CA2072217A1

CA2072217A1 - 2-(4-substituted phenylhydrazino)-2-thiazolines and 2-(4-substituted phenylazo)-2-thiazolines, their preparation, and their use for combating ectoparasites

Info

Publication number: CA2072217A1
Application number: CA002072217A
Authority: CA
Inventors: Bernd Baasner; Albrecht Marhold; Otto Behner; Wilhelm Stendel
Original assignee: Individual
Current assignee: Bayer AG
Priority date: 1991-06-27
Filing date: 1992-06-24
Publication date: 1992-12-28
Also published as: AU1803292A; JPH05186443A; EP0520274A2; DE4121208A1; ZA924745B; TW198716B; EP0520274A3

Abstract

2-(4-substituted phenylhydrazino)-2-thiazolines and 2-(4-substituted phenylazo)-2-thiazolines, their preparation, and their use for combating ectoparasites A b s t r a c t The invention relates to the use of 2-(4-substituted phenylhydrazino)-2-thiazolines and 2-(4-substituted phenylazo)-2-thiazolines of the general formula (I) (I) in which Y represents -NH-NH- or -N=N- and Z represents a direct bond, O, S, SO or SO2, and R1 represents halogen-substituted alkyl, or represents optionally substituted phenyl, and R2 and R3 represent identical or different radicals from the series comprising hydrogen, halogen, halogen-substituted alkyl, CN or NO2, for combating ectoparasites, and new thiazolines and the preparation thereof.

Le A28 434

Description

207~21 7 The invention relates to 2-(4-substituted phenylhydra-zino)-2-thiazolines and 2-(4-substituted phenylazo)-2-thiazolines, some of which are new, to processes for their preparation, and to their use for combating ecto-parasites.

It has already been disclosed that 2-phenylhydrazino-2-thiazolines and 2-phenylhydra~o-2-thiazolines, each of which is substituted in the benzene ring, have ectopara-sitic action (DE-OS (German Published Specification) 3,133,918; US Patent 4,046,753).

The present invention relates to 1. The use of thiazolines of the general formula (I) Rl-Z ~ r--~S ~ (I) in which Y represents -NH-N~- or -N=N- and Z repr~sents a direct bond, O, S, SO or SO2, and Rl represents halogen-substituted alkyl, alkyl-sulphonyl, or represents optionally substituted Le A 28 434 - 1 -phenyl, and 2 ~' 7 ~ ~ ~ 7 R2 and R3 represent identical or different radicals from the series comprising hydrogen, halogen, halogen-substituted alkyl, CN or NO2, for combating ectoparasites.

2. Thiazolines of the general formula (I) R1 z ~ y~

in which Y represents -NH-NH- or -N=N- and 10Z represents a direct bond, O, S, SO or SO2, and Rl represents halogen-substituted alkyl, alkyl-sulphonyl, or reprssents optionally substituted pher.yl, and R2 and R3 represent identical or different radicals 15from the series comprising hydrogen, halogen, halogen-substituted alkyl, CN or NO2.

3. Processes for the preparation of the thiazolines of the formula I in which Y represents the group Le A 28 434 - 2 -. _ . . . . . _ . . _ -NH-NH-, characterised in that 2 ~ 7 2 2 i 7 a) phenylhydrazines of the formula (II) R 1 _ z~NH -NH2 ( I I ) in which R~, R2, R3 and Z have the meaning given under 2.

are reacted with thiazolines of the formula (III) ~N
S~S - Ra in which Ra denotes an optionally substituted alkyl radical, in the presence of strong acids or b) thiosemicarbazides of the formula (IV) Le A 28 434 - 3 -2~7221 7 . ~ H~ Nh-C~2-CH2-X (IV)~

in which R1, R2, R3 and Z have the abovementioned meaning, X denotes a hydroxyl group, an alkyl-sulphonyloxy or arylsulphonyloxy group,or a halogen atom, are cyclised, if appropriate in the presence of a strong acid, or c) isothiosemicarbazides of the formula (V) RZ

Rl_z ~ NH~NH~6~5CH2CHZNHZ (V) in which R1l R2, R3 and Z have the abovementioned meaning, are cyclised, if appropriate in the presence of a strong acid, or Le A 28 434 - 4 -2~72217 d~ in the event that Y represents the azo group -N=N-, compounds of the formula (I) in which Y represents a hydrazino group and Rl, R2, R3 and Z have the abovementiohed meaning, are dehydrogenated with the aid of oxidants.

In formula (I), Y preferably represents a direct bond, O, S, SO or SO2, R1 preferably represents 1-9 halogeno-Cl~-alkyl, C14-alkylsulphonyl, or represents optionally sub-stituted phenyl, R2 and R3 preferably r~present hydrogen, chlorine, fluo-rine, bromine, 1-5-halogeno-C14-alkyl, CN or NO2.

In formula (I), Y particularly preferably represents a direct bond~ 0, S, SO or SO2, Rl particularly preferably represents 1-7-halogeno-Cl3-alkyl, methylsulphonyl, or represents optionally substituted phenyl, R2 and R3 particularly preferably represent hydrogen, Le A 28 434 - 5 -20722~l 7 chlorine, fluorine, bromine, 1-5-halogeno-C1z-alkyl, CN or NO2.

