WO2009003075A1 - Animal pest control method - Google Patents

Animal pest control method Download PDF

Info

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
Authority
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 MX2015011173A priority patent/MX361762B/en
Priority to BRPI0810929A priority patent/BRPI0810929B8/en
Priority to RU2010102529/15A priority patent/RU2508102C2/en
Priority to DK08771978.7T priority patent/DK2182945T3/en
Priority to CA2685072A priority patent/CA2685072C/en
Priority to MX2014010553A priority patent/MX368680B/en
Priority to EP17206287.9A priority patent/EP3351243A1/en
Priority to US12/663,848 priority patent/US11278533B2/en
Priority to AU2008268321A priority patent/AU2008268321C1/en
Priority to KR1020107001744A priority patent/KR101714059B1/en
Priority to JP2010515096A priority patent/JP6006471B2/en
Priority to EP08771978.7A priority patent/EP2182945B1/en
Priority to KR1020157020688A priority patent/KR101714291B1/en
Application filed by E.I. Du Pont De Nemours And Company filed Critical E.I. Du Pont De Nemours And Company
Priority to ES08771978.7T priority patent/ES2549731T3/en
Priority to MX2009013748A priority patent/MX2009013748A/en
Priority to SI200831504T priority patent/SI2182945T1/en
Priority to KR1020167030535A priority patent/KR101769728B1/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

Links

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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Nutrition Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Physiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Agronomy & Crop Science (AREA)
  • Plant Pathology (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Fodder In General (AREA)
  • Feed For Specific Animals (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Medicinal Preparation (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

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.
PCT/US2008/068268 2007-06-27 2008-06-26 Animal pest control method WO2009003075A1 (en)

Priority Applications (25)

Application Number Priority Date Filing Date Title
MX2015011173A MX361762B (en) 2007-06-27 2008-06-26 Animal pest control method.
KR1020157020688A KR101714291B1 (en) 2007-06-27 2008-06-26 Animal pest control method
EP08771978.7A EP2182945B1 (en) 2007-06-27 2008-06-26 Animal pest control method
RU2010102529/15A RU2508102C2 (en) 2007-06-27 2008-06-26 Method for controlling animal pests
DK08771978.7T DK2182945T3 (en) 2007-06-27 2008-06-26 PROCEDURE TO COMBAT PESTS WITH ANIMALS
CA2685072A CA2685072C (en) 2007-06-27 2008-06-26 Animal pest control method
MX2014010553A MX368680B (en) 2007-06-27 2008-06-26 Animal pest control method.
EP17206287.9A EP3351243A1 (en) 2007-06-27 2008-06-26 Animal pest control method
US12/663,848 US11278533B2 (en) 2007-06-27 2008-06-26 Animal pest control method
AU2008268321A AU2008268321C1 (en) 2007-06-27 2008-06-26 Animal pest control method
KR1020107001744A KR101714059B1 (en) 2007-06-27 2008-06-26 Animal pest control method
JP2010515096A JP6006471B2 (en) 2007-06-27 2008-06-26 Animal pest control methods
BRPI0810929A BRPI0810929B8 (en) 2007-06-27 2008-06-26 use of a compound of formula 1
CN200880019716A CN101743000A (en) 2007-06-27 2008-06-26 Animal pest control method
KR1020167030535A KR101769728B1 (en) 2007-06-27 2008-06-26 Animal pest control method
ES08771978.7T ES2549731T3 (en) 2007-06-27 2008-06-26 Method for pest control in animals
MX2009013748A MX2009013748A (en) 2007-06-27 2008-06-26 Animal pest control method.
SI200831504T SI2182945T1 (en) 2007-06-27 2008-06-26 Animal pest control method
AU2014259503A AU2014259503C1 (en) 2007-06-27 2014-11-05 Animal pest control method
HRP20150978TT HRP20150978T1 (en) 2007-06-27 2015-09-16 Animal pest control method
US15/207,999 US20160317520A1 (en) 2007-06-27 2016-07-12 Animal pest control method
AU2017203941A AU2017203941A1 (en) 2007-06-27 2017-06-09 Animal pest control method
AU2017204816A AU2017204816A1 (en) 2007-06-27 2017-07-12 Animal pest control method
US16/103,836 US20180353494A1 (en) 2007-06-27 2018-08-14 Animal pest control method
AU2018220081A AU2018220081A1 (en) 2007-06-27 2018-08-23 Animal pest control method

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US93738907P 2007-06-27 2007-06-27
US60/937,389 2007-06-27

Related Child Applications (3)

Application Number Title Priority Date Filing Date
US12/663,848 A-371-Of-International US11278533B2 (en) 2007-06-27 2008-06-26 Animal pest control method
US15/207,999 Continuation US20160317520A1 (en) 2007-06-27 2016-07-12 Animal pest control method
US16/103,836 Continuation US20180353494A1 (en) 2007-06-27 2018-08-14 Animal pest control method

Publications (1)

Publication Number Publication Date
WO2009003075A1 true WO2009003075A1 (en) 2008-12-31

Family

ID=40003056

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/068268 WO2009003075A1 (en) 2007-06-27 2008-06-26 Animal pest control method

Country Status (22)

Country Link
US (3) US11278533B2 (en)
EP (3) EP3351243A1 (en)
JP (6) JP6006471B2 (en)
KR (3) KR101714059B1 (en)
CN (2) CN105640952A (en)
AU (1) AU2008268321C1 (en)
BR (1) BRPI0810929B8 (en)
CA (2) CA2971008A1 (en)
CY (1) CY1120038T1 (en)
DK (2) DK2182945T3 (en)
ES (2) ES2666187T3 (en)
HK (3) HK1218869A1 (en)
HR (2) HRP20150978T1 (en)
HU (1) HUE037127T2 (en)
LT (1) LT2957284T (en)
MX (3) MX361762B (en)
NO (1) NO2957284T3 (en)
PL (1) PL2957284T3 (en)
PT (2) PT2957284T (en)
RU (1) RU2508102C2 (en)
SI (2) SI2957284T1 (en)
WO (1) WO2009003075A1 (en)

