DE3716685A1 - Use of N-organo-oxycarbamidates for controlling endoparasites, novel N-organo-oxycarbamidates, and processes for their preparation - Google Patents

Abstract

The present invention relates to the use of N-organo-oxycarbamidates of the formula I <IMAGE> in which R<1> represents alkyl, cycloalkyl, alkenyl, alkynyl or aryl, each of which can optionally be substituted, R<2> represents alkyl, alkenyl or alkynyl, each of which can optionally be substituted, and R<3> represents alkyl, alkenyl or alkynyl, each of which can optionally be substituted, for controlling endoparasites, to novel N-organo-oxycarbamidates, and to processes for their preparation.

Description

The present invention relates to the use of N-organooxycarbamic acid esters for controlling endoparasites, new N-organooxycarbamic acid esters and processes for their manufacture.

N-organocarbamic acid esters are already known. It is however nothing about their use against endoparasites known.

Alkyl and phenylcarbonyl substituted hydroxylamines and their anthelmintic effects are already known. However, their effect is not satisfactory in all cases.

• 1. It has been found that N-organooxycarbamic acid esters of the formula I in which R¹ is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, which may be substituted, R² is alkyl, alkenyl, alkynyl which may be substituted, R³ is alkyl, alkenyl, alkynyl, which may be substituted, to combat each other of endoparasites in medicine and veterinary medicine.
  Some of the compounds of the formula I are known and can be prepared analogously to known processes.
• 2. New N-organooxycarbamic acid esters of the formula I have been found in which R¹ is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, which are optionally substituted, R² is alkyl, alkenyl, alkynyl, which are optionally substituted, R³ is alkyl, alkenyl, alkynyl, which are optionally substituted, with the proviso that at least one of the radicals R² or R³ represents propargyl.
• 3. N-organooxycarbamic acid esters of the formula I, in which R¹ is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, which are optionally substituted, R² is alkyl, alkenyl, alkynyl, which are optionally substituted, R³ is alkyl, alkenyl, alkynyl, which are optionally substituted, with the proviso that at least one of the radicals R² or R³ is propargyl are prepared by
  • a) hydroxylamine derivatives of the formula II, in which R¹ and R² have the meaning given above,
    with compounds of the formula III, R³-X (III) in which R³ has the meaning given above and X represents halogen or p-tolylsulfonyl, in the presence of bases, or
  • b) carbonic acid esters of the formula IV, in which R¹ has the meaning given above and Y represents halogen, azido or the radical -O-R¹, with hydroxylamine derivatives of the formula V or their salts with acids, in which R² and R³ have the meaning given above,
    in the presence of bases, or
  • c) hydroxylamine derivatives of the formula VI, in which R¹ and R³ have the meaning given above,
    with compounds of the formula VII, R²-X (VII) in which X and R² have the meaning given above,
    in the presence of bases, or
  • d) carbamic acid halides of the formula VIII, in whichHal is halogen, R² and R³ have the meaning given above, with compounds of the formula IX, R¹-OH (IX) in which R¹ has the meaning given above,
    implemented in the presence of bases.

The compounds of the formula I are outstandingly suitable to fight endoparasites, especially on the Field of veterinary medicine. In addition, they let themselves be also as insecticides, fungicides and herbicides on the Areas of agriculture, forestry and household, Use hygiene, supply and material protection.

Compounds of the formula I in which

R¹ is C _1-20 alkyl, C _2-20 alkenyl, C _3-20 cycloalkyl, C _2-20 alkynyl, phenyl or naphthyl, where these radicals can be substituted by one or more of the following substituents: alkyl with preferably 1 to 4, in particular 1 or 2 carbon atoms, such as methyl, ethyl, n.- and i.-propyl and n.-, i.-, s.- and t.-butyl; Alkoxy preferably having 1 to 4, in particular 1 or 2, carbon atoms, such as methoxy, ethoxy, n.- and i.-propyloxy and n.-, i.-, s.- and t.-butyloxy; Alkylthio with preferably 1 to 4, in particular 1 or 2 carbon atoms, such as methylthio, ethylthio, n.- and i.-propylthio and n.-, i.-, s.- and t.-butylthio; Haloalkyl with preferably 1 to 4, in particular 1 or 2 carbon atoms and preferably 1 to 5, in particular 1 to 3 halogen atoms, the halogen atoms being identical or different and being halogen atoms, preferably fluorine, chlorine or bromine, in particular fluorine, such as trifluoromethyl or fluorine -, chloroethyl; Halogenalkoxy with preferably 1 to 4, in particular 1 or 2 carbon atoms and preferably 1 to 5, in particular 1 to 3 halogen atoms, the halogen atoms being the same or different and preferably being fluorine, chlorine, bromine, in particular fluorine, such as trifluoromethoxy; Haloalkylthio with preferably 1 to 4, in particular 1 or 2 carbon atoms and preferably 1 to 5, in particular 1 to 3 halogen atoms, where the halogen atoms are identical or different and are preferably fluorine, chlorine, bromine, in particular fluorine, such as trifluoromethylthio; in the case of phenyl, for alkylenedioxy with preferably 1 or 2 carbon atoms, such as methylenedioxy or ethylenedioxy; in the case of phenyl for halogen-substituted alkylenedioxy with preferably 1 or 2 carbon atoms and preferably 1 to 4, in particular 2 to 3 halogen atoms, where the halogen atoms are identical or different and are preferably fluorine or chlorine, in particular fluorine, such as difluoromethylene dioxy, trifluoroethylene dioxy, tetrafluoroethylene dioxy. Further substituents are halogen, preferably fluorine, chlorine, bromine and iodine, especially chlorine and bromine; Cyano; Nitro; Dialkylamino with preferably 1 to 4, in particular 1 or 2 carbon atoms per alkyl group, such as dimethylamino, diethylamino, methyl-n-butylamino; Alkylcarbonyl preferably having 2 to 4 carbon atoms; Carbalkoxy preferably having 2 to 4, in particular 2 or 3, carbon atoms, such as carbomethoxy and carboethoxy; Alkylsulfonyl preferably having 1 to 4, in particular 1 or 2, carbon atoms, such as methylsulfonyl and ethylsulfonyl; Arylsulfonyl preferably having 6 or 10 aryl carbon atoms, such as phenylsulfonyl; Phenyl, naphthyl, phenoxy, naphthoxy, phenylthio, naphthylthio, which in turn can be substituted. R² is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, which may optionally be substituted by halogen, in particular chlorine, fluorine, bromine, R³ is C _1-6 alkyl, C _{2- 6} -Alkenyl, C _2-6 -alkynyl, which may optionally be substituted by halogen, in particular chlorine, fluorine, bromine.