Y represents a direct bond, O, S, SO, SO2, R~ represents CF3, CF2Cl, C~Cl2, CF2E~r, CCl3, CHF2, CF3CH~, CF3CF2, CHFCi-CF2, CHF2CF2, CH2FCF2, CF3CHF, CF3CHCl, CF3CCi2, CFCl2-CF2, CF2Cl-CF2, CF3CFCl, (CHF)2CH, (CF3~2CH, CH2Cl-CH-CH2F, CH3-CH-CH2F or optionally substituted phenyl, R2 and R3 represent hydrogen, fluorine, chlorine, bromine, CN, ~02 or CF3.

Substituents of the optionally substituted radicals which may be mentioned are:

one or more identical or different radicals from the group comprising Cl-C4-alkyl, in particular methyl or ethyl, C1-C4-alkoxy, in particular methoxy, ethoxy, methylenedioxy or ethylenedioxy, each of which is option-ally substituted by fluorine or chlorine, Cl-C~-halogeno-alkoxy, in particular trifluoromethoxy, fluorochloro-ethoxy, C1-C~-alkylthio, in particular methylthio, Cl-C4-halogenoalkylthio, in particular trifluoromethylthio,fluorochloromethylthio, Cl-C4-alkylsulphonyl, in par-ticular methylsulphonyl, Cl-C4-halogenoalkylsulphonyl, in particular trifluoromethylsulphonyl, Cl-C4-halogenoalkyl, in particular trifluoromethyl, halogen, in particular fluorine or chlorine, NO2 , CN, amino, ClC4-alkyl- or Le A 28 434 - 6 -~7221 7 dialkylamino, C1-C4-halogenoalkylamino, acylamino, in particular acetylamino, or phenyl, phenylthio or phenoxy, each of which is optionally substituted by one of the abovementioned radicals.

The following compounds of the formula (I) may be men-tioned individually:

2-[(4-trifluoromethylphenyl)hydrazino~-2-thiazolines 2-~((2,4-bis-trifluoromethyl)phenyl)hydrazino]-2-thia-zoline 2[(2-trifluoromethyl-4-methanesulphonylphenyl)hydrazino]-2-thiazoline 2-[(2-trifluoromethyl-4-trifluoromethanesulphonylphenyl)-hydrazino]-2-thiazoline 2-[(4-(1,1,2-trifluoro-2-chloroethyl)sulphonylphenyl)-hydrazino]-2-thiazoline 2-[(2-trifluoromethyl-4-phenylsulphonylphenyl)hydrazino]-2-thiazoline 2-[(2,6-dichloro-4-trifluoromethanesulphonylphenyl)-hydrazino]-2-thiazoline 2-[(2-chloro-6-fluoro-4-trifluoromethylphenyl)hydrazino]-2-thiazoline 2-[(2-chloro-4-trifluoromethanesulphonylphenyl)-hydrazino]-2-thiazoline 2-[(4-trifluoromethoxyphenyl)hydrazino]-2-thiazoline 2-[(2-chloro-4-trifluoromethylphenyl)hydrazino]-2-thiazo-line 2-[(4-trifluoromethanesulphonylphenyl)hydrazino]-2-thia-zoline Le A 28 434 - 7 -2~22~ 7 2-[(2-chloro-3-fluoro-4-trifluoromethyl)hydrazino]-2-thiazoline 2-[(2-chloro-4-trifluoromethanesulphonylphenyl)-hydrazine]-2-thiazoline 2-[(2,6-dichloro-4-trifluoromethylphenyl)hydrazino]-2-thiazoline 2-[(4-trifluoromethylthiophenyl)hydrazinoj-2-thiazoline 2-[(4-difluoromethylthiophenyl)hydrazino]-2-thiazoline 2-~(4-difluoromethanesulphonylphenyl)hydrazino]-2-thiazo-line 2-[(4-(2,2,2-trifluoroethoxy)phenyl)hydrazino]-2-thiazo-line 2-[(4-difluoromethoxyphenyl)hydrazino]-2-thiazoline 2-[(4-difluorochloromethoxyphenyl)hydrazino]-2-thiazoline 2-[(4-(1,3-difluoro-2-propoxy)phenyl~hydrazino]-2-thiazo-line 2-[(4-(1-fluoro-2-propoxy)phenyl)hydrazino]-2-thiazoline 2-[(4-(2,2,2-trifluoroethylthio)phenyl)hydrazino]-2-thia-zoline 2-[(4-pentafluoroethoxyphenyl)hydrazino]-2-thiazoline 2-[(4-(2-fluoroethoxy)phenyl)hydrazino]-2-thiazoline 2-~(4-(1,1,2-trifluoro-2-chloroethylthio)phenyl)-hydrazino~-2-thiazoline 2-[(4-(1,1,2-trifluoro-2,2-dichloroethoxy)phenyl)-hydrazino]-2-thiazoline 2-[(4-(1,1,2-trifluoroethoxy)phenyl)hydrazino]-2-thiazo-line 2-[(4-(perfluoro-2-propyl)phenyl)hydrazino]-2-thiazoline 2-[(4-difluorobromomethyl)phenyl)hydrazino]-2-thiazoline 2-[(1-trifluoromethylphenyl)azo3-2-thiazoline Le A 28 434 - 8 -2 ~ 7 ~ 7 2-[((2,4-bistrifluoromethyl)phenyl)azo]-2-thiazoline 2-[(2-trifluoromethyl-4-methanesulphonylphenyl)azo]-2-thiazoline 2-(2-trifluoromethyl-4-trifluoromethanesulphonylphenyl)-azo]-2-thiazoline 2-[(4-(1,1,2-trifluoro-2-chloroethyl3sulphonylphenyl~-azo]-2-thiazoline 2-[(2-trifluoromethyl-4-phenylsulphonylphenyl)azo]-2-thiazoline 1~ 2-[(2,6-dichloro-4-trifluoromethanesulphonylphenyl)azo]-2-thiazoline 2-[(2-chloro-6-fluoro-4-trifluoromethylphenyl)azo]-2-thiazoline 2-[(2-chloro-4-trifluoromethanesulphonylphenyl)azo]-2-thia~oline 2-tl4-trifluoromethoxyphenyl)-azo~-2-thiazoline 2-[(2-chloro-4-trifluoromethylphenyl)azo]-2-thiazoline 2-[(4-trifluoromethanesulphonylphenyl)azo] 2-thiazoline ~ 2-[(2-chloro-3-fluoro-4-trifluoromethyl)azo]-2-thiazoline 2-[(2-chloro-4-trifluoromethanesulphonylphenyl)azo]-2-thiazoline 2-~(2,6-dichloro-4-trifluoromethylphenyl)azo]-2-thiazo-line 2-[(4-trifluoromethylthiophenyl)azo3-2-thiazoline 2-tt4-difluoromethylthiophenyl)azo]-2-thiazoline 2-[(4-difluoromethanesulphonylphenyl)azo]-2-thiazoline 2-[(4-(2,2,2-trifluoroethoxy)phenyl)azo]-2-thiazoline 2-[(4-difluoromethoxyphenyl)azo]-2-thiazoline 2-[(4-difluorochloromethoxyphenyl)azo]-2-thiazoline 2-[(4-(1,3-difluoro-2-propoxy)phenyl)azo]-2-thiazoline Le A 28 434 - 9 -2 ~ 7 2 2 ~ ~
2-[(4-(1-fluoro-2-propoxy)phenyl)azo]-2-thiazoline 2-[(4-(2,2,2-trifluoroethylthio)phenyl)azo]-2-thiazoline-4-methanesulphonyl [(4-pentafluoroethoxyphenyl)azo]-~-thiazoline 2-[(4-(2-fluoroethoxy)phenyl)azo]-2-thiazoline 2-[(4-(1,1,2-trifluoro-2-chloroethylthio)phenyl)azo]-2-thiazoline 2-[(4-(1,1,2-trifluoro-2,2-dichloroethoxy)phenyl)-azo]-2-thiazoline 2-[(4-(1,1,2-trifluoroethoxy)phenyl)azo]-2-thiazoline 2-[(4-(perfluoro-2-propyl)phenyl)azo]-2-thiazoline 2-[(4-difluorobromomethyl)phenyl)azo]-2-thiazoline The compounds of the formula (I) are prepared for example by process 3a), in which 2-trifluoromethyl-4-methane-sulphonylphenylhydrazine is reacted with 2-methyl-mercapto-2-thiazoline, as shown by the equation CH3025~--NH NH2 t ~ .

