Et CH(Me)C(O)NH(«-Pr) CH(Me)C(O)NH(CH2-C-Pr)
CH2CH2SO2Me CH(Me)C(O)NH(Z-Pr) CH(Me)C(O)NHCH2CH2Cl
CH2CH2SO2Et CH(Me)C(O)NH(Z-Bu) CH(Me)C(O)NHCH2CHF2
CH2CH2SO2(W-Pr) CH(Me)C(O)NH(S-Bu) CH(Me)C(O)NHCH2CF3
CH2CH2CH2SO2Me CH2(4-thiazolyl) CH(Me)C(O)NHCH2CH2CF3
CH2CH2CH2SO2Et CH2C(O)N(Me)CH2CF3 CH(Me)C(O)NHCH(Me)CF3
CH2(2-pyridinyl) CH(Me)C(O)N(Me)CH2CF3 CH(Me)C(O)NHCH2CH(Me)CF3
Figure imgf000027_0001
3
R1 is Br. R2 is CL R3 is Br
S^ S^ S^
CH2CH2SMe CH2C(O)NH2 CH2C(O)NH(C-Pr)
CH2CH2SEt CH2C(O)NH(Me) CH2C(O)NH(CH2-C-Pr)
CH2CH2S(W-Pr) CH2C(O)NH(Et) CH2C(O)NHCH2CH2Cl
CH2CH2CH2SMe CH2C(O)NH(W-Pr) CH2C(O)NHCH2CHF2
CH2CH2CH2SEt CH2C(O)NH(Z-Pr) CH2C(O)NHCH2CF3
CH2CH2S(O)Me CH2C(O)NH(Z-Bu) CH2C(O)NHCH2CH2CF3
CH2CH2S(O)Et CH2C(O)NH(S-Bu) CH2C(O)NHCH(Me)CF3 CH2CH2S(O)(W-Pr) CH(Me)C(O)NH(Me) CH2C(O)NHCH2CH(Me)CF3
CH2CH2CH2S(O)Me CH(Me)C(O)NH(Et) CH(Me)C(O)NH(C-Pr)
CH2CH2CH2S(O)Et CH(Me)C(O)NH(«-Pr) CH(Me)C(O)NH(CH2-C-Pr)
CH2CH2SO2Me CH(Me)C(O)NH(Z-Pr) CH(Me)C(O)NHCH2CH2Cl
CH2CH2SO2Et CH(Me)C(O)NH(Z-Bu) CH(Me)C(O)NHCH2CHF2
CH2CH2SO2(W-Pr) CH(Me)C(O)NH(S-Bu) CH(Me)C(O)NHCH2CF3
CH2CH2CH2SO2Me CH2(4-thiazolyl) CH(Me)C(O)NHCH2CH2CF3
CH2CH2CH2SO2Et CH2C(O)N(Me)CH2CF3 CH(Me)C(O)NHCH(Me)CF3
CH2(2-pyridinyl) CH(Me)C(O)N(Me)CH2CF3 CH(Me)C(O)NHCH2CH(Me)CF3
CH2C(O)NH(C-Pr)
CH2C(O)NH(CH2-C-Pr)
CH2C(O)NHCH2CH2Cl
CH2C(O)NHCH2CHF2
CH2C(O)NHCH2CF3
CH2C(O)NHCH2CH2CF3
CH2C(O)NHCH(Me)CF3
CH2C(O)NHCH2CH(Me)CF3
CH(Me)C(O)NH(C-Pr)
CH(Me)C(O)NH(CH2-C-Pr)
CH(Me)C(O)NHCH2CH2Cl
CH(Me)C(O)NHCH2CHF2
CH(Me)C(O)NHCH2CF3
CH(Me)C(O)NHCH2CH2CF3
CH(Me)C(O)NHCH(Me)CF3
Figure imgf000028_0001
CH(Me)C(O)NHCH2CH(Me)CF3
TABLE 3
Figure imgf000029_0001
Figure imgf000029_0002
CH2CH2S(Z-Pr) CH2C(O)NH(CH2)2CH2F C(Me)2C(O)NH(S-Bu)
CH2CH2S(Z-Bu) CH2C(O)NHCH2CH2CF3 CH2C(O)N(Me)CH2CH2F
CH2CH(Me)SMe CH2C(O)NHCH2CHFCF3 CH2C(O)N(Me)CH2CH2Cl
CH2CH(CF3)SMe CH2C(O)NHCH2CF2CF3 CH2C(O)N(Me)CH2CHF2
CH2C(Me)2SMe CH2C(O)NHCH(Me)CF3 CH2C(O)N(Me)CH2CF3
CH(Me)CH2SMe CH2C(O)NHCH(CF3)2 CH2C(O)N(Me)CH2CH2CH2F
C(Me)2CH2SMe CH2C(O)NHC(Me)2CF3 CH2C(O)N(Me)CH2CH2CF3
CH(Et)CH2SMe CH2C(O)NHCH2CH(Me)CF3 CH2C(O)N(Me)CH2CF2CF3
CH(Z-Pr)CH2SMe CH2C(O)NH(CH2)2CF2CF3 CH2C(O)N(Me)CH(Me)CF3
CH(Z-Bu)CH2SMe CH2C(O)NHCH2(CF2)2CF3 CH2C(O)N(Me)CH(CF3)2
CH2CH2CH2SMe CH(Me)C(O)NHCH2CH2F CH2C(O)N(Me)C(Me)2CF3
CH2CH2CH2SEt CH(Me)C(O)NHCH2CH2Cl CH(Me)C(O)N(Me)CH2CH2F
CH2CH2CH(Me)SMe CH(Me)C(O)NHCH2CHF2 CH(Me)C(O)N(Me)CH2CH2Cl
CH2CH2CH(CF3)SMe CH(Me)C(O)NHCH2CF3 CH(Me)C(O)N(Me)CH2CHF2
CH(Me)CH2CH2SMe CH(Me)C(O)NHCH2CH(Me)F CH(Me)C(O)N(Me)CH2CF3
CH(Et)CH2CH2SMe CH(Me)C(O)NHCH2C(Me)2F CH(Me)C(O)N(Me)(CH2)2CH2F
CH2CH(Me)CH2SMe CH(Me)C(O)NH(CH2)2CH2F CH(Me)C(O)N(Me)CH2CH2CF3
CH2C(Me)2CH2SMe CH(Me)C(O)NHCH2CH2CF3 CH(Me)C(O)N(Me)CH2CF2CF3
CH2CH2S(O)Me CH(Me)C(O)NHCH2CHFCF3 CH(Me)C(O)N(Me)CH(Me)CF3
CH2CH2S(O)Et CH(Me)C(O)NHCH2CF2CF3 CH(Me)C(O)N(Me)CH(CF3)2
CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH(Me)C(O)N(Me)C(Me)2CF3
CH2CH2S(O)(Z-Pr) CH(Me)C(O)NHCH(CF3)2 C(Me)2C(O)N(Me)CH2CH2F
CH2CH2S(O)(Z-Bu) CH(Me)C(O)NHC(Me)2CF3 C(Me)2C(O)N(Me)CH2CH2Cl
CH2CH(Me)S(O)Me CH(Me)C(O)NHCH2CH(Me)CF3 C(Me)2C(O)N(Me)CH2CHF2
CH2CH(CF3)S(O)Me CH(Me)C(O)NH(CH2)2CF2CF3 C(Me)2C(O)N(Me)CH2CF3
CH2C(Me)2S(O)Me CH(Me)C(O)NHCH2(CF2)2CF3 C(Me)2C(O)N(Me)CH2CH2CH2F
CH(Me)CH2S(O)Me C(Me)2C(O)NHCH2CH2F C(Me)2C(O)N(Me)CH2CH2CF3
CH(Et)CH2S(O)Me C(Me)2C(O)NHCH2CH2Cl C(Me)2C(O)N(Me)CH2CF2CF3
CH(Z-Bu)CH2S(O)Me C(Me)2C(O)NHCH2CHF2 C(Me)2C(O)N(Me)CH(Me)CF3
CH2CH2CH2S(O)Me C(Me)2C(O)NHCH2CF3 C(Me)2C(O)N(Me)CH(CF3)2
CH2CH2CH2S(O)Et C(Me)2C(O)NHCH2CH(Me)F C(Me)2C(O)N(Me)C(Me)2CF3
CH2CH2CH2S(O)(Z-Bu) C(Me)2C(O)NHCH2C(Me)2F C(Me)2C(O)NHCH(Me)CF3
CH2CH2CH(Me)S(O)Me C(Me)2C(O)NH(CH2)2CH2F C(Me)2C(O)NHCH(CF3)2
CH2CH2CH(CF3)S(O)Me C(Me)2C(O)NHCH2CH2CF3 C(Me)2C(O)NHC(Me)2CF3
CH(Me)CH2CH2S(O)Me C(Me)2C(O)NHCH2CHFCF3 C(Me)2C(O)NHCH2CH(Me)CF3
CH(Et)CH2CH2S(O)Me C(Me)2C(O)NHCH2CF2CF3 C(Me)2C(O)NH(CH2)2CF2CF3
CH2CH(Me)CH2S(O)Me CH2C(O)NH(C-Pr) C(Me)2C(O)NHCH2(CF2)2CF3
CH2C(Me)2CH2S(O)Me CH2C(O)NH(CH2-C-Pr) C(Me)2C(O)NHCH(Z-Pr)CF3 CH2(2-pyridinyl) CH2(4-thiazolyl) CH(Me)C(O)NH(C-Pr)
CH(Me)C(O)NH(CH2-C-Pr)
Figure imgf000031_0001
CH(Et)CH2SMe CH2C(O)NHCH2CH(Me)CF3 CH2C(O)N(Me)CH2CF2CF3
CH(Z-Pr)CH2SMe CH2C(O)NH(CH2)2CF2CF3 CH2C(O)N(Me)CH(Me)CF3
CH(Z-Bu)CH2SMe CH2C(O)NHCH2(CF2)2CF3 CH2C(O)N(Me)CH(CF3)2
CH2CH2CH2SMe CH(Me)C(O)NHCH2CH2F CH2C(O)N(Me)C(Me)2CF3
CH2CH2CH2SEt CH(Me)C(O)NHCH2CH2Cl CH(Me)C(O)N(Me)CH2CH2F
CH2CH2CH(Me)SMe CH(Me)C(O)NHCH2CHF2 CH(Me)C(O)N(Me)CH2CH2Cl
CH2CH2CH(CF3)SMe CH(Me)C(O)NHCH2CF3 CH(Me)C(O)N(Me)CH2CHF2
CH(Me)CH2CH2SMe CH(Me)C(O)NHCH2CH(Me)F CH(Me)C(O)N(Me)CH2CF3
CH(Et)CH2CH2SMe CH(Me)C(O)NHCH2C(Me)2F CH(Me)C(O)N(Me)(CH2)2CH2F
CH2CH(Me)CH2SMe CH(Me)C(O)NH(CH2)2CH2F CH(Me)C(O)N(Me)CH2CH2CF3
CH2C(Me)2CH2SMe CH(Me)C(O)NHCH2CH2CF3 CH(Me)C(O)N(Me)CH2CF2CF3
CH2CH2S(O)Me CH(Me)C(O)NHCH2CHFCF3 CH(Me)C(O)N(Me)CH(Me)CF3
CH2CH2S(O)Et CH(Me)C(O)NHCH2CF2CF3 CH(Me)C(O)N(Me)CH(CF3)2
CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH(Me)C(O)N(Me)C(Me)2CF3
CH2CH2S(O)(Z-Pr) CH(Me)C(O)NHCH(CF3)2 C(Me)2C(O)N(Me)CH2CH2F
CH2CH2S(O)(Z-Bu) CH(Me)C(O)NHC(Me)2CF3 C(Me)2C(O)N(Me)CH2CH2Cl
CH2CH(Me)S(O)Me CH(Me)C(O)NHCH2CH(Me)CF3 C(Me)2C(O)N(Me)CH2CHF2
CH2CH(CF3)S(O)Me CH(Me)C(O)NH(CH2)2CF2CF3 C(Me)2C(O)N(Me)CH2CF3
CH2C(Me)2S(O)Me CH(Me)C(O)NHCH2(CF2)2CF3 C(Me)2C(O)N(Me)CH2CH2CH2F
CH(Me)CH2S(O)Me C(Me)2C(O)NHCH2CH2F C(Me)2C(O)N(Me)CH2CH2CF3
CH(Et)CH2S(O)Me C(Me)2C(O)NHCH2CH2Cl C(Me)2C(O)N(Me)CH2CF2CF3
CH(Z-Bu)CH2S(O)Me C(Me)2C(O)NHCH2CHF2 C(Me)2C(O)N(Me)CH(Me)CF3
CH2CH2CH2S(O)Me C(Me)2C(O)NHCH2CF3 C(Me)2C(O)N(Me)CH(CF3)2
CH2CH2CH2S(O)Et C(Me)2C(O)NHCH2CH(Me)F C(Me)2C(O)N(Me)C(Me)2CF3
CH2CH2CH2S(O)(Z-Bu) C(Me)2C(O)NHCH2C(Me)2F C(Me)2C(O)NHCH(Me)CF3
CH2CH2CH(Me)S(O)Me C(Me)2C(O)NH(CH2)2CH2F C(Me)2C(O)NHCH(CF3)2
CH2CH2CH(CF3)S(O)Me C(Me)2C(O)NHCH2CH2CF3 C(Me)2C(O)NHC(Me)2CF3
CH(Me)CH2CH2S(O)Me C(Me)2C(O)NHCH2CHFCF3 C(Me)2C(O)NHCH2CH(Me)CF3
CH(Et)CH2CH2S(O)Me C(Me)2C(O)NHCH2CF2CF3 C(Me)2C(O)NH(CH2)2CF2CF3
CH2CH(Me)CH2S(O)Me CH2C(O)NH(C-Pr) C(Me)2C(O)NHCH2(CF2)2CF3
CH2C(Me)2CH2S(O)Me CH2C(O)NH(CH2-C-Pr) C(Me)2C(O)NHCH(Z-Pr)CF3
CH2(2-pyridinyl) CH2(4-thiazolyl) CH(Me)C(O)NH(C-Pr)
CH(Me)C(O)NH(CH2-C-Pr)
R1 is CF,, R3 is H
"^ R^
CH2CH2OH CH2CH2SO2Me CH2C(O)NH(Me)
CH2CH2OMe CH2CH2SO2Et CH2C(O)NH(Et) CH2CH2OEt CH2CH2SO2(W-Pr) CH2C(O)NH(W-Pr)
CH2CH2O(Z-Pr) CH2CH2SO2(Z-Pr) CH2C(O)NH(Z-Pr)
CH2CH(Me)OH CH2CH(Me)SO2Me CH2C(O)NH(W-Bu)
CH2CH(CF3)OH CH2CH(CF3)SO2Me CH2C(O)NH(Z-Bu)
CH2C(Me)2OH CH2C(Me)2SO2Me CH2C(O)NH(.s-Bu)
CH2C(CF3)(Me)OH CH(Me)CH2SO2Me CH2C(O)NMe2
CH(Me)CH2OH C(Me)2CH2SO2Me CH2C(O)NMe(Et)
C(Me)2CH2OH CH(Et)CH2SO2Me CH2C(O)NEt2
CH(Et)CH2OH CH(Z-Pr)CH2SO2Me CH2C(O)NMe(W-Pr)
CH(Z-Pr)CH2OH CH(Z-Bu)CH2SO2Me CH2C(O)NMe(Z-Pr)
CH(Z-Bu)CH2OH CH2CH2CH2SO2Me CH2C(O)NMe(S-Bu)
CH(Me)CH(CF3)OH CH2CH2CH2SO2Et CH(Me)C(O)NH(Me)
CH2CH2CH2OH CH2CH2CH(Me)SO2Me CH(Me)C(O)NH(Et)
CH2CH2CH2OMe CH2CH2CH(CF3)SO2Me CH(Me)C(O)NH(W-Pr)
CH2CH2CH2OEt CH(Me)CH2CH2SO2Me CH(Me)C(O)NH(Z-Pr)
CH2CH2CH(CF3)OH CH(Et)CH2CH2SO2Me CH(Me)C(O)NH(W-Bu)
CH(Me)CH2CH2OH CH2CH(Me)CH2SO2Me CH(Me)C(O)NH(Z-Bu)
CH2CH(Me)CH2OH CH2C(Me)2CH2SO2Me CH(Me)C(O)NH(S-Bu)
CH2C(Me)2CH2OH CH2C(O)NHCH2CH2F C(Me)2C(O)NH(Me)
CH2CH2CH(Me)OH CH2C(O)NHCH2CH2Cl C(Me)2C(O)NH(Et)
CH2CH2C(Me)2OH CH2C(O)NHCH2CHF2 C(Me)2C(O)NH(W-Pr)
CH2CH2SMe CH2C(O)NHCH2CF3 C(Me)2C(O)NH(Z-Pr)
CH2CH2SEt CH2C(O)NHCH2CH(Me)F C(Me)2C(O)NH(W-Bu)
CH2CH2S(W-Pr) CH2C(O)NHCH2C(Me)2F C(Me)2C(O)NH(Z-Bu)
CH2CH2S(Z-Pr) CH2C(O)NH(CH2)2CH2F C(Me)2C(O)NH(S-Bu)
CH2CH2S(Z-Bu) CH2C(O)NHCH2CH2CF3 CH2C(O)N(Me)CH2CH2F
CH2CH(Me)SMe CH2C(O)NHCH2CHFCF3 CH2C(O)N(Me)CH2CH2Cl
CH2CH(CF3)SMe CH2C(O)NHCH2CF2CF3 CH2C(O)N(Me)CH2CHF2
CH2C(Me)2SMe CH2C(O)NHCH(Me)CF3 CH2C(O)N(Me)CH2CF3
CH(Me)CH2SMe CH2C(O)NHCH(CF3)2 CH2C(O)N(Me)CH2CH2CH2F
C(Me)2CH2SMe CH2C(O)NHC(Me)2CF3 CH2C(O)N(Me)CH2CH2CF3
CH(Et)CH2SMe CH2C(O)NHCH2CH(Me)CF3 CH2C(O)N(Me)CH2CF2CF3
CH(Z-Pr)CH2SMe CH2C(O)NH(CH2)2CF2CF3 CH2C(O)N(Me)CH(Me)CF3
