WO2009071500A2 - Organic compounds - Google Patents

Abstract

The invention relates to to the use of a compound of Formula (I) wherein R1, R2, R2', R3, A, M, m, p and n have the meanings given in the claims, and optionally the enantiomers thereof, in the control of parasites in and on warm-blooded animals. The compounds of the present invention are especially suitable for controlling ectoparasites in or on the warm-blooded animals.

Description

Organic compounds

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.

There is an ongoing need for new active ingredients with improved pesticidal properties, for example, because currently used products cannot fulfil all the requirements concerning potency and activity spectrum. In addition, upcoming resistance formation of ectoparasites against some known pesticides represent an issue. GB-1262949 discloses terahydroindenylpyridines with a Ci-C₆-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

wherein m is an integer from 0 to 4; each R₁ is independently halogen, cyano, nitro, unsubstituted or halogen-, cyano-, nitro-, hydroxy- or d-C₄-alkoxy-substituted Ci-C₆-alkyl, unsubstituted or halogen-substituted C₃-C₆- cycloalkyl, unsubstituted or halogen-substituted C₂-C6-alkenyl, unsubstituted or halogen- substituted C₂-C₆-alkynyl, hydroxy, unsubstituted or halogen-substituted Ci-C₆-alkoxy, unsubstituted or halogen-substituted C₂-C6-alkenyloxy, unsubstituted or halogen-substituted C₂-C₆-alkynyloxy, unsubstituted or halogen-substituted C₃-C₆-cycloalkyloxy, SH, unsubstituted or halogen-substituted Ci-C₆-alkylthio, unsubstituted or halogen-substituted C₃-C₆- cycloalkylthio, unsubstituted or halogen-substituted Ci-C₆-alkylsulfinyl, unsubstituted or halogen-substituted C₃-C₆-cycloalkylsulfinyl, unsubstituted or halogen-substituted d-C₆- alkylsulfonyl, unsubstituted or halogen-substituted C₃-C₆-cycloalkylsulfonyl, SO₃R_4, S(O₂)NR₄R₅, NR₄R₅, NHC(O)R₄, C(O)R₄, C(O)OR₄, C(O)NR₄R₅, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted aryloxy, unsubstituted or substituted arylalkyloxy, unsubstituted or substituted arylthio, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted heteroaryloxy, or unsubstituted or substituted heteroarylthio, the aryl, arylalkyl, aryloxy, arylalkyloxy, arylthio, heteroaryl, heteroarylalkyl, heteroaryloxy and heteroarylthio substituents in each case independently from each other being selected from the group consisting of halogen, nitro, cyano, hydroxy, unsubstituted or halogen-, cyano-, nitro-, hydroxy- or d-C₄- alkoxy-substituted Ci-C₆-alkyl, d-C₆-alkoxy, halo-Ci-C₆-alkoxy, NH₂, N-Ci-C₆-alkylamino, N₁N- di-d-Ce-alkylamino, NHC(O)R₆, C_rC₆-alkylthio, halo-C_rC₆-alkylthio, C(O)R₆, C(O)OR₆ and

C(O)NR₆R₇, whereby, if m is greater than 1 , the signification of Ri may be identical or different;

R₂ is hydrogen, Ci-C₆-alkyl, unsubstituted or halogen-, Ci-C₄-alkyl- or Ci-C₄-alkoxy-substituted pheny or benzyl;

R₂' is hydrogen, halogen, cyano, Ci-C₆-alkyl, unsubstituted or halogen-, Ci-C₄-alkyl- or d-C₄- alkoxy-substituted pheny or benzyl;

A is straight-chain or branched Ci-Cβ-alkylene or C₂-C₈-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(O₂)-;

R₃ is Ci-C₆-alkyl, C₃-C₆-cycloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkenyl, heterocycloaliphatyl, heterocycloaliphatyl-Ci-C₆-alkyl, heterocycloaliphatyl-C₂-C₆-alkenyl, heterocycloaliphatyl-C₂-C₆-alkynyl, aryl, aryl-Ci-C₆-alkyl, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-Ci-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or heteroaryl-C₂-C₆-alkynyl, which is in each case, independently of each other, unsubstituted or substituted by halogen, nitro, cyano, hydroxy, Ci-C₆-alkyl, halo-Ci-C₆-alkyl, Ci-C₆-alkoxy, halo-Ci-C₆-alkoxy, NH₂, N-CrC₆- alkylamino, N,N-di-Ci-C₆-alkylamino, NHC(O)R₄', d-C₆-alkylthio, halo-C_rC₆-alkylthio, C(O)R₄',

C(O)OR₄Or C(O)NR₄ ¹R₅';

R₄, R₄', R₅ and R₅' are each independently of the other hydrogen, unsubstituted or halogen-, cyano-, nitro-, hydroxy- or Ci-C₄-alkoxy-substituted Ci-C₆-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, NO₂, hydroxyl, Ci-C₆-alkyl, halo-Ci-C₆- alkyl, Ci-C₆-alkoxy, halo-Ci-C₆-alkoxy, NH₂, Ci-C₆-alkylamino, di-Ci-C₆-alkylamino and d-C₆- alkylthio; and Rβ and R₇ are each independently of the other hydrogen or unsubstituted or hydroxyl-, halogen- or d-C₄-alkoxy-substituted CrC₆-alkyl, phenyl or benzyl; in the control of parasites in and on warm-blooded animals.

The general terms used hereinbefore and hereinafter have the following meanings, unless defined otherwise.

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 R₁.

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-C₆-alkyl, halo-d-Ce-alkyl, C_rC₆-alkoxy, halo-C_rC₆-alkoxy, SH, C_rC₆-alkylthio, halo-C_rC₆-alkylthio, d- C₆-alkylsulfinyl, CrC₆-alkylsulfonyl, d-C₆-alkoxycarbonyl, d-Ce-alkylcarbonylamino, acetyl, benzoyl or phenoxy. Preferred heteroaryl substituents are cyano, halogen, halogen-substituted CrC₂-alkyl, CrC₂-alkyl, d-C₂-alkoxy or halogen-substituted d-C₂-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, R₄R₅N-alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl or alkylsulfonyloxy alkylsulfonylamino - is, in each case with due consideration of - A -

the specific number of carbon atoms in the group or compound in question, either straight- chained, i.e. methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl, or branched, e.g. isopropyl, isobutyl, sec. -butyl, tert. -butyl, isopentyl, neopentyl or isohexyl. Preferred meanings of alkyl are methyl, ethyl or n- or isopropyl, in particular d-C₂-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-C₄-alkylene and even more preferably methylene or 1 ,2-ethylene.

