CA2222517C - Agents for use against parasitic protozoa - Google Patents

Abstract

The present invention relates to mixtures of substituted benzimidazoles and polyether antibiotics or synthetically prepared coccidiostats for controlling parasitic protozoa in livestock. The substituted benzimidazoles have the structure: (see formula I) wherein: R1, R2, R3 and R4 each, independently of one another, represent: (i) H or a halogen atom, or (ii) optionally substituted alkyl, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl or fused-on dioxyalkylene, with the proviso that all of the substituents R1, R2, R3 and R4 are not H and a halogen atom; R5 represents: (i) H, (ii) alkyl which is substituted one or more times, identically or differently, by OH, CN, NH2, alkyl, cycloalkyl, alkenyl, alkinyl, alkoxy, halogenoalkoxy, alkylthio, halogenoalkylthio, alkenoxy, alkinoxy, aminocarbonyl, optionally substituted alkylcarbonyl, optionally substituted (het-)arylcarbonyl, optionally substituted alkoxycarbonyl (AlkO-CO-), optionally substituted alkoxycarbonyloxy (AlkOCOO-), aminosulphonyl (SO2NH2), optionally substituted mono- or dialkylaminosulphonyl, acylated amino (AlkCON(R7)- or AlkOCON(R7)-), wherein R7 represents H, alkyl, cycloalkyl, optionally substituted alkylsulphonylamino (AlkylSO2NH-), alkylsulphonyl-N-alkylamino (ArylSO2NAlky1-), optionally substituted arylsulphonylamino (ArylSO2NH-), arylsulphonyl-N- alkylamino (ArylSO2NAlk-) or optionally substituted dialkylamino, or (iii) optionally substituted alkoxycarbonyl, optionally substituted (het-)aryloxycarbonyl, alkylsulphonyl, alkenylsulphonyl, (het-)arylsulphonyl, -SO2NR8R9, -CONR8R9 or -P(O)(NR8R9)2, wherein R8 and R9 represent H or alkyl which is optionally substituted by one or more radicals; and R6 represents fluoroalkyl.

