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WO2014099837A1 - Sulfonamide anthelmintics - Google Patents

Sulfonamide anthelmintics Download PDF

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Publication number
WO2014099837A1
WO2014099837A1 PCT/US2013/075532 US2013075532W WO2014099837A1 WO 2014099837 A1 WO2014099837 A1 WO 2014099837A1 US 2013075532 W US2013075532 W US 2013075532W WO 2014099837 A1 WO2014099837 A1 WO 2014099837A1
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WO
WIPO (PCT)
Prior art keywords
halogen
alkyl
ring
cyano
optionally substituted
Prior art date
Application number
PCT/US2013/075532
Other languages
French (fr)
Inventor
George Philip Lahm
Benjamin Kenneth Smith
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
Application filed by E. I. Du Pont De Nemours And Company filed Critical E. I. Du Pont De Nemours And Company
Publication of WO2014099837A1 publication Critical patent/WO2014099837A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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

Definitions

  • This invention relates to certain sulfonamide compounds, their N-oxides, salts and their compositions suitable for animal health uses and methods of their use for treating helminth infections in animals.
  • World Patent Application Publications WO 2005/033081 and WO 2007/104726 disclose sulfonamide compounds for control of insects and plant diseases.
  • This invention is directed to the method for treating an animal in need of such treatment for infection by helminths which comprises orally, topically, parenterally or subcutaneously administering to the animal a parasiticidally effective amount of a compound of Formula 1, or a pharmaceutically or veterinarily acceptable salt or a composition comprising it:
  • R 1 is hydrogen, C 1-C4 alkyl, C 2 -C6 alkylcarbonyl or C 2 -Cg alkoxycarbonyl;
  • R 2 and R 3 are each independently hydrogen, halogen, cyano, hydroxyl, amino, nitro, CHO, SF 5 , OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0) p R 12 or S(O) 2 NR 10 R n ; or -Q, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, Cz Cg cycloalkylalkyl or C5-C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0)pR 12 and S(O) 2 NR 10 R n ; or G; or
  • R 2 and R 3 are taken together with the carbons to which they are attached to form a 5- to 6-membered carbocyclic or heterocyclic ring optionally substituted with up to 3 substituents independently selected from R a on carbon atom ring members and R 4 ⁇ on nitrogen atom ring members;
  • G is a phenyl ring or an 8- to 10-membered carbocyclic bicyclic ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R 5a ; or
  • G is a 5- to 7-membered heterocyclic ring or an 8- to 10-membered heterocyclic
  • each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R 5a on carbon atom ring members and R 5 ⁇ on nitrogen atom ring members;
  • X is CR 4c or N
  • Y is CR 4d or N
  • Q 1 is 3- to 7-membered carbocyclic ring or an 8- to 10-membered carbocyclic bicyclic ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R 13a ; or
  • Q 1 is a 5- to 7-membered heterocyclic ring or an 8- to 10-membered heterocyclic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2
  • J is hydrogen; or phenyl or naphthalenyl each optionally substituted with up to 5
  • J is a 5- to 7-membered heterocyclic ring or an 8- to 10-membered heterocyclic
  • each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R 1 a on carbon atom ring members and
  • R 1 on nitrogen atom ring members; or J is L-Q 2 ;
  • L is O, S, SO, S0 2 , NR 15 , (CH 2 ) n , OCH 2 , or CH 2 0;
  • Q 2 is a 3- to 7-membered carbocyclic ring or an 8- to 10-membered carbocyclic
  • each ring or ring system optionally substituted with up to 5 substituents independently selected from R 16a ; or
  • Q 2 is a 3- to 7-membered heterocyclic ring or an 8- to 10-membered heterocyclic
  • each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R 16a on carbon atom ring members and R16b on nitrogen atom ring members;
  • each R 4a is independently halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF 5 , OR 6 , N R 7a R 7b c(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0) p R 12 or S(O) 2 NR 10 R n ; or C ⁇ -Cg alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl, C3-C7 cycloalkyl, Cz Cg cycloalkylalkyl or C5-C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0) p R 12 and
  • R 4b is cyano, -CHO, OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0) p R 12 or S(O) 2 NR 10 R n ; or Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, Cz Cg cycloalkylalkyl or C5 ⁇ C 7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0)pR 12 and S(O) 2 NR 10 R n ; or G;
  • R 4c and R 4 ⁇ are each independently hydrogen, halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF 5 , OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0) p R 12 or S(O) 2 NR 10 R n ; or Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, Cz Cg cycloalkylalkyl or C5 ⁇ C 7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0)pR 12 and S(O) 2 NR 10 R n ; or G;
  • each R 5a is independently halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF 5 , OR 6 , N R 7a R 7b c(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0) p R 12 or S(O) 2 NR 10 R n ; or C ⁇ -Cg alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl, C3 ⁇ C 7 cycloalkyl, Cz Cg cycloalkylalkyl or C5 ⁇ C 7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0) p R 12 and
  • R 5b is cyano, -CHO, OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0) p R 12 or S(O) 2 NR 10 R n ; or -Q, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 4 -C8 cycloalkylalkyl or C5 ⁇ C 7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0)pR 12 and S(O) 2 NR 10 R n ;
  • each R 6 is independently hydrogen, C 2 -Cg alkylcarbonyl, C 2 -Cg alkoxycarbonyl, C 2 - C ⁇ alkylaminocarbonyl, C3-C6 dialkylaminocarbonyl, C ⁇ -C ⁇ alkylsulfenyl, C ⁇ - Cg alkylsulfinyl, C ⁇ -Cg alkylsulfonyl, C 2 -Cg alkylaminosulfonyl or C3-C6 dialkylaminosulfonyl; or C ⁇ -Cg alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl or benzyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, C ⁇ -Cg alkoxy, C ⁇ -Cg alkylamino, C 2 - Cg dialkylamino, C 2 -Cg alkylcarbonyl, C 2
  • each R 7a is independently hydrogen, C 2 -Cg alkylcarbonyl, C 2 -Cg alkoxycarbonyl, C 2 - C ⁇ alkylaminocarbonyl, C3-C6 dialkylaminocarbonyl, C ⁇ -C ⁇ alkylsulfenyl, C ⁇ - Cg alkylsulfinyl or C ⁇ -Cg alkylsulfonyl, C 2 -Cg alkylaminosulfonyl or C3-C6 dialkylaminosulfonyl; or C ⁇ -Cg alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl or benzyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, C ⁇ -Cg alkoxy, C ⁇ -Cg alkylamino, C 2 - Cg dialkylamino, C 2 -Cg alkylcarbonyl, C 2
  • R 8 , R 9 , R 10 and R 12 are each independently hydrogen; or C ⁇ -Cg alkyl, C2 ⁇ Cg alkenyl, C2 ⁇ Cg alkynyl, phenyl, benzyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5- C 7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, -C4 haloalkyl, -C4 alkoxy, C1-C4 haloalkoxy, C2 ⁇ Cg alkoxycarbonyl, C2 ⁇ Cg alkylaminocarbonyl, C2 ⁇ Cg dialkylaminocarbonyl, C1-C4 alkylsulfenyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1
  • each R 1 1 is independently hydrogen; or C ⁇ -Cg alkyl, C2 ⁇ Cg alkenyl, C2 ⁇ Cg alkynyl or benzyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, -C4 haloalkyl, C - C4 alkoxy, C1-C4 haloalkoxy, -C4 alkylsulfenyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, -C4 haloalkylsulfenyl, C1-C4 haloalkylsulfinyl and -C4 haloalkylsulfenyl;
  • each R 13a is independently halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF 5 , OR 6 , N R 7a R 7b c(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0) p R 12 or S(O) 2 NR 10 R n ; or C ⁇ -Cg alkyl, C2 ⁇ Cg alkenyl, C2 ⁇ Cg alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5-C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0) p R 12 and
  • R 13b is cyano, -CHO, OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0) p R 12 or S(O) 2 NR 10 R n ; or -Cg alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5-C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0)pR 12 and S(O) 2 NR 10 R n ;
  • each R 14a is independently halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF 5 , OR 6 , N R 7a R 7b c(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0) p R 12 or S(O) 2 NR 10 R n ; or C ⁇ -Cg alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl, C3-C7 cycloalkyl, Cz Cg cycloalkylalkyl or C5-C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0) p R 12 and
  • R 14b is cyano, -CHO, OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0) p R 12 or S(O) 2 NR 10 R n ; or Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, Cz Cg cycloalkylalkyl or C5 ⁇ C 7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n ,
  • R 15 is hydrogen, cyano, -CHO, OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n ,
  • each R 16a is independently halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF 5 , OR 6 , N R 7a R 7b c(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0) p R 12 or S(O) 2 NR 10 R n ; or C !
  • R 16b is cyano, -CHO, OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R 1 ! , S(0) p R 12 or
  • n 1 or 2;
  • p 0, 1 or 2;
  • each R 13a is hydrogen
  • This invention is also directed to such compounds of Formula 1 (including all stereoisomers), N-oxides, and salts thereof, and compositions containing them and their use for treating an animal in need of such treatment, for infection by helminths.
  • This invention also provides a composition comprising a parasiticidally effective amount of compounds of Formula 1, an N-oxide, or a salt thereof, and at least one pharmaceutically or veterinarily acceptable carrier or diluent.
  • this invention also provides a composition comprising a parasiticidally effective amount of a compound of Formula 1, an N-oxide, or a salt thereof, and at least one pharmaceutically or veterinarily acceptable carrier or diluent, said composition further comprising at least one additional biologically active compound or agent.
  • This invention provides a method for treating an animal in need of such treatment, for infection by helminths which comprises orally, topically, parenterally or subcutaneously administering to the animals a parasiticdally effective amount of a compound of Formula 1, an N-oxide, or a pharmaceutically or veterinarily acceptable salt or a composition comprising it.
  • compositions comprising, “comprising”, “includes”, “including”, “has”, “having”, “contains”, “containing”, “characterized by” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated.
  • a composition, mixture, process or method 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 or method.
  • endoparasite is a parasite that lives inside an animal and "ectoparasite” is a parasite that lives on the surface of an animal.
  • helminths includes heartworms, roundworms (Nematoda), flukes (Trematoda), Acanthocephala and tapeworms (Cestoda).
  • Animal health applications include treating an animal in need of such treatment with a compound of the invention to control a present infection with a helminthic parasitic pest by administering a parasiticidally effective amount of a compound of the invention, typically in the form of a composition formulated for veterinary or pharmaceutical use, to the animal.
  • the invention contemplates the prophalactic treatment of an animal in need of such treatment with a compound of the invention such that infection with a helminthic parasitic pest is prevented lessened in severity(in comparison to a similarly situated animal in an untreated state) by administering a parasiticidally effective amount of a compound of the invention, typically in the form of a composition formulated for veterinary or pharmaceutical use, to the animal to be protected.
  • An animal can be either human (pharmaceutical use) or non-human (veterinary use).
  • a "parasiticidally effective amount” is the amount of active ingredient needed to achieve an observable effect diminishing the occurrence or activity of the helminthic parasite.
  • Parasiticidal effects typically relate to diminishing the occurrence or activity of the target helminth parasitic pest. Such effects on the pest include necrosis, death, retarded growth, diminished mobility or lessened ability to remain in the host animal, reduced feeding and inhibition of reproduction. These effects on helminth parasite pests provide control (including prevention, reduction or elimination) of parasitic infection of the animal.
  • the parasiticidally effective dose can vary for the various compounds and compositions of the present invention, the desired parasiticidal effect and duration, the target 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.
  • Treating” or “Treatment” as it applies to an infection refers to reducing the severity of any infection which may otherwise occur in the absence of treatment which may include complete control or prevention of such infection. Whithout being bound by theory such treatment may result in "control" of the infection by the inhibition or disruption of the life cycle of a parasitic helminth (including maturation, mortality, feeding reduction and/or mating disruption).
  • antihelmintic refers to substances (drugs) that are useful in controlling helminthes for example by facilitating the expulsion of parasitic worms (helminthes) from the body of an animal by either stunning or killing them.
  • An animal is in "need of treatment” if it is presently infected or in danger of infection by helminthes.
  • Parenter as a mode of administration means taken into the body or administered in a manner other than through the digestive tract, for example by injection.
  • Enteral as a mode of admininstration means take into the body or administered through the digestive tract for example oral administration.
  • Topical as a mode of admininistration means application to the skin. It is understood that topical administration may have systemic effects dependent on the compound to be admininistered and the formulation in which it is contained.
  • alkyl used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl 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 also includes moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
  • Alkylene denotes a straight-chain or branched alkanediyl.
  • alkylene examples include CH 2 , CH 2 CH 2 , CH(CH 3 ), CH 2 CH 2 CH 2 , CH 2 CH(CH 3 ), and the different butylene isomers.
  • Alkynylene denotes a straight-chain or branched alkynediyl containing one triple bond. Examples of “alkynylene” include C ⁇ C, CH 2 C ⁇ C, C ⁇ CCH 2 , and the different butynylene isomers.
  • Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the term “cycloalkylalkyl” denotes cycloalkyl substitution on an alkyl moiety. Examples of “cycloalkylalkyl” include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups.
  • Cycloalkenyl includes groups such as cyclopentenyl and cyclohexenyl as well as groups with more than one double bond such as 1,3- and 1,4-cyclohexadienyl.
  • cycloalkoxy denotes cycloalkyl attached to and linked through an oxygen atom such as cyclopentyloxy and cyclohexyloxy.
  • Alkylcycloalkylalkyl denotes an alkyl group substituted with alkylcycloalkyl. Examples of “alkylcycloalkylalkyl” include 1-, 2-, 3- or 4-methyl or -ethyl cyclohexylmethyl.
  • cycloalkylcycloalkyl denotes cycloalkyl substitution on another cycloalkyl ring, wherein each cycloalkyl ring independently has from 3 to 7 carbon atom ring members.
  • cycloalkylcycloalkyl examples include cyclopropylcyclopropyl (such as ⁇ , ⁇ -bicyclopropyl-l-yl, l,l'-bicyclopropyl-2-yl), cyclohexylcyclopentyl (such as 4- cyclopentylcyclohexyl) and cyclohexylcyclohexyl (such as ⁇ , ⁇ -bicyclohexyl-l-yl), and the different cis- and trans-cycloalkylcycloalkyl isomers, (such as (li?,25)-l,l'-bicyclopropyl-2- yl and (li?,2i?)-l,l'-bicyclopropyl-2-yl).
  • cyclopropylcyclopropyl such as ⁇ , ⁇ -bicyclopropyl-l-yl, l,l'-bicyclopropyl-2-yl
  • 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 C1, CH 2 CF 3 and CC1 2 CF 3 .
  • haloalkenyl is defined analogously to the term “haloalkyl”.
  • haloalkynyl include HC ⁇ CCHC1, CF 3 C ⁇ C, CC1 3 C ⁇ C and FCH 2 C ⁇ CCH 2 .
  • haloalkoxy examples include CF 3 0, CC1 3 CH 2 0, HCF 2 CH 2 CH 2 0 and CF 3 CH 2 0.
  • haloalkylthio examples include CC1 3 S, CF 3 S, CC1 3 CH 2 S and C1CH 2 CH 2 CH 2 S.
  • haloalkylamino examples include CF 3 (CH 3 )CHNH, (CF 3 ) 2 CHNH and CH 2 C1CH 2 NH.
  • halocycloalkyl examples include 2-chlorocyclopropyl, 2-fluorocyclobutyl, 3-bromocyclopentyl and 4-chlorocyclohexyl.
  • halodialkyl either alone or in compound words such as “halodialkylamino" means at least one of the two alkyl groups is substituted with at least one halogen atom, and independently each halogenated alkyl group may be partially or fully substituted with halogen atoms which may be the same or different.
  • halodialkylamino include (BrCH 2 CH 2 ) 2 N and BrCH 2 CH2(ClCH 2 CH2)N.
  • Alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy and the different butoxy, pentoxy and hexyloxy isomers.
  • Alkoxyalkyl denotes alkoxy substitution on alkyl. Examples of “alkoxyalkyl” include CH 2 OCH 3 , CH 2 CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 OCH 2 CH 2 CH 2 CH 3 and CH 2 CH 2 OCH 2 CH 3 .
  • alkynyloxy includes straight-chain or branched alkynyloxy moieties. Examples of “alkynyloxy” include HC ⁇ CCH 2 0, CH 3 C ⁇ CCH 2 0 and CH 3 C ⁇ CCH 2 CH 2 0.
  • alkylsulfenyl or “alkylthio” includes straight-chain or branched alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers.
  • Alkylsulfinyl includes both enantiomers of an alkylsulfinyl group.
  • Alkylamino denotes an NH radical substituted with straight-chain or branched alkyl.
  • alkylamino examples include NHCH 2 CH 3 , NHCH 2 CH 2 CH 3 , and NHCH 2 CH(CH 3 ) 2 .
  • Dialkylamino denotes an N radical substituted independently with two straight-chain or branched alkyl groups. Examples of “dialkylamino” include N(CH 3 ) 2 , N(CH 3 CH 2 CH 2 ) 2 and N(CH 3 )CH 2 CH 3 .
  • Halodialkylamino denotes one straight-chain or branched alkyl moiety and one straight-chain or branched haloalkyl moiety bonded to an N radical, or two independent straight-chain or branched haloalkyl moieties bonded to an N radical, wherein “haloalkyl” is as defined above.
  • Examples of “halodialkylamino” include
  • Alkylcarbonyl denotes a straight-chain or branched alkyl moiety bonded to a C(O) moiety.
  • alkylcarbonyl include C(0)CH 3 , C(0)CH 2 CH 2 CH 3 and C(0)CH(CH 3 ) 2 .
  • haloalkylcarbonyl include C(0)CF 3 , C(0)CC1 3 , C(0)CH 2 CF 3 and C(0)CF 2 CF 3 .
  • Alkoxycarbonyl denotes a straight-chain or branched alkyl moiety bonded to a CO2 moiety.
  • alkoxycarbonyl examples include C(0)OCH 3 , C(0)OCH 2 CH 3 , C(0)OCH 2 CH 2 CH 3 and C(0)OCH(CH 3 ) 2 .
  • Alkylaminocarbonyl denotes a straight-chain or branched alkyl moiety bonded to a
  • C(0)NH moiety The chemical abbreviations C(0)NH, and C(0)N as used herein represent an amide moiety (i.e. an aminocarbonyl group).
  • alkylaminocarbonyl examples include C(0)NHCH 3 , C(0)NHCH 2 CH 2 CH 3 and C(0)NHCH(CH 3 ) 2 .
  • Dialkylaminocarbonyl denotes two independent straight-chain or branched alkyl moieties bonded to a C(0)N moiety.
  • dialkylaminocarbonyl include C(0)N(CH 3 ) 2 and C(0)N(CH 3 )(CH 2 CH 3 ).
  • Trialkylsilyl includes 3 branched and/or straight-chain alkyl radicals attached to and linked through a silicon atom, such as trimethylsilyl, triethylsilyl and tert-butyldimethylsilyl.
  • C1-C4 alkyl designates methyl through butyl
  • C 2 alkoxyalkyl designates CH 2 OCH 3
  • C 3 alkoxyalkyl designates, for example, CH 3 CH(OCH 3 ), CH 2 CH 2 OCH 3 or CH 2 OCH 2 CH 3
  • C 4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH 2 OCH 2 CH 2 CH 3 and CH 2 CH 2 OCH 2 CH 3 .
  • the attachment point for a ring for example Q 2 rings in Exhibit 4
  • the ring Q 2 can be attached to Formula 1 through any available carbon atom ring member of the Q 2 ring or ring system.
  • both attachment points are available through any carbon atom ring member of the Q 1 ring or ring system. This means that the two attachment points between Q 1 and Formula 1 can be in just one ring of a bicyclic ring system or in different rings of the bicyclic ring system.
  • ring system denotes two or more connected rings.
  • bicyclic ring system denotes a ring system consisting of two rings sharing two or more common atoms.
  • ring member refers to an atom (e.g., C, O, N or S) forming the backbone of a ring or ring system.
  • aromatic indicates that each of the ring atoms is essentially in the same plane and has a / ⁇ -orbital perpendicular to the ring plane, and that (4n + 2) ⁇ electrons, where n is a positive integer, are associated with the ring or ring system to comply with Huckel's rule.
  • Partially saturated and “partially unsaturated” with reference to a ring or ring system means that the ring or ring system contains at least one double bond but the ring or ring system is not aromatic.
  • a ring system is aromatic if at least one component ring is aromatic.
  • carbocyclic ring denotes a ring wherein the atoms forming the ring backbone are selected only from carbon. Unless otherwise indicated, a carbocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring. When a fully unsaturated carbocyclic ring satisfies Huckel's rule, then said ring is also called an "aromatic ring". "Saturated carbocyclic ring” refers to a ring having a backbone consisting of carbon atoms linked to one another by single bonds; unless otherwise specified, the remaining carbon valences are occupied by hydrogen atoms.
  • heterocyclic ring or “heterocycle” denotes a ring wherein at least one of the atoms forming the ring backbone is other than carbon. Unless otherwise indicated, a heterocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring.
  • saturated heterocyclic ring refers to a heterocyclic ring containing only single bonds between ring members.
  • Partially saturated heterocyclic ring refers a heterocyclic ring containing at least one double bond but which is not aromatic.
  • heteroheteroaromatic ring denotes a fully unsaturated aromatic ring in which at least one atom forming the ring backbone is not carbon.
  • heteroaromatic ring typically contains no more than 4 nitrogens, no more than 1 oxygen and no more than 1 sulfur. Unless otherwise indicated, heteroaromatic rings can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
  • heteroaromatic bicyclic ring system denotes a ring system consisting of two fused rings, in which at least one of the two rings is a heteroaromatic ring as defined above.
  • radical e.g., a 5- to 7-membered heterocyclic ring in the definition of Q 1
  • the radical may be unsubstituted or substituted with a number of substituents ranging up to the high number stated (e.g., "5"), and the attached substituents are independently selected from the substituents listed.
  • a substituent e.g., when R 2 is cycloalkyl
  • R 2 when R 2 is cycloalkyl, it can be attached to the remainder of Formula 1 through any available ring member, unless otherwise described.
  • Q 1 is, inter alia, a 5- to 7-membered heterocyclic ring or an 8- to 10- membered heteroaromatic bicyclic ring system, containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S, and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R 13a on carbon atom ring members and R 13 ⁇ on nitrogen atom ring members.
  • the nitrogen atom ring members may be oxidized as N-oxides, because compounds relating to Formula 1 also include N-oxide derivatives.
  • R 13a and R 13 ⁇ substituents are optional, 0 to 5 substituents may be present, limited only by the number of available points of attachment.
  • unsubstituted in connection with a group such as a ring or ring system means the group does not have any substituents other than its one or more attachments to the remainder of Formula 1.
  • optionally substituted means that the number of substituents can be zero. Unless otherwise indicated, optionally substituted groups may be substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, the number of optional substituents (when present) ranges from 1 to 5.
  • the number of optional substituents may be restricted by an expressed limitation.
  • the phrase “optionally substituted with up to 5 substituents independently selected from Rl 3a” means that 0, 1, 2, 3, 4 or 5 substituents can be present (if the number of potential connection points allows).
  • a range specified for the number of substituents exceeds the number of positions available for substituents on a ring, the actual higher end of the range is recognized to be the number of available positions.
  • the number of optional substituents is not restricted by an expressed limitation (e.g., the phrases "optionally substituted” or “unsubstituted or substituted with at least one substituent independently selected from”), it is understood to mean that the number of optional substituents can range from 0 up to the number of positions available.
  • substituents such as halogen can be present at every available position (for example, the C2F5 substituent is a C2 alkyl group substituted with the maximum number of 5 fluorine atoms)
  • practical factors such as cost and synthetic accessibility can limit the number of occurrences of other substituents.
  • These limitations are part of the general synthetic knowledge known to those skilled in the art.
  • the number of optional substituents is up to 3 (i.e. 0, 1, 2 or 3) if accommodated by the number of available positions.
  • Compounds of this invention can exist as one or more stereoisomers.
  • the various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers.
  • one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers.
  • the compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form.
  • Non-crystalline forms include embodiments which are solids such as waxes and gums as well as embodiments which are liquids such as solutions and melts.
  • Crystalline forms include embodiments which represent essentially a single crystal type and embodiments which represent a mixture of polymorphs (i.e. different crystalline types).
  • polymorph refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms, these forms having different arrangements and/or conformations of the molecules in the crystal lattice.
  • polymorphs can have the same chemical composition, they can also differ in composition due to the presence or absence of co- crystallized water or other molecules, which can be weakly or strongly bound in the lattice. Polymorphs can differ in such chemical, physical and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability.
  • a polymorph of a compound represented by Formula 1 can exhibit beneficial effects (e.g., suitability for preparation of useful formulations, improved biological performance) relative to another polymorph or a mixture of polymorphs of the same compound represented by Formula 1.
  • Preparation and isolation of a particular polymorph of a compound represented by Formula 1 can be achieved by methods known to those skilled in the art including, for example, crystallization using selected solvents and temperatures.
  • nitrogen-containing heterocycles can form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen-containing heterocycles which can form N-oxides.
  • nitrogen-containing heterocycles which can form N-oxides.
  • tertiary amines can form N-oxides.
  • N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and 3-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.
  • salts also include those formed with organic or inorganic bases such as pyridine, triethylamine or ammonia, or amides, hydrides, hydroxides or carbonates of sodium, potassium, lithium, calcium, magnesium or barium. Accordingly, the present invention comprises compounds selected from Formula 1, N-oxides, and salts thereof.
  • Embodiments of the present invention as described in the Summary of the Invention include those described below.
  • Formula 1 includes stereoisomers, N-oxides, and salts thereof, and 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 for treating an animal in need of such treatment for infection by helminths which comprises orally, topically, parenterally or subcutaneously administering to the animal a parasiticdally effective amount of a compound of Formula 1, or a
  • Embodiment 2 The method of Embodiment 1 wherein R 1 is hydrogen, C1-C4 alkyl, C2-C4 alkylcarbonyl or C2-C4 alkoxycarbonyl.
  • Embodiment 3 The method of Embodiment 2 wherein R 1 is hydrogen.
  • Embodiment 4 The method of any one of Embodiments 1 through 3 wherein R 2 and R 3 are each independently hydrogen, halogen, cyano, hydroxyl, amino, nitro, CHO,
  • Embodiment 5 The method of Embodiment 4 wherein R 2 and R 3 are each
  • Embodiment 6 The method of Embodiment 5 wherein R 2 and R 3 are each
  • Embodiment 7 The method of Embodiment 6 wherein R 2 and R 3 are each
  • Embodiment 8 The method of Embodiment 4 wherein R 2 and R 3 are each
  • Embodiment 9 The method of any one of Embodiments 1 through 3 wherein R 2 and R 3 are taken together with the carbons to which they are attached to form a 5- to 6- membered carbocyclic or heterocyclic ring optionally substituted with up to 3 substituents independently selected from R a on carbon atom ring members and R 4 ⁇ on nitrogen atom ring members.
  • Embodiment 9a The method of Embodiment 9 wherein R 2 and R 3 are taken together with the carbons to which they are attached to form a phenyl ring optionally substituted with up to 3 substituents independently selected from R 4a .
