WO2009071500A2 - Composés organiques - Google Patents

Composés organiques Download PDF

Info

Publication number
WO2009071500A2
WO2009071500A2 PCT/EP2008/066495 EP2008066495W WO2009071500A2 WO 2009071500 A2 WO2009071500 A2 WO 2009071500A2 EP 2008066495 W EP2008066495 W EP 2008066495W WO 2009071500 A2 WO2009071500 A2 WO 2009071500A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
substituted
unsubstituted
halogen
alkoxy
Prior art date
Application number
PCT/EP2008/066495
Other languages
English (en)
Other versions
WO2009071500A3 (fr
Inventor
Jörg FRÜCHTEL
Emilie Dupont
Thomas Goebel
Sandra Schorderet Weber
Jacques Bouvier
Original Assignee
Novartis Ag
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 Novartis Ag filed Critical Novartis Ag
Publication of WO2009071500A2 publication Critical patent/WO2009071500A2/fr
Publication of WO2009071500A3 publication Critical patent/WO2009071500A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
    • A01N43/38—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/46—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom rings with more than six members
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered

Definitions

  • the present invention relates to the use of specific tetrahydroindenylpyridine compounds in the control of ectoparasites and endoparasites in warm-blooded productive livestock and domestic animals and veterinary compositions containing said compounds.
  • GB-1262949 discloses terahydroindenylpyridines with a Ci-C 6 -alkylcarbonylmethyl substituent at the tetrahydropyridyl N-atom and their use as antidepressants.
  • WO 2006/89038 discloses a tetrahydroindenopyridine derivative with an ethoxycarbonylmethyl substituent at the tetrahydropyridyl N-atom, which has, however, a very poor insecticidal and acaricidal activity only. It has now been found out that tetrahydroindenopyridines bearing an ketone substituent at the N-atom have excellent pesticidal properties, especially against ectoparasites.
  • the present invention therefore in one aspect relates to the use of a compound of formula
  • each R 1 is independently halogen, cyano, nitro, unsubstituted or halogen-, cyano-, nitro-, hydroxy- or d-C 4 -alkoxy-substituted Ci-C 6 -alkyl, unsubstituted or halogen-substituted C 3 -C 6 - cycloalkyl, unsubstituted or halogen-substituted C 2 -C6-alkenyl, unsubstituted or halogen- substituted C 2 -C 6 -alkynyl, hydroxy, unsubstituted or halogen-substituted Ci-C 6 -alkoxy, unsubstituted or halogen-substituted C 2 -C6-alkenyloxy, unsubstituted or halogen-substituted C 2 -C 6 -alkynyloxy,
  • R 2 is hydrogen, Ci-C 6 -alkyl, unsubstituted or halogen-, Ci-C 4 -alkyl- or Ci-C 4 -alkoxy-substituted pheny or benzyl;
  • R 2 ' is hydrogen, halogen, cyano, Ci-C 6 -alkyl, unsubstituted or halogen-, Ci-C 4 -alkyl- or d-C 4 - alkoxy-substituted pheny or benzyl;
  • A is straight-chain or branched Ci-C ⁇ -alkylene or C 2 -C 8 -alkenylene; p and q are each independently an integer of O, 1 , 2 or 3 with the proviso that the total of (p+q) is an integer from 2 to 4;
  • M is a group -C(O)-, S(O)- Or -S(O 2 )-;
  • R 3 is Ci-C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkenyl, heterocycloaliphatyl, heterocycloaliphatyl-Ci-C 6 -alkyl, heterocycloaliphatyl-C 2 -C 6 -alkenyl, heterocycloaliphatyl-C 2 -C 6 -alkynyl, aryl, aryl-Ci-C 6 -alkyl, aryl-C 2 -C 6 -alkenyl, aryl-C 2 -C 6 -alkynyl, heteroaryl, heteroaryl-Ci-C 6 -alkyl, heteroaryl-Ci-C 6 -alkyl, heteroaryl-Ci-C 6 -alkyl, heteroaryl-Ci-C
  • R 4 , R 4 ', R 5 and R 5 ' are each independently of the other hydrogen, unsubstituted or halogen-, cyano-, nitro-, hydroxy- or Ci-C 4 -alkoxy-substituted Ci-C 6 -alkyl, unsubstituted or substituted benzyl, unsubstituted or substituted phenyl or unsubstituted or substituted heteroaryl, the benzyl, phenyl or heteroaryl substituents in each case independently from each other being selected from the group consisting of halogen, cyano, NO 2 , hydroxyl, Ci-C 6 -alkyl, halo-Ci-C 6 - alkyl, Ci-C 6 -alkoxy, halo-Ci-C 6 -alkoxy, NH 2 , Ci-C 6 -alkylamino, di-Ci-C 6 -alkylamino and d-C 6 - alky
  • Aryl as a group per se and as structural element of other groups and compounds such as arylalkyl, aryloxy, arylalkyloxy or arylthio is , for example, naphthyl or phenyl, in particular phenyl.
  • the aryl radical may be substituted by one or more same or different substituents selected, for example, from the above-given list for R 1 .
  • the radical heteroaryl - as a group per se and as structural element of other groups and compounds such as heteroarylalkyl, heteroaryloxy and heteroarylthio is, for example, a 5- to 7- membered heteroaromatic ring having from 1 to 4 same or different heteroatoms selected from the group consisting of N, O and S, or a derivative thereof with an annulated phenyl ring.
  • Examples are thiophenyl, furanyl, pyrryl, pyrrolidinyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, pyridyl, pyrimidyl, s-triazinyl, 1 ,2,4-triazinyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl, benzothienyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benztriazolyl, indolyl or indazolyl.
  • the radical heteroaryl is preferably a 5- or 6-membered heteroaromatic ring having 1 or 2 same or different heteroatoms selected from the group consisting of N, O and S.
  • a particularly preferred radical heteroaryl is pyridyl, pyrimidyl, pyrazolyl, imidazolyl or thiophenyl.
  • the radical heteroaryl may be substituted, for example, by halogen, cyano, nitro, Ci-C 6 -alkyl, halo-d-Ce-alkyl, C r C 6 -alkoxy, halo-C r C 6 -alkoxy, SH, C r C 6 -alkylthio, halo-C r C 6 -alkylthio, d- C 6 -alkylsulfinyl, CrC 6 -alkylsulfonyl, d-C 6 -alkoxycarbonyl, d-Ce-alkylcarbonylamino, acetyl, benzoyl or phenoxy.
  • Preferred heteroaryl substituents are cyano, halogen, halogen-substituted CrC 2 -alkyl, CrC 2 -alkyl, d-C 2 -alkoxy or halogen-substituted d-C 2 -alkoxy, in particular fluorine chlorine, bromine, trifluoromethyl, methyl, ethyl, methoxy, ethoxy or trifluoromethoxy.
  • Alkyl - as a group per se and as structural element of other groups and compounds such as halogen-alkyl, hydroxyl-alkyl, alkoxy-alkyl, R 4 R 5 N-alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl or alkylsulfonyloxy alkylsulfonylamino - is, in each case with due consideration of - A -