Description

' CA 02222517 1997-11-27 BAYER AWGESEIL.d~.SCHAFT 51368 Leverl~tsen Knmxrnzentrale RP
Patente Komem Rt/li/SP
b" 1 ~.. ~.f a s ' ~ f 1'. ~ .~ ~..a-.. .:~ ~:. i~.d T~RAra~~,.~-rla~v Compositions to comt~at i6c protozoa The present invention relates to mixtures of substituted benzimidazoles with a polyether antibiotic or a synthetically prepared coccidiostat as compositions to control parasitic protozoa and, in particular, coccidia, and fish parasites and insect parasites.
Substituted benzimidazoles and their use as insecticides, fungicides and herbicides have already been disclosed (EP-OS (European Published Specifications) 87 375, 152 360, 181 826, 239 508, 260 744, 266 984, US-A 3 418 318, 3 472 865, 3 576 818, 3 728 994).
Halogenated benzimidazoles and their effect as anthelinintics, coccidiostats and pesticides have been disclosed (DE-OS (German Published Specification) 2 047 369, DE-OS (German Published Specification) 4 237 617). IVfixttlres of vitro-substituted benzimidazoles and polyether antibiotics have been disclosed as coccidiostats (US-A 5 331 003). Their effect is as yet unsatisfactory in all cases.
Coccidiosis is a disease caused by single-cell parasites (protozoa). It may cause great losses in particular in poultry rearing. In order to avoid this, the stocks are treated prophylactically with coccidiostats. The development of resistance to the compositions used results after only a relatively few years in serious problems. On the other hand, it is possible by using chemically completely new coccidiostats, in particular combinations, to control even polyresistant parasite strains.
The present invention relates to mixtures of substituted benzimidazoles of the formula (I) Le A 31 085 ' CA 02222517 1997-11-27 R~
Rz , N ~ Rs w I N
Rs ~ . Rs Ra in which Ri, R2, R3 and Ra each, independently of one another, represent hydrogen, halogen, represent in each case optionally substituted alkyl, alkoxy, alkylthio, alkylsulphinyl, allcylsulphonyl, represent optionally substituted fused-on dioxyalkylene, but where at least one of the substituents RI, R~, R3 and Ra is different from hydrogen and halogen, R; represents hydrogen, represents alkyl which is substituted one or more times, identically or differently, by OIL CN, NHS, alkyl, cycloalkyl, alkenyl, alkinyl, alkoxy, halogenoalkoxy, alkylthio, halogenoalkylthio, alkenoxy, alkinoxy, -aminocarbonyl, optionally substituted alkylcarbonyl, optionally substituted (het-)arylcarbonyl, optionally substituted alkoxycarbonyl (AlkO-CO-), optional 1y substituted alkoxycarbonyloxy (AIkOC00-), aminosulphonyl (SOZNH2), optionally substituted mono- or dialkylaminosulphonyl, acylated amino (AIkCON(R~)- or AIkOCON(R~)-), where R~ is equal to hydrogen, alkyl or cycloalkyl, or optionally substituted alkylsulphonylamino (AlkylS02NH-), or allLylsulphonyl-N-alkylamino (AtylS02NAllcy1-), optionally substituted aryl-sulphonylamino (Ary1S02NH ) or arylsulphonyl-N-alkylamino (Ary1S02NAlk-), optionally substituted dialkylamino, furthermore RS represents optionally substituted alkoxycarbonyl, optionally substituted (het-)aryloxycarbonyl, allylsulphonyl, alkenylsulphonyl, (het-)arylsulphonyl, or-SOZNRgRg, -CONR8R9 or -P(O)(NRBRg)z, where R8 and R9 represent H or alkyl which is optionally substituted by one or more radicals, R6 represents fluoroalkyl, LeA310$~ -2-~ CA 02222517 1997-11-27 with one or more of the following compounds:
Polyether antibiotics such as maduramycin, lasalocid, monensin, narasin, salinomycin or synthetic coccidiostats such as 1 (-(4-Amino-2-n-propyl-5-pyrimidinylinethyl)-2-picolinium Amprolium chloride 1(-(4-Amino-2-n-propyl-5-pyrimidinylinethyl)-2-picolinium Amprolium +
chloride + sulfaquinoxaline sulfaquinoxaline 1 (-(4-Amino-2-n-propyl-5-pyrimidinylmethyl)-2-picolinium Amprolium +
chloride + sulfaquinoxaline + ethopabate sulfaquinoxaline + .
ethopabate 4,4-Dinitrocarbanilide + 2-hydroxy-4,6-dimethylpyrimidine Nicarba7.ln_ 3,5-Dichloro-2,6-dimethyl-4-pyridinol Clopidol 3,5-Dichloro-2,6-dimethyl-4-pyridinol + methyl 7-benzyloxy- Clopidol +
6-butyl-1,4-dihydro-4-oxylquinoline-3-carboxylate methylbenzoquate Ethyl 6-n-decyloxy-7-ethoxy-4-hydroxyquinoline-3- Decoquinate carboxylate 9-(2-Chloro-6-fluorophenylmethyl)-9H-purin-6-amine Arprinocid (+)-2,6-Dichloro-alpha-(4-chlorophenyl)-4--(4,5-dihydro-3,5-Benzeneacetonitrile, dioxo-1,2,4-iriazin-2(3H)-yl)-benzeneacetonitrile diclazuril 1-[3-Methyl-4-(4'-trifluoromethylthiophenoxy)-phenyl]-3- Toltrazuril methyl-1,3,5-triazine-2,4,6(1H,3H,SH)-trione 4,4-Dinitrocarbanilide + 2-hydroxy-4,6-dimethylpyrimidine Robenidine [= nicarbazin]
7-Bromo-6-chloro-febrifugin Halofuginone 3,5-Dinitro-o-toluamide Zoalene LeA31085 -3-' CA 02222517 1997-11-27 > >
as compositions for controlling parasitic protozoa, in particular coccidia, in livestock.
The benzimidazoles which can be used according to the invention are known.
They are generally defined by the formula (I). Preferred compounds of the formula (I) are those in which Ri, R~, R3 and R4 each, independently of one another, represent hydrogen, fluorine, chlorine, bromine, iodine, represent in each case straight-chain or branched alkyl, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl with in each case 1 to 8 carbon atoms, represent cycloalkyl with 3 to 8 carbon atoms, represent in each case straight-chain or branched halogenoalkyl, halogenoalkoxy, halogenoalkylthio, halogenoalkylsulphinyl, halogenoalkylsulphonyl with in each case 1 to 6 carbon atoms and 1 to 13 identical or different halogen atoms or represent optionally singly or multiply, identically or differently by 1 to 10 halogens and/or straight-chain or branched alkyl with 1 to 4 carbon atoms and/or straight-chain or branched halogenoalkyl with 1 to 4 carbon atoms and 1 to 9 halogen atoms doubly linked dioxyalkylene with: 1 to 5 carbon atoms, but where at least one of the substituents RI, RZ, R3 and Rø is different from hydrogen and halogen, RS represents hydrogen, represents alkyl with 1 to 4 carbon atoms, which is substituted one or more times, identically or differently, by OH, CN, NH2, alkyl with 1 to 4 carbon atoms, cycloalkyl with 3 to 10 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkinyl with 2 to 6 carbon atoms, alkyloxy with 1 to 6 carbon atoms, halogenoalkoxy with 1 to 6 carbon atoms and 1 to 5 halogens, alhylthio with 1 to 6 carbon atoms, halogenoalkylthio with 1 to 6 carbon atoms and 1 to 5 halogens, alkenyloxy with 2 to 6 carbon atoms, alkinyloxy with 3 to 6 carbon atoms, optionally substituted alkylcarbonyl with 1 to 6 carbon atoms, optionally substituted phenyl- or hetarylcarbonyl, optionally substituted alkoxycarbonyl with 1 to 6 carbon atoms, optionally substituted alkoxycarbonyloxy with 1 to 6 carbon atoms, aminosulphonyl (NH2SO2-), optionally substituted mono- or dialkylaminosulphonyl with 1 to 6 carbon IxA3108~ -4-' CA 02222517 1997-11-27 atoms, acylated amino (AIkOCON(R~)- or (AIkCON(R~~) where R~ is equal to hydrogen or alkyl with 1 to 6 carbon atoms or cycloalkyl with 3 to 8 carbon atoms, with 1 to 6 carbon atoms, optionally substituted alkylsulphonylamino with 1 to 6 carbon atoms, optionally substituted alkylsulphonyl-N-alkylamino with 1 to 6 carbon atoms, optionally substituted phenylsulphonylamino, optionally substituted phenylsulphonyl-N-alkylamino with 1 to 6 carbon atoms, optionally substituted dialkylamino with 1 to 8 carbon atoms, fiu-thermore RS
represents the optionally substituted radicals alkyloxycarbonyl with 1 to 6 carbon atoms, alkylsulphonyl or alkenylsulphonyl with 1 to 6 carbon atoms, which are optionally substituted by 1 to 13 halogen atoms, optionally substituted phenylsulphonyl, optionally substituted heteroarylsulphonyl, phenoxycarbonyl, or -S02NR$R~, -CONR$Rg or -P(O)(NRgR9~, where Rg and R9 represent hydrogen or an alkyl with 1 to 4 carbon atoms, which are optionally substituted by one of the radicals mentioned above for R5, Substituents of the optionally substituted radicals which may be mentioned are the following substituents:
Halogen, OIL NH2, alkylamino with 1 to 6 carbon atoms, cyano, nitro, C02I~ in each case straight-chain or branched alkyl, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl with, in each case 1 to 6 carbon atoms, in each case straight-chain or branched halogenoalkyl, halogenoalkoxy, halogenoalkylthio, halogenoalkylsulphinyl or halogenoalkylsulphonyl with, in each case, 1 to 6 carbon atoms and 1 to 13 identical or different halogen atoms, in each case straight-chain or branched alkoxyalkyl, alko~yallcoxy, alkanoyl, alkoxycarbonyl or alkoximinoalkyl with, in each case, 1 to 6 carbon atoms in the individual alkyl moieties, doubly linked dioxyallcylene which is optionally substituted 1 to 6 times, identically or differently, by halogen and/or straight-chain or branched alkyl with 1 to 6 carbon atoms and/or straight-chain or branched halogenoalkyl with 1 to 6 carbon atoms and 1 to 13 identical or different halogen atoms and has 1 to 6 carbon atoms, or phenyl or phenoxy which is optionally substituted one to five times, identically or differently, by halogen and/or straight-chain or branched alkyl with 1 to 4 carbon atoms and 1 to 9 identical or different halogen atoms, each of which in turn can carry the abovementioned radicals.
