DE3731052A1 - Use of N-organooxycarbamic acid esters for controlling endoparasites, novel N-organooxycarbamic acid esters and process for their preparation - Google Patents

Abstract

The present invention relates to the use of N-organooxycarbamic acid esters of the formula I <IMAGE> in which R<1> stands for alkyl, cycloalkyl, alkenyl, alkynyl or aryl, which can optionally be substituted, R<2> stands for alkyl, alkenyl or alkynyl, which can optionally be substituted, R<3> stands for alkyl, alkenyl or alkynyl, which can optionally be substituted, for the control of endoparasites, novel N-organooxycarbamic acid esters and process for their preparation.

Description

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

N-organooxycarbamic acid esters are already known. It is but nothing about its use against endoparasites known.

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

• 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 optionally be substituted,
  R 2 is alkyl, alkenyl, alkynyl, which may optionally be substituted,
  R³ is alkyl, alkenyl, alkynyl, which may optionally be substituted,
  are suitable for combating endoparasites in medicine and veterinary medicine
  The compounds of the formula I are known in some cases 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 R² or R³ is propargyl.
• 3. N-organooxycarbamic acid ester 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 R² or R³ is propargyl.
  are manufactured by
  • a) hydroxylamine derivatives of the formula II, in which
    R¹ and R² have the abovementioned meaning,
    with compounds of the formula III, R³-X (III) in which
    R³ has the meaning given above and
    X is 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 is halogen, azido or the radical -O-R¹,
    with hydroxylamine derivatives of the formula V or their salts with acids, in which
    R 2 and R 3 have the abovementioned meaning,
    in the presence of bases, or
  • c) hydroxylamine derivatives of the formula VI, in which
    R¹ and R³ have the abovementioned meaning,
    with compounds of the formula VII, R²-X (VII) in which X and R 2 have the abovementioned meaning,
    in the presence of bases, or
  • d) carbamic acid halides of the formula VIII, in which,
    Hal stands for halogen,
    R 2 and R 3 have the abovementioned meaning,
    with compounds of the formula IX, R¹-OH (IX) in which
    R¹ has the meaning given above,
    in the presence of bases.

The compounds of the formula I are outstandingly suitable for the control of endoparasites, especially on the Veterinary field. Next to it, they let themselves also as insecticides, fungicides and herbicides on the Areas of agriculture, forestry and household, Use hygiene, storage and material protection.

Preference is given to 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 may 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 having preferably 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 having 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; Halogenoalkyl having 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, Fluorine, chloroethyl; Haloalkoxy having preferably 1 to 4, in particular 1 or 2 carbon atoms and preferably 1 to 5, in particular 1 to 3 halogen atoms, wherein the halogen atoms are identical or different and as halogen atoms preferably fluorine, chlorine, bromine, in particular fluorine such as trifluoromethoxy; Halogenoalkylthio having preferably 1 to 4, in particular 1 or 2 carbon atoms and preferably 1 to 5, in particular 1 to 3 halogen atoms, wherein the halogen atoms are identical or different and as halogen atoms preferably fluorine, chlorine, bromine, especially fluorine, such as trifluoromethylthio; in the case of phenyl, for alkylenedioxy having preferably 1 or 2 carbon atoms, such as methylenedioxy or ethylenedioxy; in the case of phenyl, for halogen-substituted alkylenedioxy having preferably 1 or 2 carbon atoms and preferably 1 to 4, in particular 2 to 3, halogen atoms, the halogen atoms being identical or different and preferably halogen atoms being fluorine or chlorine, in particular fluorine, such as difluoromethylenedioxy, trifluoroethylenedioxy, tetrafluoroethylenedioxy. Further substituents are halogen, preferably fluorine, chlorine, bromine and iodine, in particular chlorine and bromine; cyano; nitro; Dialkylamino having preferably 1 to 4, in particular 1 or 2 carbon atoms per alkyl group, such as dimethylamino, diethylamino, methyl-n.-butylamino; Alkylcarbonyl having preferably 2-4 carbon atoms; Carbalkoxy having preferably 2 to 4, especially 2 or 3 carbon atoms, such as carboxymethoxy and carboethoxy; Alkylsulfonyl having preferably 1 to 4, in particular 1 or 2 carbon atoms, such as methylsulfonyl and ethylsulfonyl; Arylsulfonyl having preferably 6 or 10 aryl carbon atoms, such as phenylsulfonyl; Phenyl, naphthyl, phenoxy, naphthoxy, phenylthio, naphthylthio, which in turn may be substituted again.
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 or optionally substituted aryl. Suitable optionally substituted aryl radicals are, in particular, the phenyl or naphthyl radicals mentioned in the definition of the substituent R 1, which may be substituted by the substituents mentioned there.