  • alkyl are methyl, ethyl or n- or isopropyl, in particular d-C 2 -alkyl and especially methyl or ethyl.
  • Alkylene is, in each case with due consideration of the specific number of carbon atoms in the group or compound in question, for example methylene or straight-chain or branched ethylene, propylene, butylene, pentylene, hexylene, heptylene or octylene, preferably straight-chain or branched Ci-C 4 -alkylene and even more preferably methylene or 1 ,2-ethylene.
  • Cycloalkyl - as a group per se and as structural element of other groups and compounds such as cycloalkyloxy, cycloalkylthio, cycloalkylsulfinyl or cycloalkylsulfonyl - is, in each case with due consideration of the specific number of carbon atoms in the group or compound in question, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in particular cyclopentyl or cyclohexyl.
  • Heterocycloaliphatyl - as a group per se and as structural element of other groups and compounds such as heterocycloaliphatyl-alkyl, -alkenyl or -alkynyl - is, in each case with due consideration of the specific number of carbon atoms in the group or compound in question, for example, a 4- to 7-membered, in particular a 5- or 6-membered, aliphatic ring radical comprising from 1 to 3, preferably 1 or 2, same or different heteroatoms selected from the group consisting of N, S and O. Examples are tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.
  • Alkenyl - as a group per se and as structural element of other groups and compounds such as alkenyloxy - is, in each case with due consideration of the specific number of carbon atoms in the group or compound in question and of the conjugated or isolated double bonds - either straight-chained, e.g. allyl, 2-butenyl, 3-pentenyl, 1-hexenyl or 1 ,3-hexadienyl, or branched, e.g. isopropenyl, isobutenyl, isoprenyl, tert.-pentenyl or isohexenyl.
  • Alkynyl - as a group per se and as structural element of other groups and compounds such as alkynyloxy - is, in each case with due consideration of the specific number of carbon atoms in the group or compound in question and of the conjugated or isolated double bonds - either straight-chained, e.g. propargyl, 2-butinyl, 3-pentinyl, 1-hexinyl, 1-heptinyl or 3-hexen-1-inyl, or branched, e.g. 3-methylbut-1-inyl, 4-ethylpent-1-inyl or 4-methylhex-2-inyl.
  • straight-chained e.g. propargyl, 2-butinyl, 3-pentinyl, 1-hexinyl, 1-heptinyl or 3-hexen-1-inyl, or branched, e.g. 3-methylbut-1-inyl, 4-ethylpent-1-inyl or 4-methylhex-2
  • Alkenyl and alkynyl moieties in each case can be of either (E)- or (Z)-configuration.
  • Alkoxy - as a group per se and as structural element of other groups - is for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy or tert.-butoxy; preferably d-C 2 - alkoxy, and especially methoxy or ethoxy.
  • Halogen - as a group per se and as structural element of other groups - preferably means, for example, iodine, bromine, chlorine or fluorine, preferably chlorine or fluorine.
  • Halo- or halogen-substituted carbon-containing groups and compounds such as halogen- substituted alkyl, alkylene, cycloalkyl, cycloalkylene, alkenylene, alkynylene, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, may be partially halogenated or perhalogenated, whereby in the case of multiple halogenation, the halogen substituents may be identical or different.
  • haloalkyl or halogen-substituted alkyl - as a group per se and as structural element of other groups and compounds such as halogen-alkoxy or halogen-alkylthio - are methyl which is mono- to tri-substituted by fluorine, chlorine and/or bromine, such as CHF 2 or especially CF 3 ; ethyl which is mono- to pentasubstituted by fluorine, chlorine and/or bromine, such as CH 2 CF 3 , CF 2 CF 3 , CF 2 CCI 3 , CF 2 CHCI 2 , CF 2 CHF 2 , CF 2 CFCI 2 , CF 2 CHBr 2 , CF 2 CHCIF, CF 2 CHBrF or CCIFCHCIF, in particular CF 2 CF 3 ; propyl or isopropyl, mono- to heptasubstituted by fluorine, chlorine and/or bromine, such as
  • the variables p and q are each independently of the other preferably an integer 1 or 2.
  • the total of the variables (p+q) is preferably an integer 2 or 3, in particular 3. Most preferably, p is 1 and q is 2.
  • variable R 2 is preferably hydrogen or CrC 4 -alkyl, more preferably hydrogen or Ci-C 2 -alkyl, and in particular hydrogen or especially methyl.
  • variable R 2 ' is preferably hydrogen, halogen, Ci-C 4 -alkyl, phenyl or benzyl, more preferably hydrogen chlorine, fluorine, CrC 2 -alkyl or phenyl, especially preferably hydrogen, chlorine methyl or phenyl, and in particular hydrogen.
  • variable A is preferably straight-chain or branched Ci-C 6 -alkylene, more preferably straight-chain or branched CrC 4 -alkylene, especially preferably straight-chain-Ci-C 4 -alkylene, and in particular methylene or 1 ,2-ethylene.
  • variable M is preferably a carbonyl group -C(O)-.
  • R 4 , R 4 ', R 5 and R 5 ' are each independently of the other, preferably hydrogen, unsubstituted or halogen- or hydroxyl-substituted C- ⁇ -C 6 -alkyl, or phenyl or benzyl, which is each unsubstituted or substituted by halogen, nitro, cyano, hydroxy, Ci-C 4 -alkyl, halo-Ci-C 4 -alkyl, Ci-C 4 -alkoxy, halo-CrC 4 -alkoxy, NH 2 , Ci-C 4 -alkylamino, di-C- ⁇ -C 4 -alkylamino and Ci-C 4 -alkylthio.
  • R 4 , R 4 ', R 5 and R 5 ' are each independently of the other, hydrogen, unsubstituted or halogen-substituted Ci-C 4 -alkyl, phenyl or benzyl, in particular hydrogen, methyl or ethyl.
  • R 6 and R 7 are each independently preferably hydrogen or Ci-C 4 -alkyl, in particular hydrogen, methyl or ethyl.
  • C(O)OR 4 , C(O)OR 4 ' and C(O)OR 6 are independently C(O)OH including physiologically acceptable salts thereof, C(O)OCi-C 6 -alkyl, C(O)Ophenyl or C(O)Obenzyl, in particular C(O)OC r C 4 -alkyl.
  • Preferred meanings of C(O)R 4 , C(O)R 4 ' and C(O)R 6 independently include COH; C(O)CrC 6 - alkyl, which may be substituted by halogen or hydroxyl; C(O)phenyl; or C(O)benzyl, in particular COH or C(O)C r C 4 -alkyl.
  • NHC(O)R 4 , NHC(O)R 4 ' and NHC(O)R 6 independently include NHC(O)Ci-C 6 -alkyl, which may be substituted by halogen or hydroxyl; NHC(O)phenyl; and NHC(O)benzyl, in particular NHC(O)C r C 4 -alkyl.
  • C(O)NR 4 R 5 , C(O)NR 4 1 R 5 ' and C(O)NR 6 R 7 is each C(O)NH 2 .
  • S(O 2 )NR 4 R 5 are S(O 2 )NH 2 or S(O 2 )N(C r C 2 -alkyl) 2 .