GeA3108~ -5-Acyl radicals of the listed radicals which may be mentioned are the radicals alkoxycarbonyl with 1 to 6 carbon atoms, alkylcarbonyl with 1 to 6 carbon atoms, alkoxycarbonyloxy with 1 to 6 carbon atoms, alkylsulphonyl with 1 to 6 carbon atoms, benzoyl, which is optionally substituted by one of the abovementioned radicals, alkenylcarbonyl with 2 to 6 carbon atoms.
R6 represents 1 to 15 fluoro-Cl-C,-alkyl.
The substituents in compounds of the formula (I) particularly preferably have the following meaning:
RI, R2, R3 and R~ in each case, independently of one another, represent hydrogen, fluorine, chlorine or bromine, represent in each case straight-chain or branched alkyl, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl with, in each case, 1 to 4 carbon atoms, represent cycloalkyl with 3 to 6 carbon atoms, represent in each case straight-chain or branched halogenoalkyl, halogenoalkoxy, halogenoalkylthio, halogenoalkylsulphinyl, halogenoalkylsulphonyl with, in each case, 1 to 4 carbon atoms and 1 to 9 identical or different halogen atoms, in particular fluorine and chlorine atoms or represent optionally singly or multiply, identically or differently, by 1 to 6 halogens, in particular fluorine and chlorine atoms and/or straight-chain or branched alkyl with 1 to 4 carbon atoms and/or straight-chain or branched halogenoallcyl with 1 to 4 carbon atoms and 1 to 6 halogen atoms doubly linked dioxyalkylene with 1 to 3 carbon atoms, but where at least one of the substituents RI, R2, R3 and R4 is different from hydrogen and halogen, RS represents hydrogen, represents alkyl with 1 to 3 carbon atoms, in particular represents methyl and ethyl, which is substituted by OIL CN, NHZ, alkyl, with 1 to 4 carbon atoms, in particular methyl or ethyl, alkenyl with 2 to 4 carbon atoms, alkinyl with 2 to 4 carbon atoms, alkyloxy with 1 to 4 carbon atoms, in particular alkoxy such as methoxy, ethoxy, propoxy, i-propo~y, halogenoalkoxy with 1 to 4 carbon atoms and 1 to 5 halogen atoms, in particular trifluoromethoxy, pentafluoroethoxy, fluoropropoxy, alkylthio with 1 to 4 carbon atoms, halogenoalkylthio with 1 to 4 carbon atoms and 1 to 5 halogens, l~e A 31 085 - 6 -. CA 02222517 1997-11-27 alkenyloxy with 2 to 4 carbon atoms, alkinyloxy with 3 to 4 carbon atoms, optionally substituted alkylcarbonyl with 1 to 4 carbon atoms, optionally substituted phenylcarbonyl, optionally substituted alkoxycarbonyl with 1 to 4 carbon atoms, in particular alkoxycarbonyls such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, i-propoxycarbonyl, t-buto~cycarbonyl, optionally substituted alkoxycarbonyloxy with 1 to 4 carbon atoms, aminosulphonyl (NH2S02-), optionally substituted mono- or dialkylaminosulphonyl with 1 to 4 carbon atoms, acylated amino with 1 to 6 carbon atoms, where R~ is equal to hydrogen or alkyl with 1 to 4 carbon atoms or cycloalkyl with 3 to 6 carbon atoms, optionally substituted alkylsulphonylamino with 1 to 4 carbon atoms, optionally substituted alkylsulphonyl-N-alkylamino with 1 to 4 carbon atoms, optionally substituted phenylsulphonylamino, optionally substituted phenylsulphonyl-N-alkylamino with 1 to 4 carbon atoms, optionally substituted dialkylamino with 1 to 4 carbon atoms, furthermore RS represents the optionally substituted radicals alkyloxycarbonyl with 1 to 4 carbon atoms, alkylsulphonyl or alkenylsulphonyl with 1 to 4 carbon atoms, which are optionally substituted with 1 to 9 halogens, optionally substituted phenylsulphonyl, heteroarylsulphonyl, where heteroaryl represents a 5 or 6-membered heterocycle which is optionally substituted by alkyl with 1 to 4 carbon atoms or halogen or by a substituent listed under R5, or phenoxycarbonyl, or SOZNR8R9, CONR8R9 or -P(O)(NRgRg)2, where R$ and R9 represent hydrogen or an alkyl with 1 to 4 carbon atoms, which are optionally substituted by one of the radicals mentioned above for R5.
Substituents of the optionally substituted radicals which may be mentioned are the following substituents:
Halogen, in particular fluorine or chlorine, OH, NHS, alkylamino with 1 to 4 carbon atoms, in particular methylamino, ethylamino, dimethylamino, diethylamino, bis-(trifluoromethylamino), cyano, nitro, C02I~ in each case straight-chain or branched all'yl, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl with, in each case, 1 to 4 carbon atoms, in particular methyl, ethyl, methoxy, ethoxy or methylmercapto, in each case straight-chain or branched halogenoalkyl, halogenoalkoxy, halogenoalkylthio, LeA3108~ -7-' CA 02222517 1997-11-27 halogenoalkylsulphinyl or halogenoalkylsulphonyl with, in each case, 1 to 4 carbon atoms and 1 to 9 identical or different halogen atoms, in particular trifluoromethyl, pentafluoroethyl, fluorochloroethyl, trichloroethyl, trifluoromethoxy, trichloromethoxy, trifluoromethylmercapto, in each case straight-chain or branched alkoxyalkyl, alkoxyalkoxy, in particular methoxyethoxy, ethoxyethoxy, ethoxyethyl, alkanoyl, alkoxycarbonyl or alkoxyiminoalkyl with, in each case, 1 to 4 carbon atoms in the individual alkyl moieties, in particular acetyl, phenyl or phenoxy which is optionally substituted one to five times, identically or differently, by halogen and/or straight-chain or branched alkyl with 1 to 4 carbon atoms and 1 to 9 identical or different halogen atoms, in particular phenyl or phenoxy, each of which in turn can carry the abovementioned radicals.
R6 represents 1 to 7 fluoro-Ci-C3-alkyl.
Very particularly preferred compounds of the formula (I) are those in which the radicals have the following meaning:
R,, Rv R3 and R4 represent hydrogen, halogen, in particular chlorine or bromine, represent in each case straight-chain or branched alkyl, alkoxy, alkylthio, alhylsulphinyl, alkylsulphonyl with, in each case 1 to 4 carbon atoms, in particular methyl, methoxy, methylthio, methylsulphinyl or methylsulphonyl, represent in each case straight-chain or branched halogenoalkyl, halogenoalkoxy, halogenoalkylthio, halogenoalkylsulphinyl, halogenoalkylsulphonyl with, in each case, 1 to 4 carbon atoms and 1 to 9 identical or different fluorine or chlorine atoms, in particular for trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl, trifluoromethylsulphonyl, represent doubly linked dioxyalkylene which is 2~ optionally substituted optionally by fluorine and/or chlorine atoms and has 1 to 2 carbon atoms, in particular represent OCH20, OCHZCH20, OCF2CF~0, OCF20, OCCIFCCIFO, R, represents hydrogen, represents methyl or ethyl which are substituted by CN, by allyl with 1 to 4 carbon atoms, in particular methyl, alkenyl with 2 to 4 carbon LeA3108~ -8-' CA 02222517 1997-11-27 atoms, in particular -CH~H2 or -CH~HMe, alkinyl with 2 to 4 carbon atoms, in particular -CCH or -CCMe, by alkoxy with 1 to 4 carbon atoms, in particular alkoxy such as methoxy, ethoxy, propoxy, i-propox5~, by alkinyloxy with 3 to 4 carbon atoms, in particular -OCHZCCH or -OCH2CCMe, by alkylcarbonyl with 1 to 4 carbon atoms, in particular acetyl, propionyl, i-propionyl or t-butionyl, by optionally substituted phenylcarbonyl, in particular benzoyl, by optionally substituted alkoxycarbonyl with 1 to 4 carbon atoms, in particular -C02Me, -C02Et, -COZPr, -C02i-Pr or -COZtBu, by acylated amino with 1 to 6 carbon atoms, where R~ is equal to hydrogen or alkyl with 1 to 4 carbon atoms or cycloalkyl with 3 to 6 carbon atoms, in particular N(Me)C02Me, -N(Me)COZEt, -N(Et)C02Et, N(Et)C02Me, -N(Pr)C02Et, N(Bu)C02Me, -N(t-Bu)C02Me, -N(Bu)C02Et, N(C~HII)C02Et, NHCOMe, -NHCOEt or . -NHCOPr, by optionally substituted alkylsulphonylamino with 1 to 4 carbon atoms, optionally substituted alkylsulphonyl-N alkylamino, in particular -NMeS02Me, NEtS02Et, NMeS02Et, NEtS02Me, optionally substituted phenylsulphonylamino, optionally substituted phenylsulphonyl-N-alkylamino with 1 to 4 carbon atoms, in particular -NMeS02Ph, -NEtS02Ph. R5 fiirthermore represents the optionally substituted radicals of allcyloxycarbonyl with 1 to carbon atoms, alkylsulphonyl or alkenylsulphonyl with 1 to 4 carbon atoms, in particular MeS02-, EtS02-, PrS02- or CH2~MeCHZS02-, optionally substituted phenylsulphonyl, in particular phenylsulphonyl or 2.4.6-trimethyl-phenylsulphonyl, optionally substituted heteroarylsulphonyl, where heteroaryl represents a 5 or 6-membered heterocycle which is substituted by fluorine, chlorine or bromine and/or is substituted by an alkyl with 1 to 4 carbon atoms, in particular methyl and/or by a substituent mentioned under R5, in particular Me02C and contains one to three identical or different heteroatoms, in particular nitrogen, sulphur and/or oxygen, phenoxycarbonyl, or -SOZNR8R9, -CONRBRg or -PO(NRgR9)2, were R8 and R9 represent hydrogen or an alkyl with 1 to 4 carbon atoms, which are optionally substituted by one of the radicals mentioned above for R5, in particular represent -S02NMe2 or -S02NEtv PO(NMe2~, CONMe2 or CONiPrv R6 represents CF3, CHF2 or CZF~.
Le~A31085 -9-'Ihe following substituted benzimidazoles of the general formula (I) may be specifically mentioned:
R~
R2 , N~ R6 c~) Rs ~ . Rs Ra No. R1 R2 R3 ~ RS