SMe CH3502 ~ NH-NH--~

The compounds of the general formula (II) and (III~ are reacted in the presence of diluents at temperatures Le A 28 434 - 10 -~ Q 7 ~ 2 ~ ~i between 20 and 200C, preferably between 40 and 160C, most advantageously at the reflux temperature of the diluent employed.

Suitable diluents are all inert organic solvents. These include, in particular, aliphatic and aromatic, optionally halogenated hydrocar~ons, such as pentane, hexane, heptane, cyclohexane, petroleum ether, benzine ligroine, benzene, toluene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, furthermore ethers such as diethyl ether and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, furthermore ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, moreover esters, such as methyl acetate and ethyl acetate, furthermore nitriles such as, for example, acetonitrile and propionitrile, benzonitrile, glutaro-nitrile, in addition amides such as, for example, dimethylformamide, dimethyl acetamide and N-methyl-pyrrolidone, and also dimethyl sulphoxide, tetramethylenesulphone and hexamethylphosphoric triamide and alcohols such as methanol, ethanol, 2-propanol, 3-propanol as well as mixtures thereof, also aqueous mixtures thereof.

The compounds o~ the formulae (II) and (III) are employed in equimolar amounts, a small excess of one or the other component does not provide any essential advantages.

Working-up is carried out in a manner known per se, for Le A 28 434 - 11 -2 ~3 7 ~ 7 example by treating the reaction mixture with water, separating the organic phase, removing the solvent and purifying the product by chromatography or recrystallisa-tion. In individual cases, the crystalline product which has precipitated directly after cooling of the reaction mixture can be filtered off and then, if appropriate, purified.

The compounds of the formula (III) are known (see, for example, Tetrahedron Lett. 1971, 4359).

The compounds of the formula (I) can furthermore be prepared for example by cyclising 4-(2-bromoethyl)-1-(2-trifluoromethyl-4-phenylsulphonyl)-thiosemicarbazide in accordance with process 3b:

~SC2~NH-NH-C-NH-CH2-CH2-E~r ~3SOz~NH-NH--< ~

The compounds of the general formula (IV) are cyclised in lS the presence of diluents at temperatures of between 20 and 180C, preferably between 30 and 160C, and most advantageously at the reflux temperature of the diluent Le A 28 434 - 12 -2a~22~'~

employed.