Alkenylene is, in each case with due consideration of the specific number of carbon atoms, for example, straight-chained or branched propenylene butenylene, pentenylene, pentadienylene, hexenylene or hexadienylene, preferably C₃-C₆-alkenylene or C₄-C₆- alkadienylene and in particular a radical -CH=CH-CH₂- or especially -CH₂-C(=CH₂)-.

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.

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-C₂- 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.

Examples of preferred 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 CHF₂ or especially CF₃; ethyl which is mono- to pentasubstituted by fluorine, chlorine and/or bromine, such as CH₂CF₃, CF₂CF₃, CF₂CCI₃, CF₂CHCI₂, CF₂CHF₂, CF₂CFCI₂, CF₂CHBr₂, CF₂CHCIF, CF₂CHBrF or CCIFCHCIF, in particular CF₂CF₃; propyl or isopropyl, mono- to heptasubstituted by fluorine, chlorine and/or bromine, such as CH₂CHBrCH₂Br, CF₂CHFCF₃, CH₂CF₂CF₃ or CH(CF₃)₂; butyl or one of its isomers, mono- to nonasubstituted by fluorine, chlorine and/or bromine, such as CF(CF₃)CHFCF₃ or CH₂(CF₂)₂CF₃; pentyl or one of its isomers substituted once to eleven times by fluorine, chlorine and/or bromine, such as CF(CF₃)(CHF)₂CF₃ or CH₂(CF₂)₃CF₃; and hexyl or one of its isomers substituted once to thirteen times by fluorine, chlorine and/or bromine, such as (CH₂)₄CHBrCH₂Br, CF₂(CHF)₄CF₃, CH₂(CF₂)₄CF3 or C(CFa)₂(CHF)₂CF₃.

In the compounds of formula I, 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.

The variable R₂ is preferably hydrogen or CrC₄-alkyl, more preferably hydrogen or Ci-C₂-alkyl, and in particular hydrogen or especially methyl.

The variable R₂' is preferably hydrogen, halogen, Ci-C₄-alkyl, phenyl or benzyl, more preferably hydrogen chlorine, fluorine, CrC₂-alkyl or phenyl, especially preferably hydrogen, chlorine methyl or phenyl, and in particular hydrogen.

The variable A is preferably straight-chain or branched Ci-C₆-alkylene, more preferably straight-chain or branched CrC₄-alkylene, especially preferably straight-chain-Ci-C₄-alkylene, and in particular methylene or 1 ,2-ethylene.

The variable M is preferably a carbonyl group -C(O)-.

R₄, R₄', R₅ and R₅' are each independently of the other, preferably hydrogen, unsubstituted or halogen- or hydroxyl-substituted C-ι-C₆-alkyl, or phenyl or benzyl, which is each unsubstituted or substituted by halogen, nitro, cyano, hydroxy, Ci-C₄-alkyl, halo-Ci-C₄-alkyl, Ci-C₄-alkoxy, halo-CrC₄-alkoxy, NH₂, Ci-C₄-alkylamino, di-C-ι-C₄-alkylamino and Ci-C₄-alkylthio.

More preferably, R₄, R₄', R₅ and R₅' are each independently of the other, hydrogen, unsubstituted or halogen-substituted Ci-C₄-alkyl, phenyl or benzyl, in particular hydrogen, methyl or ethyl.

R₆ and R₇ are each independently preferably hydrogen or Ci-C₄-alkyl, in particular hydrogen, methyl or ethyl.

Preferred meanings of C(O)OR₄, C(O)OR₄' and C(O)OR₆ are independently C(O)OH including physiologically acceptable salts thereof, C(O)OCi-C₆-alkyl, C(O)Ophenyl or C(O)Obenzyl, in particular C(O)OC_rC₄-alkyl. Preferred meanings of C(O)R₄, C(O)R₄' and C(O)R₆ independently include COH; C(O)CrC₆- alkyl, which may be substituted by halogen or hydroxyl; C(O)phenyl; or C(O)benzyl, in particular COH or C(O)C_rC₄-alkyl.

Preferred meanings of NHC(O)R₄, NHC(O)R₄' and NHC(O)R₆ independently include NHC(O)Ci-C₆-alkyl, which may be substituted by halogen or hydroxyl; NHC(O)phenyl; and NHC(O)benzyl, in particular NHC(O)C_rC₄-alkyl.

The preferred meaning of C(O)NR₄R₅, C(O)NR₄ ¹R₅' and C(O)NR₆R₇ is each C(O)NH₂.

Preferred meanings of S(O₂)NR₄R₅ are S(O₂)NH₂ or S(O₂)N(C_rC₂-alkyl)₂.

Preferred meanings of SO₃R₄ are SO₃H including physiologically acceptable salts thereof, or S(O₂)OCi-C₄-alkyl.

The 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-C₆- alkyl, hydroxy, unsubstituted or halogen-substituted CrC₆-alkoxy, unsubstituted or halogen- substituted d-Cβ-alkylthio, d-C₆-alkylsulfonyl, NR₄R₅, NHC(O)R₄, C(O)R₄, C(O)OR₄, C(O)NR₄R₅, unsubstituted or substituted phenyl or unsubstituted or substituted phenyl-Ci-C₂- alkyl, the phenyl substituents being selected from the group consisting of halogen, nitro, cyano, Ci-C₄-alkyl, halo-C_rC₄-alky, C_rC₄-alkoxy, halo-C_rC₄-alkoxy, NH₂, N-C_rC₄-alkylamino, N,N-di- Ci-C₄-alkylamino, acetyl and C(O)NH₂, whereby, if m is greater than 1 , the signification of Ri may be identical or different, and wherein for R₄ and R₅ the above-given meanings and preferences apply.

