DE19515296A1 - Use of oxazoline derivs. - Google Patents

Abstract

Use of oxazoline derivs. of formula (I), other than 2-(2,6-difluorophenyl)-4-(4-(4-trifluoromethoxyphenyl)-phenyl)-2-oxazo line, for controlling endoparasites in humans and other animals is new: B = opt. substd. alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl; A = A' or ZA'; A' = opt. substd. aryl, aryloxy, heteroaryl or heteroaryloxy; Z = a divalent gp.; R = H; or A+R forms an opt. substd. spirocyclic 3- to 6-membered ring which opt. contains one or more heteroatoms (O, S, N) and is opt. fused to another ring. (I) are described, e.g., in WO 9321165, 9324470, 9322297 and 9325077, JA 4-89484, 6-145155, 6-145169, 6-48907, 6-100546, 6-100560 and 6-73030, and EP 345775, 432601 and 553623.

Description

The present invention relates to the use of oxazolines for loading Fighting endoparasites and endoparasiticidal agents which entail oxazolines hold.

Oxazolines and their production and use as insecticides and Acaricides are already known. About their use against endoparasites is but did not become known.

The present invention relates to the use of compounds of the formula (I)

in which
B represents optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl,
A represents aryl, aryloxy, heteroaryl, heteroaryloxy which are optionally substituted and which are optionally bonded to the oxazoline ring via a divalent radical Z,
R stands for hydrogen or together with A and the adjacent C atom for a spirocyclic 3- to 6-membered ring which may optionally contain one or more heteroatoms of the group O, S, N and to which another ring may be fused, where the system is optionally substituted,
except 2- (2,6-difluorophenyl) -4- [4- (4-trifluoromethoxyphenyl) phenyl] -2-oxazdine, for the control of endoparasites in humans and animals.

The compounds of formula (I) are e.g. B. Subject of the following patent applications:
WO 93/21 165, WO 93/24470, JP-OS H4 89 484, JP-OS H6 145 155, JP-OS H6 145 169, JP-OS H6 48 907, JP-OS H6 100 546; JP-OS H6 100 560, JP-OS H6 73 030, EP-OS 345 775, EP-OS 432 601, EP-OS 553 623, WO 93/22 297, WO 93/25 077.

On the preferred connection groups as well as individual connections and Her The setting procedure in these applications is hereby particularly referred to.

The compounds of the formula (I) are in part the subject of older, not previously published patent applications by the applicant:
DE registration P. . . (Le A 30 774, 30 163, 30 164, 30 165, 30 167, 30 509, 30 648).

Also on the connection groups and individuals mentioned in these applications connections and manufacturing processes are hereby referred to.

Compounds of the general formula (I) in which the Definitions for the substituents have the following meanings:

Optionally substituted alkyl alone or as part of a radical in the general formulas means straight-chain or branched alkyl with preferably 1 to 20, in particular 1 to 18 carbon atoms. Exemplary and  optionally substituted methyl, ethyl, n- and i-propyl are preferred, called n-, i- and t-butyl, neopentyl, undecyl, dodecyl, pentadecyl, octadecyl.

Optionally substituted alkenyl and the alkenyl portion of a residue such as. B. optionally substituted alkenyloxy and alkenylthio in general Formulas mean straight-chain or branched alkenyl with preferably 2 to 6, in particular 2 to 4 carbon atoms. Be exemplary and preferred optionally substituted ethenyl, propenyl- (1), propenyl- (2) and butenyl- (3) called.

Optionally substituted alkynyl and the alkynyl portion of a residue such as. B. optionally substituted alkynyloxy and alkynylthio in general Formulas mean straight-chain or branched alkynyl with preferably 2 to 6, in particular 2 to 4 carbon atoms. Be exemplary and preferred optionally substituted ethynyl, propynyl (1), propynyl (2) and butynyl (3) called.

Optionally substituted cycloalkyl alone or as part of a radical in the general formulas mean mono-, bi- and tricyclic cycloalkyl preferably 3 to 10, in particular 3, 5 or 6 carbon atoms. Example wise and preferably are optionally substituted cyclopropyl, cyclo called butyl, cyclopentyl, cyclohexyl.

Optionally substituted alkoxy alone or as part of a radical in the general formulas mean straight-chain or branched alkoxy preferably 1 to 6, in particular 1 to 4 carbon atoms. Exemplary and preferably substituted methoxy, ethoxy, n- and called i-propoxy and n-, o- and t-butoxy.

Optionally substituted alkylthio alone or as part of a radical in the general formulas mean straight-chain or branched alkylthio preferably 1 to 6, in particular 1 to 4 carbon atoms. Exemplary and preferably substituted methylthio, ethylthio, n- and called i-propylthio, n-, o- and t-butylthio.  

Optionally substituted carbalkoxy alone or as part of a radical in the general formulas means straight-chain or branched carbalkoxy with preferably 2 to 7, in particular 2 to 5 carbon atoms. Exemplary and preferably optionally substituted carbomethoxy, carboethoxy, Called carbo-n- and i-propyloxy and carbo-n-, i- and t-butyloxy.

Haloalkyl alone or as part of a radical such as. B. haloalkoxy or Haloalkylthio in the general formulas contains 1 to 4, in particular 1 or 2 carbon atoms and preferably 1 to 5, in particular 1 to 3 identical or different halogen atoms, preferably halogen, fluorine, chlorine and bromine, especially fluorine and chlorine. Examples include trifluoromethyl, Chloro-di-fluoromethyl, bromomethyl, 2,2,2-trifluoroethyl and pentafluoroethyl called.

Optionally substituted aryl alone or as part of a radical such. B. Aryloxy, arylthio, arylalkyl in the general formulas preferably means optionally substituted phenyl or naphthyl, especially phenyl.