Suitable diluents are all inert organic solvents. These include, in particular, aliphatic and aromatic, optionally halogenated hydrocarbons such as pentane, hexane, heptane, cyclohexane, petroleum ether, benzine, ligroine, ~enzene, toluene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, furthermore ethers such as diethyl ether and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, furthermore ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, moreover esters such as methyl acetate and ethyl acetate, furthermore nitriles such as, for example, acetonitrile ancl propionitrile, benzonitrile, glutaronitrile, in addition amides such as, for example, dimethylformamide, dimethylacetamide and N-methyl-pyrrolidone, and also dimethyl sulphoxide, tetramethylene sulphone and hexa-methylphosphoric triamide and alcohols such as methanol, ethanol, 2-propanol, 3-propanol, as well as mixtures thereof, also aqueous mixtures thereof.

Working-up is carried out in a manner known per se. As a rule, the compounds precipitate after cooling of the reaction mixture as crystals in the form of their salts, salt~ being formed with those acids which originate during the reaction. When X represents chlorine, bromine or arylsulphonyloxy, these acids are, in particular, hydrochloric acid, hydrobromic acid or arylsulphonic Le A 28 434 - 13 -2~72~ ~ ~

acid. Liberation takes place by dissolving the salts in water, if appropriate under hot conditions, and subse-quently treating this solution with bases.

The following may be mentioned as bases: alkali metal alcoholates, alkaline earth metal alcoholates and tertiary amines. The following bases may be mentioned as being particularly preferred: triethylamine, pyridine, picolines, trimethylamine, N-methylmorpholine, N~ethyl-pyrrolidine, diazabicyclo(4,3,0)-uncecene (DBU), 1,4-diaza-bicyclo-2,2,2-octane (DABCO), diazabicyclo-(3,2,0)nonene (DBN).

The product which has precipitated under cold conditions is subsequently filtered off with suction, dried and purified by chromatography or by recrystallisation, following known methods.

Some of the compounds of the general formula (IV) are new. They are obtained in a manner known per se, by reacting isothiocyanates of the formula (VI) X-CH2-C~2-NCS (VI), in which X has the abovementioned meaning with substituted phenylhydrazines of the general formula (II).

Isothiocyanates of the formula (VI~ are known (see, for Le A 28 434 - 14 -2~72~ ~ 7 example, Chem. Lett. 1989, 965).

Phenylhydrazines of the formula (II) are known or can be prepared by known processes (Houben-Weyl Vol. X/2 (1967), 177 et seq.).

Compounds of the formula (IV) can be prepared, for example, following processes as are described in Chem.
Lett. 1989, 965 or Can. J. Chem. 49 (1971), 971.

The compounds of the formula (I) can furthermore~ be prepared by cyclising an isothiosemicarbazide in accor-dance with the equation CF~
CF~SO2 ~ H-NH- 6 - s CH2 - CH2NH2 NH

CF3S02~NH-NH~ ~

for example following process 3c.

To this end, compounds of the formula (V) are reacted in the presence of diluents between 20 and 200C, pre-ferably between 40 and 160C, most advantageously at the reflux temperature of the solvent employed. The solvents Le A 28 434 - 15 -2~72217 are mentioned further below in connection with the particularly preferred embodiment.

Working-up is carried out in a manner known per se, for example by treating the reaction mixture with water, separating the organic phase, removing the solvent and purifying the crude product obtained by chromatography or recrystallisation. In the event that the product precipi-tates directly after cooling of the reaction batch, it is filtered off and, if appropriate, subsequently purified by chromatography or crystallisation.

In the event that the compounds of the formula (V) are employed in the form of a salt, for example the hydro-bromide or hydrochloride, the end products are initially also obtained as the hydrobromide or hydrochloride. In lS these cases, the end product is liberated following the procedure described under process 3b.

The compounds of the general formula (V) are known or can be prepared by processes known per se (see, for example, Houben-Weyl IX (1955), 912-913). This preparation is carried out, for example, by reacting the thiosemicar-bazides of the general formula (VII) with, for example, 2-bromoethylamine or 2-chloroethylamine.

Le A 2B 434 16 -2~72~
The thio~emicarbazides of the formula (VII) Rl-~NH-NH-C~ tVlI), ~( 3 NH2 R

in which Rl, R2, R3 and Z have the abovementioned meaning are prepared by reacting phenylhydrazines of the formula (II) with thiocyanic acid which has preferably been prepared in situ (see, for example,` Indian J. Chem. 233 (1983), 1243). The phenylhydrazines (II) are prepared by the process cited under process 3b.

In its preferred embodiment, process 3c is carried out as a single-step process. For example, the 2-trifluoro-methyl-4-trifluoromethanesulphonylphenylthiosemicarbazide is reacted with 2-bromoethylamine to give the thiazoline according to the equation:

CF35O2 ~ NH-NH-C~ ~ Br-CHzCHz-NH2 Hsr ( CH3 ) 2CH~H ~CF3 N
CF3S02 <~ )--NH-NH~
Ref lux `--' S
The compounds of the general formula (VII) are reacted out in the presence of an inert organic solvent at temperatures from 20 to 220C, preferably at 40 to 200C, particularly preferably at the specific reflux temperature of the solvent or solvent mixture employed.

Le A 28 434 - 17 -2~72217 Suitable diluents are all inert organic solvents. These include, in particular, aliphatic and aromatic, optionally halogenated hydrocarbons such as pentane, hexane, heptane, cyclohexane, petroleum ether, benzine, ligroine, benzene, toluene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, furthermore ethers such as diethyl ether and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, furthermore ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, moreover esters such as methyl acetate and ethyl acetate, furthermore nitriles such as, for example, acetonitrile and propionitrile, benzonitrile, glutaronitrile, in addition amines such as, for example, dimethylformamide, dimethylacetamide and N-methyl-pyrrolidone, and also dimethyl sulphoxide, tetramethylene sulphone and hexa-methylphosphoric triamide and alcohols such as methanol, ethanol, 2-propanol, 3-propanol, 4-butanol and 5-pentanol as well as mixtures thereof, also aqueous mixtures thereof.