Especially preferred meanings of Ri are halogen, cyano, nitro, Ci-C₄-alkyl, halo-Ci-C₂-alkyl, hydroxy, Ci-C₂-alkoxy, halo-Ci-C₂-alkoxy, Ci-C₂-alkylthio, halo-Ci-C₂-alkylthio, N-Ci-C₂-alkyl- amino, N,N-di-Ci-C₂-alkylamino, or unsubstituted or halogen-, cyano-, Ci-C₂-alkyl-, halo-Ci-C₂- alkyl-, Ci-C₂-alkoxy-, or halo-CrC₂-alkoxy-substituted phenyl, whereby, if m is greater than 1 , the signification of Ri may be identical or different. Particularly preferred meanings of Ri are halogen, cyano, nitro, Ci-C₂-alkyl, trifluoromethyl, hydroxy, CrC₂-alkoxy, trifluoromethoxy, Ci-C₂-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, R₁ 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 R₃ is preferably Ci-C₆-alkyl, which is unsubstituted or substituted by halogen, cyano, nitro, hydroxyl, CrC₄-alkoxy, NH₂, N-Ci-C₄-alkylamino, N,N-di-C-ι-C₄-alkylamino, NHC(O)CrC₂-alkyl, C(O)OC_rC₄-alkyl, or C(O)NH₂; C₃-C₆-cycloalkyl, which is unsubstituted or substituted by Ci-C₂-alkyl; C₂-C₆-alkenyl, which is unsubstituted or substituted by halogen; C₂- C₆-alkynyl; phenyl or benzyl, which is each unsubstituted or substituted by halogen, nitro, cyano, hydroxy, Ci-C₄-alkyl, halo-CrC₄-alkyl, d-C₄-alkoxy, halo-Ci-C₄-alkoxy, NH₂, N-CrC₄- alkylamino, N,N-di-Ci-C₄-alkylamino, NHC(O)-C_rC₄-alkyl, C_rC₄-alkylthio, halo-C_rC₄-alkylthio, CHO, C(O)Ci-C₄-alkyl, C(O)OH, C(O)OC_rC₄-alkyl or C(O)NH₂; or a 5- or 6-membered heterocycloaliphatic radical comprising one or two same or different heteroatoms selected from the group consisting of N, O and S.

The variable R₃ is even more preferably CrCβ-alkyl, which is unsubstituted or substituted by halogen, cyano, Ci-C₄-alkoxy or C(O)OCi-C₄-alkyl; C₃-C₆-cycloalkyl; C₂-C₆-alkenyl; benzyl; phenyl, which is unsubstituted or substituted by halogen, nitro, cyano, hydroxy, CrC₄-alkyl, halo-Ci-C₄-alkyl, C_rC₄-alkoxy, halo-C_rC₄-alkoxy, NH₂, N-Ci-C₄-alkylamino, N,N-di-C_rC₄- alkylamino, CHO, C(O)C_rC₂-alkyl, C(O)OH, C(O)OC_rC₂-alkyl Or C(O)NH₂; or a heterocycloaliphatic radical selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.

Particularly preferred meanings of R₃ are Ci-C₆-alkyl, C₅-C₆-cycloalkyl, unsubstituted or d-C₂- alkyl-, Ci-C₂-alkoxy-, halogen- or cyano-substituted phenyl, or piperidinyl.

In case of a phenyl radical R₃ 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.

A preferred embodiment of the present invention concerns the use of a compound of formula

wherein for R₁, R₂, 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; R₂ is hydrogen or Ci-C₄-alkyl, in particular hydrogen or methyl; A is straight-chain Ci-C₄-alkylene, in particular methylene or 1 ,2-ethylene; and for R₁ and R₃ 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 R₁, R₂, R₂', m, p and q are defined as given above, with a compound of formula

Hal A M R, HI wherein R₃, M and A are defined as given above and Hal is halogen, for example chlorine, optionally in the presence of a basic catalyst.

The 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. Examples of such 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 dioxane; ketones such as acetone, methyl ethyl ketone or methyl isobutyl ketone; amides such as N,N-dimethylformamide, N,N-diethyl- formamide, N,N-dimethylacetamide, N-methylpyrrolidone or hexamethylphosphoric acid triamide; nitriles such as acetonitrile or propionitrile; and sulfoxides, such as dimethyl sulfoxide.

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. 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).

A preferred leaving group Hal is bromine or chlorine. The reaction advantageously takes place in a temperature range of ca. 0⁰C to ca. 200⁰C , preferably from ca. 50⁰C 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. For example, 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:

LG-HaI

wherein R₁ R₂, R₂' and m are as defined above, Hal is halogen, for example chlorine, and LG is a leaving group, for example, Ci-C₆-alkyl, benzyl or CrC₆-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.

Depending on the method and/or reaction conditions, 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.

According to the invention, apart from separation of corresponding isomer mixtures, generally known methods of diastereoselective or enantioselective synthesis can also be applied to obtain pure diastereoisomers or enantiomers, e.g. by carrying out the method of the invention using educts with correspondingly suitable stereochemistry. It is advantageous to isolate or synthesise the biologically more active isomer, e.g. enantiomer, provided that the individual components have differing biological efficacy.

In the method of the present invention, 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.

In the context of the present invention the term 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.

In the context of the present invention, 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. However, 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. (e.g. Haematopota pluvialis) and Tabanus spp, (e.g.Tabanus nigrovittatus) and Chrysopsinae such as Chrysops spp. (e.g. 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 irήtans, Ceratophyllus gallinae, Dermatophilus penetrans, blood-sucking lice (Anoplura) such as Linognathus spp, Haematopinus spp, Solenopotes spp, Pediculus humanis; but also chewing lice [Mallophaga) such as Bovicola (Damalinia) ovis, Bovicola (Damalinia) bovis and other Bovicola spp. . 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. Known representatives of 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.

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. 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.

They are similarly suitable as a soil insecticide against pests in the soil.

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 plant nematodes of the species

Meloidogyne, Heterodera, Pratylenchus, Ditylenchus, Radopholus, Rizoglyphus etc.

Surprisingly, 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.

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 Parascaήs. 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). As with the compositions, 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. In addition, the 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. structure building ingredients the following excipients may be used: 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.

The use of emulsifiers, wetting agents and spreading agents may also be required, in general, lecithins 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, fatty acid esters and fatty alcohol ethers of polyoxyethylene like poloxyl oleyl ether, polyoxypropylene polyoxyethylene block copolymers as e.g. Pluronic™ , 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.

As 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.

The addition of penetration enhancers like ketones, sulfoxides, amides, fatty acid esters and fatty alcohols may be necessary.