Particular preference is given to compounds of the formula I in which
R¹ is 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 as Trifluoromethylthio, phenyl which is optionally substituted, furthermore represents phenyl which is optionally substituted by C _1-4 -alkyl, in particular methyl, C _1-4 -alkoxy, in particular methoxy, ethoxy, C _1-4 -haloalkoxy, in particular trifluoromethoxy, Fluorochloroethoxy, C _1-4 -haloalkylthio, in particular trifluoromethylthio, fluorochloromethylthio, C _1-4 -alkylthio, in particular methylthio, halosulfonyl, in particular fluorosulfonyl, chlorosulfonyl, C _1-4 -alkylsulfonyl, in particular methylsulfonyl, C _1-4 -haloalkylsulfonyl, in particular Trifluoromethylsulfonyl, C _1-4 -haloalkyl, in particular trifluoromethyl, methylenedioxy or ethylenedioxy, which are optionally substituted by fluorine or chlorine, halogen, in particular fluorine or chlorine, NO₂, phen oxy, which is optionally substituted by one of the radicals given above,
R² is C _1-6 alkyl, in particular methyl, ethyl, n-propyl, i-propyl, t-butyl, C _2-4 alkenyl, in particular allyl, chloropropenyl, dichloropropenyl, butenyl, C _2-4 alkynyl, in particular Propargyl stands,
R³ is C _1-6 -alkyl, in particular methyl, ethyl, n-propyl, i-propyl, t-butyl, C _2-4 -alkenyl, in particular allyl, chloropropenyl, dichloropropenyl, butenyl, C _2-4 -alkynyl, in particular Propargyl stands,
and also C _1-4 -alkyl which is substituted by optionally substituted phenyl, in particular optionally substituted benzyl, suitable substituents being those mentioned for R 1 substituents of the phenyl radical.

Very particular preference is given to compounds of the formula I in which
R¹ is C _1-4 alkyl, in particular methyl or ethyl, benzyl, phenyl which is optionally substituted by halogen, in particular fluorine, chlorine, NO₂, CF₃, OCF₃, SCF₃, SCF₂Cl, OCH₃, OCF₂CF₂H, -OCF₂CHFO-, -O-CH₂ -O, -O-CF₂-O-substituted is,
R² is methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, allyl, 3-chloro-prop-2-enyl, 2-chloro-prop-2-enyl, 3,3-dichloro-prop-2-enyl, But-2-enyl, propargyl stands,
R³ represents methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, allyl, 3-chloro-prop-2-enyl, 2-chloroprop-2-enyl, 3,3-dichloroprop-2-enyl, butyric 2-enyl, propargyl stands,
and benzyl optionally substituted by C _1-4 -alkyl, such as methyl, ethyl, halogen, such as chlorine, fluorine, nitro, C _1-2 -haloalkyl, such as trifluoroalkyl, C _1-2 -haloalkoxy, such as trifluoromethoxy, C _1-2 . Halogen alkylthio is substituted as trifluoromethylthio.

Specifically, the following compounds of the formula I called:

If the hydroxylamine derivative of process 3a is used as the Formula II Benzyloxycarbonyl-N-propargylhydroxylamine and as the compound of formula III allyl bromide, so lets the course of the reaction by the following equation reproduced:

Preference is given to compounds of the formulas II and III used in which R¹, R² and R³ in the compounds of the formula I specified preferred and especially have preferred meanings and X is chlorine, bromine or p-tolylsulfonyl.

