CA2111146A1

CA2111146A1 - Use of cn-substituted benzimidazoles

Info

Publication number: CA2111146A1
Application number: CA002111146A
Authority: CA
Inventors: Winfried Lunkenheimer; Axel Haberkorn
Original assignee: Individual
Current assignee: Bayer AG
Priority date: 1992-12-15
Filing date: 1993-12-10
Publication date: 1994-06-16
Also published as: SK140693A3; DE4242183A1; TW255825B; PL301460A1; CZ273493A3; HUT66287A; ZA939356B; AU663631B2; NZ250401A; EP0602465A1; JPH06227919A; KR940013329A; IL108001A0; HU9303576D0; AU5206793A; MX9307609A

Abstract

Use of CN-substituted benzimidazoles Abstract The invention relates to the use of CN-substituted benzimidazoles of the general formula (I)

Description

The present invention relates to the use of CN-substituted benzimidazoles as agents for combating parasitic protozoa and in particular coccidia, as well as fish and insect parasites.

Substituted benzimidazoles and their use as insecticides, fungicides and herbicides have already been disclosed (EP-OS (European Published Specification) 87 375 and 152 360, US-P 3 472 865 and 3 576 818, US-P 3 418 318 and EP-OS 260 744, 266 984, 181 826 and 239 508).

Polyhalogenated benzimidazoles and their action as anth-elmintics, coccidiostatics and pesticides have been dis-closed ~DE-OS (German Published Specification) 2 047 36-9). However, their action is not satisfactory in all ¦ cases.

The present invention relates to the use of CN-sub-stituted benzimidazoles of the formula (I) X

;i ~CN (I) ~; :

~ X 2,CHLR

;

~ Le A 2g 484 - 1 -~", , ~ r.
:'~`;' '. ', .
. ..
~.. .

2 ~

in which Xl ~ X2 ~ X3 and X4 independently of one another in each case represent hydrogen, halogen, cyano or nitro, or represent in each case optionally substituted alkyl, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl or cycloalkyl, or represent optionally substituted, fused-on dioxyalkylene, or represent hydroxy-carbonyl, alkylcarbonyl, alkoxycarbonyl or cyclo-alkyloxycarbonyl, or represent in each case optionally substituted amino or aminocarbonyl, or represent in each case optionally substituted aryl, aryloxy, arylthio, arylsulphinyl, arylsulphonyl, arylsulphonyloxy, arylcarbonyl, aryloxycarbonyl, arylazo or arylthiomethylsulphonyl, but wherein at least one of the substituents X1, X2, X3 and X4 iS other than hydrogen and halogen, and wherein R1 represents hydrogen, alkyl or cycloalkyl, or repre-sents optionally substituted aryl, and R2 represents hydroxyl or cyano, or represents in each case optionally substituted alkyl, alkenyl, alkinyl, i alkoxy, alkenyloxy, alkinyloxy, alkylthio, amino, aminocarbonyl, alkylcarbonyl, alkoxycarbonyl, alkyl-carbonyloxy, dialkoxyphosphoryl, (hetero)aryl, . 25 (hetero~arylcarbonyl, (hetero)aryloxycarbonyl, ; (hetero)arylcarbonyloxy or (hetero)arylamino-L~ 2 -,:.....
~r' .
.~'~'.`.
i :, ,. ; .
~',:. .
. ,. ' carbonylaminocarbonyloxy, as agents for combating parasitic protozoa, and in particular coccidia.

Where appropriate, depending on the nature and number of substituents, the compounds of the formula (I) can exist as geometric and/or optical isomers or regioisomers or isomer mixtures thereof in varying compositions. Both the use of the pure isomers and that of the isomer mixtures are claimed according to the invention.

Formula (I) provides a general definition of the sub-stituted benzimidazoles which can be used according to the invention. Preferred compounds of the formula (I) are those in which Xl, X2, X3 and X4 independently of one another in each lS case represent hydrogen, fluorine, chlorine, bromine, iodine, cyano or nitro~ or represent in each case straight-chain or branched alkyl, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl having in each case 1 to 8 carbon atoms, or represent cycloalkyl having 3 to 8 carbon atoms, or represent in each case straight-chain or branched halogenoalkyl, halogenoalkoxy, halogenoalkyl~hio, halogenoalkylsulphinyl, halogenoalkylsulphonyl having in each case 1 to 6 carbon atoms and 1 to 13 identical or different halogen atoms, or represent divalent dioxyalkylene having 1 to 5 carbon atoms Le A 29 484 - 3 -IJ

which is optionally mono- or polysubstituted by identical or different substituents from the group comprising halogen and/or straight-chain or branched alkyl having 1 to 4 carbon atoms and/or straight-chain or branched halogenoalkyl having 1 to 4 carbon atoms and 1 to 9 identical or different halogen atoms, or furthermore represent hydroxycarbonyl, or represent in each case straight-chain or branched alkylcarbonyl or alkoxycarbonyl having in each case 1 to 6 carbon atoms in the alkyl moiety, or represent cycloalkyloxycarbonyl having 3 to 8 carbon atoms in the cycloalkyl moiety, or represent amino or aminocarbonyl, in each case optionally mono- or polysubstituted by identical or different sub-stituents, possible substituents on the amino in each case being:

in each case straight-chain or branched alkyl having l to 6 carbon atoms, halogenoalkyl having 1 to 6 carbon atoms and 1 to 13 halogen atoms, alkoxyalkyl or alkylcarbonyl having in each case 1 to 6 carbon atoms in the individual alkyl moieties, or aryl-carbonyl, arylsulphonyl, arylaminocarbonyl or arylmethylsulphonyl having in each case 6 to 10 carbon atoms in the aryl moiety and in each case optionally mono- or polysubstituted in the aryl moiety by identical or different substituents, possible substituents on the aryl in each case being those mentioned for Rl;

Le A 29 484 - 4 -:;. . . -". .
.,"

"",, ~, .

,3 or furthermore represent aryl, aryloxy, arylthio, arylsulphinyl, arylsulphonyl, arylsulphonyloxy, a r y l c a r b o n y l , a r y l o x y c a r b o n y l , arylthiomethylsulphonyl or arylazo having in each case 6 to 10 carbon atoms in the aryl moiety and in each case optionally mono- or polysubstituted in the aryl moiety by identical or different substituents, possible substituents on the aryl in each case being those mentioned for R1, but wherein at least one of the substituents X1, X2, X3 and X4 iS other than hydrogen and halogen, and wherein .

R1 represents hydrogen, or represents straight-chain or branched alkyl having l to 8 carbon atoms, or repre-sents phenyl which is optionally mono- or polysub-stituted by identical or different substituents, possible substituents being:

halogen, cyano, nitro, in each case straight-chain or branched alkyl, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl having in each case 1 to 6 carbon atoms, in each case straight-chain or branched halogenoalkyl, halogenoalkoxy, halogenoalkylthio, ~ :~
halogenoalkylsulphinyl or halogenoalkylsulphonyl having in each case 1 to 6 carbon atoms and l to 13 identical or different halogen atoms, in each case straight-chain or branched alkoxyalkyl, alkoxy-alkoxy, alkanoyl, alkoxycarbonyl or alkoximinoalkyl Le A 29 484 - 5 -:.
, ~, ; .
.,,~ . .
~ , .
"'.: : :
,~ , ,'~. , :

having in each case 1 to 6 carbon atoms in the individual alkyl moieties, divalent dioxyalkylene having 1 to 5 carbon atoms which is optionally mono-or polysubstituted by identical or different sub-S stituents from the group comprising halogen and/or straight-chain or branched alkyl having 1 to 6 carbon atoms and/or straight-chain or branched halogenoalkyl having 1 to 6 carbon atoms and 1 to 13 identical or different halogen atoms, or phenyl which is optionally mono- or polysubstituted by identical or different substituents from the group comprising halogen and/or straight-chain or branched alkyl having 1 to 6 carbon atoms and/or straight-chain or branched halogenoalkyl having 1 to 6 carbon atoms and 1 to 13 identical or different halogen atoms, R2 represents hydroxyl or cyano, or represents alkyl, alkenyl, alkinyl, alkoxy, alkenyloxy, alkinyloxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, alXyl-carbonyloxy or dialkoxyphosphoryl having in each case up to 8 carbon atoms in the individual alkyl or alkenyl or alkinyl moieties and in each case optionally mono- or polysubstituted by identical or different substituents, possible substituents in each case being:

halogen, straight-chain or branched alkoxy having 1 to 8 carbon atoms or aryl having 6 to 10 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents, possible Le A 29 484 - 6 -r,~
.. ~ , : . - :

~",, Ji : , . .
~r.
`': ' ,: - .
:
: ': ' , .
' : . , ''~ . . : ' : . ., substituents on the aryl being those mentioned for Rl ~

R2 furthermore represents amino or aminocarbonyl, in each case optionally mono- or disubstituted by identical or different substituents, possible sub-stituents being:
.

straight-chain or branched alkyl having 1 to 8 carbon atoms, straight-chain or branched alkenyl having 2 to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkoxycarbonyl, alkylthio-carbonyl, alkoxythiocarbonyl or alkylthio-thiocarbonyl having in each case 1 to 8 carbon atoms in the individual straight-chain or branched alkyl moieties, divalent, cyclic alkanediyloxycarbonyl having 2 to 6 carbon atoms in the alkanediyl moiety, or arylalkyl or aryl having in each case 6 to 10 carbon atoms in the aryl I moiety and, where appropriate, 1 to 6 carbon atoms in the straight-chain or branched alkyl moiety and in each case optionally mono- or polysubstituted by identical or different substituents, possible substituents on the aryl in each case being those mentioned for R1, R2 furthermore represents aryl, arylcarbonyl, aryloxy-carbonyl, arylcarbonyloxy or arylaminocarbonylamino-carbonyloxy having in each case 6 to 10 carbon atoms in the aryl moiety and in each case optionally mono-or polysubstituted by identical or different Le A 29 484 - 7 -:~
:`~
', - ~ : ~

,: : .

substituents, possible substituents on the aryl in each case being those mentioned for R1, R2 furthermore represents heteroaryl, heteroaryl-carbonyl,heteroaryloxycarbonyl,heteroarylcarbonyl-oxy or heteroarylaminocarbonylaminocarbonyloxy having in each case 2 to 9 carbon atoms and 1 to 5 identical or different hetero atoms - in particular nitrogen, oxygen and/or sulphur - in the heteroaryl moiety and in each case optionally mono- or poly-substituted by identical or different substituents, possible substituents on the heteroaryl in each case being the substituents on the aryl mentioned for R1.