Also 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. 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. Non-limitative examples of suitable insecticides and acaricides are:

1. Abamectin 96. Dioxathion 191. Omethoate

2. Acephate 97. Disulfoton 192. Oxamyl

3. Acequinocyl 98. DNOC 193. Oxydemethon M

4. Acetamiprid 99. Doramectin 194. Oxydeprofos

5. Acetoprole 100. DPX-HGW86 195. Parathion

6. Acrinathrin 101. Edifenphos 196. Parathion-methyl

7. AKD-1022 102. Emamectin 197. Permethrin

8. Alanycarb 103. Empenthrin 198. Phenothrin

9. Aldicarb 104. Endosulfan 199. Phenthoate

10. Aldoxycarb 105. Esfenvalerat 200. Phorate

1 1. Allethrin 106. Ethiofencarb 201. Phosalone

12. Alpha-cypermethrin 107. Ethion 202. Phosmet

13. Alphamethrin 108. Ethiprole 203. Phosphamidon

14. Amidoflumet 109. Ethoprophos 204. Phoxim

15. Amitraz 1 10. Etofenprox 205. Pirimicarb

16. Anabasine 1 1 1. Etoxazole 206. Pirimiphos A 17. Avermectin B1 1 12. Etrimphos 207. Pirimiphos M

18. Azadirachtin 1 13. Fenamiphos 208. Polynactins

19. Azamethiphos 1 14. Fenazaquin 209. Prallethrin

20. Azinphos-ethyl 1 15. Fenbutatin oxid 210. Profenofos

21. Azinphos-methyl 1 16. Fenitrothion 21 1. Profluthrin

22. Azocyclotin 1 17. Fenobucarb 212. Promecarb

23. Bacillus subtil, toxin 1 18. Fenothiocarb 213. Propafos

24. Bacillus thuringiensis 1 19. Fenoxycarb 214. Propargite

25. Benclothiaz 120. Fenpropathrin 215. Propoxur

26. Bendiocarb 121. Fenpyroximate 216. Prothiofos

27. Benfuracarb 122. Fenthion 217. Prothoate

28. Bensultap 123. Fenvalerate 218. Protrifenbute

29. Benzoximate 124. Fipronil 219. Pymetrozine

30. Beta-cyfluthrin 125. Flonicamid 220. Pyrachlofos

31. Beta-cypermethrin 126. Fluacrypyrim 221. Pyrafluprole

32. Bifenazate 127. Fluazinam 222. Pyresmethrin

33. Bifenthrin 128. Fluazuron 223. Pyrethrin

34. Bioallethrin 129. Flubendiamide 224. Pyrethrum

35. Bioresmethrin 130. Flucycloxuron 225. Pyridaben

36. Bistrifluron 131. Flucythrinate 226. Pyridalyl

37. BPMC 132. Flufenerim 227. Pyridaphenthion

38. Brofenprox 133. Flufenoxuron 228. Pyrifluquinazon

39. Bromophos A 134. Flufenprox 229. Pyrimidifen

40. Bromopropylate 135. Flumethrin 230. Pyriprole

41. Bufencarb 136. Fonophos 231. Pyriproxyfen

42. Buprofezin 137. Formothion 232. Quinalphos

43. Butocarboxim 138. Fosthiazate 233. Resmethrin

44. Cadusafos 139. Fubfenprox 234. Rotenone

45. Carbaryl 140. Furathiocarb 235. RU 15525

46. Carbofuran 141. Gamma-cyhalothrin 236. Sabadilla

47. Carbophenothion 142. Halfenprox 237. Salithion

48. Carbosulfan 143. Halofenozide 238. Selamectin

49. Cartap 144. HCH 239. Silafluofen 50. Chloethocarb 145. Heptenophos 240. Spinetoram

51. Chlorantraniliprole 146. Hexaflumuron 241. Spinosad

52. Chlorethoxyfos 147. Hexythiazox 242. Spirodiclofen

53. Chlorfenapyr 148. Hydramethylnon 243. Spiromesifen

54. Chlorfenvinphos 149. Hydroprene 244. Spirotetramat

55. Chlorfluazuron 150. lmidacloprid 245. Sulcofuron sodium

56. Chlormephos 151. lmiprothrin 246. Sulfluramid

57. Chlorpyrifos 152. Indoxacarb 247. Sulfotep

58. Chlorpyrifos-methyl 153. insect-active fungi 248. Sulfur

59. Chromafenozide 154. insect-active 249. Sulprofos nematodes

60. Cis-Resmethrin 155. insect-active viruses 250. Tau-fluvalinate

61. Clofentezin 156. lprobenfos 251. Tebufenozide

62. Clothianidin 157. lsofenphos 252. Tebufenpyrad

63. Coumaphos 158. lsoprocarb 253. Tebupirimfos

64. Cyanophos 159. Isoxathion 254. Teflubenzuron

65. Cycloprothrin 160. Ivermectin 255. Tefluthrin

66. Cyenopyrafen 161. Karanjin 256. Temephos

67. Cyflumetofen 162. Kinoprene 257. Terbufos

68. Cyfluthrin 163. Lamba-Cyhalothrin 258. Tetrachlorvinphos

69. Cyhalothrin 164. Lepimectin 259. Tetradifon

70. Cyhexatin 165. Lufenuron 260. Tetramethrin

71. Cymiazole 166. Malathion 261. Thiacloprid

72. Cypermethrin 167. Mecarbam 262. Thiamethoxam

73. Cyphenothrin 168. Mesulfenphos 263. Thiocyclam

74. Cyromazine 169. Metaflumizone 264. Thiodicarb

75. Deltamethrin 170. Metaldehyde 265. Thiofanox

76. Demeton M 171. Methamidophos 266. Thionazin

77. Demeton S 172. Methidathion 267. Thiosultap

78. Demeton-S-methyl 173. Methiocarb 268. Thuringiensin

79. Diafenthiuron 174. Methomyl 269. Tolfenpyrad

80. Diazinon 175. Methoprene 270. Tralomethrin

81. Dichlofenthion 176. Methothrin 271. Transfluthrin 82. Dichlorvos 177. Methoxyfenozide 272. Triarathene

83. Dicofol 178. Metofluthrin 273. Triazamate

84. Dicrotophos 179. Metolcarb 274. Triazophos

85. Dicyclanil 180. Metoxadiazone 275. Trichlorfon

86. Diethion 181. Mevinphos 276. Triflumuron

87. Diflovidazin 182. Milbemectin 277. Trimethacarb

88. Diflubenzuron 183. Milbemycin oxime 278. Vamidothion

89. Dimefluthrin 184. Monocrotophos 279. Vaniliprole

90. Dimethoate 185. Moxidectin 280. XMC (3,5,- Xylylmethylcarbamate)

91. Dimethylvinphos 186. Naled 281. Xylylcarb

92. Dinobuton 187. Nicotine 282. Zeta-cypermethrin

93. Dinocap 188. Nitenpyram 283. Zetamethrin

94. Dinotefuran 189. Novaluron 284. ZXI 8901

95. Diofenolan 190. Noviflumuron

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.

Some of them are already listed above.