Specifically, the following compounds of formula II called:

N-hydroxy-N-methyl-carbamic acid ethyl ester
N-hydroxy-N-methyl-carbamic acid methylester
N-Hydroxy-N-allyl-carbamic acid ethyl ester
N-hydroxy-N-propargyl-carbamic acid methylester
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 cyclopropylester

The compounds of formula II are known or omit can be prepared analogously to known processes (Houben Weyl, Vol. E4, p. 255, Stuttgart 1983).

Specifically, the following compounds of formula III named: methyl, ethyl, propyl, i-propyl, n-butyl, s-butyl, allyl, crotyl, 3-chloroallyl, 3,3-dichloroallyl, 2,3-dibromallyl, propargyl, 2-butynyl chloride, bromide or tosylate.

The compounds of the formula III are known or are allowed produce analogously to known methods.

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

Suitable diluents are all inert organic Solvent 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, tetrachloro carbon, 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, as well Esters, such as methyl acetate and ethyl acetate, also nitriles, such as. Acetonitrile and propionitrile, Benzonitrile, glutaric dinitrile, moreover amides,  such as B. dimethylformamide, dimethylacetamide and N- Methylpyrrolidone, as well as dimethyl sulfoxide, tetramethylene sulfone and hexamethylphosphoric triamide.

Suitable bases are inorganic and organic bases Question. As bases may be mentioned alkali and alkaline earth hydroxides, carbonates, bicarbonates, alkoxides, also amines such as in particular tertiary amines z. Trimethylamine, Triethylamine, N-methylmorpholine, pyridine, Picolines, N-ethyl pyrrolidine, diazabicyclo (4,3,0) undecane (DBU), 1,4-diazabicyclo (2,2,2) octane (DABCO), Diazabicyclo (3,2,0) nonene (DBN).

The compounds of the formulas II and III are approximately used equimolar ratio to each other. A surplus one or the other component brings no significant advantage.

After the reaction, the diluent distilled off and the compounds of formula I in an known way isolated by z. B. from the Residue with a suitable solvent, for. For example, ethers be extracted. The compounds of the formula I can then in the usual way z. B. by distillation getting cleaned.

If in process 3b as carbonic acid ester of Formula IV ethyl chloroformate and as hydroxyl amine derivative of the formula V N-allyl-O-propargylhydroxylamine a, so can the reaction course by the following Play formula scheme:  

Preference is given to compounds of the formulas IV and V used in which R¹, R² and R³ in the compounds of the formula I specified preferred and especially have preferred meanings and Y is chlorine stands. The compounds of formula IV and V are known or can be prepared analogously to known methods (EP-OS 29 171).

Specifically, the following compounds of formula IV called: methyl chloroformate, chloroformic acid ethyl ester, n-propyl chloroformate, chloroform acid isopropyl ester, cyclopropyl chloroformate, Benzyl chloroformate, chloroformic acid phenyl ester, chloroformic acid p-chlorophenyl ester, Chloroformic acid p-nitrophenyl ester, chloroformic acid p-tolyl.

Specifically, the following compounds of the formula V called:

O, N-diallylhydroxylamine, O, N-dipropargylhydroxlamine, O-ethyl N-allylhydroxlamine, O-methyl-N-propargyl-hydroxylamine, O-propargyl-N-ethylhydroxlamine, O-allyl-N-methyl hydroxylamine, O-allyl-N-propargylhydroxylamine, O-crotyl  N-i-propylhydroxylamine, O-3-chloroallyl-N-propargyl hydroxylamine, O-3,3-dichloroallyl-N-allylhydroxylamine, O-Benzyl-N-3-chloroallylhydroxylamine, O-methyl-N-2-butynyl hydroxylamine.

The hydroxylamines of the formula V can in the form of their Salts with acids z. B. used as hydrochlorides become.

The reaction takes place at temperatures of -50-50 ° C, preferably at 0 ° - 30 ° C, more preferably at Room temperatures.