Working-up is carried out in a manner known per se. As a rule, the compounds are obtained after cooling of the reaction mixture as crystals and are purified after filtration, for example by chromatography or crystallisa-tion. If bromoethylamine or chloroethylamine are employed in the form of their hydrobromides or hydrochlorides, the end products are also initially obtained in the form of Le A 28 434 - 18 -2~7?,~ L7 the hydrobromides or hydrochlorides. To liberate the end products, the salts are dissolved in water, if appro-priate under hot conditions, and this solution is sub-sequently treated with bases.

The following may be mentioned as bases: alkali metal alcoholates, alkaline earth metal alcoholates and tertiary amines. The following bases may be mentioned as being particularly preferred: triethylamine, pyridine, picolines, trimethylamine, N-methylmorpholine, N-ethyl-pyrrolidine, diazabicyclo(4,3,0)-uncecene (DBU), 1,4-diaza-bicyclo-2,2,2-octane (DABCO), diazabicyclo-(3,2,0)nonene (DBN).

The product which has precipitated under cold conditions is subsequently filtered off with suction, dried and further purified, for example by chromatography or by recrystallisation, following known methods.

The compounds of the general formula (VII) and, for example, bromoethylamine or chloroethylamine/ or their hydrohalides are employed in equimolar amounts, a small excess of one or the other component does not provide any essential advantages.

Compounds of the general formula (I) in which Y denotes an -N=N- (Azo) group are obtained by reacting 2-[(2-tri-fluoromethyl-4-trifluoromethanesulphonylphenyl)-hydrazino]-2-thiazoline with an oxidant such as, for example, hydrogen peroxide, to give 2-[(2-trifluoro-Le A 28 434 - 19 -2~7~2~7 methyl-4-trifluoromethanesulphonyl phenyl)azo]-2-thiazo-line, for example in accordance with process 3d, fol-lowing the equation CF3 N toxida~ion] CF? N
C F 3 5 2--<~NH - NH~ ~ N = N~

The reaction is carried out for example by dehydrogena-S ting compounds of the general fonmula (I) where Y is-NH-NH-, using an oxidant, if appropriate in an inert organic solvent.

Examples of suitable oxidants are metal oxides such as silver oxide, lead oxide, mercury, selenium oxide as well as atmospheric oxygen, iron~III) chloride, lead tetra-cetate, mercuxy acetate, sodium dichromate, copper sulphate,potassium hexacyanoferrate, nitrous acid, dilute or fuming nitric acid, sodium persulphate, sodium hyypo-- chloride, permanganates, elemental sulphur, sodium perborate, hydrogen peroxide and chromic acid.

Suitable diluents are all inert organic solvents. These include, in particular, aliphatic and aromatic, optionally halogenated hydrocarbons such as pentane hexane, heptane, cyclohexane, petroleum ether, benzine, ligroine, benzene, toluene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene Le A 28 434 - 20 -2~722~ ~

and o-dichlorobenzene, furthermore ethers such as diethyl ether, and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, furthermore ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, moreover esters, such as methyl acetate and ethyl acetate, furthermore nitriles such as, for example, acetonitrile and propionitrile, benzonitrile, glutaro-nitrile, in addition alcohols, such as methanol, ethanol, 2-propanol, 3-propanol, butanol and pentanol, and mix-tures thereof, also aqueous mixtures thereof. The pH of the reactions can be varied within wide limits. For example, can be carried out in acid medium such as, for example, glacial acetic acid, but also in basic medium such as, for example, aqueous sodium hydroxide solution.

The reaction temperatures are between -30 and +180C, preferably between 0 and 110C. The oxidation methods are reviewed in Houben-Weyl, Vol. X/3 (1965), pages 371-380. Working-up is carried out in a manner known per se, for example, aqueous/by extraction or separation of the reaction products after neutralisation by extraction or filtration. The product can be purified further for example by chromatography or neutralisation.

The active substances are suitable for combating animal pests such as arthropods, preferably insects and arach-nids, which occur in animal keeping and animal breeding in domestic animals and productive livestock, as well as zoo animals, laboratory anLmals, experimental animals and Le A 28 434 - 21 -2~722~7 pets, while having a favourable toxicity to warm-blooded species. In this context, they are active against all or individual development stages of the pests and against resistant and normally-sensitive pest species.

Combating the animal pests is intended to prevent disease and the transmission thereof, deaths, and reduced perfor-mance (for example in the production of meat, milk, wool, hides, eggs), so that the use of the active compounds allows more economical and simpler animal keeping, or is only made possible in certain areas.

The pests include:
From the order o~ the Anoplura, for example Haematopinus spp., Linognathus spp., Solenopotes spp., Pediculus spp., Pthirus spp.;
from the order of the Mallophaga, for example Trimenopon spp., Menopon spp., Eomenacanthus spp., Menacanthus spp., Trichodectes spp., Felicola spp., Damalinea spp., Bovicola spp;
from the order of the Diptera, for example Chrysops spp., Tabanus spp., Musca spp., Hydrotaea spp., Muscina spp., Haematobosca spp., Haematobia spp., Stomoxys spp., Fannia spp., Glossina spp., Lucilia spp., Calliphora spp., Auchmeromyia spp., Cordylobia spp., Cochliomyia spp., Chrysomyia spp., Sarcophaga spp., Wohlfartia spp., Gasterophilus spp., Oesteromyia spp., Oedemagena spp., Hypoderma spp., Oestrus spp., Rhinoestrus spp., Melophagus spp., Hippobosca spp..