Optionally substituted aralkyl means in the general formulas aralkyl optionally substituted in the aryl part and / or alkyl part preferably 6 or 10, in particular 6 carbon atoms in the aryl part (preferably phenyl or naphthyl, especially phenyl) and preferably 1 to 4, in particular 1 or 2 carbon atoms in the alkyl part, the alkyl part straight-chain or branched. Be exemplary and preferred optionally substituted benzyl and phenylethyl called.

Optionally substituted heteroaryl alone or as part of a residue such as heteroaryloxy, heteroarylthio, heteroaralkyl in general Formulas 5- to 7-membered rings with preferably 1 to 3, in particular 1 or 2 same or different heteroatoms which follow the aromatic principle of Follow the Hückel rule. The heteroatoms are oxygen, sulfur or nitrogen. Exemplified and preferred are optionally substituted thienyl, ge called.

The optionally substituted radicals of the general formula (I) can be one or more, preferably 1 to 3, in particular 1 to 2 identical or ver  carry different substituents. The substituents are exemplary and above preferably listed:

Alkyl with preferably 1 to 20, in particular 1 to 18 carbon atoms, such as Methyl, ethyl, n- and i-propyl and n-, i- and t-butyl, neopentyl, hexadecyl, Octadecyl; Alkoxy with preferably 1 to 14, in particular 1 to 4 carbon atoms such as methoxy, ethoxy, n- and i-propyloxy and n-, i- and t-butyloxy; Alkylthio with preferably 1 to 4, in particular 1 or 2 carbon atoms, such as Methylthio, ethylthio, n- and i-propylthio and n-, i- and t-butylthio; Haloalkyl with preferably 1 to 4, in particular 1 or 2 carbon atoms and preferably 1 to 5, in particular 1 to 3 halogen atoms, the Halogen atoms are the same or different and are preferred as halogen atoms Fluorine, chlorine or bromine, especially fluorine, such as difluoromethyl, Trifluoromethyl; Hydroxy; Halogen, preferably fluorine, chlorine, bromine, in particular Fluorine, chlorine, cyano; Nitro; Amino; Monoalkyl- and dialkylamino with preferably 1 to 4, in particular 1 or 2 carbon atoms per alkyl group, such as methylamino, methylethylamino, n- and i-propylamino and methyl-n- Butylamino; Acyl radicals such as formayl, alkylcarbonyl such as. B. acetyl, arylcarbonyl such as B. Benzoyl; Carboxyl; Carboxy with preferably 2 to 4, in particular 2 or 3 carbon atoms such as carbomethoxy and carboethoxy; Alkylsulfinyl with 1 to 4, in particular 1 to 2 carbon atoms, haloalkylsulfinyl with 1 to 4, in particular 1 to 2 carbon atoms and 1 to 5 halogen atoms such as Trifluoromethylsulfinyl with 1 to 4, in particular 1 to 2 carbon atoms with 1 up to 5 halogen atoms such as trifluoromethylsulfinyl; Sulfonyl (-SO₃H); Alkylsulfonyl with preferably 1 to 4, in particular 1 or 2 carbon atoms, such as Methylsulfonyl and ethylsulfonyl; Haloalkylsulfonyl with 1 to 4, in particular 1 to 2 carbon atoms and 1 to 5 halogen atoms such as trifloromethylsulfonyl, Perfluoro-t, n, s-butylsulfonyl; Arylsulfonyl, preferably 6 or 10 Aryl carbon atoms such as phenylsulfonyl; Acyl; Aryl; Aryloxy; Heteroaryl; Heteroaryloxy; which in turn carry one of the above-mentioned substituents can as well as the Formiminorest

Compounds of the formula (I) in which the Substituents have the following meaning:

B represents C₁-C₈-alkyl, which is optionally mono- or polysubstituted, substituted identically or differently by halogen, cyano, C₁-C₄-alkoxy or by in each case optionally mono- to triple, identically or differently, by halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio and / or C₁-C₄-haloalkylthio substituted phenyl, phenoxy, benzyloxy, phenylthio and benzylthio;
for C₂-C₈-alkenyl, optionally substituted one or more times, identically or differently, by halogen;
for C₃-C₈-cycloalkyl, which is optionally mono- or polysubstituted by identical or different substituents
Halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl or C₂-C₄ haloalkenyl;
for C₅-C₇-cycloalkenyl, which is optionally substituted one or more times, identically or differently by
Halogen, C₁-C₄-alkyl or C₁-C₄-haloalkyl;
for phenyl which is optionally mono- to tetrasubstituted, identically or differently, where halogen may be mentioned as substituents,
C₁-C₄ alkyl,
C₁-C₄-alkoxy-C₁-C₄-alkyl,
C₁-C₄ haloalkoxy,
C₁-C₄ haloalkyl,
C₁-C₄ alkoxy, which is optionally interrupted by a further 1-3 oxygen atoms,
C₁-C₄ alkylthio,
C₁-C₄ haloalkylthio.