Cited By (76)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2190289A2 (en) * 2007-08-17 2010-06-02 Intervet International B.V. Isoxazoline compositions and their use as antiparasitics
WO2010065852A1 (en) 2008-12-04 2010-06-10 Merial Limited Dimeric avermectin and milbemycin derivatives
EP2317856A1 (en) * 2008-07-09 2011-05-11 Basf Se Pesticidal mixtures comprising isoxazoline compounds ii
US7964204B2 (en) 2005-12-30 2011-06-21 E.I. Du Pont De Nemours And Company Isoxazolines for controlling invertebrate pests
WO2011075591A1 (en) 2009-12-17 2011-06-23 Merial Limited Anti parasitic dihydroazole compounds and compositions comprising same
WO2011095581A1 (en) 2010-02-05 2011-08-11 Intervet International B.V. S piroindoline compounds for use as anthelminthi cs
WO2011123773A1 (en) 2010-04-02 2011-10-06 Merial Limited Parasiticidal compositions comprising multiple active agents, methods and uses thereof
WO2012007426A1 (en) 2010-07-13 2012-01-19 Basf Se Azoline substituted isoxazoline benzamide compounds for combating animal pests
WO2012041873A1 (en) 2010-09-29 2012-04-05 Intervet International B.V. N-heteroaryl compounds
WO2012041872A1 (en) 2010-09-29 2012-04-05 Intervet International B.V. N-heteroaryl compounds with cyclic bridging unit for the treatment of parasitic diseases
WO2012089622A2 (en) 2010-12-27 2012-07-05 Intervet International B.V. Topical localized isoxazoline formulation
WO2012089623A1 (en) 2010-12-27 2012-07-05 Intervet International B.V. Topical localized isoxazoline formulation comprising glycofurol
US8217180B2 (en) 2007-08-17 2012-07-10 E.I. Du Pont De Nemours And Company Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives
WO2013003505A1 (en) 2011-06-27 2013-01-03 Merial Limited Amido-pyridyl ether compounds and compositions and their use against parasites
EP2550962A2 (en) 2008-11-19 2013-01-30 Merial Limited Compositions comprising an aryl pyrazole and/or a formamidine, methods and uses thereof
US8367584B2 (en) 2007-10-03 2013-02-05 E.I. Du Pont De Nemours And Company Naphthalene isoxazoline compounds for control of invertebrate pests
WO2013017678A1 (en) 2011-08-04 2013-02-07 Intervet International B.V. Novel spiroindoline compounds
WO2013039948A1 (en) 2011-09-12 2013-03-21 Merial Limited Parasiticidal compositions comprising an isoxazoline active agent, methods and uses thereof
US8410153B2 (en) 2007-06-26 2013-04-02 E.I. Du Pont De Nemours And Company Naphthalene isoxazoline invertebrate pest control agents
WO2013057624A1 (en) 2011-10-19 2013-04-25 Ah Usa 42 Llc Use of aminoacetonitrile derivatives against endoparasites
WO2013074892A1 (en) 2011-11-17 2013-05-23 Merial Limited Compositions comprising an aryl pyrazole and a substituted imidazole, methods and uses thereof
WO2013082373A1 (en) 2011-12-02 2013-06-06 Merial Limited Long-acting injectable moxidectin formulations and novel moxidectin crystal forms
US8546618B2 (en) 2008-04-09 2013-10-01 E.I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
WO2013144179A1 (en) 2012-03-28 2013-10-03 Intervet International B.V. Heteroaryl compounds with a-cyclic bridging unit
WO2013144180A1 (en) 2012-03-28 2013-10-03 Intervet International B.V. Heteroaryl compounds with cyclic bridging unit for use in the treatment helminth infection
WO2013150052A1 (en) 2012-04-04 2013-10-10 Intervet International B.V. Soft chewable pharmaceutical products
WO2013158894A1 (en) 2012-04-20 2013-10-24 Merial Limited Parasiticidal compositions comprising benzimidazole derivatives, methods and uses thereof
US8598087B2 (en) 2010-05-27 2013-12-03 E. I. Du Pont De Nemours And Company Crystalline form of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4, 5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-0X0-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1- naph-thalenecarboxamide
US8623875B2 (en) 2007-06-13 2014-01-07 E.I. Du Pont De Nemours And Company Isoxazoline insecticides
US8686014B2 (en) 2008-09-04 2014-04-01 Syngenta Limited Insecticidal compounds
US8735362B2 (en) 2009-12-01 2014-05-27 Syngenta Crop Protection, Llc Insecticidal compounds based on isoxazoline derivatives
WO2014081697A2 (en) 2012-11-20 2014-05-30 Merial Limited Anthelmintic compounds and compositions and method of using thereof
US8822502B2 (en) 2008-08-22 2014-09-02 Syngenta Crop Protection Llc Insecticidal compounds
US8853410B2 (en) 2009-04-30 2014-10-07 Basf Se Process for preparing substituted isoxazoline compounds and their precursors
US9006447B2 (en) 2010-11-03 2015-04-14 Basf Se Method for preparing substituted isoxazoline compounds and their precursors 4-chloro, 4-bromo- or 4-iodobenzaldehyde oximes
WO2015066277A1 (en) 2013-11-01 2015-05-07 Merial Limited Antiparisitic and pesticidal isoxazoline compounds
WO2015086551A1 (en) 2013-12-10 2015-06-18 Intervet International B.V. Antiparasitic use of isoxazoline compounds
WO2015091900A1 (en) 2013-12-20 2015-06-25 Intervet International B.V. Use of isoxazoline derivatives for the treatment or prevention of arthropod infestations in poultry
US9073910B2 (en) 2005-12-16 2015-07-07 E.I. Du Pont De Nemours And Company 5-aryl isoxazolines for controlling invertebrate pests
US9085541B2 (en) 2010-06-23 2015-07-21 Basf Se Process for producing imine compounds for combating invertebrate pests
WO2015179414A1 (en) 2014-05-19 2015-11-26 Merial, Inc. Anthelmintic compounds
US9216973B2 (en) 2008-08-22 2015-12-22 Syngenta Participations Ag Insecticidal compounds
WO2015196014A1 (en) 2014-06-19 2015-12-23 Merial, Inc. Parasiticidal compositions comprising indole derivatives, methods and uses thereof
EP2308857B1 (en) 2008-07-09 2016-04-27 Nissan Chemical Industries, Ltd. Process for production of isoxazoline-substituted benzoic acid amide compound
WO2016069983A1 (en) 2014-10-31 2016-05-06 Merial, Inc. Parasiticidal composition comprising fipronil
EP3082867A1 (en) * 2013-12-20 2016-10-26 Intervet International B.V. Isoxazoline compositions and use thereof in the prevention or treatment of parasite infestations in animals
US9637480B2 (en) 2010-11-19 2017-05-02 Nissan Chemical Industries, Ltd. Parasite- and hygienic pest-controlling agent
US9732051B2 (en) 2011-12-23 2017-08-15 Basf Se Isothiazoline compounds for combating invertebrate pests
WO2017147352A1 (en) 2016-02-24 2017-08-31 Merial, Inc. Antiparasitic isoxazoline compounds, long-acting injectable formulations comprising them, methods and uses thereof
US9770029B2 (en) 2008-07-09 2017-09-26 Basf Se Pesticidal active mixtures comprising isoxazoline compounds I
EP2957284B1 (en) 2007-06-27 2018-01-17 E. I. du Pont de Nemours and Company Animal pest control method
WO2018039508A1 (en) 2016-08-25 2018-03-01 Merial, Inc. Method for reducing unwanted effects in parasiticidal treatments
US10045969B2 (en) 2004-03-05 2018-08-14 Nissan Chemical Industries, Inc. Isoxazoline-substituted benzamide compound and pesticide
WO2018178345A1 (en) 2017-03-31 2018-10-04 Intervet International B.V. Pharmaceutical formulation of crotonylaminopyridine salt
WO2019091936A1 (en) 2017-11-07 2019-05-16 Intervet International B.V. Injectable isoxazoline pharmaceutical compositions and their use against parasite infestation
WO2019091940A1 (en) 2017-11-07 2019-05-16 Intervet International B.V. Process for preparing large size isoxazoline particles
EP3498696A1 (en) 2008-11-14 2019-06-19 Merial, Inc. Enantiomerically enriched aryloazol-2-yl cyanoethylamino parasiticidal compounds
WO2019115492A1 (en) 2017-12-12 2019-06-20 Intervet International B.V. Implantable isoxazoline pharmaceutical compositions and uses thereof
WO2019157241A1 (en) 2018-02-08 2019-08-15 Boehringer Ingelheim Animal Health USA Inc. Parasiticidal compositions comprising eprinomectin and praziquantel, methods and uses thereof
WO2020002593A1 (en) 2018-06-29 2020-01-02 Intervet International B.V. Compound for use against helminthic infection
WO2020150032A1 (en) 2019-01-16 2020-07-23 Boehringer Ingelheim Animal Health USA Inc. Topical compositions comprising a neonicotinoid and a macrocyclic lactone, methods and uses thereof
WO2020180635A1 (en) 2019-03-01 2020-09-10 Boehringer Ingelheim Animal Health USA Inc. Injectable clorsulon compositions, methods and uses thereof
US10799483B2 (en) 2014-12-22 2020-10-13 Intervet Inc. Use of isoxazoline compounds for treating demodicosis
WO2020225143A1 (en) 2019-05-03 2020-11-12 Intervet International B.V. Injectable pharmaceutical compositions and uses thereof
WO2021013825A1 (en) 2019-07-22 2021-01-28 Intervet International B.V. Soft chewable veterinary dosage form
US10973759B2 (en) 2012-11-20 2021-04-13 Intervet Inc. Manufacturing of semi-plastic pharmaceutical dosage units
WO2021122521A1 (en) 2019-12-16 2021-06-24 Intervet International B.V. Composition for lice control in poultry
WO2021122515A1 (en) 2019-12-16 2021-06-24 Intervet International B.V. Parasite control in ruminants
WO2021122513A1 (en) 2019-12-16 2021-06-24 Intervet International B.V. Composition for lice control
ES2863583A1 (en) * 2020-04-08 2021-10-11 Univ Leon VETERINARY COMPOSITION FOR RUMIANTS (Machine-translation by Google Translate, not legally binding)
US11179372B2 (en) 2015-06-23 2021-11-23 Intervet Inc. Isoxazoline solution containing vitamin E for use with sanitized drinking water
WO2021233967A1 (en) 2020-05-20 2021-11-25 Intervet International B.V. Injectable pharmaceutical compositions and uses thereof
WO2021242481A1 (en) 2020-05-28 2021-12-02 Boehringer Ingelheim Animal Health USA Inc. Bi-modal release intra-ruminal capsule device and methods of use thereof
WO2022140728A1 (en) 2020-12-21 2022-06-30 Boehringer Ingelheim Animam Health Usa Inc. Parasiticidal collar comprising isoxazoline compounds
WO2022269042A1 (en) 2021-06-25 2022-12-29 Intervet International B.V. Palatable veterinary compositions
RU2796536C2 (en) * 2013-12-20 2023-05-25 Интервет Интернэшнл Б.В. Use of isoxazoline compounds in poultry

