JPS63196552A - Use of n-organooxycarbamic acid esters for repelling endoparasites, novel n-organooxycarbamic acid esters and manufacture - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method for treating internal parasites (andoparasites).
The present invention relates to the use of novel N-organooxycarbamic acid esters for controlling P. es), novel N-organooxycarbamic acid esters and methods for producing them.

N-organocarbamic acid esters are already known. However, their use against endoparasites is unknown.

Alkyl- and phenylcarbonyl-substituted hydroxylamines and their anthelmintic activity are already known. However, their activity was not satisfactory in all cases.

1, Formula l R1-〇-self-N-0-R'' I■ [wherein R1 represents alkyl, cycloalkyl, alkenyl, alkynyl or aryl, which may be optionally substituted, R1 is R3 represents alkyl, alkenyl or alkynyl, which may be optionally substituted; and R3 represents alkyl, alkenyl or alkynyl, which may be optionally substituted. have been found to be suitable for controlling endoparasites in pharmaceuticals and veterinary medicines.

2, Formula I R'-0-C-N-0-R31 [wherein R1 represents alkyl, cycloalkyl, alkenyl, alkynyl or aryl, which may be optionally substituted, R2 is alkyl, represents alkenyl or alkynyl, which may be optionally substituted, and R3 represents alkyl, alkenyl or alkynyl, which may be optionally substituted, provided that at least one of the groups R2 or R3 1
represents propargyl] We have discovered novel N-organooxycarbamic acid esters.

3, Formula I R'-0-C-N-0-R31 [wherein R1 represents alkyl, cycloalkyl, alkenyl, alkynyl or aryl, which may be optionally substituted, R2 is alkyl, represents alkenyl or alkynyl, which may be optionally substituted, and R3 represents alkyl, alkenyl or alkynyl, which may be optionally substituted, provided that at least one of the groups R2 or R3 1
represents propargyl] The N-organooxycarbamate esters are a)
In the presence of a base, hydroxylamine derivatives of the formula ■ R'-0-C-N-○HI [ [wherein R1 and R1 have the above-mentioned meanings]] are converted to the formula ■ R''-X III 1 in the presence of a base. , R3 has the meaning given above and x represents halogen or p-)lylsulfonyl] or b) R'-〇-C-Y Vl [wherein R1 has the abovementioned meaning and Y represents halogen, azide or the group -0-R'] in the presence of a base to form a carbonate of the formula VHN-0-R
3V 1, where R2 and R3 have the above meanings] or their salts with acids, or C) Formula ■ R'-0-N-0-R" In the presence of a base, hydroxylamine derivatives of the formula Vl1 in which R1 and R3 have the above meanings are prepared into a compound of the formula ■ R"-X ■ 1 in which X and R"lt have the above meanings. or d) carbamic acid halides of the formula ■ ■ Hal-C-N-0-R” ■ [wherein Hal represents halogen and R1 and R3 have the meanings given above]. It is produced by a method of reacting with compounds of the formula % [wherein R1 has the above meaning] in the presence of a base.

The compounds of the formula I are very suitable for controlling internal parasites, especially in the veterinary medicine sector. moreover,
They can also be used as insecticides, fungicides and herbicides in agricultural and forestry utilities, in domestic and sanitary utilities, and in the area of preservation of electrostatic products and materials.

Preferred compounds of formula I are those in which R1 is C1-3°-alkyl, CI-! . -alkenyl, C1-8°-cycloalkyl, CI-! . - represents alkynyl, phenyl or naphthyl, these groups are 1
One or more of the following substituents: alkyl, preferably having 1-4 carbon atoms, especially 1 or 2 carbon atoms, such as methyl, ethyl, n
- and i-propyl, and n-1i-1s- and t-butyl; alkoxy, preferably with 1-4 carbon atoms, especially 1 or 2, such as methoxy, ethoxy, n-
and i-propyloxy, and n-1i-1s- and t-butyloxy: alkylthio, preferably with 1-4 carbon atoms, especially l or 2, such as methylthio, ethylthio, n- and i-propylthio, and n-1
i-1S- and t-butylthio; carbon number is preferably l
-4, especially l or 2, and the halogen number is preferably l-5, especially l-3, wherein the halogen atoms are the same or different and the halogen atoms are preferably is fluorine, chlorine or bromine, such as trifluoromethyl and fluoro- and chloro-ethyl; the number of carbon atoms is preferably l-4, especially 1 or 2, and the number of halogens is preferably l-5, especially 1-3, where the halogen atoms are the same or different and the halogen atoms are preferably fluorine, chlorine or bromine, especially fluorine, for example trifluoromethoxy; the number of carbon atoms is preferred For l-
4, especially l or 2, and the halogen number is preferably l-5, especially l-3,
The halogen atoms here are the same or different and are preferably fluorine, chlorine or bromine,
In particular fluorine, such as trifluoromethylthio; in the case of phenyl, alkylenedioxy, preferably with 1 or 2 carbon atoms, such as methylenedioxy or ethylenedioxy; and in the case of phenyl, with preferably 1 or 2 carbon atoms; is 1 or 2 and the number of halogens is preferably 1-4,
In particular 2 or 3 halogen-substituted alkylene dioxy, in which the halogen atoms are the same or different and the halogen atoms are preferably fluorine or chlorine, especially fluorine, such as difluoromethylene dioxy, oxy, trifluoroethylenedioxy and tetrafluoroethylenedioxy; additionally halogens, preferably fluorine, chlorine, bromine and iodine; especially chlorine and bromine; nitro; carbon number per alkyl is preferably l
-4, especially l or 2, dialkylaminos, such as dimethylamino, diethylamino and methyl-n-butylamino; alkylcarbonyls preferably having 2-4 carbon atoms; preferably 2-4 carbon atoms, especially 2 or 3, such as carbalkoxy, such as carbomethoxy and carbethoxy; alkylsulfonyl, such as methylsulfonyl and ethylsulfonyl, preferably having 1 to 4 carbon atoms, especially 1 or 2; aryl, preferably having 6 or 10 carbon atoms; Sulfonyl, for example phenylsulfonyl; optionally further substituted phenyl, naphthyl, phenoxy, naphthoxy, phenylthio and naphthylthio, in which R1 is CI I-alkyl, C8-6-alkenyl or C2-6- represents alkynyl, which may be optionally substituted by halogen, in particular chlorine, fluorine or bromine, and Rs represents 08-6-alkyl, C2-6-alkenyl or C,@-alkynyl; It may be optionally substituted by halogen, especially chlorine, fluorine or bromine. Particularly preferred compounds of formula 1 are those in which R1 represents C14-alkyl, which is optionally halogen, especially chlorine or bromine, C8-, -alkoxy, such as methoxy or ethoxy, CI-.