A represents optionally mono- to tetrasubstituted, identical or differently substituted phenyl, benzyl, pheneth-1-yl, pheneth-2-yl, phenoxymethyl, phenylthiomethyl, phenoxyeth-1-yl, phenylthioeth-1-yl, phenoxyeth-2-yl and Styryl, where each may be mentioned as phenyl substituent halogen,
C₁-C₁₈ alkyl,
C₁-C₈-alkoxy-C₁-C₈-alkyl,
C₁-C₅ haloalkoxy,
C₁-C₄ haloalkyl,
C₁-C₁₈ alkoxy, which is optionally interrupted by a further 1-3 oxygen atoms,
C₁-C₁₈ alkylthio,
C₁-C₈ haloalkylthio,
3,4-difluoromethylene dioxo,
3,4-tetrafluoroethylene dioxo,
benzyliminooxymethyl optionally substituted by C₁-C₄-alkyl, C₃-C₆-cycloalkyl and / or halogen,
each optionally substituted by C₁-C₆-alkyl, C₁-C₆-alkoxy, cyclohexyl or phenyl cyclohexyl and cyclohexyloxy;
optionally single or double, identical or different by halogen,
C₁-C₄ alkyl or C₁-C₄ haloalkyl substituted pyridyloxy; each optionally single to triple, identical or different, by C₁-C₁₂ alkyl, halogen, C₁-C₄-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-halo genalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁ -C₆-alkoxy-ethyleneoxy, C₁-C₆- alkylthio and / or C₁-C₆-haloalkylthio
substituted phenyl, benzyl, phenoxy, phenylthio, benzyloxy and ben zylthio.

R preferably represents hydrogen.

Compounds of the formula (I) in which the Substituents have the following meaning:  

B stands for C₁-C₆-alkyl, which is optionally substituted one or more times, identically or differently by
Fluorine, chlorine, bromine, cyano, C₁-C₂-alkoxy and, if appropriate, once or twice, identically or differently, by fluorine, chlorine, C₁-C₄-alkyl, C₁-C₂-haloalkyl, C₁-C₂-alkoxy, C₁- C₂-haloalkoxy, C₁-C₂-alkylthio and / or C₁-C₂-haloalkylthio substituted phenyl, phenoxy, benzyloxy, phenylthio and benzylthio;
for C₂-C₆-alkenyl which is optionally substituted one or more times, identically or differently, by fluorine, chlorine and / or bromine;
for C₃-C₈-cycloalkyl, which is optionally mono- or polysubstituted by identical or different substituents
Fluorine, chlorine, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₁-C₂-haloalkyl with fluorine and / or chlorine as halogen atoms and C₂-C₄-haloalkenyl with fluorine and / or chlorine as halogen atoms;
for C₅-C₇-cycloalkenyl, which is optionally substituted one or more times, identically or differently by
Fluorine, chlorine, C₁-C₄-alkyl and C₁-C₂-haloalkyl with fluorine and / or chlorine as halogen atoms;
for optionally monosubstituted to tetrasubstituted, identical or differently substituted phenyl, where substituents may be mentioned
F, Cl, Br,
C₁-C₄ alkyl,
simple to sixfold, identical or different substituted by F and / or Cl C₁-C₄ alkoxy,
single to quintuple, identical or different substituted by F and / or Cl C₁-C₂-alkyl.

A particularly preferably represents phenyl, benzyl pheneth-1-yl, phen eth-2-yl, phenoxymethyl, phenylthiomethyl, phenoxyeth-1-yl, phenoxyeth-2-yl, phenylthioeth-1, each optionally monosubstituted to tetrasubstituted by identical or different substituents -yl and styryl,
each being mentioned as a phenyl substituent
F, Cl, Br,
C₁-C₁₈ alkyl,
C₁-C₆-alkoxy-C₁-C₈-alkyl,
simple to sixfold, identical or different substituted by F and / or Cl C₁-C₈ alkoxy,
single to quintuple, identical or different, substituted by F and / or Cl C₁-C₂-alkyl,
C₁-C₁₈ alkoxy and - (OC₂H₄) _1-3 -O-C₁-C₆-alkyl,
C₁-C₁₂ alkylthio,
simple to sixfold, identical or different substituted by F and / or Cl C₁-C₈-alkylthio,
3,4-difluoromethylene dioxo,
3,4-tetratluoroethylene dioxo,
the groupings

each optionally substituted by C₁-C₄-alkyl, C₁-C₄-alkoxy, cyclohexyl or phenyl cyclohexyl and cyclohexyloxy;
optionally single or double, identical or different, substituted by F, Cl or CF₃ pyridyloxy;
each optionally monosubstituted to trisubstituted, identically or differently, by C₁-C₁₂alkyl, F, Cl, Br, CF₃, C₁-C₄alkoxy, monosubstituted to six times, identically or differently by F and / or Cl, C₁-C₄- alkoxy-C₁-C₄-alkyl, C₁-C₄-alkoxy-ethyleneoxy, C₁-C₄-alkylthio, simple to sixfold, identical or differently substituted by F and / or Cl, C₁-C₄-alkylthio
substituted phenyl, benzyl, phenoxy, phenylthio, benzyloxy and ben zylthio.

R particularly preferably represents hydrogen.

A and R of the general formula (I) can preferably together the following spiro form cyclic rings, which in turn z. B. be substituted by radicals A. can:

where A can have the meanings given above and
R² represents hydrogen or one of the substituents indicated in A.

Compounds of the formula (I) in which the radical A is characterized by the following formula, being either direct or can be bonded to the oxazoline ring via a bridge member Z:

R¹ represents radicals according to the following Table 1
(R²) _m stands for residues according to the following Table 2

Table 1

Table 2

The following radicals may be mentioned as examples of the substituent A, either are bonded to the oxazoline ring directly or via a bridge member Z:

A can furthermore be radicals of the following formula a197

in which
E represents optionally substituted alkanediyl and
X represents hydrogen or halogen.

The following alkanediyl radicals E are preferred:

The following radicals may be mentioned as examples of the substituent B:

The following radicals may be mentioned as examples of the substituent B:

The following meanings may be mentioned as examples of the divalent radical Z:

-CH₂-, -CH (CH₃) -, -CH₂CH₂-, -CH = CH-, -CH₂O-, -CH₂S-, -CH (CH₃) S-, -CH (CH₃) O-, -CH₂CH₂O-, -CH₂S (O) -, -CH₂-SO₂-.