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102010063691A1 (en) 2010-12-21 2012-06-21 Bayer Animal Health Gmbh Ectoparasiticidal drug combinations
AU2013245478A1 (en) * 2012-11-01 2014-05-15 Sumitomo Chemical Company, Limited Method for administering agent for controlling ectoparasite to dog
NZ726251A (en) 2014-04-17 2017-11-24 Merial Inc Use of malononitrile compounds for protecting animals from parasites
TWI812673B (en) * 2018-02-12 2023-08-21 美商富曼西公司 Naphthalene isoxazoline compounds for controlling invertebrate pests
WO2020201440A1 (en) * 2019-04-03 2020-10-08 Virbac Low dose fluralaner compositions for protection against parasitic invertebrate pest
CN111909143B (en) * 2020-07-30 2021-10-29 山东省联合农药工业有限公司 Isoxazoline substituted benzamide derivative and preparation method and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3879532A (en) * 1974-01-18 1975-04-22 Shell Oil Co Control by isoxazoles of endoparasitic nematodes
EP1731512A1 (en) * 2004-03-05 2006-12-13 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and noxious organism control agent
WO2007070606A2 (en) * 2005-12-14 2007-06-21 E. I. Du Pont De Nemours And Company Isoxazolines for controlling invertebrate pests
US20110059988A1 (en) 2007-08-17 2011-03-10 Intervet International B.V. Isoxazoline compositions and their use as antiparasitics