  • SO 3 R 4 are SO 3 H including physiologically acceptable salts thereof, or S(O 2 )OCi-C 4 -alkyl.
  • variable m is preferably O, 1 , 2 or 3, more preferably O, 1 or 2, even more preferably O or 1 , and in particular O.
  • the variable Ri is preferably halogen, cyano, nitro, unsubstituted or halogen-substituted d-C 6 - alkyl, hydroxy, unsubstituted or halogen-substituted CrC 6 -alkoxy, unsubstituted or halogen- substituted d-C ⁇ -alkylthio, d-C 6 -alkylsulfonyl, NR 4 R 5 , NHC(O)R 4 , C(O)R 4 , C(O)OR 4 , C(O)NR 4 R 5 , unsubstituted or substituted phenyl or unsubstituted or substituted phenyl-Ci-C 2 - alkyl, the phenyl substituents being selected from the group consisting of halogen, nitro, cyano, Ci-C 4 -alkyl, halo-C r C 4 -alky, C r C 4 -al
  • Ri are halogen, cyano, nitro, Ci-C 4 -alkyl, halo-Ci-C 2 -alkyl, hydroxy, Ci-C 2 -alkoxy, halo-Ci-C 2 -alkoxy, Ci-C 2 -alkylthio, halo-Ci-C 2 -alkylthio, N-Ci-C 2 -alkyl- amino, N,N-di-Ci-C 2 -alkylamino, or unsubstituted or halogen-, cyano-, Ci-C 2 -alkyl-, halo-Ci-C 2 - alkyl-, Ci-C 2 -alkoxy-, or halo-CrC 2 -alkoxy-substituted phenyl, whereby, if m is greater than 1 , the signification of Ri may be identical or different.
  • Ri are halogen, cyano, nitro, Ci-C 2 -alkyl, trifluoromethyl, hydroxy, CrC 2 -alkoxy, trifluoromethoxy, Ci-C 2 -alkylthio or trifluoromethylthio, whereby, if m is greater than 1 , the signification of Ri may be identical or different.
  • a particularly preferred embodiment of the invention concerns compounds of formula I, wherein m is 0, 1 or 2, R 1 is chlorine, fluorine, cyano, methyl, trifluoromethyl, hydroxyl or methoxy, and if m is 2, the signification of Ri may be different or identical.
  • the variable R 3 is preferably Ci-C 6 -alkyl, which is unsubstituted or substituted by halogen, cyano, nitro, hydroxyl, CrC 4 -alkoxy, NH 2 , N-Ci-C 4 -alkylamino, N,N-di-C- ⁇ -C 4 -alkylamino, NHC(O)CrC 2 -alkyl, C(O)OC r C 4 -alkyl, or C(O)NH 2 ; C 3 -C 6 -cycloalkyl, which is unsubstituted or substituted by Ci-C 2 -alkyl; C 2 -C 6 -alkenyl, which is unsubstituted or substituted by halogen; C 2 - C 6 -alkynyl; phenyl or benzyl, which is each unsubstituted or substituted by halogen, nitro, cyano, hydroxy, Ci-C 4
  • the variable R 3 is even more preferably CrC ⁇ -alkyl, which is unsubstituted or substituted by halogen, cyano, Ci-C 4 -alkoxy or C(O)OCi-C 4 -alkyl; C 3 -C 6 -cycloalkyl; C 2 -C 6 -alkenyl; benzyl; phenyl, which is unsubstituted or substituted by halogen, nitro, cyano, hydroxy, CrC 4 -alkyl, halo-Ci-C 4 -alkyl, C r C 4 -alkoxy, halo-C r C 4 -alkoxy, NH 2 , N-Ci-C 4 -alkylamino, N,N-di-C r C 4 - alkylamino, CHO, C(O)C r C 2 -alkyl, C(O)OH, C(O)OC r C 2 -alkyl Or
  • R 3 are Ci-C 6 -alkyl, C 5 -C 6 -cycloalkyl, unsubstituted or d-C 2 - alkyl-, Ci-C 2 -alkoxy-, halogen- or cyano-substituted phenyl, or piperidinyl.
  • said phenyl radical may be substituted by O to 5 same or different substituents, preferably O to 3 same or different substituents, more preferably O to 2 same or different substituents, and in particular by 0 or 1 substituent, wherein for said phenyl substituents each the above-given meanings and preferences apply.
  • R 1 , R 2 , R3, A and m each the above given meanings and preferences apply, in the control of parasites in and on warm-blooded animals.
  • An even more preferred embodiment of the present invention concerns the use of a compound of the above-given formula Ia, wherein m is 0, 1 or 2, preferably 0 or 1 , and in particular 0; R 2 is hydrogen or Ci-C 4 -alkyl, in particular hydrogen or methyl; A is straight-chain Ci-C 4 -alkylene, in particular methylene or 1 ,2-ethylene; and for R 1 and R 3 each the above-given meanings and preferences apply.
  • the compounds of the formula I according to the present invention may be prepared, for example, by a process, which comprises reacting a compound of formula , wherein R 1 , R 2 , R 2 ', m, p and q are defined as given above, with a compound of formula
  • reaction partners can be reacted with one another as they are, i.e. without the addition of a solvent or diluent, e.g. in the melt. In most cases, however, the addition of an inert solvent or diluent, or a mixture thereof, is of advantage.
  • solvents or diluents are: aromatic, aliphatic and alicyclic hydrocarbons and halogenated hydrocarbons, such as benzene, toluene, xylene, mesitylene, tetraline, chlorobenzene, dichlorobenzene, bromobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, trichloromethane, tetrachloromethane, dichloroethane, trichloroethene or tetrachloroethene; ethers, such as diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethylether, dimethoxydiethylether, tetrahydrofuran or dio
  • Suitable bases for facilitating the reaction are e.g. alkali metal or alkaline earth metal hydroxides, hydrides, amides, alkanolates, acetates, carbonates, dialkylamides or alkylsilyl- amides; alkylamines, alkylenediamines, optionally N-alkylated, optionally unsaturated, cyclo- alkylamines, basic heterocycles, ammonium hydroxides, as well as carbocyclic amines.
  • alkali metal or alkaline earth metal hydroxides, hydrides, amides, alkanolates, acetates, carbonates, dialkylamides or alkylsilyl- amides alkylamines, alkylenediamines, optionally N-alkylated, optionally unsaturated, cyclo- alkylamines, basic heterocycles, ammonium hydroxides, as well as carbocyclic amines.
  • Those which may be mentioned by way of example are sodium hydroxide, hydride, amide, methanolate, acetate, carbonate, potassium tert.-butanolate, hydroxide, carbonate, hydride, lithium diisopropylamide, potassium bis(trimethylsilyl)-amide, calcium hydride, triethylamine, diisopropylethylamine, triethylenediamine, cyclohexylamine, N-cyclohexyl-N,N-dimethylamine, N,N-diethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, quinuclidine, N-methylmorpholine, benzyltrimethylammonium hydroxide, as well as 1 ,5-diazabicyclo[5.4.0]undec-5-ene (DBU).
  • DBU 1 ,5-diazabicyclo[5.4.0]undec-5-ene
  • a preferred leaving group Hal is bromine or chlorine.
  • the reaction advantageously takes place in a temperature range of ca. 0 0 C to ca. 200 0 C , preferably from ca. 50 0 C to ca. 160°C .
  • the compounds of the formula III are known and commercially available, or may be prepared according to methods well known in the art, for example, from textbooks of organic chemistry.