-halogenoalkoxy, such as trifluoromethoxy,
optionally substituted by C,-,-halogenoalkylthio, such as trifluoromethylthio, or optionally substituted phenyl, or R1 further represents phenyl, which is optionally substituted with C,-,
-alkyl, especially methyl, C-, -alkoxy, especially methoxy or ethoxy, C,-,-halogenoalkoxy, especially trifluoromethoxy or trifluoromethylethoxy, Cr a-halogenoalkylthio, especially trifluoromethylthio or fluoro Chloromethylthio, C1-C1-alkylthio, especially methylthio, halogenosulfonyl, especially fluorosulfonyl or chlorosulfonyl, C,-C,-alkylsulfonyl, especially methylsulfonyl, C,-C,-halogenal°kylsulfonyl, especially trifluoro methylsulfonyl, Cl-04-halogenoalkyl, especially trifluoromethyl, methylenedioxy or ethylenedioxy optionally substituted by fluorine or chlorine,
Optionally substituted by halogen, in particular fluorine or chlorine, No, or phenoxy optionally substituted by one of the groups mentioned above, R1 is C8-6-alkyl, in particular methyl, ethyl, n-
Propyl, i-propyl or t-butyl, C8-1
- alkenyl, especially allyl, chloropropenyl, dichloropropenyl or butenyl, or c! 4-alkynyl, especially propargyl, and R3 independently of R8 represents the radicals mentioned with respect to R2.

Particularly preferred compounds of formula I are those in which R1 represents 01-4-alkyl, in particular methyl or ethyl, benzyl or phenyl, optionally halogen, in particular fluorine or chlorine, No, , CF, , o
cps, SCF,, S CF, CI.

0CHs, OCF*CF*H, -0CFtCHFO-1
-0-CH, -0 or 10-CF, -0- may be substituted, R2 is methyl, ethyl, n-propyl, i-propyl,
Butyl, pentyl, allyl, 3-chloro-prope-2-
2-chloro-propen-2-yl, 3,3-dichloropropen-2-yl, but-2-nyl or propargyl, in which R3 is written independently of R1 with respect to R2; It represents a group.

Particular mention may be made of the following compounds of formula I: RI
R2R3 CJs CHs--CHI-CH=CHC
1 c, H, CsH, --CH, -CH-rich CH.

CIII 1C3H7--CHI-c)I
<)IffiC! H1-CHI-CI-CHI
-Cut-CH"CHzC!Hs -CH
, -CH=CHC1-CHI-CH=CHC! Hs
-CHz-CHHL -CHz-CH”
CHICtHs -CL-CH=CH-C
Hs-CHI-CH=CHCxHs
-CHx-CH=CH* -CHI-CH"C
HICH, -CH, -CH, -CH=CH.

CH, -CH, -CH, -CH=CHlCH3-IC
3H7--Cu5-CH=CHlCH3--CHI-C
HsCHz -CHI-CH=CHC1I
R1R3 CJs-CH3--CHI-C H C2H, -1C8H, --CH, HC2Hs--
CH2-CHsCHx -CTo-C"CHC!
H1--CHI-C sum H-CHI-CEHC, Hl--
CI, -CH=CHC1-CH, -C sum HCzHs--
CHx-CH=CH1x-co, -c=cuC*
Hs--CHs-CBr=CHBr-CI, -C
:CHC, Hs-CsHs--Cu5-C:CHCHs
-C! Hs--CHI-CEH CHs--CHx-CH=CHs-CH*
-C button HCH, --CH, -CH=CHC1-CH,
-C yoke HCH, --CH, -C:CH-CH, -C to H
CHs--CHI-CH=CH-Cu5-CHI-C
:Benzyloxycarbonyl-N in CH method 3a
When -propargyl hydroxylamine is used as the hydroxylamine derivative of formula (1) and allyl bromide is used as the compound of formula (2), the reaction process can be represented by the following reaction scheme: R1, R1 and R3 are of the formula Preference is given to using compounds of formulas 1 and 2, which have the meaning indicated as preferred and particularly preferred in the case of compounds of I, and in which X represents chlorine, bromine or I)-tolylsulfonyl. Ru.

The following compounds of formula (1) are individually mentioned: 2N-hydroxy-N-methyl-ethyl carbamate, N-hydroxy-N-methyl-methyl carbamate, N-hydroxy-N-allyl-ethyl carbamate, N- hydroxy-
N--11' methyl robargyl lupamate, N-hydroxy-N-ethyl-phenyl carbamate, N-hydroxy-N-3-chloroallyl-carbamindroxy-N-crotyl-carbamate isopropyl,
Phenyl N-hydroxy-N-propargyl-carbamate, p-N-hydroxy-N-allyl-carbamate
Chlorophenyl, N-hydroxy-N-7'lobargyl-cyclopropylcarbamate.

Compounds of formula (1) are known or can be prepared by methods analogous to known methods (Houben-Uniil, Vol. 84, p. 255, Stuttgart, 1983).

The following compounds may be mentioned individually: methyl chloride, bromide or tosylation, ethyl, propyl, i-propyl, n-butyl, S-butyl, allyl, crotyl, 3-
Chloroallyl, 3,3-dichloroallyl, 2,3-dibromoallyl, flopargyl and 2-butynyl.

Compounds 2) are known or can be produced by methods similar to known methods.