The diluents are water and all inert 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, furthermore 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, ketones continue, as well Acetone, methylethyl, methylisopropyl and methyliso Butyl ketone, as well as esters, such as methyl acetate and ethyl, further nitriles, such as. For example acetonitrile and propionitrile, benzonitrile, glutaronitrile, In addition, amides, such as. Dimethylformamide, dimethyl acetamide and N-methylpyrrolidone, as well as dimethyl sulfoxide, Tetramethylene sulfone and hexamethyl phosphoric acid triamide.  

Suitable bases are inorganic and organic bases Question. As bases may be mentioned alkali and alkaline earth hydroxides, carbonates, bicarbonates, alkoxides, also amines such as in particular tertiary amines z. 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) nonene (DBN).

The compounds of formulas IV and V are approximately used equimolar ratio to each other. A surplus one or the other component brings no significant advantage.

Preferably, the reaction is carried out in aqueous solution of Hydrochlorides of the hydroxylamine derivatives of the formula V with Carbonic acid esters of the formula IV in the presence of aqueous inorganic bases such as potassium or sodium hydroxide or carbonate. After the implementation is the Compound I isolated in a conventional manner, for. B. by extraction with a suitable solvent. The Extract is washed several times with water, z. B. over Dried sodium sulfate and then freed from the solvent. The compounds of the formula I can subsequently in the usual way, for. B. purified by distillation become.

If the hydroxylamine derivative of process 3c is used as the Formula VI N-Propargyloxy-carbamic acid benzyl ester and as the compound of formula VIII, 1,5-dibromopentane, so can the reaction process by the following Play formula scheme:  

Preference is given to using compounds of the formulas VI and VII, in which R¹, R² and R³ in the compounds of formula I given preferred and particularly preferred Have meanings and X for chlorine, bromine or p-Tolylsulfonyl stands. The compounds of the formulas VI and VII are known or can be analogous to known Process (Houben-Weyl, Vol. E4, p. 258, Stuttgart, 1983).

Specifically, the following compounds of formula VI called: N-ethoxy-carbamic acid ethyl ester, N-allyloxy carbamic acid ethyl ester, N-propargyloxycarbamic acid ethyl ester, N-crotylox-carbamic acid methyl ester, N- (3- Chloroallyloxy) -carbamic acid methyl ester, N-propargyl oxycarbamic acid phenyl ester, N-allyloxy-carbamic acid perchlorophenyl ester, N-2-butynyloxy-carbamic acid phenylester.

Specifically, 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-  Dichloroallyl, 2,3-dibromallyl, propargyl, 2-butynyl chloride, bromide or tosylate.

In the case of compounds of formula I prepared in which R 2 is methyl or ethyl, can as compounds of formula VII and dimethyl sulfate or diethyl sulfate can be used.

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

The diluents are all inert organic Solvent 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, tetrachloro carbon, 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, as well Esters, such as methyl acetate and ethyl acetate, also nitriles, such as. Acetonitrile and propionitrile, Benzonitrile, glutaric dinitrile, moreover amides, such as B. dimethylformamide, dimethylacetamide and N- Methylpyrrolidone, as well as dimethyl sulfoxide, tetramethylene sulfone and hexamethylphosphoric triamide.

Suitable bases are inorganic and organic bases Question. As bases may be mentioned alkali and alkaline earth  hydroxides, carbonates, bicarbonates, alkoxides, also amines such as in particular tertiary amines z. B. Trimethylamine, triethylamine, N-methylmorpholine, pyridine, Picoline, N-ethyl pyrrolidine, diazabicyclo (4,3,0) undecane (DBU), 1,4-diazabicyclo (2,2,2) octane (DABCO), Diazabicyclo (3,2,0) nonene (DBN).

The compounds of formulas VI and VII are approximately used equimolar ratio to each other. A surplus one or the other component does not bring significant advantage.

After the reaction, the diluent is distilled off and the compounds of the formula Iin per se isolated manner by z. B. from the residue with a suitable solvent, e.g. Ethers, be extracted. The compounds of the formula I can then in the usual way, for. By distillation, getting cleaned.