Compounds of the formula I are particularly preferred in which

R 1 represents C _1-4 alkyl which is optionally substituted by halogen, in particular chlorine or fluorine, C _1-4 alkoxy such as methoxy or ethoxy, C _1-4 haloalkoxy such as trifluoromethoxy, C _1-4 haloalkylthio such as trifluoromethylthio, Phenyl, which is optionally substituted, furthermore stands for phenyl, which is optionally substituted by C _1-4 -alkyl, in particular methyl, C₁-C₄-alkoxy, in particular methoxy, ethoxy, C₁-C₄-haloalkoxy, in particular trifluoromethoxy, fluorochloroethoxy, C₁ - C₄-Haloalkylthio, especially trifluoromethylthio, fluorochloromethylthio, C₁-C₄-alkylthio, especially methylthio, halosulfonyl, especially fluorosulfonyl, chlorosulfonyl, C₁-C₄-alkylsulfonyl, especially methylsulfonyl, C₁-C₄-haloalkylsulfonyl, especially trif₄ especially trifluoromethyl, methylenedioxy or ethylenedioxy, which are optionally substituted by fluorine or chlorine, halogen, especially fluorine or chlorine, NO₂, phenoxy, the gege is also substituted by one of the radicals given above, R² for C _1-6 alkyl, in particular methyl, ethyl, n-propyl, i-propyl, t-butyl, C _2-6 alkenyl, in particular allyl, chloropropenyl, dichloropropenyl, butenyl , C _2-4 alkynyl, in particular propargyl, R³ independently of R² stands for the radicals indicated for R².

Compounds of the formula are very particularly preferred I, in which

R¹ for C _1-4 alkyl, especially methyl or ethyl, benzyl, phenyl, which may be replaced by halogen, especially fluorine, chlorine, NO₂, CF₃, OCF₃, SCF₃, SCF₂Cl, OCH₃, OCF₂CF₂H, -OCF₂CHFO-, -O-CH₂- O, -O-CF₂-O-substituted, R² is methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, allyl, 3-chloroprop-2-enyl, 2-chloroprop-2 - Enyl, 3,3-dichloroprop-2-enyl, but-2-enyl, propargyl, R³ independently of R² stands for the radicals indicated for R².

In particular, the following compounds of formula I are called:

Is used in process 3a as the hydroxylamine derivative Formula II benzyloxycarbonyl-N-propargylhydroxylamine and as a compound of formula III allyl bromide, so lets the course of the reaction is shown by the following formula play:

Compounds of the formula II and III are preferred used in which R¹, R² and R³ in the compounds of the formula I preferred and particularly have preferred meanings and X for chlorine, bromine or p-tolylsulfonyl.

The following compounds of the formula II may be mentioned in particular:
N-Hydroxy-N-methyl-carbamic acid ethyl ester
N-Hydroxy-N-methyl-carbamic acid methyl ester
N-Hydroxy-N-allyl-carbamic acid ethyl ester
N-Hydroxy-N-propargyl-carbamic acid methyl ester
N-Hydroxy-N-ethyl-carbamic acid phenyl ester
N-Hydroxy-N-3-chloroallyl-carbamic acid ethyl ester
N-hydroxy-N-crotyl-carbamic acid isopropyl ester
N-Hydroxy-N-propargyl-carbamic acid phenyl ester
N-Hydroxy-N-allyl carbamic acid p-chlorophenyl ester
N-Hydroxy-N-propargyl-carbamic acid cyclopropyl ester

The compounds of formula II are known or have not are produced analogously to known processes (Houben- Weyl, vol. E4, p. 255, Stuttgart 1983).