The reaction is carried out at a temperature of 0-200°C, preferably 20-100°C.
, and particularly preferably at the boiling point of the diluent.

Diluents that can be used are all inert solvents. These include in particular aliphatic and aromatic optionally halogenated hydrocarbons, such as pentane, hexane, heptane, cyclohexane, petroleum ether, benzine, ligroin, benzene, toluene, xylene, methylene chloride, ethylene chloride. , chloroform, carbon tetrachloride, chlorobenzene and 0-dichlorobenzene, and alcohols such as methanol, ethanol, isopropanol and butanol, and ethers such as diethyl ether, dibutyl ether, glycol dimethyl ether, diglycol dimethyl ether, tetrahydrofuran and dioxane. , and ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, and esters such as methyl and ethyl acetate, and nitriles,
Examples include acetonitrile, propionitrile, benzonitrile and glutaric dinitrile, and amides such as dimethylformamide, dimethylacetamide and N-methyl-pyrrolidone, as well as dimethylsulfoxide, tetramethylenesulfone and hexamethylphosphoric triamide.

Bases that can be used are inorganic and organic bases. Among the bases that may be mentioned are alkali metal and alkaline earth metal hydroxides, carbonates, hydrogen carbonates and alcoholates, as well as amines, such as especially tertiary amines, such as trimethylamine, triethylamine,
N-methylmorpholinelysine, diazabicyclo(4.3.0)-undecane (
DBU), 1,4-diazabicyclo (2.

2,2)-octane (DABCO) and diazabicyclo(3.2.0)nonene (DBN).

The compounds of formulas (1) and (2) are used in approximately equimolar ratios to each other. Excess amounts of either compound do not provide any substantial advantage.

At the end of the reaction, the diluent is distilled off and the compounds of formula 1 are isolated in a manner known per se, for example by extracting them from the residue using a suitable solvent, such as ether. . Compounds of formula I can be purified in customary manner, for example by distillation.

When ethyl chloroformate is used as the carbonate ester of formula (1) and N-allyl-0-propargylhydroxylamine is used as the hydroxylamine derivative of formula V in method 3b, the reaction steps are represented by the following reaction scheme: Preference is given to using compounds of the formulas I and V in which RISR1 and R3 which can have the meaning indicated as preferred and particularly preferred in the case of compounds of the formula I, and in which Y represents chlorine Ru. Compounds of formulas 1 and V are known or can be prepared by methods analogous to known methods (European Publication No. 29.171).

The following compounds of formula (2) may be mentioned individually: methyl chloroformate, ethyl chloroformate, n-pyl chloroformate, isopropyl chloroformate, cyclopropyl chloroformate, benzyl chloroformate, phenyl chloroformate, chloroN
p-chlorophenyl I acid, p-nitrophenyl chloroformate and p-tolyl chloroformate.

The following compounds of formula V may be mentioned individually.

N-diallylhydroxylamine, O,N-dipropargylhydroxylamine, 0-ethyl-N-allylhydroxylamine, 0-methyl-N-propargylhydroxylamine, 0-propargyl-N-ethylhydroxylamine, 0-allyl-N -Methylhydroxylamine, 0-allyl-N-7' lobargylhydroxylamine, o-crotyl-N-i-propylhydroxylamine, 0-3-chloro-allyl-N-propargylhydroxylamine, O-3,3 -dichloroallyl-N-allylhydroxylamine, 0-benzyl-N-3-chloroallylhydroxylamine and 0-methyl-N-2-
Butynylhydroxylamine.

Hydroxylamines of formula V can be used in bulk with acids, for example in the form of hydrochloride salts.

The reaction is carried out at a temperature of -50-50°C, preferably 0-30°C and particularly preferably room temperature.

Diluents that can be used are water and all inert solvents. These include in particular aliphatic and aromatic optionally halogenated hydrocarbons, such as pentane,
hexane, heptane, cyclohexane, petroleum ether,
benzine, ligroin, benzene, toluene, xylene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and 0-dichlorobenzene, and alcohols such as methanol, ethanol, impropatol and butanol, and ethers,
For example diethyl ether, dibutyl ether, glycol dimethyl ether, diglycol dimethyl ether, tetrahydroctane and dioxane, and ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, and esters such as methyl and ethyl acetate, and Nitriles, such as acetonitrile, propionitrile,
Included are benzonitrile and glutaric acid dinitrile, and amides such as dimethylboramide, dimethylacetamide and N-methyl-pyrrolidone, as well as dimethylsulfoxide, tetramethylenesulfone and hexamethylphosphoric triamide.

Bases that can be used are inorganic and organic bases. Among the bases that may be mentioned are alkali metal and alkaline earth metal hydroxides, carbonates, hydrogen carbonates and alcoholates, as well as amines, such as especially tertiary amines, such as trimethylamine, triethylamine,
N-methylmorpholine, pyridine, picolines, N-ethylpyrrolidine, diazabicyclo(4,3,0)-undecane (DBU), 1,4-diazabicyclo(2°2.2)-octane (DABCO) and diazabicyclo (3,2,0) nonene (DBN).

The compounds of formula (1) and V are used in approximately equimolar ratios to each other. Excess amounts of either compound do not provide any substantial advantage.

The reaction is preferably carried out in an aqueous solution of hydrochloride salts of hydroxylamine derivatives of formula V and carbonate esters of formula I in the presence of an aqueous organic base such as potassium hydroxide or carbonate or sodium hydroxide or carbonate. Ru. At the end of the reaction, compound I is isolated in a manner known per se, for example by extraction with a suitable solvent. The extract is washed e.g. several times with water, dried over sodium sulfate,
And then the solvent is removed. The compound of formula 1 can then be purified in conventional manner, for example by distillation.