  • Embodiment 10 The method of any one of Embodiments 1 through 9a wherein G is a phenyl ring optionally substituted with up to 5 substituents independently selected from R 5a ; or a 5- to 7-membered heterocyclic ring containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R 5a on carbon atom ring members and R 5 ⁇ on nitrogen atom ring members
  • Embodiment 11 The method of Embodiment 10 wherein wherein G is a ring selected from the group consisting of G-1 through G-27 in Exhibit 1
  • R 5 when R 5 is attached to a carbon ring member, said R 5 is selected from R 5a , and when R 5 is attached to a nitrogen ring member, said R 5 is selected from R 5 ⁇ ; and q is an integer from 0 to 5.
  • Embodiment 12 The method of any one of Embodiments 1 through 11 wherein X is CR 4c .
  • Embodiment 13 The method of any one of Embodiments 1 through 11 wherein X is N.
  • Embodiment 14 The method of any one of Embodiments 1 through 13 wherein Y is CR 4d .
  • Embodiment 15 The method of any one of Embodiments 1 through 13 wherein Y is N.
  • Embodiment 16 The method of any one of Embodiments 1 through 15 wherein each R 4a is independently halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF 5 , OR 6 , N R 7a R 7b C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0) p R 12 or S(O) 2 NR 10 R n ; or C j -Cg alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C7 cycloalkyl, C 4 -C 8 cycloalkylalkyl or C5-C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0) p R 12 and
  • Embodiment 17 The method of Embodiment 16 wherein each R a is independently halogen, cyano, nitro, OR 6 , S(0) p R 12 or C ⁇ -Cg alkyl optionally substituted with halogen.
  • Embodiment 18 The method of Embodiment 17 wherein each R a is independently halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, -C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl.
  • Embodiment 18a The method of Embodiment 18 wherein each R 4a is independently halogen.
  • Embodiment 19 The method of any one of Embodiments 1 through 15 wherein each
  • R 4a is independently G.
  • Embodiment 20 The method of any one of Embodiments 1 through 19 wherein R b is C(0)R 8 , C(0)OR 9 or -Cg alkyl.
  • Embodiment 21 The method of Embodiment 20 wherein R b is C ⁇ -Cg alkyl.
  • Embodiment 21a The method of any one of Embodiments 1 through 21 wherein R c and R d are each independently hydrogen, halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF 5 , OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n , S(0) p R 12 or S(0) 2 NR 1 °R 1 !; or -Cg alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C4-C8 cycloalkylalkyl or C5 ⁇ C 7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR 6 , NR 7a R 7b , C(0)R 8 , C(0)OR 9 , C(O)NR 10 R n ,
  • Embodiment 21b The method of Embodiment 21a wherein R c and R d are each
  • Embodiment 21c The method of Embodiment 21b wherein R c and R d are each
  • Embodiment 2 Id The method of Embodiment 21c wherein R c and R d are each
  • Embodiment 22 The method of any one of Embodiments 1 through 21d wherein each R 5a is halogen, cyano, nitro, OR 6 , S(0) p R 12 or C ⁇ -Cg alkyl optionally substituted with halogen.
  • Embodiment 23 The method of Embodiment 22 wherein each R 5a is independently halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl.
  • Embodiment 24 The method of any one of Embodiments 1 through 23 wherein R 5 ⁇ is C(0)R 8 , C(0)OR 9 or Ci-C 6 alkyl.
  • Embodiment 25 The method of Embodiment 24 wherein R 5 ⁇ is C ⁇ -C alkyl.
  • Embodiment 26 The method of any one of Embodiments 1 through 25 wherein q is an integer from 0 to 3.
  • Embodiment 27 The method of any one of Embodiments 1 through 25 wherein each R 6 is independently hydrogen, C2 ⁇ Cg alkylcarbonyl, or C2 ⁇ Cg alkoxycarbonyl; or C ⁇ -Cg alkyl or benzyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano and C ⁇ -Cg alkoxy; or C3-C7 cycloalkyl optionally substituted with substituents
  • halogen independently selected from the group consisting of halogen, C1-C4 alkyl and C1-C4 haloalkyl.
  • Embodiment 28 The method of Embodiment 27 wherein each R 6 is independently C ⁇ -
  • Embodiment 29 The method of Embodiment 27 wherein each R 6 is independently C ⁇ -
  • Embodiment 30 The method of any one of Embodiments 1 through 29 wherein each R 7a is independently hydrogen, C2 ⁇ Cg alkylcarbonyl or C2 ⁇ Cg alkoxycarbonyl; or C j -Cg alkyl or benzyl, each optionally substituted with substituents independently selected from the group consisting of halogen and cyano; or C3- C 7 cycloalkyl optionally substituted with substituents independently selected from the group consisting of halogen, C1-C4 alkyl and C1-C4 haloalkyl.
  • Embodiment 31 The method of Embodiment 30 wherein each R 7a is independently
  • Embodiment 32 The method of Embodiment 31 wherein each R 7a is independently
  • Embodiment 33 The method of any one of Embodiments 1 through 32 wherein each R 7b is independently hydrogen; or C ⁇ -Cg alkyl optionally substituted with halogen.
  • Embodiment 34 The method of Embodiment 33 wherein each R 7 ⁇ is independently hydrogen, C1-C4 alkyl or C1-C4 haloalkyl.
  • Embodiment 35 The method of any one of Embodiments 1 through 34 wherein R 8 , R 9 ,
  • R 10 and R 12 are each independently hydrogen; or C ⁇ -Cg alkyl or C3-C7 cycloalkyl, each optionally substituted with substituents independently selected from the group consisting of halogen, C1-C4 alkyl and -C4 haloalkyl.
  • Embodiment 36 The method of Embodiment 35 wherein R 8 , R 9 , R 10 and R 12 are each independently C ⁇ -Cg alkyl optionally substituted with halogen.
  • Embodiment 37 The method of Embodiment 36 wherein R 8 , R 9 , R 10 and R 12 are each independently C1-C4 alkyl or C1-C4 haloalkyl.
  • Embodiment 38 The method of any one of Embodiments 1 through 37 wherein each
  • R 1 1 is independently hydrogen; or C ⁇ -Cg alkyl optionally substituted with halogen.
  • Embodiment 39 The method of Embodiment 38 wherein each R 1 1 is independently hydrogen, C1-C4 alkyl or C1-C4 haloalkyl.
  • Embodiment 40 The method of any one of Embodiments 1 through 39 wherein Q 1 is a ring selected from the group consisting of Q 1 -! through Ql-84 in Exhibit 2
  • R 13 is selected from R 13 ⁇ ; and x is an integer from 0 to 5.
  • Embodiment 41 The method of Embodiment 40 wherein Q 1 is a ring selected from the group consisting of Q l -l through Q l -42.
  • Embodiment 42 The method of Embodiment 41 wherein Q 1 is a ring selected from the group consisting of Q 1 -! through Q l -24.
  • Embodiment 42a The method of Embodiment 42 wherein Q 1 is a ring selected from the group consisting of Q 1 -!, Q!-2, Q!-3, QU, Q!-5, Q!-10, Q l, Q!-12, Q!-20 and Q!-24.
  • Embodiment 43 The method of Embodiment 42a wherein Q 1 is a ring selected from the group consisting of Q 1 -4, Qi-12 and Q l -24.
  • Embodiment 43a The method of Embodiment 43 wherein Q 1 is Qi-4 or Qi-24.
  • Embodiment 43b The method of Embodiment 43a wherein Q 1 is Qi-24.
  • Embodiment 44 The method of any one of Embodiments 1 through 43b wherein x is an integer from 0 to 3.
  • Embodiment 45 The method of any one of Embodiments 1 through 44 wherein each
  • R 13a is halogen, cyano, nitro, OR 6 , S(0) p R 12 or C ⁇ -Cg alkyl optionally substituted with halogen.
  • Embodiment 46 The method of Embodiment 45 wherein each R 13a is independently halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl.
  • Embodiment 47 The method of any one of Embodiments 1 through 46 wherein R 13 ⁇ is
  • Embodiment 47a The method of Embodiment 47 wherein R 13 ⁇ is C ⁇ -C ⁇ alkyl.
  • Embodiment 48 The method of any one of Embodiments 1 through 47a wherein J is hydrogen; or phenyl or naphthalenyl each optionally substituted with up to 5 substituents independently selected from R 14a ; or a 5- to 7-membered heterocyclic ring or an 8- to 10-membered heterocyclic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R 1 a on carbon atom ring members and R 1 ⁇ on nitrogen atom ring members.
  • Embodiment 49 The method of Embodiment 48 wherein J is hydrogen.
  • Embodiment 50 The method of Embodiment 48 wherein J is phenyl or naphthalenyl each optionally substituted with up to 5 substituents independently selected from R 1 a ; or a 5- to 7-membered heterocyclic ring or an 8- to 10-membered heterocyclic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R 14a on carbon atom ring members and R 14 b on nitrogen atom ring members.
  • Embodiment 51 The method of Embodiment 50 wherein J is a ring selected from the group consisting of J-l through J-80 in Exhibit 3
  • J-77 J-78 J-79 J-80 wherein the floating bond is connected to Q 1 in Formula 1 through any available carbon atom of the depicted ring or ring system; when R 14 is attached to a carbon ring member, said R 14 is selected from R 1 a , and when R 14 is attached to a nitrogen ring member, said R 14 is selected from R 1 ⁇ ; and y is an integer from 0 to 5.
  • Embodiment 52 The method of Embodiment 51 wherein J is a ring selected from the group consisting of J-l through J-43.
  • Embodiment 53 The method of Embodiment 52 wherein J is a ring selected from the group consisting of J-l through J-25 and J-43.
  • Embodiment 54 The method of Embodiment 53 wherein J is a ring selected from the group consisting of J-l through J-8, J- 19 and J-25.
  • Embodiment 54a The method of Embodiment 54 wherein J is a ring selected from the group consisting of J-l, J-2, J-5, J-6 and J-25.
  • Embodiment 54b The method of Embodiment 54a wherein J is J-25.
  • Embodiment 55 The method of any one of Embodiments 1 through 54b wherein y is an integer from 0 to 3.
  • Embodiment 56 The method of any one of Embodiments 1 through 55 wherein each R 14a is halogen, cyano, nitro, OR 6 , S(0) p R 12 or Ci ⁇ C 6 alkyl optionally substituted with halogen.
  • Embodiment 57 The method of Embodiment 56 wherein each R 1 a is independently halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl.
  • Embodiment 58 The method of any one of Embodiments 1 through 57 wherein R 1 ⁇ is
  • Embodiment 59 The method of Embodiment 58 wherein R 1 ⁇ is C ⁇ -C ⁇ alkyl.
  • Embodiment 60 The method of any one of Embodiments 1 through 59 wherein J is L-
  • Embodiment 61 The method of any one of Embodiments 1 through 60 wherein L is O, S, NR 15 , (CH 2 ) n , OCH 2 , or CH 2 0
  • Embodiment 62 The method of any one of Embodiments 1 through 61 wherein R 15 is hydrogen or C ⁇ -Cg alkyl.
  • Embodiment 63 The method of any one of Embodiments 1 through 61 wherein n is 1.
  • Embodiment 64 The method of Embodiment 61 wherein L is O, S, S0 2 or CH 2 .
  • Embodiment 65 The method of Embodiment 64 wherein L is O.
  • Embodiment 66 The method of any one of Embodiments 1 through 65 wherein Q 2 is a 5- to 7-membered carbocyclic ring or an 8- to 10-membered carbocyclic bicyclic ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R 16a ; or a 5- to 7-membered heterocyclic ring or an 8- to 10-membered heterocyclic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R 16a on carbon atom ring members and R 16 ⁇ on nitrogen atom ring members.
  • Embodiment 67 The method of Embodiment 66 wherein Q 2 is a ring selected from the group consisting of Q 2 -l through Q 2 -84 in Exhibit 4
  • Embodiment 68 The method of Embodiment 67 wherein Q 2 is a ring selected from the group consisting of Q 2 -l through Q 2 -43.
  • Embodiment 69 The method of Embodiment 68 wherein Q 2 is a ring selected from the group consisting of Q 2 -l through Q 2 -25 and Q 2 -43.
  • Embodiment 70 The method of Embodiment 69 wherein Q 2 is Q 2 -25.
  • Embodiment 71 The method of any one of Embodiments 1 through 70 wherein z is an integer from 0 to 3.
  • Embodiment 72 The method of any one of Embodiments 1 through 71 wherein each R 16a is halogen, cyano, nitro, OR 6 , S(0) p R 12 or Ci ⁇ C 6 alkyl optionally substituted with halogen.
  • Embodiment 73 The method of Embodiment 72 wherein each R 16a is independently halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl.
  • Embodiment 74 The method of any one of Embodiments 1 through 73 wherein R 16 ⁇ is
  • Embodiment 75 The method of Embodiment 74 wherein R 16 ⁇ is C ⁇ -C ⁇ alkyl.
  • Embodiment 76 The method of any one of Embodiments 1 through 75 wherein J is J-l through J-46; or L-Q 2 .
  • Embodiments of this invention can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula 1 but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula 1.
  • embodiments of this invention including Embodiments 1-76 above as well as any other embodiments described herein, and any combination thereof, pertain to the compositions and methods of the present invention.
  • Embodiment A The method as described in the summary of the invention wherein
  • R 2 and R 3 are each independently hydrogen, halogen, cyano, nitro, OR 6 ,
  • R 2 and R 3 are taken together with the carbons to which they are attached to form a 5- to 6-membered carbocyclic or heterocyclic ring optionally substituted with up to 3 substituents independently selected from R 4a on carbon atom ring members and R ⁇ on nitrogen atom ring members;
  • R 4a is independently halogen, cyano, nitro, OR 6 , S(0) p R 12 or C ⁇ -Cg alkyl optionally substituted with halogen;
  • X is CR 4c ;
  • Y is CR 4d ;
  • R c and R ⁇ are each independently hydrogen, halogen, cyano, nitro, OR 6 , S(0)pR 12 or C ⁇ -Cg alkyl optionally substituted with halogen;
  • Q 1 is a ring selected from the group consisting of Q ⁇ -l through Qi-84 in
  • Exhibit 2 wherein one of the floating bonds is connected to SO2 in Formula 1 through any available carbon of the depicted ring or ring system and the other floating bond is connected to J in Formula 1 through any available carbon atom of the depicted ring or ring system; when R 13 is attached to a carbon ring member, said R 13 is selected from R 13a , and when R 13 is attached to a nitrogen ring member, said R 13 is selected from R 13b ; and x is an integer from 0 to 5;
  • each R 1 a is halogen, cyano, nitro, OR 6 , S(0) p R 12 or C ⁇ -Cg alkyl optionally substituted with halogen;
  • R 13b is C(0)R 8 , C(0)OR 9 or -Cg alkyl
  • J is a ring selected from the group consisting of J-1 through J-80 in Exhibit 3 wherein the floating bond is connected to Q 1 in Formula 1 through any available carbon atom of the depicted ring or ring system; when R 1 is attached to a carbon ring member, said R 14 is selected from R 1 a , and when R 1 is attached to a nitrogen ring member, said R 1 is selected from R 1 b ; and y is an integer from 0 to 5; or L-Q 2 ;
  • each R 1 a is halogen, cyano, nitro, OR 6 , S(0) p R 12 or C ⁇ -Cg alkyl optionally substituted with halogen;
  • R 14b is C(0)R 8 , C(0)OR 9 or -Cg alkyl
  • L is O, S, S0 2 or CH 2 ;
  • Q 2 is a ring selected from the group consisting of Q 2 -l through Q 2 -84 in
  • Exhibit 4 wherein the floating bond is connected to L in Formula 1 through any available carbon of the depicted ring or ring system; when R 16 is attached to a carbon ring member, said R 16 is selected from R 16a , and when R 16 is attached to a nitrogen ring member, said R 16 is selected from R 16b ; and z is an integer from 0 to 5;
  • each R 16a is halogen, cyano, nitro, OR 6 , S(0) p R 12 or C ⁇ -Cg alkyl optionally substituted with halogen;
  • R 16b is C(0)R 8 , C(0)OR 9 or -Cg alkyl
  • each R 6 is independently hydrogen, C 2 -Cg alkylcarbonyl, or C 2 -Cg
  • alkoxycarbonyl or C ⁇ -Cg alkyl or benzyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano and C ⁇ -Cg alkoxy; or C3-C7 cycloalkyl optionally substituted with substituents independently selected from the group consisting of halogen, C1-C4 alkyl and C1-C4 haloalkyl; and
  • R 8 , R 9 and R 12 are each independently hydrogen; or C ⁇ -Cg alkyl or C3-C7 cycloalkyl, each optionally substituted with substituents independently selected from the group consisting of halogen, -C4 alkyl and -C4 haloalkyl.
  • Embodiment B The method of Embodiment A wherein
  • R 1 is hydrogen, -C4 alkyl, C2-C4 alkylcarbonyl or C2-C4 alkoxycarbonyl;
  • R 2 and R 3 are taken together with the carbons to which they are attached to form a phenyl ring optionally substituted with up to 3 substituents independently selected from R 4a ;
  • each R 4a is independently halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, -C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl;
  • R 4c and R d are each independently hydrogen, halogen, cyano, nitro, -C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, -C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4
  • Q 1 is a ring selected from the group consisting of Q through Q l -24;
  • each R 13a is independently halogen, cyano, nitro, -C4 alkyl, -C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C 1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, -C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl;
  • R 13b is Ci-C 6 alkyl
  • x is an integer from 0 to 3;
  • J is is a ring selected from the group consisting of J-l through J-43; or L-Q 2 ; each R 1 a is independently halogen, cyano, nitro, -C4 alkyl, -C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C 1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, -C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl;
  • R 14b is Ci-C 6 alkyl
  • y is an integer from 0 to 3;
  • L is O, S, S0 2 or CH 2 ;
  • Q 2 is a ring selected from the group consisting of Q 2 -l through Q 2 -25 and Q 2 -43; each R 16a is independently halogen, cyano, nitro, C1-C4 alkyl, C1-C4
  • haloalkyl -C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, -C4 haloalkylthio, C1-C4 alkylsulfinyl, -C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl;
  • R 16b is C!-C 6 alkyl
  • z is an integer from 0 to 3.
  • Embodiment C The method of Embodiment B wherein
  • Q 1 is a ring selected from the group consisting of Q l -l, Q l -2, Q l -3, Q l -4, Q!-5, Q!-10, Q!-l l, Q!-12, Q!-20 and Q!-24; and
  • J is is a ring selected from the group consisting of J-l through J-8;J-19 and J- 25; or L-Q 2 .
  • Embodiment D The method of Embodiment C wherein
  • R 1 is hydrogen
  • Q 1 is Q!-4 or Q!-24;
  • J is is a ring selected from the group consisting of J-l, J-2, J-5, J-6 and J-25; or L-Q 2 ;
  • Q 2 is Q 2 -25;
  • each R 4a is independently halogen.
  • Specific embodiments include compounds of Formula 1 selected from the group consisting of:
  • compositions comprising a compound of any of the preceding Embodiments, as well as any other embodiments described herein, and their use for treating an animal in need of such treatment, for infection by helminths.
  • compositions comprising a compound of any of the preceding Embodiments, as well as any other embodiments described herein, in a parasiticidally effective amount and at least one pharmaceutically or veterinarily acceptable carrier or diluent.
  • compositions comprising a compound of any of the preceding Embodiments, as well as any other embodiments described herein, and at least one pharmaceutically or veterinarily acceptable carrier or diluent, said composition further comprising at least one additional biologically active compound or agent.
  • Embodiments of the invention also include an anthelmintic composition
  • an anthelmintic composition comprising a mixture of a compound of Formula 1 (including all stereoisomers) or an N-oxide or salt thereof and at least one other anthelmintic (e.g., at least one other anthelmintic having a different site of action).
  • Embodiments of the invention also include a method for treating an animal, in need of such treatment, for infection by helminths which comprises admininistration enterally, for example orally, parenterally, for example by injection, (including subcutaneous ly, intramuscularly or intravenously) or topically, to the animal, of a parasiticdally effective amount of a compound of Formula 1 (including all stereoisomers) or an N-oxide, or a pharmaceutically or veterinarily acceptable salt or a composition comprising it.
  • helminths which comprises admininistration enterally, for example orally, parenterally, for example by injection, (including subcutaneous ly, intramuscularly or intravenously) or topically, to the animal, of a parasiticdally effective amount of a compound of Formula 1 (including all stereoisomers) or an N-oxide, or a pharmaceutically or veterinarily acceptable salt or a composition comprising it.
  • Embodiments of the invention also include a method for treating an animal in need of such treatment, for infection by helminths wherein the animal is a human.
  • Embodiments of the invention also include a method for treating an animal in need of such treatment, for infection by helminths wherein the animal is non-human.
  • Embodiments of the invention also include a method for treating an animal in need of such treatment, for infection by helminths wherein the helminth is a nematode.
  • Embodiments of the invention also include a method for controlling parasitic worms comprising admininistration enterally for example orally, parenterally, for example by injection, (including subcutaneously, intramuscularly or intravenously or topically, of a parasiticidally effective amount of Formula 1 (including all stereoisomers) or an N-oxide or salt thereof (e.g., as a composition described herein)
  • a parasiticidally effective amount of Formula 1 including all stereoisomers
  • an N-oxide or salt thereof e.g., as a composition described herein
  • helminths comprising contacting the helminth or its environment with a parasiticidally effective amount of a compound of Formula 1, an N- oxide, or a salt thereof, (e.g., as a composition described herein), provided that the methods are not methods of medical treatment of a human or animal body by therapy.
  • Embodiments of the invention also include a compound of Formula 1 (including all stereoisomers) or an N-oxide or salt thereof, or any of the preceding Embodiments for use as an animal medicament, or more particularly a parasiticidal animal medicament.
  • the medicament may be in any art recognized dosage forms including oral, topical, parenteral or subcutaneous dosage forms.
  • Embodiments of the invention also include a compound of Formula 1 (including all stereoisomers) or an N-oxide or salt thereof, or any of the preceding Embodiments for the manufacture of a medicament for the protection of an animal from a helminth.
  • the medicament may be in any art recognized dosage forms including oral, topical, parenteral or subcutaneous dosage forms.
  • Embodiments of the invention also include a compound of Formula 1 (including all stereoisomers) or an N-oxide or salt thereof, or any of the preceding Embodiments, packaged and presented for the protection of an animal from a helminth.
  • the compounds of the invention may be packaged and presented as in any dosage form suitable for the mode of intended administration..
  • Embodiments of the invention also include a process for manufacturing a composition for treating an animal for an infection by helminthes, such composition characterized as comprising a compound of Formula 1 (including all stereoisomers) or an N-oxide or salt thereof, or any of the preceding Embodiments, admixed with at least one carrier or diluent.
  • the compounds of the invention may be packaged and presented in any art recognized dosage forms including oral, topical, parenteral or subcutaneous dosage forms.
  • One or more of the following methods and variations as described in Schemes 1-6 can be used to prepare the compounds of Formulae 1.
  • Compounds of Formula 1 can be prepared by the reaction of 4-pyridinemethanamines and their derivatives (e.g. pyrimidines, pyridazines, quinolines etc) of Formula 2 with aryl or heteroaryl sulfonylchlorides of Formula 3, typically in the presence of base, as shown in Scheme 1.
  • the reaction can be carried out at temperatures ranging from 0 °C to the reflux temperature of the solvent, preferably in the range of room temperature to 100 °C.
  • Typical solvents include aliphatic and aromatic hydrocarbons such as hexane or toluene; ethers such as diethyl and diisopropyl ether, tetrahydrofuran or dioxane; esters such as ethyl acetate; nitriles such as acetonitrile; ketones such as acetone or methyl ethyl ketone; amides such as dimethylformamide and dimethylacetamide; and halogenated hydrocarbons such as methylene chloride and chloroform.
  • aliphatic and aromatic hydrocarbons such as hexane or toluene
  • ethers such as diethyl and diisopropyl ether, tetrahydrofuran or dioxane
  • esters such as ethyl acetate
  • nitriles such as acetonitrile
  • ketones such as acetone or methyl ethyl ketone
  • Typical bases for the reaction include pyridine and substituted pyridines such as the picoline isomers, trialkylamines such as triethyl, tributyl diisopropylethylamine, and metal carbonates such as sodium or potassium carbonate.
  • Compounds of Formula 1, where R 1 is alkyl, acyl, and alkoxycarbonyl may be prepared by the reaction of quinoline sulfonamides of Formula 4 with various alkylating or acylating reagents, such as R l -X, in the presence of a base, as shown in Scheme 2.
  • Typical bases include pyridine and substituted pyridines such as the picoline isomers; trialkylamines such as triethyl, tributyl or diisopropylethylamine; hydrides such as sodium hydride; and carbonates such as potassium or cesium carbonate.
  • Typical solvents include acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, ethyl acetate, and toluene.
  • the reaction is typically run at room temperature but may be carried out at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • intermediate sulfonyl chlorides of Formula 3 are known or are available from commercial sources. Intermediate sulfonyl chlorides of Formula 3 may also be prepared by a wide variety of well known methods. One particularly useful method is by the diazotization and chlorosulfonation of aromatic and heteroaromatic amines of Formula 6. These methods and procedures are extensively documented in the chemical literature. A typical set of conditions includes sodium nitrite, copper chloride, and sulfur dioxide in a mixture of acetic and hydrochloric acid. The amines of Formula 6 are readily available from a variety of sources with the reduction of aromatic and heteroaromatic nitro compounds of Formula 5 being very typical.
  • An alternative useful procedure for the preparation of the intermediate sulfonyl chlorides of Formula 3 is by the oxidative chlorination of sulfides to the corresponding sulfonyl chlorides as shown in Scheme 4.
  • Treatment of sulfides of Formula 8 with chlorinating reagents including chlorine, N-chlorosuccinimide, and sodium hypochlorite provides the corresponding sulfonyl chlorides of Formula 3 under a wide range of conditions (see e.g. World Patent Publication WO2007/147762, Tetrahedron Lett. 2010, 51 418-421).
  • the intermediate sulfides 8 are available from aryl or heterocyclic halides of Formula 7 by displacement with benzyl mercaptan by a variety of known literature procedures.
  • the R 1 groups of Formula 2 may be introduced by reductive amination, or alkylation reactions.
  • the oximes of Formula 10 are available from the corresponding aldehydes of Formula 9 by treatment with hydroxylamine. Many of the aldehydes of Formula 9 are known in the literature.
  • the unsubstituted derivatives such as 4-pyridinecarboxaldehyde, 4- pyrimidinecarboxaldehyde, and 4-pyridazinecarboxaldehyde as well as numerous substituted analogs are commercially available.
  • the quinolines of Formula 2a shown in Scheme 6 and the derived sulfonamides of Formula la are a preferred subset.
  • the 4-quinolinemethanamines 2a can be made by procedures similar to those of Scheme 5 including by the reduction of the oximes with palladium and ammonium formate in methanol. Other methods for this reduction include: J. Org. Chem. 1989, 54, 1731-5 and European Patent Publication EP 1571150.
  • Quinolines of Formula 2a can also be prepared from nitriles of Formula 14 by catalytic hydrogenation.
  • references applicable to this transformation include the following: World Patent Publication WO 2008/007211, World Patent Publication WO 2008/090434, World Patent Publication WO 2007/104726, and World Patent Publication WO 2008/079292.
  • the nitriles 14 can be prepared from the corresponding bromo derivatives 13 by reaction with a cyanide source. See for example Organic Letters 2007, 9, 5525-5528; J. Med. Chem. 1992, 35, 2761-8; Bioorganic & Medicinal Chemistry Letters 2005, 15, 4520-4525.
  • Step A Preparation of 4-quinolinecarboxaldehyde oxime
  • the filtrate was then concentrated under reduced pressure to approximately 20 mL and then diluted with 300 mL of methylene chloride and washed with a saturated aqueous sodium carbonate solution (200 mL).
  • the methylene chloride phase was dried over magnesium sulfate and concentrated under reduced pressure to obtain an oil.
  • the oil was chromatographed on silica gel using a gradient of ethyl acetate :methanol (9: 1) to pure methanol to provide 6.0 g of the title compound.
  • Step C Preparation of N-(4-quinolinylmethyl)-5-[5-(trifluorometyl)-3-isoxazolyl]-2- thiophenesulfonamide
  • reaction mixture was treated with 4 mL of triethylamine and allowed to stir for 10 minutes.
  • the reaction mixture was then cooled to 0 °C and a solution of 4-iodobenzenesulfonyl chloride (2.6 g, 8.9 mmol) in 10 mL of diethyl ether was added dropwise.
  • the reaction mixture was allowed to warm up to room temperature and stirring was continued for 18 hours.
  • the reaction mixture was added to 100 mL of ethyl acetate and washed once with 100 mL of water.
  • the phases were separated and the organic phase was dried over magnesium sulfate, filtered, and concentrated under vacuum.