Substituting in process 3d as Carbamidsäurehalogenide of the formula VIII N- (2-butenoxy) -N-propargylcarbamic acid chloride and phenol as the compound of formula IX, so can the reaction mechanism by the following Play formula scheme:

Preference is given to compounds of the formula VIII and IX used in which R¹, R² and R³ in the compounds of the formula I specified preferred and especially have preferred meanings and Hal for chlorine or bromine stands.

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

Specifically, the following compounds of formula VIII called: N-methoxy-N-allyl-carbamoyl chloride, N-allyloxy allylcarbamoyl 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.

Specifically, the following compounds of formula IX may be mentioned: 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, more preferably at Room temperature.

The diluents are water and all inert 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, furthermore 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, ketones continue, as well Acetone, methylethal, methylisopropyl and methyliso Butyl ketone, as well as esters, such as methyl acetate and ethyl, further nitriles, such as. For example acetonitrile and propionitrile, benzonitrile, glutaronitrile, In addition, amides, such as. Dimethylformamide, dimethyl acetamide and N-methylpyrrolidone, as well as dimethyl sulfoxide, Tetramethylene sulfone and hexamethylphosphorus säuretriamid.

Suitable bases are inorganic and organic bases Question. As bases may be mentioned alkali and alkaline earth hydroxides, carbonates, bicarbonates, alkoxides, also amines such as in particular tertiary amines z. Trimethylamine, Triethylamine, N-methylmorpholine, pyridine, Picoline, N-ethyl pyrrolidine, diazabicyclo (4,3,0) undecane (DBU), 1,4-diazabicyclo (2,2,2) octane (DABCO), Diazabicyclo (3,2,0) nonene (DBN).

The compounds of formulas VIII and IX are approximately used equimolar ratio to each other. A surplus one or the other component brings no significant advantage.  

After the reaction, the compound I in in isolated in a known manner, for. B. by extraction with a suitable solvent. The extract is multiply washed with water, z. B. dried over sodium sulfate and then freed from the solvent. The connections of Formula I can then be converted into the usual Way, z. B. be purified by distillation.

The active ingredients are suitable for low-warmbloods toxicity to combat pathogenic endoparasites in humans and in animal husbandry and animal husbandry in livestock, breeding, zoo, laboratory, experimental and hobby animals occurrence. They are against all or individual Developmental stages of the pests and resistant and normal sensitive species effective. By fighting the pathogenic endoparasites are said to be disease, Deaths and reductions in performance (eg in production of meat, milk, wool, hides eggs, honey etc.) are reduced so that through the use of Active ingredients a more economical and easier animal husbandry is possible. To the pathogenic endoparasites include cestodes, trematodes, nematodes, acantocephals in particular:

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

From the order of Cyclophyllidea z. B .: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia spp., Avitel  lina spp., Stilesia spp., Cittotaenia spp., Andyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hyda tigera spp., Davainea spp., Railietina spp., Hymenolepis spp., Echinolepis 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., Echinoparyphium spp., Echinochasm spp., Hypoderaem spp., Fasciola spp., Fasciolides spp., Fasciolopsis spp., cyclocoelum spp., Typhlocoelum spp., Paramphistomum spp., calicophorone spp., Cotylophoron spp., Gigantocotyle spp., Fischoederius spp., Gastrothylacus spp., Notocotylus spp., Catatropis spp., Plagiorchis spp., Prosthogonimus spp., Dicrocoelium spp., Eurytrema spp., Troglotrema spp., Paragonimus spp., Collyricum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis spp., Metorchis spp., Heterophyes spp., Metagonimus spp.

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

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

From the order of Strongylida z. B: Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp. Gyaloxephalus spp., Cylindropharynx spp., Poterio stomum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanus spp., Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp., Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Haemonchus spp., Ostertagia spp., Marshallagia spp., Cooperia spp., Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp.

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

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

Among the useful and breeding animals include acid animals such. B. Cattle, horses, sheep, pigs, goats, camels, water buffalo, donkey, rabbit, fallow deer, reindeer, fur animals such as As mink, chinchilla, raccoon, birds such. B. Chickens, geese, turkeys, ducks, freshwater and saltwater fish such as Trout, carp, eels, reptiles, insects such as B. honeybee and silkworm.