When benzyl N-propargyloxy-carbamate is used as the hydroxylamine derivative of formula (1) and n-hexyl bromide is used as the compound of formula (2) in process 3c, the reaction step can be represented by the following reaction scheme: -11,3 R1, R1 and R3 have the meanings indicated as preferred and particularly preferred in the case of compounds of formula I, and X represents chlorine, bromine or p-tolylsulfonyl. Compounds of formulas (1) and (2) are preferably used. Compounds of formulas (1) and (2) are known or can be prepared by methods analogous to known methods (Houben-Uniil, Vol. 64, p. 255, Stuttgart, 1983).

The following compounds of the formula (1) are individually mentioned: ethyl di-N-ethoxycarbamate, ethyl N-allyloxycarbamate, ethyl N-propauloxycarbamate,
Methyl N-crotyloxycarbamate, Methyl N-(3-chloroallyloxy)-rubamate, Phenyl N-propargyloxycarbamate, Berchlorophenyl N-allyloxycarbamate and N-2-butynyloxycarbamate Phenyl.

The following compounds of the formula (1) may be mentioned individually: methyl chloride, bromide or tosylation, ethyl, propyl, i-propyl, n-butyl, S-butyl, allyl, crotyl, 3-
Chloroallyl, 3,3-dichloroallyl, 2,3-dibromoallyl, propargyl and 2-butynyl.

If it is desired to prepare compounds of formula I in which R2 represents methyl or ethyl, dimethyl sulfate or diethyl sulfate can also be used as compounds of formula (1).

The reaction is carried out at a temperature of 0-200°C, preferably 20-130°C,
It is particularly preferably carried out at the boiling point of the diluent.

Diluents that can be used are all inert solvents. These include in particular aliphatic and aromatic optionally halogenated hydrocarbons, such as pentane, hexane, heptane, cyclohexane, petroleum ether, benzine, ligroin, benzene, toluene, xylene, methylene chloride, ethylene chloride. , chloroform, carbon tetrachloride, chlorobenzene and 0-dichlorobenzene, and alcohols such as methanol, ethanol, isopropanol and butanol, and ethers such as diethyl ether, dibutyl ether, glycol dimethyl ether, diglycol dimethyl ether, tetrahydrofuran and dioxane. , and ketones, such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, and esters, such as methyl and ethyl acetate, and nitriles, such as acetonitrile, propionitrile, benzonitrile and dinitrile glutarate, and amides, such as Dimethylformamide, dimethylacetamide and N-
Included are methyl-pyrrolidone, as well as dimethyl sulfoxide, tetramethylene sulfone and hexamethyl phosphoric triamide.

Bases that can be used are inorganic and organic bases. Among the bases that may be mentioned are alkali metal and alkaline earth metal hydroxides, carbonates, hydrogen carbonates and alcoholates, as well as amines, such as especially tertiary amines, such as trimethylamine, triethylamine,
N-methylmorpholine, lysine, picolines, N-ethylpyrrolidine, diazabicyclo(4,3,0)-undecane (DBU), 1,4-diazabicyclo(2°2.2)-octane (DABCO), and It is diazabicyclo(3,2,0)nonene (DBN).

The compounds of formulas (1) and (2) are used in approximately equimolar ratios to each other. Excess amounts of either compound do not provide any substantial advantage.

At the end of the reaction, the diluent is distilled off and the compounds of formula I are then isolated in a manner known per se, for example by extracting them from the residue using a suitable solvent such as ether. do. Compounds of formula (1) can be purified by conventional methods, for example by distillation.

When N-(2-butenoxy)-N-propargylcarbamoyl chloride is used as the carbamic acid halide of formula (1) and phenol is used as the compound of formula (1) in process 3d, the reaction mechanism is represented by the following reaction scheme: Formula I in which Hl, R2 and R3 have the meanings indicated as preferred and particularly preferred in the case of compounds of formula I, and Hal represents chlorine or bromine;
The compounds of (1) and (2) are preferably used.

Compounds of formulas (1) and (2) are known or can be prepared by methods analogous to known methods (Houben-Uniil, Vol. R4, p. 255, Stuttgart, 1983).

The following compounds of formula (1) may be mentioned individually: N-methoxy-N-allylcarbamoyl chloride, N-allyloxy-allylcarbamoyl chloride, N-ethoxy-N-propargylcarbamoyl chloride, N-allyloxy-N- chloride.
Propargylcarbamoyl, N-propargyloxy-N-dithylcarbamoyl chloride, N-benzyloxy-N-propargyllupamoyl chloride and N-propargyloxy-N-propargyl-carbamoyl chloride.

The following compounds of the formula
1i-1S- and L-butanol, pentanols,
Hexanol, cyclohexanol, allyl alcohol, globargyl alcohol, phenol, p-cresol, p-chlorophenol, σ-naphthol and p-
Nitrochlorophenol.

The reaction is carried out at a temperature of -50-50°C, preferably 0-30°C and particularly preferably room temperature.

Diluents that can be used are water and all inert solvents. These include in particular aliphatic and aromatic optionally halogenated hydrocarbons, such as pentane,
hexane, heptane, cyclohexane, petroleum ether,
benzine, ligroin, benzene, toluene, xylene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and 0-dichlorobenzene, and alcohols such as methanol, ethanol, impropatol and butanol, and ethers,
For example, diethyl ether, dibutyl ether, glycol dimethyl ether, diglycol dimethyl ether,
Tetrahydrofuran and dioxane, and ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, such as methyl and ethyl acetate, and nitriles, such as acetonitrile, propionitrile, benzonitrile and dinitrile glutarate, and amides. , such as dimethylformamide, dimethylacetamide and N-methyl-pyrrolidone, as well as dimethylsulfoxide, tetramethylenesulfone and hexamethylphosphoric triamide.

Bases that can be used are inorganic and organic bases. Among the bases that may be mentioned are alkali metal and alkaline earth metal hydroxides, carbonates, hydrogen carbonates and alcoholates, as well as amines, such as especially tertiary amines, such as trimethylamine, triethylamine,
N-methylmorpholine, pyridine, picolines, N-ethylpyrrolidine, diazabicyclo(4,3,0)-undecane (DBU), 1,4-diazabicyclo(2°2.2)-octane (DABCO) and diazabicyclo (3,2,O)nonene (DBN).