CH(Z-Bu)CH2SMe CH2C(O)NHCH2(CF2)2CF3 CH2C(O)N(Me)CH(CF3)2
CH2CH2CH2SMe CH(Me)C(O)NHCH2CH2F CH2C(O)N(Me)C(Me)2CF3
CH2CH2CH2SEt CH(Me)C(O)NHCH2CH2Cl CH(Me)C(O)N(Me)CH2CH2F
CH2CH2CH(Me)SMe CH(Me)C(O)NHCH2CHF2 CH(Me)C(O)N(Me)CH2CH2Cl
CH2CH2CH(CF3)SMe
Figure imgf000033_0001
CH(Me)C(O)NHCH2CF3
Figure imgf000033_0002
CH(Me)C(O)N(Me)CH2CHF2 CH(Me)CH2CH2SMe CH(Me)C(O)NHCH2CH(Me)F CH(Me)C(O)N(Me)CH2CF3
CH(Et)CH2CH2SMe CH(Me)C(O)NHCH2C(Me)2F CH(Me)C(O)N(Me)(CH2)2CH2F
CH2CH(Me)CH2SMe CH(Me)C(O)NH(CH2)2CH2F CH(Me)C(O)N(Me)CH2CH2CF3
CH2C(Me)2CH2SMe CH(Me)C(O)NHCH2CH2CF3 CH(Me)C(O)N(Me)CH2CF2CF3
CH2CH2S(O)Me CH(Me)C(O)NHCH2CHFCF3 CH(Me)C(O)N(Me)CH(Me)CF3
CH2CH2S(O)Et CH(Me)C(O)NHCH2CF2CF3 CH(Me)C(O)N(Me)CH(CF3)2
CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH(Me)C(O)N(Me)C(Me)2CF3
CH2CH2S(O)(Z-Pr) CH(Me)C(O)NHCH(CF3)2 C(Me)2C(O)N(Me)CH2CH2F
CH2CH2S(O)(Z-Bu) CH(Me)C(O)NHC(Me)2CF3 C(Me)2C(O)N(Me)CH2CH2Cl
CH2CH(Me)S(O)Me CH(Me)C(O)NHCH2CH(Me)CF3 C(Me)2C(O)N(Me)CH2CHF2
CH2CH(CF3)S(O)Me CH(Me)C(O)NH(CH2)2CF2CF3 C(Me)2C(O)N(Me)CH2CF3
CH2C(Me)2S(O)Me CH(Me)C(O)NHCH2(CF2)2CF3 C(Me)2C(O)N(Me)CH2CH2CH2F
CH(Me)CH2S(O)Me C(Me)2C(O)NHCH2CH2F C(Me)2C(O)N(Me)CH2CH2CF3
CH(Et)CH2S(O)Me C(Me)2C(O)NHCH2CH2Cl C(Me)2C(O)N(Me)CH2CF2CF3
CH(Z-Bu)CH2S(O)Me C(Me)2C(O)NHCH2CHF2 C(Me)2C(O)N(Me)CH(Me)CF3
CH2CH2CH2S(O)Me C(Me)2C(O)NHCH2CF3 C(Me)2C(O)N(Me)CH(CF3)2
CH2CH2CH2S(O)Et C(Me)2C(O)NHCH2CH(Me)F C(Me)2C(O)N(Me)C(Me)2CF3
CH2CH2CH2S(O)(Z-Bu) C(Me)2C(O)NHCH2C(Me)2F C(Me)2C(O)NHCH(Me)CF3
CH2CH2CH(Me)S(O)Me C(Me)2C(O)NH(CH2)2CH2F C(Me)2C(O)NHCH(CF3)2
CH2CH2CH(CF3)S(O)Me C(Me)2C(O)NHCH2CH2CF3 C(Me)2C(O)NHC(Me)2CF3
CH(Me)CH2CH2S(O)Me C(Me)2C(O)NHCH2CHFCF3 C(Me)2C(O)NHCH2CH(Me)CF3
CH(Et)CH2CH2S(O)Me C(Me)2C(O)NHCH2CF2CF3 C(Me)2C(O)NH(CH2)2CF2CF3
CH2CH(Me)CH2S(O)Me CH2C(O)NH(C-Pr) C(Me)2C(O)NHCH2(CF2)2CF3
CH2C(Me)2CH2S(O)Me CH2C(O)NH(CH2-C-Pr) C(Me)2C(O)NHCH(Z-Pr)CF3
CH2(2-pyridinyl) CH2(4-thiazolyl) CH(Me)C(O)NH(C-Pr) CH(Me)C(O)NH(CH2-C-Pr)
Figure imgf000034_0001
C(Me)2CH2OH CH(Et)CH2SO2Me CH2C(O)NEt2
CH(Et)CH2OH CH(Z-Pr)CH2SO2Me CH2C(O)NMe(W-Pr)
CH(Z-Pr)CH2OH CH(Z-Bu)CH2SO2Me CH2C(O)NMe(Z-Pr)
CH(Z-Bu)CH2OH CH2CH2CH2SO2Me CH2C(O)NMe(S-Bu)
CH(Me)CH(CF3)OH CH2CH2CH2SO2Et CH(Me)C(O)NH(Me)
CH2CH2CH2OH CH2CH2CH(Me)SO2Me CH(Me)C(O)NH(Et)
CH2CH2CH2OMe CH2CH2CH(CF3)SO2Me CH(Me)C(O)NH(«-Pr)
CH2CH2CH2OEt CH(Me)CH2CH2SO2Me CH(Me)C(O)NH(Z-Pr)
CH2CH2CH(CF3)OH CH(Et)CH2CH2SO2Me CH(Me)C(O)NH(W-Bu)
CH(Me)CH2CH2OH CH2CH(Me)CH2SO2Me CH(Me)C(O)NH(Z-Bu)
CH2CH(Me)CH2OH CH2C(Me)2CH2SO2Me CH(Me)C(O)NH(S-Bu)
CH2C(Me)2CH2OH CH2C(O)NHCH2CH2F C(Me)2C(O)NH(Me)
CH2CH2CH(Me)OH CH2C(O)NHCH2CH2Cl C(Me)2C(O)NH(Et)
CH2CH2C(Me)2OH CH2C(O)NHCH2CHF2 C(Me)2C(O)NH(W-Pr)
CH2CH2SMe CH2C(O)NHCH2CF3 C(Me)2C(O)NH(Z-Pr)
CH2CH2SEt CH2C(O)NHCH2CH(Me)F C(Me)2C(O)NH(W-Bu)
CH2CH2S(W-Pr) CH2C(O)NHCH2C(Me)2F C(Me)2C(O)NH(Z-Bu)
CH2CH2S(Z-Pr) CH2C(O)NH(CH2)2CH2F C(Me)2C(O)NH(S-Bu)
CH2CH2S(Z-Bu) CH2C(O)NHCH2CH2CF3 CH2C(O)N(Me)CH2CH2F
CH2CH(Me)SMe CH2C(O)NHCH2CHFCF3 CH2C(O)N(Me)CH2CH2Cl
CH2CH(CF3)SMe CH2C(O)NHCH2CF2CF3 CH2C(O)N(Me)CH2CHF2
CH2C(Me)2SMe CH2C(O)NHCH(Me)CF3 CH2C(O)N(Me)CH2CF3
CH(Me)CH2SMe CH2C(O)NHCH(CF3)2 CH2C(O)N(Me)CH2CH2CH2F
C(Me)2CH2SMe CH2C(O)NHC(Me)2CF3 CH2C(O)N(Me)CH2CH2CF3
CH(Et)CH2SMe CH2C(O)NHCH2CH(Me)CF3 CH2C(O)N(Me)CH2CF2CF3
CH(Z-Pr)CH2SMe CH2C(O)NH(CH2)2CF2CF3 CH2C(O)N(Me)CH(Me)CF3
CH(Z-Bu)CH2SMe CH2C(O)NHCH2(CF2)2CF3 CH2C(O)N(Me)CH(CF3)2
CH2CH2CH2SMe CH(Me)C(O)NHCH2CH2F CH2C(O)N(Me)C(Me)2CF3
CH2CH2CH2SEt CH(Me)C(O)NHCH2CH2Cl CH(Me)C(O)N(Me)CH2CH2F
CH2CH2CH(Me)SMe CH(Me)C(O)NHCH2CHF2 CH(Me)C(O)N(Me)CH2CH2Cl
CH2CH2CH(CF3)SMe CH(Me)C(O)NHCH2CF3 CH(Me)C(O)N(Me)CH2CHF2
CH(Me)CH2CH2SMe CH(Me)C(O)NHCH2CH(Me)F CH(Me)C(O)N(Me)CH2CF3
CH(Et)CH2CH2SMe CH(Me)C(O)NHCH2C(Me)2F CH(Me)C(O)N(Me)(CH2)2CH2F
CH2CH(Me)CH2SMe CH(Me)C(O)NH(CH2)2CH2F CH(Me)C(O)N(Me)CH2CH2CF3
CH2C(Me)2CH2SMe CH(Me)C(O)NHCH2CH2CF3 CH(Me)C(O)N(Me)CH2CF2CF3
CH2CH2S(O)Me CH(Me)C(O)NHCH2CHFCF3 CH(Me)C(O)N(Me)CH(Me)CF3
CH2CH2S(O)Et CH(Me)C(O)NHCH2CF2CF3 CH(Me)C(O)N(Me)CH(CF3)2
CH2CH2S(O)(W-Pr)
Figure imgf000035_0001
CH(Me)C(O)NHCH(Me)CF3
Figure imgf000035_0002
CH(Me)C(O)N(Me)C(Me)2CF3 CH2CH2S(O)(Z-Pr) CH(Me)C(O)NHCH(CF3)2 C(Me)2C(O)N(Me)CH2CH2F
CH2CH2S(O)(Z-Bu) CH(Me)C(O)NHC(Me)2CF3 C(Me)2C(O)N(Me)CH2CH2Cl
CH2CH(Me)S(O)Me CH(Me)C(O)NHCH2CH(Me)CF3 C(Me)2C(O)N(Me)CH2CHF2
CH2CH(CF3)S(O)Me CH(Me)C(O)NH(CH2)2CF2CF3 C(Me)2C(O)N(Me)CH2CF3
CH2C(Me)2S(O)Me CH(Me)C(O)NHCH2(CF2)2CF3 C(Me)2C(O)N(Me)CH2CH2CH2F
CH(Me)CH2S(O)Me C(Me)2C(O)NHCH2CH2F C(Me)2C(O)N(Me)CH2CH2CF3
CH(Et)CH2S(O)Me C(Me)2C(O)NHCH2CH2Cl C(Me)2C(O)N(Me)CH2CF2CF3
CH(Z-Bu)CH2S(O)Me C(Me)2C(O)NHCH2CHF2 C(Me)2C(O)N(Me)CH(Me)CF3
CH2CH2CH2S(O)Me C(Me)2C(O)NHCH2CF3 C(Me)2C(O)N(Me)CH(CF3)2
CH2CH2CH2S(O)Et C(Me)2C(O)NHCH2CH(Me)F C(Me)2C(O)N(Me)C(Me)2CF3
CH2CH2CH2S(O)(Z-Bu) C(Me)2C(O)NHCH2C(Me)2F C(Me)2C(O)NHCH(Me)CF3
CH2CH2CH(Me)S(O)Me C(Me)2C(O)NH(CH2)2CH2F C(Me)2C(O)NHCH(CF3)2
CH2CH2CH(CF3)S(O)Me C(Me)2C(O)NHCH2CH2CF3 C(Me)2C(O)NHC(Me)2CF3
CH(Me)CH2CH2S(O)Me C(Me)2C(O)NHCH2CHFCF3 C(Me)2C(O)NHCH2CH(Me)CF3
CH(Et)CH2CH2S(O)Me C(Me)2C(O)NHCH2CF2CF3 C(Me)2C(O)NH(CH2)2CF2CF3
CH2CH(Me)CH2S(O)Me CH2C(O)NH(C-Pr) C(Me)2C(O)NHCH2(CF2)2CF3
CH2C(Me)2CH2S(O)Me CH2C(O)NH(CH2-C-Pr) C(Me)2C(O)NHCH(Z-Pr)CF3
CH2(2-pyridinyl) CH2(4-thiazolyl) CH(Me)C(O)NH(C-Pr) CH(Me)C(O)NH(CH2-C-Pr)
Figure imgf000036_0001
CH2CH2CH2OEt CH(Me)CH2CH2SO2Me CH(Me)C(O)NH(Z-Pr)
CH2CH2CH(CF3)OH CH(Et)CH2CH2SO2Me CH(Me)C(O)NH(«-Bu)
CH(Me)CH2CH2OH CH2CH(Me)CH2SO2Me CH(Me)C(O)NH(Z-Bu)
CH2CH(Me)CH2OH CH2C(Me)2CH2SO2Me CH(Me)C(O)NH(S-Bu)
CH2C(Me)2CH2OH CH2C(O)NHCH2CH2F C(Me)2C(O)NH(Me)
CH2CH2CH(Me)OH CH2C(O)NHCH2CH2Cl C(Me)2C(O)NH(Et)
CH2CH2C(Me)2OH CH2C(O)NHCH2CHF2 C(Me)2C(O)NH(W-Pr)
CH2CH2SMe CH2C(O)NHCH2CF3 C(Me)2C(O)NH(Z-Pr)
CH2CH2SEt CH2C(O)NHCH2CH(Me)F C(Me)2C(O)NH(W-Bu)
CH2CH2S(W-Pr) CH2C(O)NHCH2C(Me)2F C(Me)2C(O)NH(Z-Bu)
CH2CH2S(Z-Pr) CH2C(O)NH(CH2)2CH2F C(Me)2C(O)NH(S-Bu)
CH2CH2S(Z-Bu) CH2C(O)NHCH2CH2CF3 CH2C(O)N(Me)CH2CH2F
CH2CH(Me)SMe CH2C(O)NHCH2CHFCF3 CH2C(O)N(Me)CH2CH2Cl
CH2CH(CF3)SMe CH2C(O)NHCH2CF2CF3 CH2C(O)N(Me)CH2CHF2
CH2C(Me)2SMe CH2C(O)NHCH(Me)CF3 CH2C(O)N(Me)CH2CF3
CH(Me)CH2SMe CH2C(O)NHCH(CF3)2 CH2C(O)N(Me)CH2CH2CH2F
C(Me)2CH2SMe CH2C(O)NHC(Me)2CF3 CH2C(O)N(Me)CH2CH2CF3
CH(Et)CH2SMe CH2C(O)NHCH2CH(Me)CF3 CH2C(O)N(Me)CH2CF2CF3
CH(Z-Pr)CH2SMe CH2C(O)NH(CH2)2CF2CF3 CH2C(O)N(Me)CH(Me)CF3
CH(Z-Bu)CH2SMe CH2C(O)NHCH2(CF2)2CF3 CH2C(O)N(Me)CH(CF3)2
CH2CH2CH2SMe CH(Me)C(O)NHCH2CH2F CH2C(O)N(Me)C(Me)2CF3
CH2CH2CH2SEt CH(Me)C(O)NHCH2CH2Cl CH(Me)C(O)N(Me)CH2CH2F
CH2CH2CH(Me)SMe CH(Me)C(O)NHCH2CHF2 CH(Me)C(O)N(Me)CH2CH2Cl
CH2CH2CH(CF3)SMe CH(Me)C(O)NHCH2CF3 CH(Me)C(O)N(Me)CH2CHF2
CH(Me)CH2CH2SMe CH(Me)C(O)NHCH2CH(Me)F CH(Me)C(O)N(Me)CH2CF3
CH(Et)CH2CH2SMe CH(Me)C(O)NHCH2C(Me)2F CH(Me)C(O)N(Me)(CH2)2CH2F
CH2CH(Me)CH2SMe CH(Me)C(O)NH(CH2)2CH2F CH(Me)C(O)N(Me)CH2CH2CF3
CH2C(Me)2CH2SMe CH(Me)C(O)NHCH2CH2CF3 CH(Me)C(O)N(Me)CH2CF2CF3
CH2CH2S(O)Me CH(Me)C(O)NHCH2CHFCF3 CH(Me)C(O)N(Me)CH(Me)CF3
CH2CH2S(O)Et CH(Me)C(O)NHCH2CF2CF3 CH(Me)C(O)N(Me)CH(CF3)2
CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH(Me)C(O)N(Me)C(Me)2CF3
CH2CH2S(O)(Z-Pr) CH(Me)C(O)NHCH(CF3)2 C(Me)2C(O)N(Me)CH2CH2F
CH2CH2S(O)(Z-Bu) CH(Me)C(O)NHC(Me)2CF3 C(Me)2C(O)N(Me)CH2CH2Cl
CH2CH(Me)S(O)Me CH(Me)C(O)NHCH2CH(Me)CF3 C(Me)2C(O)N(Me)CH2CHF2
CH2CH(CF3)S(O)Me CH(Me)C(O)NH(CH2)2CF2CF3 C(Me)2C(O)N(Me)CH2CF3
CH2C(Me)2S(O)Me CH(Me)C(O)NHCH2(CF2)2CF3 C(Me)2C(O)N(Me)CH2CH2CH2F
CH(Me)CH2S(O)Me C(Me)2C(O)NHCH2CH2F C(Me)2C(O)N(Me)CH2CH2CF3
CH(Et)CH2S(O)Me
Figure imgf000037_0001
C(Me)2C(O)NHCH2CH2Cl
Figure imgf000037_0002
C(Me)2C(O)N(Me)CH2CF2CF3 CH(Z-Bu)CH2S(O)Me C(Me)2C(O)NHCH2CHF2 C(Me)2C(O)N(Me)CH(Me)CF3
CH2CH2CH2S(O)Me C(Me)2C(O)NHCH2CF3 C(Me)2C(O)N(Me)CH(CF3)2
CH2CH2CH2S(O)Et C(Me)2C(O)NHCH2CH(Me)F C(Me)2C(O)N(Me)C(Me)2CF3
CH2CH2CH2S(O)(Z-Bu) C(Me)2C(O)NHCH2C(Me)2F C(Me)2C(O)NHCH(Me)CF3
CH2CH2CH(Me)S(O)Me C(Me)2C(O)NH(CH2)2CH2F C(Me)2C(O)NHCH(CF3)2