The preparation of the oxazolines of the formula (I) is known in principle. she can be done by

• a) amino alcohols of the formula (II) in which
  A and R have the meanings given above,
  with a carboxylic acid of formula (III) B-COOH (III) in which
  B has the meaning given above,
  with a dehydrating agent and optionally in the presence of a diluent;
  or
• b) amide alcohols of the formula (IV) in which
  A, B and R have the meanings given above,
  with a dehydrating agent, optionally in the presence of a diluent;
  or
• c) amide derivatives of the formula (V) in which
  A, B and R have the meanings given above; and
  X represents a leaving group, such as halogen, alkylsulfonyloxy or arylsulfonyloxy,
  with a base, optionally in the presence of a diluent.

The in process (a) for the preparation of the compounds of formula (I) as Aus Amino alcohols to be used are known and / or can be added known methods by reducing the corresponding amino acids can be prepared (cf. Heterocycles 9 (1978), 1277-1285; J. Org. Chem. 43 (1978), 2539-2541; Liebigs Ann. Chem. 1980, 122-139; Tetrahedron Lett. 26 (1985), 4971-4974).

The further than in process (a) for the preparation of the compounds of formula (I) Carboxylic acids of the formula (III) to be used as starting materials are known organic synthetic chemicals, or available in a known manner.

Processes (a) and (b) are performed using a dehydrating By means of. It can be the usual water in organic chemistry withdrawal agents are used. Sulfur can preferably be used acid, polyphosphoric acid (PPS), phosphorus (V) oxide, dicyclohexylcarbodiimide (DCC), phosphorus (V) sulfide and the triphenylpliosphine / triethylamine / tetra system chloromethane.  

As a diluent for carrying out process (a) to (c) the usual organic solvents come into consideration. Preferably aliphatic, alicyclic or aromatic, optionally halo can be used Hydrogenated hydrocarbons, such as gasoline, benzene, toluene, xylene, Chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, Chloroform, carbon tetrachloride; Ethers, such as diethyl ether, diisopropyl ether, dioxane, Tetrahydrofuran or ethylene glycol dimethyl or diethyl ether; Ketones like Acetone, butanone or methyl isobutyl ketone; Nitriles, such as acetonitrile, propiohitrile or benzonitrile; Amides, such as N, N-dimethylformamide and N, N-dimethylacetamide, N-methyl-pyrrolidone or hexamethylphosphoric triamide; Esters such as acetic acid methyl ester or ethyl acetate, and also sulfoxides, such as dimethyl sulfoxide, optionally also alcohols such as methanol or ethanol.

The reaction temperatures can be carried out when carrying out the process according to the invention Process (a) can be varied over a wide range. Generally works one at temperatures between 0 ° C and 150 ° C, preferably at temperatures between 10 ° C and 100 ° C.

Process (a) according to the invention is generally carried out under atmospheric pressure carried out. However, it is also possible to increase or decrease it Pressure - generally between 0.1 bar and 10 bar - to work.

To carry out process (a) according to the invention, the respective be necessary starting materials are generally used in approximately equimolar amounts puts. However, it is also possible to use one of the two coms used in each case components in a larger excess. The reactions are in the generally in a suitable diluent in the presence of a water Withdrawal agent performed, and the reaction mixture is several hours the stirred at the required temperature. The processing takes place according to usual methods.

In a special embodiment of the method (a) according to the invention Corresponding nitriles can also be used instead of the carboxylic acids of the formula (III) are set, then preferably in place of a dehydrating By means of a catalyst, such as. B. zinc (II) chloride is used.  

The in process (b) for the preparation of the compounds of formula (I) as Aus Amide alcohols to be used are known and / or can be used known processes are produced.

The amide alcohols of the formula (IV) are obtained, for example, if one of the Carboxylic acids of the formula (III) derived acid chlorides with amino alcohols Formula (II) in the presence of an acid binder, such as. B. triethylamine, pyridine, Potassium carbonate, sodium hydroxide or potassium t-butoxide, and in the presence of a Diluents, such as. B. toluene, chlorobenzene, acetone or acetonitrile Temperatures between 0 ° C and 100 ° C implemented.

The acid chlorides derived from the carboxylic acids of the formula (III) are largely known and / or can be made by methods known per se, for example by reacting the carboxylic acids of the formula (III) with a Halogenating agents such as thionyl chloride, optionally in the presence of a Diluent can be produced.

For example, αFluoro-β, β-dichloro-acrylic acid chloride of formula (VI) can be obtained by adding 2-fluoro-1,1,3,3,3-pentachloropropene, optionally in Hydrolyzed in the presence of a catalyst. Lewis- come as catalysts Acids, inorganic acids and their acid salts, such as. B. FeCl₃, BF₃, H₂SO₄, HCl, KHSO₄, NaHSO₄ u. a. in question.

Depending on the reaction conditions (such as the residence time of the acid chloride in the reaction mixture) and of the added water the primary amount of α-fluoro-β, β-dichloro-acrylic acid chloride is added if necessary partially hydrolyzed to the corresponding acrylic acid, which subsequently for example by reaction with thionyl chloride back into the acid chloride can be transferred.

The reaction temperatures can be carried out in carrying out process (b) can be varied over a wide range. Generally one works at Tem temperatures between -20 ° C and + 150 ° C, preferably at temperatures between 0 ° C and 100 ° C.  

Process (b) according to the invention is generally carried out under normal pressure carried out. However, it is also possible to increase or decrease it Pressure - generally between 0.1 bar and 10 bar - to work.