Le A 28 434 - 22 -2Q72~1 ~

From the order of the Siphonaptera, for example Ctenocephalides spp., Echidnophaga spp., Ceratophyllus spp..

From the order of the Metastigmata, for example Hyalomma 5 sPP- r Rhipicephalus spp., Boophilus spp., Amblyomma spp., Haemophysalis spp., Dermacentor spp., Ixodes spp., Argas spp., Ornithodorus spp., Otobius spp.;
from the order of the Mesastigmata, for example Dermanyssus spp., Ornithonyssus spp., Pneumonyssus spp..

From the order of the Prostigmata, for example Cheyletiella spp., Psorergates spp., Myobia spp., Demodex spp., Neotrombicula spp.;
from the order of the Astigmata, for example Acarus spp., Myocoptes spp., Psoroptes spp., Chorioptes spp., Otodec-15 tes spp., Sarcoptes spp., Notoedres spp., Knemidocoptesspp., Neoknemidocoptes spp. Lytodites spp., Laminosioptes spp..

The domestic animals and productive livestock include mammals such as, for example, cattle, sheep, goats, horsesl pigs, dogs, cats, camels, water buffaloes, donkeys, rabbits, fall~w deer, reindeer, pett-bearing animals such as, for example, minks, chinchilla and raccoon, and birds such as, for example, chickens, turkeys, pheasants, geese and ducks.

25 Laboratory and experimental animals include, for example, mic~, rats, guinea pigs, golden hamsters, dogs and cats.

Le A 28 434 ~ 23 ~

, _ . . . _ 20722~

The pets include, for example, dogs and cats.

The administration can be carried out both prophylacti-cally and therapeutically.

The active compounds are administered directly or in the form of suitable preparations enterally, parenterally, dermally, nasally, by environment treatment, or with the aid of active-compound-containing shaped articles such as, for example, strips, plates, tapes, collars, ear tags, limb bands, markin~ devices.

Enteral administration of the active compounds is effec-ted, for example, orally in the form of powders, tablets, capsules, pastes, boli, drinks or granules, or solutions, suspensions or emulsions which can be administered orally, medicated feed or drinking water. Dermal adminis-tration is effected, for example, in the form of dipping,spraying or pouring-on and spotting-on and powdering.
Parenteral administration is effected, for example, in the form of injection tfor example intramuscularly, subcutaneously or intravenously) or by implants.

Particular emphasis is given to the preparations for dermal administration. These include solutions, suspen-sion concentrates and emulsion concentrates, and also microemulsions which are diluted with water prior to administration, or pour- and spot-on formulations, powders and dusts, aerosols and active-compound-con-Le A 28 434 - 24 -20722~7 taining shaped articles as well as dust bags or back rubber.

The surface-active substances include:
emulsifiers and wetting agents such as anionic surfac-tants, for example alkylsulphonates, alkyl sulphates,arylsulphonates, sodium lauryl sulphates, fatty alcohol ether sulphates, monoethanolamine salt o~ mono/dialkyl-polyglycol ether orthophosphate, calcium alkylaryl-sulphonate;
cationic surfactants, for example cetyltrimethylammonium chloride;
ampholytic surfactants, for example disodium N-lauryl beta-iminodipropionate or lecithin;
non-ionic surfactants, for example polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, poly-oxyethylated sor~itan monostearate, glycerol mono-stearate, polyoxyethylene stearate, alkylphenol poly-glycol ethers, polyoxyethylated sorbitan monopalmitate, polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, polyoxyethylene mannitan monolaurate, alkyl polyglycol ether, oleyl polyglycol ether, dodecyl poly-glycol ether, ethoxylated nonylphenol or isooctylphenol-polyethoxyethanol.

The preparations can furthermore contain:
adhesion promoters~ for example carboxymethylcellulose, methylcellulose and other cellulose and starch deriva-tives, polyacrylates, alginates, gelatin, gum arabic, polyvinyl pyrrolidone, polyvinyl alcohol, methyl vinyl Le A_28 434 - 25 -ether/maleic anhydride copolymers, polyethylene glycols, paraffins, oils, waxes, hydrogenated castor oil, lecithins and synthetic phospholipids.

The preparations can contain colorants such as inorganic pigments, for example iron oxide, titanium oxide, Prus-sian Blue, and organic dyestuffs such as alizarin, azo and metal phthalocyanin dyestuffs.

The preparations can contain spreading agents, for example silicone oils having various viscosities, fatty acid esters such as ethyl stearate, di-n-butyl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with satura-- ted fatty alcohols Cl6-Cl8, isopropyl myristate, isopropyl palmitate, caprylic/caproic esters of saturated fatty alcohols of chain length Cl2-C~8, isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate, waxy fatty acid esters, dibutyl phthalate, diisopropyl adipate, ester mixtures relating to the latter, and others;
triglycerides such as caprylic/caproic triglyceride, triglyceride mixtures with vegetable fatty acids of chain length C8-Cl~ or other specifically selected natural fatty acids, partial glyceride mixtures of saturated or unsatu-rated, optionally also hydroxyl-containing fatty acids, monodiglycerides of the C~/C10-fatty acids and others;
fatty alcohols such as isotridecyl alcohol, 2-octyl-dodecanol, cetylstearyl alcohol or oleyl alcohol.