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

Hobby animals include dogs and cats.

The application can be both prophylactic and therapeutically.

The application of the active ingredients takes place directly or in the form of suitable preparations enteral, parenteral, dermal, nasal, by treatment of the environment or with help active ingredient shaped body such. B. strips, plates, Ligaments, collars, ear tags, limb bands, Marking devices.  

The enteral application of the active ingredients happens z. B. orally in the form of powders, tablets, capsules, pastes, Impregnators, granules, orally administrable solutions, Suspensions and emulsions, boluses, medicated feed or drinking water. The dermal application happens z. B. in the form of diving (dipping), spraying (spraying) or Infusion (pour-on and spot-on). The parenteral Application happens z. In the form of injection (intra muscular, subcutaneous, intravenous, intraperitoneal) or through implants.

Suitable preparations are:

Solutions such as solutions for injection, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, Infusion formulations, gels;

Emulsions and suspension for oral or dermal Application and injection; Semi-solid preparations;

Formulations in which the active ingredient in an ointment basis 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 Inhalates, active substance-containing shaped body.

Injection solutions are given intravenously, intramuscularly and administered subcutaneously.  

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

As solvents may be mentioned: Physiologically acceptable Solvents such as water, alcohols such as ethanol, Butanol, benzyl alcohol, glycerine, propylene glycol, Polyethylene glycols, N-methyl-pyrrolidone, and mixtures the same.

The active ingredients can be optionally in physiological compatible with plant or synthetic Dissolve oils suitable for injection.

As solubilizers may be mentioned: solvents, the Promote the solution of the active ingredient in the main solvent or prevent its failing. Examples are polyvinyl pyrrolidone, polyoxyethylated castor oil, polyoxyethylated Sorbitan.

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

Oral solutions are applied directly. concentrates be after previous dilution on the application Concentration applied. Oral solutions and concentrations  be as above with the injection solutions prepared, while working on sterile can be waived.

Solutions for use on the skin are dripped, brushed, rubbed, sprayed on or sprayed on. These solutions are as above for the injection solutions described prepared.

It may be beneficial in making thickeners inflict. Thickeners are: Inorganic Thickeners such as bentonites, colloidal Silica, aluminum monostearate, organic thickener such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates.

Gels are applied to the skin or painted on or introduced into body cavities. Gels are made by using solutions like the injection solutions have been prepared described with so much Thickeners are added that a clear Mass with ointment-like consistency arises. When Thickeners are those indicated above Thickener used.

Infusion formulations are limited to areas the skin is poured or injected, the active ingredient The skin penetrates and acts systemically.  

Pour-on formulations are prepared by the Active substance in suitable skin-compatible solvents or solvent mixtures dissolved, suspended or 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, glycerin, aromatic alcohols, such as benzyl alcohol, phenylethanol, Phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as alkylene glycol alkyl ethers such as Dipro pylene glycol monomethyl ether, diethylene glycol mono-butyl ether, Ketones such as acetone, methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, N-methyl pyrrolidone, 2-dimethyl-4-oxy-methylene-1,3-dioxolane.

Dyes are all approved for animal use Dyes that may be dissolved or suspended.

Absorption promoting substances are z. 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, butylhydroxytoluene, Butylhydroxyanisole, tocopherol.

Light stabilizers are z. B. Novantisolic acid.  

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

Emulsions may be oral, dermal or injections be applied.

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

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

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

Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, esters of a medium-chain branched fatty acid with saturated fatty alcohols of chain length C _16-18 , isopropyl myristate, isopropyl palmitate, caprylic / capric acid ester of saturated fatty alcohols of chain length C _{12- 18} , isopropyl stearate, oleyl oleate, oleic acid decyl ester, ethyl oleate, ethyl lactate, waxy fatty acid esters such as artificial duckbald gland fat, dibutyl phthalate, adipic acid diisopropyl ester, the latter related ester mixtures, inter alia

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

Fatty acids such. As oleic acid and its mixtures.

As hydrophilic phase may be mentioned: Water, alcohols such. For example, propylene glycol, glycerol, Sorbitol and its mixtures.