1 H Br CF3 H H CF3 2 H Br CF3 H CH2CN CF3 3 H CF3 Br H CH2CN CF3 4 H Br CF3 H CH20Et CF3 5 H CF3 Br H CH20Et CF3 6 H Br CF3 H CH2OiPr CF3 7 H CF3 Br H CH20iPr CF3 8 H Br CF3 H CHZCOMe CF3 9 H CF3 Br H CH2COMe CF3 10 H Br CF3 H CH20CH(CHZF)2 CF3 11 H CF3 Br H CH20CH(CH2F~ CF3 12 H Br CF3 H CH2N(Me)COZMe CF3 13 H CF3 Br H CH2N(Me)C02Me CF3 14 H Br CF3 H CH2N(Bu)C02Et CF3 15 H CF3 Br H CH2N(Bu)C02Et CF3 16 H Br CF3 H CH2N(t-Bu)C02Et CF3 ~x A 31 085 - 10 -No. R1 R2 R3 R4 R5 R6 17 H CF3 Br H CH2N(t-Bu)C02Et CF3 18 H Br CF3 H CH2N(C6H1,rC02Et CF3 19 H CF3 Br H CH2N(C6H11~COZEt CF3 20 H Cl CF3 H H CF3 S 21 H Cl CF3 H CH2CN CF3 22 H CF3 Cl H CH2CN CF3 23 H Cl CF3 H CH20Et CF3 24 H CF3 Cl H CH20Et CF3 2S H Cl CF3 H CH2COMe CF3 26 H CF3 Cl H CH2COMe CF3 27 H Cl CF3 H CH(Me)COMe . CF3 28 H CF3 Cl H CH(Me)COMe CF3 29 H Cl CF3 H CH2COtBu CF3 30 H CF3 Cl H CH2COtBu CF3 1 31 H Cl CF3 H CH2COPh CF3 S