The following compounds of the formula III may be mentioned individually:
Methyl, ethyl, propyl, i-propyl, n-butyl, s-butyl, allyl, crotyl, 3-chloroallyl, 3,3-dichlorallyl, 2,3-dibromoallyl, propargyl -, 2-butynyl chloride, bromide or tosylate.

The compounds of formula III are known or have not produce themselves analogously to known processes.

The reaction takes place at temperatures of 0-200 ° C, preferably at 20-100 ° C, particularly preferably at boiling temperature of the diluent.

All inert organic come as diluents Solvent in question. These include in particular aliphatic and aromatic, optionally halogenated Hydrocarbons, such as pentane, hexane, heptane, cyclohexane, Petroleum ether, petrol, ligroin, benzene, toluene, Methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, Chlorobenzene and o-dichlorobenzene, further Alcohols such as methanol, ethanol, isopropanol, butanol, furthermore ethers such as diethyl and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, furthermore ketones, such as acetone, methylethyl, Methyl isopropyl and methyl isobutyl ketone, also Esters, such as methyl acetate and ethyl acetate, also nitriles, such as. B. acetonitrile and propionitrile, Benzonitrile, glutaronitrile, and also amides,  such as B. dimethylformamide, dimethylacetamide and N- Methylpyrrolidone, and also dimethyl sulfoxide, tetramethylene sulfone and hexamethylphosphoric triamide.

Inorganic and organic bases come in as bases Question. Alkali and alkaline earth metal hydroxides are mentioned as bases, -carbonates, -hydrogencarbonates, -alcoholates, furthermore amines such as, in particular, tertiary amines, e.g. B. trimethylamine, Triethylamine, N-methylmorpholine, pyridine, Picoline, N-ethylpyrrolidine, diazabicyclo (4,3,0) -undecane (DBU), 1,4-diazabicyclo (2,2,2) octane (DABCO), Diazabicyclo (3,2,0) nonen (DBN).

The compounds of formulas II and III are approximately equimolar relationship used. An excess the one or the other component brings none significant advantage.

After implementation, the diluent distilled off and the compounds of formula I in isolated in a known manner by z. B. from the Residue with a suitable solvent e.g. B. ether be extracted. The compounds of formula I can then in the usual way z. B. by distillation getting cleaned.

If method 3b is used as the carbonic acid ester Formula IV ethyl chloroformate and as a hydroxylamine derivative of the formula V N-allyl-O-propargylhydroxylamine , the course of the reaction can be determined by the following Play formula scheme:  

Compounds of the formulas IV and V are preferred used in which R¹, R² and R³ in the compounds of the formula I preferred and particularly have preferred meanings and Y for chlorine stands. The compounds of formula IV and V are known or can be produced analogously to known processes (EP-OS 29 171).

The following compounds of the formula IV may be mentioned individually:
Methyl chloroformate, ethyl chloroformate, n-propyl chloroformate, isopropyl chloroformate, cyclopropyl chloroformate, benzyl chloroformate, p-chlorophenyl chloroformate, p-nitrophenyl chloroformate, p-nitrophenyl chloroformate.

The following compounds of the formula V may be mentioned in detail:
O, N-diallylhydroxylamine, O, N-dipropargylhydroxlamine, O- ethyl-N-allylhydroxlamine, O-methyl-N-propargyl-hydroxylamine, O-propargyl-N-ethylhydroxlamine, O-allyl-N-methylhydroxylamine, O-allyl- N-propargylhydroxylamine, O-crotyl-Ni-propylhydroxylamine, O-3-chloroallyl-N-propargylhydroxylamine, O-3,3-dichloroallyl-N-allylhydroxylamine, O-benzyl-N-3-chloroallylhydroxylamine, O-methyl-N- 2-butynyl hydroxylamine.

The hydroxylamines of the formula V can be in the form of their Salts with acids e.g. B. can be used as hydrochloride.

The reaction takes place at temperatures of -50 - 50 ° C, preferably at 0 ° C - 30 ° C, particularly preferably at room temperature.

Water and all inert substances come as diluents organic solvents in question. These include in particular aliphatic and aromatic, optionally halogenated hydrocarbons, such as pentane, hexane, Heptane, cyclohexane, petroleum ether, gasoline, ligroin, Benzene, toluene, methylene chloride, ethylene chloride, chloroform, Carbon tetrachloride, chlorobenzene and o-dichlorobenzene, alcohols such as methanol, ethanol, isopropanol, Butanol, also ethers such as diethyl and dibutyl ether, Glycol dimethyl ether and diglycol dimethyl ether, Tetrahydrofuran and dioxane, ketones, such as Acetone, methyl ethyl, methyl isopropyl and methyl isobutyl ketone, also esters, such as methyl acetate and ethyl ester, also nitriles, such as. B. acetonitrile and propionitrile, benzonitrile, glutaronitrile, in addition amides, such as. B. dimethylformamide, dimethylacetamide and N-methylpyrrolidone and dimethyl sulfoxide, Tetramethylene sulfone and hexamethylphosphoric triamide.  