Particularly preferred compounds of the formula (I) are those in which Xl~ X2, X3 and X4 independently of one another in each case represent hydrogen, fluorine, chlorine, bromine, cyano or nitro, or represent in éach case straight-chain or branched alkyl, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl having in each case 1 to 6 carbon atoms, or represent cycloalkyl having 3 to 7 carbon atoms, or represent in each case straight-chain or branched halogenoalkyl, halogeno-alkoxy, halogenoalkylthio, halogenoalkylsulphinyl or halogenoalkylsulphonyl having in each case 1 to 4 carbon atoms and 1 to 9 identical or different halogen atoms, or represent divalent dioxyalkylene having 1 to 4 carbon atoms which is optionally mono-Le A 29 484 - 8 -2 ~

to hexasubstituted by identical or different sub-stituents from the group comprising halogen and/or straight chain or branched alkyl having 1 to 4 carbon atoms and/or straight-chain or branched halogenoalkyl having 1 to 4 carbon atoms and 1 to 9 identical or different halogen atoms, or further represent hydroxycarbonyl, or represent in each case straight-chain or branched alkylcarbonyl or alkoxy-carbonyl having in each case 1 to 4 carbon atoms in the alkyl moiety, or represent cycloalkyloxycarbonyl having 3 to 7 carbon atoms in the cycloalkyl moiety, or represent amino or aminocarbonyl, in each case optionally mono- or disubstituted by identical or different substituents, possible substituents on the amino in each case being:

in each case straight-chain or branched alkyl having 1 to 4 carbon atoms, halogenoalkyl having 1 to 4 carbon atoms and 1 to 9 halogen atoms, alkoxyalkyl or alkylcarbonyl having in each case 1 to 4 carbon atoms in the individual alkyl moieties, or aryl-carbonyl, arylsulphonyl, arylaminocarbonyl or aryl-methylsulphonyl having in each case 6 or 10 carbon atoms in the aryl moiety and in each case optionally mono- to pentasubstituted in the aryl moiety by identical or different substituents, possible substituents on the aryl in each case being those mentioned for R1;
or furthermore represent aryl, aryloxy, arylthio, Le A 29 484 - 9 -s,. ~ . ;
.. :
j, :

,j. :
arylsulphinyl, arylsulphonyl, arylsulphonyloxy, arylcarbonyl, aryloxycarbonyl, arylthiomethyl-sulphonyl or arylazo having in each case 6 or 10 ~ carbon atoms in the aryl moiety and in each case : 5 optionally mono- to pentasubstituted in the aryl moiety by identical or different substituents, pos-~; sible substituents on the aryl in each case being those mentioned for R1, but wherein at least one of the substituents Xl, X2, 0 X3 and X4 iS other than hydrogen and halogen, and wherein R1 represent~ hydrogen, or represents straight-chain or branched alkyl having 1 to 6 carbon atoms, or repre-¦ sents phenyl which is optionally mono- to trisub-stituted by identical or different substituents, possible substituents being:

halogen, cyano, nitro, in each case straight-chain or branched alkyl, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl having in each case 1 to 4 carbon atoms, in each case straight-chain or branched halogenoalkyl, halogenoalkoxy, halogenoalkylthio, halogenoalkylsulphinyl or halogenoalkylsulphonyl having in each case 1 to 4 carbon atoms and 1 to 9 identical or different halogen atoms, in each case straight-chain or branched alkoxyalkyl, alkoxy-alkoxy, alkanoyl, alkoxycarbonyl or alkoximinoalkyl having in each case 1 to 4 carbon atoms in the Le A 29 484 - 10 - :

individual alkyl moieties, divalent dioxyalkylene having l to 4 carbon atoms which is optionally mono-to hexasubstituted by identical or different sub-stituents from the group comprising halogen and/or straight-chain or branched alkyl having 1 to 4 carbons atoms and/or straight-chain or branched halogenoalkyl having l to 4 carbon atoms and 1 to 9 identical or different halogen atoms, or phenyl which is optionally mono- to pentasubstituted by identical or different substituents from the group comprising halogen and/or straight-chain or branched alkyl having 1 to 4 carbon atoms and/or straight-chain or branched halogenoalkyl having l to 4 carbon atoms and 1 to 9 identical or different halogen atoms, RZ represent~ hydroxyl or cyano, or represents alkyl, alkenyl, alkinyl, alkoxy, alkenyloxy, alkinyloxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkyl-carbonyloxy or dialkoxyphosphoryl having in each case up to 6 carbon atoms in the individual alkyl or alkenyl or alkinyl moieties and in each case optionally mono- to pentasubstituted by identical or different halogen atoms, or represents alkyl, alkenyl, alkinyl, alkoxy, alkenyloxy, alkinyloxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy or dialkoxyphosphoryl having in each case up to 6 carbon atoms in the individual alkyl or alkenyl or alkinyl moieties and in each case optionally mono- to trisubstituted by identical Le A 29 484 - 11 - :

- .

~;. .

1 4 ~

or different substituents, possible substituents in ~! each case being-straight-chain or branched alkoxy having 1 to 6 carbon atoms, or aryl having 6 or 10 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents, possible sub-stituents on the aryl being those mentioned for R1, R2 furthermore represents amino or aminocarbonyl, in each case optionally mono- or disubstituted by identical or different substituents, possible sub-stituents being:

straight-chain or branched alkyl having l to 6 carbon atoms, straight-chain or branched alkenyl having 2 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, alkoxycarbonyl, alkylthio-carbonyl, alkoxythiocarbonyl or alkylthio-thiocarbonyl having in each case 1 to 6 carbon atoms in the individual straight-chain or branched alkyl moieties, divalent, cyclic alkanediyloxycarbonyl having 2 to S carbon atoms in the alkanediyl moiety, or arylalkyl or aryl having in each case 6 or 10 carbon atoms in the aryl moiety and, where appropriate, 1 to 6 carbon atoms in the straight-chain or branched alkyl moiety and in each case optionally mono- to trisubstituted by identical or different substituents, possible substituents on the aryl in each case being those mentioned for R1, -Le A 29 484 - 12 -~7,,. ~

7A'. ~ :
:~ "

furthermore represents aryl, arylcarbonyl, aryloxy-carbonyl, arylcarbonyloxy or arylaminocarbonylamino-carbonyloxy having in each case 6 or 10 carbon atoms in the aryl moiety and in each case optionally mono-to pentasubstituted by identical or different sub-stituents, possible substituents on the aryl in each case being those mentioned for R1, R2 furthermore represents heteroaryl, heteroaryl-carbonyl,heteroaryloxycarbonyl,heteroarylcarbonyl-oxy or heteroarylaminocarbonylaminocarbonyloxy having in each case 2 to 9 carbon atoms and 1 to 4 identical or different hetero atoms - in particular nitrogen, oxygen and/or sulphur - in the heteroaryl moiety and in each case optionally mono- to penta-substituted by identical or different substituents, possible substituents on the heteroaryl in each case being the substituents on the aryl mentioned for R1.

Aryl radicals which may be mentioned are phenyl or naphthyl, and heteroaryl radicals which may be mentioned are pyridyl.

Very particularly preferred compounds of the formula (I) are those in which Xl ~ X2~ X3 and X4 independently of one another in each case represent hydrogen, chlorine, bromine, cyano or nitro, or represent in each case straight-chain or branched alkyl, alkoxy, alkylthio, alkylsulphinyl or Le A 29 484 - 13 -~ .

!~;, ?C ~ :

,~ . .

alkylsulphonyl having in each case l to 4 carbon atoms, or represent cycloalkyl having 3, 5 or 6 carbon atoms, or represent in each case straight-chain or branched halogenoalkyl, halogenoalkoxy, halogenoalkylthio, halogenoalkylsulphinyl or halo-genoalkylsulphonyl having in each case 1 to 3 carbon atoms and l to 7 identical or different halogen atoms, or represent divalent dioxyalkylene having 1 to 3 carbon atoms which is optionally mono- to tetrasubstituted by identical or different sub-stituents from the group comprising halogen and/or straight-chain or branched alkyl having l to 3 carbon atoms and/or straight-chain or branched halogenoalkyl having 1 to 3 carbon atoms and l to 7 identical or different halogen atoms, or furthermore represent hydroxycarbonyl, or represent in each case straight-chain or branched alkylcarbonyl or alkoxy-carbonyl having in each case 1 to 3 carbon atoms in the alkyl moiety, or represent cycloalkyloxycarbonyl having 3, 5 or 6 carbon atoms in the cycloalkyl moiety, or represent amino or aminocarbonyl, in each case optionally mono- or disubstituted by identical or different substituents, possible substituents on the amino in each case being:

in each case straight-chain or branched alkyl having 1 to 3 carbon atoms, halogenoalkyl having 1 to 3 carbon atoms and 1 to 7 halogen atoms, alkoxyalkyl or alkylcarbonyl having in each case 1 to 3 carbon atoms in the individual alkyl moieties, or Le A 29 484 - 14 -~.'. ' ~ ' ;~.' ~ "
. ' .