To carry out process (b) for the preparation of the compounds of Formula (I) is generally 1 per mol of amide alcohol of the formula (IV) to 20 moles, preferably 1 to 5 moles of dehydrating agent.

In a preferred embodiment of process (b) according to the invention the amide alcohol of the formula (IV) is placed in a diluent and the dehydrating agent is then metered in. The reaction mixture is at the required temperature until the end of the reaction and stirred finally worked up in the usual way.

The in process (c) for the preparation of the compounds of formula (I) as Aus Amide derivatives to be used are known and / or can be used known processes are produced.

The amide derivatives of the formula (V) are obtained if the corresponding amide alcohols of formula (IV) with chlorinating agents, such as. B. thionyl chloride or Phosphorus (V) chloride, or with sulfonylating agents, such as. B. methanesulfone acid chloride or p-toluenesulfonic acid chloride in the usual manner, if appropriate in Presence of a base and optionally in the presence of a diluent implements.

Process (c) is carried out in the presence of a base. Everyone comes here usual inorganic or organic bases into consideration. Preferably ver reversible are alkaline earth or alkali metal hydrides, hydroxides, amides, alcoholates, acetates, carbonates or bicarbonates, such as sodium hydride, Sodium amide, sodium methylate, sodium ethylate, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium acetate, potassium acetate, Calcium acetate, ammonium acetate, sodium carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate or ammonium carbonate and ter tertiary amines, such as trimethylamine, triethylamine, tributylamine, N, N-dimethylaniline,  Pyridine, N-methylpiperidine, N, N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclonones (DBN) or diazabicycloundecene (DBU).

The reaction temperatures can be carried out in carrying out process (c) can be varied over a wide range. Generally one works at Tem temperatures between -20 ° C and + 150 ° C, preferably at temperatures between 0 ° C and 100 ° C.

Process (c) is generally carried out under normal pressure. However, it is also possible, under increased or reduced pressure - in general between 0.1 bar and 10 bar - to work.

To carry out process (c) for the preparation of the compounds of Formula (I) is generally 1 per mole of amide derivative of the formula (V) to 3 moles, preferably 1.0 to 1.5 moles of a base.

In a preferred embodiment of process (c), the amide Derivative of formula (V) and a base in a suitable diluent ver mixes; the mixture is at the required temperature until the end of Reaction stirred and then worked up in the usual way.

The active ingredients are suitable for combating pathogenic endoparasites in humans and in animal husbandry and breeding occur in livestock, breeding, zoo, laboratory, experimental and hobby animals. you are against all or individual stages of development of the pests and against resistant and normally sensitive species are effective. By fighting the Pathogenic endoparasites are said to cause illness, death and reduced performance (e.g. in the production of meat, milk, wool, skins, eggs, honey, etc.) and possibly also transmission to humans can be reduced, so that through the use of the active ingredients a more economical and simple Animal husbandry is possible. Pathogenic endoparasites include cestodes, Trematodes, nematodes, in particular:

From the order of the Pseudophyllidea z. E.g .: Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoorus spp.  

From the order of the Cyclophyllidea z. For example: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosma spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Anhyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepsis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp.

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

From the subclass of Digenea z. E.g .: Diplostomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinostoma spp., Echinoparyphium spp., Echinochasmus spp., Hypoderaeum spp., Fasciola spp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhloccelum spp., Paramphistomum spp., Calicophoron spp., Cotylophoron spp., Gigantocotyle spp., Fischoederius spp., Gastrothylacus spp., Notocotylus spp., Catatropis spp., Plagiorchis spp., Prosthogonismus spp., Dicrocoelium spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis spp., Metorchis spp., Heterophyes spp., Metagonimus spp.

From the order of the Enoplida z. E.g. Trichuris spp., Capillaria spp., Trichlomosoides spp., Trichinella spp.

From the order of the Rhabditia z. E.g. Micronema spp., Strongyloides spp.

From the order of Strongylida z. E.g. Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostromum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus spp., Acylostoma 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 the Oxyurida z. E.g .: Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp.

From the order of Ascaridia z. For example: Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp.

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

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

From the group of the Gigantohynchida z. E.g. Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp.

The livestock and breeding animals include mammals such as B. cattle, horses, sheep, Pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, Fur animals such as B. mink, chinchilla, raccoon, birds such. B. chickens, geese, Turkeys, ducks.

Laboratory and experimental animals include mice, rats, guinea pigs, gold hamsters, dogs and cats.

The pets include dogs and cats.

The application can be prophylactic as well as therapeutic.

The active ingredients are used directly or in the form of suitable accessories riding enterally, parenterally, dermally, nasally, by treating the environment or  with the help of active ingredient-containing shaped bodies such. B. strips, plates, ribbons, neck bands, ear tags, limb bands, marking devices.

The enteral application of the active ingredients happens, for. B. orally in the form of powder, Suppositories, tablets, capsules, fasting, watering, granules, drenches, boluses, medicated feed or drinking water. The dermal application happens for. B. in Form of diving (dipping), spraying (spraying), bathing, washing, pouring (pour-on and spot-on) and powdering. Parenteral use happens e.g. B. in the form of injection (intramuscular, 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 suspensions for oral or dermal use and for injection; Semi-solid preparations;

Formulations in which the active ingredient is in an ointment base or in an oil is processed in water or water in oil emulsion base;

Solid preparations such as powders, premixes or concentrates, granules, pellets, Tablets, boluses, capsules; Aerosols and inhalants, molded articles containing active ingredients.

Solutions for injection are administered intravenously, intramuscularly and subcutaneously.

Injection solutions are made by adding the active ingredient in a suitable Solvent is dissolved and possibly additives such as solubilizers, acids, Bases, buffer salts, antioxidants, preservatives can be added. The Solutions are sterile filtered and filled.