The compounds of formulas (1) and (2) are used in approximately equimolar ratios to each other. Excess amounts of either compound do not provide any substantial advantage.

At the end of the reaction, the diluent is distilled off and the compounds of the formula I are isolated in a manner known per se, for example from the residue, for example by extraction with a suitable solvent. The extract is washed several times with water, dried, for example over sodium sulfate, and then the solvent is removed. Compounds of formula 1 can be purified in conventional manner, for example by distillation.

The active compounds have a favorable toxicity towards warm-blooded animals and control pathogenic endoparasites occurring in humans as well as domestic and domestic animals, farm animals, zoos, laboratories and experimental animals and companion animals. suitable for. They are effective against all or individual growth stages of pests and against resistant and normally sensitive species. Control of pathogenic endoparasites is said to reduce disease, mortality, and production loss (e.g. in the production of meat, milk, wool, leather, eggs, honey, etc.), resulting in The use of active substances allows for more economical and easier animal husbandry. Pathogenic endoparasites include cestodes, trematodes, nematodes and talonia, especially the following: Pseudophyllides
a), such as Schiff (Oposulium sp.
llobothrium spp,), Spirometra spp, Schistocephalus spp,
Ligula species (Ligula 5pp-), Bostridium @
(Bothridium spp,), Diph 1 ogonoporus sp.
p.)) Cyclophyllidea
those of Mesocestoides sp.
oides spp, ), Anoprocephala spp.
procephala spp・)s Paranobrocephala spp.
, Moniezia spp, Thysanosomsa spp,
Thysan iez 1aspp,
), Avitellina spp.
), Stilesia spp, ), Cittaenia 5pp-)
, Andyra spp, Bertiella spp, Taenia spp, Echinococcus spp.
hinococcus s99. ), Hidachigera species (H
ydatigera spp, )s Davainea sp.
Davainea spp, ), Raliechina sp.
illietina spp, ), Hymelpis sp.
menolepis spp,), Echirubis species (E
chinolepis spp, ), Echinochochil species (
Diorchis spp., Diorchis spp., Dipyridium spp.
ipy l id ium spp, ), joyeuxiella spp, ), Diplopylidium spp, )
, those of the Monogenea lateral network, such as Gyrodactylus sp.
p, ), Dactylogyrus sp.
spp, ), Polystoma species (Patystoma 5
l) I), )% Digenea lateral webs, such as Diplostomum spp, Posthodiplosto
mum 5p1)・)% Schistuma species
osoma spp,), Trichobilharzia sp.
ichobilharzia spp,), Ornithobilharzia spp.
pp, ), Austrovirha/L/Sia sp.
obilharzia spp, ), Gigantobilharzia spp,
), Leucochloridium sp.
ium spp, ), Brachylaima spp.
aima sppυ, Echinostoma sp.
toma spp, ), Ech.
inoparyphium spp, ), Echinochasmus spp, Hypoderaeum spp,
, 7 Fasciola spp, Fasciolides 5pp-,
Fsciolopsis spp.
), Cyclocoelum sp.
p, ), Typhlocoelum sp.
spp, ), Paramfistomum species (Paraa+p
histomum spp, ), Calicophoron species (C
alicophoron spp,), Cotylophoron species (Cotylophoron 5pp->s Gigantocotyle spp,),
Fischoederius sp.
spp, ), Gastrothiracus sp.
ylacus spp, ), Notocotisle spp.'' (NOt
oCOtylus spp, ), Catatrobis species (Ca
tatropis spp, ), Plagiorchis species (P
lagiorchis spp, ), Prostogonimus spp, Dicrocoelium spp,
), Eurytrema spp.
, Troglotrema spp.
), Parago-nimus s
pp, ), Collyriclum 11 species (Collyriclum
spp, ), Nanophyetus sp.
us 5pp-), Opistho spp.
rchis spp, ), Chronorchis species (C1ono
rchis spp, ), Metorc spp.
his spp+), Heterophies sp.
phyes spp, ), and Metagonimus sp.
tagonimus spp,), Enopridales (En
oplida), such as Tricris sp.
huris spp, ), Cabiraria spp.
1aria spp,), Triphmosoides species (Tr.
i chomoso 1desspp, ), and Trichinella spp, of the order Rhabditia, such as Micronema spp, Strongyloides spp.
), those of the order Strongylida, such as Stronylus spp.
pp-), Triodontophorus sp.
ophorus spp, ), Ethagodontus spp. (
Oesophagodontus spp, ), Trichonema spp, Gyalocephalus spp,
), Cylindo 077 Lynx species (Cylindroph
arynx spp, ), Boteliostomum species (Pot
eriostomum spp,), Cyclococercus sp.

cocercus 5pp-), Silicostephanus sp.

5tephanus spp+)”, Oesophagostomum species (Oes.

phagostoa+um spp, ), Chabertia spp., Stephanurus spp., Ancylosto+aa spp., Uncinaria spp., Bunostomum spp. stoa+um spp, ), Globocaphalus spp. ,
), Syngamus spp, Cyathostoma spp,
Metastrongylus sp.
spp, ), Dictyokaurus sp.
ulus spp, ), Muelle spp.
rius spp,), Protostrongylus sp.
ostrogylus spp, ), Neostrongylus spp, ) t
Cystocaulus spp.
, Pneumasstrongylus sp.
ngylus 5pp-), Subicocaurus sp.
cocaulus spp,), gill 7 year old strongylus species (Elaphostrongylus spp,),
Pare 1aphst
longylus spp, ), Crenosoma spp.
nosoa+aspp, ), Barakrenotsuma species (Par
acrenosoma spp,), Angiostrongylus spp,
, Aelrostrongylus sp.
ylus spp, ), Fifaroides sp.
oides spp, ), Rosaphylloides spp. (Pa.
rafilaroides spp,), Trichostrongylus spp.
), Haemonchus spp.
), Ostertagia spp.
, ), Marshallagia sp.
5ppL), Cooperiaspp,
), Nematodirus spp.
), Biost 0F 1111 species (Hyostrongy
lus spp, ), Operiscoides species (Obeli
scoides 5pp-), Amidostomum species (Am
idostomua+ spp, ), and Ollulanus spp, ), those of the order Oxyurida, such as Oxylaris spp.
Oxyuris 5pp-), Enterobius sp.
terobius spp, ), Patusarurus sp.
ssalurus spp, ), Schiffasia species (Syp
hacia 5pp-), Aspicullis sp.
culuris spp, ), and Heterakis sp. (H
eterakis 5pp-), Ascaridiales (As
caridia), such as those of Ascaris sp.
aris 5pp-), Toxascaris sp.
caris spp, ), Toxocara spp.
ra spp, ), Parascaris sp.
is spp, ), Anisakis spp.
5pp-), and Ascaridi sp.
a spp, ), those of the order Spirurida, such as Gnathostoma spp, Physaloptera spp,
), Thelaziaspp, Gongylonema spp, Habronema spp, Parabronema spp, Draschiaspp, Dracunculus spp. acunculus spp,).