-~ ~` 2 ~ 1 1 1 L~ ~3 s phenylcarbonyl,phenylsulphonyl,phenylaminocarbonyl or phenylmethylsulphonyl, in each case optionally mono- to trisubstituted in the phenyl moiety by identical or different substituents, possible substituents on the phenyl in each case being those mentioned for Rl;

or furthermore for phenyl, phenyloxy, phenylthio, phenylsulphinyl, phenylsulphonyl, phenylsulphonyl-oxy, phenylcarbonyl, phenyloxycarbonyl, phenylthio-methylsulphonyl or phenylazo, in each case optionally mono- to trisubstituted in the phenyl moiety by identical or different substituents, pos-sible substituents on the phenyl in each case being those mentioned for R1, but wherein at least one of the substituents X1, X2, X3 or X4 iS other than hydrogen and halogen, and wherein R1 represents hydrogen, or represents straight-chain or branched alkyl having 1 to 4 carbon atoms, or represents phenyl which is optionally mono- or disubstituted by identical or different sub-stituents, possible substituents being:

halogen, cyano, nitro, in each case straight-chain or branched alkyl, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl having in each case 1 to 3 carbon atoms, in each case straight-chain or branched Le A 29 484 - 15 -, r~
~,.......... .

' ~''' ' ' .', i halogenoalkyl, halogenoalkoxy, halogenoalkylthio, ¦ halogenoalkylsulphinyl or halogenoalkylsulphonyl having in each case 1 to 3 carbon atoms and 1 to 7 identical or different halogen atoms, in each case straight-chain or branched alkoxyalkyl, alkoxy-alkoxy, alkanoyl, alkoxycarbonyl or alkoximinoalkyl having in each case 1 to 3 carbon atoms in the individual alkyl moieties, divalent dioxyalkylene having 1 to 3 carbon atoms which is optionally mono-to tetrasubstituted by identical or different substituents from the group comprising halogen and/or straight-chain or branched alkyl having 1 to 3 carbon atoms and/or straight-chain or branched halogenoalkyl having 1 to 3 carbon atoms and 1 to 7 identical or different halogen atoms, or phenyl which is optionally mono- to tris~bstituted by identical or different substituents from the group comprising halogen and/or straight-chain or branched alkyl having 1 to 3 carbon atoms and/or straight-chain or branched halogenoalkyl having 1 to 3 carbon atoms and 1 to 7 identical or different halogen atoms, R2 represents hydroxyl or cyano, or represents alkyl, alkenyl, alkinyl, alkoxy, alkenyloxy, alkinyloxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkyl-carbonyloxy or dialkoxyphosphoryl having in each case up to 4 carbon atoms in the individual alkyl or alkenyl or alkinyl moieties and in each case optionally mono- to trisubstituted by identical or Le A 29 484 - 16 --,, "
:,:

...
~ -different halogen atoms, or represents alkyl, alkenyl, alkinyl, alkoxy, alkenyloxy, alkinyloxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy or dialkoxyphosphoryl having in each case up to 4 carbon atoms in the individual alkyl or alkenyl or alkinyl moieties and in each case optionally mono- or disubstituted by identical or different substituents, possible substituents in each case being:

straight-chain or branched alkoxy having 1 to 3 carbon atoms or phenyl which is optionally mono- or disubstituted by identical or different sub-stituents, possible substituents on the phenyl being those mentioned for R1, R2 furthermore represents amino or aminocarbonyl in each case optionally mono- or disubstituted by identical or different substituents, possible substituents being:

straight-chain or branched alkyl having 1 to 4 carbon atoms, straight-chain or branched alkenyl having 2 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, alkoxycarbonyl, alkylthio-carbonyl, alkoxythio-carbonyl or alkylthio-thiocarbonyl having in each case 1 to 4 carbon atoms in the individual straight-chain or branched alkyl moieties, divalent, cyclic alkanediyloxycarbonyl having 2 to 4 carbon atoms in the alkanediyl moiety, or phenylalkyl or Le A 29 484 - 17 -'~c~ ' . . . ~
~....... .

. .~ .
, . . .
. ~ :

phenyl having, where appropriate, 1 to 3 carbon ; atoms in the straight-chain or branched alkyl moiety and in each case optionally mono- or disubstituted $` by identical or different substituents, possible substituents on the phenyl in each case being those mentioned for R1, R2 furthermore represents phenyl, phenylcarbonyl, phenyloxycarbonyl, phenylcarbonyloxy or phenylamino-carbonylaminocarbonyloxy, in each case optionally mono-to trisubstituted by identical or different substituents, possible substituents on the phenyl in each case being those mentioned for R1, R2 furthermore represents heteroaryl, heteroaryl-carbonyl,heteroaryloxycarbonyl,heteroarylcarbonyl-oxy or heteroarylaminocarbonylaminocarbonyloxy having in each case 2 to 9 carbon atoms and 1 to 3 identical or different hetero atoms - in particular nitrogen, oxygen and/or sulphur - in the heteroaryl moiety and in each case optionally mono- to tri-substituted by identical or different substituents, possible substituents on the heteroaryl in each case being the substituents on the phenyl mentioned for Rl, Heteroaryl which may be mentioned is pyridyl.

The following substituted benzimidazoles of the general formula (I) may be mentioned specifically, in addition to Le A 29 484 - 18 -r:,. ' ~ , ir~
1.~

.,~',: . ~ .

... ~ .

.~ .

t ~ ~
.

the compounds mentioned in the Preparation Examples X

! x 2,CHLR

¦ Xl X2 X3 X~ A
Br H CF3-S- H
--~ N~CC~X~
Br H CF3-S- H -CH2-O-C2Hs Br HClFCH-CF2-S- H
,N~
Br HClFCH-CF2-S- H -CH2-O-C2Hs : -:
Br HF3C-CHF-CF2-S- H ,N~ ::~

Br HF3C-CHF-CF2 S- H -CH2-O-C2Hs Br H F3C- H -CH2-O-C2Hs ~ -Br H F3C-O- H
,N~
~ COOC~
Br H F3C-O- H -CH2-O-C2H
Br H NO2 ,N~
--CE~ COOC2H~
Br H N02 H-CH2-O C2Hs Le A 29 484 - 19 -. ' , , ~ ;

. . -, . ~
!,,. ~ " ., ---` 2 ~

X~ ~2 X3 X4 A
Cl H CF3-S- H ~2~

--CH2 N~COOC2H5 Cl HCF3-S- H-CH2-O-C2H5 Cl HClFCH-CF2-S- H C2~
,N~ H5 Cl HClFCH-CF2--S- H--CH2~O~C2Hs Cl HF3C-CHF-CF2-S- H ,N~

Cl HF3C-CHF-CF2-S- H--CH2--O-C2Hs Cl H F3C- H
~z ~COOC~Hs Cl HF3C-O- Hf211, Cl HF3C-O- H--CH2~O-C2Hs Cl H NO2 H~2Hs ,N~
Cl H N02 H-CH2-O-C2Hs CF3 HCF3-S- H Ç2Hs ~H2 N~aX~C2H~s CF3 HCF3-S- H-CH2-O-C2Hs CF3 HClFCH-CF2--S- H ,N~

~ C~H5 CF3 HClFCH-CF2-S- H-CH2-O-C2Hs LeA 29 484 - 20 -.:.: -- - : : .
: - - .

~1 ~2 ~3 X4 A
CF3 H F3C-CHF-CF2-S- H~zH5 ,N~
CF3 H F3C-CHF-CF2-S- H-CH2-O-C2Hs CF3 H F3C- H ~2Hs ,N~

CF3 H F3C-O- H f2Hs ,N~
CF3 H F3C--O- H-CH2-O-C2Hs ,N~
--C:H2 CC2~ ' CF3 H NO2 H-CH2--O-C2Hs 10COOCH3 H CF3-S- H C2E~
,N~
COOCH3 H CF3~S- H-CH2-O-C2Hs COOCH3 H ClFCH--CF2-5-- H

--CH2 N~C2Hs COOCH3 H ClFCH-CF2-S- H-CH2-O-C2Hs COOCH3 H F3C-CHF--CF2--S-- H ,N~

15COOCH3 H F3C-CHF-CF2-S- H-CH2-O-C2Hs COOCH3 H F3C- H ~2Hs --CH2 ~C~C2H5 COOCH3 H F3C- H-CH2-O-C2Hs Le A 29 484 - 21 -.: : . : .
; - - . - . :
: ,~ .: .

,,: - . . - ;

_ _ X X2 X3 X4 A
COOCH3 H F3C-O- Hf2H~
,N~
~ ~H5 , COOCH3 H F3C-O- H--CH2--O-c2Hs ,N~ :
~H2 a)OC~H~ -5COOCH3 H NO2 H--CH2--O-c2Hs COO-n-C3H7 H CF3-S- ,N

--CH2 ~COOC2,H~
COO-n-C3H7 H CF3-S- H-CH2-O-C2Hs COO-n-C3H7 HClFCH-CF2-S- H
,N~
~ ~}1, COO-n-C3H7 HClFCH-CF2-S- H-CH2-O-C2H5 10COO-n-C3H7 HF3C-CHF-CF2-S- H
,N~
--CE~ COOC2H5 COO-n-C3H7 HF3C-CHF-CF2-S- H-CH2-O-C2Hs COO-n-C3H7 H F3C- H
,N~
COO-n-C3H7 H F3C- H-CH2-O-C2H5 COO-n-C3H7 H F3C-O- H ~H~
~z ~CO~C2H5 15COO-n-C3H7 H F3C-O- H-CH2-O-C2H5 COO-n-C3H7 H N2 Hf2H~
,N~
--~ ~

Le A 29 484 - 22 --;~ - , , .