Family Cites Families (90)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US431857A (en) 1890-07-08 Joseph d
US623912A (en) 1899-04-25 Charles j
GB331242A (en) 1929-03-26 1930-06-26 Joseph Harrison Thomson Robert Improved means for driving kinematographs and sound recording or reproducing means in synchronism
US3950360A (en) 1972-06-08 1976-04-13 Sankyo Company Limited Antibiotic substances
US3984564A (en) 1972-06-08 1976-10-05 Sankyo Company Limited Antibiotic substances B-41, their production and their use as insecticides and acaricides
US3968207A (en) * 1973-12-10 1976-07-06 American Cyanamid Company Method of controlling fleas and ticks on cats and dogs
SE434277B (en) 1976-04-19 1984-07-16 Merck & Co Inc SET TO MAKE NEW ANTIHELMINTICALLY EFFECTIVE ASSOCIATIONS BY CULTIVATING STREPTOMYCS AVERMITILIS
US4129568A (en) 1977-05-12 1978-12-12 Monsanto Company 2-[3-Aryl-2-isoxazolin-5-yl]benzoates
US4199569A (en) 1977-10-03 1980-04-22 Merck & Co., Inc. Selective hydrogenation products of C-076 compounds and derivatives thereof
EP0074069B1 (en) 1981-09-03 1986-01-08 Daikin Kogyo Co., Ltd. Process for preparing chlorotrifluoromethylbenzene
US4820695A (en) 1982-09-13 1989-04-11 Eli Lilly And Company C-20-dihydro-deoxy-(cyclic amino)-derivatives of macrolide antibiotics
IT1173213B (en) 1984-02-03 1987-06-18 Zambon Spa PROCEDURE TO FLUORINE SOME DERIVATIVES FROM 1L-FENYL-2-AMINO-1,3-PROPANDIOL AND THEIR INTERMEDIATES
US5105009A (en) 1983-06-02 1992-04-14 Zambon S.P.A. Intermediates for the preparation of 1-(phenyl)-1-hydroxy-2-amino-3-fluoropropane derivatives
US5332835A (en) 1984-02-03 1994-07-26 Zambon S.P.A. Process for fluorinating 1-phenyl-2-amino-1,3-propanediol compounds and new oxazoline compounds useful in this process
US4973750A (en) 1984-09-19 1990-11-27 Schering Corporation Preparation of (threo)-1-aryl-2-acylamido-3-fluoro-1-propanols
US4582918A (en) 1984-09-19 1986-04-15 Schering Corporation Preparation of intermediates for (threo)-1-aryl-2-acylamido-3-fluoro-1-propanols
ES8800986A1 (en) 1985-07-27 1987-12-01 Pfizer Antiparasitic avermectin and milbemycin derivatives and process for their preparation.
GB8523126D0 (en) 1985-09-19 1985-10-23 Ici Plc Aryl pyridones
US4916154A (en) 1986-09-12 1990-04-10 American Cyanamid Company 23-Imino derivatives of LL-F28249 compounds
US4876352A (en) 1988-09-14 1989-10-24 Schering Corporation Pressurized fluorination of hydroxy alkyl groups
US5227494A (en) 1988-09-14 1993-07-13 Schering Corporation Process for preparing oxazoline compounds
US5075320A (en) 1989-01-04 1991-12-24 Rehmert Chalmer V Jr Method and composition for treating parasitic infestation of animals
IL98599A (en) 1990-06-28 1995-06-29 Merck & Co Inc Stable salts of 4"-deoxy-4"-epi-methylamino avermectin b1a/b1b and insecticidal compositions containing them
EP0555340B1 (en) 1990-10-25 1994-12-07 Schering Corporation Process for preparing florfenicol, its analogs and oxazoline intermediates thereto
RU2106088C1 (en) 1992-05-23 1998-03-10 Циба-Гейги АГ Domestic animal flea control method and substance for preventing flea infection of domestic animals
US5352832A (en) 1992-12-18 1994-10-04 Schering Corporation Asymmetric process for preparing florfenicol, thiamphenicol chloramphenicol and oxazoline intermediates
US5399717A (en) 1993-09-29 1995-03-21 Merck & Co., Inc. Glycosidation route to 4"-epi-methylamino-4"-deoxyavermectin B1
US5849736A (en) 1993-11-24 1998-12-15 The Dupont Merck Pharmaceutical Company Isoxazoline and isoxazole fibrinogen receptor antagonists
GB9505651D0 (en) 1995-03-21 1995-05-10 Agrevo Uk Ltd AgrEvo UK Limited
DE69728761T2 (en) 1996-04-26 2004-08-12 Nippon Soda Co. Ltd. HETEROCYCLICALLY SUBSTITUTED BENZENE DERIVATIVES AND HERBICIDES
CA2206151A1 (en) 1996-06-06 1997-12-06 Rohm And Haas Company Benzyloxy substituted aromatics and their use as fungicides and insecticides
US5958888A (en) 1996-07-02 1999-09-28 Merial, Inc. Water miscible macrolide solutions
US6271255B1 (en) 1996-07-05 2001-08-07 Biotica Technology Limited Erythromycins and process for their preparation
FR2750861B1 (en) * 1996-07-11 1998-12-24 Rhone Merieux PROCESSES FOR REMOVING PARASITES, ESPECIALLY VERTEBRATE ECTOPARASITES, ESPECIALLY MAMMALS AND COMPOSITIONS FOR CARRYING OUT THIS PROCESS
US5663361A (en) 1996-08-19 1997-09-02 Schering Corporation Process for preparing intermediates to florfenicol
US5932766A (en) 1997-05-30 1999-08-03 Abbott Laboratories Process for the preparation of substituted keto-enamines
US6339063B1 (en) 1997-09-10 2002-01-15 Merck & Co., Inc. 9a-azalides as veterinary antimicrobial agents
JP2003512290A (en) 1997-09-10 2003-04-02 メルク エンド カムパニー インコーポレーテッド 8a-azalide as a livestock antibacterial agent
AP9801420A0 (en) 1998-01-02 1998-12-31 Pfizer Prod Inc Novel macrolides.
EP1063992B1 (en) 1998-03-19 2005-05-11 Merck & Co., Inc. Sulfurpenta fluorophenyl pyrazoles for controlling ectoparasitic infestations
US6136838A (en) 1998-03-19 2000-10-24 Merck & Co., Inc. Sulfurpentafluorophenylpyrazoles for controlling ectoparasitic infestations
US6140350A (en) 1998-06-08 2000-10-31 Sumitomo Chemical Company, Limited Method for controlling ectoparasites
AU757825B2 (en) 1998-10-09 2003-03-06 Novartis Ag Oral combination of lufenuron and nitenpyram against fleas
CA2411293A1 (en) 1999-01-28 2000-07-28 Pfizer Products Inc. Novel azalides and methods of making same
EG22187A (en) 1999-04-15 2002-10-31 Aventis Cropscience Sa New composition
GB2351081A (en) 1999-06-18 2000-12-20 Lilly Forschung Gmbh Pharmaceutically active imidazoline compounds and analogues thereof
ES2261229T3 (en) 1999-08-12 2006-11-16 Eli Lilly And Company USE OF SPINOSAD OR A FORMULATION THAT SPINOSAD INCLUDES.
CN1402713A (en) 1999-12-02 2003-03-12 阿温提斯作物科学股份有限公司 Control of arthropods in animals
GB9928568D0 (en) 1999-12-03 2000-02-02 Zeneca Ltd Chemical compounds
BRPI0017013B8 (en) 2000-01-27 2022-11-16 Pfizer Prod Inc azalide antibiotic composition and method for obtaining it
DE10114597A1 (en) 2001-03-23 2002-10-02 Bayer Cropscience Gmbh Arylisoxazoline derivatives, process for their preparation and their use as pesticides
IL158059A0 (en) 2001-04-27 2004-03-28 Pfizer Prod Inc Process for preparing 4"-substituted-9-deoxo-9a-aza-9a-homoerythromycin a derivatives
TW200724033A (en) 2001-09-21 2007-07-01 Du Pont Anthranilamide arthropodicide treatment
JP2005538937A (en) 2002-03-08 2005-12-22 シェーリング−プラウ， リミテッド New florfenicol antibiotics
BR0313943A (en) 2002-08-26 2005-08-02 Nissan Chemical Ind Ltd Substituted benzanilide compound and harmful organism control agent
US20040069235A1 (en) 2002-09-27 2004-04-15 Rasa Cordelia G. Flea feeding apparatus
DE10320782A1 (en) 2003-05-09 2004-11-25 Bayer Cropscience Ag Substituted oxyarenes
AR045142A1 (en) 2003-07-30 2005-10-19 Novartis Ag BUEN SABOR DUCTILE MASTICABLE VETERINARY COMPOSITION
DE602004017347D1 (en) 2003-11-04 2008-12-04 Intervet Int Bv AZOL-PESTICIDES
GB0402677D0 (en) 2003-11-06 2004-03-10 Novartis Ag Organic compounds
NZ547592A (en) 2003-12-23 2009-07-31 Schering Plough Ltd Florfenicol prodrug having improved water solubility
KR20060110344A (en) 2003-12-31 2006-10-24 쉐링-프라우 리미티드 Control of parasites in animals by the use of imidazo[1,2-b]pyridazine derivatives
WO2005066119A2 (en) 2003-12-31 2005-07-21 Schering-Plough Ltd. Antibacterial 1-(4-mono-and di-halomethylsulphonylphenyl)-2-acylamino-3-fluoropropanols and preparation thereof
JP2005272452A (en) 2004-02-23 2005-10-06 Nissan Chem Ind Ltd Substituted benzanilide compound and pesticide
BRPI0507818A (en) 2004-03-26 2007-07-10 Cytokine Pharmasciences Inc compound and inhibition methods
CA2574335C (en) 2004-07-28 2013-10-01 Intervet International B.V. Veterinary composition comprising an arylpyrazole and a nitroenamine with antiparasitic activity
ATE406348T1 (en) 2004-09-23 2008-09-15 Schering Plough Ltd FIGHTING PARASITES IN ANIMALS BY USING NEW TRIFLUOROMETHANE SULFONANILIDOXIMETHER DERIVATIVES
WO2006079162A1 (en) 2005-01-25 2006-08-03 Gcc Ip Pty Ltd Toner detection window cleaning apparatus
JP5051340B2 (en) 2005-06-06 2012-10-17 日産化学工業株式会社 Substituted isoxazoline compounds and pest control agents
CA2609574A1 (en) 2005-06-09 2006-12-21 Schering-Plough Ltd. Control of parasites in animals by n-[(phenyloxy)phenyl]-1,1,1-trifluoromethanesulfonamide and n-[(phenylsulfanyl)phenyl]-1,1,1-trifluoromethanesulfonamide derivatives
MY146795A (en) 2005-06-09 2012-09-28 Novartis Ag Process for the synthesis of organic compounds
WO2007026965A1 (en) * 2005-09-02 2007-03-08 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and harmful organism-controlling agent
JP2007106756A (en) 2005-09-14 2007-04-26 Nissan Chem Ind Ltd Substituted isoxazoline compound and pesticide
TWI266597B (en) * 2005-09-27 2006-11-11 Delta Electronics Inc Electronic apparatus capable of dissipating heat uniformly
TW200803740A (en) 2005-12-16 2008-01-16 Du Pont 5-aryl isoxazolines for controlling invertebrate pests
EP1975149B1 (en) 2005-12-26 2012-02-15 Nissan Chemical Industries, Ltd. 1,3-bis(substituted phenyl)-3-hydroxypropan-1-one or 2-propen-1-one compound, and salt thereof
TWI412322B (en) 2005-12-30 2013-10-21 Du Pont Isoxazolines for controlling invertebrate pests
PL1997813T3 (en) 2006-03-10 2010-10-29 Nissan Chemical Ind Ltd Substituted isoxazoline compound and pest control agent
KR20090005201A (en) 2006-04-20 2009-01-12 이 아이 듀폰 디 네모아 앤드 캄파니 Pyrazolines for controlling invertebrate pests
WO2007125984A1 (en) 2006-04-28 2007-11-08 Nihon Nohyaku Co., Ltd. Isoxazoline derivative, pest-controlling agent, and use of the pest-controlling agent
JP2008044880A (en) 2006-08-15 2008-02-28 Bayer Cropscience Ag Insecticidal isooxazolines
EP2151437A4 (en) 2007-03-07 2012-05-02 Nissan Chemical Ind Ltd Isoxazoline-substituted benzamide compound and pest control agent
MX2009010071A (en) 2007-04-10 2009-10-16 Bayer Cropscience Ag Insecticidal aryl isoxazoline derivatives.
MX2009013469A (en) 2007-06-13 2010-01-20 Du Pont Isoxazoline insecticides.
TWI430995B (en) 2007-06-26 2014-03-21 Du Pont Naphthalene isoxazoline invertebrate pest control agents
US8952175B2 (en) 2007-06-27 2015-02-10 Nissan Chemical Industries, Ltd. Method for production of 3-hydroxypropan-1-one compound, method for production of 2-propen-1-one compound and method for production of isoxazoline compound
CN105640952A (en) 2007-06-27 2016-06-08 杜邦公司 Animal pest control method
TWI600639B (en) 2007-08-17 2017-10-01 杜邦股份有限公司 Compound for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives
KR20100075996A (en) 2007-10-03 2010-07-05 이 아이 듀폰 디 네모아 앤드 캄파니 Naphthalene isoxazoline compounds for control of invertebrate pests
TW201444787A (en) 2008-04-09 2014-12-01 Du Pont Method for preparing 3-trifluoromethyl chalcones