Those of the order Filariida, such as Stephanofilaria sp.
ia 5pp-), Parafilaria sp.
aria spp, '), Setaria spp.
spp, ), Loa spp, ), Dirofilaria spp, ), Lito+nosoides spp,
), Brugia spp, ), Wuchereria spp, and Onchocerca 5l I),
)% Gigantorhynch
ida), such as those of Filicolis sp.
llis 5pp-), Monilia ormis sp.
liformis spp, ), Macracanthorhynchus spp.
), and Prostenortis sp.
rchis Sl)ri・)+1 Useful domestic animals include:
Mammals such as cows, horses, sheep, pigs, goats, camels, buffaloes,
Donkeys, rabbits, deer and reindeer, hair animals such as mink, chinchillas and raccoons, birds such as chickens, geese, turkeys and ducks, freshwater and saltwater fish such as rainbow trout, carp and eels, reptiles and insects such as honey bees. and silkworms.

Laboratory and experimental animals include mice, mice,
Includes guinea pigs, golden hamsters, dogs and cats.

Pets include dogs and cats.

The active compounds can be used prophylactically or therapeutically.

The active compounds are in the form of preparations suitable for direct or enteral, parenteral, dermal, intranasal administration, and by treatment of the environment.
Alternatively, molded articles containing the active compound, such as strips, plates, tapes, collars, ear tags, leg bands or marking devices, are used as auxiliaries.

Enteral use of the active compound is for example in the form of powders, tablets, capsules, pastes, drenches, granules, solutions, suspensions and emulsions, polys, or drug-filled feeds or drinking water for oral administration. It is administered orally. Dermal use takes place, for example, in the form of dipping, spraying or pouring and drop preparations. Parenteral use takes place, for example, in the form of an injection (intramuscular, subcutaneous, intravenous or intraperitoneal) or by implantation.

Suitable preparations are: solutions such as injection solutions, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin and in body cavities, cold infusions and gels;
Emulsions and suspensions for oral or dermal use and injection; semi-solid preparations, preparations in which the active compound is added in an ointment matrix or in an oil-in-water or water-in-oil emulsion matrix; solid preparations 10 For example powders, premixes or concentrates, granules, pellets, tablets, polys or capsules; aerosols and inhalants as well as shaped articles containing the active compound.

Injectable solutions are applied intravenously, intramuscularly and subcutaneously.

Injectable solutions are prepared by dissolving the active compound in a suitable solvent and adding additives such as solubilizing agents, acids, bases, buffer salts, antioxidants and preservatives. The solution is sterile filtered and bottled.

Solvents include: physiologically acceptable solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerol,
Propylene glycol and polyethylene glycols, N-methyl-pyrrolidone and mixtures thereof.

If appropriate, the active compound can be dissolved in physiologically acceptable vegetable or synthetic oils suitable for injection.

Those which may be mentioned as solubilizers are those which promote the dissolution of the active compound in the main solvent and prevent its precipitation. Examples are polyvinylpyrrolidone, polyoxyethylated castor oil and polyoxyethylated sorbitan esters.

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

Oral solutions can be used directly. Concentrates are used orally after prior dilution to the working concentration. Oral solutions and concentrates are prepared as described above for injectable solutions, and sterilization operations can be omitted.

Solutions for use on the skin may be dropped, dabbed, rubbed in, sprinkled or sprayed. These solutions are prepared as described above for injection solutions.

It is advantageous to add a thickening agent during production. The thickening agent is
Inorganic thickeners-1 such as bentonites, colloidal silicic acid and aluminum monostearate, and organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates.

Gels are applied or brushed onto the skin or added into body cavities. Gels are prepared by adding an amount of a thickening agent to a solution prepared as described above for injection solutions such that a clear composition having an ointment-like consistency is produced. The thickening agents used are those mentioned above.

Pour preparations are poured or sprinkled onto a limited area of the skin, the active compound penetrates through the skin and has systemic activity.

Pour-on preparations are prepared by dissolving, suspending or emulsifying the active compound in suitable solvents or solvent mixtures that can be tolerated by the skin.

If appropriate, other additives are added, such as dyes, absorption-enhancing substances, antioxidants, light stabilizers and adhesives.

Solvents include: water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols such as benzyl alcohol, phenylethanol and phenoxyethanol, esters such as ethyl acetate, acetic acid. butyl and benzyl benzoate, ethers such as alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether and diethylene glycol monobutyl ether, ketones such as acetone and methyl ethyl ketone, aromatic and/or aliphatic hydrocarbons, vegetable or synthetic Oils, dimethylformamide, dimethylacetamide, N
-Methylpyrrolidone and 2-dimethyl-4-oxy-
Methylene-1,3-dioxolane.

Dyes are all dyes approved for use on animals, and they can be dissolved or suspended.

Examples of absorption-promoting substances are dimethyl sulfoxide, spreading oils such as isopropyl myristate, dipropylene glycol pera rugonate and silicone oils, fatty acid esters, triglycerides and fatty alcohols.