  • the residue was chromatographed on a silica gel column (50% ethyl acetate/hexanes as eluent) to provide the title compound as solid (98 mg).
  • Step C Preparation of 2',4'-dichloro-N-(4-quinolinylmethyl)-[l, -biphenyl]-4- sulfonamide
  • # is the point of attachment of the 1 group to the J group in Formula 1.
  • the present disclosure also includes Tables 2 A through 14 A, each of which is constructed the same as Table 1A above except that the row heading in Table 1A (i.e. "Q 1 is Q-1.") below the Markush structure is replaced with the respective row heading shown below.
  • Table 2A the row heading is "Q 1 is Q-2 is as defined in Table 1A above.
  • the first entry in Table IB specifically discloses N-(4-quinolinylmethyl)[l, - biphenyl]-3 -sulfonamide .
  • Table 2B is identical to Table 2A, except that the chemical structure in the Table 2B heading is replaced with the following structure:
  • the first compound in Table 2B is the structure shown immediately above wherein J is J-l, the attachment is the 2 position and (R 1 ) y is not present (y is 0).
  • Table 2C is identical to Table 2A, except that the chemical structure in the Table 2C heading is replaced with the following structure:
  • the first compound in Table 2C is the structure shown immediately above wherein J is J-l, the attachment is the 2 position and (R 1 ) y is not present (y is 0).
  • Table 2D is identical to Table 2A, except that the chemical structure in the Table 2D heading is replaced with the following structure:
  • the first compound in Table 2D is the structure shown immediately above wherein J is J-l, the attachment is the 2 position and (R 1 ) y is not present (y is 0).
  • Table 2E is identical to Table 2A, except that the chemical structure in the Table 2E heading is replaced with the following structure:
  • the first compound in Table 2E is the structure shown immediately above wherein J is J-1, the attachment is the 2 position and (R 14 ) y is not present (y is 0).
  • Table 2F is identical to Table 2A, except that the chemical structure in the Table 2F heading is replaced with the following structure:
  • the first compound in Table 2F is the structure shown immediately above wherein J is J-1, the attachment is the 2 position and (R 14 ) y is not present (y is 0).
  • a compound of this invention will generally be used as a helminth control active ingredient in a composition, i.e. formulation, with at least one additional component selected from the pharmaceutically or veterinarily acceptable carriers or diluents.
  • a composition i.e. formulation
  • additional component selected from the pharmaceutically or veterinarily acceptable carriers or diluents.
  • the formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of administration and factors such as the type of animal to be treated.
  • the compounds of Formula 1 are preferably employed in unmodified form or preferably together with the adjuvants conventionally used in the art of pharmaceutical or veterinary formulation and may therefore be processed in a known manner to give, for example, emulsifiable concentrates, directly dilutable solutions, dilute emulsions, soluble powders, granules or microencapsulations in polymeric substances.
  • the methods of application are selected in accordance with the intended objectives and the prevailing circumstances.
  • veterinary sector applications in the veterinary sector are by conventional means such as by enteral administration in the form of, for example, tablets including effervescent tablets, capsules, micro-capsules, drinks, drenching preparations (solutions, emulsions, suspensions), granulates, pastes, powders, boli, food additives or suppositories; or by parenteral administration, such as by injection (including intramuscular, subcutaneous, intravenous, intraperitoneal) or implants; by nasal administration; by topical administration, for example, in the form of immersion or dipping, spraying, washing, coating with powder, or application to a small area of the animal via a pour-on formulations, and through articles such as neck collars, ear tags, tail bands, limb bands or halters which comprise compounds or compositions of the present invention.
  • enteral administration in the form of, for example, tablets including effervescent tablets, capsules, micro-capsules, drinks, drenching preparations (solutions, emulsions,
  • the compounds of the present invention may be administered in a controlled release form, e.g., in a subcutaneous slow release formulation.
  • the formulation i.e. the agents, preparations or compositions containing the active ingredient of Formula 1, or combinations of these active ingredients with other active ingredients, and optionally a solid or liquid adjuvant, are produced in a manner known in the art, for example by intimately mixing and/or grinding the active ingredients with spreading compositions, for example with solvents, solid carriers, and optionally surface-active compounds (surfactants).
  • spreading compositions for example with solvents, solid carriers, and optionally surface-active compounds (surfactants).
  • the solvents in question may be: alcohols, such as ethanol, propanol or butanol, and glycols and their ethers and esters, such as propylene glycol, dipropylene glycol ether, ethylene glycol, ethylene glycol monomethyl or -ethyl ether, ketones, such as cyclohexanone, isophorone or diacetanol alcohol, strong polar solvents, such as N-methyl-2- pyrrolidone, dimethyl sulfoxide or dimethylformamide, or water, vegetable oils, such as rape, castor, coconut, or soybean oil, and also, if appropriate, silicone oils.
  • alcohols such as ethanol, propanol or butanol
  • glycols and their ethers and esters such as propylene glycol, dipropylene glycol ether, ethylene glycol, ethylene glycol monomethyl or -ethyl ether, ketones, such as cyclohexanone, isophorone or
  • a compound of the present invention 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 the present invention may also be formulated for bolus injection or continuous infusion.
  • Pharmaceutical and veterinary 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 and veterinary 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.
  • 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 the present invention 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 the present invention 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 the present invention 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.
  • compositions 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 the invention, one or more carriers selected from binders and fillers suitable for oral administration and feed concentrate carriers).
  • a compound of the present invention 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
  • 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.
  • the carriers used are e.g. performance feeds, feed grain or protein concentrates.
  • Such feed concentrates or compositions may contain, apart from the active ingredients, also additives, vitamins, antibiotics, chemotherapeutics or other pesticides, primarily bacteriostats, fungistats, coccidiostats, or even hormone preparations, substances having anabolic action or substances which promote growth, which affect the quality of meat of animals for slaughter or which are beneficial to the organism in another way.
  • the compositions or the active ingredients of Formula 1 contained therein are added directly to feed or to the drinking troughs, then the formulated feed or drink contains the active ingredients preferably in a concentration of ca. 0.0005 to 0.02 % by weight (5-200 ppm).
  • 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.
  • Formulations for topical administration are typically in the form of a powder, cream, suspension, spray, emulsion, foam, paste, aerosol, ointment, salve or gel. More typically a topical formulation is a water-soluble solution, which can be in the form of a concentrate that is diluted before use.
  • Parasiticidal compositions suitable for topical administration typically comprise a compound of the present invention and one or more topically suitable carriers. In applications of a parasiticidal composition topically to the exterior of an animal as a line or spot (i.e. "spot-on" treatment), the active ingredient migrates over the surface of the animal to cover most or all of its external surface area.
  • formulations for topical localized administration often comprise at least one organic solvent to facilitate transport of the active ingredient over the skin and/or penetration into the epidermis of the animal.
  • Carriers in such formulations include propylene glycol, paraffins, aromatics, esters such as isopropyl myristate, glycol ethers, alcohols such as ethanol, n-propanol, 2-octyl dodecanol or oleyl alcohol; solutions in esters of monocarboxylic acids, such as isopropyl myristate, isopropyl palmitate, lauric acid oxalic ester, oleic acid oleyl ester, oleic acid decyl ester, hexyl laurate, oleyl oleate, decyl oleate, caproic acid esters of saturated fatty alcohols of chain length C ⁇ - Ci ; solutions of esters of dicarboxylic acids, such as dibutyl phthalate, diis
  • the pour-on or spot-on method consists in applying the parasiticidal composition to a specific location of the skin or coat, advantageously to the neck or backbone of the animal. This takes place by applying a swab or spray of the pour-on or spot-on formulation to a relatively small area of the coat, from where the active substance is dispersed almost automatically over wide areas of the fur owing to the spreading nature of the components in the formulation and assisted by the animal's movements.
  • the pour-on formulation is typically applied by pouring in one or several lines or in a spot-on the dorsal midline (back) or shoulder of an animal. More typically, the formulation is applied by pouring it along the back of the animal, following the spine.
  • the formulation can also be applied to the animal by other conventional methods, including wiping an impregnated material over at least a small area of the animal, or applying it using a commercially available applicator, by means of a syringe, by spraying or by using a spray race.
  • Pour-on or spot-on formulations suitably contain carriers, which promote rapid dispersement over the skin surface or in the coat of the host animal, and are generally regarded as spreading oils.
  • Suitable carriers are, for example, oily solutions; alcoholic and isopropanolic solutions such as solutions of 2-octyldodecanol or oleyl alcohol; solutions in esters of monocarboxylic acids, such as isopropyl myristate, isopropyl palmitate, lauric acid oxalate, oleic acid oleyl ester, oleic acid decyl ester, hexyllaurate, oleyl oleate, decyl oleate, capric acid esters of saturated fat alcohols of chain length C i 2-Ci ; solutions of esters of dicarboxylic acids, such as dibutyl phthalate, diisopropyl isophthalate, adipic acid diisopropyl ester, di-n-butyl adipate or also solutions of esters of aliphatic acids, for example glycols.
  • esters of monocarboxylic acids such as isopropyl my
  • a dispersing agent such as one known from the pharmaceutical or cosmetic industry.
  • examples are 2-pyrrolidone, 2-(N-alkyl)pyrrolidone, acetone, polyethylene glycol and the ethers and esters thereof, propylene glycol or synthetic triglycerides.
  • the oily solutions include, for example, vegetable oils such as olive oil, groundnut oil, sesame oil, pine oil, linseed oil or castor oil.
  • the vegetable oils may also be present in epoxidised form. Paraffins and silicone oils may also be used.
  • a pour-on or spot-on formulation generally contains 1 to 20 % by weight of a compound of Formula 1, 0.1 to 50 % by weight of dispersing agent and 45 to 98.9 % by weight of solvent.
  • the pour-on or spot-on method is especially advantageous for use on herd animals such as cattle, horses, sheep or pigs, in which it is difficult or time-consuming to treat all the animals orally or by injection. Because of its simplicity, this method can of course also be used for all other animals, including individual domestic animals or pets, and is greatly favoured by the keepers of the animals, as it can often be carried out without the specialist presence of the veterinarian.
  • the formulations of this invention typically include an antioxidant, such as BHT (butylated hydroxytoluene).
  • BHT butylated hydroxytoluene
  • the antioxidant is generally present in amounts of at 0.1-5% (wt/vol).
  • compositions may also contain further additives, such as stabilisers, e.g. where appropriate epoxidised vegetable oils (epoxidised coconut oil, rapeseed oil, or soybean oil); antifoams, e.g. silicone oil, preservatives (e.g. methylparaben and propylparaben), viscosity regulators, thickners (e.g. carbomers, corn starch, polyethylene, polyvinylpyrrolidones, edible clay or xanthan gum) binders and tackifiers or other active ingredients to achieve special effects.
  • stabilisers e.g. where appropriate epoxidised vegetable oils (epoxidised coconut oil, rapeseed oil, or soybean oil); antifoams, e.g. silicone oil, preservatives (e.g. methylparaben and propylparaben), viscosity regulators, thickners (e.g. carbomers, corn starch, polyethylene, polyvinylpyrrol
  • the anthelmintic compositions according to the invention contain 0.1 to 99 % by weight, especially 0.1 to 95 % by weight of active ingredient of Formula 1, 99.9 to 1 % by weight, especially 99.8 to 5 % by weight of a solid or liquid admixture, including 0 to 25 % by weight, especially 0.1 to 25 % by weight of a surfactant.
  • the active ingredients of Formula 1 can be used in all of their steric configurations or in mixtures thereof.
  • the invention also includes a method of prophylactically protecting warm-blooded animals, especially productive -livestock, domestic animals and pets, against parasitic helminths, which is characterised in that the active ingredients of the formula or the active ingredient formulations prepared therefrom are administered to the animals as an additive to the feed, or to the drinks or also in solid or liquid form, orally or by injection or parenterally.
  • the invention also includes the compounds of Formula 1 according to the invention for usage in one of the said methods.
  • the active ingredient is dissolved in methylene chloride, sprayed onto the carrier and the solvent subsequently concentrated by evaporation under vacuum. Granulates of this kind can be mixed with the animal feed.
  • the finely ground active ingredient is evenly applied in a mixer to the kaolin which has been moistened with polyethylene glycol. In this way, dust-free coated granules are obtained.
  • Methyl cellulose is stirred into water. After the material has swollen, silicic acid is stirred in and the mixture homogeneously suspended. The active ingredient and the corn starch are mixed. The aqueous suspension is worked into this mixture and kneaded to a dough. The resulting mass is granulated through a 12 M sieve and dried. 2) All 4 excipients are mixed thoroughly.
  • the active ingredient is dissolved in part of the oil while stirring and, if required, with gentle heating, then after cooling made up to the desired volume and sterile-filtered through a suitable membrane filter with a pore size of 0.22 ⁇ .
  • “ad” means enough of this component is added to a mixture of the other components to make a specified total volume (100 mL in this case) for the formulation.
  • the active ingredient is dissolved in part of the solvent while stirring, made up to the desired volume and sterile-filtered through a suitable membrane filter with a pore size of 0.22 ⁇ .
  • the active ingredient is dissolved in the solvents and the surfactant, and made up with water to the desired volume.
  • the solution is then sterile-filtered through a suitable membrane filter with a pore size of 0.22 ⁇ .
  • the aqueous systems may also preferably be used for oral and/or intraruminal application.
  • a compound of Formula 1, an N-oxide, or salt thereof is administered in a parasiticidally effective amount to an animal to be protected from helminth parasite pests.
  • a parasiticidally effective amount is the amount of active ingredient needed to achieve an observable effect diminishing the occurrence or activity of the target helminth parasite pest.
  • the parasitically effective dose can vary in accordance with the mode and frequency of administration for the various compounds and compositions of the present invention, the desired parasitical effect and duration, the target helminth 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.
  • the daily dosage of a compound of the present invention typically ranges from about 0.01 mg/kg to about 100 mg/kg, more typically from about 0.5 mg/kg to about 100 mg/kg, of animal body weight.
  • dips and sprays typically contain from about 0.5 ppm to about 5000 ppm, more typically from about 1 ppm to about 3000 ppm, of a compound of the present invention.
  • Compounds of the present invention have activity on members of the classes Nematoda (roundworms), Trematoda (flukes), Acanthocephala and Cestoda (tapeworms).
  • Important helminths are those that cause serious diseases of mammals and poultry, e.g. sheep, pigs, goats, cattle, horses, donkeys, dogs, cats, guinea-pigs and birds.
  • Typical nematodes of this indication are: Haemonchus, Trichostrongylus, Teladorsagia, Dirofilaria, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostonum, Oesophagostonum, Charbertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris.
  • the trematodes include the family of Fasciolideae, especially Fasciola hepatica.
  • Parasites of the families Filariidae and Setariidae may be found in the internal cell tissue and in the organs, e.g. the heart, the blood vessels, the lymph vessels and the subcutaneous tissue.
  • a notable parasite is the heartworm of the dog, Dirofilaria immitis.
  • Important pests of the class Cestoda include, the families Anoplocephalidae, especially of the genus Moniezia, in particular M expansa; Mesocestoidae, especially of the genus Mesocestoides, in particular M.
  • Trilepidide especially Dipylidium caninum, Joyeuxiella spp., in particular Joyeuxiella pasquali, and Diplopylidium spp.
  • Taeniidae especially Taenia pisiformis, Taenia cervi, Taenia ovis, Taneia hydatigena, Taenia multiceps, Taenia taeniaeformis, Taenia serialis, and Echinocuccus spp., most preferably Taneia hydatigena, Taenia ovis, Taenia multiceps, Taenia serialis; Echinocuccus granulosus and Echinococcus multilocularis, as well as Multiceps multiceps.
  • Another notable parasite is Anoplocephala perfoliata in horses.
  • the compounds of the present invention may be suitable for the control of human pathogenic parasites.
  • typical representatives that appear in the digestive tract are those of the species Ancylostoma, Necator, Ascaris, Strongy hides, Trichinella, Capillaria, Trichuris and Enterobius.
  • the compounds of the present invention may also be effective against parasites of the species Wuchereria, Brugia, Onchocerca and Loa from the family of Filariidae, which appear in the blood, in the tissue and in various organs, and also against Dracunculus and parasites of the species Strongyloides and Trichinella, which infect the gastrointestinal tract in particular.
  • Compounds and compositions of the present invention are suitable for combating parasites that infest animal subjects including those in the wild, livestock and agricultural working animals such as cattle, sheep, goats, llamas, horses, pigs, donkeys, camels, bison, buffalos, deer, moose, elk, antelope, rabbits, hens, turkeys, ducks and geese (e.g., raised for meat, milk, butter, eggs, fur, leather, feathers and/or wool).
  • livestock and agricultural working animals such as cattle, sheep, goats, llamas, horses, pigs, donkeys, camels, bison, buffalos, deer, moose, elk, antelope, rabbits, hens, turkeys, ducks and geese (e.g., raised for meat, milk, butter, eggs, fur, leather, feathers and/or wool).
  • Compounds and compositions of the present invention are suitable for combating parasites that infest companion animals and pets (e.g., dogs, cats and pet birds), research and experimental animals (e.g., hamsters, guinea pigs, rats and mice), as well as animals raised for/in zoos, wild habitats (e.g., giraffes, zebras, rhinoceros and gazelles) and/or circuses.
  • companion animals and pets e.g., dogs, cats and pet birds
  • research and experimental animals e.g., hamsters, guinea pigs, rats and mice
  • animals raised for/in zoos e.g., wild habitats, e.g., giraffes, zebras, rhinoceros and gazelles
  • circuses e.g., giraffes, zebras, rhinoceros and gazelles
  • the animal is preferably a vertebrate, and more preferably a mammal or avian.
  • 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, bison, 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
  • 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).
  • 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 e.g.,
  • Birds treated or protected by the inventive compounds 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.
  • 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
  • Psittacines such as parakeets, macaws, and parrots raised for the pet or collector market, among others.
  • a further essential aspect of the present invention relates to combination preparations for the control of parasites on warm-blooded animals, characterised in that they contain, in addition to a compound of Formula 1, at least one further active ingredient having the same or different sphere of activity and at least one physiologically acceptable carrier.
  • the present invention is not restricted to two-fold combinations.
  • the compounds of Formula 1 according to the invention may be used alone or in combination with other biocides. They may be combined with pesticides having the same sphere of activity e.g. to increase activity, or with substances having another sphere of activity e.g. to broaden the range of activity. It can also be sensible to add so-called repellents if the formulation is applied externally. They can also be used in combination with antibacterial compositions. Compounds which attack the juvenile stages of parasites may be very advantageous to add to those that function primarily as adulticides. In this way, the greatest range of those parasites that produce great economic damage will be covered. Moreover, this action will contribute substantially to avoiding the formation of resistance. Many combinations may also lead to synergistic effects, i.e. the total amount of active ingredient can be reduced, which is desirable from an ecological point of view. Preferred groups of combination partners and especially preferred combination partners are named in the following, whereby combinations may contain one or more of these partners in addition to a compound of Formula 1.
  • anthelmintics such as, for example, macrocyclic lactones including but not limited to avermectins and derivatives thereof (e.g., ivermectin, moxidectin, milbemycin), benzimidazoles (e.g., albendazole, triclabendazole, cambendazole, fenbendazole, flubendazole,, mebendazole, oxfendazole, oxibendazole, parbendazole), salicylanilides (e.g., closantel, oxyclozanide), substituted phenols (e.g., nitroxynil), tetrahydropyrimidines (e.g., pyrantel pamoate, oxantel, morantel), imidazothiazoles (e.g., levamisole, tetramizole) and praziquante
  • macrocyclic lactones including but not limited to a
  • Additonal art-known anthelmintics include analogs and derivatives of the paraherquamide/marcfortine class, nitroscanate, and cyclic depsipeptides, e.g., emodepside.
  • biologically active compounds or agents useful in the compositions of the present invention selected from the antiparasitic class of avermectin compounds mentioned above.
  • the avermectin family of compounds is a series of very potent antiparasitic agents known to be useful against a broad spectrum of endoparasites and ectoparasites in mammals.
  • a notable compound in this class 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 ⁇ .
  • avermectins are abamectin, doramectin, dimadectin, latidectin, lepimectin, selamectin, milbemycin and derivatives thereof including but not limited to milbemectin, moxidectin, nemadectin and milbemycin D, emamectin, and eprinomectin.
  • Eprinomectin is chemically known as 4"-epi-acetylamino-4"-deoxy-avermectin B ⁇ . 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 ecto- parasites while also leaving minimal residues in meat and milk. It has the additional advantage of being highly potent when delivered topically.
  • nodulisporic acids and their derivatives known in the art as a class of compounds that are potent endo- and ectopantiparasitic agents.
  • the isolation and purification of three naturally occurring nodulisporic acids are disclosed in US 5,399,582.
  • Derivatives of these compounds are described in WO 96/29073 and US Patent Nos. 5,945,317, 5,962,499, 5,834,260, 6,399,796, 6,221,894, 6,136,838, 5,595,991, 5,299,582, and 5,614,546.
  • composition of the present invention optionally comprises combinations of one or more of the following antiparasite compounds: imidazo[l,2-b]pyridazine compounds as described by U.S. application Ser. No. 11/019,597, filed on Dec. 22, 2004, and published on Aug. 18, 2005 as U.S. 2005-0182059A1; trifluoromethanesulfonanilide oxime ether derivatives, as described by U.S. application Ser. No. 11/231,423, filed on Sep. 21, 2005, now U.S.
  • Patent 7,312,248 N-[(phenyloxy)phenyl]-l,l,l-trifluoromethanesulfonamide and N-[(phenylsulfanyl)phenyl]-l,l,l-trifluoromethanesulfonamide derivatives, as described by U.S. Provisional Application Ser. No. 60/688,898, filed on Jun. 9, 2005, and published as US 2006-0281695A1 on Dec. 14, 2006.
  • compositions of the present invention can also further comprise a flukicide.
  • Suitable flukicides include, for example, triclabendazole, fenbendazole, albendazole, clorsulon and oxibendazole. It will be appreciated that the above combinations can further include combinations of antibiotic, antiparasitic and anti-fluke active compounds.
  • such anti-infectives include one or more antibiotics that are optionally co-administered during treatment using the inventive compounds or 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.
  • chloramphenicol analogs such as florfenicol, also known as D- (threo)- 1 -(4-methylsulfonylphenyl)-2-dichloroacetamido-3-fluoro- 1 -propanol.
  • chloramphenicol analogs include thiamphenicol and D-(threo)-l-(4-methylsulfonyphenyl)-2- difluoroacetamido-3-fluoro-l-propanol.
  • 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 (e.g., U.S. Patent Application Publication No.
  • antibiotics for use in the present invention are macrolide antibiotics such as tilmicosin.and tulathromycin.
  • 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. 6,514,945, U.S. 6,472,371, U.S. 6,270,768, U.S. 6,437,151, U.S. 6,271,255, U.S. 6,239,112, U.S. 5,958,888, U.S. 6,339,063 and U.S. 6,054,434.
  • antibiotics may include ⁇ -lactams such as cephalosporins, e.g., ceftiofur, cefquinome, etc., and penicillins, e.g., penicillin, ampicillin, amoxicillin, or a combination of amoxicillin with clavulanic acid or other beta lactamase inhibitors.
  • cephalosporins e.g., ceftiofur, cefquinome, etc.
  • penicillins e.g., penicillin, ampicillin, amoxicillin, or a combination of amoxicillin with clavulanic acid or other beta lactamase inhibitors.
  • Another useful antibiotic class includes the fluoroquinolones, such as, for example, enrofloxacin, danofloxacin, difloxacin, orbifloxacin and marbofloxacin.
  • antibiotics include the tetracyclines, particularly chlortetracycline and oxytetracycline.
  • Cmpd means Compound
  • CF 3 means trifluoromethyl
  • t is tertiary
  • s is secondary
  • n normal
  • i is iso
  • c is cyclo
  • Me is methyl
  • Et is ethyl
  • Pr is propyl
  • z ' -Pr is isopropyl
  • t-Bu is tert-bvXy ⁇
  • Ph is phenyl
  • OMe methoxy
  • OEt is ethoxy
  • SMe is methylthio
  • CN is cyano
  • N02 is nitro
  • Me2NCO is dimethyl amide.
  • the wavy line in the Index Tables indicates the point of attachment of each group to Formula 1.
  • the naming convention used for Qi-J substituents is for example (compound 1): 4-(2,4-dichlorophenyl)phenyl indicates that J is a phenyl group with two chloro substituents in the 2 and 4 positions, bonded to the Q 1 phenyl ring in the Q 1 ring's 4 position. The Q 1 phenyl ring is bonded to rest of Formula 1 in the 1 position.
  • An alternative nomenclature for the Q!-J substituents is for example (compound 1): 2',4'-dichloro[l, -biphenyl]-4-yl.
  • a NMR data are in ppm downfield from tetramethylsilane.
  • CDCI3 solution unless indicated otherwise.
  • DMSO-dg is CD3S(0)CD3.
  • Couplings are designated by (s)-singlet, (d)-doublet, (t)-triplet, (m) -multiple t, (dd)-doublet of doublets, (br s)-broad singlet.
  • Tests demonstrate the control efficacy of compounds of this invention on specific parasitic pests.
  • the pest control protection afforded by the compounds is not limited, however, to these species.
  • Compound numbers refer to compounds in Index Tables A-F.
  • test compound was solubilized in culture media (Earle's Balanced Salt Solution) containing Haemonchus contortus eggs to obtain a final test compound concentration of 2.0 ppm.
  • culture media Earle's Balanced Salt Solution
  • the test unit was evaluated for mortality 120 hours later after which the eggs had hatched and had advanced to the L3 stage.