Inorganic and organic bases come in as bases Question. Alkali and alkaline earth metal hydroxides are mentioned as bases, -carbonates, -hydrogencarbonates, -alcoholates, furthermore amines such as, in particular, tertiary amines, e.g. B. trimethylamine, Triethylamine, N-methylmorpholine, pyridine, Picoline, N-ethylpyrrolidone, diazabicyclo (4,3,0) -undecane (DBU), 1,4-diazabicyclo (2,2,2) octane (DABCO), Diazabicyclo (3,2,0) nonen (DBN).

The compounds of formulas IV and V are approximately equimolar relationship used. An excess the one or the other component brings none significant advantage.

The reaction is preferably carried out in aqueous solution Hydrochloride of the hydroxylamine derivatives of formula V with Carbonic acid esters of formula IV in the presence of aqueous inorganic bases such as potassium or sodium hydroxide or carbonate. After the implementation is complete, the connection I isolated in a conventional manner, e.g. B. by extraction with a suitable solvent. The Extract is washed several times with water, e.g. B. about Dried sodium sulfate and then freed from the solvent. The compounds of formula I can then in the usual way, e.g. B. purified by distillation will.

Is used in process 3c as the hydroxylamine derivative Formula VI N-propargyloxy-carbamic acid benzyl ester and as a compound of formula VIII 1,5-dibromopentane, so can the course of the reaction by the following formula play:  

Compounds of the formulas VI and VII are preferably used, in which R¹, R² and R³ those in the compounds of the formula I preferred and particularly preferred Have meanings and X for chlorine, bromine or p-tolylsulfonyl. The compounds of the formulas VI and VII are known or can be analogous to known ones Establish process (Houben-Weyl, Vol. E4, p. 258, Stuttgart, 1983).

The following compounds of the formula VI may be mentioned in detail:
N-ethoxy-carbamic acid ethyl ester, N-allyloxycarbamic acid ethyl ester, N-propargyloxy carbamic acid ethyl ester, N-crotylox carbamic acid methyl ester, N- (3-chloroallyloxy) carbamic acid methyl ester, N-propargyloxy carbamic acid phenyloxy-phenyl ester, N-allyl 2-Butynyloxy carbamic acid phenyl ester.

In particular, the following compounds of formula VII called:

Methyl, ethyl, n-propyl, i-propyl, n-butyl, i- Butyl, n-hexyl, allyl, crotyl, 3-chloroallyl, 3,3-  Dichlorallyl, 2,3-dibromoallyl, propargyl, 2-butynyl chloride, bromide or tosylate.

In the event that compounds of the formula I are prepared in which R² is methyl or ethyl, can also be used as compounds of formula VII dimethyl sulfate or diethyl sulfate can be used.

The reaction takes place at temperatures of 0-200 ° C, preferably at 20-130 ° C, particularly preferably at boiling temperature of the diluent.

All inert organic come as diluents Solvent in question. These include in particular aliphatic and aromatic, optionally halogenated Hydrocarbons, such as pentane, hexane, heptane, cyclohexane, Petroleum ether, petrol, ligroin, benzene, toluene, Methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, Chlorobenzene and o-dichlorobenzene, further Alcohols such as methanol, ethanol, isopropanol butanol, furthermore ethers such as diethyl and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, furthermore ketones, such as acetone, methylethyl, Methyl isopropyl and methyl isobutyl ketone, also Esters, such as methyl acetate and ethyl acetate, also nitriles, such as. B. acetonitrile and propionitrile, Benzonitrile, glutaronitrile, and also amides, such as B. dimethylformamide, dimethylacetamide and N- Methylpyrrolidone, and also dimethyl sulfoxide, tetramethylene sulfone and hexamethylphosphoric triamide.

Inorganic and organic bases come in as bases Question. Alkali and alkaline earth metal hydroxides are mentioned as bases,  -carbonates, -hydrogencarbonates, -alcoholates, furthermore amines such as, in particular, tertiary amines, e.g. B. trimethylamine, Triethylamine, N-methylmorpholine, pyridine, Picoline, N-ethylpyrrolidine, diazabicyclo (4,3,0) -undecane (DBU), 1,4-diazabicyclo (2,2,2) octane (DABCO), Diazabicyclo (3,2,0) nonen (DBN).

The compounds of formulas VI and VII are approximately equimolar relationship used. An excess the one or the other component brings none significant advantage.

After the reaction, the diluent is distilled off andd the compounds of formula I in themselves known manner isolated by z. B. from the residue with a suitable solvent, e.g. B. ether, be extracted. The compounds of formula I can then in the usual manner, e.g. B. by distillation, getting cleaned.

Is used in process 3d as carbamic acid halides of the formula VIII N- (2-butenoxy) -N-propargylcarbamic acid chloride and phenol as a compound of formula IX, so the reaction mechanism can be represented by the following formula play:

Compounds of the formulas VIII and IX are preferred used in which R¹, R² and R³ in the compounds of the formula I preferred and particularly have preferred meanings and Hal for chlorine or bromine.

The compounds of formulas VIII and IX are known or can be produced analogously to known processes. (Houben-Weyl, Vol. E4, Stuttgart 1983, p. 258).