The following may be mentioned as solvents: Physiologically compatible solvents such as Water, alcohols such as ethanol, butanol, benzyl alcohol, glycerin, coal  Hydrogen, propylene glycol, polyethylene glycols, N-methylpyrrolidone, and Mixtures of these.

The active ingredients can, if appropriate, also be physiologically tolerated Dissolve vegetable or synthetic oils that are suitable for injection.

The following may be mentioned as solubilizers: solvents which are the solution of the active ingredient Promote substance in the main solvent or prevent it from falling out. Examples are polyvinyl pyrrolidone, polyoxyethylated castor oil, polyoxyethylated Sorbitan esters.

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

Oral solutions are applied directly. Concentrates are made according to the previous one Dilution to the application concentration applied orally. Oral solutions and concentrates are prepared as described above for the injection solutions provided, whereby sterile work can be dispensed with.

Solutions for use on the skin are dripped on, spread on, on rubbed, sprayed on, sprayed on or by diving (dipping, bathing or washing upset. These solutions are the same as for the injection solutions described.

It may be advantageous to add thickeners during manufacture. Thickeners are: inorganic thickeners such as bentonites, colloidal Silica, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and metacrylates.

Gels are applied or spread onto the skin or in body cavities brought in. Gels are made by using solutions similar to Injek tion solutions have been prepared with so much thickener are added so that a clear mass with ointment-like consistency arises. As Thickeners are the thickeners given above set.  

Pour-on formulations are poured onto limited areas of the skin or sprayed on, the active ingredient either penetrating the skin and acts systemically or is distributed on the surface of the body.

Pour-on formulations are made by adding the active ingredient in appropriate Skin-compatible solvents or solvent mixtures dissolved, suspended or is emulsified. If necessary, other 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, phenyl ethanol, phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ether such as alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether, ketones such as acetone, methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, Dimethylacetamide, N-methylpyrrolidone, 2-dimethyl-4-oxy-methylene-1,3-dioxolane.

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

Resorption promoting substances are e.g. B. DMSO, spreading oils such as Isopro pylmyristat, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, Fatty alcohols.

Antioxidants are sulfites or metabisulfites such as potassium metabisulfate, Ascor bic acid, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol.

Light stabilizers are e.g. B. substances from the class of benzophenones or Novan tisolic acid.

Adhesives are e.g. B. cellulose derivatives, starch derivatives, polyacrylates, natural Polymers such as alginates, gelatin.

Emulsions can be used orally, dermally or as an injection.  

Emulsions are either water in oil or oil in water.

They are made by placing the active ingredient in either the hydrophobic or dissolved in the hydrophilic phase and this more suitable with the help Emulsifiers and optionally other auxiliaries such as dyes, resorb promotional substances, preservatives, antioxidants, light stabilizers, viscosity increasing substances, with the solvent of the other phase homo embarrassed.

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

Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipro pylene glycol pelargonate, ester of a branched fatty acid with medium chain length saturated fatty alcohols of chain length C₁₆-C₁₈, isopropyl myristate, Isopro pylpalmitate, cypryl / capric acid ester of saturated fatty alcohols of chain length C₁₂-C₁₈, isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, milk acid ethyl esters, waxy fatty acid esters such as artificial duck pancreas fat, Dibutyl phthalate, diisopropyl adipate, ester mixtures related to the latter u. a.

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

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

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

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

The following may be mentioned as further auxiliaries: viscosity-increasing agents and the emulsion sta bilizing substances such as carboxymethyl cellulose, methyl cellulose and others Cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, Polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and Maleic anhydride, polyethylene glycols, waxes, colloidal silica or Mixtures of the listed substances.

Suspensions can be used orally, dermally or as an injection. she are produced by placing the active ingredient in a carrier liquid if necessary with the addition of other auxiliaries such as wetting agents, dyes, resorp Promotional substances, preservatives, antioxidants, light stabilizers sus oscillates.

Carrier liquids are all homogeneous solvents and solvents called mix.

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

Further additives mentioned are those mentioned above.

Semi-solid preparations can be administered orally or dermally. You under only differ from the suspensions and emulsions described above due to their higher viscosity.  

To prepare solid preparations, the active ingredient is used with a suitable carrier substances may be mixed with additives and added to the brought the desired shape.

All physiologically compatible solid inert substances may be mentioned as carriers. All of these serve inorganic and organic substances. Inorganic substances are e.g. B. table salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, silicas, clays, precipitated or colloidal silicon dioxide, Phos phate.

Organic substances are e.g. B. sugar, cellulose, food and feed such as Milk powder, animal meal, cereal flour and meal, starches.

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

Other suitable auxiliaries are lubricants and lubricants such as. B. Magne sium stearate, stearic acid, talc, bentonite, decay promoting substances such as Starch or cross-linked polyvinylpyrrolidone, binders such. B. Starke, Gela tine or linear polyvinylpyrrolidone and dry binders such as microcri stalline cellulose.

The active ingredients can also be mixed with synergists in the preparations or with other active substances that act against pathogenic endoparasites lie. Such active ingredients are e.g. B. L-2,3,5,6-tetrahydro-6-phenyl-imidazolothiazole, Benzimidazole carbamates, praziquantel, pyrantel, febantel.

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

Preparations that are diluted before use contain the active ingredient in Concentrations from 0.5 to 90% by weight, preferably from 5 to 50% by weight.  

In general, it has proven advantageous to use amounts of about 1 to 100 mg of active ingredient per kg of body weight per day to achieve effective results nisse to administer.