  • the compounds of the formula Il are likewise known at least in part.
  • a useful process for the manufacture of compounds of formula II, wherein p is 1 and q is 2, is outlined in the reaction sceme below:
  • R 1 R 2 , R 2 ' and m are as defined above, Hal is halogen, for example chlorine, and LG is a leaving group, for example, Ci-C 6 -alkyl, benzyl or CrC 6 -alkoxycarbonyl, in particular methyl or benzyl.
  • Salts of compounds I may be produced in known manner. Acid addition salts, for example, are obtainable from compounds I by treating with a suitable acid or a suitable ion exchange reagent, and salts with bases are obtainable by treating with a suitable base or a suitable ion exchange reagent.
  • Salts of compounds I can be converted into the free compounds I by the usual means, acid addition salts e.g. by treating with a suitable basic composition or with a suitable ion exchange reagent, and salts with bases e.g. by treating with a suitable acid or a suitable ion exchange reagent.
  • Salts of compounds I can be converted into other salts of compounds I in a known manner; acid addition salts can be converted for example into other acid addition salts, e.g. by treating a salt of an inorganic acid, such as a hydrochloride, with a suitable metal salt, such as a sodium, barium, or silver salt, of an acid, e.g. with silver acetate, in a suitable solvent, in which a resulting inorganic salt, e.g. silver chloride, is insoluble and thus precipitates out from the reaction mixture.
  • a salt of an inorganic acid such as a hydrochloride
  • a suitable metal salt such as a sodium, barium, or silver salt
  • a resulting inorganic salt e.g. silver chloride
  • the compounds of formula I with salt- forming characteristics can be obtained in free form or in the form of salts.
  • the compounds of formula I can also be obtained in the form of their hydrates and/or also can include other solvents, used for example where necessary for the crystallisation of compounds present in solid form.
  • the compounds of the formula I or Ia may be optionally present as optical and/or geometric isomers or as a mixture thereof.
  • the invention relates both to the pure isomers and to all possible isomeric mixtures, and is hereinbefore and hereinafter understood as doing so, even if stereochemical details are not specifically mentioned in every case.
  • Diastereoisomeric mixtures of compounds of formula I and Ia which are obtainable by the process or in another way, may be separated in known manner, on the basis of the physical- chemical differences in their components, into the pure diastereoisomers, for example by fractional crystallisation, distillation and/or chromatography.
  • Splitting of mixtures of enantiomers, that are obtainable accordingly, into the pure isomers may be achieved by known methods, for example by recrystallisation from an optically active solvent, by chromatography on chiral adsorbents, e.g. high-pressure liquid chromatography (HPLC) on acetyl cellulose, with the assistance of appropriate micro-organisms, by cleavage with specific immobilised enzymes, through the formation of inclusion compounds, e.g. using chiral crown ethers, whereby only one enantiomer is complexed.
  • HPLC high-pressure liquid chromatography
  • the starting materials and intermediates used are preferably those that lead to the compounds I described at the beginning as being especially useful.
  • the compounds of the formula I according to the invention are notable for their broad activity spectrum and are valuable active ingredients for use in pest control. They are particularly suitable in the control of ectoparasites and to a certain extent also for controlling endoparasites on and in animals and in the hygiene field, whilst being well tolerated by warm-blooded animals.
  • warm-blooded animals includes, for example, productive livestock, zoo animals, laboratory animals and pets, in particular productive livestock and pets.
  • Productive livestock includes, for example, cattle, horses, sheep, pigs, goats, donkeys, deer, reindeer, fur-bearing animals such as mink, foxes, chinchilla, rabbits and racoon, and birds such as, for example, chickens, geese, guineafowls, turkeys and ducks.
  • Pets include, for example, ferrets, guinea pigs, golden hamsters, rats, dogs and cats, in particular dogs and cats.
  • ectoparasites are understood to be in particular insects, acari (mites and ticks), and crustaceans (sea lice). These include insects of the following orders: Lepidoptera, Coleoptera, Homoptera, Hemiptera, Heteroptera, Diptera, Dictyoptera, Thysanoptera, Orthoptera, Anoplura, Siphonaptera, Mallophaga, Thysanura, Isoptera, Psocoptera and Hymenoptera.
  • the ectoparasites which may be mentioned in particular are those which trouble humans or animals and carry pathogens, for example flies such as Musca domestica, Musca vetustissima, Musca autumnalis, Fannia canicularis, Sarcophaga carnaria, Lucilia cuprina, Lucilia sericata, Hypoderma bovis, Hypoderma lineatum, Chrysomyia chloropyga, Dermatobia hominis, Cochliomyia hominivorax, Gasterophilus intestinalis, Oestrus ovis, biting flies such as Haematobia irritans irritans, Haematobia irritans exigua, Stomoxys calcitrans, horse-flies (Tabanids) with the subfamilies of Tabanidae such as Haematopota spp.
  • flies such as Musca domestica, Musca vetustissima, Musca autumnalis, Fanni
  • Chrysopsinae such as Chrysops spp.
  • Chrysops caecutiens Hippoboscids such as Melophagus ovinus (sheep ked); tsetse flies, such as Glossinia spp,; other biting insects like midges, such as Ceratopogonidae (biting midges like Culicoides spp), Simuliidae (Blackflies), Psychodidae (Sandflies); but also blood-sucking insects, for example mosquitoes, such as Anopheles spp, Aedes spp and Culex spp, fleas, such as Ctenocephalides felis and Ctenocephalides canis (cat and dog fleas), Xenopsylla cheopis, Pulex ir ⁇ tans, Ceratophyllus gallinae, Dermatophilus penetrans, blood-sucking lice (Anoplura) such as Linognathus spp, Haematopinus spp, Solen
  • Ectoparasites also include members of the order Acarina, such as mites (e.g. Chorioptes bovis, Cheyletiella spp., Dermanyssus gallinae, Ortnithonyssus spp., Demodex canis, Sarcoptes scabiei, Psoroptes ovis and Psorergates spp. and ticks.