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3879532A (en) * 1974-01-18 1975-04-22 Shell Oil Co Control by isoxazoles of endoparasitic nematodes
EP1731512A1 (en) * 2004-03-05 2006-12-13 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and noxious organism control agent
US20070066617A1 (en) 2004-03-05 2007-03-22 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and pesticide
WO2007070606A2 (en) * 2005-12-14 2007-06-21 E. I. Du Pont De Nemours And Company Isoxazolines for controlling invertebrate pests
US20110059988A1 (en) 2007-08-17 2011-03-10 Intervet International B.V. Isoxazoline compositions and their use as antiparasitics

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2182945A1

Cited By (148)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10045969B2 (en) 2004-03-05 2018-08-14 Nissan Chemical Industries, Inc. Isoxazoline-substituted benzamide compound and pesticide
US10596157B2 (en) 2004-03-05 2020-03-24 Nissan Chemical Corporation Isoxazoline-substituted benzamide compound and pesticide
US10874645B2 (en) 2004-03-05 2020-12-29 Nissan Chemical Corporation Isoxazoline-substituted benzamide compound and pesticide
US9073910B2 (en) 2005-12-16 2015-07-07 E.I. Du Pont De Nemours And Company 5-aryl isoxazolines for controlling invertebrate pests
US7964204B2 (en) 2005-12-30 2011-06-21 E.I. Du Pont De Nemours And Company Isoxazolines for controlling invertebrate pests
US8552218B2 (en) 2005-12-30 2013-10-08 E.I. Du Pont De Nemours And Company Isoxazolines for controlling invertebrate pests
US8231888B2 (en) 2005-12-30 2012-07-31 E.I. Du Pont De Nemours And Company Isoxazolines for controlling invertebrate pests
US8871941B2 (en) 2005-12-30 2014-10-28 E.I. Du Pont De Nemours And Company 8-bromo-5-quinolinecarboxaldehyde oxime
US8623875B2 (en) 2007-06-13 2014-01-07 E.I. Du Pont De Nemours And Company Isoxazoline insecticides
US9095138B2 (en) 2007-06-13 2015-08-04 E.I. Du Pont De Nemours And Company Isoxazoline insecticides
US8410153B2 (en) 2007-06-26 2013-04-02 E.I. Du Pont De Nemours And Company Naphthalene isoxazoline invertebrate pest control agents
US11278533B2 (en) 2007-06-27 2022-03-22 E.I. Du Pont De Nemours And Company Animal pest control method
EP2957284B1 (en) 2007-06-27 2018-01-17 E. I. du Pont de Nemours and Company Animal pest control method
EP2545777B1 (en) * 2007-08-17 2020-03-11 Intervet International B.V. Use of an isoxazoline composition as antiparasitic
EP2190289A2 (en) * 2007-08-17 2010-06-02 Intervet International B.V. Isoxazoline compositions and their use as antiparasitics
EP2545777B2 (en) † 2007-08-17 2023-01-18 Intervet International B.V. Use of an isoxazoline composition as antiparasitic
EP3473101B1 (en) 2007-08-17 2021-05-12 Intervet International B.V. Isoxazoline compositions and their use as antiparasitics for felines
EP3473101A1 (en) * 2007-08-17 2019-04-24 Intervet International B.V. Isoxazoline compositions and their use as antiparasitics for felines
JP2016147888A (en) * 2007-08-17 2016-08-18 インターベット インターナショナル ベー． フェー． Isoxazoline compositions and their use as antiparasitics
US8217180B2 (en) 2007-08-17 2012-07-10 E.I. Du Pont De Nemours And Company Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives
US20210061775A1 (en) * 2007-08-17 2021-03-04 Intervet Inc. Isoxazoline compositions and their use as antiparasitics
EP2190289B1 (en) * 2007-08-17 2013-05-01 Intervet International B.V. Isoxazoline compositions and their use as antiparasitics
US20160332975A1 (en) * 2007-08-17 2016-11-17 Intervet Inc. Isoxazoline compositions and their use as antiparasitics
US20180155301A1 (en) * 2007-08-17 2018-06-07 Intervet Inc. Isoxazoline compositions and their use as antiparasitics
US8513431B2 (en) 2007-08-17 2013-08-20 E.I. Du Pont De Nemours And Company Method for preparing 5-haloalkyl-4, 5-dihydroisoxazole derivatives
US8367584B2 (en) 2007-10-03 2013-02-05 E.I. Du Pont De Nemours And Company Naphthalene isoxazoline compounds for control of invertebrate pests
US8546618B2 (en) 2008-04-09 2013-10-01 E.I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
US9938248B2 (en) 2008-04-09 2018-04-10 E.I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
US10160731B2 (en) 2008-04-09 2018-12-25 E.I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
US9834523B2 (en) 2008-04-09 2017-12-05 E.I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
US9035101B2 (en) 2008-04-09 2015-05-19 E.I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
US9611231B2 (en) 2008-04-09 2017-04-04 E.I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
US9527822B2 (en) 2008-04-09 2016-12-27 E.I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
US9770029B2 (en) 2008-07-09 2017-09-26 Basf Se Pesticidal active mixtures comprising isoxazoline compounds I
US10888094B2 (en) 2008-07-09 2021-01-12 Basf Se Pesticidal active mixtures comprising isoxazoline compounds I
US10231455B2 (en) 2008-07-09 2019-03-19 Basf Se Pesticidal active mixtures comprising isoxazoline compounds I
EP2317856A1 (en) * 2008-07-09 2011-05-11 Basf Se Pesticidal mixtures comprising isoxazoline compounds ii
EP2308857B1 (en) 2008-07-09 2016-04-27 Nissan Chemical Industries, Ltd. Process for production of isoxazoline-substituted benzoic acid amide compound
US8822502B2 (en) 2008-08-22 2014-09-02 Syngenta Crop Protection Llc Insecticidal compounds
US9216973B2 (en) 2008-08-22 2015-12-22 Syngenta Participations Ag Insecticidal compounds
US8686014B2 (en) 2008-09-04 2014-04-01 Syngenta Limited Insecticidal compounds
US9282742B2 (en) 2008-09-04 2016-03-15 Syngenta Participations Ag Insecticidal compounds
EP3498696A1 (en) 2008-11-14 2019-06-19 Merial, Inc. Enantiomerically enriched aryloazol-2-yl cyanoethylamino parasiticidal compounds
EP2550962A2 (en) 2008-11-19 2013-01-30 Merial Limited Compositions comprising an aryl pyrazole and/or a formamidine, methods and uses thereof
WO2010065852A1 (en) 2008-12-04 2010-06-10 Merial Limited Dimeric avermectin and milbemycin derivatives
US8853410B2 (en) 2009-04-30 2014-10-07 Basf Se Process for preparing substituted isoxazoline compounds and their precursors
US8735362B2 (en) 2009-12-01 2014-05-27 Syngenta Crop Protection, Llc Insecticidal compounds based on isoxazoline derivatives
US10206400B2 (en) 2009-12-01 2019-02-19 Syngenta Participations Ag Insecticidal compounds based on isoxazoline derivatives
US11357231B2 (en) 2009-12-01 2022-06-14 Syngenta Crop Protection Llc Insecticidal compounds based on isoxazoline derivatives