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Abstract

Disclosed is a method for treating an animal for infection by helmintha which comprises administering to the animal a parasiticidally effective anount of a compound of Formula (1), or a pharmaceutically or veterinarily acceptable salt or a composition comprising it wherein R1, R2, R3, Q1 and J are as defined in the disclosure.

Description

TITLE
SULFONAMIDE ANTHELMINTICS
FIELD OF THE INVENTION
This invention relates to certain sulfonamide compounds, their N-oxides, salts and their compositions suitable for animal health uses and methods of their use for treating helminth infections in animals.
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 need continues for new compounds that are more effective, less costly, less toxic or have different sites of action to control animal parasites.
World Patent Application Publications WO 2005/033081 and WO 2007/104726 disclose sulfonamide compounds for control of insects and plant diseases.
The method of the present invention is not disclosed in these publications.
SUMMARY OF THE INVENTION
This invention is directed to the method for treating an animal in need of such treatment for infection by helminths which comprises orally, topically, parenterally or subcutaneously administering to the animal a parasiticidally effective amount of a compound of Formula 1, or a pharmaceutically or veterinarily acceptable salt or a composition comprising it:
Figure imgf000002_0001
wherein
R1 is hydrogen, C 1-C4 alkyl, C2-C6 alkylcarbonyl or C2-Cg alkoxycarbonyl;
R2 and R3 are each independently hydrogen, halogen, cyano, hydroxyl, amino, nitro, CHO, SF5, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or -Q, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, Cz Cg cycloalkylalkyl or C5-C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and S(O)2NR10Rn; or G; or
R2 and R3 are taken together with the carbons to which they are attached to form a 5- to 6-membered carbocyclic or heterocyclic ring optionally substituted with up to 3 substituents independently selected from R a on carbon atom ring members and R4^ on nitrogen atom ring members;
G is a phenyl ring or an 8- to 10-membered carbocyclic bicyclic ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R5a; or
G is a 5- to 7-membered heterocyclic ring or an 8- to 10-membered heterocyclic
bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R5a on carbon atom ring members and R5^ on nitrogen atom ring members;
X is CR4c or N;
Y is CR4d or N;
Q1 is 3- to 7-membered carbocyclic ring or an 8- to 10-membered carbocyclic bicyclic ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R13a; or
Q1 is a 5- to 7-membered heterocyclic ring or an 8- to 10-membered heterocyclic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2
O, up to 2 S and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R13a on carbon atom ring members and R13^ on nitrogen atom ring members;
J is hydrogen; or phenyl or naphthalenyl each optionally substituted with up to 5
substituents independently selected from R1 a; or
J is a 5- to 7-membered heterocyclic ring or an 8- to 10-membered heterocyclic
bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R1 a on carbon atom ring members and
R1 ^ on nitrogen atom ring members; or J is L-Q2;
L is O, S, SO, S02, NR15, (CH2)n, OCH2, or CH20;
Q2 is a 3- to 7-membered carbocyclic ring or an 8- to 10-membered carbocyclic
bicyclic ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R16a; or
Q2 is a 3- to 7-membered heterocyclic ring or an 8- to 10-membered heterocyclic
bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R16a on carbon atom ring members and R16b on nitrogen atom ring members;
each R4a is independently halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF5, OR6, NR7aR7b c(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or C^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-C7 cycloalkyl, Cz Cg cycloalkylalkyl or C5-C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and
S(O)2NR10Rn; or G;
R4b is cyano, -CHO, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, Cz Cg cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and S(O)2NR10Rn; or G;
R4c and R4^ are each independently hydrogen, halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF5, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, Cz Cg cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and S(O)2NR10Rn; or G;
each R5a is independently halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF5, OR6, NR7aR7b c(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or C^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3~C7 cycloalkyl, Cz Cg cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and
S(O)2NR10Rn;
R5b is cyano, -CHO, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or -Q, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and S(O)2NR10Rn;
each R6 is independently hydrogen, C2-Cg alkylcarbonyl, C2-Cg alkoxycarbonyl, C2- C^ alkylaminocarbonyl, C3-C6 dialkylaminocarbonyl, C^-C^ alkylsulfenyl, C^- Cg alkylsulfinyl, C^-Cg alkylsulfonyl, C2-Cg alkylaminosulfonyl or C3-C6 dialkylaminosulfonyl; or C^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl or benzyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, C^-Cg alkoxy, C^-Cg alkylamino, C2- Cg dialkylamino, C2-Cg alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-Cg alkylaminocarbonyl, C3-C6 dialkylaminocarbonyl, C^-C^ alkylsulfenyl, C^-C^ alkylsulfinyl, C^-Cg alkylsulfonyl, C2-Cg alkylaminosulfonyl and C3-C6 dialkylaminosulfonyl; or C3~C7 cycloalkyl, Cz Cg cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylsulfenyl, C1-C4 alkylsulfinyl and C1-C4 alkylsulfonyl;
each R7a is independently hydrogen, C2-Cg alkylcarbonyl, C2-Cg alkoxycarbonyl, C2- C^ alkylaminocarbonyl, C3-C6 dialkylaminocarbonyl, C^-C^ alkylsulfenyl, C^- Cg alkylsulfinyl or C^-Cg alkylsulfonyl, C2-Cg alkylaminosulfonyl or C3-C6 dialkylaminosulfonyl; or C^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl or benzyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, C^-Cg alkoxy, C^-Cg alkylamino, C2- Cg dialkylamino, C2-Cg alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-Cg alkylaminocarbonyl, C3-C6 dialkylaminocarbonyl, C^-C^ alkylsulfenyl, C^-C^ alkylsulfinyl, C^-Cg alkylsulfonyl, C2-Cg alkylaminosulfonyl and C3-C6 dialkylaminosulfonyl; or C3~C7 cycloalkyl, C4~Cg cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylsulfenyl, C1-C4 alkylsulfinyl and C1-C4 alkylsulfonyl; each R7b is independently hydrogen; or C^-Cg alkyl, C2~Cg alkenyl, C2~Cg alkynyl or benzyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, C^-Cg alkoxy, C^-Cg alkylamino, C2~Cg dialkylamino, C2~Cg alkylcarbonyl, C2~Cg alkoxycarbonyl, C2~Cg alkylaminocarbonyl, C3~Cg dialkylaminocarbonyl, C^-Cg alkylsulfenyl, C^-Cg alkylsulfinyl, C^-Cg alkylsulfonyl, C2~Cg alkylaminosulfonyl and C3~Cg dialkylaminosulfonyl;
R8, R9, R10 and R12 are each independently hydrogen; or C^-Cg alkyl, C2~Cg alkenyl, C2~Cg alkynyl, phenyl, benzyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5- C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, -C4 haloalkyl, -C4 alkoxy, C1-C4 haloalkoxy, C2~Cg alkoxycarbonyl, C2~Cg alkylaminocarbonyl, C2~Cg dialkylaminocarbonyl, C1-C4 alkylsulfenyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylsulfenyl, C1-C4
haloalkylsulfinyl and C1-C4 haloalkylsulfenyl;
each R1 1 is independently hydrogen; or C^-Cg alkyl, C2~Cg alkenyl, C2~Cg alkynyl or benzyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, -C4 haloalkyl, C - C4 alkoxy, C1-C4 haloalkoxy, -C4 alkylsulfenyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, -C4 haloalkylsulfenyl, C1-C4 haloalkylsulfinyl and -C4 haloalkylsulfenyl;
each R13a is independently halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF5, OR6, NR7aR7b c(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or C^-Cg alkyl, C2~Cg alkenyl, C2~Cg alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5-C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and
S(O)2NR10Rn;
R13b is cyano, -CHO, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or -Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5-C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and S(O)2NR10Rn;
each R14a is independently halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF5, OR6, NR7aR7b c(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or C^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-C7 cycloalkyl, Cz Cg cycloalkylalkyl or C5-C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and
S(O)2NR10Rn;
R14b is cyano, -CHO, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, Cz Cg cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn,
S(0)pR12 and S(O)2NR10Rn;
R15 is hydrogen, cyano, -CHO, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn,
S(0)pR12 or S(O)2NR10Rn; or Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, Cz Cg cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and S(O)2NR10Rn;
each R16a is independently halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF5, OR6, NR7aR7b c(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or C!-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and
S(O)2NR10Rn; or G;
R16b is cyano, -CHO, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10R1 !, S(0)pR12 or
S(O)2NR10Rn; or -Q, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, Cz Cg cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and S(O)2NR10Rn; or G;
n is 1 or 2; and
p is 0, 1 or 2;
provided that
(a) when J is phenyl and Q1 is phenyl, then each R13a is hydrogen; and
(b) when L is S, SO, S02, NR15, (CH2)n, OCH2, or CH20, then Q2 is other than
phenyl. This invention is also directed to such compounds of Formula 1 (including all stereoisomers), N-oxides, and salts thereof, and compositions containing them and their use for treating an animal in need of such treatment, for infection by helminths.
This invention also provides a composition comprising a parasiticidally effective amount of compounds of Formula 1, an N-oxide, or a salt thereof, and at least one pharmaceutically or veterinarily acceptable carrier or diluent. In one embodiment, this invention also provides a composition comprising a parasiticidally effective amount of a compound of Formula 1, an N-oxide, or a salt thereof, and at least one pharmaceutically or veterinarily acceptable carrier or diluent, said composition further comprising at least one additional biologically active compound or agent.
This invention provides a method for treating an animal in need of such treatment, for infection by helminths which comprises orally, topically, parenterally or subcutaneously administering to the animals a parasiticdally effective amount of a compound of Formula 1, an N-oxide, or a pharmaceutically or veterinarily acceptable salt or a composition comprising it.
DETAILS OF THE INVENTION
As used herein, the terms "comprises", "comprising", "includes", "including", "has", "having", "contains", "containing", "characterized by" or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition, mixture, process or method 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 or method.
The transitional phrase "consisting of excludes any element, step or ingredient not specified. If in the claim, such would close the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith. When the phrase "consisting of appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole.
The transitional phrase "consisting essentially of is used to define a composition or method that includes materials, steps, features, components or elements, in addition to those literally disclosed, provided that these additional materials, steps, features, components or elements do not materially affect the basic and novel characteristic(s) of the claimed invention. The term "consisting essentially of occupies a middle ground between "comprising" and "consisting of. Where applicants have defined an invention or a portion thereof with an open-ended term such as "comprising", it should be readily understood that (unless otherwise stated) the description should be interpreted to also describe such an invention using the terms "consisting essentially of or "consisting of.
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 term "endoparasite" is a parasite that lives inside an animal and "ectoparasite" is a parasite that lives on the surface of an animal.
As referred to in this disclosure, the term "helminths" includes heartworms, roundworms (Nematoda), flukes (Trematoda), Acanthocephala and tapeworms (Cestoda).
Animal health applications include treating an animal in need of such treatment with a compound of the invention to control a present infection with a helminthic parasitic pest by administering a parasiticidally effective amount of a compound of the invention, typically in the form of a composition formulated for veterinary or pharmaceutical use, to the animal. Additionally the invention contemplates the prophalactic treatment of an animal in need of such treatment with a compound of the invention such that infection with a helminthic parasitic pest is prevented lessened in severity(in comparison to a similarly situated animal in an untreated state) by administering a parasiticidally effective amount of a compound of the invention, typically in the form of a composition formulated for veterinary or pharmaceutical use, to the animal to be protected. An animal can be either human (pharmaceutical use) or non-human (veterinary use).
A "parasiticidally effective amount" is the amount of active ingredient needed to achieve an observable effect diminishing the occurrence or activity of the helminthic parasite. Parasiticidal effects typically relate to diminishing the occurrence or activity of the target helminth parasitic pest. Such effects on the pest include necrosis, death, retarded growth, diminished mobility or lessened ability to remain in the host animal, reduced feeding and inhibition of reproduction. These effects on helminth parasite pests provide control (including prevention, reduction or elimination) of parasitic infection of the animal. One skilled in the art will appreciate that the parasiticidally effective dose can vary for the various compounds and compositions of the present invention, the desired parasiticidal effect and duration, the target 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.
"Treating" or "Treatment" as it applies to an infection refers to reducing the severity of any infection which may otherwise occur in the absence of treatment which may include complete control or prevention of such infection. Whithout being bound by theory such treatment may result in "control" of the infection by the inhibition or disruption of the life cycle of a parasitic helminth (including maturation, mortality, feeding reduction and/or mating disruption).
As referred to in the present disclosure the term "antihelmintic" refers to substances (drugs) that are useful in controlling helminthes for example by facilitating the expulsion of parasitic worms (helminthes) from the body of an animal by either stunning or killing them.
An animal is in "need of treatment" if it is presently infected or in danger of infection by helminthes.
"Parenteral" as a mode of administration means taken into the body or administered in a manner other than through the digestive tract, for example by injection.
"Enteral" as a mode of admininstration means take into the body or administered through the digestive tract for example oral administration.
"Topical" as a mode of admininistration means application to the skin. It is understood that topical administration may have systemic effects dependent on the compound to be admininistered and the formulation in which it is contained.
In the above recitations, the term "alkyl", used either alone or in compound words such as "alkylthio" or "haloalkyl" includes straight-chain or branched alkyl 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" also includes moieties comprised of multiple triple bonds such as 2,5-hexadiynyl. "Alkylene" denotes a straight-chain or branched alkanediyl. Examples of "alkylene" include CH2, CH2CH2, CH(CH3), CH2CH2CH2, CH2CH(CH3), and the different butylene isomers. "Alkenylene" denotes a straight-chain or branched alkenediyl containing one olefmic bond. Examples of "alkenylene" include CH=CH, CH2CH=CH, CH=C(CH3) and the different butenylene isomers. "Alkynylene" denotes a straight-chain or branched alkynediyl containing one triple bond. Examples of "alkynylene" include C≡C, CH2C≡C, C≡CCH2, and the different butynylene isomers.
"Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "cycloalkylalkyl" denotes cycloalkyl substitution on an alkyl moiety. Examples of "cycloalkylalkyl" include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups. "Cycloalkenyl" includes groups such as cyclopentenyl and cyclohexenyl as well as groups with more than one double bond such as 1,3- and 1,4-cyclohexadienyl. The term "cycloalkoxy" denotes cycloalkyl attached to and linked through an oxygen atom such as cyclopentyloxy and cyclohexyloxy. "Alkylcycloalkylalkyl" denotes an alkyl group substituted with alkylcycloalkyl. Examples of "alkylcycloalkylalkyl" include 1-, 2-, 3- or 4-methyl or -ethyl cyclohexylmethyl. The term "cycloalkylcycloalkyl" denotes cycloalkyl substitution on another cycloalkyl ring, wherein each cycloalkyl ring independently has from 3 to 7 carbon atom ring members. Examples of cycloalkylcycloalkyl include cyclopropylcyclopropyl (such as Ι,Γ-bicyclopropyl-l-yl, l,l'-bicyclopropyl-2-yl), cyclohexylcyclopentyl (such as 4- cyclopentylcyclohexyl) and cyclohexylcyclohexyl (such as Ι,Γ-bicyclohexyl-l-yl), and the different cis- and trans-cycloalkylcycloalkyl isomers, (such as (li?,25)-l,l'-bicyclopropyl-2- yl and (li?,2i?)-l,l'-bicyclopropyl-2-yl).
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, CH2C1, CH2CF3 and CC12CF3. The terms "haloalkenyl", "haloalkynyl" "haloalkoxy", "haloalkylthio", "haloalkylamino", "haloalkylsulfinyl", "haloalkylsulfonyl", "halocycloalkyl", and the like, are defined analogously to the term "haloalkyl". Examples of "haloalkenyl" include (C1)2C=CHCH2 and CF3CH2CH=CHCH2. Examples of "haloalkynyl" include HC≡CCHC1, CF3C≡C, CC13C≡C and FCH2C≡CCH2. Examples of "haloalkoxy" include CF30, CC13CH20, HCF2CH2CH20 and CF3CH20. Examples of "haloalkylthio" include CC13S, CF3S, CC13CH2S and C1CH2CH2CH2S. Examples of "haloalkylamino" include CF3(CH3)CHNH, (CF3)2CHNH and CH2C1CH2NH. Examples of "haloalkylsulfinyl" include CF3S(=0), CC13S(=0), CF3CH2S(=0) and CF3CF2S(=0). Examples of "haloalkylsulfonyl" include CF3S(=0)2, CC13S(=0)2, CF3CH2S(=0)2 and CF3CF2S(=0)2. Examples of "halocycloalkyl" include 2-chlorocyclopropyl, 2-fluorocyclobutyl, 3-bromocyclopentyl and 4-chlorocyclohexyl. The term "halodialkyl", either alone or in compound words such as "halodialkylamino", means at least one of the two alkyl groups is substituted with at least one halogen atom, and independently each halogenated alkyl group may be partially or fully substituted with halogen atoms which may be the same or different. Examples of "halodialkylamino" include (BrCH2CH2)2N and BrCH2CH2(ClCH2CH2)N.
"Alkoxy" includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy and the different butoxy, pentoxy and hexyloxy isomers. "Alkoxyalkyl" denotes alkoxy substitution on alkyl. Examples of "alkoxyalkyl" include CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, CH2OCH2CH2CH2CH3 and CH2CH2OCH2CH3. "Alkenyloxy" includes straight-chain or branched alkenyl attached to and linked through an oxygen atom. Examples of "alkenyloxy" include H2C=CHCH20, (CH3)2C=CHCH20, (CH3)CH=CHCH20,
(CH3)CH=C(CH3)CH20 and CH2=CHCH2CH20. "Alkynyloxy" includes straight-chain or branched alkynyloxy moieties. Examples of "alkynyloxy" include HC≡CCH20, CH3C≡CCH20 and CH3C≡CCH2CH20.
The term "alkylsulfenyl" or "alkylthio" includes straight-chain or branched alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers. "Alkylsulfinyl" includes both enantiomers of an alkylsulfinyl group. Examples of "alkylsulfinyl" include CH3S(=0), CH3CH2S(=0), CH3CH2CH2S(=0), (CH3)2CHS(=0) and the different butylsulfinyl, pentylsulfmyl and hexylsulfmyl isomers. Examples of "alkylsulfonyl" include CH3S(=0)2, CH3CH2S(=0)2, CH3CH2CH2S(=0)2, (CH3)2CHS(=0)2, and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers. The chemical abbreviations S(O) and S(=0) as used herein represent a sulfmyl moiety. The chemical abbreviations S02, S(0)2 and S(=0)2 as used herein represent a sulfonyl moiety.
"Alkylamino" denotes an NH radical substituted with straight-chain or branched alkyl. Examples of "alkylamino" include NHCH2CH3, NHCH2CH2CH3, and NHCH2CH(CH3)2. "Dialkylamino" denotes an N radical substituted independently with two straight-chain or branched alkyl groups. Examples of "dialkylamino" include N(CH3)2, N(CH3CH2CH2)2 and N(CH3)CH2CH3. "Halodialkylamino" denotes one straight-chain or branched alkyl moiety and one straight-chain or branched haloalkyl moiety bonded to an N radical, or two independent straight-chain or branched haloalkyl moieties bonded to an N radical, wherein "haloalkyl" is as defined above. Examples of "halodialkylamino" include
N(CH2CH3)(CH2CH2C1) and N(CF2CF3)2.
"Alkylcarbonyl" denotes a straight-chain or branched alkyl moiety bonded to a C(O) moiety. The chemical abbreviations C(O) and C(=0) as used herein represent a carbonyl moiety. Examples of "alkylcarbonyl" include C(0)CH3, C(0)CH2CH2CH3 and C(0)CH(CH3)2. Examples of "haloalkylcarbonyl" include C(0)CF3, C(0)CC13, C(0)CH2CF3 and C(0)CF2CF3. "Alkoxycarbonyl" denotes a straight-chain or branched alkyl moiety bonded to a CO2 moiety. The chemical abbreviations CO2, C(0)0 and C(=0)0 as used herein represent an oxycarbonyl moiety. Examples of "alkoxycarbonyl" include C(0)OCH3, C(0)OCH2CH3, C(0)OCH2CH2CH3 and C(0)OCH(CH3)2.
"Alkylaminocarbonyl" denotes a straight-chain or branched alkyl moiety bonded to a
C(0)NH moiety. The chemical abbreviations C(0)NH, and C(0)N as used herein represent an amide moiety (i.e. an aminocarbonyl group). Examples of "alkylaminocarbonyl" include C(0)NHCH3, C(0)NHCH2CH2CH3 and C(0)NHCH(CH3)2. "Dialkylaminocarbonyl" denotes two independent straight-chain or branched alkyl moieties bonded to a C(0)N moiety. Examples of "dialkylaminocarbonyl" include C(0)N(CH3)2 and C(0)N(CH3)(CH2CH3).
"Trialkylsilyl" includes 3 branched and/or straight-chain alkyl radicals attached to and linked through a silicon atom, such as trimethylsilyl, triethylsilyl and tert-butyldimethylsilyl.
"CHO" means formyl, "OCN" means -0-C≡N, and "SCN" means -S-C≡N.
The total number of carbon atoms in a substituent group is indicated by the "C -Cj" prefix where i and j are numbers from 1 to 14. For example, C1-C4 alkyl designates methyl through butyl; C2 alkoxyalkyl designates CH2OCH3; C3 alkoxyalkyl designates, for example, CH3CH(OCH3), CH2CH2OCH3 or CH2OCH2CH3; and C4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH2OCH2CH2CH3 and CH2CH2OCH2CH3.
When a group contains a substituent which can be hydrogen, for example R1, then when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted. When a variable group is shown to be optionally attached to a position, for example (R13)x in Exhibit 2 wherein x may be 0, then hydrogen can be at the position even if not recited in the variable group definition. When one or more positions on a group are said to be "not substituted" or "unsubstituted", then hydrogen atoms are attached to take up any free valency.
When the attachment point between for example (R13)x in Exhibit 2 and bicyclic ring systems is illustrated as floating. This means that (R13)x can be attached to any available carbon atom or nitrogen atom ring member of the bicyclic ring system.
When the attachment point for a ring, for example Q2 rings in Exhibit 4, is illustrated as floating this means that the ring Q2 can be attached to Formula 1 through any available carbon atom ring member of the Q2 ring or ring system. When there are two floating attachment points for a ring, for example Q1 rings in Exhibit 2, then both attachment points are available through any carbon atom ring member of the Q1 ring or ring system. This means that the two attachment points between Q1 and Formula 1 can be in just one ring of a bicyclic ring system or in different rings of the bicyclic ring system.
The term "ring system" denotes two or more connected rings. The term "bicyclic ring system" denotes a ring system consisting of two rings sharing two or more common atoms.
The term "ring member" refers to an atom (e.g., C, O, N or S) forming the backbone of a ring or ring system. The term "aromatic" indicates that each of the ring atoms is essentially in the same plane and has a /^-orbital perpendicular to the ring plane, and that (4n + 2) π electrons, where n is a positive integer, are associated with the ring or ring system to comply with Huckel's rule.
"Partially saturated" and "partially unsaturated" with reference to a ring or ring system means that the ring or ring system contains at least one double bond but the ring or ring system is not aromatic. A ring system is aromatic if at least one component ring is aromatic.
The term "carbocyclic ring" denotes a ring wherein the atoms forming the ring backbone are selected only from carbon. Unless otherwise indicated, a carbocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring. When a fully unsaturated carbocyclic ring satisfies Huckel's rule, then said ring is also called an "aromatic ring". "Saturated carbocyclic ring" refers to a ring having a backbone consisting of carbon atoms linked to one another by single bonds; unless otherwise specified, the remaining carbon valences are occupied by hydrogen atoms.
The terms "heterocyclic ring" or "heterocycle" denotes a ring wherein at least one of the atoms forming the ring backbone is other than carbon. Unless otherwise indicated, a heterocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring. "Saturated heterocyclic ring" refers to a heterocyclic ring containing only single bonds between ring members. "Partially saturated heterocyclic ring" refers a heterocyclic ring containing at least one double bond but which is not aromatic. The term "heteroaromatic ring" denotes a fully unsaturated aromatic ring in which at least one atom forming the ring backbone is not carbon. Typically a heteroaromatic ring contains no more than 4 nitrogens, no more than 1 oxygen and no more than 1 sulfur. Unless otherwise indicated, heteroaromatic rings can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen. The term "heteroaromatic bicyclic ring system" denotes a ring system consisting of two fused rings, in which at least one of the two rings is a heteroaromatic ring as defined above.
When a radical (e.g., a 5- to 7-membered heterocyclic ring in the definition of Q1) is optionally substituted with listed substituents with the number of substituents stated (e.g., "up to 5"), then the radical may be unsubstituted or substituted with a number of substituents ranging up to the high number stated (e.g., "5"), and the attached substituents are independently selected from the substituents listed.
When a substituent (e.g., when R2 is cycloalkyl) is a ring or ring system, it can be attached to the remainder of Formula 1 through any available ring member, unless otherwise described.
As noted above, Q1 is, inter alia, a 5- to 7-membered heterocyclic ring or an 8- to 10- membered heteroaromatic bicyclic ring system, containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S, and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R13a on carbon atom ring members and R13^ on nitrogen atom ring members. The nitrogen atom ring members may be oxidized as N-oxides, because compounds relating to Formula 1 also include N-oxide derivatives. As the R13a and R13^ substituents are optional, 0 to 5 substituents may be present, limited only by the number of available points of attachment.
The term "unsubstituted" in connection with a group such as a ring or ring system means the group does not have any substituents other than its one or more attachments to the remainder of Formula 1. The term "optionally substituted" means that the number of substituents can be zero. Unless otherwise indicated, optionally substituted groups may be substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, the number of optional substituents (when present) ranges from 1 to 5.
The number of optional substituents may be restricted by an expressed limitation. For example, the phrase "optionally substituted with up to 5 substituents independently selected from Rl3a" means that 0, 1, 2, 3, 4 or 5 substituents can be present (if the number of potential connection points allows). When a range specified for the number of substituents exceeds the number of positions available for substituents on a ring, the actual higher end of the range is recognized to be the number of available positions.