(A1 ) Abamectin (A2) Albendazole (A3) Cambendazole

(A4) Closantel (A5) Diethylcarbamazine (A6) Doramectin

(A7) Emodepside (A8) Eprinomectin (A9) Febantel

(A10) Fendendazole (A1 1 ) Flubendazole (A12) Ivermectin

(A13) Levamisol (A14) Mebendazole (A15) Milbemectin

(A16) Milbemycin Oxime (A17) Morantel (A18) Moxidectin

(A19) Nitroscanate (A20) Omphalotin (A21 ) Oxantel

(A22) Oxfendazole (A23) Oxibendazole (A24) Phenothiazine

(A25) Piperazine (A26) PNU-97333 (A27) PNU-141962

(A28) Praziquantel (A29) Pyrantel (A30) Thiabendazole

(A31 ) Triclabendazole amino acetonitrile derivatives named in WO2005044784

Non-limitative examples of suitable repellents and detachers are: (R1 ) DEET (N, N-diethyl-m-toluamide) (R2) KBR 3023 N-butyl-2-oxycarbonyl-(2-hydroxy)-piperidine (R3) Cymiazole = N,-2,3-dihydro-3-methyl-1 ,3-thiazol-2-ylidene-2,4-xylidene

Non-limitative examples of suitable synergists are:

(51 ) Piperonyl butoxide (S4) Piprotal (S7) Sesamolin

(52) Ethylenediaminetetraacetic acid (S5) Propyl isome (S8) Sulfoxide (S2) Cyclodextrin (S6) Sesamex (S9) Tribufos

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.

The above-specified combination partners are best known to specialists in this field. Most are described in various editions of the Pesticide Manual, The British Crop Protection Council, London, and others in the various editions of The Merck Index, Merck & Co., Inc., Rahway, New Jersey, USA or in patent literature. Therefore, the following listing is restricted to a few places where they may be found by way of example.

The commercially available compounds described in the table above can be found in The Pesticide Manual, 14th Ed. (2006), The British Crop Protection Council, London except for 99, 160, 183, 185, 238, A2, A6, A8, A9, A10, A12, A13, A16, A17, A18, A22, A23, A25, A28, A29, A30, which are described in the Compendium of Veterinary Products, 9th Ed. (2006), North American Compendiums, Inc.. Compounds Nos. 5, 7, 14, 66, 67, 100, 132, 163, 218, 221 , 228, 230, 240, 244, 268, and 279 can be found in the Internet, for example, in the online Merck Veterinary Manual and Compendium of Pesticide Common Names. 154: a preparation which contains insect-active nematodes, preferably Heterorhabditis bacteriophora and Heterorhabditis megidis, from The Pesticide Manual, 1 1 thEd. (1997), The British Crop Protection Council, London, page 671 ; Steinernema feltiae, from The Pesticide Manual, 1 1 thEd. (1997), The British Crop Protection Council, London, page 1 115 and Steinernema scapterisci, from The Pesticide Manual, 1 1thEd. (1997), The British Crop Protection Council, London, page 1 1 16;

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. (1997), The British Crop Protection Council, London, page 1342; Mamestra brassicae NPV, from The Pesticide Manual, 1 1thEd. (1997), The British Crop Protection Council, London, page 759 and Cydia pomonella granulosis virus, from The Pesticide Manual, 1 1 thEd. (1997), The British Crop Protection Council, London, page 291.

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 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.

As a rule, the 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.

Application of the compositions according to the invention to the animals to be treated 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 Ci₂-Ci₈; 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, e.g. 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 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.

Whereas it is preferred to formulate commercial products as concentrates, the end user will normally use dilute formulations.

Such 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.

Compositions of this type, which are used by the end user, similarly form a constituent of the present invention.

In each of the processes according to the invention for pest control or in each of the pest control compositions according to the 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. The invention also includes the compounds of formula I according to the invention for usage in one of the said processes. Preferred formulations of the compounds of the invention are made up as follows: (% = percent by weight) Formulation examples

1. 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.

2. Granulate active ingredient 3 % polyethylene glycol (mw 200) 3 % kaolin 94 %

(mw = molecular weight)

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.

3. Tablets or boli

I active ingredient 33.00 % methylcellulose 0.80 % silicic acid, highly dispersed 0.80 % corn starch 8.40 %

II lactose, cryst. 22.50 % corn starch 17.00 % microcryst. cellulose 16.50 % magnesium stearate 1.00 %

I 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.

II All 4 excipients are mixed thoroughly.

III The preliminary mixes obtained according to I and Il are mixed and pressed into tablets or boli.

4. Injectables A. Oily vehicle (slow release)

1. active ingredient 0.1-1.O g groundnut oil ad 100 ml

2. active ingredient 0.1-1.0 g sesame oil ad 100 ml

Preparation: The active ingredient is dissolved in part of the oil whilst 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 mm.

B Water-miscible solvent (average rate of release) active ingredient 0.1-1.0 g

4-hydroxymethyl-1 ,3-dioxolane (glycerol formal) 40 g

1 ,2-propanediol ad 100 ml active ingredient 0.1-1.0 g glycerol dimethyl ketal 40 g

1 ,2-propanediol ad 100 ml

Preparation: The active ingredient is dissolved in part of the solvent whilst stirring, made up to the desired volume and sterile-filtered through a suitable membrane filter with a pore size of 0.22 mm. C. Aqueous solubilisate (rapid release)

1. 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

2. 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

A. active ingredient 5 g isopropyl myristate 10 g isopropanol ad 100 ml

B active ingredient 2 g hexyl laurate 5 g medium-chained triglyceride 15 g ethanol ad 100 ml

C. active ingredient 2 g oleyl oleate 5 g

N-methyl-pyrrolidone 4O g isopropanol ad 100 ml

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.

Further biologically active substances or additives, which are neutral towards the compounds of formula I 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.

The following examples serve merely to illustrate the invention. MP = melting point,

Example 1 :

A: 6g of (4-Chloro-phenyl)-pyridin-4-yl-methanone are dissolved in 55ml of diethylether and cooled to 0⁰C. 17ml of methylmagnesium iodide (3M in Et₂O) is added during 30 minutes, the temperature of the reaction mixture is kept below 10⁰C. The mixture is allowed to come to room temperature and is stirred for 3 hours. The reaction is quenched with 10% NH₄CI in water (w/w) and extracted three times with Et₂O. Recrystallisation from acetonitrile gives 1-(4-Chloro- phenyl)-1 -pyridin-4-yl-ethanol which was used without further purification. MP: 154-157°C.