  • mites e.g. Chorioptes bovis, Cheyletiella spp., Dermanyssus gallinae, Ortnithonyssus spp.
  • Demodex canis Sarcoptes scabiei
  • Psoroptes ovis e.g. ovis and Psorergates spp. and ticks.
  • ticks are, for example, Boophilus, Amblyomma, Anocentor, Dermacentor, Haemaphysalis, Hyalomma, Ixodes, Rhipicentor, Margaropus, Rhipicephalus, Argas, Otobius and Ornithodoros and the like, which preferably infest warm-blooded animals including farm animals, such as cattle, horses, pigs, sheep and goats, poultry such as chickens, turkeys, guineafowls and geese, fur-bearing animals such as mink, foxes, chinchillas, rabbits and the like, as well as companion animals such as ferrets, guinea pigs, rats, hamster, cats and dogs, but also humans.
  • farm animals such as cattle, horses, pigs, sheep and goats
  • poultry such as chickens, turkeys, guineafowls and geese
  • fur-bearing animals such as mink,
  • the compounds of the formula I according to the invention are also active against all or individual development stages of animal pests showing normal sensitivity, as well as those showing resistance to widely used parasiticides. This is especially true for resistant insects and members of the order Acarina.
  • the insecticidal, ovicidal and/or acaricidal effect of the active substances of the invention can manifest itself directly, i.e. killing the pests either immediately or after some time has elapsed, for example when moulting occurs, or by destroying their eggs, or indirectly, e.g. reducing the number of eggs laid and/or the hatching rate, good efficacy corresponding to a pesticidal rate (mortality) of at least 60%.
  • Compounds of the formula I can also be used against hygiene pests, especially of the order Diptera of the families Muscidae, Sarcophagidae, Anophilidae and Culicidae; the orders Orthoptera, Dictyoptera (e.g. the family Blattidae (cockroaches), such as Blatella germanica, Blatta orientalis, Periplaneta americana) and Hymenoptera (e.g. the families Formicidae (ants) and Vespidae (wasps).
  • Compounds of formula I also have sustainable efficacy on parasitic mites and insects of plants.
  • spider mites of the order Acarina In the case of spider mites of the order Acarina, they are effective against eggs, nymphs and adults of Tetranychidae (Tetranychus spp. and Panonychus spp.). They have high activity against sucking insects of the order Homoptera, especially against pests of the families Aphididae, Delphacidae, Cicadellidae, Psyllidae, Loccidae, Diaspididae and Eriophydidae (e.g. rust mite on citrus fruits); the orders Hemiptera, Heteroptera and Thysanoptera, and on the plant-eating insects of the orders Lepidoptera, Coleoptera, Diptera and Orthoptera.
  • the compounds of formula I are therefore effective against all stages of development of sucking insects and eating insects on crops such as cereals, cotton, rice, maize, soya, potatoes, vegetables, fruit, tobacco, hops, citrus, avocados and other crops.
  • the compounds of formula I are also effective against ectoparasites of fishes, especially the sub-class of Copepoda (e.g. order of Siphonostognatoidae (sea lice), whilst being well tolerated by fish.
  • Copepoda e.g. order of Siphonostognatoidae (sea lice)
  • Certain compounds of the formula I are also effective against certain species of helminths.
  • Helminths are commercially important because they cause serious diseases in mammals and poultry, e.g. in sheep, pigs, goats, cattle, horses, donkeys, camels, dogs, cats, rabbits, guinea- pigs, hamsters, chicken, turkeys, guinea fowls and other farmed birds, as well as exotic birds.
  • Typical nematodes are: Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostonum, Oesophagostonum, Charbertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parasca ⁇ s.
  • the trematodes include, in particular, the family of Fasciolideae, especially Fasciola hepatica.
  • the good pesticidal activity of the compounds of formula I according to the invention corresponds to a mortality rate of at least 60% of the pests mentioned, more preferably to a mortality rate over 80%, most preferably to 90-100%.
  • the compounds of formula I are preferably employed internally and externally in unmodified form or preferably together with the adjuvants conventionally used in the art of formulation and may therefore be processed in a known manner to give, for example, liquid formulations (e.g. spot-on, pour-on, spray-on, emulsions, suspensions, solutions, emulsifiable concentrates, solution concentrates), semisolid formulations (e.g. creams, ointments, pastes, gels, liposomal preparations) and solid preparations (e.g.
  • food additives tablets including e. g. capsules, powders including soluble powders, granules, or embeddings of the active ingredient in polymeric substances, like collars, implants and microparticles).
  • the methods of application are selected in accordance with the intended objectives and the prevailing circumstances.
  • the formulation i.e. preparations containing the active ingredient of formula I, or combinations of these active ingredients with other active ingredients, and optionally a solid, semi-solid or liquid adjuvant, are produced in a manner known per se, for example by intimately mixing, kneading or dispersing the active ingredients with compositions of excipients, whereby the physiological compatibility of the formulation excipients must be taken into consideration.
  • the solvents in question may be: alcohols (aliphatic and aromatic), such as benzylalcohol, ethanol, propanol, isopropanol or butanol, fatty alcohols, such as oleyl alcohol and glycols and their ethers and esters, such as glycerin, propylene glycol, dipropylene glycol ether, ethylene glycol, ethylene glycol monomethyl or -ethyl ether and butyl dioxytol, carbonates, such as propylene carbonate, ketones, such as cyclohexanone, isophorone or diacetanol alcohol and polyethylene glycols, such as PEG 300.
  • alcohols aliphatic and aromatic
  • benzylalcohol such as benzylalcohol
  • ethanol propanol
  • fatty alcohols such as oleyl alcohol and glycols and their ethers and esters
  • glycerin prop
  • compositions may comprise strong polar solvents, such as N-methyl-2-pyrrolidone, dimethyl sulfoxide or dimethylformamide, or water, fatty acid esters, such as ethyl oleate or isopropylpalmitate, vegetable oils, such as rape, castor, coconut, or soybean oil, synthetic mono-, di-, triglycerides like e.g. glyceryl monostearate and medium chain triglycerides and also, if appropriate, silicone oils.