US9609869B2 (en) 2009-12-01 2017-04-04 Syngenta Crop Protection, Llc Insecticidal compounds based on isoxazoline derivatives
US10750745B2 (en) 2009-12-01 2020-08-25 Syngenta Crop Protection, Llc Insecticidal compounds based on isoxazoline derivatives
EP3078664A1 (en) 2009-12-17 2016-10-12 Merial Inc. Antiparasitic dihydroazole compositions
WO2011075591A1 (en) 2009-12-17 2011-06-23 Merial Limited Anti parasitic dihydroazole compounds and compositions comprising same
EP3560923A1 (en) 2009-12-17 2019-10-30 Boehringer Ingelheim Animal Health USA Inc. Anti parasitic dihydroazole compounds and compositions comprising same
US8618126B2 (en) 2009-12-17 2013-12-31 Merial Limited Antiparisitic dihydroazole compounds and compositions comprising same
US9376434B2 (en) 2009-12-17 2016-06-28 Merial Inc. Antiparisitic dihydroazole compounds and compositions comprising same
US9776999B2 (en) 2009-12-17 2017-10-03 Merial Inc. Antiparisitic dihydroazole compounds and compositions comprising same
WO2011095581A1 (en) 2010-02-05 2011-08-11 Intervet International B.V. S piroindoline compounds for use as anthelminthi cs
WO2011123773A1 (en) 2010-04-02 2011-10-06 Merial Limited Parasiticidal compositions comprising multiple active agents, methods and uses thereof
US8598087B2 (en) 2010-05-27 2013-12-03 E. I. Du Pont De Nemours And Company Crystalline form of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4, 5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-0X0-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1- naph-thalenecarboxamide
US9085541B2 (en) 2010-06-23 2015-07-21 Basf Se Process for producing imine compounds for combating invertebrate pests
WO2012007426A1 (en) 2010-07-13 2012-01-19 Basf Se Azoline substituted isoxazoline benzamide compounds for combating animal pests
WO2012041872A1 (en) 2010-09-29 2012-04-05 Intervet International B.V. N-heteroaryl compounds with cyclic bridging unit for the treatment of parasitic diseases
WO2012041873A1 (en) 2010-09-29 2012-04-05 Intervet International B.V. N-heteroaryl compounds
US9006447B2 (en) 2010-11-03 2015-04-14 Basf Se Method for preparing substituted isoxazoline compounds and their precursors 4-chloro, 4-bromo- or 4-iodobenzaldehyde oximes
US9637480B2 (en) 2010-11-19 2017-05-02 Nissan Chemical Industries, Ltd. Parasite- and hygienic pest-controlling agent
WO2012089623A1 (en) 2010-12-27 2012-07-05 Intervet International B.V. Topical localized isoxazoline formulation comprising glycofurol
US10864195B2 (en) 2010-12-27 2020-12-15 Intervet Inc. Topical localized isoxazoline formulation
US9532978B2 (en) 2010-12-27 2017-01-03 Intervet Inc. Topical localized isoxazoline formulation
EP2658541B1 (en) 2010-12-27 2022-01-26 Intervet International B.V. Topical localized isoxazoline formulation comprising glycofurol
US9173870B2 (en) 2010-12-27 2015-11-03 Intervet Inc. Topical localized isoxazoline formulation
WO2012089622A2 (en) 2010-12-27 2012-07-05 Intervet International B.V. Topical localized isoxazoline formulation
EP2658542B1 (en) 2010-12-27 2022-01-26 Intervet International B.V. Topical localized isoxazoline formulation
WO2013003505A1 (en) 2011-06-27 2013-01-03 Merial Limited Amido-pyridyl ether compounds and compositions and their use against parasites
WO2013017678A1 (en) 2011-08-04 2013-02-07 Intervet International B.V. Novel spiroindoline compounds
EP3788874A1 (en) 2011-09-12 2021-03-10 Boehringer Ingelheim Animal Health USA Inc. Parasiticidal compositions comprising an isoxazoline active agent, method and uses thereof
WO2013039948A1 (en) 2011-09-12 2013-03-21 Merial Limited Parasiticidal compositions comprising an isoxazoline active agent, methods and uses thereof
WO2013057624A1 (en) 2011-10-19 2013-04-25 Ah Usa 42 Llc Use of aminoacetonitrile derivatives against endoparasites
WO2013074892A1 (en) 2011-11-17 2013-05-23 Merial Limited Compositions comprising an aryl pyrazole and a substituted imidazole, methods and uses thereof
EP3351546A1 (en) 2011-12-02 2018-07-25 Merial, Inc. Long-acting injectable moxidectin formulations
WO2013082373A1 (en) 2011-12-02 2013-06-06 Merial Limited Long-acting injectable moxidectin formulations and novel moxidectin crystal forms
US9732051B2 (en) 2011-12-23 2017-08-15 Basf Se Isothiazoline compounds for combating invertebrate pests
WO2013144179A1 (en) 2012-03-28 2013-10-03 Intervet International B.V. Heteroaryl compounds with a-cyclic bridging unit
WO2013144180A1 (en) 2012-03-28 2013-10-03 Intervet International B.V. Heteroaryl compounds with cyclic bridging unit for use in the treatment helminth infection
WO2013150052A1 (en) 2012-04-04 2013-10-10 Intervet International B.V. Soft chewable pharmaceutical products
WO2013150055A1 (en) 2012-04-04 2013-10-10 Intervet International B.V. Solid oral pharmaceutical compositions for isoxazoline compounds
US11712416B2 (en) 2012-04-04 2023-08-01 Intervet Inc. Solid oral pharmaceutical compositions for isoxazoline compounds
US11337917B2 (en) 2012-04-04 2022-05-24 Intervet Inc. Soft chewable pharmaceutical products
US11285101B2 (en) 2012-04-04 2022-03-29 Intervet Inc. Soft chewable pharmaceutical products
US9770440B2 (en) 2012-04-04 2017-09-26 Intervet Inc. Solid oral pharmaceutical compositions for isoxazoline compounds
EP3763706A1 (en) 2012-04-20 2021-01-13 Boehringer Ingelheim Animal Health USA Inc. Parasiticidal compositions comprising benzimidazole derivatives, methods and uses thereof
EP3453702A2 (en) 2012-04-20 2019-03-13 Merial, Inc. Parasiticidal compositions comprising benzimidazole derivatives, methods and uses thereof
WO2013158894A1 (en) 2012-04-20 2013-10-24 Merial Limited Parasiticidal compositions comprising benzimidazole derivatives, methods and uses thereof
EP3964198A1 (en) 2012-11-20 2022-03-09 Intervet International B.V. Manufacturing of semi-plastic pharmaceutical dosage units
EP3428162A1 (en) 2012-11-20 2019-01-16 Merial Inc. Anthelmintic compounds and compositions and method of using thereof
US10973759B2 (en) 2012-11-20 2021-04-13 Intervet Inc. Manufacturing of semi-plastic pharmaceutical dosage units
WO2014081697A2 (en) 2012-11-20 2014-05-30 Merial Limited Anthelmintic compounds and compositions and method of using thereof
US11911503B2 (en) 2012-11-20 2024-02-27 Intervet Inc. Manufacturing of semi-plastic pharmaceutical dosage units
WO2015066277A1 (en) 2013-11-01 2015-05-07 Merial Limited Antiparisitic and pesticidal isoxazoline compounds
EP3733664A1 (en) 2013-11-01 2020-11-04 Boehringer Ingelheim Animal Health USA Inc. Antiparisitic and pesticidal isoxazoline compounds