CH2CH2CH(CF3)S(O)Me C(Me)2C(O)NHCH2CH2CF3 C(Me)2C(O)NHC(Me)2CF3
CH(Me)CH2CH2S(O)Me C(Me)2C(O)NHCH2CHFCF3 C(Me)2C(O)NHCH2CH(Me)CF3
CH(Et)CH2CH2S(O)Me C(Me)2C(O)NHCH2CF2CF3 C(Me)2C(O)NH(CH2)2CF2CF3
CH2CH(Me)CH2S(O)Me CH2C(O)NH(C-Pr) C(Me)2C(O)NHCH2(CF2)2CF3
CH2C(Me)2CH2S(O)Me CH2C(O)NH(CH2-C-Pr) C(Me)2C(O)NHCH(Z-Pr)CF3
CH2(2-pyridinyl) CH2(4-thiazolyl) CH(Me)C(O)NH(C-Pr) CH(Me)C(O)NH(CH2-C-Pr)
Figure imgf000038_0001
CH2CH2SMe CH2C(O)NHCH2CF3 C(Me)2C(O)NH(Z-Pr)
CH2CH2SEt CH2C(O)NHCH2CH(Me)F C(Me)2C(O)NH(W-Bu)
CH2CH2S(W-Pr) CH2C(O)NHCH2C(Me)2F C(Me)2C(O)NH(Z-Bu)
CH2CH2S(Z-Pr) CH2C(O)NH(CH2)2CH2F C(Me)2C(O)NH(S-Bu)
CH2CH2S(Z-Bu) CH2C(O)NHCH2CH2CF3 CH2C(O)N(Me)CH2CH2F
CH2CH(Me)SMe CH2C(O)NHCH2CHFCF3 CH2C(O)N(Me)CH2CH2Cl
CH2CH(CF3)SMe CH2C(O)NHCH2CF2CF3 CH2C(O)N(Me)CH2CHF2
CH2C(Me)2SMe CH2C(O)NHCH(Me)CF3 CH2C(O)N(Me)CH2CF3
CH(Me)CH2SMe CH2C(O)NHCH(CF3)2 CH2C(O)N(Me)CH2CH2CH2F
C(Me)2CH2SMe CH2C(O)NHC(Me)2CF3 CH2C(O)N(Me)CH2CH2CF3
CH(Et)CH2SMe CH2C(O)NHCH2CH(Me)CF3 CH2C(O)N(Me)CH2CF2CF3
CH(Z-Pr)CH2SMe CH2C(O)NH(CH2)2CF2CF3 CH2C(O)N(Me)CH(Me)CF3
CH(Z-Bu)CH2SMe CH2C(O)NHCH2(CF2)2CF3 CH2C(O)N(Me)CH(CF3)2
CH2CH2CH2SMe CH(Me)C(O)NHCH2CH2F CH2C(O)N(Me)C(Me)2CF3
CH2CH2CH2SEt CH(Me)C(O)NHCH2CH2Cl CH(Me)C(O)N(Me)CH2CH2F
CH2CH2CH(Me)SMe CH(Me)C(O)NHCH2CHF2 CH(Me)C(O)N(Me)CH2CH2Cl
CH2CH2CH(CF3)SMe CH(Me)C(O)NHCH2CF3 CH(Me)C(O)N(Me)CH2CHF2
CH(Me)CH2CH2SMe CH(Me)C(O)NHCH2CH(Me)F CH(Me)C(O)N(Me)CH2CF3
CH(Et)CH2CH2SMe CH(Me)C(O)NHCH2C(Me)2F CH(Me)C(O)N(Me)(CH2)2CH2F
CH2CH(Me)CH2SMe CH(Me)C(O)NH(CH2)2CH2F CH(Me)C(O)N(Me)CH2CH2CF3
CH2C(Me)2CH2SMe CH(Me)C(O)NHCH2CH2CF3 CH(Me)C(O)N(Me)CH2CF2CF3
CH2CH2S(O)Me CH(Me)C(O)NHCH2CHFCF3 CH(Me)C(O)N(Me)CH(Me)CF3
CH2CH2S(O)Et CH(Me)C(O)NHCH2CF2CF3 CH(Me)C(O)N(Me)CH(CF3)2
CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH(Me)C(O)N(Me)C(Me)2CF3
CH2CH2S(O)(Z-Pr) CH(Me)C(O)NHCH(CF3)2 C(Me)2C(O)N(Me)CH2CH2F
CH2CH2S(O)(Z-Bu) CH(Me)C(O)NHC(Me)2CF3 C(Me)2C(O)N(Me)CH2CH2Cl
CH2CH(Me)S(O)Me CH(Me)C(O)NHCH2CH(Me)CF3 C(Me)2C(O)N(Me)CH2CHF2
CH2CH(CF3)S(O)Me CH(Me)C(O)NH(CH2)2CF2CF3 C(Me)2C(O)N(Me)CH2CF3
CH2C(Me)2S(O)Me CH(Me)C(O)NHCH2(CF2)2CF3 C(Me)2C(O)N(Me)CH2CH2CH2F
CH(Me)CH2S(O)Me C(Me)2C(O)NHCH2CH2F C(Me)2C(O)N(Me)CH2CH2CF3
CH(Et)CH2S(O)Me C(Me)2C(O)NHCH2CH2Cl C(Me)2C(O)N(Me)CH2CF2CF3
CH(Z-Bu)CH2S(O)Me C(Me)2C(O)NHCH2CHF2 C(Me)2C(O)N(Me)CH(Me)CF3
CH2CH2CH2S(O)Me C(Me)2C(O)NHCH2CF3 C(Me)2C(O)N(Me)CH(CF3)2
CH2CH2CH2S(O)Et C(Me)2C(O)NHCH2CH(Me)F C(Me)2C(O)N(Me)C(Me)2CF3
CH2CH2CH2S(O)(Z-Bu) C(Me)2C(O)NHCH2C(Me)2F C(Me)2C(O)NHCH(Me)CF3
CH2CH2CH(Me)S(O)Me C(Me)2C(O)NH(CH2)2CH2F C(Me)2C(O)NHCH(CF3)2
CH2CH2CH(CF3)S(O)Me C(Me)2C(O)NHCH2CH2CF3 C(Me)2C(O)NHC(Me)2CF3
CH(Me)CH2CH2S(O)Me
Figure imgf000039_0001
C(Me)2C(O)NHCH2CHFCF3 C(Me)2C(O)NHCH2CH(Me)CF3 CH(Et)CH2CH2S(O)Me C(Me)2C(O)NHCH2CF2CF3 C(Me)2C(O)NH(CH2)2CF2CF3
CH2CH(Me)CH2S(O)Me CH2C(O)NH(C-Pr) C(Me)2C(O)NHCH2(CF2)2CF3
CH2C(Me)2CH2S(O)Me CH2C(O)NH(CH2-C-Pr) C(Me)2C(O)NHCH(Z-Pr)CF3
CH2(2-pyridinyl) CH2(4-thiazolyl) CH(Me)C(O)NH(C-Pr)
CH(Me)C(O)NH(CH2-C-Pr)
Figure imgf000040_0001
CH2C(Me)2SMe CH2C(O)NHCH(Me)CF3 CH2C(O)N(Me)CH2CF3
CH(Me)CH2SMe CH2C(O)NHCH(CF3)2 CH2C(O)N(Me)CH2CH2CH2F
C(Me)2CH2SMe CH2C(O)NHC(Me)2CF3 CH2C(O)N(Me)CH2CH2CF3
CH(Et)CH2SMe CH2C(O)NHCH2CH(Me)CF3 CH2C(O)N(Me)CH2CF2CF3
CH(Z-Pr)CH2SMe CH2C(O)NH(CH2)2CF2CF3 CH2C(O)N(Me)CH(Me)CF3
CH(Z-Bu)CH2SMe CH2C(O)NHCH2(CF2)2CF3 CH2C(O)N(Me)CH(CF3)2
CH2CH2CH2SMe CH(Me)C(O)NHCH2CH2F CH2C(O)N(Me)C(Me)2CF3
CH2CH2CH2SEt CH(Me)C(O)NHCH2CH2Cl CH(Me)C(O)N(Me)CH2CH2F
CH2CH2CH(Me)SMe CH(Me)C(O)NHCH2CHF2 CH(Me)C(O)N(Me)CH2CH2Cl
CH2CH2CH(CF3)SMe CH(Me)C(O)NHCH2CF3 CH(Me)C(O)N(Me)CH2CHF2
CH(Me)CH2CH2SMe CH(Me)C(O)NHCH2CH(Me)F CH(Me)C(O)N(Me)CH2CF3
CH(Et)CH2CH2SMe CH(Me)C(O)NHCH2C(Me)2F CH(Me)C(O)N(Me)(CH2)2CH2F
CH2CH(Me)CH2SMe CH(Me)C(O)NH(CH2)2CH2F CH(Me)C(O)N(Me)CH2CH2CF3
CH2C(Me)2CH2SMe CH(Me)C(O)NHCH2CH2CF3 CH(Me)C(O)N(Me)CH2CF2CF3
CH2CH2S(O)Me CH(Me)C(O)NHCH2CHFCF3 CH(Me)C(O)N(Me)CH(Me)CF3
CH2CH2S(O)Et CH(Me)C(O)NHCH2CF2CF3 CH(Me)C(O)N(Me)CH(CF3)2
CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH(Me)C(O)N(Me)C(Me)2CF3
CH2CH2S(O)(Z-Pr) CH(Me)C(O)NHCH(CF3)2 C(Me)2C(O)N(Me)CH2CH2F
CH2CH2S(O)(Z-Bu) CH(Me)C(O)NHC(Me)2CF3 C(Me)2C(O)N(Me)CH2CH2Cl
CH2CH(Me)S(O)Me CH(Me)C(O)NHCH2CH(Me)CF3 C(Me)2C(O)N(Me)CH2CHF2
CH2CH(CF3)S(O)Me CH(Me)C(O)NH(CH2)2CF2CF3 C(Me)2C(O)N(Me)CH2CF3
CH2C(Me)2S(O)Me CH(Me)C(O)NHCH2(CF2)2CF3 C(Me)2C(O)N(Me)CH2CH2CH2F
CH(Me)CH2S(O)Me C(Me)2C(O)NHCH2CH2F C(Me)2C(O)N(Me)CH2CH2CF3
CH(Et)CH2S(O)Me C(Me)2C(O)NHCH2CH2Cl C(Me)2C(O)N(Me)CH2CF2CF3
CH(Z-Bu)CH2S(O)Me C(Me)2C(O)NHCH2CHF2 C(Me)2C(O)N(Me)CH(Me)CF3
CH2CH2CH2S(O)Me C(Me)2C(O)NHCH2CF3 C(Me)2C(O)N(Me)CH(CF3)2
CH2CH2CH2S(O)Et C(Me)2C(O)NHCH2CH(Me)F C(Me)2C(O)N(Me)C(Me)2CF3
CH2CH2CH2S(O)(Z-Bu) C(Me)2C(O)NHCH2C(Me)2F C(Me)2C(O)NHCH(Me)CF3
CH2CH2CH(Me)S(O)Me C(Me)2C(O)NH(CH2)2CH2F C(Me)2C(O)NHCH(CF3)2
CH2CH2CH(CF3)S(O)Me C(Me)2C(O)NHCH2CH2CF3 C(Me)2C(O)NHC(Me)2CF3
CH(Me)CH2CH2S(O)Me C(Me)2C(O)NHCH2CHFCF3 C(Me)2C(O)NHCH2CH(Me)CF3
CH(Et)CH2CH2S(O)Me C(Me)2C(O)NHCH2CF2CF3 C(Me)2C(O)NH(CH2)2CF2CF3
CH2CH(Me)CH2S(O)Me CH2C(O)NH(C-Pr) C(Me)2C(O)NHCH2(CF2)2CF3
CH2C(Me)2CH2S(O)Me CH2C(O)NH(CH2-C-Pr) C(Me)2C(O)NHCH(Z-Pr)CF3
CH2(2-pyridinyl) CH2(4-thiazolyl) CH(Me)C(O)NH(C-Pr) CH(Me)C(O)NH(CH2-C-Pr)
Figure imgf000042_0001
CH(Z-Bu)CH2SMe CH2C(O)NHCH2(CF2)2CF3 CH2C(O)N(Me)CH(CF3)2
CH2CH2CH2SMe CH(Me)C(O)NHCH2CH2F CH2C(O)N(Me)C(Me)2CF3
CH2CH2CH2SEt CH(Me)C(O)NHCH2CH2Cl CH(Me)C(O)N(Me)CH2CH2F
CH2CH2CH(Me)SMe CH(Me)C(O)NHCH2CHF2 CH(Me)C(O)N(Me)CH2CH2Cl
CH2CH2CH(CF3)SMe CH(Me)C(O)NHCH2CF3 CH(Me)C(O)N(Me)CH2CHF2
CH(Me)CH2CH2SMe CH(Me)C(O)NHCH2CH(Me)F CH(Me)C(O)N(Me)CH2CF3
CH(Et)CH2CH2SMe CH(Me)C(O)NHCH2C(Me)2F CH(Me)C(O)N(Me)(CH2)2CH2F
CH2CH(Me)CH2SMe CH(Me)C(O)NH(CH2)2CH2F CH(Me)C(O)N(Me)CH2CH2CF3
CH2C(Me)2CH2SMe CH(Me)C(O)NHCH2CH2CF3 CH(Me)C(O)N(Me)CH2CF2CF3
CH2CH2S(O)Me CH(Me)C(O)NHCH2CHFCF3 CH(Me)C(O)N(Me)CH(Me)CF3
CH2CH2S(O)Et CH(Me)C(O)NHCH2CF2CF3 CH(Me)C(O)N(Me)CH(CF3)2
CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH(Me)C(O)N(Me)C(Me)2CF3
CH2CH2S(O)(Z-Pr) CH(Me)C(O)NHCH(CF3)2 C(Me)2C(O)N(Me)CH2CH2F
CH2CH2S(O)(Z-Bu) CH(Me)C(O)NHC(Me)2CF3 C(Me)2C(O)N(Me)CH2CH2Cl
CH2CH(Me)S(O)Me CH(Me)C(O)NHCH2CH(Me)CF3 C(Me)2C(O)N(Me)CH2CHF2
CH2CH(CF3)S(O)Me CH(Me)C(O)NH(CH2)2CF2CF3 C(Me)2C(O)N(Me)CH2CF3
CH2C(Me)2S(O)Me CH(Me)C(O)NHCH2(CF2)2CF3 C(Me)2C(O)N(Me)CH2CH2CH2F
CH(Me)CH2S(O)Me C(Me)2C(O)NHCH2CH2F C(Me)2C(O)N(Me)CH2CH2CF3
CH(Et)CH2S(O)Me C(Me)2C(O)NHCH2CH2Cl C(Me)2C(O)N(Me)CH2CF2CF3
CH(Z-Bu)CH2S(O)Me C(Me)2C(O)NHCH2CHF2 C(Me)2C(O)N(Me)CH(Me)CF3
CH2CH2CH2S(O)Me C(Me)2C(O)NHCH2CF3 C(Me)2C(O)N(Me)CH(CF3)2
CH2CH2CH2S(O)Et C(Me)2C(O)NHCH2CH(Me)F C(Me)2C(O)N(Me)C(Me)2CF3
CH2CH2CH2S(O)(Z-Bu) C(Me)2C(O)NHCH2C(Me)2F C(Me)2C(O)NHCH(Me)CF3
CH2CH2CH(Me)S(O)Me C(Me)2C(O)NH(CH2)2CH2F C(Me)2C(O)NHCH(CF3)2
CH2CH2CH(CF3)S(O)Me C(Me)2C(O)NHCH2CH2CF3 C(Me)2C(O)NHC(Me)2CF3
CH(Me)CH2CH2S(O)Me C(Me)2C(O)NHCH2CHFCF3 C(Me)2C(O)NHCH2CH(Me)CF3
CH(Et)CH2CH2S(O)Me C(Me)2C(O)NHCH2CF2CF3 C(Me)2C(O)NH(CH2)2CF2CF3
CH2CH(Me)CH2S(O)Me CH2C(O)NH(C-Pr) C(Me)2C(O)NHCH2(CF2)2CF3
CH2C(Me)2CH2S(O)Me CH2C(O)NH(CH2-C-Pr) C(Me)2C(O)NHCH(Z-Pr)CF3
CH2(2-pyridinyl) CH2(4-thiazolyl) CH(Me)C(O)NH(C-Pr) CH(Me)C(O)NH(CH2-C-Pr)
Figure imgf000043_0001
CH2CH(Me)OH CH2CH(Me)SO2Me CH2C(O)NH(W-Bu)
CH2CH(CF3)OH CH2CH(CF3)SO2Me CH2C(O)NH(Z-Bu)
CH2C(Me)2OH CH2C(Me)2SO2Me CH2C(O)NH(.s-Bu)
CH2C(CF3)(Me)OH CH(Me)CH2SO2Me CH2C(O)NMe2
CH(Me)CH2OH C(Me)2CH2SO2Me CH2C(O)NMe(Et)
C(Me)2CH2OH CH(Et)CH2SO2Me CH2C(O)NEt2
CH(Et)CH2OH CH(Z-Pr)CH2SO2Me CH2C(O)NMe(W-Pr)
CH(Z-Pr)CH2OH CH(Z-Bu)CH2SO2Me CH2C(O)NMe(Z-Pr)
CH(Z-Bu)CH2OH CH2CH2CH2SO2Me CH2C(O)NMe(S-Bu)
CH(Me)CH(CF3)OH CH2CH2CH2SO2Et CH(Me)C(O)NH(Me)
CH2CH2CH2OH CH2CH2CH(Me)SO2Me CH(Me)C(O)NH(Et)
CH2CH2CH2OMe CH2CH2CH(CF3)SO2Me CH(Me)C(O)NH(«-Pr)
CH2CH2CH2OEt CH(Me)CH2CH2SO2Me CH(Me)C(O)NH(Z-Pr)
CH2CH2CH(CF3)OH CH(Et)CH2CH2SO2Me CH(Me)C(O)NH(W-Bu)