  • the mentioned ingredients may also serve as carrier for particulate application froms. As ointment base resp.
  • Petroleum based substances such as Vaseline or paraffines, bases made from wool fat, like e.g. lanolin or lanolin alcohols, polyethylene glycols like e.g. macrogols and lipid bases like e.g. phospholipids or triglycerids, such as hydrogenated vegetable oils.
  • emulsifiers like soy lecithin
  • salts of fatty acids with alkaline earth and alkali metals alkyl sulfates like sodium cetylstearyl sulphate
  • cholates fatty alcohols like cetyl alcohol, sterols like cholestesterol
  • polyoxyethylene sorbitan fatty acid esters like polysorbate 20 sorbitan fatty acid esters like sorbitan mono laureate
  • PluronicTM saccharose esters like saccharose distearate, polyglyceryl fatty acid esters like polyglycerol oleate and fatty acid esters like e.g. ethyl oleate or isopropylmyristate.
  • the formulations may also include gelifying and stiffening agents, like e.g. polyacrylic acid derivatives, cellulose ethers, polyvinyl alcohols, polyvinylpyrrolidone and fine disperse silicium dioxide.
  • polymeric agents with controlled release properties may be applied derivatives made by e.g. polylactic acid, polylactic coglycolic acid, poly orthoester, polyethylene carbonate, poly anhydrids and starch and PVC based matrices.
  • penetration enhancers like ketones, sulfoxides, amides, fatty acid esters and fatty alcohols may be necessary.
  • preservatives like sorbic acid, benzyl alcohol and parabenes, and antioxidants as e.g. alpha tocopherol may be added.
  • the active ingredient or combinations of the active ingredient may also applied in capsules, like hard gelatine capsules or soft capsules.
  • the binders for tablets and boli may be chemically modified polymeric natural substances that are soluble in water or in alcohol, such as starch, cellulose or protein derivatives (e.g. methyl cellulose, carboxymethyl cellulose, ethyl hydroxyethyl cellulose, proteins such as zein, gelatin and the like), as well as synthetic polymers, such as polyvinyl alcohol, polyvinyl pyrrolidone etc.
  • the tablets also contain fillers (e.g. starch, microcrystalline cellulose, sugar, lactose etc.), lubricants (e.g. magnesium stearate), glidants (e.g. colloidal silicon dioxide) and disintegrants (e.g. cellulose derivatives) and acid resistant coatings, like e.g. acrylic acid esters.
  • the compounds of formula I 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.
  • repellents By combining the compounds of the formula I with other suitable parasiticides not only the parasiticidal activity can be enhanced but the greatest part 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 I.
  • Suitable partners in the mixture may be biocides, e.g. the insecticides and acaricides with a varying mechanism of activity, which are named in the following and have been known to the person skilled in the art for a long time, e.g. chitin synthesis inhibitors, growth regulators; active ingredients which act as juvenile hormones; active ingredients which act as adulticides; broadband insecticides, broad-band acaricides and nematicides; and also the well known anthelminthics and insect- and/or acarid-deterring substances, said repellents or detachers.
  • suitable insecticides and acaricides are:
  • Bacillus subtil, toxin 1 18. Fenothiocarb 213. Propafos
  • Beta-cyfluthrin 125 Flonicamid 220. Pyrachlofos
  • Beta-cypermethrin 126 Fluacrypyrim 221. Pyrafluprole
  • Cis-Resmethrin 155 insect-active viruses 250. Tau-fluvalinate
  • Non-limitative examples of suitable anthelmintics are named in the following, a few representatives have anthelmintic activity in addition to the insecticidal and acaricidal activity.
  • Non-limitative examples of suitable synergists are:
  • Synergists S1 to S9 are well-known or can be found in the Internet, for example, in the Compendium of Pesticide Common Names. Synergists are compounds which increase the action of the active compounds without it being necessary for the synergist added to be active itself.
  • 153 a preparation which contains insect-active fungi, preferably Verticillium lecanii, from The Pesticide Manual, 1 1thEd. (1997), The British Crop Protection Council, London, page 1266; Beauveria brogniartii, from The Pesticide Manual, 1 1thEd. (1997), The British Crop Protection Council, London, page 85 and Beauveria bassiana, from The Pesticide Manual, 1 1 thEd. (1997), The British Crop Protection Council, London, page 83; 155: a preparation which contains insect-active viruses, preferably Neodipridon Sertifer NPV, from The Pesticide Manual, 1 1thEd.
  • 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 I, 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.
  • compositions according to the invention contain 0.1 to 99 % by weight, especially 0.1 to 95 % by weight of active ingredient of formula I, Ia or mixtures thereof, 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.
  • compositions according to the invention may take place topically, perorally, parenterally or subcutaneously, the composition being present in the form of solutions, emulsions, suspensions, (drenches), powders, tablets, boli, capsules and pour-on formulations.
  • the pour-on or spot-on method consists in applying the compound of formula I to a specific location of the skin or coat, advantageously to the neck or backbone of the animal. This takes place e.g. 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.
  • 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 e.g. 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, hexyl laurate, oleyl oleate, decyl oleate, capric acid esters of saturated fat alcohols of chain length Ci 2 -Ci 8 ; solutions of esters of dicarboxylic acids, such as dibutyl phthalate, diisopropyl isophthalate, adipic acid diisopropyl ester, di-
  • glycols may be advantageous for a dispersing agent to be additionally present, such as one known from the pharmaceutical or cosmetic industry.
  • 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 e.g. 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 I, 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.