WO2015086551A1 (en) 2013-12-10 2015-06-18 Intervet International B.V. Antiparasitic use of isoxazoline compounds
EP3079474B1 (en) 2013-12-10 2019-07-03 Intervet International B.V. Antiparasitic use of isoxazoline compounds
US11304934B2 (en) 2013-12-20 2022-04-19 Intervet Inc. Use of isoxazoline derivatives for the treatment or prevention of arthropod infestations in poultry
US10456358B2 (en) 2013-12-20 2019-10-29 Intervet Inc. Isoxazoline compositions and use thereof in the prevention or treatment of parasite infestations in animals
EP4306168A3 (en) * 2013-12-20 2024-03-13 Intervet International B.V. Isoxazoline compositions and use thereof in the prevention or treatment of parasite infestations in animals
RU2688167C1 (en) * 2013-12-20 2019-05-20 Интервет Интернэшнл Б.В. Use of isoxazoline compounds on poultry
US10272071B2 (en) 2013-12-20 2019-04-30 Intervet Inc. Use of isoxazoline derivatives for the treatment or prevention of arthropod infestations in poultry
WO2015091900A1 (en) 2013-12-20 2015-06-25 Intervet International B.V. Use of isoxazoline derivatives for the treatment or prevention of arthropod infestations in poultry
US10653675B2 (en) 2013-12-20 2020-05-19 Intervet Inc. Use of isoxazoline derivatives for the treatment or prevention of arthropod infestations in poultry
RU2796536C2 (en) * 2013-12-20 2023-05-25 Интервет Интернэшнл Б.В. Use of isoxazoline compounds in poultry
RU2796536C9 (en) * 2013-12-20 2023-07-12 Интервет Интернэшнл Б.В. Use of isoxazoline compounds in poultry
US11883530B2 (en) 2013-12-20 2024-01-30 Intervet Inc. Isoxazoline compositions and use thereof in the prevention or treatment of parasite infestations in animals
EP3082867A1 (en) * 2013-12-20 2016-10-26 Intervet International B.V. Isoxazoline compositions and use thereof in the prevention or treatment of parasite infestations in animals
EP3878281A1 (en) 2013-12-20 2021-09-15 Intervet International B.V. Use of isoxazoline compounds in poultry
EP3082867B1 (en) * 2013-12-20 2024-01-17 Intervet International B.V. Isoxazoline compositions and use thereof in the prevention or treatment of parasite infestations in animals
EP4306168A2 (en) 2013-12-20 2024-01-17 Intervet International B.V. Isoxazoline compositions and use thereof in the prevention or treatment of parasite infestations in animals
WO2015179414A1 (en) 2014-05-19 2015-11-26 Merial, Inc. Anthelmintic compounds
EP3517524A1 (en) 2014-06-19 2019-07-31 Merial Inc. Parasiticidal compositions comprising indole derivatives, methods and uses thereof
WO2015196014A1 (en) 2014-06-19 2015-12-23 Merial, Inc. Parasiticidal compositions comprising indole derivatives, methods and uses thereof
WO2016069983A1 (en) 2014-10-31 2016-05-06 Merial, Inc. Parasiticidal composition comprising fipronil
EP4008329A1 (en) 2014-12-22 2022-06-08 Intervet International B.V. Isoxazoline compounds for use in treating demodicosis
US10799483B2 (en) 2014-12-22 2020-10-13 Intervet Inc. Use of isoxazoline compounds for treating demodicosis
US11878006B2 (en) 2015-06-23 2024-01-23 Intervet Inc. Isoxazoline solution containing vitamin E for use with sanitized drinking water
US11179372B2 (en) 2015-06-23 2021-11-23 Intervet Inc. Isoxazoline solution containing vitamin E for use with sanitized drinking water
WO2017147352A1 (en) 2016-02-24 2017-08-31 Merial, Inc. Antiparasitic isoxazoline compounds, long-acting injectable formulations comprising them, methods and uses thereof
EP3763211A1 (en) 2016-02-24 2021-01-13 Boehringer Ingelheim Animal Health USA Inc. Antiparasitic isoxazoline compounds, long-acting injectable formulations comprising them, methods and uses thereof
WO2018039508A1 (en) 2016-08-25 2018-03-01 Merial, Inc. Method for reducing unwanted effects in parasiticidal treatments
WO2018178345A1 (en) 2017-03-31 2018-10-04 Intervet International B.V. Pharmaceutical formulation of crotonylaminopyridine salt
WO2019091940A1 (en) 2017-11-07 2019-05-16 Intervet International B.V. Process for preparing large size isoxazoline particles
EP4316522A2 (en) 2017-11-07 2024-02-07 Intervet International B.V. Injectable isoxazoline pharmaceutical compositions and their use against parasite infestation
WO2019091936A1 (en) 2017-11-07 2019-05-16 Intervet International B.V. Injectable isoxazoline pharmaceutical compositions and their use against parasite infestation
US11858904B2 (en) 2017-11-07 2024-01-02 Intervet Inc. Process for preparing large size isoxazoline particles
US11648238B2 (en) 2017-12-12 2023-05-16 Intervet Inc. Implantable isoxazoline pharmaceutical compositions and uses thereof
WO2019115492A1 (en) 2017-12-12 2019-06-20 Intervet International B.V. Implantable isoxazoline pharmaceutical compositions and uses thereof
WO2019157241A1 (en) 2018-02-08 2019-08-15 Boehringer Ingelheim Animal Health USA Inc. Parasiticidal compositions comprising eprinomectin and praziquantel, methods and uses thereof
WO2020002593A1 (en) 2018-06-29 2020-01-02 Intervet International B.V. Compound for use against helminthic infection
WO2020150032A1 (en) 2019-01-16 2020-07-23 Boehringer Ingelheim Animal Health USA Inc. Topical compositions comprising a neonicotinoid and a macrocyclic lactone, methods and uses thereof
WO2020180635A1 (en) 2019-03-01 2020-09-10 Boehringer Ingelheim Animal Health USA Inc. Injectable clorsulon compositions, methods and uses thereof
WO2020225143A1 (en) 2019-05-03 2020-11-12 Intervet International B.V. Injectable pharmaceutical compositions and uses thereof
WO2021013825A1 (en) 2019-07-22 2021-01-28 Intervet International B.V. Soft chewable veterinary dosage form
WO2021122521A1 (en) 2019-12-16 2021-06-24 Intervet International B.V. Composition for lice control in poultry
WO2021122515A1 (en) 2019-12-16 2021-06-24 Intervet International B.V. Parasite control in ruminants
WO2021122513A1 (en) 2019-12-16 2021-06-24 Intervet International B.V. Composition for lice control
ES2863583A1 (en) * 2020-04-08 2021-10-11 Univ Leon VETERINARY COMPOSITION FOR RUMIANTS (Machine-translation by Google Translate, not legally binding)
WO2021233967A1 (en) 2020-05-20 2021-11-25 Intervet International B.V. Injectable pharmaceutical compositions and uses thereof
WO2021242481A1 (en) 2020-05-28 2021-12-02 Boehringer Ingelheim Animal Health USA Inc. Bi-modal release intra-ruminal capsule device and methods of use thereof
WO2022140728A1 (en) 2020-12-21 2022-06-30 Boehringer Ingelheim Animam Health Usa Inc. Parasiticidal collar comprising isoxazoline compounds
WO2022269042A1 (en) 2021-06-25 2022-12-29 Intervet International B.V. Palatable veterinary compositions