32 H CF3 Cl H CH2COPh CF3 33 H Cl CF3 H CH2CCH CF3 3-1 H CF3 Cl H CH2CCH CF3 3~ H Cl CF3 H CHZNHCOMe CF3 36 H CF3 Cl H CH2NHCOMe CF3 37 H Cl CF3 H CH2N(tBu)C02Me CF3 38 H CF3 Cl H CH2N(tBu)COZMe CF3 Ix A 31 08S - 11 -No. R1 R2 R3 R4 RS R6 39 H Cl CF3 H CH2N(Me)C02Me CF3 40 H CF3 Cl H CH2N(Me)C02Me CF3 41 H CF3 CI H CH2N(Et)COZMe CF3 42 H CI CF3 H CH2N(Et)C02Me CF3 43 H CF3 Cl H CH2N(Me)S02Ph CF3 44 H Cl CF3 H CH2N(Me)S02Ph CF3 45 H CF3 Cl H CHZN(Me)S02Me CF3 46 H Cl CF3 H CH2N(Me)SOZMe CF3 47 H SOCF3 Cl H H CF3 48 H S02CF3 Cl H H CF3 50 H OCF3 Cl H CH2N(Bu)C02Et CF3 51 H CI OCF3 H CH2N(Bu)C02Et CF3 52 H OCF3 Cl H CH2N(Pr)C02Et CF3 I 53 H Cl OCF3 H CHZN(Pr)COZEt CF3 S

54 H OCF3 CI H CH2N(Me)C02Me CF3 55 H CI OCF3 H CH2N(Me)COZMe CF3 ~6 H OCF3 CI H CH2CN CF3 ~7 H CI OCF3 H CH2CN CF3 ~ H Br OCF3 H H CF3 59 H Br OCF3 H CH2CN CF3 60 H OCF3 Br H CH2CN CF3 Le A 31 085 - 12 -No. R1 R2 R3 ~ ~

61 H Br OCF3 H CH20Et CF3 62 H OCF3 Br H CH20Et CF3 63 H OCF3 Br H S02NMe2 CF3 64 H Br OCF3 H CH2N(Me)C02Me CF3 65 H OCF3 Br H CH2N(Me)C02Me CF3 66 H Br OCF3 H CH2N(Et)C02Et CF3 67 H OCF3 Br H CH2N(Et)C02Et CF3 68 H Br OCF3 H CH2N(Me)C02Et CF3 71 H OCF3 OCF3 H SOZNMe2 CF3 78 H OCF2CF20 H CHZOEt CF3 _ 79 H OCFZCF20 H CHZOiPr CF3 80 H OCF2CF20 H CH2N(Me)C02Et CF3 81 H OCFZCFZO H CH2N(Me)C02Me CF3 82 H OCF2CF20 H CHZN(C6H,1)C02Et CF3 IxA31085 -13-No. R, R2 R3 R4 RS R6 83 H OCFZCF20 H CH2N(C6H11)C02Et CHF2 85 H O(CCIF)20 H H CF3 86 H O(CCIF)20 H CHZOEt CF3 87 H O(CCIF)ZO H CH2N(Me)COZEt CF3 88 H O(CCIF)20 H CH2CN CF3 89 H O(CH2)20 H CHZOEt CF3 90 Cl H S02CF3 H H CF3 91 Cl H S02CF3 H H CHF2 92 Br H CF3 H CHZCOtBu CF3 93 Br H CF3 H CH20Et CF3 94 Br H CF3 H CHZC02Bu CF3 95 Br H CF3 H CH2N(Me)C02Me CF3 96 Br H CF3 H CHZCH~H2 CF3 97 Br H CF3 H H CF3 98 Br H CF3 H CHZN(iPr)COZEt CF3 99 Br H CF3 H CH2N(C6HI,)C02Et CF3 100 Br H SOZMe H H CF3 101 Br H S02CF2 H H CF3 102 CF3 H Cl H H CF3 103 CF3 H Cl H CH2CN CF3 104 CF3 H Cl H CH2COPh CF3 Ix A 31 085 - 14 -No. R1 R2 R3 R4 R5 R6 105 CF3 H Cl H CH20Et CF3 106 CF3 H Cl H CH2N(Me)COZMe CF3 107 CF3 H Cl H CH2N(Me)COZEt CF3 108 CF3 H Cl H CH2N(tBu)C02Et CF3 109 CF3 H Cl H CH2N(Bu)C02Et CF3 1I0 CF3 H Cl H CH2N(Et)C02Et CF3 111 CF3 H Cl H CH2N(C6H11)C02Et CF3 112 CF3 H Br H H CF3 113 CF3 H Br H H CHF2 114 CF3 H Br H CHZCN CF3 115 CF3 H Br H CH2N(Me)S02Me CF3 116 CF3 H Br H CH20Pr CF3 117 CF3 H Br H CH2N(Me)C02Me CF3 118 CF3 H Br H CH2N(Pr)C02Et CF3 119 CF3 H Br H CHZN(Et)C02Et CF3 120 CF3 H Br H CH2N(C6H11)C02Et CF3 124 CF3 H CF3 H CH2N(Et)C02Et CF3 125 CF3 H CF3 H CHZN(Pr)C02Et CF3 126 CF3 H CF3 H CH2N(C6HI1)C02Et CF3 LeA31085 -15-No. R, R2 R3 R4 RS R6 127 Br H SCF3 H H CF3 128 Br H SCF3 H CH2N(Pr)C02Et CF3 131 CF3 OCF2- H H SOZNMe2 CF3 .

I33 H SCF3 CH20Et CF3 134 H SOZMe H CF3 137 Br H CF3 H CON(CH3)2 CF3 ~

138 Br H CF3 H soz s ci CF3 \ /

139 Br H CF3 H SO~CH2C(CH3)CH2 CF3 140 Br H CF3 H sot S CF3 \ /

141 Br H CF3 H sot s Br CF3 \ /
Br LeA31085 -16-No. R1 R2 R3 R4 R5 R6 142 Br H CF3 H CH3 CF3 So2 O

i -N

143 Br H CF3 H COOCH(CH3}z CF3 144 Br H CF3 H S02-CH3 CF3 145 Br H CF3 H PO(N(CH3)z)2 CF3 146 H OCFZO H soz CF3 I ~ CH3 147 H OCF20 H sot CF3 ~

148 H OCF20CF20 H sot S CF3 I ~ ci 149 H OCF20CF20 H CON(C(CH3)2~ CF3 150 H OCF20CF20 H cH3 CF3 sot . I \N

H3C ~ i Le A 31 085 - 17 -No. ( Rl ~ RZ ~ R3 R4 RS R6 sot S Oz I

153 H OCF20CF20_ H cH3 CF3 CHZ
v I ~N
HsC O
154 H OCF20 H S02CH2C(CH3)CH2CF3 CF3 15~ H OCF20 H sot s CF3 I / ci 156 H OCFZOCF20 H sot s CF3 I /
15 7 H OCFZO H s o 2 s CF3 I /
L,e A 31 085 - 18 -No. R1 RZ R3 Rø RS R6 158 H OCF20CF20 H cH3 CF3 sot I \N
CI N