:, - - - :. : ~ -::: . , .
.~ .' ' ' " . ' .
' ' ' ' ~ ' ' ' ': .
:~, . ' , , , ', . ' .

~ ' ' ' ' .
~, . .

L ~ 1 4 ~
:

Xl x2 X3 X4 A
COO-n-C3H7 H NO2 H -CH2-O-C2Hs Some of the substituted benzimidazoles of the formula (I) . are known (compare, for example, DE 20 47 369;
DE 20 14 293; EP 448 206; J. Chem. Soc. C, 1967, 2536-2540).

Substituted benzimidazoles which are not yet known but are the subject-matter of a previous Application which has been filed by the Applicant Company are those of the formula (Ia) x'-l N
X CH--R
l2 in which X1~1, X2~1, X3-l and X4-1 independently of one another in each case represent hydrogen, halogen, cyano or nitro, or represent in each case optionally substituted alkyl, alkoxy, alkylthio, alkyl-sulphinyl, alkylsulphonyl or cycloalkyl, or represent optionally substituted, fused-on dioxyalkylene, or represent hydroxycarbonyl, alkylcarbonyl, alkoxycarbonyl or cycloalkyloxy-carbonyl, or represent in each case optionally Le A 29 484 - 23 -'. ' , : :

'.: ' ~ , substituted amino or aminocarbonyl, or represent in each case optionally substituted aryl, aryloxy, arylthio, arylsulphinyl, arylsulphonyl, arylsulphonyloxy, arylcarbonyl, aryloxycarbonyl, arylazo or arylthiomethylsulphonyl, but wherein at least one of the substituents X1~l, X2~1, X3-1 and X4-1 represents nitro, halogenoalkyl, halogenoalkoxy, halogenoalkylthio, halogenoalkylsulphinyl,halogenoalkylsulphonylor alkylsulphonyl, or represents optionally substituted, fused-on dioxyalkylene, or repre-sents hydroxycarbonyl, alkylcarbonyl, alkoxy-carbonyl or cycloalkyloxycarbonyl, or represents in each case optionally substituted amino or aminocarbonyl, or represents in each case optionally substi~uted aryl, arylthio, aryl-sulphinyl, arylsulphonyl, arylsulphonyloxy, arylcarbonyl, aryloxycarbonyl, arylazo or arylthiomethylsulphonyl, and wherein R1 represents hydrogen or alkyl, or represents optionally substituted aryl, R2 represents hydroxyl or cyano, or represents in each case optionally substituted alkyl, alkenyl, alkinyl, alkoxy, alkenyloxy, alkinyloxy, alkylthio, amino, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, dialkoxyphosphoryl, (hetero)aryl, (hetero)arylcarbonyl, (hetero)-Le A 29 484 - 24 -,.... .

aryloxycarbonyl, (hetero)arylcarbonyloxy or (hetero)arylaminocarbonylaminocarbonyloxy.

The substituted benzimidazoles of the formulae (I) and (Ia) which are known and are not yet known are obtained by a process in which a) lH-benzimidazoles of the formula (II) X ~ -N

in which Xl, X2, X3 and X4 have the abovementioned meaning, are reacted with alkylating agents of the formula (III) R
E - CH (m) .
R :::
in which E represents a suitable leaving group and R1 and R2 have the abovementioned meaning, if appropriate in the presence of a diluent and if Le A 29 484 - 25 -. .. , . ~ , . :
, :- ~
~ . , -' . ' ' :
': ~ : ' ' , - :' : .

2 1 1 ~

appropriate in the presence of a reaction auxiliary.

If, for example, 5-nitro-2-cyano-benzimidazole and chloromethyl ethyl ether are used as starting compounds, the course of the reaction of the preparation process can be represented by the following equation:

02N ~ ~ ~ 2 ~ O----{~
H

~N ~ N

- ~a \CH2--O~ H5 base 02NJ~N~
, C~O~

Formula (II) provides a general definition of the lH-benzimidazoles required as starting substances for carrying out the preparation process. In this formula (II), Xl, X2, X3 and X4 preferably represent those radicals which have already been mentioned as preferred for these substituents in connection with the description of the compounds of the formula (I) which can be used according to the invention.

Le A 29 484 - 26 --r~

2 1 ~
,!
¦ The lH-benzLmidazoles of the formula (II) are known orare obtainable by processes analogous to known processes (compare, for example, J. Amer. Chem. Soc. 75, 2192 [lq53]; US 3,576,818) ¦ 5 Formula (III) provides a general definition of the alkylating agents furthenmore required as starting products for carrying out the preparation process. In this formula (III), R1 and R2 preferably represent those radicals which have already been mentioned as prepared for these substituents in connection with the description of the substances of the formula (I) which can be used according to the invention.

E represents a leaving radical customary in alkylating agents, and preferably represents halogen, in particular represents chlorine, bromine or iodine, or represents in each case optionally substituted alkylsulphonyloxy, alkoxysulphonyloxy or arylsulphonyloxy, such as, in particular, methanesulphonyloxy, trifluoromethane-sulphonyloxy, methoxysulphonyloxy, ethoxysulphonyloxy or p-toluenesulphonyloxy.

E furthermore also repre~ents an alcohol, alkanoyloxy or alkoxy group, such as, for example, a hydroxyl, acetoxy or methoxy group, in particular if compounds of the formula (I) in which R1 is other than hydrogen are to be prepared with the aid of the process according to the invention.

Le A 29 484 - 27 -, .

A
~"'"" ' '' ' ' ' ~ , ~" .~ ' ' ' ' , ~ ~ - 2 ~

The compounds of the formula (III) are generally known or are obtainable by processes analogous to known processes (compare, for example, DE 20 40 175; DE 21 19 518;
Synthesis 1973, 703).
Possible diluents for carrying out the preparation process are inert organic solvents. These include, in particular, aliphatic, alicyclic or aromatic, optionally halogenated hydrocarbons, such as, for example, benzine, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petxoleum ether, hexane, cyclohexane, methylene chloride, chloroform or carbon tetrachloride; ethers, such as diethyl ether, diisopropyl ether, dioxane, tetrahydro-furan or ethylene glycol dimethyl or diethyl ether;
ketones, such as acetone, butanone or methyl isobutyl ketone; nitriles, such as acetonitrile, propionitrile or benzonitrile; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methyl-pyrrolidone or hexamethylphosphoric acid triamide;
esters, such as methyl acetate or ethyl acetate, or bases, such as pyridine, or organic acids, such as formic acid or acetic acid.

The preparation process is preferably carried out in the presence of a suitable reaction auxiliary. Possible reaction auxiliaries are all customary inorganic or organic bases. These include, for example, alkaline earth metal or alkali metal hydrides, hydroxides, amides, alcoholates, acetates, carbonates or hydrogencarbonates, such as, for example, sodium hydride, sodium amide, lithium diethylamide, sodium methylate, sodium ethylate, :' Le A 29 484 - 28 -,...
,,,., . :

'~ u potassium tert-butylate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium acetate, potassium acetate, calcium acetate, ammonium acetate, sodium carbonate, potassium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate or ammonium carbonate, organolithium compounds, such as n-butyllithium, and tertiary amines, such as trimethylamine, triethylamine, tributylamine, diisopropylethylamine, tetramethylguanidine, N,N-dimethylaniline, pyridine, piperidine, N-methyl-piperidine,N,N-dimethylaminopyridine,diazabicyclooctane (DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU).
Alternatively, possible reaction auxiliaries are also organic or inorganic acids, such as, for example, sulphuric acid, hydrochloric acid, p-toluenesulphonic acid, perfluorobutanesulphonic acid or strongly acid ion exchangers, especially if E in the alkylating agents of the formula (III) used represents a hydroxyl, acyloxy or alkoxy radical.
If appropriate, the preparation process can also be carried out in a two-phase system, such as, for example, water/toluene or water/methylene chloride, if appropriate in the presence of a suitable phase transfer catalyst.
Examples of such catalysts which may be mentioned are:
tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, tributylmethylphosphonium bromide, trimethyl-C13/C15-alkylammonium chloride, Le A 29 484 - 29 -... ~
., !,.' ' : ' .~,'""` :
~,,' ~ ' `~

trimethyl-Cl3/Cl5-alkylammonium bromide, dibenzyldimethyl-ammonium methyl sulphate, dimethyl-Cl2/Cl4-alkylbenzyl-ammonium chloride, dimethyl-Cl2/Cl~-alkylbenzylammonium ¦ bromide, tetrabutylammonium hydroxide, triethylbenzyl-ammonium chloride, methyltrioctylammonium chloride, trimethylbenzylammonium chloride, 15-crown-5, 18-crown-6 or tris-[2-(2-methoxyethoxy)-ethyl]-amine.

The reaction temperatures can be varied within a sub-¦ stantial range when carrying ou~ the preparation process.
The reaction is in general carried out at temperatures between -70C and +200C, preferably at temperatures between OC and 130C.

The preparation process is usually carried out under normal pressure. However, it is also possible to carry out the preparation under increased or reduced pressure.

For carrying out the preparation process, in general 1.0 to 5.0 mol, preferably 1.0 to 2.5 mol, of alkylating agent of the formula (III) and if appropriate 0.01 to 5.0 mol, preferably 1.0 to 3.0 mol, of reaction auxiliary are employed per mole of lH-benzimidazole of the formula (II)-In a particular embodiment, it is also possible for the lH-benzimidazoles of the formula (II) first to be silyla-ted in a prior reaction step with the aid of customary silylating processes, for example with hexamethyl-disilazane or trimethylsilyl chloride, if appropriate in Le A 29 484 - 30 -.r -.

the presence of a suitable catalyst, such as, for example, sulphuric acid, trifluoroacetic acid, ammonium sulphate, imidazole or saccharin, at temperatures between -20C and +150C and for the l-trimethylsilylbenzimidazoles thus obtainable to be reacted in a subsequent second stage with alkylating agents of the formula (II) in accordance with the preparation process. In this case, it is advantageous to add tin tetrachloride to the alkylation reaction as a catalyst (compare, for example, Chem. Heterocycl. Comp. USSR 24, 514 [1988]).