When the number of optional substituents is not restricted by an expressed limitation (e.g., the phrases "optionally substituted" or "unsubstituted or substituted with at least one substituent independently selected from"), it is understood to mean that the number of optional substituents can range from 0 up to the number of positions available. One skilled in the art will appreciate that while some substituents such as halogen can be present at every available position (for example, the C2F5 substituent is a C2 alkyl group substituted with the maximum number of 5 fluorine atoms), practical factors such as cost and synthetic accessibility can limit the number of occurrences of other substituents. These limitations are part of the general synthetic knowledge known to those skilled in the art. Of note are embodiments wherein in the absence of expressed limitation of number of optional substituents, the number of optional substituents is up to 3 (i.e. 0, 1, 2 or 3) if accommodated by the number of available positions.
Compounds of this invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. 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 of the invention may be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form.
Compounds selected from Formula 1 (including all stereoisomers, N-oxides, and salts thereof) typically exist in more than one form, and Formula 1 thus includes all crystalline and non-crystalline forms of the compounds that Formula 1 represents. Non-crystalline forms include embodiments which are solids such as waxes and gums as well as embodiments which are liquids such as solutions and melts. Crystalline forms include embodiments which represent essentially a single crystal type and embodiments which represent a mixture of polymorphs (i.e. different crystalline types). The term "polymorph" refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms, these forms having different arrangements and/or conformations of the molecules in the crystal lattice. Although polymorphs can have the same chemical composition, they can also differ in composition due to the presence or absence of co- crystallized water or other molecules, which can be weakly or strongly bound in the lattice. Polymorphs can differ in such chemical, physical and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability. One skilled in the art will appreciate that a polymorph of a compound represented by Formula 1 can exhibit beneficial effects (e.g., suitability for preparation of useful formulations, improved biological performance) relative to another polymorph or a mixture of polymorphs of the same compound represented by Formula 1. Preparation and isolation of a particular polymorph of a compound represented by Formula 1 can be achieved by methods known to those skilled in the art including, for example, crystallization using selected solvents and temperatures.
One skilled in the art will appreciate that not all nitrogen-containing heterocycles can form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen-containing heterocycles which can form N-oxides. One skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and 3-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 N-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 animal parasites (i.e. are suitable for animal health use). 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. When a compound of Formula 1 contains an acidic moiety such as a carboxylic acid or phenol, salts also include those formed with organic or inorganic bases such as pyridine, triethylamine or ammonia, or amides, hydrides, hydroxides or carbonates of sodium, potassium, lithium, calcium, magnesium or barium. Accordingly, the present invention comprises compounds selected from Formula 1, N-oxides, and salts thereof.
Embodiments of the present invention as described in the Summary of the Invention include those described below. In the following Embodiments Formula 1 includes stereoisomers, N-oxides, and salts thereof, and 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.
In the Embodiments that follow, recitation of the word "independently" before more than one variable being defined means that the definition can be applied to each variable independently of the other variables. Embodiment 1. The method described in the Summary of the Invention for treating an animal in need of such treatment for infection by helminths which comprises orally, topically, parenterally or subcutaneously administering to the animal a parasiticdally effective amount of a compound of Formula 1, or a
pharmaceutically or veterinarily acceptable salt or a composition comprising it.
Embodiment 2. The method of Embodiment 1 wherein R1 is hydrogen, C1-C4 alkyl, C2-C4 alkylcarbonyl or C2-C4 alkoxycarbonyl.
Embodiment 3. The method of Embodiment 2 wherein R1 is hydrogen.
Embodiment 4. The method of any one of Embodiments 1 through 3 wherein R2 and R3 are each independently hydrogen, halogen, cyano, hydroxyl, amino, nitro, CHO,
SF5, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or
S(O)2NR10Rn; or -Q, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10R1 \
S(0)pR12 and S(O)2NR10Rn; or G.
Embodiment 5. The method of Embodiment 4 wherein R2 and R3 are each
independently hydrogen, halogen, cyano, hydroxyl, amino, nitro, CHO, SF5, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or C^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3~C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and
S(O)2NR10Rn.
Embodiment 6. The method of Embodiment 5 wherein R2 and R3 are each
independently hydrogen, halogen, cyano, nitro, OR6, S(0)pR12 or C^-Cg alkyl optionally substituted with halogen.
Embodiment 7. The method of Embodiment 6 wherein R2 and R3 are each
independently hydrogen, halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, 1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 halo alky lthio, -C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, -C4 alkylsulfonyl or C1-C4
haloalkylsulfonyl.
Embodiment 8. The method of Embodiment 4 wherein R2 and R3 are each
independently G.
Embodiment 9. The method of any one of Embodiments 1 through 3 wherein R2 and R3 are taken together with the carbons to which they are attached to form a 5- to 6- membered carbocyclic or heterocyclic ring optionally substituted with up to 3 substituents independently selected from R a on carbon atom ring members and R4^ on nitrogen atom ring members.
Embodiment 9a. The method of Embodiment 9 wherein R2 and R3 are taken together with the carbons to which they are attached to form a phenyl ring optionally substituted with up to 3 substituents independently selected from R4a.
Embodiment 10. The method of any one of Embodiments 1 through 9a wherein G is a phenyl ring optionally substituted with up to 5 substituents independently selected from R5a; or a 5- to 7-membered heterocyclic ring containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R5a on carbon atom ring members and R5^ on nitrogen atom ring members
Embodiment 11. The method of Embodiment 10 wherein wherein G is a ring selected from the group consisting of G-1 through G-27 in Exhibit 1
Exhibit 1
Figure imgf000019_0001
G-1 G-2 G-3 G-4
Figure imgf000019_0002
G-5 G-6 G-7 G-8
Figure imgf000019_0003
G-9 G-10 G-l l G-12
Figure imgf000020_0001
G-13 G-14 G-15 G-16
Figure imgf000020_0002
G-17 G-18 G-19 G-20
Figure imgf000020_0003
G-21 G-22 G-23 G-24
Figure imgf000020_0004
G-25 G-26 G-27
wherein when R5 is attached to a carbon ring member, said R5 is selected from R5a, and when R5 is attached to a nitrogen ring member, said R5 is selected from R5^; and q is an integer from 0 to 5.
Embodiment 12. The method of any one of Embodiments 1 through 11 wherein X is CR4c.
Embodiment 13. The method of any one of Embodiments 1 through 11 wherein X is N. Embodiment 14. The method of any one of Embodiments 1 through 13 wherein Y is CR4d.
Embodiment 15. The method of any one of Embodiments 1 through 13 wherein Y is N.
Embodiment 16. The method of any one of Embodiments 1 through 15 wherein each R4a is independently halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF5, OR6, NR7aR7b C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or Cj-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5-C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and
S(O)2NR10Rn.
Embodiment 17. The method of Embodiment 16 wherein each R a is independently halogen, cyano, nitro, OR6, S(0)pR12 or C^-Cg alkyl optionally substituted with halogen.
Embodiment 18. The method of Embodiment 17 wherein each R a is independently halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, -C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl.
Embodiment 18a. The method of Embodiment 18 wherein each R4a is independently halogen.
Embodiment 19. The method of any one of Embodiments 1 through 15 wherein each
R4a is independently G.
Embodiment 20. The method of any one of Embodiments 1 through 19 wherein R b is C(0)R8, C(0)OR9 or -Cg alkyl.
Embodiment 21. The method of Embodiment 20 wherein R b is C^-Cg alkyl.
Embodiment 21a. The method of any one of Embodiments 1 through 21 wherein R c and R d are each independently hydrogen, halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF5, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(0)2NR1°R1 !; or -Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn,
S(0)pR12 and S(O)2NR10Rn.
Embodiment 21b. The method of Embodiment 21a wherein R c and R d are each
independently hydrogen, halogen, cyano, nitro, OR6, S(0)pR12 or C^-Cg alkyl optionally substituted with halogen.
Embodiment 21c. The method of Embodiment 21b wherein R c and R d are each
independently hydrogen, halogen, cyano, nitro, -C4 alkyl, -C4 haloalkyl, -C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, -C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, -C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl.
Embodiment 2 Id. The method of Embodiment 21c wherein R c and R d are each
independently hydrogen. Embodiment 22. The method of any one of Embodiments 1 through 21d wherein each R5a is halogen, cyano, nitro, OR6, S(0)pR12 or C^-Cg alkyl optionally substituted with halogen.
Embodiment 23. The method of Embodiment 22 wherein each R5a is independently halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl.
Embodiment 24. The method of any one of Embodiments 1 through 23 wherein R5^ is C(0)R8, C(0)OR9 or Ci-C6 alkyl.
Embodiment 25. The method of Embodiment 24 wherein R5^ is C^-C alkyl.
Embodiment 26. The method of any one of Embodiments 1 through 25 wherein q is an integer from 0 to 3.
Embodiment 27. The method of any one of Embodiments 1 through 25 wherein each R6 is independently hydrogen, C2~Cg alkylcarbonyl, or C2~Cg alkoxycarbonyl; or C^-Cg alkyl or benzyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano and C^-Cg alkoxy; or C3-C7 cycloalkyl optionally substituted with substituents
independently selected from the group consisting of halogen, C1-C4 alkyl and C1-C4 haloalkyl.
Embodiment 28. The method of Embodiment 27 wherein each R6 is independently C^-
Cg alkyl optionally substituted with halogen.
Embodiment 29. The method of Embodiment 27 wherein each R6 is independently C^-
C4 alkyl or C1-C4 haloalkyl.
Embodiment 30. The method of any one of Embodiments 1 through 29 wherein each R7a is independently hydrogen, C2~Cg alkylcarbonyl or C2~Cg alkoxycarbonyl; or Cj-Cg alkyl or benzyl, each optionally substituted with substituents independently selected from the group consisting of halogen and cyano; or C3- C7 cycloalkyl optionally substituted with substituents independently selected from the group consisting of halogen, C1-C4 alkyl and C1-C4 haloalkyl.
Embodiment 31. The method of Embodiment 30 wherein each R7a is independently
Cj-Cg alkyl optionally substituted with halogen.
Embodiment 32. The method of Embodiment 31 wherein each R7a is independently
C1-C4 alkyl or C1-C4 haloalkyl.
Embodiment 33. The method of any one of Embodiments 1 through 32 wherein each R7b is independently hydrogen; or C^-Cg alkyl optionally substituted with halogen. Embodiment 34. The method of Embodiment 33 wherein each R7^ is independently hydrogen, C1-C4 alkyl or C1-C4 haloalkyl.
Embodiment 35. The method of any one of Embodiments 1 through 34 wherein R8, R9,
R10 and R12 are each independently hydrogen; or C^-Cg alkyl or C3-C7 cycloalkyl, each optionally substituted with substituents independently selected from the group consisting of halogen, C1-C4 alkyl and -C4 haloalkyl.
Embodiment 36. The method of Embodiment 35 wherein R8, R9, R10 and R12 are each independently C^-Cg alkyl optionally substituted with halogen.
Embodiment 37. The method of Embodiment 36 wherein R8, R9, R10 and R12 are each independently C1-C4 alkyl or C1-C4 haloalkyl.
Embodiment 38. The method of any one of Embodiments 1 through 37 wherein each
R1 1 is independently hydrogen; or C^-Cg alkyl optionally substituted with halogen.
Embodiment 39. The method of Embodiment 38 wherein each R1 1 is independently hydrogen, C1-C4 alkyl or C1-C4 haloalkyl.
Embodiment 40. The method of any one of Embodiments 1 through 39 wherein Q1 is a ring selected from the group consisting of Q1-! through Ql-84 in Exhibit 2
Exhibit 2
Figure imgf000023_0001
!-2 Q!-3 Q!-4
Figure imgf000023_0002
!-5 !-6 !-7 !-8
Figure imgf000023_0003
Q!-9 Q!-IO Q1-! ! Q!-12
Figure imgf000024_0001
Figure imgf000025_0001
(^-61 (^-62 (^-63 (^-64
Figure imgf000026_0001
Figure imgf000026_0002
Q!-81 Q!-82 Q!-83 Q!-84 wherein one of the floating bonds is connected to SO2 in Formula 1 through any
available carbon of the depicted ring or ring system and the other floating bond is connected to J in Formula 1 through any available carbon atom of the depicted ring or ring system; when R13 is attached to a carbon ring member, said R13 is selected from R13a, and when R13 is attached to a nitrogen ring member, said
R13 is selected from R13^; and x is an integer from 0 to 5.
Embodiment 41. The method of Embodiment 40 wherein Q1 is a ring selected from the group consisting of Ql-l through Ql-42.
Embodiment 42. The method of Embodiment 41 wherein Q1 is a ring selected from the group consisting of Q1-! through Ql-24. Embodiment 42a. The method of Embodiment 42 wherein Q1 is a ring selected from the group consisting of Q1-!, Q!-2, Q!-3, QU, Q!-5, Q!-10, Q l, Q!-12, Q!-20 and Q!-24.
Embodiment 43. The method of Embodiment 42a wherein Q1 is a ring selected from the group consisting of Q1-4, Qi-12 and Ql-24.
Embodiment 43a. The method of Embodiment 43 wherein Q1 is Qi-4 or Qi-24.
Embodiment 43b. The method of Embodiment 43a wherein Q1 is Qi-24.
Embodiment 44. The method of any one of Embodiments 1 through 43b wherein x is an integer from 0 to 3.
Embodiment 45. The method of any one of Embodiments 1 through 44 wherein each
R13a is halogen, cyano, nitro, OR6, S(0)pR12 or C^-Cg alkyl optionally substituted with halogen.
Embodiment 46. The method of Embodiment 45 wherein each R13a is independently halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl.
Embodiment 47. The method of any one of Embodiments 1 through 46 wherein R13^ is
C(0)R8, C(0)OR9 or -Q, alkyl.
Embodiment 47a. The method of Embodiment 47 wherein R13^ is C^-C^ alkyl.
Embodiment 48. The method of any one of Embodiments 1 through 47a wherein J is hydrogen; or phenyl or naphthalenyl each optionally substituted with up to 5 substituents independently selected from R14a; or a 5- to 7-membered heterocyclic ring or an 8- to 10-membered heterocyclic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R1 a on carbon atom ring members and R1 ^ on nitrogen atom ring members.
Embodiment 49. The method of Embodiment 48 wherein J is hydrogen.
Embodiment 50. The method of Embodiment 48 wherein J is phenyl or naphthalenyl each optionally substituted with up to 5 substituents independently selected from R1 a; or a 5- to 7-membered heterocyclic ring or an 8- to 10-membered heterocyclic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R14a on carbon atom ring members and R14b on nitrogen atom ring members.
Embodiment 51. The method of Embodiment 50 wherein J is a ring selected from the group consisting of J-l through J-80 in Exhibit 3
Exhibit 3
Figure imgf000028_0001
J-5 J-6 J-7 J-8
Figure imgf000028_0002
J-9 -10 J-l 1 J-12
Figure imgf000028_0003
-13 J-14 J-15 J-16
Figure imgf000028_0004
J-17 J-18 J-19 J-20
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
J-77 J-78 J-79 J-80 wherein the floating bond is connected to Q1 in Formula 1 through any available carbon atom of the depicted ring or ring system; when R14 is attached to a carbon ring member, said R14 is selected from R1 a, and when R14 is attached to a nitrogen ring member, said R14 is selected from R1 ^; and y is an integer from 0 to 5.
Embodiment 52. The method of Embodiment 51 wherein J is a ring selected from the group consisting of J-l through J-43.
Embodiment 53. The method of Embodiment 52 wherein J is a ring selected from the group consisting of J-l through J-25 and J-43.
Embodiment 54. The method of Embodiment 53 wherein J is a ring selected from the group consisting of J-l through J-8, J- 19 and J-25.
Embodiment 54a. The method of Embodiment 54 wherein J is a ring selected from the group consisting of J-l, J-2, J-5, J-6 and J-25.
Embodiment 54b. The method of Embodiment 54a wherein J is J-25.
Embodiment 55. The method of any one of Embodiments 1 through 54b wherein y is an integer from 0 to 3.
Embodiment 56. The method of any one of Embodiments 1 through 55 wherein each R14a is halogen, cyano, nitro, OR6, S(0)pR12 or Ci~C6 alkyl optionally substituted with halogen.
Embodiment 57. The method of Embodiment 56 wherein each R1 a is independently halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl.
Embodiment 58. The method of any one of Embodiments 1 through 57 wherein R1 ^ is
C(0)R8, C(0)OR9 or -Q, alkyl.
Embodiment 59. The method of Embodiment 58 wherein R1 ^ is C^-C^ alkyl. Embodiment 60. The method of any one of Embodiments 1 through 59 wherein J is L-
Q2-
Embodiment 61. The method of any one of Embodiments 1 through 60 wherein L is O, S, NR15, (CH2)n, OCH2, or CH20
Embodiment 62. The method of any one of Embodiments 1 through 61 wherein R15 is hydrogen or C^-Cg alkyl.
Embodiment 63. The method of any one of Embodiments 1 through 61 wherein n is 1.
Embodiment 64. The method of Embodiment 61 wherein L is O, S, S02 or CH2.
Embodiment 65. The method of Embodiment 64 wherein L is O.
Embodiment 66. The method of any one of Embodiments 1 through 65 wherein Q2 is a 5- to 7-membered carbocyclic ring or an 8- to 10-membered carbocyclic bicyclic ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R16a; or a 5- to 7-membered heterocyclic ring or an 8- to 10-membered heterocyclic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R16a on carbon atom ring members and R16^ on nitrogen atom ring members.
Embodiment 67. The method of Embodiment 66 wherein Q2 is a ring selected from the group consisting of Q2-l through Q2-84 in Exhibit 4
Exhibit 4
Figure imgf000032_0001
Q2-5 Q2-6 Q2-7 Q2-8
Figure imgf000033_0001
Q2-9 Q2-10 Q2-ll Q2-12
Figure imgf000033_0002
-17 Q -18 2-19 Q -20
Figure imgf000033_0003
Q2-29 Q -30 Q -31 Q -32
Figure imgf000034_0001
Figure imgf000034_0002
Figure imgf000034_0003
Figure imgf000034_0004
Figure imgf000034_0005
^57 Q2-58 Q2-59 Q2-60
Figure imgf000035_0001
Figure imgf000035_0002
Figure imgf000035_0003
Q2-81 Q2-82 Q2-83 Q2-84 wherein the floating bond is connected to L in Formula 1 through any available carbon of the depicted ring or ring system; when R16 is attached to a carbon ring member, said R16 is selected from R16a, and when R16 is attached to a nitrogen ring member, said R16 is selected from R16^; and z is an integer from 0 to 5. Embodiment 68. The method of Embodiment 67 wherein Q2 is a ring selected from the group consisting of Q2-l through Q2-43.
Embodiment 69. The method of Embodiment 68 wherein Q2 is a ring selected from the group consisting of Q2-l through Q2-25 and Q2-43. Embodiment 70. The method of Embodiment 69 wherein Q2 is Q2-25.
Embodiment 71. The method of any one of Embodiments 1 through 70 wherein z is an integer from 0 to 3.
Embodiment 72. The method of any one of Embodiments 1 through 71 wherein each R16a is halogen, cyano, nitro, OR6, S(0)pR12 or Ci~C6 alkyl optionally substituted with halogen.
Embodiment 73. The method of Embodiment 72 wherein each R16a is independently halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl.
Embodiment 74. The method of any one of Embodiments 1 through 73 wherein R16^ is
C(0)R8, C(0)OR9 or -Q, alkyl.
Embodiment 75. The method of Embodiment 74 wherein R16^ is C^-C^ alkyl.
Embodiment 76. The method of any one of Embodiments 1 through 75 wherein J is J-l through J-46; or L-Q2.
Embodiments of this invention, including Embodiments 1-76 above as well as any other embodiments described herein, can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula 1 but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula 1. In addition, embodiments of this invention, including Embodiments 1-76 above as well as any other embodiments described herein, and any combination thereof, pertain to the compositions and methods of the present invention.
Combinations of Embodiments 1-76 are illustrated by:
Embodiment A. The method as described in the summary of the invention wherein
R2 and R3 are each independently hydrogen, halogen, cyano, nitro, OR6,
S(0)pR12 or Cj-Cg alkyl optionally substituted with halogen; or R2 and R3 are taken together with the carbons to which they are attached to form a 5- to 6-membered carbocyclic or heterocyclic ring optionally substituted with up to 3 substituents independently selected from R4a on carbon atom ring members and R ^ on nitrogen atom ring members; R4a is independently halogen, cyano, nitro, OR6, S(0)pR12 or C^-Cg alkyl optionally substituted with halogen;
X is CR4c;
Y is CR4d; R c and R ^ are each independently hydrogen, halogen, cyano, nitro, OR6, S(0)pR12 or C^-Cg alkyl optionally substituted with halogen;
Q1 is a ring selected from the group consisting of Q^-l through Qi-84 in
Exhibit 2 wherein one of the floating bonds is connected to SO2 in Formula 1 through any available carbon of the depicted ring or ring system and the other floating bond is connected to J in Formula 1 through any available carbon atom of the depicted ring or ring system; when R13 is attached to a carbon ring member, said R13 is selected from R13a, and when R13 is attached to a nitrogen ring member, said R13 is selected from R13b; and x is an integer from 0 to 5;
each R1 a is halogen, cyano, nitro, OR6, S(0)pR12 or C^-Cg alkyl optionally substituted with halogen;
R13b is C(0)R8, C(0)OR9 or -Cg alkyl;
J is a ring selected from the group consisting of J-1 through J-80 in Exhibit 3 wherein the floating bond is connected to Q1 in Formula 1 through any available carbon atom of the depicted ring or ring system; when R1 is attached to a carbon ring member, said R14 is selected from R1 a, and when R1 is attached to a nitrogen ring member, said R1 is selected from R1 b; and y is an integer from 0 to 5; or L-Q2;
each R1 a is halogen, cyano, nitro, OR6, S(0)pR12 or C^-Cg alkyl optionally substituted with halogen;
R14b is C(0)R8, C(0)OR9 or -Cg alkyl;
L is O, S, S02 or CH2;
Q2 is a ring selected from the group consisting of Q2-l through Q2-84 in
Exhibit 4 wherein the floating bond is connected to L in Formula 1 through any available carbon of the depicted ring or ring system; when R16 is attached to a carbon ring member, said R16 is selected from R16a, and when R16 is attached to a nitrogen ring member, said R16 is selected from R16b; and z is an integer from 0 to 5;
each R16a is halogen, cyano, nitro, OR6, S(0)pR12 or C^-Cg alkyl optionally substituted with halogen;
R16b is C(0)R8, C(0)OR9 or -Cg alkyl;
each R6 is independently hydrogen, C2-Cg alkylcarbonyl, or C2-Cg
alkoxycarbonyl; or C^-Cg alkyl or benzyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano and C^-Cg alkoxy; or C3-C7 cycloalkyl optionally substituted with substituents independently selected from the group consisting of halogen, C1-C4 alkyl and C1-C4 haloalkyl; and
R8, R9 and R12 are each independently hydrogen; or C^-Cg alkyl or C3-C7 cycloalkyl, each optionally substituted with substituents independently selected from the group consisting of halogen, -C4 alkyl and -C4 haloalkyl.
Embodiment B. The method of Embodiment A wherein
R1 is hydrogen, -C4 alkyl, C2-C4 alkylcarbonyl or C2-C4 alkoxycarbonyl;
R2 and R3 are taken together with the carbons to which they are attached to form a phenyl ring optionally substituted with up to 3 substituents independently selected from R4a;
each R4a is independently halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, -C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl;
R4c and R d are each independently hydrogen, halogen, cyano, nitro, -C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, -C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4
haloalkylsulfinyl, C1-C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl;
Q1 is a ring selected from the group consisting of Q through Ql-24;
each R13a is independently halogen, cyano, nitro, -C4 alkyl, -C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C 1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, -C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl;
R13b is Ci-C6 alkyl;
x is an integer from 0 to 3;
J is is a ring selected from the group consisting of J-l through J-43; or L-Q2; each R1 a is independently halogen, cyano, nitro, -C4 alkyl, -C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C 1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, -C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl;
R14b is Ci-C6 alkyl;
y is an integer from 0 to 3;
L is O, S, S02 or CH2;
Q2 is a ring selected from the group consisting of Q2-l through Q2-25 and Q2-43; each R16a is independently halogen, cyano, nitro, C1-C4 alkyl, C1-C4
haloalkyl, -C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, -C4 haloalkylthio, C1-C4 alkylsulfinyl, -C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl;
R16b is C!-C6 alkyl; and
z is an integer from 0 to 3.
Embodiment C. The method of Embodiment B wherein
Q1 is a ring selected from the group consisting of Ql-l, Ql-2, Ql-3, Ql-4, Q!-5, Q!-10, Q!-l l, Q!-12, Q!-20 and Q!-24; and
J is is a ring selected from the group consisting of J-l through J-8;J-19 and J- 25; or L-Q2.
Embodiment D. The method of Embodiment C wherein
R1 is hydrogen;
Q1 is Q!-4 or Q!-24;
J is is a ring selected from the group consisting of J-l, J-2, J-5, J-6 and J-25; or L-Q2;
L is O;
Q2 is Q2-25; and
each R4a is independently halogen.
Specific embodiments include compounds of Formula 1 selected from the group consisting of:
4- phenoxy-N-(4-quinolinylmethyl)benzenesulfonamide;
2',4'-dichloro-N-(4-quinolinylmethyl)-[ 1 , 1 '-biphenyl]-4-sulfonamide;
N-(4-quinolinylmethyl)-5 -[5 -(trifluorometyl)-3 -isoxazolyl] -2- thiophenesulfonamide; and
5- [ 1 -methyl-3-(trifluoromethyl)- lH-pyrazol-5-yl]-N-(4-quinolinylmethyl)-2- thiophenesulfonamide .
Also noteworthy as embodiments of the present invention are compositions comprising a compound of any of the preceding Embodiments, as well as any other embodiments described herein, and their use for treating an animal in need of such treatment, for infection by helminths.
Also noteworthy as embodiments of the present invention are compositions comprising a compound of any of the preceding Embodiments, as well as any other embodiments described herein, in a parasiticidally effective amount and at least one pharmaceutically or veterinarily acceptable carrier or diluent.
Further noteworthy as embodiments of the present invention are compositions comprising a compound of any of the preceding Embodiments, as well as any other embodiments described herein, and at least one pharmaceutically or veterinarily acceptable carrier or diluent, said composition further comprising at least one additional biologically active compound or agent.
Embodiments of the invention also include an anthelmintic composition comprising a mixture of a compound of Formula 1 (including all stereoisomers) or an N-oxide or salt thereof and at least one other anthelmintic (e.g., at least one other anthelmintic having a different site of action).
Embodiments of the invention also include a method for treating an animal, in need of such treatment, for infection by helminths which comprises admininistration enterally, for example orally, parenterally, for example by injection, (including subcutaneous ly, intramuscularly or intravenously) or topically, to the animal, of a parasiticdally effective amount of a compound of Formula 1 (including all stereoisomers) or an N-oxide, or a pharmaceutically or veterinarily acceptable salt or a composition comprising it.
Embodiments of the invention also include a method for treating an animal in need of such treatment, for infection by helminths wherein the animal is a human.
Embodiments of the invention also include a method for treating an animal in need of such treatment, for infection by helminths wherein the animal is non-human.