Le A 28 434 - 26 -20722~ 7 To produce solid preparations, the active compound is mixed with suitahle excipients, if appropriate with the addition of adjuvants, and the mixture is formulated as desired.

Excipients which may be mentioned are all physiologically acceptable solid inert substances. Substances which can be used are inorganic and organic substances. Inorganic substances are optionally crushed and fractioned, for example synthetic and natural ground rocks such as kaolins, talc, chalk, quartz, diatomaceous earth, sodium chloride, carbonates such as calcium carbonate, hydrogen carbonates, aluminas, silicas, clays, precipitated or colloidal silicon dioxide, or phosphates.

Examples of organic substances are sugars, cellulose, foodstuffs and feedstuffs such as dried milk, animal meals, cereal meals, crushed cereals, starches or saw-dust.

Adjuvants are preservatives, ~ntioxidants, colorants which have already been mentioned further above.

Other suitable adjuvants are lubricants and glidinq ~gents such as, for exa~ple, magnesium stearate, stearic acid, talc, bentonite, sukstances which promote disinte-gration such as starc~ or crosslinked polyvinyl pyrroli-done, binders such as, for example, starch, gelatin or linear polyvinylpyrrolidone as well as dry binding agents such as microcrystalline cellulose.

Le A 28 434 - 27 -2~722~

The active compounds, in the form of their abovementioned solid or liquid formulations, can also exist in encapsu-lated form.

The active compounds can also be administered in the form of an aerosol. To this end, the active compound in a suitable formulation is distributed finely under pres-sure.
.
It can also be advantageous to administer the active compounds in formulations which release the active compound in a delayed manner. Examp~es which may be mentioned are active-compound-containing shaped articles such as plates, tapes, strips, collars, eartags, tail tags, limb bands, halters or marking devices. Other formulations which may be mentioned are active-compound-containing implants and boli.

The active compounds can also be administered togetherwith the feed and/or the drinking water.

,, ~he active compounds can exist in the formulations on their own or as a mixture with other active compounds or synergists.

Formulations which are administered directly contain between 10-7 and 5 per cent by weight, preferably between 10-4 and 1 per cent by weight, of active compound.

Le A 2fl 434 - 28 -, .

Formulations which are only administered after further dilution contain 1 - 95 per cent by weight, preferably 5 - 90 per cent by weight, of active compound.

Example A

5 In-vivo mini dip test with ticks Test animals:

Boophilus microplus (all parasitising devPlopment stages/larvae, metalarvae, nymphs, metanymphs, adults) of Boophilus microplus (SP-resistant Parkhurst strain).

Solvent:

35 parts by weight of ethylene glycol monomethyl ether 35 parts by weight of nonylphenol polyglycol ether ~osts:

Before the beginning of the test, the cattle are shorn in such a manner that hairy areas of 8 x 8 cm in size remain on the back and on the sides. The distance of the areas to each other is approx. 20 cm, and they are arranged so that they are offset diagonally.

Testing procedure:

Cattle are infected 12 times at 2-day intervals with Le A 28 434 - 29 -2~7221'~
batches of 2000-4000 starved Boophilus microplus larvae aged 14-28 days. The female adults which develop from day 21 - 23 after the infection are counted as a measure for the infection pressure in each of the areas. On day 24, the individual areas are wetted thoroughly (2 minutes) with 200 ml of a dilution of the formulated test sub-stance by placing the mini dip apparatus on the areas.
To produce a suitable formulation, three parts by weight of active compound are mixed with seven parts of the abovementioned solvent/emulsifier mixture, and the resulting emulsion concentrate is diluted with water~to the specific concentration desired. After the treated areas have dried, gauze bags are attached around the areas with the aid of a dermatologically acceptable adhesive in such a way that they surround the areas completely. The bags are made of gauze and are cylindri-cal in shape, ~ 12 cm, and have attached to them a 3 cm wide base ring. This bag is closed by means of rubber bands.

Testinq criteria:

From day 24 - 45 after the infestation, the female adults which develop on the animal in the individual bags are counted. The reduction in the number of developi~g female adults with fertile egg clusters on the treated areas in comparison with untreated control areas is used as a criterion for the effectiveness. The effectiveness is expressed as a percentage. Here denotes that 211 ticks hav~ been killed, 0~ denotes that no ticks have been Le A 28 434 - 30 -2~72217 killed.

Active compound Active compound Cure effectiveness Ex. No.concentrationin % Boophilus in ppm of a.i. microplus in the mini dip Example B

Scab mite test Test animals: Psoroptes ovis (larvae, nymphs, adults) Solvent: 35 parts by weight of ethylene glycol mono-methyl ether 35 parts by weight of nonylphenolpolyglycol ether To produce a suitable formulation, three parts by weight of active compound are mixed with seven parts of the abovementioned solvent/emulsifier mixture, and the resulting emulsion concentrate is diluted with water to the specific concentration desired.

1 ml of this active compound preparation is pipetted into PP blister films of suitable size. Approx. 25 mites are Le A 28 434 - 31 -2 Q 7 2 ~ 1 ~

then transferred into the active compound preparation.

The effectiveness of the active compound preparation is determined after 24 hours. The effectiveness is expressed as a percentage. 100~ here denotes that all mites have been killed; 0% denotes that no mites have been killed.