159 H OCFZO H sot CF3 Br S
Br 160 H OCFZCFZO H sot CF3 Br s Br sot I ~~N
HsC O
162 H Br CF3 H SOZCH3 CF3 163 H Br CF3 H CH3 CF3 sot I \N
, HsC O
16-~ H Br CF3 H S02N(CH3)2 CF3 16~ H OCF2CF20 H S02CH2C(CH3)CHZ CF3 L.eA3108~ -19-No. R1 R2 R3 R4 R5 167 H OCFZCF20 H PO-(N(CH3)2)2 CF

168 H Br CF3 H CO-OCH(CH3~ CF3 169 H Br CF3 H C02N(CH3)2 CF3 170 H Br CF3 H PO-(N(CH3)~ CF3 I~e A 31 085 - 20 -Particularly preferred compounds from the series of substituted benzimidazoles which may be particularly mentioned are:
R, R2 ~ N ~ R6 N
Rs ~ . Rs No. ~ Rl ( R2 ~ R3_ R4 R5 R6 _4 1 H Br CF3 H H CF3 2 H Br CF3 H CHZCN CF3 3 H CF3 Br H CHZCN CF3 4 H Br CF3 H CH20Et CF3 5 H CF3 Br H CH20Et CF3 58 H Br OCF3 H H CF3 59 H Br OCF3 H CH2CN CF3 60 H OCF3 Br H CH2CN CF3 83 H OCF2-CF20 H CH2N(C6H11)-C02Et CF3 92 Br H CF3 H CH2COtBu CF3 9~ Br H CF3 H CH2N(Me)C02Me CF3 96 Br H CF3 H CH2CH~H2 CF3 99 Br H CF3 H CHZN(C6HI1)-COZEt CF3 102 CF3 H Cl H H CF3 LeA31 085 -21 -The parasitic protazoa include:
Mastigophora (Flagellate) such as, for example Trypanosomatidae, for example Trypanosome b. brucei, T.b. gambiense, T.b. rhodesiense, T. congolense, T.
cruzi, T.
evansi, T. equinum, T. lewisi, T. percae, T. simiae, T. vivax, Leishmania brasiliensis, L. donovani, L. tropics, such as, for example, Trichomonadidae, for example Giardia lamblia, G. cams.
Sarcomastigophora (Rhizopoda) such as Entamoebidae, for example Entamoeba histolytica, Harlxnanellidae, for example Acanthamoeba sp., HaWnanella sp.
Apicomplexa (Sporozoa) such as Eimeridae, for example Eimeria acervulina, E.
adenoides, E. alabahmensis, E. anatis, E. anseris, E. arloingi, E. ashata, E.
auburnensis, E. bovis, E. bnmetti, E. cams, E. chinchillae, E. clupearurn, E. columbae, E.
contorts, E. crandalis, E. debliecki, E. disperse, E. ellipsoidales, E. falciformis, E.
faurei, E.
flavescens, E. gallopavonis, E. hagani, E. intestinalis, E. iroquoina, E.
irresidua, E.
labbeana, E. leucarti, E. magna, E. maxima, E. media, E. meleagridis, E.
meleagrimitis, E. mitis, E. necatrix, E. ninakohlyakimovae, E. ovis, E. parva, E. pavonis, E.
perforans, E. phasani, E. piriformis, E. praecox, E. residua, E. scabra, E. spec., E.
stiedai, E. suis, E. tenella, E. truncate, E. truttae, E. zuernii, Globidium spec., Isospora belli, I. cams, I. felis, I. ohioensis, I. rivolta, I. spec., I. suis, C~stisospora spec., Cryptosporidium spec. such as Toxoplasmadidae, for example Toxoplasma gondii, such as Sarcocystidae, for example Sarcocystis bovicanis, S. bovihominis, S. ovicanis, S. ovifelis, S. spec., S.
suihominis such as Leucozoidae, for example Leucozytozoon simondi, such as plasmodiidae, for example plasmodium berghei, P. falcipar<un, P. malariae, P.
ovate, P.
vivax, P. spec., such as Piroplasmea, for example Babesia argentine, B. bovis, B. cams, B. spec., Theileria parva, Theileria spec., such as Adeleina, for example Hepatozoon canis, H. spec.
The useful and breeding livestock include mammals such as, for example, cattle, horses. sheep, pigs, goats, camels, water. buffalo, donkeys, rabbits, fallow deer, LeA310$5 -23-reindeer, fur-bearing livestock such as, for example, mink, chinchilla, raccoon, birds such as, for example, chickens, geese, turkeys, ducks, pigeons, bird species for keeping at home and in zoos.
Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.
Pet animals include dogs and cats.
Both prophylactic and therapeutic use is possible.
The active compounds are used directly or in the form of suitable preparations, enterally, parenterally, dermally, nasally.
Enteral use of the active compounds takes place, for example, orally in the form of powders, suppositories, tablets, capsules, pastes, drinks, granules, drenches, boli, medicated feed or drinking water. Dermal use takes place, for example, in the form of dipping, spraying, bathing, washing, pouring on and spotting on, and dusting.
Parenteral use takes place, for example, in the form of injection (intramuscular, subcutaneous, intravenous, inh-aperitoneal) or by implants.
Suitable preparations are:
Solutions such as injection solutions, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, pour-on formulations, gels:
Emulsions and suspension for oral or dermal use and for injection; semisolid preparations;
Formulations in which the active compound is incorporated in an ointent base or in Le A 31 085 - 24 -an oil-in-water or water-in-oil emulsion base;
Solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boli, capsules; aerosols and inhalations, shaped articles containing active compound.
Injection solutions are administered intravenously, intramuscularly and subcutaneously.
Injection solutions are prepared by dissolving the active compound in a suitable solvent and possibly adding additives such as solubilizers, acids, bases, buffer salts, antioxidants, preservatives. The solutions are sterilized by filtration and bottled.
Solvents which may be mentioned are, physiologically tolerated solvents such as water, alcohols such as ethanol, butanol, benzylalcohol, glycerol, hydrocarbons, propylene glycol, polyethylene glycol, N-methylpyrrolidone, and mixtures thereof.
The active compounds can., where appropriate, also be dissolved in physiologically tolerated vegetable or synthetic oils which are suitable for injection.
Solubilizers which may be mentioned are: solvents which promote dissolution of the active compound in the main solvent or prevent its precipitation. Examples are polyvinylpyrrolidone, polyethoxylated castor oil, polyethoxylated sorbitan esters.
Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic esters, n-butanol.
Oral solutions are used directly. Concentrates are used orally after previous dilution to their use concentration. Oral solutions and concentrates are prepared, as described above for injection solutions, it being possible to dispense with sterile operation.
Solutions for use on the skin are spotted on, painted on, rubbed in, applied by spraying or jetting. or applied by dipping, bathing or washing. These solutions are prepared, as described above for the injection solutions.
Le A i 1 085 - 25 -It may be advantageous to add thickeners during preparation. Thickeners are:
inorganic thickeners such as bentonites, colloidal silica, aluminium monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and metacrylates.
Gels are introduced onto the applied or painted on or into body cavities. Gels are prepared by adding su~cient thickeners to solutions, which have been prepared as described for the injection solutions, to result in a clear composition with an ointment-like consistency. The thickeners used are the thickeners indicated hereinbefore.
Pour-on formulations are poured onto or sprayed onto limited areas of the skin, in which case the active compound either penetrates through the skin and acts systemically or is dispersed on the surface of the body.
Pour-on formulations are prepared by dissolving, suspending or emulsifying the active compound in suitable skin-compatible solvents or solvent mixtiu-es. Where appropriate, other auxiliaries such as colourants, absorption-promoting substances, antioxidants, sunscreen agents, adherents are added Solvents which may be mentioned are: water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols such as benzyl alcohol, phenyl ethanol, phenoxy ethanol, esters such as ethyl acetate, butyl acetate, benzylbenzoate, ethers such as alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether, ketones such as acetone, methyl ethyl ketone, aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, N-methylpyrrolidone, 2-dimethyl-4.-oxy-methylene-1,3-dioxolane.
Colourants are all colourants approved for use on livestock, and can be dissolved or suspended.
Absorption-promoting substances are, for example, DMSO, spreading oils such as Le A 31 085 - 26 -isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols.
Antioxidants are sulphites or metabisulphites such as potassium metabisulphite, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol.
Sunscreen agents are, for example, substances from the class of benzophenones or novantisolic acid.
Adherents are, for example, cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin.
Emulsions can be used orally, dermally or as injections.
Emulsions are either of the water-in-oil type or of the oil-in-water type.
They a~ a prepared by dissolving the active compound either in the hydrophobic or in the hydrophilic phase and homogenizing the latter with the assistance of suitable emulsifiers and, where appropriate, other auxiliaries such as colourants, absorption promoting substances, preservatives, antioxidants, sunscreen agents, viscosity-increasing substances, with a solvent of the other phase.
The following may be mentioned as hydrophobic phase (oils): paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic/capric acid biglyceride, triglyceride mixture with vegetable fatty acids of chain length C8_,2 or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated, possibly also hydroxyl group-containing fatty acids, mono- and diglycerides of C8/Clo fatty acids.
Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with LeA310$5 -27-saturated fatty alcohols of chain length C16-C18, isopropyl myristate, isopropyl palmitate, caprylic%apric esters of saturated fatty alcohols of chain length Ci2-C,s, isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate, waxy fatty acid esters such as dibutyl phthalate, diisopropyl adipate, ester mixtures related to the latter, including fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.
Fatty acids such as, for example, oleic acid and mixtures thereof.
The following may be mentioned as hydrophilic phase:
Water, alcohols such as, for example, propylene glycol, glycerol, sorbitol and mixtures thereof.
Emulsifiers which may be mentioned are:
nonionic surfactants, for example polyethoxylated castor oil, polyethoxylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ether;
ampholytic surfactants such as di-Na-N-lauryl-(3-iminodipropionate or lecithin;
anionic surfactants, such as Na-lauryl sulphate, fatty alcohol ether sulphates, mono/dialkylpolyglycol ether orthophosphoric ester monoethanolami.ne salt;
cationic surfactants such as cetyltrimethylammonium chloride.
Further auxiliaries which may be mentioned are:
Viscosity-increasing and emulsion-stabilizing substances such as carbo~ymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, copol~~rners of methyl vinyl ether and malefic anhydride, polyethylene glycols, waxes, colloidal silica or mixtures of the substances mentioned.
Le A 31 0$5 - 28 -Suspensions can be used orally, dermally or as injection. They are prepared by suspending the active compound in a liquid vehicle, where appropriate with the addition of further auxiliaries such as wetting agents, colourants, absorption-promoting substances, preservatives, antioxidants, sunscreen agents.
Liquid vehicles which may be mentioned are all homogeneous solvents and solvent mixtures.
Wetting agents (dispersants) which may be mentioned are the surfactants indicated hereinbefore.
Further auxiliaries which may be mentioned are those indicated hereinbefore.
Semisolid preparations can be administered orally or dermally. They differ from the suspensions and emulsions described above only by their higher viscosity.
To prepare solid preparations, the active compound is mixed with suitable excipients, where appropriate with the addition of auxiliaries, and converted into the desired shape.
Excipients which may be mentioned are all physiologically tolerated solid inert substances. Used as such are inorganic and organic substances. Inorganic substances are, for example, sodium chloride, carbonates such as calcium carbonate, bicarbonates, aluminium oxides, silicas, aluminas, precipitated or colloidal silicon dioxide, phosphates.
Organic substances are, for example, sugars, cellulose, foodstuffs and feedstuffs, such as milk powder, animal meals, .cereals meals and coarse meals, starches.
Auxiliaries are preservatives, antioxidants, colourants, which have already been listed hereinbefore.
Further suitable auxiliaries are lubricants and glidants, such as, for example, Le A 31 085 - 29 -magnesium stearate, stearic acid, talc, bentonites, disintegration-promoting substances such as starch or crosslinked polyvinylpyrrolidone, binders such as, for example, starch, gelatine or linear polyvinylpyrrolidone, and dry binders such as microcrystalline cellulose.
The active compounds may also be present in the preparations mixed with synergists or with other active compounds.
Preparations ready for use contain the active compounds in concentrations of 10 ppm to 20 per cent by weight, preferably from 0.1 to 10 per cent by weight.
The benzimidazoles of the formula (I) are in this case present in the following ratio by weight to the synthetic coccidiostats or polyether antibiotics: 1 to 0.1 - 10, preferably ltol-10.
Preparations which are diluted before use contain the active compounds in concentrations of 0.5 to 90 per cent by weight, preferably from 1 to 50 per cent by weight.
It has in general proved advantageous to administer amounts of about 0.5 to about 50 mg, preferably 1 to 20 mg, of active compounds per kg of bodyweight per day to achieve effective results.
The active compounds can also be administered to the livestock together with the feed or drinking water.
Feedstuffs and foodstuffs contain 0.01 to 250 ppm, preferably 0.5 to 100 ppm, of the active compound in combination with a suitable edible material.
Such a feedstuff and foodstuff can be used both for curative purposes and for prophylactic purposes.
LeA310$~ -30-Such a feedstuff or foodstuff is prepared by mixing a concentrate or a premix which contains 0.5 to 30 %, preferably 1 to 20 % by weight, of an active substance mixed with an edible organic or inorganic vehicle, with customary feedstuffs. Edible vehicles are, for example, maize meal or maize and Soya bean meal or mineral salts, which preferably contain a small amount of an edible dust-preventing oil, for example corn oil or soya oil. The premix obtained in this way can then be added to the complete foodstuff before it is fed to the livestock.
The use for coccidiosis may be mentioned by way of example:
For the cure and prophylaxis, for example, of coccidiosis in poultry, in particular in chickens, ducks, geese and turkeys, 0.1 to 100 ppm, preferably 0.5 to 100 ppm, of an active compound are mixed with a suitable edible material, for example a nutritious feedstuff. If required, these amounts can be increased, especially if the active compound is well tolerated by the recipient. Administration via the drinking water can take place correspondingly.
For the treatment of single animals, for example in the case of treatment of coccidiosis in mammals or of toxoplasmosis, preferably amounts of active compound of 0.5 to 100 mg/kg of bodyweight are administered each day in order to achieve the desired results. It may, nevertheless, be necessary on occasions to deviate from the stated amounts, in particular as a function of the bodyweight of an experimental animal or of the nature of the method of administration, but also because of the animal genus and its individual reaction to the active compound or the type of formulation and the time or interval over which administration takes place. Thus, it may suffice in certain cases to make, do with less than the abovementioned minimum amount, whereas in other cases the stated upper limit must be exceeded. On administration of larger amounts, it may be expedient to divide these into several individual administrations over the course of the day.
The efficacy of the mixtures according to the invention can be demonstrated, for LeA31085 -31-example, in cage tests with the following test design, in which the livestock are treated with the particular individual components and with the mixtures of the individual components.
Cage test on coccidiosis/chicks Male chicken chicks (for example LSL Brinkschulte/Senden) which have been reared coccidia-free and are 8 to 12 days old receive the compounds according to the invention (test substances) in the concentration stated in ppm with the feed from 3 days before (day -3) the infection (= a.i.) to 8 (9) days after the infection (=
p.i.). Three birds are kept in each cage. One or more such groups are used per dosage. The infection takes place using a tube direct into the crop with about 50,000 sporulated oocysts of Eimeria acervulina and with in each case about 20,000 sporulated oocysts of E. maxima and E. tenella. Highly virulent strains of these are used. The exact infection dose is adjusted so that, where possible, one in three untreated experimentally infected chicks dies from the infection. The following criteria are taken into account for assessing the efficacy: weight gain from start of test to end of test, mortality rate from the infection, macroscopic assessment of the faeces with regard to diarrhoea and excretion of blood on days 5 and 7 p.i. (score 0 to 6), macroscopic assessment of the intestinal mucosa, especially of the caeca (score 0 to 6) and excretion of oocysts, and the proportion (in %) of oocysts sporulating within 24 hours. The number of oocysts in the faeces was determined using a McMaster counting chamber (see Engelbrecht and coworkers "Parasitologische Arbeitsmethoden in Medizin and Veterinarmedizin, Akademie-Verlag, Berlin (1965)). The individual findings are related to the untreated uninfected control groups, and a total score is calculated (cf. A. Haberkorn (1986) pages 263- to- 270 in Research in Avian Coccidiosis ed. L.R. McDougald, L.P:
Joyner, P.L. Long Proceedings of the Georgia Coccidiosis Conference Nov, 18. - 20.