  • compositions may also contain further additives, such as stabilisers, anti-foaming agents, viscosity regulators, binding agents or tackifiers, as well as other active ingredients, in order to achieve special effects.
  • further additives such as stabilisers, anti-foaming agents, viscosity regulators, binding agents or tackifiers, as well as other active ingredients, in order to achieve special effects.
  • compositions of this type which are used by the end user, similarly form a constituent of the present invention.
  • the active ingredients of formula I 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 pests, which is characterised in that the active ingredients of 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.
  • Granulate a) b) active ingredient 5 % 10 % kaolin 94 % - highly dispersed silicic acid 1 % - attapulgite - 90 %
  • 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.
  • active ingredient 0.1-1.0 g sesame oil ad 100 ml
  • active ingredient 0.1-1.0 g polyethoxylated castor oil (40 ethylene oxide units) 10 g 1 ,2-propanediol 2O g benzyl alcohol 1 g aqua ad inject. ad 100 ml
  • active ingredient 0.1-1.0 g polyethoxylated sorbitan monooleate (20 ethylene oxide units) 8 g 4-hydroxymethyl-1 ,3-dioxolane (glycerol formal) 20 g benzyl alcohol 1 g aqua ad inject. ad 100 ml
  • Preparation The active ingredient is dissolved in the solvents and the surfactant, and made up with water to the desired volume. Sterile filtration through an appropriate membrane filter of 0.22 mm pore size. 5. Pour on
  • the aqueous systems may also preferably be used for oral and/or intraruminal application.
  • 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, viscosity regulators, binders, tackifiers, as well as fertilisers 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, viscosity regulators, binders, tackifiers, as well as fertilisers or other active ingredients to achieve special effects.
  • step B 4.5g of 1-(4-Chloro-phenyl)-1 -pyridin-4-yl-ethanol obtained according to step A is added slowly to an ice cold solution of 4.9ml iodomethane in 160ml of methanol.
  • the reaction mixture is allowed to come to room temperature and heated 12h at 55°C.
  • TLC After completion of the conversion (TLC) the solvent is removed and the remaining residue is dissolved in 60ml of methanol and cooled to 0 0 C. 6.62g of sodium boronhydride is slowly added while keeping the reaction temperature below 20 0 C.
  • the mixture is stirred for 17 hours at room temperature.
  • the solvent is removed and the remaining residue is taken up in water and extracted three times with dichloromethane.
  • step C 181 mg 6-Chloro-3,9-dimethyl-2,3,4,4a-tetrahydro-1 H-3-aza-fluorene perchlorate obtained according to step C is treated with saturated KHCO3 and extracted with dichloromethane. The organic layer is dried using MgSO 4 and filtered. The solvent is removed in vacuum to give the free base. 6-Chloro-3,9-dimethyl-2,3,4,4a-tetrahydro-1 H-3-aza-fluorene is dissolved in toluene and 9mg K 2 CO 3 is added. 249mg of 2,2,2-trichloro ethyl chloroformiate is slowly added.
  • reaction mixture is then heated for two hours in a sealed tube to 160 0 C in a microwave oven (Biotage).
  • the reaction mixture is poured in to a mixture of dichloromethane/water 1 :1 (v/v).
  • the organic layer is separated and the water phase is extracted two times with dichloromethane.
  • the combined organic layers are washed with brine, dried over MgSO 4 and filtered.
  • step D 97mg of 6-Chloro-9-methyl-2,3,4,4a-tetrahydro-1 H-3-aza-fluorene obtained according to step D are dissolved in 0.101 ml DIPEA and 1.5ml DMF.
  • the reaction mixture is heated to 70 0 C and 58mg of 3-chloropropiophenone dissolve in 0.5ml of DMF are slowly added. After additional 15min. at 70 0 C the mixture is cooled to room temperature and filtered. The solvent is removed and treated with 2.5ml of MeOH/DMF 1 :1 (v/v).
  • Solvent A Water + 0.01 % formic acid
  • Solvent B Acetonitrile + 0.01 % formic acid
  • Gradient Time %A %B 0 90 10 1 90 10
  • a mixed adult population of fleas is placed in a suitably formatted 96-well plate allowing fleas to access and feed on treated blood via an artificial feeding system.
  • Fleas are fed on treated blood for 24 hours, after which the compound's effect is recorded, lnsecticidal activity is determined on the basis of the number of dead fleas recovered from the feeding system.
  • a clean adult tick population is used to seed a suitably formatted 96-well plate containing the test substances to be evaluated for antiparasitic activity. Each compound is tested by serial dilution in order to determine its minimal effective dose (MED). Ticks are left in contact with the test compound for 10 minutes and are then incubated at 28°C and 80% relative humidity for 7 days, during which the test compound's effect is monitored. Acaricidal activity is confirmed if adult ticks are dead.
  • MED minimal effective dose
  • Efficacy is expressed in percent reduced egg hatch, reduced development of L3, or paralysis & death of larvae of all stages.
  • the following compounds show more than 80% (EC 8 o) efficacy against both worms at 32ppm: 1.26, 2.1 , 2.10, 2.27, 2.33, 2.37, 2.40, 5.30, 5.39, 7.20, 7.21 , 7.27, 7.29.
  • gerbils are treated with the test compound at a given dose by spray or spot-on application.
  • the animals are infested with a mixed adult population of cat fleas. Evaluation of efficacy is performed 24h and 48h infestation by counting the numbers of live fleas recovered from the gerbils. Efficacy is expressed as comparison with a placebo treated group using the Abbot's formula. Infestations can be repeated at weekly intervals until efficacy drops.
  • gerbils are treated with the test compound at a given dose by spray (or spot-on) application.
  • +1 (+2) the animals are infested with nymphs of R. sanguineus. Ticks are left on the animals until full repletion. Seven days after infestation nymphs dropped off fully engorged are collected and counted. They are kept until molting to also evaluate growth regulating activity of the test compound. Efficacy in killing (and growth regulating) is expressed as a tick number (and molted tick number) reduction in comparison with a placebo treated group, using the Abbot's formula.