The reaction is carried out and the reaction products are worked up and isolated by known processes tin this context, compare also the Preparation Examples).

The end products of the formula (I) are purified with the aid of customary processes, for example by column chroma-tography or by recrystallisation.

The products are characterised with the aid of the melting point or, in the case of non-crystallising compounds - especially in the case of regioisomer mixtures - with the aid of proton nuclear magnetic resonance spectroscopy (lH-NMR).

The active compounds are suitable for combating parasitic protozoa which occur on stock, breeding, zoo, laboratory and test animals and pets in animal husbandry and animal rearing, and have a favourable toxicity to warm-blooded animals. They are active here against all or some stages Le A 29 484 - 31 -VJ~

"~'~" ' ~'~

'~.
.; .~ .

of development of the pests ancl against resistant and normally sensitive strains. By combating the parasitic protozoa, illness, fatalities and reductions in output (for example in the production of meat, milk, wool, skins, eggs, honey and the like) are to be reduced, so that more economical and easier animal husbandry is possible by using the active compounds.

The parasitic protozoa include:

Mastigophora (Flagellata), such as, for example, ~rypanosomatidae, for example Trypanosoma 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. tropica, such as, for example, Trichomonadidae, for example Giardia lamblia, G. canis.

Sarcomastigophora (Rhizopoda), such as Entamoebidae, for example Entamoeba histolytica, Hartmanellidae, for example Acanthamoeba sp., Hartmanella 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. brunetti, E. canis, E.
chinchillae, E. clupearum, E. columbae, E. contorta, E.
crandalis, E. debliecki, E. dispersa, E. ellipsoidales, E. falciformis, E. faurei, E. flavescens, E.
gallopavonis, E. hagani, E. intestinalis, E. iroquoina, Le A 29 484 - 32 -.'`'~ ,~
. . ,~

~' '' ;~

-` 2 ~

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, ~. residua, E. scabra, E. spec., E. stiedai, E. suis, E. tenella, E. truncata, E. truttae, E. zuernii, Globidium spec., Isospora belli, I. canis, I.
felis, I. ohioensis, I. rivolta, I. spec., I. suis, Cystisospora spec., Cryptosporidium spec., such as Toxoplasmadidae, for example Toxoplasma gondii, such as Sarcocystidae, for exEmple 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. falciparum, P. malariae, P. ovale, P. vivax, P. spec., such as Piroplasmea, for example Babesia argentina, B. bovis, B. canis, B. spec., Theileria parva, Theileria spec., such as Adeleina, for example Hepatozoon canis, H. spec.

Furthermore, Myxospora and Microspora, for example Glugea spec. Nosema spec.

Furthermore, Pneumocystis carinii, as well as Ciliophora (Ciliata), such as, for example, Balantidium coli, Ichthiophthirius spec., Trichodina spec., Epis~ylis spec.

The compounds according to the invention are also active against protozoa which occur as parasites on insects.
Such parasites which may be men~ioned are those of the Le A 29 484 - 33 -. ~
.: :
'', ~ ' .

2 ;~
~, phylum Microsporida, in particular of the genus Nosema.
Nosema apis on honey bees may be mentioned in particular.

The stock and breeding animals include mammals, such as, for example, cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer and rein-deer, fur-bearing animals, such as, for example, mink, chinchillas and raccoons, and birds, such as, for example, chickens, geese, turkeys, ducks, pigeons and species of birds for keeping at home and in zoos. The animals also include stock and ornamental fish.

; The laboratory and test animals include mice, rats, ~ guinea-pigs, golden hamsters, dogs and cats.
, .
The pets include dogs and cats.

The fish include stock, breeding, aquarium and ornamental ; 15 fish of all ages which live in fresh water and salt water. The stock and breeding fish include, for example, carp, eel, trout, white fish, salmon, bream, roach, chub, sole, plaice, halibut, Japanese yellowtail (Seriola quinqueradiata), Japanese eel (Anguilla japonica), Red seabream (Pagurus major), Seabass (Dicentrarchus labrax), Grey mullet (Mugilus cephalus), Pompano, Gilthread seabream (Sparus auratus), Tilapia spp., Chichlidae species, such as, for example, Plagioscion, Channel catfish. The agents according to the invention are particularly suitable for treating fish fry, for example carp of body length 2 to 4 cm. The agents are also very Le A 29 484 - 34 -, ~ ~

:
:. .

~"j~
, suitable for eel fattening.

They can be used either prophylactically or therapeuti-cally.

The active compounds are used enterally, parenterally, dermally or nasally, directly or in the form of suitable formulations.

Enteral use of the active compounds is effected, for example, orally in the form of powders, suppositories, tablets, capsules, pastes, drinks, granules, drenches, boli, medicated feed or drinking water. Dermal use is effected, for example, in the form of dipping (dips), spraying (sprays), bathing, washing, pouring on (pour-on and spot-on) and powdering. Parenteral use is effected, for example, in the form of injection (intramuscular, subcutaneous, intravenous or intraperitoneal) or by implants .

Suitable formulations 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 and gels;

Emulsions and suspension for oral or dermal use and for injection; semi-solid formulations;

Le A 29 484 - 35 -,~.
, -, -! ' . ' ' ' .~
",".': . .
~' ' ' ' ' ` ' ' ' '~ ~ ' ' " ' ' .

,. 2 ~
Formulations in which the active compound is processed in an ointment base or in an oil-in-water or water-in-oil emulsion base;
I

Solid formulations, such as powders, premixes or concen-trates, granules, pellets, tablets, boli or capsules;
aerosols and inhalants, and shaped articles containing the active compound.

Injection solutions are administered intravenously, intramuscularly and subcutaneously.

Injection solutions are prepared by dissolving the active compound in a suitable solvent and adding any additives, such as solubilising agents, acids, bases, buffer salts, antioxidants and preservatives. The solutions are sub-jected to sterile filtration and bottled.

Solvents which may be mentioned are: physiologically tolerated solvents, such as water, alcohols, such as ethanol, butanol, benzyl alcohol or glycerol, hydro-carbons, propylene glycol, polyethylene glycols, N-methylpyrrolidone and mixtures thereof.

If appropriate, the active compounds can also be dissolved in physiologically tolerated vegetable or synthetic oils which are suitable for iniection.

Solubilising agents which may be mentioned are: solvents which promote solution of the active compound in the main Le A 29 484 - 36 --~: -.~` - : ~ .

~: ~
. -- , 2 1 1 ~

solvent or prevent its precipitation. Examples are polyvinylpyrrolidone, polyoxyethylated castor oil and polyoxyethylated sorbitan esters.

~< Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid esters and n-butanol.

Oral solutions are used directly. Concentrates are used orally after prior dilution to the use concentration.
Oral solutions and concentrates are prepared as described above for the injection solutions, but sterile working can be dispensed with.
r Solutions for use on the skin are dripped on, brushed on, massaged in, sprayed on, atomised on or applied by dipping, bathing or washing. These solutions are prepared as described above for the injection solutions.

It may be advantageous to add thickening agents during the preparation. Thickening agents are: inorganic thicke-ning agents, such as bentonites, colloidal silicic acid and aluminium monostearate, and organic thickening agents, such as cellulose derivatives, polyvinyl alcohols and copolymers thereof, acrylates and metacrylates.

Gels are applied or brushed onto the or introduced into body cavities. Gels are prepared by adding to solutions, which have been prepared as described for the injection solutions, thickening agents in an amount such that a clear mass having an ointment-like consistency is formed.

Le A 29 484 - 37 -.: . .
. . .. .. . .

~ 2 1 ~

Thickening agents which are employed are the thickening agents mentioned above.
Pour-on formulations are poured or sprayed onto limited areas of the skin, the active compound either penetrating j 5 through the skin and having a systemic action or I spreading over the body surface.
-Pour-on formulations are prepared by dissolving, suspen-ding or emulsifying the active compound in suitable solvents or solvent mixtures which are tolerated by the skin. If appropriate, further auxiliaries, such as dyestuffs, absorption-promoting substances, antioxidants, light stabilisers and adhesion promoters, are added.

Solvents which may be mentioned are: water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols, such as benzyl alcohol, phenylethanol and phenoxyethanol, esters, such as ethyl acetate, butyl acetate and benzyl benzoate, ethers, such as alkylene glycol alkyl ethers, such as dipropylene glycol monomethyl ether and diethylene glycol monobutyl ether, ketones, such as acetone and methyl ethyl ketone, aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oils, dLmethylformamide, dimethylacetamide~ N-methylpyrrolidone or 2-dimethyl-4-oxymethylene-1,3-dioxolane.

Dyestuffs are all the dyestuffs approved for use on animals and can be dissolved or suspended.

Le A 29 484 - 38 -~' , ~ ::

s~, :

Absorption-promoting substances are, for example, DMSO, ` spreading oils, such as isopropylmyristate, dipropylene glycol pelargonate and silicone oils, fatty acid esters, triglycerides and fatty alcohols.
Antioxidants are sulphites or metabisulphites, such as potassium metabisulphite, ascorbic acid, butylhydroxy-toluene, butylhydroxyanisole and tocopherol.
..
. Light stabilisers are, for example, substances from the ~ class of benzophenones or novantisol acid.
;' Adhesion promoters are, for example, cellulose deriva-tives, starch derivatives, polyacrylates and naturally occurring polymers, such as alginates and 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 are prepared by dissolving the active compound either in the hydrophobic or in the hydrophilic phase and homogenising this phase with the solvent of the other phase with the aid of suitable emulsifiers and if appro-priate other auxiliaries, such as dyestuffs, absorption-promoting substances, preservatives, antioxidants, light ! stabilisers and viscosity-increasing substances.