The following compounds of the formula VIII may be mentioned individually:
N-methoxy-N-allyl-carbamoyl chloride, N-allyloxyallylcarbamoyl chloride, N-ethoxy-N-propargyl-carbamoyl chloride, N-allyloxy-N-propargyl-carbamoyl chloride, N-propargyloxy-N-ethyl-carbamoyl chloride, N-benzyloxy-N- propargyl-carbamoyl chloride, N-propargyloxy-N-propargyl-carbamoyl chloride.

The following compounds of the formula IX may be mentioned individually:
Methanol, ethanol, propanol, isopropanol, n-, i-, s- and t-butanol, pentanols, hexanol, cyclohexanol, allyl alcohol, propargyl alcohol, phenol, p-cresol, p-chlorophenol, α- naphthol, p-nitrochlorophenol.

The reaction takes place at temperatures of -50 -50 ° C, preferably at 0 ° -30 ° C, especially at room temperature.

Water and all inert substances come as diluents organic solvents in question. These include in particular  aliphatic and aromatic, optionally halogenated hydrocarbons, such as pentane, hexane, Heptane, cyclohexane, petroleum ether, petrol, ligroin, benzene, Toluene, methylene chloride, ethylene chloride, chloroform, Carbon tetrachloride, chlorobenzene, and o-dichlorobenzene, alcohols such as methanol, ethanol, isopropanol, Butanol, also ethers such as diethyl and dibutyl ether, Glycol dimethyl ether and diglycol dimethyl ether, Tetrahydrofuran and dioxane, ketones, such as Acetone, methyl ethyl, methyl isopropyl and methyl isobutyl ketone, also esters, such as methyl acetate and ethyl ester, also nitriles, such as. B. acetonitrile and propionitrile, benzonitrile, glutaronitrile, in addition amides, such as. B. dimethylformamide, dimethylacetamide and N-methylpyrrolidone and dimethyl sulfoxide, Tetramethylene sulfone and hexamethylphosphoric triamide.

Inorganic and organic bases come in as bases Question. Alkali and alkaline earth metal hydroxides are mentioned as bases, -carbonates, -hydrogencarbonates, -alcoholates, furthermore amines such as, in particular, tertiary amines, e.g. B. trimethylamine, Triethylamine, N-methylmorpholine, pyridine, Picoline, N-ethylpyrrolidine, diazabicyclo (4,3,0) -undecane (DBU), 1,4-diazabicyclo (2,2,2) octane (DABCO), Diazabicyclo (3,2,0) nonen (DBN).

The compounds of formulas VIII and IX are approximately equimolar relationship used. An excess the one or the other component brings none significant advantage.  

After the implementation, the compound I in on isolated in a known manner, e.g. B. by extraction with a suitable solvent. The extract is repeated washed with water, e.g. B. dried over sodium sulfate and then freed from the solvent. The connections of the formula I can then in the usual Way, e.g. B. cleaned by distillation.

The active ingredients are suitable for favorable warm-blood toxicity to fight pathogenic endoparasites that in humans and in animal husbandry and animal breeding in livestock, breeding, zoo, laboratory, experimental and hobby animals occurrence. You are against everyone or some Stages of development of the pests and against resistant and normally sensitive species are effective. By fighting the pathogenic endoparasites are said to be disease, Deaths and reduced performance (e.g. during production of meat, milk, wool, skins, eggs, honey etc.) can be reduced, so that by using the Active ingredients a more economical and easier animal husbandry is possible. Pathogenic endoparasites include cestodes, trematodes, nematodes, acantocephals in particular:

From the order of the Pseudophyllidea z. B .:
Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoporus spp.

From the order of the Cyclophyllidea z. B .:
Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Andrya spp., Bertiella spp., Echinococ ., Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepsis spp., Echinolepsis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp.

From the subclass of Monogenea z. B .:
Gyrodactylus spp., Dactylogyrus spp., Polystoma spp.

From the subclass of Digenea z. B .:
Diplostomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinostoma spp., Echinopumochin., Echinoparyphin ., Fasciola spp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhlocoelum spp., Paramphistomum spp., Calicophoron spp., Cotylophoron spp., Gigantocotyle spp., Fischoederius spp., Gastrothyocus. Catatropis spp., Plagiorchis spp., Prosthogonimus spp., Dicrocoelium spp., Eurytrema spp., Troglotrema spp., Paragonimus spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis spp. Metorchis spp., Heterophyes spp., Metagonimus spp.

From the order of the Enoplida z. B.
Trichuris spp., Capillaria spp., Trichomosoides spp., Trichinella spp.

From the order of the Rhabditia z. B .:
Micronema spp., Strongyloides spp.

From the order of Strongylida z. B .:
Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostomum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Stephanabostoma ., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp., Cystocaulusrppyl. Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Parailaroides spp., Trichostrongyluschia. Spp., Haich. Sppia ., Cooperia spp., Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp.

From the order of the Oxyurida z. B.
Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp.

From the order of Ascaridia z. B.
Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp.

From the order of the Spirurida z. B .:
Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp.

From the order of the Filariida z. B .:
Stephanofilaria spp., Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp., Onchocerca spp.

From the order of the Gigantorhynchida z. B .:
Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp.