Active ingredient (1) is used in the following examples.  

example 1

SC- (suspension concentrate) formulation:
368 g of active ingredient 1
35 g block polymer of emulsifier ethylene oxide and propylene oxide
12 g ditolyl ether sulfonate formaldehyde condensate (emulsifier)
3.5 g water-soluble polyvinyl alcohol
58.0 g NH₄Cl
116.0 g urea
1.2 g (37% aqueous hydrochloric acid)
4.6 g xanthan gum
560.5 g of distilled water

Example 2

WP (dispersible powder) formulation:
25.0 g of active ingredient 1
1.0 g diisobutyl naphthalene Na sulfonate
10.0 g of n-dodecylbenzylsulfonic acid calcium
12.0 g of highly disperse silicic acid-containing alkylaryl polyglycol ether
3.0 g ditolyl ether sulfonate formaldehyde condensate (emulsifier)
2.0 g ®Baysilon-E, a silicone-containing defoamer from Bayer AG
2.0 g of finely divided silica and
45.0 g kaolin

Example 3

SL (water-soluble concentrate) formulation:
18.3 g of active ingredient 1
2.5 g neutral emulsifier based on alkylaryl polyglycol ether
3.5 g diisooctyl sodium sulfosuccinate
38.4 g of dimethyl sulfoxide and
37.5 g of 2-propanol

Example 4

SL (water-soluble concentrate) formulation:
185 g of active ingredient 1
5.0 g of diisooctyl sodium sulfonate and
76.5 g dimethyl sulfoxide
are made up of a 100 g shampoo formulation
44.4% by weight of Marlon AT 50, a triethanolamine salt of alkylbenzenesulfonic acids from Huls AG
11.1% by weight of Marlon A 350, sodium salt of alkylbenzenesulfonic acids from Huls AG
3.0% by weight condensation product of oleic acids and diethanolamine from Hüls AG and
41.5% by weight polyethylene glycol
added.

Example 5

Spray formulation consisting of
2.0 g of active ingredient 1
10.0 g dimethyl sulfoxide
35.0 g of 2-propanol and
53.0 g acetone

Example A In vivo nematode test Haemonchus contortus / sheep

Sheep experimentally infected with Haemonchus contortus were identified after the expiration of the Prepatency of the parasite treated. The active ingredients were as a pure active ingredient Orally applied in gelatin capsules.

The efficiency is determined by using the manure eliminated worm eggs quantitatively before and after treatment.

A complete sistering of the egg excretion after treatment means that the Worms have been aborted or are so damaged that they no longer have eggs produce (dose effectiva).

Tested active ingredients and effective doses (dose effectiva) are from the following table.

Example B Example Hymenolepis nana / mouse

Experimentally orally initiated with infectious eggs from proglottids. After expiration the prepatent time is treated (4 times on 4 consecutive days orally). After 7 days, the number of scolices is determined in the intestine. The effectiveness is calculated according to the formula

Active ingredient: Efficacy: 100% with oral application of 25 mg / kg.

Manufacturing examples example 1

To 1 g (6 mmol) of 4-t-butyl-thiophenol in 50 ml of methanol, 0.3 g (6 mmol) of sodium methylate (slightly exothermic). Drip to this solution 2.1 g (6 mmol) of 2- (2,6-difluorophenyl) -4- (p-tdylsulfonyloxymethyl) at 40 ° C. 1,3-oxazoline in 30 ml of methanol. The reaction mixture is left for 2 hours Stir at 40 ° C and then reflux for 16 hours. After that it will The solvent is distilled off, the residue is taken up in 100 ml of ethyl acetate and washed three times with 50 ml of water. The solvent is removed and the residue on silica gel column chromatography with toluene / toluene, ethyl acetate Chromatographed 10: 1 as eluent.

0.9 g (41.6% of theory) of 2- (2,6-difluorophenyl) -4- (4-t-butylphenylthio) are obtained methyl) -1,3-oxazoline with a distribution coefficient log P (octanol / water) of 4.64 and a refractive index n = 1.5660.  

Establishing the output connection Example 1a

To 5.3 g (0.023 mol) of 2- (2,6-difluorophenyl) -4-hydroxymethyl-1,3-oxazoline in 100 ml of ethyl acetate are added 5.6 ml (0.069 mol) of pyridine and then 4.4 g are added dropwise (0.023 mol) of p-toluenesulfonic acid chloride in 50 ml of ethyl acetate. The increases Temperature to 50 ° C. The mixture is stirred at 50 ° C. for 2.5 hours and then 8 Hours after reflux. The organic phase is four times with 50 ml Washed water and distilled off the solvent. The backlog is over Silica gel column chromatography with eluent using toluene under a gradient Eluent chromatographed ethyl acetate.

2.1 g (24.8% of theory) of 2- (2,6-difluorophenyl) -4- (p-tolylsulfonyloxy) are obtained methyl) -1,3-oxazoline with a distribution coefficient log P (octanol / water) of 2.68 and a refractive index n = 1.5491.

Example 1b

6.5 g (0.0168 mol) of N- [1-chloro-3- (4-t-butylbenzoyloxy) -2-propyl] -2,6-difluorobenz amide are dissolved in 100 ml of methanol. 2 ml (0.033 mol) of 45% strength are added Sodium hydroxide solution and allowed to stir under reflux for 4 hours. After distilling off the The residue is taken up in 100 ml of ethyl acetate, three times washed with 50 ml of water each time and the solvent was distilled off.  

2.8 g (72% of theory) of 2- (2,6-difluorophenyl) -4-hydroxymethyl-1,3 are obtained oxazoline with a melting point of 82 ° C.