Embodiments of the invention also include a method for treating an animal in need of such treatment, for infection by helminths wherein the helminth is a nematode.
Embodiments of the invention also include a method for controlling parasitic worms comprising admininistration enterally for example orally, parenterally, for example by injection, (including subcutaneously, intramuscularly or intravenously or topically, of a parasiticidally effective amount of Formula 1 (including all stereoisomers) or an N-oxide or salt thereof (e.g., as a composition described herein)Embodiments of the invention also include methods for controlling helminths comprising contacting the helminth or its environment with a parasiticidally effective amount of a compound of Formula 1, an N- oxide, or a salt thereof, (e.g., as a composition described herein), provided that the methods are not methods of medical treatment of a human or animal body by therapy.
Embodiments of the invention also include a compound of Formula 1 (including all stereoisomers) or an N-oxide or salt thereof, or any of the preceding Embodiments for use as an animal medicament, or more particularly a parasiticidal animal medicament. The medicament may be in any art recognized dosage forms including oral, topical, parenteral or subcutaneous dosage forms.
Embodiments of the invention also include a compound of Formula 1 (including all stereoisomers) or an N-oxide or salt thereof, or any of the preceding Embodiments for the manufacture of a medicament for the protection of an animal from a helminth. The medicament may be in any art recognized dosage forms including oral, topical, parenteral or subcutaneous dosage forms.
Embodiments of the invention also include a compound of Formula 1 (including all stereoisomers) or an N-oxide or salt thereof, or any of the preceding Embodiments, packaged and presented for the protection of an animal from a helminth. The compounds of the invention may be packaged and presented as in any dosage form suitable for the mode of intended administration..
Embodiments of the invention also include a process for manufacturing a composition for treating an animal for an infection by helminthes, such composition characterized as comprising a compound of Formula 1 (including all stereoisomers) or an N-oxide or salt thereof, or any of the preceding Embodiments, admixed with at least one carrier or diluent. The compounds of the invention may be packaged and presented in any art recognized dosage forms including oral, topical, parenteral or subcutaneous dosage forms. One or more of the following methods and variations as described in Schemes 1-6 can be used to prepare the compounds of Formulae 1. The definitions of Ql, J, R1, R2 and R3 in the compounds of Formulae 1-14 and Formulae la-2a are as defined above in the Summary of the Invention unless otherwise noted. Formulae la is a subset of Formula 1, and all substituents for Formulae la are as defined above for Formula 1 unless otherwise noted. Ambient or room temperature is defined as about 20-25 °C.
Compounds of Formula 1 can be prepared by the reaction of 4-pyridinemethanamines and their derivatives (e.g. pyrimidines, pyridazines, quinolines etc) of Formula 2 with aryl or heteroaryl sulfonylchlorides of Formula 3, typically in the presence of base, as shown in Scheme 1. The reaction can be carried out at temperatures ranging from 0 °C to the reflux temperature of the solvent, preferably in the range of room temperature to 100 °C. Typical solvents include aliphatic and aromatic hydrocarbons such as hexane or toluene; ethers such as diethyl and diisopropyl ether, tetrahydrofuran or dioxane; esters such as ethyl acetate; nitriles such as acetonitrile; ketones such as acetone or methyl ethyl ketone; amides such as dimethylformamide and dimethylacetamide; and halogenated hydrocarbons such as methylene chloride and chloroform. Typical bases for the reaction include pyridine and substituted pyridines such as the picoline isomers, trialkylamines such as triethyl, tributyl diisopropylethylamine, and metal carbonates such as sodium or potassium carbonate.
Scheme 1
Figure imgf000042_0001
2 3 1
Compounds of Formula 1, where R1 is alkyl, acyl, and alkoxycarbonyl may be prepared by the reaction of quinoline sulfonamides of Formula 4 with various alkylating or acylating reagents, such as Rl-X, in the presence of a base, as shown in Scheme 2. Typical bases include pyridine and substituted pyridines such as the picoline isomers; trialkylamines such as triethyl, tributyl or diisopropylethylamine; hydrides such as sodium hydride; and carbonates such as potassium or cesium carbonate. Typical solvents include acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, ethyl acetate, and toluene. The reaction is typically run at room temperature but may be carried out at temperatures ranging from room temperature to the reflux temperature of the solvent.
Scheme 2
Figure imgf000042_0002
wherein X is CI, Br or I
is alkyl, alkylcarbonyl or alkoxycarbonyl
A variety of the intermediate sulfonyl chlorides of Formula 3 are known or are available from commercial sources. Intermediate sulfonyl chlorides of Formula 3 may also be prepared by a wide variety of well known methods. One particularly useful method is by the diazotization and chlorosulfonation of aromatic and heteroaromatic amines of Formula 6. These methods and procedures are extensively documented in the chemical literature. A typical set of conditions includes sodium nitrite, copper chloride, and sulfur dioxide in a mixture of acetic and hydrochloric acid. The amines of Formula 6 are readily available from a variety of sources with the reduction of aromatic and heteroaromatic nitro compounds of Formula 5 being very typical.
Scheme 3
Figure imgf000043_0001
An alternative useful procedure for the preparation of the intermediate sulfonyl chlorides of Formula 3 is by the oxidative chlorination of sulfides to the corresponding sulfonyl chlorides as shown in Scheme 4. Treatment of sulfides of Formula 8 with chlorinating reagents including chlorine, N-chlorosuccinimide, and sodium hypochlorite provides the corresponding sulfonyl chlorides of Formula 3 under a wide range of conditions (see e.g. World Patent Publication WO2007/147762, Tetrahedron Lett. 2010, 51 418-421). The intermediate sulfides 8 are available from aryl or heterocyclic halides of Formula 7 by displacement with benzyl mercaptan by a variety of known literature procedures.
Scheme 4
Figure imgf000043_0002
7 8
3
wherein XI is halogen
Many of the 4-pyridinemethanamines and their derivatives (e.g pyrimidines, pyridazines etc.) of Formula 2 are known in the literature or can be prepared by a variety of known methods such as those shown in Scheme 5. Oximes of Formula 10 can be readily reduced to the amines of Formula 2 by treatment with palladium and ammonium formate in methanol. The reduction is demonstrated for 4-pyridinecarboxaldehyde in the following reference: Journal fuer Praktische Chemie/Chemiker-Zeiturig, 1994, 336(8), 695-7. Other methods useful for this reduction can be found in the following references: World Patent Publication WO 2008/06201 1 and Inorganic Chemistry, 2Θ12, 51( 12), 6428-6430. The R1 groups of Formula 2 may be introduced by reductive amination, or alkylation reactions. The oximes of Formula 10 are available from the corresponding aldehydes of Formula 9 by treatment with hydroxylamine. Many of the aldehydes of Formula 9 are known in the literature. The unsubstituted derivatives such as 4-pyridinecarboxaldehyde, 4- pyrimidinecarboxaldehyde, and 4-pyridazinecarboxaldehyde as well as numerous substituted analogs are commercially available.
Scheme 5
Figure imgf000044_0001
The quinolines of Formula 2a shown in Scheme 6 and the derived sulfonamides of Formula la are a preferred subset. The 4-quinolinemethanamines 2a can be made by procedures similar to those of Scheme 5 including by the reduction of the oximes with palladium and ammonium formate in methanol. Other methods for this reduction include: J. Org. Chem. 1989, 54, 1731-5 and European Patent Publication EP 1571150. Quinolines of Formula 2a can also be prepared from nitriles of Formula 14 by catalytic hydrogenation. References applicable to this transformation include the following: World Patent Publication WO 2008/007211, World Patent Publication WO 2008/090434, World Patent Publication WO 2007/104726, and World Patent Publication WO 2008/079292. The nitriles 14 can be prepared from the corresponding bromo derivatives 13 by reaction with a cyanide source. See for example Organic Letters 2007, 9, 5525-5528; J. Med. Chem. 1992, 35, 2761-8; Bioorganic & Medicinal Chemistry Letters 2005, 15, 4520-4525.
Scheme 6
Figure imgf000045_0001
It is recognized that some reagents and reaction conditions described above for preparing compounds of Formula 1 may not be compatible with certain functionalities present in the intermediates. In these instances, the incorporation of protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be apparent to one skilled in chemical synthesis (see, for example, Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formula 1. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula 1.
One skilled in the art will also recognize that compounds of Formula 1 and the intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents.
Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Synthesis Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Steps in the following Synthesis Examples illustrate a procedure for each step in an overall synthetic transformation, and the starting material for each step may not have necessarily been prepared by a particular preparative run whose procedure is described in other Examples or Steps. Ambient or room temperature is defined as about 20-25 °C. Percentages are by weight except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. MPLC refers to medium pressure liquid chromatography on silica gel. !H NMR spectra are reported in ppm downfield from tetramethylsilane; "s" means singlet, "d" means doublet, "dd" means doublet of doublets, "ddd" means doublet of doublet of doublets, "t" means triplet, "m" means multiplet, and "br s" means broad singlet. For mass spectral data, the numerical value reported is the molecular weight of the parent molecular ion (M) formed by addition of H+ (molecular weight of 1) to the molecule to give a M+l peak observed by mass spectrometry using atmospheric pressure chemical ionization (AP+).
SYNTHESIS EXAMPLE 1
Preparation of N-(4-quinolinylmethyl)-5 - [5 -(trifluorometyl)-3 -isoxazolyl]-2- thiophenesulfonamide (compound number 181)
Step A: Preparation of 4-quinolinecarboxaldehyde oxime
To 4-quinolinecarboxaldehyde (10.0 g, 62.5 mmol) in 65 mL ethanol was added hydroxylamine HCl (4.81 g, 68.75 mmol) and 3.1 mL water and then pyridine (11.2 mL, 137 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. Water (30 mL) was added and the reaction mixture was cooled in an ice bath to precipitate a solid. This solid was filtered and washed with ethanol and water and dried under nitrogen to obtain 11.0 g of the title compound.
!H NMR (DMSO) δ 12.02 (s, 1H) 8.94 (d, 1H), 8.85 (s, 1H), 8.65 (d, 1H), 8.08 (d, 1H), 7.83 (t, 1H), 7.75 (d, 1H), 7.68 (t, 1H).
Step B: Preparation of 4-quinolinemethanamine
To a 500 mL round bottom flask under nitrogen was added 10 % Pd/C (0.85 g) followed by 4-quinolinecarboxaldehyde oxime (11.0 g, 63 mmol) (i.e. the product of Example 1, Step A) and ammonium formate (16.8 g, 257 mmol). Methanol (200 mL) was carefully added and the reaction mixture was heated to 40-45 °C for 8 hours and then stirred overnight at room temperature. The reaction mixture was then filtered through celite and washed with methanol. The filtrate was then concentrated under reduced pressure to approximately 20 mL and then diluted with 300 mL of methylene chloride and washed with a saturated aqueous sodium carbonate solution (200 mL). The methylene chloride phase was dried over magnesium sulfate and concentrated under reduced pressure to obtain an oil. The oil was chromatographed on silica gel using a gradient of ethyl acetate :methanol (9: 1) to pure methanol to provide 6.0 g of the title compound.
!H NMR (CDCI3) δ 8.89 (d, 1H), 8.15 (d, 1H), 8.01 (d, 1H), 7.72 (t, 1H), 7.58 (t, 1H), 7.48 (d, 1H), 4.38 (s, 2H).
Step C: Preparation of N-(4-quinolinylmethyl)-5-[5-(trifluorometyl)-3-isoxazolyl]-2- thiophenesulfonamide
To the 4-quinolinemethanamine (160 mgs, 1.01 mmol) (i.e. the product of Example 1, Step B) in 20 mL tetrahydrofuran and diisopropylethylamine (460 μΐ , 2.52 mmol) was added 5-[5-(trifluoromethyl) isoxazol-3-yl] thiophene-2-sulfonyl chloride (321 mg, 1.01 mmol, Maybridge) and the reaction mixture was stirred at room temperatue overnight. The reaction was then concentrated under reduced pressure and the residue was chromatographed on silica gel using a gradient of hexane: ethyl acetate (7:3) to pure ethyl acetate to provide a residue which was precipitated from ethyl acetate/diethyl ether and filtered to obtain 184 mg of the title compound, a compound of the invention, as a white solid.
!H NMR (CDCI3) δ 8.78 (d, 1H), 8.15 (d, 1H), 7.95 (d,lH), 7.68 (t, 1H), 7.58 (m, 2H), 7.40 (d, 1H), 7.35 (d,lH), 6.95 (s, 1H), 6.05 (br s, 1H), 4.75 (s, 2H).
SYNTHESIS EXAMPLE 2
Preparation of 4-phenoxy-N-(4-quinolinylmethyl)benzenesulfonamide (compound
number 4)
To a solution of 4-quinolinemethanamine (72 mg, 0.456 mmol) in tetrahydrofuran (20 mL) was added diisopropylethylamine (0.175 mL, 1.0 mmol), followed by 4- phenoxybenzenesulfonyl chloride (135 mg, 0.50, Maybridge). The reaction mixture was stirred at room temperature overnight. To the reaction was added lmL of 1 N HC1 and then excess water to precipitate a solid after stirring for 1 hour. The solid was filtered, washed with water, and chromatographed on silica gel using dichloromethane:methanol (6:4). The residue was triturated with diethyl ether/hexane to afford the title compound, a compound of the invention, as a solid (17 mg).
!H NMR (CDCI3) δ 8.82 (d, 1H), 8.15 (d, 1H), 7.90 (d,lH), 7.80 (d, 2H), 7.75 (m, 1H), 7.58 (m, 1H), 7.43 (t,2H), 7.30 (d, 1H), 7.24 (m, 1H), 7.08 (d, 2H), 6.99 (d, 2H), 4.95 (t, 1H) 4.64 (d, 2H). SYNTHESIS EXAMPLE 3
Preparation of 2',4'-dichloro-N-(4-quinolinylmethyl)-[l, -biphenyl]-4-sulfonamide
(compound number 1)
Step A: Preparation of 4-cyanoquinoline
To a solution of N-methylpyrrolidinone (100 mL) and CuCN (21.5 g, 240 mmol) was added 4-bromoquinoline (25.0 g, 120 mmol) in one portion with vigorous stirring under nitrogen. The reaction was heated to 180 °C for 3 hours. The reaction mixture was allowed to cool, and then added to water (300 mL). The crude solid product was filtered and dried in a vacuum oven overnight to give the title product (8.03 g).
!H NMR (CDC13) δ 7.73-7.81 (m, 2 H) 7.89 (ddd, J=8.47, 7.01, 1.34 Hz, 1 H) 8.11-8.34 (m, 2 H) 9.06 (d, J=4.39 Hz, 1 H).
Step B: Preparation of 4-iodo-N-(4-quinolinylmethyl)benzenesulfonamide
4-Cyanoquinoline (the product of Step A) (1.25 g, 8.10 mmol) was dissolved in tetrahydrofuran (100 mL) and heated to reflux until the reaction resulted in a clear solution. To this heated reaction mixture was added borane dimethyl sulfide complex (0.801 g, 10.5 mmol) and the heating continued for 90 minutes. The reaction mixture was cooled to room temperature and concentrated under a vaccum to remove all volatiles. The resulting crude oil was dissolved in 10 mL of tetrahydrofuran and treated with 5 mL of 5 N HC1. This reaction mixture was heated to reflux for 90 minutes. The reaction mixture was concentrated to an oil which was dissolved in 10 mL of diethyl ether. The reaction mixture was treated with 4 mL of triethylamine and allowed to stir for 10 minutes. The reaction mixture was then cooled to 0 °C and a solution of 4-iodobenzenesulfonyl chloride (2.6 g, 8.9 mmol) in 10 mL of diethyl ether was added dropwise. The reaction mixture was allowed to warm up to room temperature and stirring was continued for 18 hours. The reaction mixture was added to 100 mL of ethyl acetate and washed once with 100 mL of water. The phases were separated and the organic phase was dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was chromatographed on a silica gel column (50% ethyl acetate/hexanes as eluent) to provide the title compound as solid (98 mg).
!H NMR (CDCI3) δ 8.83 (d, J=4.41 Hz, 1 H), 8.14 (d, J=8.51 Hz, 1 H), 7.82-7.90 (m, 3 H), 7.75 (td, J=7.65, 1.26 Hz, 1 H), 7.51-7.65 (m, 3 H), 7.31 (d, J=4.26 Hz, 1 H), 4.88 (d, J=5.20 Hz, 1 H), 4.65 (d, J=6.15 Hz, 2 H).
Step C: Preparation of 2',4'-dichloro-N-(4-quinolinylmethyl)-[l, -biphenyl]-4- sulfonamide
4-Iodo-N-(4-quinolinylmethyl)benzenesulfonamide (the product of Step B) (98.0 mg, 0.23 mmol) was dissolved in 5 mL of dioxane and 0.1 mL of saturated aqueous sodium carbonate solution in a microwave vessel. To this solution was added 2,4-dichlorobenzene boronic acid (44.1 mg, 0.23 mmol) and 10 mg of dichlorobis(triphenylphosphine)palladium(II). The reaction vessel was sealed, and heated to 150 °C for 15 minutes in the microwave. The resulting reaction mixture was added to 20 mL of saturated aqueous sodium bicarbonate solution and extracted three times with 10 mL of ethyl acetate. The combined organic phases were dried with magnesium sulfate, filtered, and concentrated under vacuum to give a crude oil. The residue was chromatographed on a silica gel column (50% ethyl acetate/hexanes to 40% methanol in ethyl acetate as eluent) to provide the title compound, a compound of the present invention, as solid (41.6 mg).
lH NMR (CDCI3) δ 8.81 (d, J=4.39 Hz, 1H), 8.11 (d, J=8.54 Hz, 1H), 7.83-7.99 (m, 3H), 7.73 (td, J = 7.68, 1.22 Hz, 1H), 7.44-7.63 (m, 4H), 7.16-7.41 (m, 4H) 4.96 (t, J = 6.34 Hz, NH), 4.72 (d, J = 6.10 Hz, 2H).
By the procedures described herein together with methods known in the art, the following compounds of Tables 1 to 18 can be prepared. The following abbreviations are used in Tables 1A to 4 which follow: The following abbreviations are used in the Tables which follow: CF3 means trifluoromethyl, Me is methyl, Et is ethyl, Ph is phenyl, OMe is methoxy, SMe is methylthio, CN is cyano, Ν(¾ is nitro, S(O) is sulfoxide and C(O) is carbonyl. A dash "-" indicates an optional substituent is not present, for example, when (R1 )y is listed as a dash then that means that y is 0.
Fra ments Q-l through Q-14 shown below are referred to in Tables 1A through IN.
Figure imgf000049_0001
Q-5 Q-6 Q-7 Q-8
Figure imgf000049_0002
Q-9 Q-10 Q-11 Q-12
Figure imgf000050_0001
Q-13 Q-14
* is the point of attachment of the Q1 group to the sulfonyl (SO2) in Formula 1.
# is the point of attachment of the 1 group to the J group in Formula 1.
Figure imgf000050_0002
TABLE 1A
Figure imgf000050_0003
Figure imgf000051_0001
Figure imgf000052_0001
R4d Rl R4a R4d
(R14)v Rl (R14)v
H Me 3-F, 4-Cl 6-Cl H H 3-F, 5-Cl
H Me 3-F, 5-Cl 6-Cl H H 2-Cl, 4-CF3
H Me 2-Cl, 4-CF3 6-Cl H H 3 -CI, 4-CF3
H Me 3 -CI, 4-CF3 6-Cl H H 3 -CI, 5-CF3
H Me 3 -CI, 5-CF3 6-Cl H H 2,4-di(CF3)
H Me 2,4-di(CF3) 6-Cl H H 3,5-di(CF3)
H Me 3,5-di(CF3)
The present disclosure also includes Tables 2 A through 14 A, each of which is constructed the same as Table 1A above except that the row heading in Table 1A (i.e. "Q1 is Q-1.") below the Markush structure is replaced with the respective row heading shown below. For example, in Table 2A the row heading is "Q1 is Q-2 is as defined in Table 1A above. Thus, the first entry in Table IB specifically discloses N-(4-quinolinylmethyl)[l, - biphenyl]-3 -sulfonamide .
Table Table Headings Table Table Headings
IB Q1 is Q-2 II Q1 is Q-9
1C Q1 is Q-3 1J Q1 is Q-10
ID Q1 is Q-4 IK Q1 is Q-l l
IE Q1 is Q-5 1L Q1 is Q-12
IF Q1 is Q-6 1M Q1 is Q-13
1G Q1 is Q-7 IN Q1 is Q-14
1H Q1 is Q-8
The fragments shown below are referred to in Tables 2A through 2F.
Figure imgf000053_0001
J-1 J-2 J-4 J-5
Figure imgf000054_0001
J-6A -19
Figure imgf000054_0002
Figure imgf000055_0001
TABLE 2B
Table 2B is identical to Table 2A, except that the chemical structure in the Table 2B heading is replaced with the following structure:
Figure imgf000056_0001
For example, the first compound in Table 2B is the structure shown immediately above wherein J is J-l, the attachment is the 2 position and (R1 )y is not present (y is 0).
TABLE 2C
Table 2C is identical to Table 2A, except that the chemical structure in the Table 2C heading is replaced with the following structure:
Figure imgf000056_0002
For example, the first compound in Table 2C is the structure shown immediately above wherein J is J-l, the attachment is the 2 position and (R1 )y is not present (y is 0).
TABLE 2D
Table 2D is identical to Table 2A, except that the chemical structure in the Table 2D heading is replaced with the following structure:
Figure imgf000056_0003
For example, the first compound in Table 2D is the structure shown immediately above wherein J is J-l, the attachment is the 2 position and (R1 )y is not present (y is 0).
TABLE 2E
Table 2E is identical to Table 2A, except that the chemical structure in the Table 2E heading is replaced with the following structure:
Figure imgf000057_0001
For example, the first compound in Table 2E is the structure shown immediately above wherein J is J-1, the attachment is the 2 position and (R14)y is not present (y is 0).
TABLE 2F
Table 2F is identical to Table 2A, except that the chemical structure in the Table 2F heading is replaced with the following structure:
Figure imgf000057_0002
For example, the first compound in Table 2F is the structure shown immediately above wherein J is J-1, the attachment is the 2 position and (R14)y is not present (y is 0).
Figure imgf000057_0003
TABLE 3
Rl R2 R3 (R14)v Rl R2 R3 (R14)v
H H H - H Me H 2-F
H H H 2-F H Me H 3-F
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000060_0002
TABLE 4
JisH
Rl R2 R3 (R13)x Rl R2 R3 (Rl3)
H H H - H Me H 2- F
H H H 2-F H Me H 3- F
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
A compound of this invention will generally be used as a helminth control active ingredient in a composition, i.e. formulation, with at least one additional component selected from the pharmaceutically or veterinarily acceptable carriers or diluents. The formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of administration and factors such as the type of animal to be treated.
The compounds of Formula 1 are preferably employed in unmodified form or preferably together with the adjuvants conventionally used in the art of pharmaceutical or veterinary formulation and may therefore be processed in a known manner to give, for example, emulsifiable concentrates, directly dilutable solutions, dilute emulsions, soluble powders, granules or microencapsulations in polymeric substances. As with the compositions, the methods of application are selected in accordance with the intended objectives and the prevailing circumstances. Applications in the veterinary sector are by conventional means such as by enteral administration in the form of, for example, tablets including effervescent tablets, capsules, micro-capsules, drinks, drenching preparations (solutions, emulsions, suspensions), granulates, pastes, powders, boli, food additives or suppositories; or by parenteral administration, such as by injection (including intramuscular, subcutaneous, intravenous, intraperitoneal) or implants; by nasal administration; by topical administration, for example, in the form of immersion or dipping, spraying, washing, coating with powder, or application to a small area of the animal via a pour-on formulations, and through articles such as neck collars, ear tags, tail bands, limb bands or halters which comprise compounds or compositions of the present invention.
The compounds of the present invention may be administered in a controlled release form, e.g., in a subcutaneous slow release formulation.
The formulation, i.e. the agents, preparations or compositions containing the active ingredient of Formula 1, or combinations of these active ingredients with other active ingredients, and optionally a solid or liquid adjuvant, are produced in a manner known in the art, for example by intimately mixing and/or grinding the active ingredients with spreading compositions, for example with solvents, solid carriers, and optionally surface-active compounds (surfactants).
The solvents in question may be: alcohols, such as ethanol, propanol or butanol, and glycols and their ethers and esters, such as propylene glycol, dipropylene glycol ether, ethylene glycol, ethylene glycol monomethyl or -ethyl ether, ketones, such as cyclohexanone, isophorone or diacetanol alcohol, strong polar solvents, such as N-methyl-2- pyrrolidone, dimethyl sulfoxide or dimethylformamide, or water, vegetable oils, such as rape, castor, coconut, or soybean oil, and also, if appropriate, silicone oils.
For parenteral administration including intravenous, intramuscular and subcutaneous injection, a compound of the present invention 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 the present invention may also be formulated for bolus injection or continuous infusion. Pharmaceutical and veterinary 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 and veterinary 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 above, the compounds of the present invention 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 the present invention 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 the present invention 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 the present invention have been discovered to have 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 the invention in the bloodstream protect the treated animal from blood-sucking pests. 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 the invention, 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 the present invention 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.
If the anthelmintics are present in the form of feed concentrates, then the carriers used are e.g. performance feeds, feed grain or protein concentrates. Such feed concentrates or compositions may contain, apart from the active ingredients, also additives, vitamins, antibiotics, chemotherapeutics or other pesticides, primarily bacteriostats, fungistats, coccidiostats, or even hormone preparations, substances having anabolic action or substances which promote growth, which affect the quality of meat of animals for slaughter or which are beneficial to the organism in another way. If the compositions or the active ingredients of Formula 1 contained therein are added directly to feed or to the drinking troughs, then the formulated feed or drink contains the active ingredients preferably in a concentration of ca. 0.0005 to 0.02 % by weight (5-200 ppm).
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.
Formulations for topical administration are typically in the form of a powder, cream, suspension, spray, emulsion, foam, paste, aerosol, ointment, salve or gel. More typically a topical formulation is a water-soluble solution, which can be in the form of a concentrate that is diluted before use. Parasiticidal compositions suitable for topical administration typically comprise a compound of the present invention and one or more topically suitable carriers. In applications of a parasiticidal composition topically to the exterior of an animal as a line or spot (i.e. "spot-on" treatment), the active ingredient migrates over the surface of the animal to cover most or all of its external surface area. Therefore formulations for topical localized administration often comprise at least one organic solvent to facilitate transport of the active ingredient over the skin and/or penetration into the epidermis of the animal. Carriers in such formulations include propylene glycol, paraffins, aromatics, esters such as isopropyl myristate, glycol ethers, alcohols such as ethanol, n-propanol, 2-octyl dodecanol or oleyl alcohol; solutions in esters of monocarboxylic acids, such as isopropyl myristate, isopropyl palmitate, lauric acid oxalic ester, oleic acid oleyl ester, oleic acid decyl ester, hexyl laurate, oleyl oleate, decyl oleate, caproic acid esters of saturated fatty alcohols of chain length C^- Ci ; solutions of esters of dicarboxylic acids, such as dibutyl phthalate, diisopropyl isophthalate, adipic acid diisopropyl ester, di-n-butyl adipate or solutions of esters of aliphatic acids, e.g., glycols. It may be advantageous for a crystallization inhibitor or a dispersant known from the pharmaceutical or cosmetic industry also to be present.