Athens/Georgia USA).
A feed containing active compound is prepared in such a way that the required amount of active compound is thoroughly mixed with an animal feed which is balanced in Le A 31 085 - 32 -nutrient terms, for example with the chick feed indicated below.
If a concentrate or a premix is to be prepared and is finally diluted to be in the feed to the figures mentioned in the test, in general about 1 to 30 %, preferably about 10 to 20 % by weight of active compound are mixed with an edible organic or inorganic vehicle, for example maize and Soya meal or mineral salts, which contain a small amount of an edible anti-dusting oil, for example corn oil or soya bean oil.
The premix obtained in this way can then be added to the complete poultry feed before administration.
An example of a suitable composition for use of the substances according to the invention in poultry feed is the following.
52.00 % coarse cereal feed meal, in particular: 40 % maize, 12 % wheat 17.00 % extr. coarse soya meal 5.00 % maize gluten feed 5.00 % wheat feed meal 3.00 % fish meal 3.00 mineral mixture %

3.00 alfalfa meal %

2.50 vitamin premix %

2.00 wheatgerms, % crushed 2.00 % Soya oil 2.00 % meat and bone meal 1.50 % whey powder 1.00 % molasses 1.00 % brewers' yeast, bound to brewers' grains 2~ 100.00 Such a feed contains 18 % crude protein, 5 % crude fibre, 1 % Ca, 0.7 % P and, per kg, 1,200 LU. of vitamin A, 1,200 LU. of vitamin D3, 10 mg of vitamin E, 20 mg of Le A 31 085 - 33 -~ CA 02222517 1997-11-27 zinc bacitracin.
Test results with combinations according to the invention are listed by way of example in the following tables. The synergistic activity of the combinations by comparison with the individual components is particularly evident from a reduction in oocyst excretion, but also in respect of the necropsy findings, weight gain and better tolerability.
In the following tables, the meanings in the "treatment" column are:
n.infcontr. = non-infected control group inf:contr. = infected control group ampfol comb. = amprolium combined with sulphaquinoxaline and ethopabate 1 = benzimidazole ex. No.
In the "ppm" column, the concentration of active compound used in the feed is stated In ppm.
In the "mortality" column, the percentage of birds which die is indicated under %, and the number of birds which died/birds used in the test is indicated under n.
In the "weight % of not inf. control" column, the ratio of the weight of the treated birds to the weight of the uninfected control group is indicated.
In the "dropping scores", "lesion score" and "oocyst control" columns, individual data on the effect are given.
In the "% efficay" column, the overall evaluation is scored; 0 % means no effect, 100 % means complete effect.
Le A 31 085 - 34 -Table 1 Experimental infection of chicks with Eimeria acervulina, E. maXima and E.
tenella.
Treat-ppm mortality weight drop-lesionoocyst % in %
of inf.
control ment of not ping score effi-n ~ ~~ ac. max ten. tot.~3' control tot.

n. 0 0 0/6 100 0 0 0 0 0 0 100 inf:

contr.

inf. 0 50 3/6 46 6 6 100 100 100 100 0 contr. 915*55* 1520*2490*

amprol.50 0 0/3 71 0,7 63 36 46 52 36 comb.

amprol. 0 0/3 89 0 0 1.5 2 1 1.5 82 comb. 50 +

1 +5 75 0 0/3 95 0 0.7 0.260 0.32 0.2998 +5 * = X 1 000 LeA31085 -35-Table 2 Treat-ppm mortality weightdrop-lesionoocyst % in %
of inf:
control ment of ping score effi-not n i~ ~~ ac. max.ten. tot.~Y

control tot.

n. 0 0 0/6 100 0 0 0 0 0 0 100 inf.

contr.

inf. 0 0 0/6 61 6 100 100 100 100 0 contr. 3810*480*2980*7270*

rnonen-25 0 0/3 44 6 44 100 100 81 7 sin 1 1 2.5 33 t/3 83 6 6 14 38 41 31 35 ~

5 0 0/3 76 6 5.7 0.6 3 3 2.1 69 10 33 I/3#100 0-2 3.5 0 0 0 0 92 monen- 0 0/3 66 6 6 13 29 24 22 32 ' sin 25 +

I 2.55 25 0 0/3 102 0-2 4.3 <0. <0.10.1 0.1 92 + I

25 0 0/3 102 0-2 0.7 0 0 <0.1 <0.198 +

50 0 0/3 97 I 0.3 ~.1 0.1 <0.1 <0.196 +

2.5 * = X I ~~~
15 # = because of toxicity LeA310$5 -36-Table 3 Treat- ppm mortality weightdrop-lesionoocyst io % in %
of inf.
control ment of ping score effi-not n inf. scores ~, n~ ten. tot. ~~

control tot.

n. inf:0 0 0/6 100 0 0 0 0 0 0 100 contr.

inf: 0 83 5/6 64 6 6 100 100 100 100 0 contr. 1420220 3560*5200 robeni-16.50 0/3 95 I 5 38 9 23 23 60 dine 10 33 1/3#83 6 6 0.8 0.9 0.6 0.8 71 robeni- 0 0/3 114 0 1.3 1.2 4 2 9 88 dine 16.5 +

1 +5 16.533 I/3'#96 0 4 0.010 0 <0.0 94 + 1 * = x 1 000 1 ~ # = because of toxicity Le A 31 085 - 37 -Table 4 Treat- ppm mortality weightdrop-lesionoocyst % in ~o of inf:
control ment of ping score efti-not n i~ scorns ~. max.ten. tot.

control tot.

n. inf:0 0 0/6 100 0 0 0 0 0 0 100 contr.

inf. 0 83 5/6 64 6 6 100 100 100 100 0 contr. taso*220*3560*5200*

toltra-10 0 0/3 84 3 6 3 4 I 3 68 zuiil 15 0 0/3 106 ~ 3.3 0.6 0 0.4 0.3 88 I I ~ 67 2/3 87 6 6 11 15 11 12 40 ~

10 33 I/3#83 6 6 0.8 0.9 0.6 0.8 71 toltra- 0 0/3 76 6 6. 0.7 2 0.6 1.1 72 zuril 10 +

1 +5 ' I 0 0/3 94 0 4.3 0 0 0 0 98 S

T

* = X 1 1 ~ # = because of poisoning LeA3108~ -38-T e5 Treat-ppm mortality weight drop-lesionoocyst % in %
of inf.
control ment of not ping score effi-n i~ ~=~ ac. max.tea tot. ~Y

control tot.

n. 0 0 0/6 100 0 0 0 0 0 0 100 inf:

contr.

inf: 0 0 0.6 62 6 6 100 100 100 100 0 contr. 1260*150*1640*3050*

monen-25 0 0/3 72 4 5.3 86 >100>100 95 0 sin 100 0 0/3 92 0 2.7 I1 7 20 13 69 74 5 0 0/3 59 6 6 >100 40 >100 80 4.3 10 33 I/3#80 0 4.5 0.7 3 2 1.9 75 Monen-25+ 0 0/3 83 0 5.3 8 9 15 I1 58 sin 5 +

25 0 0/3 80 4 43 I 0 0.9 0.6 69 +

50 0 0/3 90 0 2.3 0.08 0 0.13 0.07 98 +

50 33 I/3#98 0 0.5 0.7 0 0.05 0.25 100 + I

100 0 0/3 89 0 1.3 1 0.7 4 1.9 85 +5 100 0 0/3 87 0 0.7 0 0 0.02 0.01 87 +5 * X 1 000 # = because of poisoning 1,~A~108~ -39-Table 6 Treat- ppm mortality weightdrop- lesionoocyst in %
of inf.
control ment % of ping score efft-n not scores ~. may.ten. tot. ~Y
inf.

control tot.

n. inf:0 0 0/6100 0 0 0 0 0 0 100 contr.

inf: 0 0 0/659 6 6 100 100 100 100 0 contr.