Active compound Active compound Cure effectiveness Ex. No. concentration in % Psoroptes ovis in ppm of a.l.

Examples a) General procedure for the preparation of the com-pounds of the general formula (I) (Y = NH-NH) according to process c) in its specific embodiment RZ

Rl_Z~NH-NH-C~ t Br-CH2CH2-N~2 ~ HBr R

R 1 - Z~NH - NH~

Le A 28 434 - 32 -2Q722~ 7 0.15 mol of 1-(4-substituted phenyl)-3-thiosemi-carbazide and 0.15 mol of 2-bromoethylamine hydro-bromide are refluxed for 12 hours in 800 ml of isopropanol. After cooling, the mixture is stirred with saturated sodium hydrogen carbonate solution and extracted by shaking with methylene chloride, and the volatile components are stripped off in vacuo. The residue is recrystallised from petroleum ether.

The compounds of the general formula (I) where Y = -NH-NH-, which are listed below in Table 1, are obtained according to this process.

Table 1 R 1 - z~NH - NH~ ~ ( I ) EX . No . Z Rl R2/R3M . p . [ C ]

S02 CF2CHFCl H 120 6 50Z {~ Z-CF3 61 Le A 28 434 - 33 -20722~7 Table 1 (Continuation) Ex. No. Z Rl RZ/R3 M.p. tC]

7 52 CF3 2,6-Cl2 8 ~ CF3 2-Cl-6-F 144 0 CF3 H l90 1~ - CF3 2-Cl-3-F

~ CF3 2,6-C12 01 l7 5 CHF2 H

C~2H H
21 0 CFzCl H

CH2F`

CH2F`

oCF3CF2 H

Le A 28 434 - 34 -2~'722~

Table 1 (Continuation) Ex. No. Z Rl R2/R3 M.p. [C]

2~ 0 CH2FCH2 H
27 S CHFClCF2 H

2~ 0 CFH2CH2 H
CF3~
- CF H

31 - CF2Br H
b) General procedure for the preparation of the com-pounds of the general formula (I~ where Y is -N=N-by oxidation ~) with ~22 A mixture of 0.05 mol of 2-(4-substituted phenyl-hydrazino)-2-thiazoline in 120 ml of methylene chloride and 100 ml of 2-normal sodium hydroxide solution is treated with 7 ml of 30~ strength H2O2 and refluxed for 18 hours. 2 ml portions of 30%
s~rength H2O2 are then added after 8 hours and then a further 6 hours. The organic phase is su~sequently separated off, the aqueous phase is extracted with methylene chloride, the combined organic phases are concentrated in vacuo, and the residue is recrystal-lised from hexane/ether.

- Le A 28 434 - 35 -2~7~2~ ~

~) with silver oxide 1.7 g of silver oxide are added to a solution of 0O02 mol of 2-(4-substituted phenyl)-3-thiosemi-carbazide in 200 ml of ethyl acetate. The mixture is subsequently stirred for 18 hours at room tempera-ture, the liquid is filtered off and concentrated in vacuo, and the crystalline residue i9 stirred with petroleum ether.

The compounds of the general formula (I) where Y is -N=N-, which are listed in Table 2 below, are obtained according to these processes ~) and/or ~).

Table 2 R~
R1_z ~ N=N~

Exo No. Z Rl R2~3 M.p [C]

32 ~ CF3 H
33 - CF~ 2-CF~

S02 CF~ 2-CF3 36 S02 CF2CHFCl H

37 S02 ~ 2-CF3 Le A 28 434 - 36 -2!~7~,2~ 7 Table 2 ( Continuation Ex. No. Z Rl RZ/R3 M.p. [C]
-38 SO2 CF3 ~,6-C12 52 CF3 2-Cl 42 ~ CF3 Z-Cl 130 SO2 CF3 2-Cl 4~ - CF3 2,6-~:12 ~ ~ S CHF2 H
4 9 52 C~F2 H
5 0 O CF ~CH2 H

CH2F`

CH2F`

5 6 o CF3CF2 H

Le A 28 434 - 37 -2~7~2~7 Table 2 ( Continuation Ex. No. Z R1 R2/R3 M.p. t C]

5 8 S CHFC l CF2 H
5 9 0 CFC l 2CF2 H
6 0 o CFH2CH2 H
CF3~

6 Z - CF2Br H

Le A 28 434 - 38 -

Claims

1. Use of thiazolines of the general formula (I) (I) (I) in which Y represents -NH-NH- or -N=N- and Z represents a direct bond, O, S, SO or SO2, and R1 represents halogen-substituted alkyl, alkylsulphonyl, or represents optionally substituted phenyl, and R2 and R3 represent identical or different radicals from the series comprising hydrogen, halogen, halogen-substituted alkyl, CN or NOz, for combating ectoparasites.

2. Thiazolines of the general formula (I) Le A 28 434 - 39 - (I) in which Y represents -NH-NH- or -N=N- and Z represents a direct bond, O, S, SO or SO2, and R1 represents halogen-substituted alkyl, alkylsulphonyl, or represents optionally subqtituted phenyl, and R2 and R3 represent identical or different radicals from the series comprising hydrogen, halogen, halogen-substituted alkyl, CN or NO2.

3. Ectoparasiticidal agents, characterised in that they contain at least one thiazoline of the formula (I) according to Claim

4. Method of combating ectoparasites, characterised in that thiazolines of the formula (I) according to Claim 1 are allowed to act on ectoparasites and/or their habitats.

Le A 28 434 - 40 -