The pour-on or spot-on method consists in applying the parasiticidal composition to a specific location of the skin or coat, advantageously to the neck or backbone of the animal. This takes place by applying a swab or spray of the pour-on or spot-on formulation to a relatively small area of the coat, from where the active substance is dispersed almost automatically over wide areas of the fur owing to the spreading nature of the components in the formulation and assisted by the animal's movements. The pour-on formulation is typically applied by pouring in one or several lines or in a spot-on the dorsal midline (back) or shoulder of an animal. More typically, the formulation is applied by pouring it along the back of the animal, following the spine. The formulation can also be applied to the animal by other conventional methods, including wiping an impregnated material over at least a small area of the animal, or applying it using a commercially available applicator, by means of a syringe, by spraying or by using a spray race. Pour-on or spot-on formulations suitably contain carriers, which promote rapid dispersement over the skin surface or in the coat of the host animal, and are generally regarded as spreading oils. Suitable carriers are, for example, oily solutions; alcoholic and isopropanolic solutions such as solutions of 2-octyldodecanol or oleyl alcohol; solutions in esters of monocarboxylic acids, such as isopropyl myristate, isopropyl palmitate, lauric acid oxalate, oleic acid oleyl ester, oleic acid decyl ester, hexyllaurate, oleyl oleate, decyl oleate, capric acid esters of saturated fat alcohols of chain length C i 2-Ci ; solutions of esters of dicarboxylic acids, such as dibutyl phthalate, diisopropyl isophthalate, adipic acid diisopropyl ester, di-n-butyl adipate or also solutions of esters of aliphatic acids, for example glycols. It may be advantageous for a dispersing agent to be additionally present, such as one known from the pharmaceutical or cosmetic industry. Examples are 2-pyrrolidone, 2-(N-alkyl)pyrrolidone, acetone, polyethylene glycol and the ethers and esters thereof, propylene glycol or synthetic triglycerides.
The oily solutions include, for example, vegetable oils such as olive oil, groundnut oil, sesame oil, pine oil, linseed oil or castor oil. The vegetable oils may also be present in epoxidised form. Paraffins and silicone oils may also be used.
A pour-on or spot-on formulation generally contains 1 to 20 % by weight of a compound of Formula 1, 0.1 to 50 % by weight of dispersing agent and 45 to 98.9 % by weight of solvent.
The pour-on or spot-on method is especially advantageous for use on herd animals such as cattle, horses, sheep or pigs, in which it is difficult or time-consuming to treat all the animals orally or by injection. Because of its simplicity, this method can of course also be used for all other animals, including individual domestic animals or pets, and is greatly favoured by the keepers of the animals, as it can often be carried out without the specialist presence of the veterinarian.
The formulations of this invention typically include an antioxidant, such as BHT (butylated hydroxytoluene). The antioxidant is generally present in amounts of at 0.1-5% (wt/vol).
The compositions may also contain further additives, such as stabilisers, e.g. where appropriate epoxidised vegetable oils (epoxidised coconut oil, rapeseed oil, or soybean oil); antifoams, e.g. silicone oil, preservatives (e.g. methylparaben and propylparaben), viscosity regulators, thickners (e.g. carbomers, corn starch, polyethylene, polyvinylpyrrolidones, edible clay or xanthan gum) binders and tackifiers or other active ingredients to achieve special effects.
Further biologically active substances or additives, which are neutral towards the compounds of Formula 1 and do not have a harmful effect on the host animal to be treated, as well as mineral salts or vitamins, may also be added to the described compositions.
As a rule, the anthelmintic compositions according to the invention contain 0.1 to 99 % by weight, especially 0.1 to 95 % by weight of active ingredient of Formula 1, 99.9 to 1 % by weight, especially 99.8 to 5 % by weight of a solid or liquid admixture, including 0 to 25 % by weight, especially 0.1 to 25 % by weight of a surfactant.
Whereas it is preferred to formulate commercial products as concentrates, the end user will normally use dilute formulations.
In each of the methods according to the invention for pest control or in each of the pest control compositions according to the invention, the active ingredients of Formula 1 can be used in all of their steric configurations or in mixtures thereof.
The invention also includes a method of prophylactically protecting warm-blooded animals, especially productive -livestock, domestic animals and pets, against parasitic helminths, which is characterised in that the active ingredients of the formula or the active ingredient formulations prepared therefrom are administered to the animals as an additive to the feed, or to the drinks or also in solid or liquid form, orally or by injection or parenterally. The invention also includes the compounds of Formula 1 according to the invention for usage in one of the said methods.
In the following Examples, all formulations are prepared in conventional ways. Compound numbers refer to compounds in Index Tables A through C. Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Percentages are by weight except where otherwise indicated. Example A
Figure imgf000069_0001
The active ingredient is dissolved in methylene chloride, sprayed onto the carrier and the solvent subsequently concentrated by evaporation under vacuum. Granulates of this kind can be mixed with the animal feed.
Example B
Figure imgf000069_0002
The finely ground active ingredient is evenly applied in a mixer to the kaolin which has been moistened with polyethylene glycol. In this way, dust-free coated granules are obtained.
Example C
Figure imgf000069_0003
1) Methyl cellulose is stirred into water. After the material has swollen, silicic acid is stirred in and the mixture homogeneously suspended. The active ingredient and the corn starch are mixed. The aqueous suspension is worked into this mixture and kneaded to a dough. The resulting mass is granulated through a 12 M sieve and dried. 2) All 4 excipients are mixed thoroughly.
3) The preliminary mixes obtained according to 1 and 2 are mixed and pressed into tablets or boli.
Example D
Figure imgf000070_0001
The active ingredient is dissolved in part of the oil while stirring and, if required, with gentle heating, then after cooling made up to the desired volume and sterile-filtered through a suitable membrane filter with a pore size of 0.22 μιη.
"ad" means enough of this component is added to a mixture of the other components to make a specified total volume (100 mL in this case) for the formulation.
Example E
Figure imgf000070_0002
The active ingredient is dissolved in part of the solvent while stirring, made up to the desired volume and sterile-filtered through a suitable membrane filter with a pore size of 0.22 μπι.
Example F
Injectable: Aqueous Solubilisate (rapid release)
1) compound 181 0.1 - 1.0 g
1) polyethoxylated castor oil (40 ethylene oxide units) 10 g
1) 1 ,2-propanediol 20 g Injectable: Aqueous Solubilisate (rapid release)
1) benzyl alcohol i g
1) water for injection ad 100 mL
2) compound 1 0.1 - 1.0 g
2) polyethoxylated sorbitan monooleate (20 ethylene oxide 8 g
units)
2) 4-hydroxymethyl-l,3-dioxolane (glycerol formal) 20 g
2) benzyl alcohol i g
2) water for injection ad 100 mL
The active ingredient is dissolved in the solvents and the surfactant, and made up with water to the desired volume. The solution is then sterile-filtered through a suitable membrane filter with a pore size of 0.22 μιη.
Example G
Figure imgf000071_0001
The aqueous systems may also preferably be used for oral and/or intraruminal application.
In general for veterinary use, a compound of Formula 1, an N-oxide, or salt thereof, is administered in a parasiticidally effective amount to an animal to be protected from helminth parasite pests. A parasiticidally effective amount is the amount of active ingredient needed to achieve an observable effect diminishing the occurrence or activity of the target helminth parasite pest. One skilled in the art will appreciate that the parasitically effective dose can vary in accordance with the mode and frequency of administration for the various compounds and compositions of the present invention, the desired parasitical effect and duration, the target helminth 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 administration to homeothermic animals, the daily dosage of a compound of the present invention typically ranges from about 0.01 mg/kg to about 100 mg/kg, more typically from about 0.5 mg/kg to about 100 mg/kg, of animal body weight. For topical (e.g., dermal) administration, dips and sprays typically contain from about 0.5 ppm to about 5000 ppm, more typically from about 1 ppm to about 3000 ppm, of a compound of the present invention.
Compounds of the present invention have activity on members of the classes Nematoda (roundworms), Trematoda (flukes), Acanthocephala and Cestoda (tapeworms). Important helminths are those that cause serious diseases of mammals and poultry, e.g. sheep, pigs, goats, cattle, horses, donkeys, dogs, cats, guinea-pigs and birds. Typical nematodes of this indication are: Haemonchus, Trichostrongylus, Teladorsagia, Dirofilaria, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostonum, Oesophagostonum, Charbertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris. The trematodes include the family of Fasciolideae, especially Fasciola hepatica. Certain pests of the species Nematodirus, Cooperia and Oesophagostonum infest the intestinal tract of the host animal, while others of the species Haemonchus and Ostertagia are parasitic in the stomach and those of the species Dictyocaulus are parasitic in the lung tissue. Parasites of the families Filariidae and Setariidae may be found in the internal cell tissue and in the organs, e.g. the heart, the blood vessels, the lymph vessels and the subcutaneous tissue. A notable parasite is the heartworm of the dog, Dirofilaria immitis. Important pests of the class Cestoda (tapeworms) include, the families Anoplocephalidae, especially of the genus Moniezia, in particular M expansa; Mesocestoidae, especially of the genus Mesocestoides, in particular M. lineatus; Dilepidide, especially Dipylidium caninum, Joyeuxiella spp., in particular Joyeuxiella pasquali, and Diplopylidium spp., and Taeniidae, especially Taenia pisiformis, Taenia cervi, Taenia ovis, Taneia hydatigena, Taenia multiceps, Taenia taeniaeformis, Taenia serialis, and Echinocuccus spp., most preferably Taneia hydatigena, Taenia ovis, Taenia multiceps, Taenia serialis; Echinocuccus granulosus and Echinococcus multilocularis, as well as Multiceps multiceps. Another notable parasite is Anoplocephala perfoliata in horses.
The compounds of the present invention may be suitable for the control of human pathogenic parasites. Of these, typical representatives that appear in the digestive tract are those of the species Ancylostoma, Necator, Ascaris, Strongy hides, Trichinella, Capillaria, Trichuris and Enterobius. The compounds of the present invention may also be effective against parasites of the species Wuchereria, Brugia, Onchocerca and Loa from the family of Filariidae, which appear in the blood, in the tissue and in various organs, and also against Dracunculus and parasites of the species Strongyloides and Trichinella, which infect the gastrointestinal tract in particular.
Numerous other Helminth genera and species are known to the art, and are also contemplated to be treated by the compounds of the invention. 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.
Compounds and compositions of the present invention are suitable for combating parasites that infest animal subjects including those in the wild, livestock and agricultural working animals such as cattle, sheep, goats, llamas, horses, pigs, donkeys, camels, bison, buffalos, deer, moose, elk, antelope, 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 the present invention allows more economic and simple husbandry of animals.
Compounds and compositions of the present invention are suitable for combating parasites that infest companion animals and pets (e.g., dogs, cats and pet birds), research and experimental animals (e.g., hamsters, guinea pigs, rats and mice), as well as animals raised for/in zoos, wild habitats (e.g., giraffes, zebras, rhinoceros and gazelles) and/or circuses.
In an embodiment of this invention, the animal is preferably a vertebrate, and more preferably a mammal or avian. 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, bison, 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 inventive compounds 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.
As a consequence of the above details, a further essential aspect of the present invention relates to combination preparations for the control of parasites on warm-blooded animals, characterised in that they contain, in addition to a compound of Formula 1, at least one further active ingredient having the same or different sphere of activity and at least one physiologically acceptable carrier. The present invention is not restricted to two-fold combinations.
The compounds of Formula 1 according to the invention may be used alone or in combination with other biocides. They may be combined with pesticides having the same sphere of activity e.g. to increase activity, or with substances having another sphere of activity e.g. to broaden the range of activity. It can also be sensible to add so-called repellents if the formulation is applied externally. They can also be used in combination with antibacterial compositions. Compounds which attack the juvenile stages of parasites may be very advantageous to add to those that function primarily as adulticides. In this way, the greatest range of those parasites that produce great economic damage will be covered. Moreover, this action will contribute substantially to avoiding the formation of resistance. Many combinations may also lead to synergistic effects, i.e. the total amount of active ingredient can be reduced, which is desirable from an ecological point of view. Preferred groups of combination partners and especially preferred combination partners are named in the following, whereby combinations may contain one or more of these partners in addition to a compound of Formula 1.
Of note are additional biologically active compounds or agents selected from art- known anthelmintics, such as, for example, macrocyclic lactones including but not limited to avermectins and derivatives thereof (e.g., ivermectin, moxidectin, milbemycin), benzimidazoles (e.g., albendazole, triclabendazole, cambendazole, fenbendazole, flubendazole,, mebendazole, oxfendazole, oxibendazole, parbendazole), salicylanilides (e.g., closantel, oxyclozanide), substituted phenols (e.g., nitroxynil), tetrahydropyrimidines (e.g., pyrantel pamoate, oxantel, morantel), imidazothiazoles (e.g., levamisole, tetramizole) and praziquantel. Additonal art-known anthelmintics include analogs and derivatives of the paraherquamide/marcfortine class, nitroscanate, and cyclic depsipeptides, e.g., emodepside. Of particular note are biologically active compounds or agents useful in the compositions of the present invention selected from the antiparasitic class of avermectin compounds mentioned above. The avermectin family of compounds is a series of very potent antiparasitic agents known to be useful against a broad spectrum of endoparasites and ectoparasites in mammals. A notable compound in this class 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 B^.
Other notable avermectins are abamectin, doramectin, dimadectin, latidectin, lepimectin, selamectin, milbemycin and derivatives thereof including but not limited to milbemectin, moxidectin, nemadectin and milbemycin D, emamectin, and eprinomectin. Eprinomectin is chemically known as 4"-epi-acetylamino-4"-deoxy-avermectin B^. 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 ecto- parasites while also leaving minimal residues in meat and milk. It has the additional advantage of being highly potent when delivered topically.
Also of note are nodulisporic acids and their derivatives, known in the art as a class of compounds that are potent endo- and ectopantiparasitic agents. The isolation and purification of three naturally occurring nodulisporic acids are disclosed in US 5,399,582. Derivatives of these compounds are described in WO 96/29073 and US Patent Nos. 5,945,317, 5,962,499, 5,834,260, 6,399,796, 6,221,894, 6,136,838, 5,595,991, 5,299,582, and 5,614,546.
The composition of the present invention optionally comprises combinations of one or more of the following antiparasite compounds: imidazo[l,2-b]pyridazine compounds as described by U.S. application Ser. No. 11/019,597, filed on Dec. 22, 2004, and published on Aug. 18, 2005 as U.S. 2005-0182059A1; trifluoromethanesulfonanilide oxime ether derivatives, as described by U.S. application Ser. No. 11/231,423, filed on Sep. 21, 2005, now U.S. Patent 7,312,248; and N-[(phenyloxy)phenyl]-l,l,l-trifluoromethanesulfonamide and N-[(phenylsulfanyl)phenyl]-l,l,l-trifluoromethanesulfonamide derivatives, as described by U.S. Provisional Application Ser. No. 60/688,898, filed on Jun. 9, 2005, and published as US 2006-0281695A1 on Dec. 14, 2006.
The compositions of the present invention can also further comprise a flukicide. Suitable flukicides include, for example, triclabendazole, fenbendazole, albendazole, clorsulon and oxibendazole. It will be appreciated that the above combinations can further include combinations of antibiotic, antiparasitic and anti-fluke active compounds.
In addition to the above combinations, it is also contemplated to provide combinations of the inventive methods and compounds, as described herein, with other animal health remedies such as trace elements, anti-inflammatories, anti-infectives, hormones, dermatological preparations, including antiseptics and disinfectants, and immunobiologicals such as vaccines and antisera for the prevention of disease.
For example, such anti-infectives include one or more antibiotics that are optionally co-administered during treatment using the inventive compounds or 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.
Useful antibiotics are chloramphenicol analogs such as florfenicol, also known as D- (threo)- 1 -(4-methylsulfonylphenyl)-2-dichloroacetamido-3-fluoro- 1 -propanol. Other notable chloramphenicol analogs include thiamphenicol and D-(threo)-l-(4-methylsulfonyphenyl)-2- difluoroacetamido-3-fluoro-l-propanol. 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 (e.g., U.S. Patent Application Publication No. 2004/0082553, now US Patent 7,041,670, U.S. patent application Ser. No. 11/016,794, now US Patent 7,153,842, and U.S. application Ser. No. 11/018,156, filed on Dec. 21, 2004, now US Patent 7,361,689).
Other useful antibiotics for use in the present invention are macrolide antibiotics such as tilmicosin.and tulathromycin.
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. 6,514,945, U.S. 6,472,371, U.S. 6,270,768, U.S. 6,437,151, U.S. 6,271,255, U.S. 6,239,112, U.S. 5,958,888, U.S. 6,339,063 and U.S. 6,054,434.
Other antibiotics may include β-lactams such as cephalosporins, e.g., ceftiofur, cefquinome, etc., and penicillins, e.g., penicillin, ampicillin, amoxicillin, or a combination of amoxicillin with clavulanic acid or other beta lactamase inhibitors.
Another useful antibiotic class includes the fluoroquinolones, such as, for example, enrofloxacin, danofloxacin, difloxacin, orbifloxacin and marbofloxacin.
Other useful antibiotics include the tetracyclines, particularly chlortetracycline and oxytetracycline.
Representative compounds of this invention prepared by the methods described herein are shown in Index Tables A-F. See Index Table G for 1H NMR data. For mass spectral data (AP+ (M+l)), the numerical value reported is the molecular weight of the parent molecular ion (M) formed by addition of H+ (molecular weight of 1) to the molecule to give a M+l peak observed by mass spectrometry using atmospheric pressure chemical ionization (AP+). The alternate molecular ion peaks (e.g., M+2 or M+4) that occur with compounds containing multiple halogens are not reported. The reported M+l peaks were observed by mass spectrometry using atmospheric pressure chemical ionization (AP+) or electrospray ionization (ESI).
The following abbreviations are used in the Index Tables which follow: Cmpd means Compound, CF3 means trifluoromethyl, t is tertiary, s is secondary, n is normal, i is iso, c is cyclo, Me is methyl, Et is ethyl, Pr is propyl, z'-Pr is isopropyl, t-Bu is tert-bvXy\, Ph is phenyl, OMe is methoxy, OEt is ethoxy, SMe is methylthio, CN is cyano ,N02 is nitro and Me2NCO is dimethyl amide.
The wavy line in the Index Tables indicates the point of attachment of each group to Formula 1. The naming convention used for Qi-J substituents is for example (compound 1): 4-(2,4-dichlorophenyl)phenyl indicates that J is a phenyl group with two chloro substituents in the 2 and 4 positions, bonded to the Q1 phenyl ring in the Q1 ring's 4 position. The Q1 phenyl ring is bonded to rest of Formula 1 in the 1 position. An alternative nomenclature for the Q!-J substituents is for example (compound 1): 2',4'-dichloro[l, -biphenyl]-4-yl.
Figure imgf000077_0001
AP+
Cmpd. (M+l) m.p. (°C)
1 4 - (2 ,4 -dichlorophenyl)phenyl 173-174
2 4 - (4 , 6 -dichloropyridin- 3 -yl)phenyl 167-168
3 4 - (4 , 6 -dichloropyridin- 3 -yl)phenyl 172-173
4 4-(phenoxy)phenyl 115-116
5 4 - (4 - formylphenyl)phenyl 170-172
6 4- (4 - acetylphenyl)phenyl 178-179
7 4 - (4 - cy anophenyl)phenyl 195-196
8 4-[(4-Me2NCO)phenyl]phenyl 107-108
9 4 - (4 -methylsulfonylphenyl)phenyl 159-160
10 4 - (4-methylthiophenyl)phenyl 169-170
11 4-[(3-C02Et)phenyl]phenyl 100-101
13 4 -methoxyphenyl 150-152
14 4 - (trifluoromethoxy)phenyl 142-143
15 4-(feri-butyl)phenyl 146-147 AP+
Cmpd. (M+l) m.p. (°C)
19 4 - (2 -methylsulfonylphenyl)phenyl 224-226
21 3 -(6-phenoxy)pyridin-3 -yl 108-110
23 4-nitrophenyl 203-206
24 4-iodophenyl 198-200
25 4-bromophenyl 166-168
26 5-bromothien-2-yl 172-175
27 6-(4-cyano-3 -fluorophenyl)pyridin-3 -yl 205-208
28 6-(3 -cyanophenyl)pyridin-3 -yl 210-213
29 6-(4-cyanophenyl)pyridin-3 -yl 233-236
30 4-(MeCONH)phenyl 136-137
31 4-cyanophenyl 188-189
32 4-ethylphenyl 155-156
33 6-(3 -cyano-5-fluorophenyl)pyridin-3 -yl 195-198
34 6-(3 -chloro-4-cyanophenyl)pyridin-3 -yl 219-222
35 5 - (3 - cy ano- 5 - fluorophenyl)thien-2 -yl 208-211
36 5 - (4- cy ano- 3 - fluorophenyl)thien-2 -yl 217-220
37 6 -bromopyridin- 3 -yl 197-199
39 5 - (3 - cy anophenyl)thien-2 -yl 214-216
40 4-(«-butoxy)phenyl 128-129
41 5 - (4 - cy anopheny 1) thien- 2 -yl 213-216
42 3-iodophenyl 165-168
43 5 -(3 -chloro-4-cyanophenyl)thien-2-yl 212-214
45 4-(HC≡CCH20)phenyl 135-137
46 4-(EtCONH)phenyl 146-149
47 4-(MeC≡CCH20)phenyl 135-137
48 4-(/-PrCONH)phenyl 195-198
169 4 -fluorophenyl 163-165
172 3-bromophenyl 377
174 4-(CH=CHCH2CH2Cl)phenyl 387
175 6 - chloronaphthalen-2 -yl 383
176 4-(2-nitrophenyl)phenyl 420
177 4-(3 -cyanophenyl)phenyl 400
178 4 - (2 - cy anophenyl)phenyl 400
179 4-[3-(MeS02)phenyl]phenyl 453 AP+
Cmpd. Q!-J (M+1)
180 4-(4-nitrophenyl)phenyl 420
182 naphthalen-2-yl
183 4-[2,4-di(trifluoromethyl)phenyl]phenyl 511
184 4-[2-chloro-4-(tri£luoromethyl)phenyl]plienyl 477
185 4-(2,3-dimethylphenyl)phenyl 404
186 4-(2,5-dichlorophenyl)phenyl 443
** See Index Table G for 1 H NMR data.
Figure imgf000079_0001
Figure imgf000079_0002
Figure imgf000080_0001
Figure imgf000081_0001
AP+ m.p.
Cm d. Structure (M+l) (°Q
Figure imgf000082_0001
INDEX TABLE D
Figure imgf000082_0002
Cmpd. m.p. (°C)
55 2-nitrophenyl 155-160 56 4 -bromo-2 - (trifluoromethoxy)phenyl 164-169 57 4 - (phenyl)phenyl 180-181 58 4 -( feri-butyl)phenyl 174-176 Cmpd. m.p. (°C)
59 4-(3-chloro-2-cyanophenoxy)phenyl 122-124
60 4-methylphenyl 155- 158
61 4 - (tri fluoromethoxy)phenyl 122-126
62 2 -nitro-4 - (tri fluoromethyl)pheny 1 173-175
63 3 -chloro-4-(MeCONH)phenyl 105-110
64 4-bromophenyl 176-177
65 4 -bromo- 2 -methylphenyl 118-120
66 4-bromo-2-ethylphenyl 125- 129
67 4-chloro-3 -nitrophenyl 163-165
68 4 - (2 - chlorophenyl)phenyl 75-78
69 4-(3 -nitrophenyl)phenyl 163-172
70 4-(3 -methylphenyl)phenyl 134-138
71 4 - (2 ,4 -dichlorophenyl)phenyl 165-169
72 4-iodophenyl 184- 186
73 2-(trifluoromethoxy)-4-(3-trifluoromethylphenyl)phenyl 143-147
74 2 -(trifluoromethoxy ) -4- (4 - chlorophenyl)pheny 1 206-210
75 2 - (trifluoromethoxy) -4 - (3 -methylphenyl)phenyl 126-129
76 2 -methyl-4 - (4 - chlorophenyl)phenyl 181-184
77 2-methyl-4-(3-methylphenyl)phenyl 104-106
78 2-ethyl-4-(3-methylphenyl)phenyl 1 15- 1 19
79 2 -ethy 1-4 - (4 - chlorophenyl)pheny 1 190-197
81 4-(HOCH2C≡C)phenyl 155-156
85 4-(C02H)phenyl 240-241
86 4-(C02Me)phenyl 155-157
94 2-bromophenyl 144- 146
95 3-bromophenyl 138- 140
103 4-bromo-2,5-dichlorothien-3-yl 151-153
109 2-chloro-4-fluorophenyl 126-127
110 5 -bromo- 6 - chloropyridin-3 -yl 143-145
111 2,4,6- trime thy lpheny 1 147-149
112 4 - chloro- 2 , 5 -dimethylphenyl 139- 140
1 13 2,3 ,4-trichlorophenyl 176- 177
114 2,4-dicyanophenyl 172-174
115 2 , 5 -dichlorophenyl 178-180
116 1 -naphthalenyl 163-164 Cmpd. Q^J m.p. (°C)
117 2-chlorophenyl 142-144
133 4-cyanophenyl 157-161
134 3-cyanophenyl 170-172 157 3-(C02Et)phenyl 81-84
162 4-(phenoxy)phenyl 116-118
166 4-(4-fluorophenoxy)phenyl 101-103
167 4-(4-chlorophenoxy)phenyl 108-110
Figure imgf000084_0001
J is H
m.p.
Cmpd. Rl (R13)x (°C)
80 H 4-[C≡CC(OH)Me2] 153-155
82 Me 4 -phenyl 158-160
83 Et 4 -phenyl 118-120
84 Me 4-Br 102-104
87 Me 4-(2,4-dichlorophenyl) 93-96
88 Me 4-(3 -fluorophenyl) 95-100
89 Me 4-(3 -methylphenyl) 110-113
90 Me 4 - [ 3 - (tri fluoromethyl)pheny 1] 82-84
91 Me 4-(3 -nitrophenyl) 136-139
92 Me 4-(3 -chlorophenyl) 87-90
93 Me 4 - (4 - chlorophenyl) 137-141
96 H 4-[COOCH2 [4-(trifluoromethyl)phenyl] ] 161-164
97 H 4-[COOCH2[4-(feri-butyl)phenyl]] 161-163
98 H 4-[COOCH2(4-methoxyphenyl)] 119-124
99 H 4-[COOCH2[3-(trifluoromethyl)phenyl]] 124-125 m.p.
Cmpd. Rl (R13)x (°C)
100 H 4-[COOCH2(2-chlorophenyl)] 142- 143
101 H 4-[COOCH2(2-methoxyphenyl)] 132-133
102 H 4-[COOCH2(2-methylphenyl)] 154-155
105 H 3-[CONH(4-bromophenyl)] 214-216
106 H 3-[CONH(phenyl)] 136-139
107 H 3-[CONH[4-(«-butyl)phenyl]] 173-175
108 H 3-[CONH[4-(tri£luoromethoxy)phenyl]] 130- 133
118 H 3-[CONH(4-cyanophenyl)] 199-201
119 H 3 -[CONH[4-(trifluoromethyl)phenyl] ] 186-192
120 H 3-[CONH[4-(ter/-butyl)phenyl]] 98- 103
121 H 3 - [CONH(3 -bromophenyl)] 110-1 12
122 H 3 -[CONH(3 -methylphenyl)] 89-93
123 H 3 - [CONH(3 -ethylphenyl)] 72-76
124 H 3 - [CONH(3 -methoxyphenyl)] 80-86
125 H 3 -[CONH[3 -(trifluoromethyl)phenyl] ] 131-133
126 H 3-[CONH[3-(tri£luoromethoxy)phenyl]] 116- 118
127 H 3 -[CONH(3 -nitrophenyl)] 194-196
128 H 4-[CONH(phenyl)] 211-216
129 H 4-[CONH[4-(tri£luoromethoxy)phenyl]] 218-221
130 H 4-[CONH(4-bromophenyl)] 229-233
131 H 4-[CONH[4-(feri-butyl)phenyl]] 210-212
132 H 4-[CONH[4-(«-butyl)phenyl]] 182- 185
137 H 4-[CONH(4-cyanophenyl)] 223-225
138 H 4-[CONH[4-(trifluoromethyl)phenyl]] 223-225
139 H 4-[CONH(3-bromophenyl)] 168- 170
140 H 4-[CONH(3-methylphenyl)] 200-210
141 H 4-[CONH(3-ethylphenyl)] 165-166
142 H 4-[CONH(3-methoxyphenyl)] 205-208
143 H 4-[CONH[3 -(trifluoromethyl)phenyl] ] 174-175
144 H 4-[CONH[3-(trifluoromethoxy)phenyl]] 160-162
145 H 4-[CONH(3-nitrophenyl)] 181- 183
160 H 3-CO(phenyl) 124-126
161 H 4-CO(phenyl) 150-151
163 H 4-CO(4-methylphenyl) 189- 191 (R13)x
4-CO(4-fluorophenyl)
4-CO(4-fluoro-3 -methylphenyl)
INDEX TABLE F
m.p.
Cmpd. °C)
Figure imgf000086_0001
m.p.
Cmpd. Structure (°Q
Figure imgf000087_0001
m.p.
Cmpd. Structure (°Q
Figure imgf000088_0001
Figure imgf000089_0001
INDEX TABLE G
Cmpd No. 1 H NMR Data a
182 δ (CDC13) 8.74 (1H, d), 8.47 (1H, d), 8.05 (1H, d), 7.90 (5H, m), 7.66 (3H, m), 7.50 (1H, dd), 7.28 (1H, d), 5.13 (1H, bs.), 4.66 (2H, d).
a NMR data are in ppm downfield from tetramethylsilane. CDCI3 solution unless indicated otherwise. DMSO-dg is CD3S(0)CD3. Couplings are designated by (s)-singlet, (d)-doublet, (t)-triplet, (m) -multiple t, (dd)-doublet of doublets, (br s)-broad singlet.
The following Tests demonstrate the control efficacy of compounds of this invention on specific parasitic pests. The pest control protection afforded by the compounds is not limited, however, to these species. Compound numbers refer to compounds in Index Tables A-F.
BIOLOGICAL EXAMPLES OF THE INVENTION
TEST A
For evaluating control of the barber pole worm {Haemonchus contortus), a test compound was solubilized in culture media (Earle's Balanced Salt Solution) containing Haemonchus contortus eggs to obtain a final test compound concentration of 2.0 ppm. The test unit was evaluated for mortality 120 hours later after which the eggs had hatched and had advanced to the L3 stage.
Of the compounds tested, the following caused 100% mortality: 1, 2, 3, 4, 7, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 25, 26, 27, 31, 32, 33, 34, 35, 36, 39, 40, 41, 43, 44, 57, 68, 70, 71, 76, 78, 82, 87, 89, 90, 92, 93, 132, 159, 162, 163, 166, 167, 168, 171, 172, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185 and 186.