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. After completion of the conversion (TLC) the solvent is removed and the remaining residue is dissolved in 60ml of methanol and cooled to 0⁰C. 6.62g of sodium boronhydride is slowly added while keeping the reaction temperature below 20⁰C. 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. The organic layer is dried with MgSO₄ and filtered. Removal of the solvent and recrystallisation from MeOH gives 1-(4-Chloro-phenyl)-1-(1-methyl-1 ,2,3,6- tetrahydro-pyridin-4-yl)-ethanol, which was used without further purification. MP: 181-185°C

C: A suspension of 1.6g 1-(4-Chloro-phenyl)-1-(1-methyl-1 ,2,3,6-tetrahydro-pyridin-4-yl)- ethanol obtained according to step B in 30% HCIO₄ is heated 1.5h in a sealed tube to 160⁰C using a microwave oven (Biotage). The precipitate is filtered off, washed with 10ml of water and dried in vacuum. 6-Chloro-3,9-dimethyl-2,3,4,4a-tetrahydro-1 H-3-aza-fluorene perchlorate is obtained as a yellow solid, which was used without further purification.

D: 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 MgSO₄ 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 K₂CO₃ is added. 249mg of 2,2,2-trichloro ethyl chloroformiate is slowly added. The reaction mixture is then heated for two hours in a sealed tube to 160⁰C 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 MgSO₄ and filtered. Removal of the solvent gives 6-Chloro-9-methyl-1 ,2,4,4a-tetrahydro-3-aza-fluorene-3- carboxylic acid 2,2,2-trichloro-ethyl ester as a yellowish oil which was further purified by preparative RP-HPLC using a water+0.01 % formic acid / acetonitrile+0.01% formic acid gradient.

760mg θ-Chloro-θ-methyl-i ^^^a-tetrahydro-S-aza-fluorene-S-carboxylic acid 2,2,2-trichloro- ethyl ester is treated with 64mg of Zn powder and 1.5ml of acetic acid. The mixture is stirred for 14 hours and then diluted with 1 ml of water. The solvent is removed and the residue is taken up with dichloromethane. The white precipitated is filtered off and washed with dichloromethane. The combined organic phases are washed with 1 N NaHCO₃ and dried using Na₂SC>₄. Removal of the solvent and treatment of the residue with 2M HCI/diethylether gives 6- Chloro-9-methyl-2,3,4,4a-tetrahydro-1 H-3-aza-fluorene hydrochloride which was used without further purification.

Alternatively, 144mg of 6-Chloro-3,9-dimethyl-2,3,4,4a-tetrahydro-1 H-3-aza-fluorene is dissolved in 3.5ml of dichloroethane and cooled to 0⁰C. 0.133ml Chloro-1 -ethyl chloroform iate is slowly added. The reaction mixture is heated to 180⁰C in a sealed tube for three hours using a microwave oven (Biotage). The solvent is removed in vacuum and the remaining residue is treated with MeOH and heated 30min. to 85°C in a sealed tube using a microwave oven (Biotage). The solvent is removed and the remaining residue recrystalized from acetonitrile to give 6-Chloro-9-methyl-2,3,4,4a-tetrahydro-1 H-3-aza-fluorene which is transformed to its hydrochloride by treating it with 2M HCI/diethylether.

E: 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 70⁰C and 58mg of 3-chloropropiophenone dissolve in 0.5ml of DMF are slowly added. After additional 15min. at 70⁰C 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). The remaining solid is treated with 2ml of 2M HCI/diethylether to give 3-(6-Chloro-9-methyl-1 ,2,4,4a-tetrahydro-3-aza-fluoren-3-yl)-1- phenyl-propan-1-one hydrochloride. MW_ca|_C: 351.14, m/z: 352.04 [M+H], retention time: 5.20min.

Analysis of the purified samples is done using a Waters Autopurification (HPLC/MS) system. The samples are characterized by m/z and retention time

Column: Reversed Phase Column (150x3mm) from Bischoff, Leonberg, Germany; column material: Daisogel SP-120-ODS-AP 5μm Flow Rate: 2ml/min;

Solvent A: Water + 0.01 % formic acid, Solvent B: Acetonitrile + 0.01 % formic acid Gradient: Time %A %B 0 90 10 1 90 10

7 5 95

9 5 95

10 90 10

1 1 90 10

The following compounds as outlined in Tables 1 to 7 are obtained using the method as described in Example 1 ).

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Biological Examples:

1. Activity in vitro against Ctenocephalides felis (Cat flea).

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.

The following compounds showed more than 60% (EC₆o) efficacy at 100ppm: 2.1 , 2.28, 2.33,

2.37, 2.40, 3.1 , 3.2, 7.30.

2. Activity in vitro against Rhipicephalus sanguineus (Dog tick).

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.

In this test the following examples showed more than 80% (EC₈o) efficacy at 640ppm: 1.1 , 1.26, 1.36, 1.39, 2.1 , 2.2, 2.3, 2.5, 2.6, 2.10, 2.1 1 , 2.27, 2.31 , 2.32, 2.33, 2.37, 2.40, 2.42, 2.46, 2.47, 2.60, 2.64, 2.72, 2.77, 2.83, 4.1 , 4.6, 4.26, 5.1 , 5.2, 5.6, 5.10, 5.30, 5.31 , 5.39, 5.42, 5.45, 5.46, 5.47, 5.63, 5.76, 6.1 , 7.4, 7.5, 7.9, 7.10, 7.15, 7.17, 7.25,7.26, 7.30,7.31. Moreover, 1.1 , 1.26, 2.2, 2.3, 2.6, 2.10, 2.32, 3.33, 3.40, 3.46, 3.47, 5.1 , 5.2, 5.6, 5.10, 5.31 , 5.39, 5.42, 5.46, 5.47, 7.26 showed more than 80% efficacy at 200ppm.

Comparative Tests

The compounds as outlined in the Table below are made using the procedure as outlined in WO 2006/89038. The compounds are then tested against R. Sanguineus at a concentration of 640ppm using the test setup described above. The results are shown in the Table below.

Table 8

3. Activity in vitro against Trichostrongylus colubriformis and Haemonchus contortus Freshly harvested and cleaned nematode eggs are 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 MED. The test compounds are embedded in an agar-based nutritive medium allowing the full development of eggs through to 3^rd instar larvae. The plates are incubated for 6 days at 25°C and 60% relative humidity (RH). Egg- hatching and ensuing larval development are recorded to identify a possible nematodicidal activity.

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% (EC₈o) 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.

4. Activity in vivo against Ctenocephalides felis (cat flea) on Mongolian gerbils (Meriones unguiculatus) (spray application)

On day 0, gerbils are treated with the test compound at a given dose by spray or spot-on application. On day +1 , 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.

5. Activity in vivo against Rhipicephalus sanguineus nymphs on Mongolian gerbils (Meriones unguiculatus) (spray application)

On day 0, gerbils are treated with the test compound at a given dose by spray (or spot-on) application. On day +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.