2760*200*1820*4780*

halo- I 0 0/367 2 2 50 50 96 66 26 fuginone 3 0 0/372 0 0.7 5 4 19 9 70 halo- 1 0 0/355 0 0.7 2.5 6 13 7.2 53 +

fuginone10 3 0 0/376 0 0 3 0 5 2.7 85 +

* = x 1 000 L,e A 31 085 - 40 -Table 7 Treat-ppm mortality weight drop-lesionoocyst io % in %
of inf.
control ment of not ping score eff-inf. scores cay control tot.

n ac. max.ten. tot.

n. 0 0 0/6 100 0 0 0 0 0 0 100 inf.

contr.

inf: 0 33 Z6 62 6 6 100 100 100 100 0 contr. 645* 115*865* 1625*

salino-15 0 0/3 85 6 6 81 87 58 75 16 mycin 30 0 0/3 100 3-5 2.3 9 0 22 10 74 40 0 0/3 112 0 0 2.5 5 1.7 3 90 12.5 0 0/3 86 6 6 71 100 65 79 16 20 0 0/3 84 4-6 2.3 31 87 40 53 32 salino-15 0 0/3 100 6 2.3 28 70 53 50 37 +

mycin 10 +

15 0 0/3 100 0 0.3 0.09 0.5 0.2 0.27100 +

12.5 30 0 0/3 98 ~ 0 0.3 0 0 0 0 100 +

30 0 0/3 96 0 0 0 0.2 0 0.07100 +

12.5 +

30 0 0/3 101 0 ~0.7 0 0 0 0 98 +

LeA3~ 0$~ -41-Treat-ppm mortality weight drop-lesionoocyst % in %
of inf.
control ment of not pingscore effi-inf. scores cav control tot.

40 0 0/3 100 0 0 0.030 0.1 0.03 100 +

40 0 0/3 94 2 0.7 0 0 0 0 95 +

12.~

+

* = X 1 ~0~
LeA310$~ -42-Table $
Treat-ppm mortality weight drop-lesionoocyst ro in %
of inf.
control ment of not pingscore effi-n inf. scores ac. mat.ten. tot.

control tot.

n. 0 0 0/6 100 0 0 0 0 0 0 100 inf:

contr.

inf. 0 17 1/6 61 6 6 100 100 100 100 0 contr. 1080*220*2550*3850*

tolu~a-2.5 0 0/3 59 6 5.3 12 9 I1 II 25 zuril 25 33 I/3#84 I 5 0 0 0.2 0.1 79 59 2.5 0 0/3 69 6 5.7 11 9 12 1 35 + + I

toltra-5 zuril 2.5 0 0/3 92 0 2 0 0 0 0 100 +

* = x 1 000 # = because of toxicity LeA310$~ -43-Table 9 Treat- ppm mortality weightdrop-lesionoocyst ment % ping score in effi-of %
not of inf.
control n inf: scores ~. ~_ ten.tot. ~y control tot.

n. inf.0 0 0/6 100 0 0 0 0 0 0 100 contr.

inf. 0 0 0/6 54 6 6 100 100 100 100 0 contr. 1570*70* 1057*2697*

halofu-I 33 1/3 81 4-6 6 41 100 49 63 24 ginone 3 0 0/3 87 0 0 ~.1 0 <D.1<0.1 91 5 0 0/3 88 0-2 6 0.8 10 2.4 4.4 77 Halofu-33 1/3 88 6 6 12 100 17 43 30 ginone 1 + I

3+ 1 0/3 102 0 0 1 0 0.7 0.6 96 3 + 5 0/3 83 0 1.7 m. 0.6 0.2 0.1 89 * = x 1 000 LeA3I0$5 -44-

Claims (6)

CLAIMS:

1. A composition for controlling a parasitic protozoa in livestock, comprising a mixture of a substituted benzimidazole of the general formula (I):

wherein:

R1, R2, R3 and R4 each, independently of one another, represent: (i) H or a halogen atom, or (ii) optionally substituted alkyl, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl or fused-on dioxyalkylene, with the proviso that all of the substituents R1, R2, R3 and R4 are not H and a halogen atom;

R5 represents: (i) H, (ii) alkyl which is substituted one or more times, identically or differently, by OH, CN, NH2, alkyl, cycloalkyl, alkenyl, alkinyl, alkoxy, halogenoalkoxy, alkylthio, halogenoalkylthio, alkenoxy, alkinoxy, aminocarbonyl, optionally substituted alkylcarbonyl, optionally substituted (het-)arylcarbonyl, optionally substituted alkoxycarbonyl (AlkO-CO-), optionally substituted alkoxycarbonyloxy (AlkOCOO-), aminosulphonyl (SO2NH2), optionally substituted mono- or dialkylaminosulphonyl, acylated amino (AlkCON(R7)- or AlkOCON(R7)-), wherein R7 represents H, alkyl, cycloalkyl, optionally substituted alkylsulphonylamino (AlkylSO2NH-), alkylsulphonyl-N-alkylamino (ArylSO2NAlkyl-), optionally substituted arylsulphonylamino (ArylSO2NH-), arylsulphonyl-N-alkylamino (ArylSO2NAlk-) or optionally substituted dialkylamino, or (iii) optionally substituted alkoxycarbonyl, optionally substituted (het-)aryloxycarbonyl, alkylsulphonyl, alkenylsulphonyl, (het-) arylsulphonyl, -SO2NR8R9, -CONR8R9 or -P(O)(NR8R9)2, wherein R8 and R9 represent H or alkyl which is optionally substituted by one or more radicals; and R6 represents fluoroalkyl;

with a polyether antibiotic or a synthetic coccidiostat.

2. The composition of claim 1, wherein the polyether antibiotic is maduramycin, lasalocid, monensin, narasin or salinomycin.

3. The composition of claim 1, wherein the synthetic coccidiostat is:

1-(4-Amino-2-n-propyl-5-pyrimidinylmethyl)- ~Amprolium, 2-picolinium chloride 1-(4-Amino-2-n-propyl-5-pyrimidinylmethyl)- ~Amprolium +
2-picolinium chloride + sulfaquinoxaline ~sulfaquinoxaline, 1-(4-Amino-2-n-propyl-5-pyrimidinylmethyl)- ~Amprolium +
2-picolinium chloride + sulfaquinoxaline + ~sulfaquinoxaline +
ethopabate ~~~~~ethopabate, 4,4-Dinitrocarbanilide + 2-hydroxy-4,6- ~Nicarbazin, dimethylpyrimidine 3,5-Dichloro-2,6-dimethyl-4-pyridinol ~Clopidol, 3,5-Dichloro-2,6-dimethyl-4-pyridinol + ~Clopidol +
methyl 7-benzyloxy-6-butyl-1,4-dihydro-4- ~methylbenzoquate, oxylquinoline-3-carboxylate Ethyl 6-n-decyloxy-7-ethoxy-4- Decoquinate, hydroxyquinoline-3-carboxylate 9-(2-Chloro-6-fluorophenylmethyl)-9H-purin- Arprinocid, 6-amine (~)-2,6-Dichloro-alpha-(4-chlorophenyl)-4- Benzeneacetonitrile (4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)- diclazuril, yl)-benzeneacetonitrile 1-[3-Methyl-4-(4'- Toltrazuril, trifluoromethylthiophenoxy)-phenyl]-3-methyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione 4,4-Dinitrocarbanilide + 2-hydroxy-4,6- Robenidine, dimethylpyrimidine [= nicarbazin]
7-Bromo-6-chloro-febrifugin Halofuginone, or 3,5-Dinitro-o-toluamide Zoalene.

4. Use of a composition as defined in any one of claims 1 to 3, for the preparation of a medicament to combat a parasitic protozoa in livestock.

5. Use of a composition as defined in any one of claims 1 to 3, for controlling a parasitic protozoa in livestock.

6. The use of claim 4 or 5, wherein the parasitic protozoa is coccidia.