Antioxidants are sulphites or metahyposulphites, such as potassium metahyposulphite, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole or tocopherol.

A light stabilizer is, for example, novantisolic acid.

Adhesives include, for example, cellulose derivatives, starch derivatives,
Polyacrylates, natural polymers such as alginates, and gelatin.

Emulsions can be used orally, cutaneously or as injections.

Emulsions are either water-in-oil or oil-in-water.

They dissolve the active compound in a monohydric or hydrophilic phase and incorporate it with suitable emulsifiers and, if appropriate, such as dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers and viscosity-increasing substances. With other auxiliaries such as substances for
It is produced by homogenization with other phases of solvent.

Hydrophobic phases (oils) include: paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil and castor oil, synthetic triglycerides such as caprylic/capric biglyceride. , c, -1□ chain length vegetable fatty acids or other specially selected naturally occurring fatty acids, triglyceride mixtures, saturated or unsaturated fatty acids which may also contain hydroxyl groups and Ca/Cr. - Partial glyceride mixtures of fatty acids with di- and diglycerides.

Fatty acid esters, such as ethyl stearate, di-n-butyryl adipate, hexyl laurate and dipropylene glycol pelargonate, branched fatty acids of medium chain length and saturated fatty alcohols of C, -C, chain length. Isopropyl myristate, isopropino palmitate, Crz-C8, caprylic/capric esters of chain-length saturated fatty alcohols, inglovir stearate, oleyl oleate, decyl oleate, ethyl oleate and Ethyl lactate, waxy fatty acid esters such as synthetic uropigil gland fat, dibutyl phthalate and diisopropyl adipate, and related ester mixtures of the latter.

Fatty alcohols, such as intridecyl alcohol,
2-Oftoldodecanol, cetylstearyl alcohol and oleyl alcohol.

Fatty acids such as oleic acid and mixtures thereof.

Hydrophilic substrates include water, alcohols such as propylene glycol, glycerol and sorbitol, and mixtures thereof.

Emulsifiers include: nonionic surfactants such as polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate and glycerol monostearate, Polyoxyethyl stearate and alkylphenyl polyglycol ethers: amphoteric surfactants, such as di-Na N-lauryl-β-iminodipropionate or lecithin; anionic surfactants, such as sodium lauryl sulfate, fatty alcohol ethers Sulfates and mono/dialkyl polyglycol ether-orthophosphate monoethanolamine salts; and cationic surfactants such as cetyltrimethylammonium chloride.

Other auxiliaries include: substances that increase the viscosity and stabilize the emulsion, such as carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates,
Alginates, gelatin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes, colloidal silicic acid or mixtures of the above substances.

Suspensions can be used orally, cutaneously or as an injection. They contain active compounds as appropriate, such as wetting agents, dyes, etc.
They are prepared by suspending them in a suitable carrier liquid with the addition of additives such as absorption enhancers, preservatives, antioxidants and light stabilizers.

Carrier liquids include all homogeneous solvents and solvent mixtures.

Examples of the wetting agent (dispersing agent) include the above-mentioned surfactants.

Other auxiliaries that may be mentioned are those mentioned above.

Semi-solid formulations can be administered orally or dermally. They differ from the suspensions and emulsions mentioned above only in their relatively high viscosity.

For preparing solid preparations, the active compound is mixed with suitable excipients, optionally with the addition of auxiliaries, and the mixture is brought into the desired form.

Mentioned as excipients are all physiologically acceptable solid inert substances. Substances that can be used are inorganic and organic substances. Inorganic substances are, for example, sodium chloride, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, silicates, aluminas, precipitated or colloidal silicon dioxide and phosphates.

Organic substances include, for example, sugars, cellulose, food and feedstuffs such as milk powder, animal flour, cereal flour and shredded cereals,
and starches.

Auxiliary agents are the preservatives, oxidation inhibitors and dyes mentioned above.

Other suitable auxiliaries are lubricants and slip agents, such as magnesium stearate, stearic acid, talc and bentonites, disintegration-promoting substances, such as starch or cross-linked polyvinylpyrrolidone, binders, such as starch. , gelatin or linear polyvinylpyrrolidone, and a dry binder such as microcrystalline cellulose.

The active compounds can also be present in the preparations in mixtures with synergists or with other active compounds acting against pathogenic endoparasites. Examples of such active compounds are L-2,3,5,6-tetrahydro-6-phenylimidazothiazole, benzimidazole carbamates, praziquantel, vilantyl and 7-evantel.

Ready-to-mix preparations contain 10 ppm-20% by weight of active compound
, preferably 1-10% by weight of O.

Preparations that are diluted before use contain the active compound at 0°5-90°C.
% by weight, preferably 5-50% by weight.

In general, it has proven advantageous to administer amounts of from about 1 to about 100 mg of active compound per kg of body weight per day to obtain effective results.

Example A In vivo nematode test Ascarides / Toxascar leonina in nature
A dog infected with isleonina) was treated. The active compound was administered orally in pure active compound form in gelatin capsules.

Activity was determined by counting the number of roundworms excreted with stool. The number of roundworms excreted without dying due to treatment was determined after the dogs were dissected.

3 Toxas liss. 25 leonina Example B In vivo nematode test Hookworm / Large experimental test of Ancylostoma caninum
.

ma caninum) or Unicinaria 5tenocphal
Dogs infected with a) were treated once after the incubation period of the parasite had passed. The active compound was administered orally in pure active compound form in gelatin capsules.

Activity was determined by counting the number of roundworms excreted with stool. The number of roundworms excreted without dying due to treatment was determined after the dogs were dissected.

3 Unicinaria 25!1U19 In-vivo nematode test Nippo strongilius brasiliensis (Nipp
ostrongylus brasiliensis)
/ Mice Experimentally infected rats with Nitubostrongilios brasiliensis were continuously infected for 3 days starting 6 days after infection.
The patient was treated orally using a stomach tube for several days. Animals were sacrificed 12 days after infection and parasite numbers were determined.