Also Published As

Publication number Publication date
PL2957284T3 (en) 2018-08-31
US20100173948A1 (en) 2010-07-08
JP2018065849A (en) 2018-04-26
ES2666187T3 (en) 2018-05-03
CN105640952A (en) 2016-06-08
US20150272938A2 (en) 2015-10-01
NO2957284T3 (en) 2018-06-16
RU2508102C2 (en) 2014-02-27
EP3351243A1 (en) 2018-07-25
KR20100045444A (en) 2010-05-03
BRPI0810929B8 (en) 2022-12-06
JP2016216473A (en) 2016-12-22
CY1120038T1 (en) 2018-12-12
AU2008268321A1 (en) 2008-12-31
CA2685072A1 (en) 2008-12-31
SI2182945T1 (en) 2015-12-31
AU2008268321C1 (en) 2018-09-27
CA2971008A1 (en) 2008-12-31
JP2015057399A (en) 2015-03-26
JP2019014728A (en) 2019-01-31
LT2957284T (en) 2018-04-10
CN101743000A (en) 2010-06-16
JP2017075152A (en) 2017-04-20
RU2010102529A (en) 2011-08-10
KR20150091544A (en) 2015-08-11
JP6099610B2 (en) 2017-03-22
EP2182945B1 (en) 2015-08-05
HK1218869A1 (en) 2017-03-17
AU2008268321B2 (en) 2014-08-07
DK2957284T3 (en) 2018-02-05
MX361762B (en) 2018-12-17
EP2957284A1 (en) 2015-12-23
HUE037127T2 (en) 2018-08-28
MX2009013748A (en) 2010-01-26
HK1225622A1 (en) 2017-09-15
SI2957284T1 (en) 2018-04-30
KR101714059B1 (en) 2017-03-08
JP6006471B2 (en) 2016-10-12
JP2010531893A (en) 2010-09-30
BRPI0810929A2 (en) 2014-12-23
CA2685072C (en) 2017-08-01
JP6258410B2 (en) 2018-01-10
HRP20150978T1 (en) 2015-11-06
HK1250648A1 (en) 2019-01-11
KR20160130328A (en) 2016-11-10
HRP20180453T1 (en) 2018-04-20
ES2549731T3 (en) 2015-11-02
PT2957284T (en) 2018-04-23
JP6411621B2 (en) 2018-10-24
US11278533B2 (en) 2022-03-22
EP2957284B1 (en) 2018-01-17
BRPI0810929B1 (en) 2019-04-09
PT2182945E (en) 2015-11-18
KR101769728B1 (en) 2017-08-18
KR101714291B1 (en) 2017-03-08
US20180353494A1 (en) 2018-12-13
US20160317520A1 (en) 2016-11-03
DK2182945T3 (en) 2015-11-16
JP6167217B2 (en) 2017-07-19
MX368680B (en) 2019-10-11
EP2182945A1 (en) 2010-05-12

Similar Documents

Publication Publication Date Title
AU2008268321B2 (en) Animal pest control method
CA2587495A1 (en) Control of parasites in animals by the use of parasiticidal 2-phenyl-3-(1h-pyrrol-2-yl) acrylonitrile derivatives
AU2014259503C1 (en) Animal pest control method
WO2012049327A2 (en) Pesticidal mixtures

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200880019716.9

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08771978

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 580470

Country of ref document: NZ

Ref document number: 2008268321

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2685072

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2008771978

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 12663848

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: MX/A/2009/013748

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2010515096

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 126/MUMNP/2010

Country of ref document: IN

ENP Entry into the national phase

Ref document number: 20107001744

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2010102529

Country of ref document: RU

ENP Entry into the national phase

Ref document number: PI0810929

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20091123