As emulsifiers called its: nonionic surfactants, eg. Polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerin mono stearate, 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.

As further aids may be mentioned: Viscosity increasing and emulsion stabilizing substances such as Carboxymethylcellulose, methylcellulose and others Cellulose and starch derivatives, polyacrylates, alginates, Gelatin, gum arabic, polyvinyl pyrollidone, polyvinyl alcohol, copolymers of methyl vinyl ether and Maleic anhydride, polyethylene glycols, waxes, colloidal Silica or mixtures of the listed Substances.

Suspensions may be oral, dermal or as an injection be applied. They are manufactured by using the Active ingredient in a carrier liquid optionally with the addition of further auxiliaries, such as wetting agents, dyes, absorption promoting substances, preservatives, Antioxidants suspended light stabilizer.

As carrier liquids are all homogeneous solvents and solvent mixtures called.

As wetting agents (dispersants) are the above mentioned surfactants mentioned.

As further auxiliaries are those specified above called.  

Semi-solid preparations may be administered orally or dermally become. They are different from the ones above described suspensions and emulsions only by their higher viscosity.

For the preparation of solid preparations, the active ingredient with suitable excipients, if appropriate with addition of excipients and into the desired shape brought.

Suitable carriers are all physiologically acceptable solid inert materials. As such serve inorganic and organic substances. Inorganic substances are z. As sodium chloride, carbonates such as calcium carbonate, hydrogen carbonate, aluminas, silicas, clays, precipitated or colloidal silica, phosphates.

Organic substances are z. Sugar, cellulose, food and feeds such as milk powder, animal meal, cereal flours and -schrots, strengths.

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

Other suitable auxiliaries are lubricants and lubricants such as As magnesium stearate, stearic acid, talc, Bentonites, disintegrating 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 agents that are active against pathogenic endoparasites. Such Active ingredients are z. For example, L-2,3,5,6-tetrahydro-6-phenyl imidazothiazole, benzimidazole carbamate, praziquantel, Pyrantel, Febantel.

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

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

example A In vivo nematode test Ascarides / Dog

Of course, dogs infected with Toxascaris leonina were treated. The active substances were as pure active substance applied orally in gelatine capsules.

The efficiency is determined by that with the wean excreted worms counts. Subsequently, will the number of not killed by the treatment and excreted worms after section of the dogs certainly.

example B In vivo nematode test Hookworm / Dog

Experimental with Ancylostoma or Unicinaria stenocephala infected dogs were after expiration of the Treatment time of the parasite treated. The active ingredients were used as pure active ingredient in gelatine capsules orally applied.

The efficiency is determined by that with the wean excreted worms counts. Subsequently, will the number of not killed by the treatment and excreted worms after section of the dogs certainly.

example C In vivo nematode test Nippostronglyos brasiliensis / rat

Experimentally infected with Nippostrongylus brasiliensis Rats become three days after infection consecutive days orally by gavage treated. The animals will be 12 days after infection killed and the number of parasites determined. It will be the Drug concentration indicated at 95% of Parasites were killed (effective dose):

active substance effective dose Example no. mg / kg 4 250 1 100 30 250 31 250 19 100 34 100 38 100 41 100 52 100

example D In vivo nematode test Haemonchus contortus / sheep

Sheep experimentally infected with Haemonchus contortus were after expiration of the prepatent period of the parasite treated. The active ingredients were used as pure active ingredient in Gelatin capsules administered orally.

The efficiency is determined by that with excreted worms before and after treatment counted quantitatively.

A complete suspension of egg excretion after the Treatment means that the worms were aborted or are so damaged that they no longer have eggs produce (dose effektiva).

Tested active substances and effective dosages (dose Effektiva) are from the table below seen:

active substance Dose effectiva in Example no. mg / kg 4 50 3 25 30 10 34 10 48 10 50 25 45 25 43 25 31 25

example e In vivo nematode test Trichostrongylus colubriformis / sheep

Experimental with Trichostrongylus colubriformis infected sheep were at the end of the prepatent period treated by the parasite. The active substances were as pure active ingredient in gelatin capsules administered orally.