In this test the following compounds show more than 80% killing efficacy at 100mg/kg: 1.1 , 1.26, 2.1 , 2.2, 2.31 , 2.33, 2.40, 2.42, 2.60, 5.1 , 5.30, 5.42, 7.25, 7.31.

Claims

What we claim is:

1. The use of a compound of formula

wherein m is an integer from 0 to 4; each R₁ is independently halogen, cyano, nitro, unsubstituted or halogen-, cyano-, nitro-, hydroxy- or d-C₄-alkoxy-substituted Ci-C₆-alkyl, unsubstituted or halogen-substituted C₃-C₆- cycloalkyl, unsubstituted or halogen-substituted C₂-C6-alkenyl, unsubstituted or halogen- substituted C₂-C₆-alkynyl, hydroxy, unsubstituted or halogen-substituted Ci-C₆-alkoxy, unsubstituted or halogen-substituted C₂-C6-alkenyloxy, unsubstituted or halogen-substituted C₂-C₆-alkynyloxy, unsubstituted or halogen-substituted C₃-C₆-cycloalkyloxy, SH, unsubstituted or halogen-substituted Ci-C₆-alkylthio, unsubstituted or halogen-substituted C₃-C₆- cycloalkylthio, unsubstituted or halogen-substituted Ci-C₆-alkylsulfinyl, unsubstituted or halogen-substituted C₃-C₆-cycloalkylsulfinyl, unsubstituted or halogen-substituted d-C₆- alkylsulfonyl, unsubstituted or halogen-substituted C₃-C₆-cycloalkylsulfonyl, SO₃R_4, S(O₂)NR₄R₅, NR₄R₅, NHC(O)R₄, C(O)R₄, C(O)OR₄, C(O)NR₄R₅, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted aryloxy, unsubstituted or substituted arylalkyloxy, unsubstituted or substituted arylthio, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted heteroaryloxy, or unsubstituted or substituted heteroarylthio, the aryl, arylalkyl, aryloxy, arylalkyloxy, arylthio, heteroaryl, heteroarylalkyl, heteroaryloxy and heteroarylthio substituents in each case independently from each other being selected from the group consisting of halogen, nitro, cyano, hydroxy, unsubstituted or halogen-, cyano-, nitro-, hydroxy- or d-C₄- alkoxy-substituted Ci-C₆-alkyl, Ci-C₆-alkoxy, halo-Ci-C₆-alkoxy, NH₂, N-Ci-C₆-alkylamino, N, N- di-Ci-C₆-alkylamino, NHC(O)R₆, C_rC₆-alkylthio, halo-C_rC₆-alkylthio, C(O)R₆, C(O)OR₆ and C(O)NR₆R₇, whereby, if m is greater than 1 , the signification of Ri may be identical or different; R₂ is hydrogen, Ci-C₆-alkyl, unsubstituted or halogen-, Ci-C₄-alkyl- or Ci-C₄-alkoxy-substituted pheny or benzyl;

R₂' is hydrogen, halogen, cyano, Ci-C₆-alkyl, unsubstituted or halogen-, Ci-C₄-alkyl- or d-C₄- alkoxy-substituted pheny or benzyl; A is straight-chain or branched C-i-Cs-alkylene or C₂-Cs-alkenylene; p and q are each independently an integer of 0, 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(O₂)-;

R₃ is CrC₆-alkyl, C₃-C₆-cycloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkenyl, heterocycloaliphatyl, heterocycloaliphatyl-d-Ceralkyl, heterocycloaliphatyl-d-Ceralkenyl, heterocycloaliphatyl-C₂-C₆-alkynyl, aryl, aryl-CrC₆-alkyl, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-CrC₆-alkyl, heteroaryl-C₂-C₆-alkenyl or heteroaryl-C₂-C₆-alkynyl, which is in each case, independently of each other, unsubstituted or substituted by halogen, nitro, cyano, hydroxy, Ci-C₆-alkyl, halo-CrC₆-alkyl, d-C₆-alkoxy, halo-Ci-C₆-alkoxy, NH₂, N-CrC₆- alkylamino, N,N-di-Ci-C₆-alkylamino, NHC(O)R₄', C_rC₆-alkylthio, halo-C_rC₆-alkylthio, C(O)R₄',

C(O)OR₄Or C(O)NR₄ ¹R₅';

R₄, R₄', R₅ and R₅' are each independently of the other hydrogen, unsubstituted or halogen-, cyano-, nitro-, hydroxy- or Ci-C₄-alkoxy-substituted Ci-C₆-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, NO₂, hydroxyl, Ci-C₆-alkyl, halo-Ci-C₆- alkyl, d-C₆-alkoxy, halo-Ci-C₆-alkoxy, NH₂, Ci-C₆-alkylamino, di-Ci-C₆-alkylamino and CrC₆- alkylthio; and

R₆ and R₇ are each independently of the other hydrogen or unsubstituted or hydroxyl-, halogen- or Ci-C₄-alkoxy-substituted Ci-C₆-alkyl, phenyl or benzyl; in the control of parasites in and on warm-blooded animals.

2. The use of a compound of formula I according to claim 1 , wherein p is 1 and q is 2.

3. The use of a compound of formula I according to claim 1 or 2, wherein R₂ is hydrogen or d- C₄-alkyl, and R₂' is hydrogen.

4. The use of a compound of formula I according to any one of claims 1 to 3, wherein M is a carbonyl group -C(O)-.

5. The use of a compound of formula I according to any one of claims 1 to 3, wherein A is straight-chain or branched CrC₆-alkylene, in particular straight-chain Ci-C₄-alkylene.

6. The use of a compound of formula

wherein R₁, R₃ and m are as defined in claim 1 , R₂ is hydrogen or Ci-C₄-alkyl, in particular methyl, and A is straight-chain d-C₄-alkylene.

7. The use according to any one of claims 1 to 6, wherein m is 0, 1 or 2, and Ri is halogen, cyano, nitro, unsubstituted or halogen-substituted Ci-C₆-alkyl, hydroxy, unsubstituted or halogen-substituted Ci-C₆-alkoxy, unsubstituted or halogen-substituted Ci-C₆-alkylthio, d-C₆- alkylsulfonyl, NR₄R₅, NHC(O)R₄, C(O)R₄, C(O)OR₄, C(O)NR₄R₅, unsubstituted or substituted phenyl or unsubstituted or substituted phenyl-Ci-C₂-alkyl, the phenyl substituents being selected from the group consisting of halogen, nitro, cyano, Ci-C₄-alkyl, halo-Ci-C₄-alky, d-C₄- alkoxy, halo-Ci-C₄-alkoxy, NH₂, N-Ci-C₄-alkylamino, N,N-di-Ci-C₄-alkylamino, acetyl and C(O)NH₂, whereby, if m is 2, the signification of Ri may be identical or different, and wherein R₄ and R₅ are each independently hydrogen, unsubstituted or halogen-substituted Ci-C₄-alkyl, or phenyl or benzyl.