As the hydrophobic phase (oils) there may be mentioned:
paraffin oils, silicone oils, naturally occurring ' ' Le A 29 484 - 39 --:~,,. ., ~ , ~ ~ -` 211111~

vegetable oils, such as sesame oil, almond oil and castor ~;~ oil, synthetic triglycerides, such as caprylic/capric acid biglyceride, a triglyceride mixture with vegetable fatty acids of chain length C812 or other specifically S selected naturally occurring fatty acids, partial glyceride mixtures of saturated or unsaturated fatty acids, which may also contain hydroxyl groups, and mono-and diglycerides of C8/C1O-fatty acids.
3 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 saturated fatty alcohols of chain length C16-C18, isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated fatty alcohols of chain length C12-C18, isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate, waxy fatty acid esters, such as dibutyl phthalate, diisopropyl adipate and ester mixtures related to the latter, and also fatty alcohols, such as isotridecyl alcohol, 2-octyldodecanol, cetyl-stearyl alcohol and oleyl alcohol.

Fatty acids, such as, for example oleic acid and its mixtures.

As the hydrophilic phase there may be mentioned:
water, alcohols, such as, for example, propylene glycol, glycerol, sorbitol and their mixtures.

Emulsifiers which may be mentioned are:
non-ionic surfactants, for example polyoxyethylated /

Le A 29 484 - 40 -~. ~

2 ~

castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate and alkylphenol polyglycol ether;

ampholytic surfactants, such as di-Na N-lauryl--imino-dipropionate or lecithin;

anionic surfactants, such as Na lauryl sulphate, fatty alcohol ether sulphates, mono/dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt;
cationic surfactants, such as cetyltrimethylammonium chloride.

Other auxiliaries which may be mentioned are:
substances which increase the viscosity and stabilise the emulsion, such as carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, poly-acrylates, alginates, gelatin, gum arabic, polyvinyl-pyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes, colloidal silicic acid or mixtures of the sub-stances listed.

Suspensions can be used orally, dermally or as an in~ec-tion. They are prepared by suspending the active compound in a carrier liquid, if appropriate with the addition of other auxiliaries, such as wetting agents, dyestuffs, absorption-promoting substances, preservatives, anti-oxidants and light stabilisers.

Le A 29 484 - 41 -~ ......... . . . .
;~. . :

.

~, .
,..

Carrier liquids which may be mentioned are all the homogeneous solvents and solvent mixtures.

Wetting agents (dispersing agents) which may be mentioned are the surfactants mentioned above.
:' Other auxiliaries which may be mentioned are those mentioned above.

Semi-solid formulations can be administered orally or dermally. They differ from the suspensions and emulsions described above only by their higher viscosity.

To prepare solid formulations, the active compound is mixed with suitable excipients, if appropriate with addition of auxiliaries, and the mixture is brought into the desired form.
,:~
Excipients which may be mentioned are all the physiologi-cally tolerated solid inert substances. All such serve inorganic and organic substances. Inorganic substances are, for example, sodium chloride, carbonates, such as , calcium carbonate, hydrogencarbonates, aluminium oxides, silicic acids, aluminas, precipitated or colloidal silicon dioxide and phosphates.

~, Organic substances are, for example, sugars, cellulose, foodstuffs and feedstuffs, such as milk powder, animal flours, cereal flours and crushed cereal and starcheK.

' ~

~ ' Le A 29 484 - 42 -r - .
.

~ ~ ~ 114~

Auxiliaries are preservatives, antioxidants and dyestuffs which have already been listed above.
.~
Other suitable auxiliaries are lubricants and slip agents, such as, for example, magnesium stearate, stearic acid, talc and bentonites, substances which promote disintegration, such as starch or crosslinked polyvinyl-pyrrolidone, binders, such as, for example, starch, gelatin or linear polyvinylpyrrolidone, and dry binders, such as microcrystalline cellulose.

The active compounds can also be present in the formula-tions as a mixture with synergists or with other active compounds.

Ready-to-use formulations comprise the active compound in concentrations of 10 ppm to 20 per cent by weight, preferably 0.1 to 10 per cent by weight.

Formulations which are diluted before use comprise the active compound in concentrations of 0.5 to 90 per cent by weight, preferably 1 to 50 per cent by weight.

In general, it has proved advantageous to administer amounts of about 0.5 to about 50 mg, preferably 1 to 20 mg, of active compound per kg of body weight per day in order to achieve effective results.

The active compounds can also be administered to the animals together with the feed or drinking water.

Le A 29 484 - 43 -y~
~. ~ ' .- .
,.. :: .
~::

. . .

,.. .

9 Feedstuffs and foodstuffs comprise 0.01 to 250 ppm, preferably 0.5 to 100 ppm of the active compound in combination with a suitable edible material.
.~
Such a foodstuff and feedstuff can be sent either for healing purposes or for prophylactic purposes.

Such a feedstuff or foodstuff is prepared by mixing a concentrate or a premix comprising 0.5 to 30~, preferably 1 to 20% by weight of an active compound mixed with an edible organic or inorganic carrier, with customary feedstuffs. Edible carriers are, for example, maize flour or maize flour and soya bean flour or mineral salts, which preferably contain a small amount of an edible dust-preventing oil, for example maize oil or soya oil.
The premix obtained by this procedure can then be added to the complete feedstuff before this is fed to the animals.

Use for coccidiosis may be mentioned by way of example:

For curing 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 desired, these amounts can be increased, especially if the active compound is tolerated well by the recipient. Administra-tion can be effected accordingly via the drinking water.

Le A 29 484 - 44 -. . .

~. ~
., . . " ,., ~ "r For the treatment of individual animals, for example in the case of the treatment of coccidiosis in mammals or of toxoplasmosis, amounts of active compound of 0.5 to 100 mg/kg of body weight are preferably administered daily in order to achieve the desired results. Neverthe-less, it may sometimes be necessary to deviate from the amounts mentioned, in particular as a function of the body weight of the test animal or of the nature of the administration method, but also because of the animal genus and its individual reaction to the active compound or the nature of the formulation and the time or interval at which the latter is administered. Thus, in certain cases it may suffice to manage with less than the abovementioned minLmum amount, while in other cases the upper limit mentioned must be exceeded. If relatively large amounts are administered, it may be expedient to divide these into several individual doses in the course of the day.

The compounds according to the invention moreover are effective against various fish parasites which belong to the helminths (worms).

Parasites on fiah include, from the subkingdom of the protozoa, species from the phylum of the Ciliata, for example Ichthyophthirius multifiliis, Chilodonella cyprini, ~richodina spp., Glossatella spp., Epistylis spp. of the phylum of the Myxosporidia, for example Myxosoma cerebralis, Myxidium spp., Myxobolus spp., Heneguya spp., Hoferellus spp., of the class of Le A 29 484 - 45 -i: .' S.' ~' ~'.'~ .
~' ' . ~.

Microsporidia, for example Glugea spp., Thelohania spp., Pleistophora spp., from the phylum of the Plathelminths:
Trematodes; Monogenea, for example Dactylogyrus spp., Gyrodactylus spp., Pseudodactylogyrus spp., Diplozoon spp., Cestodes, for example from the groups of the Caryphyllidea (for example Caryophyllaeus laticeps), Pseudophyllidea (for example Diphyllobothrium spp.), Tetraphyllidea (for example Phyllobothrium spp.) and Protocephalida (for example species of the genus Proteocephalus) and, from the phylum of the Arthropoda, various parasitic Crustacea, in particular from the subclasses of the Branchiura (fish lice) and Copepoda (copepods) and the orders of the Isopoda (isopods) and Amphipoda (amphipods).

Treatment of the fish is carried out either orally, for example via the feed, or by short-term treatment, a "medicinal bath", into which the fish are put and in which they are kept for a certain period (minutes up to several hours), for example when they are transferred from one breeding tank to another.

However, temporary or permanent treatment of the environ-ment of the fish (for example entire pond systems, aquaria, tanks or troughs) in which the fish are kept can also be carried out.

The active compound is administered in formulations which are appropriate for the applications.

Le A 29 484 - 46 -.,.
,i - , '''' The concentration of the active compound in the formula-tions is 1 ppm to 10% by weight.

Preferred formulations for short-term treatment in application as a ~medicinal bath~, for example for treatment when transferring the fish or for treatment of the environment (pond treatment) of the fish, are solu-tions of the active compound in one or more polar sol-~, vents which give an alkaline reaction on dilution with water.

To prepare these solutions, the active compound is dissolved in a polar, water-soluble solvent, which either gives an alkaline reaction or to which an alkaline water-soluble substance is added. The latter is advantageously ¦ likewise dissolved in the solvent, but can al~o be 3 15 suspended in the solvent and dissolves only in the water.
¦ After addition of the active compound solution, the water I should have a pH of 7 to 10, but preferably a pH of 8 to I 10. ~' I .. ' The concentration of ~he active compound can be in the range from 0.5 to 50%, but preferably in a range from 1 to 25%.

Possible solvents are all the water-soluble solvents in which the active compound is soluble in a sufficient concentration and which are physiologically acceptable.

These are ethyl alcohol, isopropyl alcohol, benzyl Le A 29 484 - 47 -. ,- . .
,;,........................ .

~. : . , ~
~, :, alcohol, glycerol, propylene glycol, polyethylene glycols, poly(oxoethylene)-poly(oxypropylene) polymers, basic alcohols, such as mono-, di- and triethanolamine, ketones, such as acetone or methyl ethyl ketone, esters, such as ethyl lactate, and furthermore N-methyl-pyrrolidon~, dimethylacetamide and dimethylformamide, and furthermore dispersing and emulsifying agents, such as polyoxyethylated castor oil, polyethylene glycol sorbitan monooleate, polyethylene glycol stearate or polyethylene glycol ether and polyethylene glycol alkylamines.