CH(Me)CH2CH2OH CH2CH(Me)CH2SO2Me CH(Me)C(O)NH(Z-Bu)
CH2CH(Me)CH2OH CH2C(Me)2CH2SO2Me CH(Me)C(O)NH(S-Bu)
CH2C(Me)2CH2OH CH2C(O)NHCH2CH2F C(Me)2C(O)NH(Me)
CH2CH2CH(Me)OH CH2C(O)NHCH2CH2Cl C(Me)2C(O)NH(Et)
CH2CH2C(Me)2OH CH2C(O)NHCH2CHF2 C(Me)2C(O)NH(W-Pr)
CH2CH2SMe CH2C(O)NHCH2CF3 C(Me)2C(O)NH(Z-Pr)
CH2CH2SEt CH2C(O)NHCH2CH(Me)F C(Me)2C(O)NH(W-Bu)
CH2CH2S(W-Pr) CH2C(O)NHCH2C(Me)2F C(Me)2C(O)NH(Z-Bu)
CH2CH2S(Z-Pr) CH2C(O)NH(CH2)2CH2F C(Me)2C(O)NH(S-Bu)
CH2CH2S(Z-Bu) CH2C(O)NHCH2CH2CF3 CH2C(O)N(Me)CH2CH2F
CH2CH(Me)SMe CH2C(O)NHCH2CHFCF3 CH2C(O)N(Me)CH2CH2Cl
CH2CH(CF3)SMe CH2C(O)NHCH2CF2CF3 CH2C(O)N(Me)CH2CHF2
CH2C(Me)2SMe CH2C(O)NHCH(Me)CF3 CH2C(O)N(Me)CH2CF3
CH(Me)CH2SMe CH2C(O)NHCH(CF3)2 CH2C(O)N(Me)CH2CH2CH2F
C(Me)2CH2SMe CH2C(O)NHC(Me)2CF3 CH2C(O)N(Me)CH2CH2CF3
CH(Et)CH2SMe CH2C(O)NHCH2CH(Me)CF3 CH2C(O)N(Me)CH2CF2CF3
CH(Z-Pr)CH2SMe CH2C(O)NH(CH2)2CF2CF3 CH2C(O)N(Me)CH(Me)CF3
CH(Z-Bu)CH2SMe CH2C(O)NHCH2(CF2)2CF3 CH2C(O)N(Me)CH(CF3)2
CH2CH2CH2SMe CH(Me)C(O)NHCH2CH2F CH2C(O)N(Me)C(Me)2CF3
CH2CH2CH2SEt CH(Me)C(O)NHCH2CH2Cl CH(Me)C(O)N(Me)CH2CH2F
CH2CH2CH(Me)SMe CH(Me)C(O)NHCH2CHF2 CH(Me)C(O)N(Me)CH2CH2Cl
CH2CH2CH(CF3)SMe CH(Me)C(O)NHCH2CF3 CH(Me)C(O)N(Me)CH2CHF2
CH(Me)CH2CH2SMe CH(Me)C(O)NHCH2CH(Me)F CH(Me)C(O)N(Me)CH2CF3
CH(Et)CH2CH2SMe
Figure imgf000044_0001
CH(Me)C(O)NHCH2C(Me)2F
Figure imgf000044_0002
CH(Me)C(O)N(Me)(CH2)2CH2F CH2CH(Me)CH2SMe CH(Me)C(O)NH(CH2)2CH2F CH(Me)C(O)N(Me)CH2CH2CF3
CH2C(Me)2CH2SMe CH(Me)C(O)NHCH2CH2CF3 CH(Me)C(O)N(Me)CH2CF2CF3
CH2CH2S(O)Me CH(Me)C(O)NHCH2CHFCF3 CH(Me)C(O)N(Me)CH(Me)CF3
CH2CH2S(O)Et CH(Me)C(O)NHCH2CF2CF3 CH(Me)C(O)N(Me)CH(CF3)2
CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH(Me)C(O)N(Me)C(Me)2CF3
CH2CH2S(O)(Z-Pr) CH(Me)C(O)NHCH(CF3)2 C(Me)2C(O)N(Me)CH2CH2F
CH2CH2S(O)(Z-Bu) CH(Me)C(O)NHC(Me)2CF3 C(Me)2C(O)N(Me)CH2CH2Cl
CH2CH(Me)S(O)Me CH(Me)C(O)NHCH2CH(Me)CF3 C(Me)2C(O)N(Me)CH2CHF2
CH2CH(CF3)S(O)Me CH(Me)C(O)NH(CH2)2CF2CF3 C(Me)2C(O)N(Me)CH2CF3
CH2C(Me)2S(O)Me CH(Me)C(O)NHCH2(CF2)2CF3 C(Me)2C(O)N(Me)CH2CH2CH2F
CH(Me)CH2S(O)Me C(Me)2C(O)NHCH2CH2F C(Me)2C(O)N(Me)CH2CH2CF3
CH(Et)CH2S(O)Me C(Me)2C(O)NHCH2CH2Cl C(Me)2C(O)N(Me)CH2CF2CF3
CH(Z-Bu)CH2S(O)Me C(Me)2C(O)NHCH2CHF2 C(Me)2C(O)N(Me)CH(Me)CF3
CH2CH2CH2S(O)Me C(Me)2C(O)NHCH2CF3 C(Me)2C(O)N(Me)CH(CF3)2
CH2CH2CH2S(O)Et C(Me)2C(O)NHCH2CH(Me)F C(Me)2C(O)N(Me)C(Me)2CF3
CH2CH2CH2S(O)(Z-Bu) C(Me)2C(O)NHCH2C(Me)2F C(Me)2C(O)NHCH(Me)CF3
CH2CH2CH(Me)S(O)Me C(Me)2C(O)NH(CH2)2CH2F C(Me)2C(O)NHCH(CF3)2
CH2CH2CH(CF3)S(O)Me C(Me)2C(O)NHCH2CH2CF3 C(Me)2C(O)NHC(Me)2CF3
CH(Me)CH2CH2S(O)Me C(Me)2C(O)NHCH2CHFCF3 C(Me)2C(O)NHCH2CH(Me)CF3
CH(Et)CH2CH2S(O)Me C(Me)2C(O)NHCH2CF2CF3 C(Me)2C(O)NH(CH2)2CF2CF3
CH2CH(Me)CH2S(O)Me CH2C(O)NH(C-Pr) C(Me)2C(O)NHCH2(CF2)2CF3
CH2C(Me)2CH2S(O)Me CH2C(O)NH(CH2-C-Pr) C(Me)2C(O)NHCH(Z-Pr)CF3
CH2(2-pyridinyl) CH2(4-thiazolyl) CH(Me)C(O)NH(C-Pr) CH(Me)C(O)NH(CH2-C-Pr)
Figure imgf000045_0001
CH(Z-Pr)CH2OH CH(Z-Bu)CH2SO2Me CH2C(O)NMe(Z-Pr)
CH(Z-Bu)CH2OH CH2CH2CH2SO2Me CH2C(O)NMe(S-Bu)
CH(Me)CH(CF3)OH CH2CH2CH2SO2Et CH(Me)C(O)NH(Me)
CH2CH2CH2OH CH2CH2CH(Me)SO2Me CH(Me)C(O)NH(Et)
CH2CH2CH2OMe CH2CH2CH(CF3)SO2Me CH(Me)C(O)NH(«-Pr)
CH2CH2CH2OEt CH(Me)CH2CH2SO2Me CH(Me)C(O)NH(Z-Pr)
CH2CH2CH(CF3)OH CH(Et)CH2CH2SO2Me CH(Me)C(O)NH(«-Bu)
CH(Me)CH2CH2OH CH2CH(Me)CH2SO2Me CH(Me)C(O)NH(Z-Bu)
CH2CH(Me)CH2OH CH2C(Me)2CH2SO2Me CH(Me)C(O)NH(S-Bu)
CH2C(Me)2CH2OH CH2C(O)NHCH2CH2F C(Me)2C(O)NH(Me)
CH2CH2CH(Me)OH CH2C(O)NHCH2CH2Cl C(Me)2C(O)NH(Et)
CH2CH2C(Me)2OH CH2C(O)NHCH2CHF2 C(Me)2C(O)NH(W-Pr)
CH2CH2SMe CH2C(O)NHCH2CF3 C(Me)2C(O)NH(Z-Pr)
CH2CH2SEt CH2C(O)NHCH2CH(Me)F C(Me)2C(O)NH(W-Bu)
CH2CH2S(W-Pr) CH2C(O)NHCH2C(Me)2F C(Me)2C(O)NH(Z-Bu)
CH2CH2S(Z-Pr) CH2C(O)NH(CH2)2CH2F C(Me)2C(O)NH(S-Bu)
CH2CH2S(Z-Bu) CH2C(O)NHCH2CH2CF3 CH2C(O)N(Me)CH2CH2F
CH2CH(Me)SMe CH2C(O)NHCH2CHFCF3 CH2C(O)N(Me)CH2CH2Cl
CH2CH(CF3)SMe CH2C(O)NHCH2CF2CF3 CH2C(O)N(Me)CH2CHF2
CH2C(Me)2SMe CH2C(O)NHCH(Me)CF3 CH2C(O)N(Me)CH2CF3
CH(Me)CH2SMe CH2C(O)NHCH(CF3)2 CH2C(O)N(Me)CH2CH2CH2F
C(Me)2CH2SMe CH2C(O)NHC(Me)2CF3 CH2C(O)N(Me)CH2CH2CF3
CH(Et)CH2SMe CH2C(O)NHCH2CH(Me)CF3 CH2C(O)N(Me)CH2CF2CF3
CH(Z-Pr)CH2SMe CH2C(O)NH(CH2)2CF2CF3 CH2C(O)N(Me)CH(Me)CF3
CH(Z-Bu)CH2SMe CH2C(O)NHCH2(CF2)2CF3 CH2C(O)N(Me)CH(CF3)2
CH2CH2CH2SMe CH(Me)C(O)NHCH2CH2F CH2C(O)N(Me)C(Me)2CF3
CH2CH2CH2SEt CH(Me)C(O)NHCH2CH2Cl CH(Me)C(O)N(Me)CH2CH2F
CH2CH2CH(Me)SMe CH(Me)C(O)NHCH2CHF2 CH(Me)C(O)N(Me)CH2CH2Cl
CH2CH2CH(CF3)SMe CH(Me)C(O)NHCH2CF3 CH(Me)C(O)N(Me)CH2CHF2
CH(Me)CH2CH2SMe CH(Me)C(O)NHCH2CH(Me)F CH(Me)C(O)N(Me)CH2CF3
CH(Et)CH2CH2SMe CH(Me)C(O)NHCH2C(Me)2F CH(Me)C(O)N(Me)(CH2)2CH2F
CH2CH(Me)CH2SMe CH(Me)C(O)NH(CH2)2CH2F CH(Me)C(O)N(Me)CH2CH2CF3
CH2C(Me)2CH2SMe CH(Me)C(O)NHCH2CH2CF3 CH(Me)C(O)N(Me)CH2CF2CF3
CH2CH2S(O)Me CH(Me)C(O)NHCH2CHFCF3 CH(Me)C(O)N(Me)CH(Me)CF3
CH2CH2S(O)Et CH(Me)C(O)NHCH2CF2CF3 CH(Me)C(O)N(Me)CH(CF3)2
CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH(Me)C(O)N(Me)C(Me)2CF3
CH2CH2S(O)(Z-Pr) CH(Me)C(O)NHCH(CF3)2 C(Me)2C(O)N(Me)CH2CH2F
CH2CH2S(O)(Z-Bu)
Figure imgf000046_0001
CH(Me)C(O)NHC(Me)2CF3
Figure imgf000046_0002
C(Me)2C(O)N(Me)CH2CH2Cl CH2CH(Me)S(O)Me CH(Me)C(O)NHCH2CH(Me)CF3 C(Me)2C(O)N(Me)CH2CHF2
CH2CH(CF3)S(O)Me CH(Me)C(O)NH(CH2)2CF2CF3 C(Me)2C(O)N(Me)CH2CF3
CH2C(Me)2S(O)Me CH(Me)C(O)NHCH2(CF2)2CF3 C(Me)2C(O)N(Me)CH2CH2CH2F
CH(Me)CH2S(O)Me C(Me)2C(O)NHCH2CH2F C(Me)2C(O)N(Me)CH2CH2CF3
CH(Et)CH2S(O)Me C(Me)2C(O)NHCH2CH2Cl C(Me)2C(O)N(Me)CH2CF2CF3
CH(Z-Bu)CH2S(O)Me C(Me)2C(O)NHCH2CHF2 C(Me)2C(O)N(Me)CH(Me)CF3
CH2CH2CH2S(O)Me C(Me)2C(O)NHCH2CF3 C(Me)2C(O)N(Me)CH(CF3)2
CH2CH2CH2S(O)Et C(Me)2C(O)NHCH2CH(Me)F C(Me)2C(O)N(Me)C(Me)2CF3
CH2CH2CH2S(O)(Z-Bu) C(Me)2C(O)NHCH2C(Me)2F C(Me)2C(O)NHCH(Me)CF3
CH2CH2CH(Me)S(O)Me C(Me)2C(O)NH(CH2)2CH2F C(Me)2C(O)NHCH(CF3)2
CH2CH2CH(CF3)S(O)Me C(Me)2C(O)NHCH2CH2CF3 C(Me)2C(O)NHC(Me)2CF3
CH(Me)CH2CH2S(O)Me C(Me)2C(O)NHCH2CHFCF3 C(Me)2C(O)NHCH2CH(Me)CF3
CH(Et)CH2CH2S(O)Me C(Me)2C(O)NHCH2CF2CF3 C(Me)2C(O)NH(CH2)2CF2CF3
CH2CH(Me)CH2S(O)Me CH2C(O)NH(C-Pr) C(Me)2C(O)NHCH2(CF2)2CF3
CH2C(Me)2CH2S(O)Me CH2C(O)NH(CH2-C-Pr) C(Me)2C(O)NHCH(Z-Pr)CF3
CH2(2-pyridinyl) CH2(4-thiazolyl) CH(Me)C(O)NH(C-Pr) CH(Me)C(O)NH(CH2-C-Pr)
Figure imgf000047_0001
CH(Me)CH2CH2OH CH2CH(Me)CH2SO2Me CH(Me)C(O)NH(Z-Bu)
CH2CH(Me)CH2OH CH2C(Me)2CH2SO2Me CH(Me)C(O)NH(S-Bu)
CH2C(Me)2CH2OH CH2C(O)NHCH2CH2F C(Me)2C(O)NH(Me)
CH2CH2CH(Me)OH CH2C(O)NHCH2CH2Cl C(Me)2C(O)NH(Et)
CH2CH2C(Me)2OH CH2C(O)NHCH2CHF2 C(Me)2C(O)NH(W-Pr)
CH2CH2SMe CH2C(O)NHCH2CF3 C(Me)2C(O)NH(Z-Pr)
CH2CH2SEt CH2C(O)NHCH2CH(Me)F C(Me)2C(O)NH(W-Bu)
CH2CH2S(W-Pr) CH2C(O)NHCH2C(Me)2F C(Me)2C(O)NH(Z-Bu)
CH2CH2S(Z-Pr) CH2C(O)NH(CH2)2CH2F C(Me)2C(O)NH(S-Bu)
CH2CH2S(Z-Bu) CH2C(O)NHCH2CH2CF3 CH2C(O)N(Me)CH2CH2F
CH2CH(Me)SMe CH2C(O)NHCH2CHFCF3 CH2C(O)N(Me)CH2CH2Cl
CH2CH(CF3)SMe CH2C(O)NHCH2CF2CF3 CH2C(O)N(Me)CH2CHF2
CH2C(Me)2SMe CH2C(O)NHCH(Me)CF3 CH2C(O)N(Me)CH2CF3
CH(Me)CH2SMe CH2C(O)NHCH(CF3)2 CH2C(O)N(Me)CH2CH2CH2F
C(Me)2CH2SMe CH2C(O)NHC(Me)2CF3 CH2C(O)N(Me)CH2CH2CF3
CH(Et)CH2SMe CH2C(O)NHCH2CH(Me)CF3 CH2C(O)N(Me)CH2CF2CF3
CH(Z-Pr)CH2SMe CH2C(O)NH(CH2)2CF2CF3 CH2C(O)N(Me)CH(Me)CF3
CH(Z-Bu)CH2SMe CH2C(O)NHCH2(CF2)2CF3 CH2C(O)N(Me)CH(CF3)2
CH2CH2CH2SMe CH(Me)C(O)NHCH2CH2F CH2C(O)N(Me)C(Me)2CF3
CH2CH2CH2SEt CH(Me)C(O)NHCH2CH2Cl CH(Me)C(O)N(Me)CH2CH2F
CH2CH2CH(Me)SMe CH(Me)C(O)NHCH2CHF2 CH(Me)C(O)N(Me)CH2CH2Cl
CH2CH2CH(CF3)SMe CH(Me)C(O)NHCH2CF3 CH(Me)C(O)N(Me)CH2CHF2
CH(Me)CH2CH2SMe CH(Me)C(O)NHCH2CH(Me)F CH(Me)C(O)N(Me)CH2CF3
CH(Et)CH2CH2SMe CH(Me)C(O)NHCH2C(Me)2F CH(Me)C(O)N(Me)(CH2)2CH2F
CH2CH(Me)CH2SMe CH(Me)C(O)NH(CH2)2CH2F CH(Me)C(O)N(Me)CH2CH2CF3
CH2C(Me)2CH2SMe CH(Me)C(O)NHCH2CH2CF3 CH(Me)C(O)N(Me)CH2CF2CF3
CH2CH2S(O)Me CH(Me)C(O)NHCH2CHFCF3 CH(Me)C(O)N(Me)CH(Me)CF3
CH2CH2S(O)Et CH(Me)C(O)NHCH2CF2CF3 CH(Me)C(O)N(Me)CH(CF3)2
CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH(Me)C(O)N(Me)C(Me)2CF3
CH2CH2S(O)(Z-Pr) CH(Me)C(O)NHCH(CF3)2 C(Me)2C(O)N(Me)CH2CH2F