8. The use according to any one of claims 1 to 6, wherein m is 0, 1 or 2, and Ri is halogen, cyano, nitro, Ci-C₂-alkyl, trifluoromethyl, hydroxy, Ci-C₂-alkoxy, trifluoromethoxy, Ci-C₂-alkylthio or trifluoromethylthio, whereby, if m is 2, the signification of Ri may be identical or different.

9. The use according to any one of claims 1 to 8, wherein R₃ is CrCβ-alkyl, which is unsubstituted or substituted by halogen, cyano, nitro, hydroxyl, CrC₄-alkoxy, NH₂, N-CrC₄- alkylamino, N,N-di-Ci-C₄-alkylamino, NHC(O)C_rC₂-alkyl, C(O)OC_rC₄-alkyl,or C(O)NH₂; C₃-C₆- cycloalkyl, which is unsubstituted or substituted by Ci-C₂-alkyl; C₂-C₆-alkenyl, which is unsubstituted or substituted by halogen; C₂-C₆-alkynyl; phenyl or benzyl, which is each unsubstituted or substituted by halogen, nitro, cyano, hydroxy, Ci-C₄-alkyl, halo-CrC₄-alkyl, d- d-alkoxy, halo-d-C₄-alkoxy, NH₂, N-d-d-alkylamino, N,N-di-d-C₄-alkylamino, NHC(O)-Cr C₄-alkyl, C_rC₄-alkylthio, halo-C_rC₄-alkylthio, CHO, C(O)C_rC₄-alkyl, C(O)OH, C(O)OC_rC₄-alkyl or C(O)NH₂; or a 5- or 6-membered heterocycloaliphatic radical comprising one or two same or different heteroatoms selected from the group consisting of N, O and S.

10. The use according to any one of claims 1 to 8, wherein R₃ is CrC₆-alkyl, which is unsubstituted or substituted by halogen, cyano, Ci-C₄-alkoxy or C(O)OCi-C₄-alkyl; C₃-C₆- cycloalkyl; C₂-C₆-alkenyl; benzyl; phenyl, which is unsubstituted or substituted by halogen, nitro, cyano, hydroxy, Ci-C₄-alkyl, halo-Ci-C₄-alkyl, Ci-C₄-alkoxy, halo-Ci-C₄-alkoxy, NH₂, N-C₁- C₄-alkylamino, N,N-di-C_rC₄-alkylamino, CHO, C(O)C_rC₂-alkyl, C(O)OH, C(O)OC_rC₂-alkyl or C(O)NH₂; or a heterocycloaliphatic radical selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.

1 1. The use of a compound of formula I according to claim 1 , wherein m is 0, 1 or 2; R₁ is halogen, cyano, nitro, Ci-C₂-alkyl, trifluoromethyl, hydroxy, Ci-C₂-alkoxy, trifluoromethoxy, C₁- C₂-alkylthio or trifluoromethylthio, whereby, if m is 2, the signification of Ri may be identical or different; R₂ is hydrogen or Ci-C₄-alkyl; R₂' is hydrogen, halogen, Ci-C₄-alkyl, phenyl or benzyl; p is 1 ; q is 2; A is Ci-C₄-alkylene or C₃-C₆-alkenylene; M is -C(O)-; and R₃ is Ci-C₆-alkyl, which is unsubstituted or substituted by halogen, cyano, nitro, hydroxyl, Ci-C₄-alkoxy, NH₂, N-C₁-C₄- alkylamino, N,N-di-C_rC₄-alkylamino, NHC(O)C_rC₂-alkyl, C(O)OC_rC₄-alkyl,or C(O)NH₂; C₃-C₆- cycloalkyl, which is unsubstituted or substituted by Ci-C₂-alkyl; C₂-C₆-alkenyl, which is unsubstituted or substituted by halogen; C₂-C₆-alkynyl; phenyl or benzyl, which is each unsubstituted or substituted by halogen, nitro, cyano, hydroxy, Ci-C₄-alkyl, halo-Ci-C₄-alkyl, C₁- C₄-alkoxy, halo-C_rC₄-alkoxy, NH₂, N-C_rC₄-alkylamino, N,N-di-C_rC₄-alkylamino, NHC(O)-C₁- C₄-alkyl, C_rC₄-alkylthio, halo-C_rC₄-alkylthio, CHO, C(O)C_rC₄-alkyl, C(O)OH, C(O)OC_rC₄-alkyl or C(O)NH₂; or a 5- or 6-membered heterocycloaliphatic radical comprising one or two same or different heteroatoms selected from the group consisting of N, O and S.

12. The use of a compound of formula Ia according to claim 6, wherein m is 0, 1 or 2; R₁ is halogen, cyano, nitro, CrC₂-alkyl, trifluoromethyl, hydroxy, CrC₂-alkoxy, trifluoromethoxy, C₁- C₂-alkylthio or trifluoromethylthio, whereby, if m is 2, the signification of R₁ may be identical or different; A is straight-chain CrC₄-alkylene; and R₃ is CrC₆-alkyl, which is unsubstituted or substituted by halogen, cyano, CrC₄-alkoxy or C(0)0CrC₄-alkyl; C₃-C₆-cycloalkyl; C₂-C₆- alkenyl; benzyl; phenyl, which is unsubstituted or substituted by halogen, nitro, cyano, hydroxy, C_rC₄-alkyl, halo-C_rC₄-alkyl, C_rC₄-alkoxy, halo-C_rC₄-alkoxy, NH₂, N-C_rC₄-alkylamino, N,N-di- CrC₄-alkylamino, CHO, C(O)C_rC₂-alkyl, C(O)OH, C(O)OC_rC₂-alkyl Or C(O)NH₂; or a heterocycloaliphatic radical selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.

13. A composition for the control of parasites in or on warm-blooded animals, which contains as active ingredient an physiologically effective amount of a compound of formula I according to any one of claims 1 to 12, in addition to a veterinarily acceptable carrier and/or dispersant.

14. Method of controlling parasites on warm-blooded animals, whereby an physiologically effective amount of a compound of formula I according to any one of claims 1 to 12 is used on the parasites or their locus.

15. Use of a compound of formula I according to any one of claims 1 to 12 in a process for controlling parasites on warm-blooded animals excluding humans.

16. Use of a compound of formula I according to any one of claims 1 to 12 in the preparation of a pharmaceutical composition against parasites on warm-blooded animals.