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Environmental Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • Plant Pathology (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

L'invention porte sur l'utilisation d'un composé de Formule (I), dans laquelle R1, R2, R2', R3, A, M, m, p et n ont les significations données dans les revendications, et, facultativement, ses énantiomères, pour la lutte contre les parasites dans et sur des animaux à sang chaud. Les composés selon la présente invention sont particulièrement appropriés pour la lutte contre les ectoparasites dans ou sur les animaux à sang chaud.
PCT/EP2008/066495 2007-12-03 2008-12-01 Composés organiques WO2009071500A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP07122093 2007-12-03
EP07122093.3 2007-12-03

Publications (2)

Publication Number Publication Date
WO2009071500A2 true WO2009071500A2 (fr) 2009-06-11
WO2009071500A3 WO2009071500A3 (fr) 2010-07-08

Family

ID=39791406

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2008/066495 WO2009071500A2 (fr) 2007-12-03 2008-12-01 Composés organiques

Country Status (1)

Country Link
WO (1) WO2009071500A2 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011157748A1 (fr) 2010-06-17 2011-12-22 Novartis Ag 5-aryl-isoxazolines pour lutter contre les nuisibles
WO2012107533A1 (fr) 2011-02-10 2012-08-16 Novartis Ag Dérivées d'isoxazoline pour la lutte contre des animaux nuisibles invertébrés
WO2012120135A1 (fr) 2011-03-10 2012-09-13 Novartis Ag Dérivés d'isoxazole
WO2013079407A1 (fr) 2011-11-29 2013-06-06 Novartis Ag Dérivés arylés pour lutter contre les ectoparasites
WO2014096381A1 (fr) 2012-12-20 2014-06-26 Novartis Ag (hétéro)acrylamides utilisés en vue de la lutte contre les ectoparasites
WO2015071417A1 (fr) 2013-11-18 2015-05-21 Novartis Tiergesundheit Ag Nouveaux composés
EP3018129A1 (fr) 2014-11-10 2016-05-11 Novartis Tiergesundheit AG Composé d'isoxazoline de diaryle
CN117000216A (zh) * 2023-10-07 2023-11-07 国能龙源环保有限公司 螯合剂、燃煤电厂脱硫废水的工业化处理系统及处理方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1262949A (en) * 1968-06-25 1972-02-09 Sandoz Ltd Indenopyridine derivatives
US3928360A (en) * 1969-09-23 1975-12-23 Sandoz Ltd 1,3,4,9B-Tetrahydro-2H-indeno{8 1,2-c{9 pyridines
US3991066A (en) * 1971-01-26 1976-11-09 Sandoz Ltd. 1,3,4,9B-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridines
WO2006089038A2 (fr) * 2005-02-17 2006-08-24 Bayer Cropscience Ag Derives de tetrahydroindenopyridine insecticide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1262949A (en) * 1968-06-25 1972-02-09 Sandoz Ltd Indenopyridine derivatives
US3928360A (en) * 1969-09-23 1975-12-23 Sandoz Ltd 1,3,4,9B-Tetrahydro-2H-indeno{8 1,2-c{9 pyridines
US3991066A (en) * 1971-01-26 1976-11-09 Sandoz Ltd. 1,3,4,9B-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridines
WO2006089038A2 (fr) * 2005-02-17 2006-08-24 Bayer Cropscience Ag Derives de tetrahydroindenopyridine insecticide

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011157748A1 (fr) 2010-06-17 2011-12-22 Novartis Ag 5-aryl-isoxazolines pour lutter contre les nuisibles
WO2012107533A1 (fr) 2011-02-10 2012-08-16 Novartis Ag Dérivées d'isoxazoline pour la lutte contre des animaux nuisibles invertébrés
WO2012120135A1 (fr) 2011-03-10 2012-09-13 Novartis Ag Dérivés d'isoxazole
WO2013079407A1 (fr) 2011-11-29 2013-06-06 Novartis Ag Dérivés arylés pour lutter contre les ectoparasites
WO2014096381A1 (fr) 2012-12-20 2014-06-26 Novartis Ag (hétéro)acrylamides utilisés en vue de la lutte contre les ectoparasites
WO2015071417A1 (fr) 2013-11-18 2015-05-21 Novartis Tiergesundheit Ag Nouveaux composés
US9820488B2 (en) 2013-11-18 2017-11-21 Elanco Tiergesundheit Ag Compounds for the control of endoparasites
EP3018129A1 (fr) 2014-11-10 2016-05-11 Novartis Tiergesundheit AG Composé d'isoxazoline de diaryle
WO2016077158A1 (fr) 2014-11-10 2016-05-19 Novartis Tiergesundheit Ag Composé d'isoxazoline de dyaryle
CN117000216A (zh) * 2023-10-07 2023-11-07 国能龙源环保有限公司 螯合剂、燃煤电厂脱硫废水的工业化处理系统及处理方法
CN117000216B (zh) * 2023-10-07 2023-12-08 国能龙源环保有限公司 螯合剂、燃煤电厂脱硫废水的工业化处理系统及处理方法

Also Published As

Publication number Publication date
WO2009071500A3 (fr) 2010-07-08

Similar Documents

Publication Publication Date Title
TWI511966B (zh) 有機化合物
AU2005219559B2 (en) Use of pyrimidine compounds in the preparation of parasiticides
WO2009071500A2 (fr) Composés organiques
JP2009007372A (ja) 病虫害防除剤特性を有するｎ−スルホニルアミノアセトニトリル
US20080194693A1 (en) Aminoacetonitrile Derivatives and Their Use for Controlling Parasites on Warm-Blooded Animals
CA2657745C (fr) Derives de pyrimidine et leur utilisation comme pesticides
WO2002050052A1 (fr) N-acyl aminoacetonitriles aux proprietes pesticides
US20080227863A1 (en) Organic Compounds
AU2003279395B2 (en) Aminoacetonitrile derivatives suitable for controlling parasites
US20110021543A1 (en) Heterocyclic compounds and their use as pesticides
CA2892883C (fr) (hetero)acrylamides utilises en vue de la lutte contre les ectoparasites
WO2008074757A1 (fr) Composés organiques
NZ613191B2 (en) Isoxazoline derivatives for controlling invertebrate pests

Legal Events

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

Ref document number: 08858166

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08858166

Country of ref document: EP

Kind code of ref document: A2