CH2CH2S(O)(Z-Bu) CH(Me)C(O)NHC(Me)2CF3 C(Me)2C(O)N(Me)CH2CH2Cl
CH2CH(Me)S(O)Me CH(Me)C(O)NHCH2CH(Me)CF3 C(Me)2C(O)N(Me)CH2CHF2
CH2CH(CF3)S(O)Me CH(Me)C(O)NH(CH2)2CF2CF3 C(Me)2C(O)N(Me)CH2CF3
CH2C(Me)2S(O)Me CH(Me)C(O)NHCH2(CF2)2CF3 C(Me)2C(O)N(Me)CH2CH2CH2F
CH(Me)CH2S(O)Me C(Me)2C(O)NHCH2CH2F C(Me)2C(O)N(Me)CH2CH2CF3
CH(Et)CH2S(O)Me C(Me)2C(O)NHCH2CH2Cl C(Me)2C(O)N(Me)CH2CF2CF3
CH(Z-Bu)CH2S(O)Me C(Me)2C(O)NHCH2CHF2 C(Me)2C(O)N(Me)CH(Me)CF3
CH2CH2CH2S(O)Me
Figure imgf000048_0001
C(Me)2C(O)NHCH2CF3 C(Me)2C(O)N(Me)CH(CF3)2 CH2CH2CH2S(O)Et C(Me)2C(O)NHCH2CH(Me)F C(Me)2C(O)N(Me)C(Me)2CF3
CH2CH2CH2S(O)(Z-Bu) C(Me)2C(O)NHCH2C(Me)2F C(Me)2C(O)NHCH(Me)CF3
CH2CH2CH(Me)S(O)Me C(Me)2C(O)NH(CH2)2CH2F C(Me)2C(O)NHCH(CF3)2
CH2CH2CH(CF3)S(O)Me C(Me)2C(O)NHCH2CH2CF3 C(Me)2C(O)NHC(Me)2CF3
CH(Me)CH2CH2S(O)Me C(Me)2C(O)NHCH2CHFCF3 C(Me)2C(O)NHCH2CH(Me)CF3
CH(Et)CH2CH2S(O)Me C(Me)2C(O)NHCH2CF2CF3 C(Me)2C(O)NH(CH2)2CF2CF3
CH2CH(Me)CH2S(O)Me CH2C(O)NH(C-Pr) C(Me)2C(O)NHCH2(CF2)2CF3
CH2C(Me)2CH2S(O)Me CH2C(O)NH(CH2-C-Pr) C(Me)2C(O)NHCH(Z-Pr)CF3
CH2(2-pyridinyl) CH2(4-thiazolyl) CH(Me)C(O)NH(C-Pr)
CH(Me)C(O)NH(CH2-C-Pr)
TABLE 4
Figure imgf000049_0001
CH2C(O)NH(C-Pr)
CH2C(O)NH(CH2-C-Pr)
CH2C(O)NHCH2CH2Cl
CH2C(O)NHCH2CHF2
CH2C(O)NHCH2CF3
CH2C(O)NHCH2CH2CF3
CH2C(O)NHCH(Me)CF3
CH2C(O)NHCH2CH(Me)CF3
CH(Me)C(O)NH(C-Pr)
CH(Me)C(O)NH(CH2-C-Pr)
CH(Me)C(O)NHCH2CH2Cl
CH(Me)C(O)NHCH2CHF2
CH(Me)C(O)NHCH2CF3
CH(Me)C(O)NHCH2CH2CF3
CH(Me)C(O)NHCH(Me)CF3
Figure imgf000049_0002
CH(Me)C(O)NHCH2CH(Me)CF3
Figure imgf000050_0001
3
CH2C(O)NH(C-Pr)
CH2C(O)NH(CH2-C-Pr)
CH2C(O)NHCH2CH2Cl
CH2C(O)NHCH2CHF2
CH2C(O)NHCH2CF3
CH2C(O)NHCH2CH2CF3
CH2C(O)NHCH(Me)CF3
CH2C(O)NHCH2CH(Me)CF3
CH(Me)C(O)NH(C-Pr)
CH(Me)C(O)NH(CH2-C-Pr)
CH(Me)C(O)NHCH2CH2Cl
CH(Me)C(O)NHCH2CHF2
CH(Me)C(O)NHCH2CF3
CH(Me)C(O)NHCH2CH2CF3
CH(Me)C(O)NHCH(Me)CF3
Figure imgf000050_0002
CH(Me)C(O)NHCH2CH(Me)CF3
Figure imgf000051_0001
3
CH2C(O)NH(C-Pr)
CH2C(O)NH(CH2-C-Pr)
CH2C(O)NHCH2CH2Cl
CH2C(O)NHCH2CHF2
CH2C(O)NHCH2CF3
CH2C(O)NHCH2CH2CF3
CH2C(O)NHCH(Me)CF3
CH2C(O)NHCH2CH(Me)CF3
CH(Me)C(O)NH(C-Pr)
CH(Me)C(O)NH(CH2-C-Pr)
CH(Me)C(O)NHCH2CH2Cl
CH(Me)C(O)NHCH2CHF2
CH(Me)C(O)NHCH2CF3
CH(Me)C(O)NHCH2CH2CF3
CH(Me)C(O)NHCH(Me)CF3
Figure imgf000051_0002
CH(Me)C(O)NHCH2CH(Me)CF3
Figure imgf000052_0001
3
CH2C(O)NH(C-Pr)
CH2C(O)NH(CH2-C-Pr)
CH2C(O)NHCH2CH2Cl
CH2C(O)NHCH2CHF2
CH2C(O)NHCH2CF3
CH2C(O)NHCH2CH2CF3
CH2C(O)NHCH(Me)CF3
CH2C(O)NHCH2CH(Me)CF3
CH(Me)C(O)NH(C-Pr)
CH(Me)C(O)NH(CH2-C-Pr)
CH(Me)C(O)NHCH2CH2Cl
CH(Me)C(O)NHCH2CHF2
CH(Me)C(O)NHCH2CF3
CH(Me)C(O)NHCH2CH2CF3
CH(Me)C(O)NHCH(Me)CF3
Figure imgf000052_0002
CH(Me)C(O)NHCH2CH(Me)CF3 3
Figure imgf000053_0001
3 3
Figure imgf000054_0001
3 Compositions of Formula 1 compounds may also contain formulation auxiliaries and additives, known to those skilled in the art as formulation aids (some of which may be considered to also function as solid diluents, liquid diluents or surfactants). Such formulation auxiliaries and additives may control: pH (buffers), foaming during processing (antifoams such polyorganosiloxanes), sedimentation of active ingredients (suspending agents), viscosity (thixotropic thickeners), in-container microbial growth (antimicrobials), product freezing (antifreezes), color (dyes/pigment dispersions), wash-off (film formers or stickers), evaporation (evaporation retardants), and other formulation attributes. Film formers include, for example, polyvinyl acetates, polyvinyl acetate copolymers, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers and waxes. Examples of formulation auxiliaries and additives include those listed in McCutcheon 's Volume 2: Functional Materials, annual International and North American editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; and PCT Publication WO 03/024222.
Of note is the present method using a combination of a compound of Formula 1 with at least one other parasitic invertebrate pest control active ingredient. Of particular note is such a method where the other parasitic invertebrate pest control active ingredient has a different site of action from the compound of Formula 1. In certain instances, a combination with at least one other parasitic invertebrate pest control active ingredient having a similar spectrum of control but a different site of action will be particularly advantageous for resistance management. Thus, a composition comprising a compound of Formula 1 useful in the present method can further comprise a biologically effective amount of at least one additional parasitic invertebrate pest control active ingredient having a similar spectrum of control but a different site of action.
The compounds of Formula 1 can be applied without other adjuvants, but most often application will be of a formulation comprising one or more active ingredients with suitable carriers, diluents, and surfactants and possibly in combination with a food depending on the contemplated end use. One method of application involves spraying a water dispersion or refined oil solution of a compound of Formula 1. Combinations with spray oils, spray oil concentrations, spreader stickers, adjuvants, other solvents, and synergists such as piperonyl butoxide often enhance compound efficacy. Such sprays can be applied from spray containers such as a can, a bottle or other container, either by means of a pump or by releasing it from a pressurized container, e.g., a pressurized aerosol spray can. Such spray compositions can take various forms, for example, sprays, mists, foams, fumes or fog. Such spray compositions thus can further comprise propellants, foaming agents, etc. as the case may be. Of note is a spray composition comprising a biologically effective amount of a compound or a composition of Formula 1 and a carrier. One embodiment of such a spray composition comprises a biologically effective amount of a compound or a composition of Formula 1 and a propellant. Representative propellants include, but are not limited to, methane, ethane, propane, butane, isobutane, butene, pentane, isopentane, neopentane, pentene, hydrofluorocarbons, chlorofluorocarbons, dimethyl ether, and mixtures of the foregoing. Of note is a spray composition (and a method utilizing such a spray composition dispensed from a spray container) used to control at least one parasitic invertebrate pest selected from the group consisting of mosquitoes, black flies, stable flies, deer flies, horse flies, wasps, yellow jackets, hornets, ticks, spiders, ants, gnats, and the like, including individually or in combinations. The controlling of animal parasites includes controlling external parasites that are parasitic to the surface of the body of the host animal (e.g., shoulders, armpits, abdomen, inner part of the thighs) and internal parasites that are parasitic to the inside of the body of the host animal (e.g., stomach, intestine, lung, veins, under the skin, lymphatic tissue). External parasitic or disease transmitting pests include, for example, chiggers, ticks, lice, mosquitoes, flies, mites and fleas. Internal parasites include heartworms, hookworms and helminths. Compounds and compositions of Formula 1 are particularly suitable for combating external parasitic pests. Compounds and compositions of Formula 1 are suitable for systemic and/or non-systemic control of infestation or infection by parasites on animals.
Compounds and compositions of Formula 1 are suitable for combating parasitic invertebrate pests that infest animal subjects including those in the wild, livestock and agricultural working animals. Livestock is the term used to refer (singularly or plurally) to a domesticated animal intentionally reared in an agricultural setting to make produce such as food or fiber, or for its labor; examples of livestock include cattle, sheep, goats, horses, pigs, donkeys, camels, buffalo, rabbits, hens, turkeys, ducks and geese (e.g., raised for meat, milk, butter, eggs, fur, leather, feathers and/or wool). By combating parasites, fatalities and performance reduction (in terms of meat, milk, wool, skins, eggs, etc.) are reduced, so that applying a composition comprising a compound of Formula 1 allows more economic and simple husbandry of animals.