Indicates the active compound concentration (effective dose) at which at least 95% of the parasites are dead: 52 100 Examples In Vivo Nematode Test Haemonchus c.
Sheep experimentally infected with Haemonchus chondrus were treated after the incubation period of the parasite had passed.

The active compound was administered orally in pure active compound form in gelatin capsules.

Activity was measured by counting the number of roundworms excreted with stool before and after treatment.

Complete cessation of egg excretion after treatment means that the roundworms have been eradicated or have been so damaged that they can no longer lay eggs (effective dose).

The active compounds tested and effective doses are shown in the table below.

Example E In Vivo Nematode Test Trichostrongylus colpriformis (Tri
chostrongylus colubriforn
+is)/Sheep Sheep experimentally infected with Trichostrongylus colubriformis were treated after the incubation period of the parasite had passed. The active compound was administered orally in pure active compound form in gelatin capsules.

Activity was measured by counting the number of roundworm eggs excreted with stool before and after treatment.

Complete cessation of egg excretion after treatment means that the roundworms have been eradicated or have been so damaged that they can no longer lay eggs (effective dose).

The active compounds tested and effective doses are shown in the table below.

30 2.514
t.

41O Example F In vivo nematode test Faciloa hepati
ica) / Mice Mice experimentally infected with Metacercania 7. A. hepatica were treated orally using a stomach tube for 3 consecutive days after infection. Animals were sacrificed 2 weeks after infection and the number of young liver flukes in the liver parenchyma was determined.

The doses required to obtain a 95% reduction in parasites (effective doses) compared to the untreated control are shown in the table below: Preparation Examples a) N-organos of formula I according to method 3'a) General instructions for the preparation of oxycarbamic acid esters: 6 g of 0.1 mol of N-alkyl-N-hydroxy-carbamic ester of formula 1 and 0.1 mol of alkylating agent of formula 2
of potassium hydroxide in 30 ml of ethanol and the mixture was boiled under reflux for 5 hours. The alcohol was distilled off and the crude ester was extracted with ether. After evaporating the ether, the residue was distilled in vacuo.

b) General instructions according to method 3b) 0.1 mol of N,O-dialkylhydroxylamine hydrochloride of formula (V), 25 ml of water and 100 ml of ether are provided and 0.2 mol of sodium bicarbonate was added at room temperature with vigorous stirring. The mixture was then stirred at room temperature for 40 minutes, then cooled to 0°C and heated to 0°C.
．． 1 mol of chloroformic acid ester of formula (1) was added dropwise.

The mixture was then stirred at room temperature for 24 hours, the ether phase was separated, dried over Na, SO, and concentrated. The residue was analyzed (gas chromatography) and vacuum distilled as appropriate.

C) General instructions according to method 3c) 0.1 mol of N-alkoxycarbamate of formula
1 of methanol and 10 ml of water, and 0.1 mol of alkylating reagent of formula (1) was added at room temperature. The mixture was then stirred at room temperature for 48 hours, the alcohol was evaporated and the residue was extracted with ether. The ether extract was dried, the ether was distilled off, and the residue was distilled.

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

Claims (1)

[Claims] 1. Formula I for controlling internal parasites ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I [In the formula, R^1 represents alkyl, cycloalkyl, alkenyl, alkynyl or aryl] R^2 represents alkyl, alkenyl or alkynyl, which may be optionally substituted, and R^3 represents alkyl, alkenyl or alkynyl, which may be optionally substituted; may be optionally substituted] Use of N-organooxycarbamic acid esters. 2. Formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I [In the formula, R^1 represents alkyl, cycloalkyl, alkenyl, alkynyl, or aryl, which may be optionally substituted, R^2 represents alkyl, alkenyl or alkynyl, which may be optionally substituted, and R^3 represents alkyl, alkenyl or alkynyl, which may be optionally substituted, provided that the group R^ At least one of 2 or R^3 represents propargyl.] Novel N-organooxycarbamic acid esters. 3. Formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I [In the formula, R^1 represents alkyl, cycloalkyl, alkenyl, alkynyl, or aryl, which may be optionally substituted, R^2 represents alkyl, alkenyl or alkynyl, which may be optionally substituted, and R^3 represents alkyl, alkenyl or alkynyl, which may be optionally substituted, provided that the group R^ At least one of 2 or R^3 represents propargyl] In the method for producing N-organooxycarbamic acid esters, a) Formula II ▲There are mathematical formulas, chemical formulas, tables, etc.▼II [In the formula, R ^1 and R^2 have the meanings given above] in the presence of bases to form hydroxylamine derivatives of the formula III R^3-XIII [wherein R^3 has the meanings given above and X is halogen or p-tolylsulfonyl], or b) Formula IV ▲ Numerical formula, chemical formula, table, etc. ▼IV [wherein R^1 has the above meaning, and Y represents a halogen, azide, or a group -O-R^1] In the presence of a base, carbonate esters of the formula V ▲There are mathematical formulas, chemical formulas, tables, etc.▼V [In the formula, R^2 and R^3 has the above meaning] or their salts with acids, or c) Formula VI ▲There are mathematical formulas, chemical formulas, tables, etc.▼VI [wherein R^1 and R^ 3 has the abovementioned meaning] with compounds of formula VII R^2-XVII [wherein X and R^2 have the abovementioned meaning] in the presence of a base. , or d) Carbamic acid halides of the formula VIII ▲There are mathematical formulas, chemical formulas, tables, etc.▼VIII [In the formula, Hal represents a halogen, and R^2 and R^3 have the above meanings] are converted into bases. A method of reacting with compounds of the formula IX R^1-OHIX, in which R^1 has the abovementioned meaning, in the presence of. 4. At least one type of formula (
An internal parasite extermination agent characterized by containing the N-organooxycarbamate ester of I). 5. The N-organooxycarbamate ester of formula (I) described in claim 1 is combined with an extender and/or
Or, a method for producing an internal parasite repellent, which is characterized by mixing it with a surfactant. 6. Use of the N-organooxycarbamate ester of formula (I) according to claim 1 for producing an internal parasite repellent.