The livestock and breeding animals include mammals such as B. Cattle, horses, sheep, pigs, goats, camels, water buffalos, Donkeys, rabbits, fallow deer, reindeer, fur animals such as B. mink, chinchilla, raccoon, birds such. B. Chickens, geese, turkeys, ducks, fresh and salt water fish such as B. trout, carp, eels, reptiles, insects such as B. honey bee and silkworm.

Laboratory and experimental animals include mice, rats, Guinea pigs, golden hamsters, dogs and cats.

The pets include dogs and cats.

The application can be prophylactic as well as therapeutic respectively.

The active ingredients are used directly or in the form of suitable preparations enterally, parenterally, dermally, nasally, by treating the environment or with the help active substance-containing shaped bodies such. B. strips, plates, Ribbons, collars, ear tags, limb straps, marking devices.  

The enteral application of the active ingredients happens, for. B. orally in the form of powder, tablets, capsules, pastes, Watering, granules, orally applicable solutions, Suspensions and emulsions, boluses, medicated feed or drinking water. The dermal application happens e.g. B. in the form of diving (dipping), spraying (spraying) or Pour-on and spot-on. The parenteral Application happens z. B. in the form of injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or through implants.

Suitable preparations are:

• Solutions such as injection solutions, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, Infusion formulations, gels;
• Emulsions and suspensions for oral or dermal use as well as for injection; Semi-solid preparations;
• Formulations in which the active ingredient in an ointment base or in an oil in water or water in oil Emulsion base is processed;
• Solid preparations such as powders, premixes or concentrates, Granules, pellets, tablets, boluses, capsules; Aerosols and Inhaled tablets containing active ingredients.

Solutions for injection become intravenous, intramuscular and administered subcutaneously.  

Injection solutions are made by the active ingredient is dissolved in a suitable solvent and possibly additives such as solubilizers, acids, bases, Buffer salts, antioxidants, preservatives added will. The solutions are sterile filtered and filled.

The following may be mentioned as solvents:
Physiologically acceptable solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerin, propylene glycol, polyethylene glycols, N-methyl-pyrrolidone, and mixtures thereof.

The active ingredients can optionally also be physiologically compatible vegetable or synthetic Dissolve oils that are suitable for injection.

The following may be mentioned as solution mediators:
Solvents that promote the dissolution of the active ingredient in the main solvent or prevent its precipitation. Examples are polyvinyl pyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters.

Preservatives are:
Benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid ester, n-butanol.

Oral solutions are used directly, concentrates after dilution to the application concentration applied orally. Oral solutions and concentrates  are as described above for the injection solutions manufactured, doing without sterile work can be.

Solutions for use on the skin are instilled, spread on, rubbed in, sprayed on or sprayed on. These solutions are the same as for the injection solutions described manufactured.

It may be advantageous in the manufacture of thickeners inflict. Thickeners are: Inorganic Thickeners such as bentonites, colloidal Silica, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and metacrylates.

Gels are applied or spread on the skin or placed in body cavities. Gels are made by providing solutions that are like injection solutions described with so much Thickeners are added that are clear Mass with ointment-like consistency arises. As Thickeners are those given above Thickeners used.

Infusion formulations are limited to areas poured or sprayed on the skin, the active ingredient penetrates the skin and has a systemic effect.  

Infusion formulations are made by the Active ingredient in suitable skin-compatible solvents dissolved or solvent mixtures, suspended or is emulsified. If necessary, more Auxiliaries such as dyes, absorption-promoting substances, Antioxidants, light stabilizers, adhesives added.

The following may be mentioned as solvents:
Water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol, esters such as Essigester, butyl acetate, benzyl benzoate, ethers such as alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether, diethylene glycol mono-butyl ether, ketones such as acetone, methyl ethyl ketone, aromatic and / or aliphatisache Hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, N-methylpyrrolidone, 2-dimethyl-4-oxy-methylene-1,3-dioxolane.

Dyes are all approved for use on animals Dyes that can be dissolved or suspended.

Resorption promoting substances are e.g. B. DMSO, spreading Oils such as isopropyl myristate, dipropylene glycol pelargonate, Silicone oils, fatty acid esters, triglycerides, fatty alcohols.

Antioxidants are sulfites or metabisulfites like Potassium metabisulfite, ascorbic acid, butylated hydroxytoluene, Butylated hydroxyanisole, tocopherol.

Light stabilizers are e.g. B. Novantisol acid.  

Adhesives are e.g. B. cellulose derivatives, starch derivatives, Polyacrylates, natural polymers such as alginates, Gelatin.

Emulsions can be applied orally, dermally or as injections will.

Emulsions are either of the water in oil type or of the Type oil in water.

They are made by either the active ingredient dissolves in the hydrophobic or in the hydrophilic phase and this with the help of suitable emulsifiers and optionally other auxiliaries such as dyes, absorption-promoting substances, preservatives, Antioxidants, light stabilizers, viscosity increasing Substances homogenized with the solvent of the other phase.

The following may be mentioned as hydrophobic phase (oils): paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic / capric acid bigylceride, triglyceride mixture with vegetable fatty acids of chain length C _8-12 or other specially selected natural fatty acids, partial glyceride mixtures saturated or unsaturated, possibly also hydroxyl-containing fatty acids, mono- and diglycerides of C₈ / C₁₀ fatty acids.

Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, Hexyl laurate, dipropylene glycol pelargonate, Ester of a medium chain branched fatty acid with saturated fatty alcohols of chain length C₁₆-C₁₈, Isopropyl myristate, isopropyl palmitate, caprylic / capric acid ester of saturated fatty alcohols of chain length C₁₂-C₁₈, isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, Ethyl oleate, lactic acid ethyl ester, waxy Fatty acid esters such as artificial duckling glandular fat, Dibutyl phthalate, diisopropyl adipate, the latter related ester mixtures u. a.

Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, Cetylstearyl alcohol, oleyl alcohol.

Fatty acids such as B. oleic acid and its mixtures.

The following are mentioned as the hydrophilic phase:
Water, alcohols such as B. propylene glycol, glycerin, sorbitol and their mixtures.

The following may be mentioned as emulsifiers:
non-ionic surfactants, e.g. B. polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ether;
ampholytic surfactants such as di-Na-N-lauryl- β -iminodipropionate or lecithin;
anionic surfactants such as Na lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt;
cationic surfactants such as cetyltrimethylammonium chloride.

The following may be mentioned as further auxiliaries:
Viscosity-increasing and emulsion-stabilizing substances such as carboxymethyl cellulose, methyl cellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes, colloidal silicic acid or listed substances .

Suspensions can be taken orally, dermally or as an injection be applied. They are made by using the Active ingredient in a carrier liquid if necessary with the addition of other auxiliaries such as wetting agents, dyes, absorption-promoting substances, preservatives, Antioxidants suspended in light stabilizers.

All homogeneous solvents are carrier liquids and solvent mixtures called.

As wetting agents (dispersants) are the above specified surfactants called.

Further auxiliaries are those mentioned above called.  

Semi-solid preparations can be administered orally or dermally will. They differ from those described above Suspensions and emulsions only through their higher viscosity.

The active ingredient is used to produce solid preparations with suitable carriers, if necessary with the addition of auxiliaries mixed and into the desired shape brought.

All physiologically compatible are mentioned as carriers solid inert substances. All of these serve inorganic and organic matter. Inorganic substances are e.g. B. common salt, carbonates such as calcium carbonate, hydrogen carbonates, Aluminum oxides, silicas, clays, precipitated or colloidal silicon dioxide, phosphates.

Organic substances are e.g. B. sugar, cellulose, food and feed such as milk powder, animal meal, cereal meal and meal, strengths.

Excipients are preservatives, antioxidants, Dyes that have already been listed above are.

Other suitable auxiliaries are lubricants and lubricants such as B. magnesium stearate, stearic acid, talc, Bentonites, decay-promoting substances such as starch or cross-linked polyvinylpyrrolidone, binders such. B. Starch, gelatin or linear polyvinylpyrrolidone as well  Dry binders such as microcrystalline cellulose.

The active ingredients can also be mixed in the preparations with synergists or with other active ingredients that act against pathogenic endoparasites. Such Active ingredients are e.g. B. L-2,3,5,6-tetrahydro-6-phenylimidazothiazole, Benzimidazole carbamates, praziquantel, Pyrantel, Febantel.

Ready-to-use preparations contain the active ingredient in concentrations of 10 ppm - 20 percent by weight, preferably from 0.1-10 percent by weight.

Preparations that are diluted before use contain the active ingredient in concentrations of 0.5-90 percent by weight, preferably from 5 to 50 percent by weight.

In general, it has proven to be advantageous Amounts from about 1 to about 100 mg of active ingredient per kg of body weight per day for effective results to administer.  

Example A In vivo nematode test Ascarids / dog

Dogs infected with Toxascaris leonina, of course treated. The active ingredients were as a pure active ingredient Orally applied in gelatin capsules.

The efficiency is determined by using the excreted worms counts. Then will the number of those not killed by the treatment and excreted worms by section of the dogs certainly.

Example B In vivo nematode test Hookworm / dog

Experimental with Ancylostoma caninum or Unicinaria stenocephala infected dogs were found after the expiry of Preparation time of the parasite treated. The active ingredients were oral as a pure active ingredient in gelatin capsules applied.

The efficiency is determined by using the excreted worms counts. Then will the number of those not killed by the treatment and excreted worms determined by section of the dogs.

Example C In vivo nematode test Nippostronglyos brasiliensis / rat

Experimentally infected with Nippostrongylus brasiliensis Rats are given three to 6 days after infection consecutive days orally using a pharyngeal tube treated. The animals become 12 days after infection killed and the number of parasites determined. It will be the Drug concentration specified at which 95% of the Parasites were killed (effective dose):

Drug effective dose Example Nr.mg/kg

4250 1100

Example D In vivo nematode test Haemonchus contortus / sheep

Sheep experimentally infected with Haemonchus contortus were treated after the parasite's prepatent period. The active substances were used as pure active substances in Oral gelatin capsules.

The efficiency is determined by using the excreted worms before and after treatment counts quantitatively.

Complete suspension of egg excretion after treatment means that the worms have been aborted or are so damaged that they no longer produce eggs (Effective dose).