Compounds and compositions of Formula 1 are especially suitable for combating parasitic invertebrate pests that infest companion animals and pets (e.g., dogs, cats, pet birds and aquarium fish), research and experimental animals (e.g., hamsters, guinea pigs, rats and mice), as well as animals raised for/in zoos, wild habitats and/or circuses.
In an embodiment of this invention, the animal is preferably a vertebrate, and more preferably a mammal, avian or fish. In a particular embodiment, the animal subject is a mammal (including great apes, such as humans). Other mammalian subjects include primates (e.g., monkeys), bovine (e.g., cattle or dairy cows), porcine (e.g., hogs or pigs), ovine (e.g., goats or sheep), equine (e.g., horses), canine (e.g., dogs), feline (e.g., house cats), camels, deer, donkeys, buffalos, antelopes, rabbits, and rodents (e.g., guinea pigs, squirrels, rats, mice, gerbils, and hamsters). Avians include Anatidae (swans, ducks and geese), Columbidae (e.g., doves and pigeons), Phasianidae (e.g., partridges, grouse and turkeys), Thesienidae (e.g., domestic chickens), Psittacines (e.g., parakeets, macaws, and parrots), game birds, and ratites (e.g., ostriches). Birds treated or protected by the compounds of Formula 1 can be associated with either commercial or noncommercial aviculture. These include Anatidae, such as swans, geese, and ducks, Columbidae, such as doves and domestic pigeons, Phasianidae, such as partridge, grouse and turkeys, Thesienidae, such as domestic chickens, and Psittacines, such as parakeets, macaws and parrots raised for the pet or collector market, among others. For purposes of the present invention, the term "fish" shall be understood to include without limitation, the Teleosti grouping of fish, i.e., teleosts. Both the Salmoniformes order (which includes the Salmonidae family) and the Perciformes order (which includes the Centrarchidae family) are contained within the Teleosti grouping. Examples of potential fish recipients include the Salmonidae, Serranidae, Sparidae, Cichlidae, and Centrarchidae, among others.
Other animals are also contemplated to benefit from the inventive methods, including marsupials (such as kangaroos), reptiles (such as farmed turtles), and other economically important domestic animals for which the inventive methods are safe and effective in treating or preventing parasite infection or infestation. Examples of parasitic invertebrate pests controlled by administering a pesticidally effective amount of a compound of Formula 1 to an animal to be protected include ectoparasites (arthropods, acarines, etc.) and endoparasites (helminths, e.g., nematodes, trematodes, cestodes, acanthocephalans, etc.).
The disease or group of diseases described generally as helminthiasis is due to infection of an animal host with parasitic worms known as helminths. The term 'helminths' is meant to include nematodes, trematodes, cestodes and acanthocephalans. Helminthiasis is a prevalent and serious economic problem with domesticated animals such as swine, sheep, horses, cattle, goats, dogs, cats and poultry.
Among the helminths, the group of worms described as nematodes causes widespread and at times serious infection in various species of animals. Nematodes that are contemplated to be treated by the compounds of this invention and by the inventive methods include, without limitation, the following genera: Acanthocheilonema, Aelurostrongylus, Ancylostoma, Angiostrongylus, Ascaridia, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia, Crenosoma, Dictyocaulus, Dioctophyme, Dipetalonema, Diphyllobothrium, Dirofilaria, Dracunculus, Enterobius, Filaroides, Haemonchus, Heterakis, Lagochilascaris, Loa, Mansonella, Muellerius, Necator, Nematodirus, Oesophagostomum, Ostertagia, Oxyuris, Parafilaria, Parascaris, Physaloptera, Protostrongylus, Setaria, Spirocerca, Stephanofilaria, Strongyloides, Strongylus, Thelazia, Toxascaris, Toxocara, Trichinella, Trichonema, Trichostrongylus, Trichuris, Uncinaria and
Wuchereria.
Of the above, the most common genera of nematodes infecting the animals referred to above are Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostomum, Oesophagostomum, Chabertia, Trichuris, Strongylus, Trichonema,
Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria,
Toxascaris and Parascaris. Certain of these, such as Nematodirus, Cooperia and
Oesophagostomum attack primarily the intestinal tract while others, such as Haemonchus and Ostertagia, are more prevalent in the stomach while others such as Dictyocaulus are found in the lungs. Still other parasites may be located in other tissues such as the heart and blood vessels, subcutaneous and lymphatic tissue and the like.
Trematodes that are contemplated to be treated by the compounds of this invention and by the inventive methods include, without limitation, the following genera: Alaria, Fasciola,
Nanophyetus, Opisthorchis, Paragonimus and Schistosoma. Cestodes that are contemplated to be treated by the compounds of this invention and by the inventive methods include, without limitation, the following genera:
Diphyllobothrium, Diplydium, Spirometra and Taenia.
The most common genera of parasites of the gastrointestinal tract of humans are
Ancylostoma, Necator, Ascaris, Strongy hides, Trichinella, Capillaria, Trichuris and Enterobius. Other medically important genera of parasites which are found in the blood or other tissues and organs outside the gastrointestinal tract are the filarial worms such as
Wuchereria, Brugia, Onchocerca and Loa, as well as Dracunculus and extra intestinal stages of the intestinal worms Strongyloides and Trichinella.
Numerous other helminth genera and species are known to the art, and are also contemplated to be treated by the compounds of Formula 1. These are enumerated in great detail in Textbook of Veterinary Clinical Parasitology, Volume 1, Helminths, E. J. L.
Soulsby, F. A. Davis Co., Philadelphia, Pa.; Helminths, Arthropods and Protozoa, (6th
Edition of Monnig's Veterinary Helminthology and Entomology), E. J. L. Soulsby, The
Williams and Wilkins Co., Baltimore, Md. The compounds of Formula 1 are effective against a number of animal ectoparasites
(e.g., arthropod ectoparasites of mammals and birds).
Insect and acarine pests include, e.g., biting insects such as flies and mosquitoes, mites, ticks, lice, fleas, true bugs, parasitic maggots, and the like.
Adult flies include, e.g., the horn fly or Haematobia irritans, the horse fly or Tabanus spp., the stable fly or Stomoxys calcitrans, the black fly or Simulium spp., the deer fly or
Chrysops spp., the louse fly or Melophagus ovinus, and the tsetse fly or Glossina spp.
Parasitic fly maggots include, e.g., the bot fly (Oestrus ovis and Cuterebra spp.), the blow fly or Phaenicia spp., the screwworm or Cochliomyia hominivorax, the cattle grub or Hypoderma spp., the fleeceworm and the Gastrophilus of horses. Mosquitoes include, for example, Culex spp., Anopheles spp. and Aedes spp.
Mites include Mesostigmαtα spp. e.g., mesostigmatids such as the chicken mite,
Dermαnyssus gαllinαe; itch or scab mites such as Sarcoptidae spp. for example, Sαrcoptes scαbiei; mange mites such as Psoroptidae spp. including Chorioptes bovis and Psoroptes ovis; chiggers e.g., Trombiculidae spp. for example the North American chigger, Trombiculα αlfreddugesi.