Bases which may be mentioned for establishing the alkaline pH are organic bases, such as basic amino acids, such as L- or D, L-arginine, L- or D, L-lysine, methyl-glucosamine and 2-amino-2-hydroxymethylpropane-1,3-diol, and furthermore such as N,N,N',N'-tetraki~-(2-hydroxy-propyl)-ethylenediamine, or polyether-tetrol based on ethylenediamine (molecular weight 480-420), and inorganic bases, such as ammonia or sodium carbonate - if appro-priate with addition of water.
.
The formulations can also comprise 0.1 to 20~ by weight, preferably 0.1 to 10% by weight, of other formulation auxiliaries, such as antioxidants, surfactants, suspen-sion stabilisers and thickening agents, such as, for example, methylcellulose, alginates, polysaccharides, galactomannans and colloidal silicic acid. The addition of colour, flavour and builder substances for anLmal nutrition is also possible. Acids which form a buffer system together with the base initially introduced or Le A 29 484 - 48 -,:
':, r .

': -which reduce the pH of the solution may also be mentioned here.

The concentration of the active compound during use I depends on the nature and duration of the treatment and i 5 the age and condition of the fish treated. It is, for ¦ example, 2 to 50 mg of active compound per litre of water, preferably 5 to 10 mg per litre, over a treatment ¦ duration of 3 to 4 hours for short-term treatment. For treatment of young carp a concentration of, for example, 5 to 10 mg/l and a treatment tLme of about 1 to 4 hours are used.

Eels are treated with concentrations of about 5 mg/l for ~
about 4 hours. -For a longer treatment duration or for long-term treat-ment, the concentration chosen can be correspondingly lower.

For pond treatments, 0.1 to 5 mg of active compound per litre of water can be used.

Formulations for use as a feed additive have, for example, the following composition:

a) Active compound of the formula I 1 - 10 part~ by weLght Soya bean protein 49 - 90 parts by weight b) Active compound of the formula I 0.5 - 10 parts by weight Benzyl alcohol 0.08 - 1.4 parts by weight Hydroxypropylmethylcellulose 0 - 3.5 parts by weight Le A_29 484 - 49 -x~
~ .
~'; .: ' ": .

:' ~\
Water remainder to 100 .
u Formulations for use in ~medicinal baths~ and for pond :~. treatment have, for example, the following composition ~ and are prepared as follows.
.~
`., 5 c) 2.5 g of active compound of the formula (I) are di~solved in 100 ml of triethanolamine, while heating.
d) 2.5 g of active compound of the formula (I) and 12.5 g of lactic acid are dissolved in 100 ml of triethanolamine, while heating and stirring.
e) 10.0 g of active compound of the formula (I) i8 dissolved in 100 ml of monoethanolamine.
~J; f) Active compound of the formula I 5.0 g I Propylene glycol 50.0 g Sodium carbonate 5.0 g Water to 100 ml g) Active compound of the formula I 5.0 g Monoethanolamine 10 g N-Methylpyrrolidone to 100 ml h) Active compound of the formula I 2.5 g Sodium carbonate 5.0 g Polyothylene glycol 200 to 100 ml The active compound i8 dissolved in the polyethylene glycol, while heating, and sodium carbonate is suspended therein.

Le A 29 484 - 50 -., .
.
, . : .

~:
., .

2 ~

l~xample A

j Coccidiosis in chickens Chicks 9 to 11 days old were infected with 40,000 sporu-lated oocysts of highly virulent strains of Eimeria acervuline, E. maxima and E. tenella, the pathogens of intestinal coccidiosis.

3 days before the infection and 8 days after the infec-tion (end of the experiment), the active compound was administered in the stated concentration as a mixture in the feed of the animals.

The number of oocysts in the faeces was determined with the aid of the McMaster chamber [see Engelbrecht and colleagues ~Parasitologische Arbeitsmethoden in Medizin und Veterinarmedizin~ (Parasitological working methods in medicine and veterinary medicine), page 172, Akademie-Verlag, Berlin (1965)].

The active compound doses and excretion of oocysts in %
are stated for the individual pathogens in the following Table. In this Table, 100~ denotes no action and 0%
denotes a complete action, that is to say no excretion of oocysts.

Le A 29 484 - 51 -' . : ,, , ~ : .

: ~ :
r ~ , . ~, . ' , ,, :

- ~ . ' ' . .

~ !
Table 1 Coccidiosis in chickens E.acervulina E. maxima E. tenella Excretion of Excretion Exa M ple Dose oocysts in % of oocytes No. ppm in comparison in % in with the comparison untreated with the infected con- non-trol infected untreated control Untreated infected control 0 100 100 100 _ 37 250 0.5 0 0 _ _ 100 28 26 32 215000 llo.l 8 5 5-25~ 100 0.015.3 9 Le A 29 484 - 52 -". ~ : , .. .
,.. .. . .
,, , :

,'' ' ~ ' , , ~ 2111146 Preparation Examples:
., Example 1:
Br l ~

F3C ~ ~ ~

~r,"

A mixture of 9.0 g (0.03 mol) of 4-bromo-2-cyano-6-tri-fluoromethyl-lH-benzimidazole ~compare, for example, EP 239 508), 8.3 g (0.06 mol) of potassium carbonate, 4.2 g (0.03 mol) of methyl N-chloromethyl-N-methyl-carbamate and 105 ml of ethyl acetate i5 heated at the reflux temperature for 4 hours. For working up, the -cooled reaction mixture is filtered and the filtrate is washed with water, dried over sodium sulphate and concen-trated in vacuo. The residue can be purified by recrystallisation from ether/petroleum ether (1:10) and subsequent column chromatography over silica gel (mobile phase: methylene chloride).

6.0 g (51% of theory) of methyl N-(4-bromo-2-cyano-6-trifluoromethyl-lH-benzimidazol-l-yl-methyl)-N-methyl-carbdmate of melting point 13a-14lC are obtained.

Le A 29 484 - 53 -.i,i. . : .: ~

~,.. .

-- 2 1 1 ~

The following substituted benzimidazoles of the general formula (I) are obtained in a corresponding manner and in accordance with the general information regarding the preparation:
X .-X~ A

Pxample Xl X2 ~3 X~ APhy~ical 2 H No2 H H C~M.p 120-(H)(NO2) 1 121 DC
-o~N`ooo~ (69:31) 3 H NO2 H H~ M.p. 99-(H)(NO2) 1 102C
~ ~oooo~ (65:35) 4 H N2 H Hc~ M.p. 92-(H) (NO2), 96C
-_o~N`ooo~ (59:41) H NO2 H H ~ M.p. 65-(H) (NO2) ~ 70C
-~34 `ooo~(59:41) 6 H No2 H H ~ H-NMR*):
(H)(NO2) 1 6.0; 6.05 --o~ ~ooo~ (72:28) 7 H No2 H H C4~M.p. 78- :
(H) (N0z) ~N~ 82 C
8 Br H CP3 H C~M.p. 107-,N 110 C
--CH2 `am~

Le A 29 484 - 54 -.. .. . .
.

: - . . ~ : , .

,, .

: : . -3. ~

..
Example Xl X2 X3 X4 A Physical No. properties 9 Br H CF3 Hn~H7 lH-NMR ):
1 6.03 ~'N~ax~3 10 H CF3 H Br ~ M.p. 163-~ ~COOC2~
11Br H CF3 H ~ M.p. 110-~ 113 C
C4 ~
12Br H CF3 H ~ 8i C
~ `ax~
13Br H CF3 H ~ lH-NMR):
~ 6.02 14 H NO2 H H C~ M.p. 127-(H)(N02) ~ 131C
- o~ ~ovoo~ (65:31) 15Br H CF3 H-CH2-COOCH3 M.p. 160-10 16Br H CF3 H-CH2-COOC2HsM.p. 113-17Br H CF3 H CH~ M.p. 105-CH
`COOC~
18Br H CF3 H-CH2-NH-COOCH3M.p. 205-` 208C
lgBr H CF3 H-CH2-CN, M.p. 157-20 H NO2 H H ~ M.p. 87-(H)(N02) / 91C
- CH ~57:43) 15 21 H NO2 H H-CH2-COOC2HsM.p. 9 6 -(H) (NO2) 100C
(1 1) Le A 29 484 - 55 -i ~f ~
.

~-\ 2 ~ 6 Example Xl X2 X3 X4 A Phy~icalNo. properties 22 H NO2 H H -CH2-COOCH3 M.p. 141-(H) (NO2) 143C
(1:1) 23 Br H CF3 H N M.p. 154-( H )( CF3) ( H )( Br ) ~ N~6537:37C) 24 Br H CF3 H o M.p. 212-~3 217 C

Br H CF3 H -CH2-CH=CH2N.p. 9 5 -(H) (CF3) (H) (Br) 99C
(78:22) 26 H CF3 H Br -CH2-CN M.p; 170-27 Br H CF3 H ~ M.p. 147-(H) (CF3) (H) (Br) ~a~ 150C
(86:14) 28 Br H CF3 H -CH2-C6Hs M.p. 140-(H) (CF3) (H) (Br) 143C
(95:5) 29 Br H CF3 H -CH2-COOH M.p.
~195 C ( d) Br H CF3 H ~ M.p. 83-~ `ax~
31 Br H CF3 M. p 90-32 Br H CF3 H ~ M.p. 97-,~ 101C
33 Br H CF3 H ~ M.p. 120-(H) (CF3) (H)(Br) ~ N I (û4 ;6) 34 Br H CF3 H ~ M.p. 101-,N 105 C

Le A 29 484 - 56 -;, . . . . . .

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. .
,.
,. . .
,;
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21 ~ o .!