The efficiency is determined by that with the worm excreted the worm before and after the Counting treatment quantitatively.

A complete suspension of egg excretion after the Treatment means that the worms were aborted or are so damaged that they no longer have eggs produce (dose effektiva).

Tested active substances and effective dosages (dose Effektiva) are from the table below seen:

active substance Dose effectiva in Example no. mg / kg 1 10 3 5 30 2.5 41 5 26 5 14 10 21 10 22 10 44 10

example F In vivo nematode test Fasciloa hepatica / rat

Experimental with metacercariae of Fasciola hepatica infected rats were orally after infection Gavage on three consecutive days treated. The animals were 2 weeks after infection killed and the number of juvenile liver flukes in the Liver parenchyma determined.

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

active substance Effective dose Example no. ED₉₅ (mg / kg × 3) 1 25 3 10 4 100 9 250 14 50 30 25 21 50 22 25 31 50 19 10 34 25 38 25 44 50

Preparation Examples a) General rule for the production of Organooxycarbamic acid esters of the formula I: according to Method 3a)

0.1 mol of the N-alkyl-N-hydroxycarbamide acid ester of Formula II and 0.1 mole of the alkylating agent of the formula III are added to a solution of 6 g of potassium hydroxide 20 ml of ethanol and boiled for 5 h at reflux. The Alcohol is distilled off and the crude ester with ether extracted. After evaporation of the ether, the residue distilled in vacuo.

b) General rules according to procedure 3b)

0.1 mole of the N, O-dialkylhydroxylamine hydrochloride of 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 bicarbonate. Man stirs 40 min. at room temperature, then cool to 0 ° C and 0.1 mol of the chloroformate of the formula IV is added dropwise to. The mixture is then stirred for 24 h at room temperature, the ether phase separated, dried over Na₂SO₄ and concentrated. The residue is analyzed (Gas chromatography) and optionally in vacuo 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 and at room temperature with 0.1 mol of the Alkylierungsreagenzes of formula VII. The mixture is stirred for 48 h at room temperature, the evaporated Alcohol and extracted with ether. The ether extracts are dried, the ether distilled off and the Distilled distilled.

Analogously to one of the processes 3a-c, the active compounds of the following examples are obtained.

Claims (6)

1. Use of N-organooxycarbamic acid esters of the formula I, in which
R¹ is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, which may optionally be substituted,
R 2 is alkyl, alkenyl, alkynyl, which may optionally be substituted,
R³ is alkyl, alkenyl, alkynyl, which may optionally be substituted,
for the control of endoparasites 2. New N-organooxycarbamic acid esters of the formula I have been found, 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 R² or R³ is propargyl. 3. A process for the preparation of N-Organooxycarbamid acid ester 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 R² or R³ is propargyl,
are manufactured by

• a) hydroxylamine derivatives of the formula II, in which
  R¹ and R² have the abovementioned meaning,
  with compounds of the formula III, R³-X (III) in which
  R³ has the meaning given above and
  X is 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 is halogen, azido or the radical -O-R¹,
  with hydroxylamine derivatives of the formula V or their salts with acids, in which
  R 2 and R 3 have the abovementioned meaning,
  in the presence of bases, or
• c) hydroxylamine derivatives of the formula VI, in which
  R¹ and R³ have the abovementioned meaning,
  with compounds of the formula VII, R²-X (VII) in which
  X and R 2 are as defined above,
  in the presence of bases, or
• d) carbamic acid halides of the formula VIII, in which
  Hal stands for halogen,
  R 2 and R 3 have the abovementioned meaning,
  with compounds of the formula IX, R¹-OH (IX) in which
  R¹ has the meaning given above,
  in the presence of bases.

4. Endoparasiticides agent, characterized by a Content of at least one N-organooxycarbamic acid ester of the formula (I) according to claim 1. 5. Process for the preparation of endoparasiticides Means, characterized in that N-organo Oxycarbamidsäureester of formula (I) according to claim 1 with extenders and / or surface-active Mixtures mixed. 6. Use of N-Organoxycarbamidsäureestern the Formula (I) according to claim 1 for the preparation of endoparasiticides.