Ticks include, e.g., soft-bodied ticks including Argasidae spp. for example Argαs spp. and Ornithodoros spp.; hard-bodied ticks including Ixodidae spp., for example Rhipicephαlus sanguineus, Dermacentor variabilis, Dermacentor andersoni, Amblyomma americanum, Ixodes scapularis and other Rhipicephalus spp. (including the former
Boophilus genera).
Lice include, e.g., sucking lice, e.g., Menopon spp. and Bovicola spp.; biting lice, e.g., Haematopinus spp., Linognathus spp. and Solenopotes spp. Fleas include, e.g., Ctenocephalides spp., such as dog flea (Ctenocephalides canis) and cat flea {Ctenocephalides felis); Xenopsylla spp. such as oriental rat flea (Xenopsylla cheopis); and Pulex spp. such as human flea (Pulex irritans).
True bugs include, e.g., Cimicidae or e.g., the common bed bug (Cimex lectularius); Triatominae spp. including triatomid bugs also known as kissing bugs; for example Rhodnius prolixus and Triatoma spp.
Generally, flies, fleas, lice, mosquitoes, gnats, mites, ticks and helminths cause tremendous losses to the livestock and companion animal sectors. Arthropod parasites also are a nuisance to humans and can vector disease-causing organisms in humans and animals.
Numerous other parasitic invertebrate pests are known to the art, and are also contemplated to be treated by the compounds of Formula 1. These are enumerated in great detail in Medical and Veterinary Entomology, D. S. Kettle, John Wiley & Sons, New York and Toronto; Control of Arthropod Pests of Livestock: A Review of Technology, R. O.
Drummand, J. E. George, and S. E. Kunz, CRC Press, Boca Raton, FIa.
In particular, the compounds of Formula 1 are especially effective against ectoparasites including Stomoxys calcitrans (stable fly); ticks such as Ixodes spp., Boophilus spp.,
Rhipicephalus spp., Amblyomma spp., Dermacentor spp., Hyalomma spp. and
Haemaphysalis spp.; and fleas such as Ctenocephalides felis (cat flea) and Ctenocephalides canis (dog flea).
The compounds of Formula 1 may also be effective against ectoparasites including: flies such as Haematobia (Lyperosia) irritans (horn fly), Simulium spp. (blackfly), Glossina spp. (tsetse flies), Hydrotaea irritans (head fly), Musca autumnalis (face fly), Musca domestica (house fly), Morellia simplex (sweat fly), Tabanus spp. (horse fly), Hypoderma bovis, Hypoderma lineatum, Lucilia sericata, Lucilia cuprina (green blowfly), Calliphora spp. (blowfly), Protophormia spp., Oestrus ovis (nasal botfly), Culicoides spp. (midges), Hippobosca equine, Gastrophilus intestinalis, Gastrophilus haemorrhoidalis and Gastrophilus nasalis; lice such as Bovicola (Damalinia) bovis, Bovicola equi, Haematopinus asini, Felicola subrostratus, Heterodoxus spiniger, Lignonathus setosus and Tήchodectes canis; keds such as Melophagus ovinus; and mites such as Psoroptes spp., Sarcoptes scabei, Chorioptes bovis, Demodex equi, Cheyletiella spp., Notoedres cati, Trombicula spp. and Otodectes cyanotis (ear mites).
Other biologically active compounds or agents may be administered at the same or different times as the compounds of Formula 1. Such compounds, for example, may be useful adjuncts in Formula 1 compositions for the present method. As noted below, such biologically active compounds may be included in the composition of Formula 1. Such biologically active compounds for use in the present invention include the organophosphate pesticides. This class of pesticides has very broad activity as insecticides and, in certain instances, anthelmintic activity. Organophosphate pesticides include, e.g., dicrotophos, terbufos, dimethoate, diazinon, disulfoton, trichlorfon, azinphos-methyl, chlorpyrifos, malathion, oxydemeton-methyl, methamidophos, acephate, ethyl parathion, methyl parathion, mevinphos, phorate, carbofenthion and phosalone. Compositions of Formula 1 compounds for the present method are also comtemplated to include carbamate -type pesticides, including, e.g., carbaryl, carbofuran, aldicarb, molinate, methomyl, carbofuran, etc., as well as combinations with the organochlorine type pesticides. Compositions of Formula 1 compounds are further contemplated to include combinations with biological pesticides, including repellents, the pyrethrins (as well as synthetic variations thereof, e.g., allethrin, resmethrin, permethrin, tralomethrin), and nicotine, that is often employed as an acaricide. Other contemplated combinations are with miscellaneous pesticides including: Bacillus thuringiensis, chlorobenzilate, formamidines (e.g., amitraz), copper compounds (e.g., copper hydroxide and cupric oxychloride sulfate), cyfluthrin, cypermethrin, dicofol, endosulfan, esfenvalerate, fenvalerate, lambda-cyhalothrin, methoxychlor and sulfur.
Of note are additional biologically active compounds or agents selected from art- known anthelmintics, such as, for example, avermectins (e.g., ivermectin, moxidectin, milbemycin), benzimidazoles (e.g., albendazole, triclabendazole), salicylanilides (e.g., closantel, oxyclozanide), substituted phenols (e.g., nitroxynil), pyrimidines (e.g., pyrantel), imidazothiazoles (e.g., levamisole) and praziquantel.
Other biologically active compounds or agents useful in the Formula 1 compositions for the present method can be selected from Insect Growth Regulators (IGRs) and Juvenile Hormone Analogues (JHAs) such as diflubenzuron, triflumuron, fluazuron, cyromazine, methoprene, etc., thereby providing both initial and sustained control of parasites (at all stages of insect development, including eggs) on the animal subject, as well as within the environment of the animal subject. Of note are biologically active compounds or agents useful in the Formula 1 compositions for the present method selected from the avermectin class of antiparasitic compounds. As stated above, the avermectin family of compounds includes very potent antiparasitic agents known to be useful against a broad spectrum of endoparasites and ectoparasites in mammals.
A preferred compound for use within the scope of the present invention is ivermectin. Ivermectin is a semi-synthetic derivative of avermectin and is generally produced as a mixture of at least 80% 22,23-dihydroavermectin Bla and less than 20% 22,23- dihydroavermectin B1^. Ivermectin is disclosed in U.S. Patent No. 4,199,569. Abamectin is an avermectin that is disclosed as avermectin B1^B1J5 in U.S. Patent No.
4,310,519. Abamectin contains at least 80% of avermectin Bla and not more than 20% of avermectin B1^.
Another preferred avermectin is doramectin, also known as 25-cyclohexyl-avermectin B1. The structure and preparation of doramectin is disclosed in U.S. Patent No. 5,089,480. Another preferred avermectin is moxidectin. Moxidectin, also known as LL-F28249 alpha, is known from U.S. Patent No. 4,916,154.
Another preferred avermectin is selamectin. Selamectin is 25-cyclohexyl-25-de(l- methylpropyl)-5 -deoxy-22,23 -dihydro-5 -(hydroxyimino)-avermectin B 1 monosaccharide .
Milbemycin, or B41, is a substance which is isolated from the fermentation broth of a milbemycin-producing strain of Streptomyces. The microorganism, the fermentation conditions and the isolation procedures are described in U.S. Patent Nos. 3,950,360 and 3,984,564.
Emamectin (4"-deoxy-4"-epi-methylaminoavermectin B1), which can be prepared as described in U.S. Patent Nos. 5,288,710 and 5,399,717, is a mixture of two homologues, 4"- deoxy-4"-epi-methylaminoavermectin Bla and 4"-deoxy-4"-epi-methylaminoavermectin B1^.
Preferably, a salt of emamectin is used. Non-limiting examples of salts of emamectin which may be used in the present invention include the salts described in U.S. Patent No.
5,288,710, e.g., salts derived from benzoic acid, substituted benzoic acid, benzenesulfonic acid, citric acid, phosphoric acid, tartaric acid, maleic acid, and the like. Most preferably, the emamectin salt used in the present invention is emamectin benzoate.
Eprinomectin is chemically known as 4"-epi-acetylamino-4"-deoxy-avermectin B1. Eprinomectin was specifically developed to be used in all cattle classes and age groups. It was the first avermectin to show broad-spectrum activity against both endo- and ectoparasites while also leaving minimal residues in meat and milk. It has the additional advantage of being highly potent when delivered topically.
The Formula 1 compositions for the present method optionally comprise combinations of one or more of the following antiparasite compounds: imidazo[l,2-b]pyridazine compounds as described by U.S. Patent Application Publication No. 2005/0182059 Al; l-(4- mono and di-halomethylsulphonylphenyl)-2-acylamino-3-fluoropropanol compounds, as described by U.S. Patent No. 7,361,689; trifluoromethanesulfonanilide oxime ether derivatives, as described by U.S. Patent No. 7,312,248; and n- [(phenyloxy)phenyl]- 1,1,1 - trifluoromethanesulfonamide and /?-[(phenylsulfanyl)phenyl]- 1 ,1,1 -trifluoromethane- sulfonamide derivatives, as described by PCT Patent Application Publication WO 2006/135648.
The Formula 1 compositions may also further comprise a flukicide. Suitable flukicides include, for example, triclabendazole, fenbendazole, albendazole, clorsulon and oxibendazole. It will be appreciated that the above combinations may further include combinations of antibiotic, antiparasitic and anti-fluke active compounds.
In addition to the above combinations, it is also contemplated to provide Formula 1 compositions, as described herein for the present method, with other animal health remedies such as trace elements, antiinflammatories, anti-infectives, hormones, dermatological preparations, including antiseptics and disinfectants, and immunobiologicals such as vaccines and antisera for the prevention of disease.
For example, such antinfectives include one or more antibiotics that are optionally coadministered during treatment using the inventive methods, e.g., in a combined composition and/or in separate dosage forms. Art-known antibiotics suitable for this purpose include, for example, those listed herein below. One useful antibiotic is florfenicol, also known as D-(threo)-l-(4- methylsulfonylphenyl)-2-dichloroacetamido-3-fluoro- 1 -propanol. Another preferred antibiotic compound is D-(threo)-l-(4-methylsulfonylphenyl)-2-difluoroacetamido-3-fluoro- 1 -propanol. Another useful antibiotic is thiamphenicol. Processes for the manufacture of these antibiotic compounds, and intermediates useful in such processes, are described in U.S. Patent Nos. 4,31,857; 4,582,918; 4,973,750; 4,876,352; 5,227,494; 4,743,700; 5,567,844; 5,105,009; 5,382,673; 5,352,832; and 5,663,361. Other florfenicol analogs and/or prodrugs have been disclosed and such analogs also can be used in the compositions and methods of the present invention (see e.g., U.S. Patent Nos. 7,041,670 and 7,153,842).
Another useful antibiotic compound is tilmicosin. Tilmicosin is a macrolide antibiotic that is chemically defined as 20-dihydro-20-deoxy-20-(cώ-3,5-dimethylpiperidin-l-yl)- desmycosin and is disclosed in U.S. Patent No. 4,820,695.
Another useful antibiotic for use in the present invention is tulathromycin. Tulathromycin may be prepared in accordance with the procedures set forth in U.S. Patent No. 6,825,327. Further antibiotics for use in the present invention include the cephalosporins such as, for example, ceftiofur, cefquinome, etc. The concentration of the cephalosporin in the formulation of the present invention optionally varies between about 1 mg/mL to 500 mg/mL. Another useful antibiotic includes the fluoroquinolones, such as, for example, enrofloxacin, danofloxacin, difloxacin, orbifloxacin and marbofloxacin. In the case of enrofloxacin, it may be administered in a concentration of about 100 mg/mL. Danofloxacin may be present in a concentration of about 180 mg/mL. Other useful macrolide antibiotics include compounds from the class of ketolides, or, more specifically, the azalides. Such compounds are described in, for example, U.S. Patent Nos. 6,514,945; 6,472,371; 6,270,768; 6,437,151; 6,271,255; 6,239,12; 5,958,888; 6,339,063; and 6,054,434.
Other useful antibiotics include the tetracyclines, particularly chlortetracycline and oxytetracycline. Other antibiotics may include β-lactams such as penicillins, e.g., penicillin, ampicillin, amoxicillin, or a combination of amoxicillin with clavulanic acid or other beta lactamase inhibitors.
Treatments of the invention are by conventional means such as by enteral administration in the form of, for example, tablets, capsules, drinks, drenching preparations, granulates, pastes, boli, feed-through procedures, or suppositories; or by parenteral administration, such as, for example, by injection (including intramuscular, subcutaneous, intravenous, intraperitoneal) or implants; or by nasal administration.
The compounds of Formula 1 may be administered in a controlled release form, for example in subcutaneous or orally adminstered slow release formulations. Typically a parasiticidal composition according to the present invention comprises a mixture of a compound of Formula 1, an JV-oxide or a salt thereof, with one or more pharmaceutically or veterinarily acceptable carriers comprising excipients and auxiliaries selected with regard to the intended route of administration (e.g., oral or parenteral administration such as injection) and in accordance with standard practice. In addition, a suitable carrier is selected on the basis of compatibility with the one or more active ingredients in the composition, including such considerations as stability relative to pH and moisture content. Therefore of note is a composition for protecting an animal from an invertebrate parasitic pest comprising a parasitically effective amount of a compound of Formula 1 and at least one carrier. For parenteral administration including intravenous, intramuscular and subcutaneous injection, a compound of Formula 1 can be formulated in suspension, solution or emulsion in oily or aqueous vehicles, and may contain adjuncts such as suspending, stabilizing and/or dispersing agents. The compounds of Formula 1 may also be formulated for bolus injection or continuous infusion. Pharmaceutical compositions for injection include aqueous solutions of water-soluble forms of active ingredients (e.g., a salt of an active compound), preferably in physiologically compatible buffers containing other excipients or auxiliaries as are known in the art of pharmaceutical formulation. Additionally, suspensions of the active compounds may be prepared in a lipophilic vehicle. Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
In addition to the formulations described supra, the compounds of Formula 1 may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular or subcutaneous injection. The compounds of Formula 1 may be formulated for this route of administration with suitable polymeric or hydrophobic materials (for instance, in an emulsion with a pharmacologically acceptable oil), with ion exchange resins, or as a sparingly soluble derivative such as, without limitation, a sparingly soluble salt.
For administration by inhalation, the compounds of Formula 1 can be delivered in the form of an aerosol spray using a pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be controlled by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
Compounds of Formula 1 have been discovered to have surprisingly favorable pharmacokinetic and pharmacodynamic properties providing systemic availability from oral administration and ingestion. Therefore after ingestion by the animal to be protected, parasiticidally effective concentrations of compounds of Formula 1 in the bloodstream protect the treated animal from blood-sucking pests such as fleas, ticks and lice. Therefore of note is a composition for protecting an animal from an invertebrate parasite pest in a form for oral administration (i.e. comprising, in addition to a parasiticidally effective amount of a compound of Formula 1, one or more carriers selected from binders and fillers suitable for oral administration and feed concentrate carriers).