Tested active ingredients and effective doses (dose effectiva) are shown in the table below:

Active ingredient dose effectiva in Example Nr.mg/kg

450 325

Example E In vivo nematode test Trichostrongylus colubriformis / sheep

Experimental with Trichostrongylus colubriformis infected sheep became after the prepatent period of the parasite. The active substances were called pure active ingredient administered orally in gelatin capsules.

The efficiency is determined by using the Excreted worm eggs before and after treatment counts quantitatively.

Complete suspension of egg excretion after treatment means that the worms have been aborted or are so damaged that they no longer produce eggs (Effective dose).

Tested active ingredients and effective doses (dose effectiva) are shown in the table below.

Active ingredient dose effectiva in Example Nr.mg/kg

110 3 5

Example F In vivo trematode test Fasciloa hepatica / rat

Experimental with metacercariae from Fasciola hepatica infected rats were orally administered after infection Gavage treated for three consecutive days. The animals were sacrificed 2 weeks after infection and the number of juvenile liver fluke in the liver parenchyma certainly.

The following table shows which dose (effective dose) is required to be 95% Parasite reduction compared to an untreated one To achieve control.

Effective dose Example No.ED₉₅ (mg / kg × 3)

1 25 3 10 4100  

Manufacturing examples a) General regulation for the production of the N- Organooxycarbamic acid esters of the formula I: according to Process 3a)

0.1 mol of the N-alkyl-N-hydroxy-carbamide acid ester Formula II and 0.1 mole of the alkylating agent of the formula III become a solution of 6 g of potassium hydroxide in 30 ml of ethanol were added and the mixture was refluxed for 5 hours. The Alcohol is distilled off and the crude ester with ether extracted. After evaporation of the ether, the residue distilled in vacuo.

b) General rule according to procedure 3b)

0.1 mole of the N, O-dialkylhydroxylamine hydrochloride Formula (V) and 25 ml of water and 100 ml of ether submitted and at room temperature with vigorous stirring mixed with 0.2 mol of sodium hydrogen carbonate. You stir 40 min. at room temperature, then cools to 0 ° C and drips 0.1 mol of the chloroformic acid ester of the formula IV to. The mixture is then stirred at room temperature for 24 h, the ether phase separated, dried over Na₂SO₄ and constricted. The residue is analyzed (gas chromatography) and optionally in a vacuum distilled.  

c) General rule according to procedure 3c

0.1 mol of the N-alkoxycarbamic acid ester of the formula VI and 0.1 mol of sodium hydroxide solution in 100 ml of methanol and 10 ml of water are introduced and at room temperature 0.1 mole of the alkylating reagent of the formula VII was added. The mixture is stirred for 48 h at room temperature, the evaporated Alcohol and extracted with ether. The ether extracts are dried, the ether is distilled off and the residue distilled.

The active compounds of the following examples are obtained analogously to one of processes 3a-c:

Claims (6)

1. Use of N-organooxycarbamic acid ester of the formula I, in which R¹ is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, which can be optionally substituted, R² is alkyl, alkenyl, alkynyl, which can be optionally substituted, R³ is alkyl, alkenyl, alkynyl, which can be optionally substituted, for combating Endoparasites. 2. N-organooxycarbamic acid esters of the formula I in which R¹ is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, which are optionally substituted, R² is alkenyl, alkynyl, which are optionally substituted, R³ is alkyl, alkenyl, alkynyl, which are optionally substituted, with the proviso that at least one of the radicals R² or R³ stands for propargyl. 3. Process for the preparation of N-organooxycarbamic acid esters of the formula I, in which R¹ is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, which are optionally substituted, R² is alkyl, alkenyl, alkynyl, which are optionally substituted, R³ is alkyl, alkenyl, alkynyl, which are optionally substituted, with the proviso that at least one of the radicals R² or R³ is propargyl, characterized in that

• a) hydroxylamine derivatives of the formula II, in which R¹ and R² have the meaning given above,
  with compounds of the formula III, R³-X (III) in which R³ has the meaning given above and X represents halogen or p-tolylsulfonyl, in the presence of bases, or
• b) carbonic acid esters of the formula IV, in which R¹ has the meaning given above and Y represents halogen, azido or the radical -O-R¹, with hydroxylamine derivatives of the formula V or their salts with acids, in which R² and R³ have the meaning given above,
  in the presence of bases, or
• c) hydroxylamine derivatives of the formula VI, in which R¹ and R³ have the meaning given above,
  with compounds of the formula VII, R²-X (VII) in which X and R² have the meaning given above,
  in the presence of bases, or
• d) carbamic acid halides of the formula VIII, in whichHal is halogen, R² and R³ have the meaning given above, with compounds of the formula IX, R¹-OH (IX) in which R¹ has the meaning given above,
  implemented in the presence of bases.

4. Endoparasiticidal agents, characterized by a Content of at least one N-organooxycarbamic acid ester of formula (I) according to claim 1. 5. Process for the preparation of endoparasiticides Agents, characterized in that N-organooxycarbamic acid esters of formula (I) according to claim 1 with extenders and / or surfactants Means mixed. 6. Use of N-organooxycarbamic acid esters Formula (I) according to claim 1 for the preparation of endoparasiticidal agents.