Claims

CLAIMS What is claimed is:
1. A method for treating an animal in need of such treatment for infection by helminths which comprises orally, topically, parenterally or subcutaneously administering to the animal a parasiticidally effective amount of a compound of Formula 1, or a
pharmaceutically or veterinarily acceptable salt or a composition comprising it,
Figure imgf000090_0001
wherein
R1 is hydrogen, C1-C4 alkyl, C2-Cg alkylcarbonyl or C2-Cg alkoxycarbonyl;
R2 and R3 are each independently hydrogen, halogen, cyano, hydroxyl, amino, nitro,
CHO, SF5, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or
S(O)2NR10Rn; or -Q, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn,
S(0)pR12 and S(O)2NR10Rn; or G; or
R2 and R3 are taken together with the carbons to which they are attached to form a 5- to 6-membered carbocyclic or heterocyclic ring optionally substituted with up to 3 substituents independently selected from R4a on carbon atom ring members and
R4b on nitrogen atom ring members;
G is a phenyl ring or an 8- to 10-membered carbocyclic bicyclic ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R5a; or
G is a 5- to 7-membered heterocyclic ring or an 8- to 10-membered heterocyclic
bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R5a on carbon atom ring members and
R5^ on nitrogen atom ring members;
X is CR4c or N;
Y is CR4d or N;
Q1 is 3- to 7-membered carbocyclic ring or an 8- to 10-membered carbocyclic bicyclic ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R13a; or
Q1 is a 5- to 7-membered heterocyclic ring or an 8- to 10-membered heterocyclic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2
O, up to 2 S and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R13a on carbon atom ring members and R13b on nitrogen atom ring members;
J is hydrogen; or phenyl or naphthalenyl each optionally substituted with up to 5
substituents independently selected from R14a; or
J is a 5- to 7-membered heterocyclic ring or an 8- to 10-membered heterocyclic
bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R1 a on carbon atom ring members and
R1 ^ on nitrogen atom ring members; or
J is L-Q2;
L is O, S, SO, S02, NR15, (CH2)n, OCH2, or CH20;
Q2 is a 3- to 7-membered carbocyclic ring or an 8- to 10-membered carbocyclic
bicyclic ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R16a; or
Q2 is a 3- to 7-membered heterocyclic ring or an 8- to 10-membered heterocyclic bicyclic ring system, each ring or ring system containing ring members selected from carbon atoms and up to 4 heteroatoms independently selected from up to 2 O, up to 2 S and up to 4 N atoms, and optionally substituted with up to 5 substituents independently selected from R16a on carbon atom ring members and Rl6b on nitrogen atom ring members;
each R a is independently halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF5, OR6, NR7aR7b c(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or ^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-C7 cycloalkyl, Cz Cg cycloalkylalkyl or C5-C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and
S(O)2NR10Rn; or G;
R4b is cyano, -CHO, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or -Q, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and S(O)2NR10Rn; or G;
R c and R ^ are each independently hydrogen, halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF5, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or -Q, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and S(O)2NR10Rn; or G;
each R5a is independently halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF5, OR6, NR7aR7b c(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or C^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3~C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and
S(O)2NR10Rn;
R5b is cyano, -CHO, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or -Q, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and S(O)2NR10Rn;
each R6 is independently hydrogen, C2-Cg alkylcarbonyl, C2-Cg alkoxycarbonyl, C2- C^ alkylaminocarbonyl, C3-C6 dialkylaminocarbonyl, C^-C^ alkylsulfenyl, C^- Cg alkylsulfinyl, C^-Cg alkylsulfonyl, C2-Cg alkylaminosulfonyl or C3-C6 dialkylaminosulfonyl; or C^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl or benzyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, C^-Cg alkoxy, C^-Cg alkylamino, C2- Cg dialkylamino, C2-Cg alkylcarbonyl, C2-Cg alkoxycarbonyl, C2-Cg alkylaminocarbonyl, C3-C6 dialkylaminocarbonyl, C^-Cg alkylsulfenyl, C^-Cg alkylsulfinyl, C^-Cg alkylsulfonyl, C2~Cg alkylaminosulfonyl and C3~Cg dialkylaminosulfonyl; or C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5-C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, -C4 haloalkyl, C1-C4 alkoxy, -C4 alkylsulfenyl, C1-C4 alkylsulfinyl and -C4 alkylsulfonyl;
each R7a is independently hydrogen, C2~Cg alkylcarbonyl, C2~Cg alkoxycarbonyl, C2- Cg alkylaminocarbonyl, C3~Cg dialkylaminocarbonyl, C^-Cg alkylsulfenyl, C^- Cg alkylsulfinyl or C^-Cg alkylsulfonyl, C2~Cg alkylaminosulfonyl or C3~Cg dialkylaminosulfonyl; or C^-Cg alkyl, C2~Cg alkenyl, C2~Cg alkynyl or benzyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, C^-Cg alkoxy, C^-Cg alkylamino, C2- Cg dialkylamino, C2~Cg alkylcarbonyl, C2~Cg alkoxycarbonyl, C2~Cg alkylaminocarbonyl, C3~Cg dialkylaminocarbonyl, C^-Cg alkylsulfenyl, C^-Cg alkylsulfinyl, C^-Cg alkylsulfonyl, C2~Cg alkylaminosulfonyl and C3~Cg dialkylaminosulfonyl; or C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5-C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, -C4 alkyl, -C4 haloalkyl, -C4 alkoxy, -C4 alkylsulfenyl, C1-C4 alkylsulfinyl and -C4 alkylsulfonyl;
each R7b is independently hydrogen; or C^-Cg alkyl, C2~Cg alkenyl, C2~Cg alkynyl or benzyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, Cj-Cg alkoxy, C^-Cg alkylamino, C2~Cg dialkylamino, C2~Cg alkylcarbonyl, C2~Cg alkoxycarbonyl, C2~Cg alkylaminocarbonyl, C3~Cg dialkylaminocarbonyl, C^-Cg alkylsulfenyl, C^-Cg alkylsulfinyl, C^-Cg alkylsulfonyl, C2~Cg alkylaminosulfonyl and C3~Cg dialkylaminosulfonyl;
R8, R9, R10 and R12 are each independently hydrogen; or C^-Cg alkyl, C2~Cg alkenyl, C2~Cg alkynyl, phenyl, benzyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5- C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, -C4 alkyl, -C4 haloalkyl, -C4 alkoxy, -C4 haloalkoxy, C2~Cg alkoxycarbonyl, C2~Cg alkylaminocarbonyl, C2~Cg dialkylaminocarbonyl, C1-C4 alkylsulfenyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylsulfenyl, C1-C4
haloalkylsulfmyl and C1-C4 haloalkylsulfenyl; each R1 1 is independently hydrogen; or C^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl or benzyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C - C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylsulfenyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylsulfenyl, C1-C4 haloalkylsulfinyl and C1-C4 haloalkylsulfonyl;
each R13a is independently halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF5, OR6, NR7aR7b c(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or C^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5-C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and
S(O)2NR10Rn;
R13b is cyano, -CHO, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(0)2NR1°R1 !; or -Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and S(O)2NR10Rn;
each R14a is independently halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF5, OR6,
NR7aR7b c(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or C^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3~C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10R1 !, S(0)pR12 and
S(O)2NR10Rn;
R14b is cyano, -CHO, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or -Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and S(O)2NR10Rn;
R15 is hydrogen, cyano, -CHO, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn,
S(0)pR12 or S(O)2NR10Rn; or Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C7 cycloalkyl, C4-C8 cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and S(O)2NR10Rn;
each R16a is independently halogen, cyano, hydroxyl, amino, nitro, -CHO, -SF5, OR6, NR7aR7b c(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 or S(O)2NR10Rn; or ^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-C7 cycloalkyl, Cz Cg cycloalkylalkyl or C5-C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and
S(O)2NR10Rn; or G;
R16b is cyano, -CHO, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10R1 !, S(0)pR12 or
S(O)2NR10Rn; or Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, Cz Cg cycloalkylalkyl or C5~C7 cycloalkenyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano, nitro, OR6, NR7aR7b, C(0)R8, C(0)OR9, C(O)NR10Rn, S(0)pR12 and S(O)2NR10Rn; or G;
n is 1 or 2; and
p is 0, 1 or 2;
provided that
(a) when J is phenyl and Q1 is phenyl, then each R13a is hydrogen; and
(b) when L is S, SO, S02, NR15, (CH2)n, OCH2, or CH20, then Q2 is other than
phenyl.
2. The method of Claim 1 wherein
R2 and R3 are each independently hydrogen, halogen, cyano, nitro, OR6, S(0)pR12 or
C^-Cg alkyl optionally substituted with halogen; or
R2 and R3 are taken together with the carbons to which they are attached to form a 5- to 6-membered carbocyclic or heterocyclic ring optionally substituted with up to
3 substituents independently selected from R a on carbon atom ring members and R b on nitrogen atom ring members;
R4a is independently halogen, cyano, nitro, OR6, S(0)pR12 or C^-Cg alkyl optionally substituted with halogen;
X is CR4c;
Y is CR4d;
R c and R d are each independently hydrogen, halogen, cyano, nitro, OR6, S(0)pR12 or Cj-Cg alkyl optionally substituted with halogen;
Q1 is a ring selected from the group consisting of Q^-l through Q1-84 in Exhibit 2 wherein one of the floating bonds is connected to S02 in Formula 1 through any available carbon of the depicted ring or ring system and the other floating bond is connected to J in Formula 1 through any available carbon atom of the depicted ring or ring system; when R13 is attached to a carbon ring member, said R13 is selected from R13a, and when R13 is attached to a nitrogen ring member, said R13 is selected from R13b; and x is an integer from 0 to 5;
each R1 a is halogen, cyano, nitro, OR6, S(0)pR12 or C^-Cg alkyl optionally
substituted with halogen;
R13b is C(0)R8, C(0)OR9 or Ci-C6 alkyl;
J is a ring selected from the group consisting of J-1 through J-80 in Exhibit 3 wherein the floating bond is connected to Q1 in Formula 1 through any available carbon atom of the depicted ring or ring system; when R14 is attached to a carbon ring member, said R14 is selected from R1 a, and when R14 is attached to a nitrogen ring member, said R14 is selected from R1 b; and y is an integer from 0 to 5; or L-Q2;
each R1 a is halogen, cyano, nitro, OR6, S(0)pR12 or C^-Cg alkyl optionally
substituted with halogen;
R14b is C(0)R8, C(0)OR9 or -Cg alkyl;
L is O, S, S02 or CH2;
Q2 is a ring selected from the group consisting of Q2-l through Q2-84 in Exhibit 4 wherein the floating bond is connected to L in Formula 1 through any available carbon of the depicted ring or ring system; when R16 is attached to a carbon ring member, said R16 is selected from R16a, and when R16 is attached to a nitrogen ring member, said R16 is selected from R16b; and z is an integer from 0 to 5; each R16a is halogen, cyano, nitro, OR6, S(0)pR12 or C^-Cg alkyl optionally
substituted with halogen;
R16b is C(0)R8, C(0)OR9 or -Cg alkyl;
each R6 is independently hydrogen, C2-Cg alkylcarbonyl, or C2-Cg alkoxycarbonyl; or Cj-Cg alkyl or benzyl, each optionally substituted with substituents independently selected from the group consisting of halogen, cyano and C^-Cg alkoxy; or C3-C7 cycloalkyl optionally substituted with substituents
independently selected from the group consisting of halogen, C1-C4 alkyl and C1-C4 haloalkyl; and
R8, R9 and R12 are each independently hydrogen; or C^-Cg alkyl or C3-C7 cycloalkyl, each optionally substituted with substituents independently selected from the group consisting of halogen, -C4 alkyl and C1-C4 haloalkyl.
3. The method of Claim 2 wherein R1 is hydrogen, C1-C4 alkyl, C2-C4 alkylcarbonyl or C2-C4 alkoxycarbonyl;
R2 and R3 are taken together with the carbons to which they are attached to form a phenyl ring optionally substituted with up to 3 substituents independently selected from R4a;
each R4a is independently halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylsulfinyl, -C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or -C4 haloalkylsulfonyl;
R4c and R d are each independently hydrogen, halogen, cyano, nitro, C1-C4 alkyl, C - C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4
alkylsulfonyl or C1-C4 haloalkylsulfonyl;
Q1 is a ring selected from the group consisting of Ql-l through Ql-24;
each R13a is independently halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C - C4 alkoxy, C1-C4 haloalkoxy, -C4 alkylthio, C1-C4 haloalkylthio, -C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or -C4 haloalkylsulfonyl;
R13b is Ci-Q, alkyl;
x is an integer from 0 to 3;
J is is a ring selected from the group consisting of J-l through J-43; or L-Q2;
each R1 a is independently halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C^- C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl;
R14b is C!-C6 alkyl;
y is an integer from 0 to 3;
L is O, S, S02 or CH2;
Q2 is a ring selected from the group consisting of Q2-l through Q2-25 and Q2-43; each R16a is independently halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C^- C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C1-C4 alkylsulfonyl or C1-C4 haloalkylsulfonyl;
R16b is C!-C6 alkyl; and
z is an integer from 0 to 3.
4. The method of Claim 3 wherein Q1 is a ring selected from the group consisting of Ql-l, Ql-2, Ql-3, Ql-4, Ql-5,
Q!-10, Q!-l l, Q!-12, Q!-20 and Q!-24; and
J is is a ring selected from the group consisting of J-1 through J-8;J-19 and J-25; or L-
Q2-
5. The method of Claim 4 wherein
R1 is hydrogen;
Q1 is Q!-4 or Q!-24;
J is is a ring selected from the group consisting of J-1, J-2, J-5, J-6 and J-25; or L-Q2; L is O;
Q2 is Q2-25; and
each R4a is independently halogen.
6. The method of Claim 1 wherein the compound of Formula 1 is selected from the group consisting of:
4- phenoxy-N-(4-quinolinylmethyl)benzenesulfonamide;
2',4'-dichloro-N-(4-quinolinylmethyl)-[ 1 , 1 '-biphenyl]-4-sulfonamide;
N-(4-quinolinylmethyl)-5 -[5 -(trifluorometyl)-3 -isoxazolyl] -2- thiophenesulfonamide; and
5- [ 1 -methyl-3-(trifluoromethyl)- lH-pyrazol-5-yl]-N-(4-quinolinylmethyl)-2- thiophenesulfonamide .
7. A method for treating an animal by administering to the animal a composition comprising a parasiticidally effective amount of a compound of Claim 1 , and at least one pharmaceutically or veterinarily acceptable carrier or diluent.
8. A method for treating an animal by administering to the animal a composition comprising (a) a parasiticidally effective amount of a compound of Claim 1 ; and (b) at least one additional biologically active compound or agent.
9. The method of Claim 1 wherein the administration is enteral.
10. The method of Claim 9 wherein the administration is oral.
1 1. The method of Claim 1 wherein the administration is parenteral.
12. The method of Claim 11 wherein the administration is topical.
13. The method of Claim 1 wherein the helminth is Haemonchus contortus.
14. The method of Claim 13 wherein the administration is oral.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104292157A (en) * 2014-09-15 2015-01-21 湖南华腾制药有限公司 Preparation method of 1-(quinoline-4-yl) ethylamine
US10548911B2 (en) 2014-06-16 2020-02-04 University Of Rochester Small molecule anti-scarring agents
WO2022173727A1 (en) * 2021-02-09 2022-08-18 Celgene Corporation Sulfonamides and their use for treatment of helminthic infections and diseases

Citations (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4005199A (en) * 1975-01-16 1977-01-25 Merck & Co., Inc. Substituted benzenesulfonamides as anthelmintics
US5299582A (en) 1991-09-16 1994-04-05 Little Rapids Corporation Surgical isolation apparatus
US5399582A (en) 1993-11-01 1995-03-21 Merck & Co., Inc. Antiparasitic agents
WO1996029073A1 (en) 1995-03-20 1996-09-26 Merck & Co., Inc. Nodulisporic acid derivatives
US5595991A (en) 1995-03-20 1997-01-21 Merck & Co., Inc. Anthelmintic use of nodulisporic acid and analogs thereof
US5834260A (en) 1996-08-30 1998-11-10 Merck & Co., Inc. Antiparasitic agents
US5958888A (en) 1996-07-02 1999-09-28 Merial, Inc. Water miscible macrolide solutions
US5962499A (en) 1995-03-20 1999-10-05 Merck & Co., Inc. Nodulisporic acid derivatives
US6054434A (en) 1997-09-10 2000-04-25 Merck & Co., Inc. 8a-azalides as veterinary antimicrobal agents
US6136838A (en) 1998-03-19 2000-10-24 Merck & Co., Inc. Sulfurpentafluorophenylpyrazoles for controlling ectoparasitic infestations
US6221894B1 (en) 1995-03-20 2001-04-24 Merck & Co., Inc. Nodulisporic acid derivatives
US6239112B1 (en) 1998-07-09 2001-05-29 Merial, Inc. Water miscible macrolide solutions
US6270768B1 (en) 1999-01-28 2001-08-07 Pfizer Inc Azalides and methods of making same
US6271255B1 (en) 1996-07-05 2001-08-07 Biotica Technology Limited Erythromycins and process for their preparation
US6339063B1 (en) 1997-09-10 2002-01-15 Merck & Co., Inc. 9a-azalides as veterinary antimicrobial agents
US6399796B2 (en) 2000-03-17 2002-06-04 Roche Vitamins Inc. Activation of a Diels-Alder reaction of a sterol 5,7-diene
US6472371B1 (en) 1998-01-02 2002-10-29 Pfizer, Inc. Macrolides
US6514945B1 (en) 2000-01-27 2003-02-04 Pfizer Inc. Azalide antibiotic compositions
WO2005033081A1 (en) 2003-09-18 2005-04-14 Basf Aktiengesellschaft 4-piridinylmethylsulphonamide derivatives as fungicidal plant protection agents
US20050182059A1 (en) 2003-12-31 2005-08-18 Schering-Plough Animal Health Corporation Control of parasites in animals by the use of imidazo[1,2-b]pyridazine derivatives
EP1571150A1 (en) 2004-03-02 2005-09-07 Aventis Pharma Deutschland GmbH Process for the preparation of tryptase inhibitors
US7041670B2 (en) 2002-03-08 2006-05-09 Schering-Plough Animal Health Corporation Florfenicol-type antibiotics
WO2006097489A1 (en) * 2005-03-16 2006-09-21 Basf Aktiengesellschaft Biphenyl-n-(4-pyridyl) methylsufonamides
US20060281695A1 (en) 2005-06-09 2006-12-14 Schering-Plough Animal Health Corporation Control of parasites in animals by N-[(phenyloxy)phenyl]-1,1,1-trifluoromethanesulfonamide and N-[(phenylsulfanyl)phenyl]-1,1,1-trifluoromethanesulfonamide derivatives
US7153842B2 (en) 2003-12-23 2006-12-26 Schering-Plough Animal Health Corporation Florfenicol prodrug having improved water solubility
WO2007093599A1 (en) * 2006-02-14 2007-08-23 Basf Se Pyridin-4 -ylmethylamides for combating pests
WO2007104726A1 (en) 2006-03-15 2007-09-20 Basf Se Quinoline derivatives and their use as pesticides
US7312248B2 (en) 2004-09-23 2007-12-25 Schering-Plough Animal Health Corporation Control of parasites in animals by the use of novel trifluoromethanesulfonanilide oxime ether derivatives
WO2007147762A1 (en) 2006-06-20 2007-12-27 F. Hoffmann-La Roche Ag Arylsulfonamidyl tetralin derivatives and uses thereof
WO2008007211A1 (en) 2006-07-11 2008-01-17 Pfizer Japan Inc. Substituted n-bicyclicalkyl bicyclic carboxyamide compounds
WO2008022937A1 (en) * 2006-08-22 2008-02-28 Basf Se Thiophene-sulfonic acid picolyl amides
WO2008031824A1 (en) * 2006-09-12 2008-03-20 Basf Se Quinolinylmethyl compounds
US7361689B2 (en) 2003-12-31 2008-04-22 Schering-Plough Animal Health Corporation Antibacterial 1-(4-mono- and di-halomethylsulphonylphenyl)-2-acylamino-3-fluoroproponals and preparation thereof
WO2008062012A1 (en) * 2006-11-22 2008-05-29 Basf Se Pyridazin-4-ylmethyl-sulfonamides used as fungicides and against arthropods
WO2008062011A1 (en) 2006-11-22 2008-05-29 Basf Se Pyrimidylmethyl-sulfonamide compounds useful as fungicides and against arthropods
WO2008079292A1 (en) 2006-12-20 2008-07-03 Amgen Inc. Heterocyclic compounds and their use in treating inflammation, angiogenesis and cancer
WO2008090434A1 (en) 2007-01-25 2008-07-31 Pfizer Japan Inc. Substituted n-bicyclicalkyl bicyclic carboxyamide compounds
WO2010129500A2 (en) * 2009-05-04 2010-11-11 E. I. Du Pont De Nemours And Company Nematocidal sulfonamides
WO2010151797A2 (en) * 2009-06-26 2010-12-29 University Of Massachusetts Compounds for modulating rna binding proteins and uses therefor
WO2012177668A1 (en) * 2011-06-20 2012-12-27 E. I. Du Pont De Nemours And Company Heterocyclic compounds for treating helminth infections
WO2013081783A1 (en) * 2011-11-28 2013-06-06 E. I. Du Pont De Nemours And Company N- (4 -quinolinylmethyl) sulfonamide derivatives and their use as anthelmintics

Patent Citations (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4005199A (en) * 1975-01-16 1977-01-25 Merck & Co., Inc. Substituted benzenesulfonamides as anthelmintics
US5299582A (en) 1991-09-16 1994-04-05 Little Rapids Corporation Surgical isolation apparatus
US5399582A (en) 1993-11-01 1995-03-21 Merck & Co., Inc. Antiparasitic agents
US5614546A (en) 1993-11-01 1997-03-25 Merck & Co., Inc. Antiparasitic agents
US5962499A (en) 1995-03-20 1999-10-05 Merck & Co., Inc. Nodulisporic acid derivatives
WO1996029073A1 (en) 1995-03-20 1996-09-26 Merck & Co., Inc. Nodulisporic acid derivatives
US5595991A (en) 1995-03-20 1997-01-21 Merck & Co., Inc. Anthelmintic use of nodulisporic acid and analogs thereof
US6221894B1 (en) 1995-03-20 2001-04-24 Merck & Co., Inc. Nodulisporic acid derivatives
US5958888A (en) 1996-07-02 1999-09-28 Merial, Inc. Water miscible macrolide solutions
US6437151B2 (en) 1996-07-05 2002-08-20 Biotica Technology Limited Erythromycins and process for their preparation
US6271255B1 (en) 1996-07-05 2001-08-07 Biotica Technology Limited Erythromycins and process for their preparation
US5834260A (en) 1996-08-30 1998-11-10 Merck & Co., Inc. Antiparasitic agents
US5945317A (en) 1996-08-30 1999-08-31 Merck & Co., Inc. Antiparasitic agents
US6054434A (en) 1997-09-10 2000-04-25 Merck & Co., Inc. 8a-azalides as veterinary antimicrobal agents
US6339063B1 (en) 1997-09-10 2002-01-15 Merck & Co., Inc. 9a-azalides as veterinary antimicrobial agents
US6472371B1 (en) 1998-01-02 2002-10-29 Pfizer, Inc. Macrolides
US6136838A (en) 1998-03-19 2000-10-24 Merck & Co., Inc. Sulfurpentafluorophenylpyrazoles for controlling ectoparasitic infestations
US6239112B1 (en) 1998-07-09 2001-05-29 Merial, Inc. Water miscible macrolide solutions
US6270768B1 (en) 1999-01-28 2001-08-07 Pfizer Inc Azalides and methods of making same
US6514945B1 (en) 2000-01-27 2003-02-04 Pfizer Inc. Azalide antibiotic compositions
US6399796B2 (en) 2000-03-17 2002-06-04 Roche Vitamins Inc. Activation of a Diels-Alder reaction of a sterol 5,7-diene
US7041670B2 (en) 2002-03-08 2006-05-09 Schering-Plough Animal Health Corporation Florfenicol-type antibiotics
WO2005033081A1 (en) 2003-09-18 2005-04-14 Basf Aktiengesellschaft 4-piridinylmethylsulphonamide derivatives as fungicidal plant protection agents
US7153842B2 (en) 2003-12-23 2006-12-26 Schering-Plough Animal Health Corporation Florfenicol prodrug having improved water solubility
US20050182059A1 (en) 2003-12-31 2005-08-18 Schering-Plough Animal Health Corporation Control of parasites in animals by the use of imidazo[1,2-b]pyridazine derivatives
US7361689B2 (en) 2003-12-31 2008-04-22 Schering-Plough Animal Health Corporation Antibacterial 1-(4-mono- and di-halomethylsulphonylphenyl)-2-acylamino-3-fluoroproponals and preparation thereof
EP1571150A1 (en) 2004-03-02 2005-09-07 Aventis Pharma Deutschland GmbH Process for the preparation of tryptase inhibitors
US7312248B2 (en) 2004-09-23 2007-12-25 Schering-Plough Animal Health Corporation Control of parasites in animals by the use of novel trifluoromethanesulfonanilide oxime ether derivatives
WO2006097489A1 (en) * 2005-03-16 2006-09-21 Basf Aktiengesellschaft Biphenyl-n-(4-pyridyl) methylsufonamides
US20060281695A1 (en) 2005-06-09 2006-12-14 Schering-Plough Animal Health Corporation Control of parasites in animals by N-[(phenyloxy)phenyl]-1,1,1-trifluoromethanesulfonamide and N-[(phenylsulfanyl)phenyl]-1,1,1-trifluoromethanesulfonamide derivatives
WO2007093599A1 (en) * 2006-02-14 2007-08-23 Basf Se Pyridin-4 -ylmethylamides for combating pests
WO2007104726A1 (en) 2006-03-15 2007-09-20 Basf Se Quinoline derivatives and their use as pesticides
WO2007147762A1 (en) 2006-06-20 2007-12-27 F. Hoffmann-La Roche Ag Arylsulfonamidyl tetralin derivatives and uses thereof
WO2008007211A1 (en) 2006-07-11 2008-01-17 Pfizer Japan Inc. Substituted n-bicyclicalkyl bicyclic carboxyamide compounds
WO2008022937A1 (en) * 2006-08-22 2008-02-28 Basf Se Thiophene-sulfonic acid picolyl amides
WO2008031824A1 (en) * 2006-09-12 2008-03-20 Basf Se Quinolinylmethyl compounds
WO2008062012A1 (en) * 2006-11-22 2008-05-29 Basf Se Pyridazin-4-ylmethyl-sulfonamides used as fungicides and against arthropods
WO2008062011A1 (en) 2006-11-22 2008-05-29 Basf Se Pyrimidylmethyl-sulfonamide compounds useful as fungicides and against arthropods
WO2008079292A1 (en) 2006-12-20 2008-07-03 Amgen Inc. Heterocyclic compounds and their use in treating inflammation, angiogenesis and cancer
WO2008090434A1 (en) 2007-01-25 2008-07-31 Pfizer Japan Inc. Substituted n-bicyclicalkyl bicyclic carboxyamide compounds
WO2010129500A2 (en) * 2009-05-04 2010-11-11 E. I. Du Pont De Nemours And Company Nematocidal sulfonamides
WO2010151797A2 (en) * 2009-06-26 2010-12-29 University Of Massachusetts Compounds for modulating rna binding proteins and uses therefor
WO2012177668A1 (en) * 2011-06-20 2012-12-27 E. I. Du Pont De Nemours And Company Heterocyclic compounds for treating helminth infections
WO2013081783A1 (en) * 2011-11-28 2013-06-06 E. I. Du Pont De Nemours And Company N- (4 -quinolinylmethyl) sulfonamide derivatives and their use as anthelmintics

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 15, 2005, pages 4520 - 4525
E. J. L. SOULSBY: "Helminths, Arthropods and Protozoa", THE WILLIAMS AND WILKINS CO., article "6th Edition of Monnig's Veterinaiy Helminthology and Entomology"
G. W. H. CHEESEMAN; E. S. G. WERSTIUK: "Advances in Heterocyclic Chemistry", vol. 22, ACADEMIC PRESS, pages: 390 - 392
GREENE, T. W.; WUTS, P. G. M: "Protective Groups in Organic Synthesis, 2nd ed.;", 1991, WILEY
HELMINTHS, E. J. L; SOULSBY, F. A: "Textbook of Veterinary Clinical Parasitology", vol. 1, DAVIS CO.
INORGANIC CHEMISTRY, vol. 51, no. 12, 2012, pages 6428 - 6430
J. MED. CHEM., vol. 35, 1992, pages 2761 - 8
J. ORG. CHEM., vol. 54, 1989, pages 1731 - 5
JOURNAL FUER PRAKTISCHE CHEMIE/CHEMIKER-ZEITUNG, vol. 336, no. 8, 1994, pages 695 - 7
M. R. GRIMMETT; B. R. T. KEENE: "Advances in Heterocyclic Chemistry", vol. 43, ACADEMIC PRESS, pages: 149 - 161
M. TISLER; B. STANOVNIK: "Advances in Heterocyclic Chemistry", vol. 9, ACADEMIC PRESS, pages: 285 - 291
M. TISLER; B. STANOVNIK: "Comprehensive Heterocyclic Chemistry", vol. 3, PERGAMON PRESS, pages: 18 - 20
ORGANIC LETTERS, vol. 9, 2007, pages 5525 - 5528
T. L. GILCHRIST: "Comprehensive Organic Synthesis", vol. 7, PERGAMON PRESS, pages: 748 - 750
TETRAHEDRON LETT., vol. 51, 2010, pages 418 - 421

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WO2022173727A1 (en) * 2021-02-09 2022-08-18 Celgene Corporation Sulfonamides and their use for treatment of helminthic infections and diseases

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