For oral administration in the form of solutions (the most readily available form for absorption), emulsions, suspensions, pastes, gels, capsules, tablets, boluses, powders, granules, rumen-retention and feed/water/lick blocks, a compound of Formula 1 can be formulated with binders/fillers known in the art to be suitable for oral administration compositions, such as sugars and sugar derivatives (e.g., lactose, sucrose, mannitol, sorbitol), starch (e.g., maize starch, wheat starch, rice starch, potato starch), cellulose and derivatives (e.g., methylcellulose, carboxymethylcellulose, ethylhydroxycellulose), protein derivatives (e.g., zein, gelatin), and synthetic polymers (e.g., polyvinyl alcohol, polyvinylpyrrolidone). If desired, lubricants (e.g., magnesium stearate), disintegrating agents (e.g., cross-linked polyvinylpyrrolidinone, agar, alginic acid) and dyes or pigments can be added. Pastes and gels often also contain adhesives (e.g., acacia, alginic acid, bentonite, cellulose, xanthan gum, colloidal magnesium aluminum silicate) to aid in keeping the composition in contact with the oral cavity and not being easily ejected.
A preferred embodiment is a composition of the present method formulated into a chewable and/or edible product (e.g., a chewable treat or edible tablet). Such a product would ideally have a taste, texture and/or aroma favored by the animal to be protected so as to facilitate oral administration of the compound of Formula 1. If the parasiticidal compositions are in the form of feed concentrates, the carrier is typically selected from high-performance feed, feed cereals or protein concentrates. Such feed concentrate-containing compositions can, in addition to the parasiticidal active ingredients, comprise additives promoting animal health or growth, improving quality of meat from animals for slaughter or otherwise useful to animal husbandry. These additives can include, for example, vitamins, antibiotics, chemotherapeutics, bacteriostats, fungistats, coccidiostats and hormones.
The compounds of Formula 1 may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides. The formulations for the method of this invention may include an antioxidant, such as
BHT (butylated hydroxytoluene). The antioxidant is generally present in amounts of at 0.1- 5% (wt/vol). Some of the formulations require a solubilizer, such as oleic acid, to dissolve the active agent, particularly if spinosad is included. Common spreading agents used in these pour-on formulations include isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated C12-C18 fatty alcohols, oleic acid, oleyl ester, ethyl oleate, triglycerides, silicone oils and dipropylene glycol methyl ether. The pour-on formulations for the method of this invention are prepared according to known techniques. Where the pour-on is a solution, the parasiticide/insecticide is mixed with the carrier or vehicle, using heat and stirring if required. Auxiliary or additional ingredients can be added to the mixture of active agent and carrier, or they can be mixed with the active agent prior to the addition of the carrier. Pour-on formulations in the form of emulsions or suspensions are similarly prepared using known techniques.
Other delivery systems for relatively hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well-known examples of delivery vehicles or carriers for hydrophobic drugs. In addition, organic solvents such as dimethylsulfoxide may be used, if needed.
The rate of application required for effective parasitic invertebrate pest control (i.e. "pesticidally effective amount") will depend on such factors as the species of parasitic invertebrate pest to be controlled, the pest's life cycle, life stage, its size, location, time of year, host crop or animal, feeding behavior, mating behavior, ambient moisture, temperature, and the like. One skilled in the art can easily determine the pesticidally effective amount necessary for the desired level of parasitic invertebrate pest control. In general for veterinary use, a compound or composition of Formula 1 is administered in a pesticidally effective amount to an animal, particularly a homeothermic animal, to be protected from parasitic invertebrate pests. A pesticidally effective amount is the amount of active ingredient needed to achieve an observable effect diminishing the occurrence or activity of the target parasitic invertebrate pest. One skilled in the art will appreciate that the pesticidally effective dose can vary for the various compounds and compositions useful for the method of the present invention, the desired pesticidal effect and duration, the target parasitic invertebrate pest species, the animal to be protected, the mode of application and the like, and the amount needed to achieve a particular result can be determined through simple experimentation. For oral or parenteral administration to animals, a dose of a compound of the present invention administered at suitable intervals typically ranges from about 0.01 mg/kg to about
100 mg/kg, and preferably from about 0.01 mg/kg to about 30 mg/kg of animal body weight.
Suitable intervals for the administration of compounds of the present invention to animals range from about daily to about yearly. Of note are administration intervals ranging from about weekly to about once every 6 months. Of particular note are monthly adminstration intervals (i.e. administering the compound to the animal once every month).
The following Tests demonstrate the control efficacy of compounds of Formula 1 on specific pests. "Control efficacy" represents inhibition of parasitic invertebrate pest development (including mortality) that causes significantly reduced feeding. The pest control protection afforded by the compounds is not limited, however, to these species. See Index Tables A and B for compound descriptions.
INDEX TABLE A
Figure imgf000066_0001
Cmpd Ri R-: R! Sl R6. mp (°C
1 Cl H Cl CH3 CH2(2-pyridinyl) 67-69
2 Cl H Cl CH3 CH2CH2SCH3 *
3 Cl H Cl CH3 CH2C(O)NHCH2CF3 *
4 Cl H Cl CH3 CH(CH3)CH2CH2SCH3 *
5 Cl H Cl CH3 CH2CH2S(O)CH3 *
6 Cl H Cl CH3 CH2CH2S(O)2CH3 *
7 Cl H Cl F CH2(2-pyridinyl) *
8 Cl H Cl CH3 C(CH3)2CH2SCH3 *
9 Cl H Cl CH3 (^)-CH(CH3)C(O)NHCH2CF3
10 Cl H Cl CH3 C(CH3)2CH2S(O)2CH3 * See Index Table B for 1H NMR data.
INDEX TABLE B
Compound 1 H NMR Data (CDCl3 solution unless indicated otherwise)a
2 δ 7.52 (m, 4H), 7.43 (m, 2H), 6.20 (br s, IH), 4.08 (d, IH), 3.72 (d, IH), 3.66 (m, 2H), 2.76 (t, 2H), 2.49 (s, 3H), 2.15 (s, 3H).
3 δ 7.43-7.54 (m, 6H), 6.99 (br t, IH), 6.75 (br t, IH), 4.21 (d, 2H), 4.08 (d, IH), 3.95 (m, 2H), 3.70 (d, IH), 2.47 (s, 3H).
4 δ 7.51 (m, 4H), 7.43 (m, 2H), 5.74 (br d, IH), 4.08 (d, IH), 3.70 (d, IH), 2.60 (t, 2H), 2.47 (s, 3H), 2.13 (s, 3H), 1.3 (d, 3H).
5 δ 7.5 (m, 4H), 7.43 (m, IH), 7.0 (s, IH), 6.84 (br s, IH), 4.08 (d, IH), 4.0 (m, 2H), 3.71 (d, IH),
3.17 (m, IH), 2.91 (m, IH), 2.68 (s, 3H), 2.49 (s, 3H).
6 δ 7.5 (m, 4H), 7.43 (m, 2H), 7.0 (s, IH), 6.58 (br s, IH), 4.08 (d, IH), 4.0 (m, 2H), 3.71 (d, IH), 3.36 (m, 2H), 3.0 (s, 3H), 2.49 (s, 3H).
7 δ 8.6 (d, IH), 8.2 (t, IH), 8.1 (m, IH), 7.7 (dt, IH), 7.6-7.4 (m, 5H), 7.35 (d, IH), 7.25 (m, IH), 4.8 (d, 2H), 4.1 (d, IH), 3.7 (d, IH).
8 δ 7.5 (m, 4H), 7.43 (m, 2H), 5.75 (br s, IH), 4.08 (d, IH), 3.71 (d, IH), 3.07 (s, 2H), 2.48 (s, 3H),
2.18 (s, 3H), 1.51 (s, 6H).
9 δ 7.36-7.51 (m, 7H), 6.85 (dd, IH), 4.83 (m, IH), 4.09 (d, IH), 3.88 (m, 2H), 3.71 (d, IH), 2.40 (s, 3H), 1.51 (d, 3H).
10 δ 7.5 (m, 5H), 7.43 (s, IH), 6.03 (br s, IH), 4.08 (d, IH), 3.79 (s, 2H), 3.71 (d, IH), 2.95 (s, 3H), 2.47 (s, 3H), 1.69 (s, 6H). a ^H NMR data are in ppm downfield from tetramethylsilane. Couplings are designated by (s)-singlet, (d)-doublet, (t)-triplet, (q)-quartet, (dd)-doublet of doublets, (dt)-doublet of triplets, (br)-broad peaks, (m)-multiplet. Methods for preparing the compounds listed in Index Table A are disclosed in PCT Patent Publication WO 2005/085216. To the extent necessary to teach the methods of preparing the compounds Formula 1, (and only to the extent that they are not inconsistent with the disclosure herein) this patent publication is herein incorporated by reference. BIOLOGICAL EXAMPLES OF THE INVENTION
TEST A
For evaluating control of the cat flea (Ctenocephalides felis), a CD-I® mouse (about 30 g, male, obtained from Charles River Laboratories, Wilmington, MA) was orally dosed with a test compound in an amount of 10 mg/kg solubilized in propylene glycol/glycerol formal (60:40). Two hours after oral administration of the test compound, approximately 8 to 16 adult fleas were applied to each mouse. The fleas were then evaluated for mortality 48 hours after flea application to the mouse.
Of the compounds tested, the following compounds resulted in at least 50% mortality: 1, 2, 3 and 4. TEST B
For evaluating control of the cat flea {Ctenocephalides felis), a CD-I® mouse (about 30 g, male, obtained from Charles River Laboratories, Wilmington, MA) was orally dosed with a test compound in an amount of 10 mg/kg solubilized in propylene glycol/glycerol formal (60:40). Twenty four hours after oral administration of the test compound, approximately 8 to 16 adult fleas were applied to each mouse. The fleas were then evaluated for mortality 48 hours after flea application to the mouse.
Of the compounds tested, the following compounds resulted in at least 20% mortality: 1, 2 and 3. The following compounds resulted in at least 50% mortality: 2 and 3.
TEST C For evaluating control of the cat flea {Ctenocephalides felis), a CD-I® mouse (about 30 g, male, obtained from Charles River Laboratories, Wilmington, MA) was subcutaneously dosed with a test compound in an amount of 10 mg/kg solubilized in propylene glycol/glycerol formal (60:40). Two hours after oral administration of the test compound, approximately 8 to 16 adult fleas were applied to each mouse. The fleas were then evaluated for mortality 48 hours after flea application to the mouse.
Of the compounds tested, the following compounds resulted in at least 20% mortality: 1, 2 and 3. The following compounds resulted in at least 50% mortality: 1 and 3.
TEST D
For evaluating control of the cat flea {Ctenocephalides felis), a test compound was solubilized in propylene glycol/glycerol formal (60:40) and then diluted in bovine blood to a final test rate of 30 ppm. The treated blood was placed in a tube, and the bottom of the tube was covered with a membrane. Approximately 10 adult cat fleas were allowed to feed through the membrane on the treated blood. The adult fleas were then evaluated for mortality 72 hours later.
Of the compounds tested, the following compounds resulted in at least 50% mortality: 1, 2, 3, 5, 6, 7, 8, 9 and 10.

Claims

CLAIMSWhat is claimed is:
1. A method for protecting an animal from a parasitic invertebrate pest comprising orally or parenterally administering to the animal a pesticidally effective amount of a compound of Formula 1, an JV-oxide or a salt thereof
Figure imgf000070_0001
wherein R1 is halogen, C1-C3 haloalkyl or C1-C3 haloalkoxy;
R2 is H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or cyano; R3 is H, halogen, C1-C3 haloalkyl or C1-C3 haloalkoxy; R4 is halogen, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 haloalkoxy; R5 is H, CH3, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl, C2-C5 alkoxycarbonyl or CH2O(C1-C3 alkyl);
R6 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or C3-C6 halocycloalkyl, each group substituted with one R7; or R6 is (CH2)mQ; Q is a 4- to 6-membered saturated ring containing carbon atoms and one O or S(O)n as ring members and optionally substituted with 1 or 2 R8a and one R8^; R7 is OR9, S(O)nR10 or C(O)NR11R12; or R7 is pyridine or thiazole, each optionally substituted with 1 or 2 R15; each R8a is independently halogen, cyano or C1-C2 alkyl; RSb is OR9, S(O)nR10 or C(O)NR11R12;
R9 is H, CHO, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl or C2-C5 alkoxycarbonyl; or R9 is C1-C4 alkyl or C1-C4 haloalkyl, each optionally substituted with one R13; or R9 is pyridine or thiazole, each optionally substituted with 1 or 2 R15; R10 is C1-C4 alkyl or C1-C4 haloalkyl, each optionally substituted with one R13; or
R10 is pyridine or thiazole, each optionally substituted with 1 or 2 R15; R11 is H, CHO, C1-C4 alkyl, C1-C4 haloalkyl, CH2O(C1-C3 alkyl), C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl or C2-C5 alkoxycarbonyl; R12 is C1-C4 alkyl, C1-C4 haloalkyl or C3-C6 cycloalkyl, each optionally substituted with one R13; or R12 is H, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl or
OR14; R13 is cyano, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, OH, OR14 or S(O)nR16; or R13 is pyridine or thiazole, each optionally substituted with 1 or 2 R15; R14 is C1-C4 alkyl or C1-C4 haloalkyl; each R15 is independently halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 haloalkoxy;
R16 is C1-C4 alkyl or C1-C4 haloalkyl; m is 0 or 1 ; and n is 0, 1 or 2.
2. The method of Claim 1 wherein R4 is Cl or CH3;
R5 is H;
R6 is C1-C6 alkyl substituted with one R7; and R7 is OR9, S(O)nR10 or C(O)NR11R12.
3. The method of Claim 2 wherein R1 is Cl, Br, CF3, OCF3 or OCH2CF3; R2 is H; and
R3 is H, F, Cl, Br or CF3.
4. The method of Claim 3 wherein
R4 is CH3; and R7 is C(O)NR11R12.
5. The method of Claim 4 wherein R1 is CF3; and R3 is Cl, Br or CF3.
6. The method of Claim 4 wherein R11 is H; and
R12 is C1-C4 alkyl or C1-C4 haloalkyl.
7. The method of Claim 4 wherein R11 is H; and
R12 is cyclopropyl or cyclopropylmethyl.
8. The method of Claim 1 wherein the pesticidally effective amount of a compound of Formula 1 is administered orally.
9. The method of Claim 1 wherein the pesticidally effective amount of a compound of Formula 1 is administered parenterally.
10. The method of Claim 9 wherein the pesticidally effective amount of a compound of Formula 1 is administered by injection.
11. The method of Claim 1 wherein the animal to be protected is a mammal.
12. The method of Claim 11 wherein the mammal to be protected is livestock.
13. The method of Claim 11 wherein the mammal to be protected is a canine.
14. The method of Claim 11 wherein the mammal to be protected is a feline.
15. The method of Claim 1 wherein the parasitic invertebrate pest is an ectoparasite.
16. The method of Claim 1 wherein the parasitic invertebrate pest is an arthropod.
17. The method of Claim 1 wherein the parasitic invertebrate pest is a fly, mosquito, mite, tick, louse, flea, true bug or maggot.
18. The method of Claim 17 wherein the animal to be protected is a cat or dog and the parasitic invertebrate pest is a flea, tick or mite.
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