E~ample ~1 X2 X3 X4 A Physical i No. properties ~ , Br H CF3 H N M.p. 160-(H)(CF3) (H) (Br) ~ N ~ 163C
~N (75:25) 36 Br H CF3 H ~ 1H-NMR ):
,N 6.11 3~ Br H CF3 H u~ 5.94 --~'N~COOC~I3 38 Br H CF3 H (CE~EII lH-NMR ):
1 6.06 ~'N~
39 Br H CF3 H ~, 90 C
~ axx:~
Br H CF3 H C~ M.p. 137-~'N~
41 Br H CF3 H -O-n-C3H7 M.p. 105-(H)(CF3) (H) (Br) 109C
(86:14) 42 Br H CF3 H -O-i-C3H7 1H-NMR~):
(H)(CF3) tH) (Br) 5.98; 6.06 (53:47) 43Br (H) H CF3 H-O--CH2-C~CH M.p. 73-(CF3) (H) (Br) 76 C
(53:47) 44 Br H CF3 H ~=\ M.p. 75-(H)(CF3) (H) (Br)~ ~ ~ a 78C
(36:64) Br H CF3 H -CH2-O-CO-t- lH-NNR ):
(H) (CF3) (H) (Br) C4H9 1 6.49 (66:34) 46 Br H CF3 H-CH2-O- ( CH2) 3- 1H-NMR~ ):
(H) (CF3) (H) (Br) C6H5 5.96;
6.05 47 Br H CF3 H o O M.p. 175-~C-NH~C~ 180C :-LeA 29 484 - 57 -~, :

, .

,:- : ~-:
1 4~3 Example 2~1 X2 X3 X~ A Physical No. properties 48 Br H CF3 H ~ H-NMR~):
(CF3) (H) (Br) 1 6.03 (H) ~ (76: 24 49 Br H CF3 H c~" 93"C0 ~`ax~
Br H CF3 H t~,,H9M. p . 105-~ 108 C
--C8, ~,, 51 Br H CF3 H ~ M . p . 86 -(H)(CF3) (H) (Br) 1 90C
~ ~, (81: 19) 52 Br H CF3 H ~C~ H-NMR~):
(H)(CF3~ (H) (Br) 1 5.95; 6.35 ~~ H, (sn 20) 53 Br H CF3 H n~H~I lH-NMR~):
,N 6.05 54 Br H CF3 H ~{" lH-NMR~):
(H)(CF3) (H) (Br) 1 5.95 CH~'N~cco~,H, (76: 24) Br H CF3 H n~H~ lH--NMR~):
(H)(CF3) (H) (Br) 1 5.95; 6.35 ~ ~OOC2H,(72: 28) 56 Br H CF3 H u~, M.p. 115-,~ 120 C
57 Br H CF3 H ~, M. p. 112-~ co~ , 58 Br H CF3H ~c ~ ~ a M.p 135-59 H H CF3 H -O-C2Hs M.p. 173-H HF2CH-CF2- H -O-C2H5 M.p. 35-o_ 40C

Le A 29 484 - 58 -'Y~

: - ... .
.. .. .

t Example ~1 X2 X3 X~ A Physic~l No. properties _ , . , ,_ . .... _ 61 H CF3-O- CF3-O- H -O-C2H51H-NMR*):

5.91 62 H C6H5 H H -O-C2H51H-NMR):
(H)~CsHs) 5.87; 5.92 63 H-O~(CH2)2-O- H -O-C2HsM.p. 150-64 H-O-(CH2)2-O- H o~ M.p. 162-65H -O-CF2-CFCl- H c~ M.p. 127-(-O-CFCl-CFz-O_) 66H -O-CF2-CFCl- H -O-C2Hs M.p. 96-o_ 100 C
(-O-CFCl- (1:1) CF2-O-) 67H -O-CF2-CFCl- H ~ 1H-NMR~):
O- ~ 5.91 (-O-CFCl- -c~ 'ox~4 CF2-O- ) 68 H-O-CF2-CFCl- H ~ M.p. 130-o_ ~ 133C
(-O-CFCl_ _~4 ~ox CF2-O- ) 69H -O-CF2-CFCl- H ~ M.p. 62-o_ ~ 66C
(-0-CFCl- _~4 o~
CF2-O- ) 70H -O-CFz-CF2-O- H -O-C2HsM.p. 90-71 H-O-CF2-CF2-O- H ~ M.p. 140-~4 ~ ~
72 H-O-CFz-CF2-O- H -CH2-O-(C~2)2- M.p. 60- ::
OC~3 54C : -73 H -0-CF2-CF2-O- H ~ M.p. 53-~ 57C
a~ a~
74 H -O-CF2-cF2-O- H ~ M.p. 123- -~ 125C

Le A 29 484 - 59 -, . . -.. , , , . . ~ ~ : .
~,.,........ . '' ~ :
~:
., :
,........... .

Example Xl XZ X3 ~4 A Physical No. properties 7 5 H-O~CF2-CF2-O- H ~H~ M . p . 7 0-~ ~H, 7 6 H-O-CF2-CHF-O- H -O--C2Hs M . p . 7 5--S 7 7 H--O-CF2-O- H -O-C2Hs M . p . 110-78 H-O-CF2-O-- H ~ M.p. 147--~ ~ .
*) ThelH-NMR spectra were recorded in :
deuterochloroform (CDC13) or hexadeutero-dimethyl sulphoxide (DMSO-d6) using tetramethylsilane (TMS) as the internal standard. The chemical shift of the N-CH2-N- group is stated as the value in ppm.

Le A 29 484 - 60 -.. ;;
;,s.,. .

...

:.. '. : :
~?::
~, .
,. .

- -. 21~I116 Preparation of the starting compounds:

Example II-l:

P3C ~ N

A solution of 120 g (0.3 mol) of 4-bromo-2-trichloro-methyl-6-trifluoromethyl-lH-benzimidazole (compare, for example, EP 239 508) in 300 ml of ethanol is added dropwise to 900 ml of saturated aqueous ammonia solution at 15C to 25C, while stirring, and, when the addition has ended, the mixture is stirred at room temperature for one hour. For working up, the reaction mixture is brought to pH 1 with 4000 ml of 20 per cent strength hydrochloric acid and extracted three times with 300 ml of methylene chloride each time. The combined organic phases are dried with sodium sulphate and concentrated in vacuo and the oil which remains is purified by chromatography over silica gel (mobile phase: cyclohexane/ethyl acetate 2:1) and crystallisation from petroleum ether.

49.1 g (55% of theory) of 4-bromo-2-cyano-6-trifluoro-methyl-lH-benzimidazole of melting point 130-134C are obtained.

Le A 29 484 - 61 - ~ -4 ~

The following substituted lH-benzimidazoles of the general formula (II) are obtained in a corresponding manner:
s ~U\~ ~

Example Xlx2 X3 X~Physical No. propertie~
II-2 HNO2 H H M.p.
>240 C
II-3 H-O-CF2-CFCl-O- H M.p.
( -O-CFCl -CF2-O- ) > 230 C
I I--4 H-O--CF2-CF2--O- H M . p .
>230 C
II-5 H H CF3 H M.p. 173-(CF3) (H) 176 C
II-6 H X C2Hs--O-- H M.p. 86-(C2H5_O- (H) 90 C
II--7 H H F2CH-CF2-O- HM.p. 130-( F2CH-CF2-O--( H ) 132 C
II-8 HCF3 0-- CF3 0~-- H M.p. 194-~ ~ 198C
II--9 H H C6Hs H M.p.
(CsHs) (H) >230C
II--10 H-O-(CH2)3-O- H M.p.
>230 C
15 II-ll H-O-CF2-CHF-O- H M.p. 50-( -O-CHF-CF2-O- ) 60 C
I I - 12 H-O-CF2-O- H M . p .
>220 C

Le A 29 484 - 62 -~,." ~
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Claims

1. Use of CN-substituted benzimidazoles of the general formula (I) (I) in which X1, X2, X3 and X4 independently of one another in each case represent hydrogen, halogen, cyano or nitro, or represent in each case optionally substituted alkyl, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl or cycloalkyl, or represent optionally substituted, fused-on dioxyalkylene, or represent hydroxycarbonyl, alkylcarbonyl, alkoxycarbonyl or cycloalkyl-oxycarbonyl, or represent in each case optionally substituted amino or aminocarbonyl, or represent in each case optionally substituted aryl, aryloxy, arylthio, arylsulphinyl, arylsulphonyl, arylsulphonyloxy, arylcarbonyl, aryloxycarbonyl, arylazo or arylthiomethylsulphonyl, but wherein at least one of the substituents X1, X2, X3 and X4 is other than hydrogen and halogen, and wherein R1 represents hydrogen or alkyl, or represents optionally substituted aryl and R2 represents hydroxyl or cyano, or represents in each case optionally substituted alkyl, alkenyl, alkinyl, alkoxy, alkenyloxy, alkinyloxy, alkylthio, amino, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, dialkoxyphosphoryl, (hetero)-aryl, (hetero)arylcarbonyl, (hetero)aryloxy-carbonyl, (hetero)arylcarbonyloxy or (hetero)arylaminocarbonylaminocarbonyloxy, as agents for combating parasitic protozoa, and in particular coccidia.

2. Agents against parasitic protozoa, characterised in that they contain at least one substituted benzimi-dazole of the formula (I) according to Claim 1.

3. Method of combating parasitic protozoa, characterised in that substituted benzimidazoles of the formula (I) accordins to Claim 1 are allowed to act on these and/or their environment.

4. Process for the preparation of agents against parasitic protozoa, characterised in that sub-stituted benzimidazoles of the formula (I) according to Claim 1 are mixed with extenders and/or surface-active agents.

5. Use of substituted benzimidazoles of the formula (I) according to Claim 1 for the preparation of agents against parasitic protozoa.