Example 1c

9 g (0.023 mol) of N- [1-hydroxy-3- (4-t-butylbenzoyloxy) -2-propyl] -2,6-difluorobenz amide are suspended in 60 ml carbon tetrachloride, with 1.7 ml (0.023 mol) Thionyl chloride was added and the mixture was heated under reflux for 1.5 hours. The solvent is distilled off.

9.3 g of N- [1-chloro-3- (4-t-butylbenzoyloxy) -2-propyl] -2,6-difluorobenz are obtained amide with a distribution coefficient log P (octanol / water) of ∼3.86.

Example 1d

To 21 g of 2-amino-3- (4-t-butylbenzoyloxy) -1-propanol hydrochloride in 400 ml of vinegar esters are first added to 21.9 ml (0.158 mol) of triethylamine and then at 0 ° C 13.9 g of 2,6-difluorobenzoic acid chloride in 20 ml of ethyl acetate dripped. The mixture is stirred at 20 ° C for 1 hour; the precipitation is abge sucks, the organic phase washed three times with 100 ml of water, the Lö distilled off solvent and the residue stirred with diisopropyl ether.  

After drying, 14 g (48% of theory) of N- [1-hydroxy-3- (4-t- butylbenzoyloxy) -2-propyl] -2,6-difluorobenzamide with a partition coefficient ten log P (octanol / water) of 2.82.

Example 2

To 4.3 g (0.013 mol) of N- [2-chloro-1- (4-t-butylphenyl) ethyl] -2,2-bis (fluoromethyl) propionic acid amide in 100 ml of methanol are refluxed 1.6 ml (0.026 mol) 45% sodium hydroxide solution dripped into 5 ml of water. The reaction mixture is left 1 Stir hour under reflux and then concentrated by distilling off the Solvent. The residue is stirred with water, the precipitate sucked and dried.

3.8 g (99% of theory) of 2- (1,3-difluoro-2-methyl-prop-2-yl) -4- (4-t- butylphenyl) -1,3-oxazoline, melting point 62-63 ° C.

Preparation of the starting compounds for Example 2 Example 2a (Step 1)

To 3.9 g (0.02 mol) of 2-amino-2- (4-t-butylphenyl) -1-ethanol in 150 ml of ethyl acetate are added 3.3 ml (0.024 mol) of triethylamine and then mixed at 0 ° C. dropwise with 3.7 g (0.024 mol) of 2,2-bis (fluoromethyl) propionic acid chloride. There  after the mixture is allowed to warm to room temperature and stirred overnight. The precipitate is then filtered off, the filtrate several times with water washed, the organic phase separated, dried over sodium sulfate, filtered and concentrated.

4.5 g (71.9% of theory) of N- [2-hydroxy-1- (4-t-butylphenyl) ethyl] - are obtained. 2,2-bis (fluoromethyl) propionic acid amide with a melting point of 141 ° C.

Example 2b (Level 2)

To 4.5 g (0.0144 mol) of N- [2-hydroxy-1- (4-t-butylphenyl) ethyl] -2,2-bis (fluorme thyl) propionic acid amide (see. Step 1) in 100 ml carbon tetrachloride Added 1.05 ml (0.0144 mol) of thionyl chloride. The reaction mixture is left react under reflux for 1 hour. After distilling off the solvent 4.3 g (90% of theory) of N- [2-chloro-1- (4-t-butylphenyl) ethyl] -2,2-bis- (fluoromethyl) propionic acid amide, melting point 98 ° C.

Example 3

To a solution of 2.0 g (5.2 moles) of n- [1- (4-tert-butylphenyl) -2-chloroethyl] - 2,3,5,6-tetrafluorobenzoic acid amide in 30 ml of tetrahydrofuran are added 0.75 g (6.7 m mol) of potassium tert-butoxide and stirred at 50 ° C. After 3 hours you pour it Reaction mixture on water and extracted with methylene chloride. The organic  Extracts are washed with water, dried over magnesium sulfate and then concentrated in vacuo. The residue is by means of column chromatography graphie (eluent chloroform) cleaned.

0.8 g (44.7% of theory) of 4- (4-tert-butylphenyl) -2- (2,3,5,6-tetra) are obtained fluorophenyl) -1,3-oxazoline with a distribution coefficient log P (octanol / water) of 4.70 (pH: 7.4).

Preparation of the starting compounds for Example 3 Example 3a

2.1 g (5.7 moles) of N- [1- (4-tert-butylphenyl) -2-hydroxyethyl) -2,3,5,6-tetrafluoro benzoic acid amide in 50 ml of toluene with 5 ml of thionyl chloride for 18 hours Reflux heated. Then excess thionyl chloride in vacuo and the solvent is removed.

2.2 g (100% of theory) of N- [1- (4-tert-butylphenyl) -2-chloroethyl] - are obtained. 2,3,5,6-tetrafluorobenzoic acid amide, which is directly implemented further.

Example 3b

To a solution of 1.45 g (7.5 moles) of 2-amino-2- (4-tert-butylphenyl) ethanol and 0.75 g (7.5 m mol) of triethylamine in 20 ml of methylene chloride are added dropwise  Stir at 20 ° C 1.6 g (7.5 m mol) 2,3,5,6-tetratluorobenzoyl chloride, dissolved in 10 ml of methylene chloride, too. After boiling overnight, dilute with methylene chloride, washes with water and concentrates the organic phase in vacuo. Of the The residue is stirred with a little n-pentane and suction filtered.

2.3 g (83.1% of theory) of N- [1- (4-tert-butylphenyl) -2-hydroxyethyl) - are obtained. 2,3,5,6-tetrafluorobenzoic acid amide, melting point 158-1 60 ° C.

Example 4

3.4 g (8.7 mmol) of 2-phenyl-5- (2,6-dichlorobenzoylamino) -5-hydroxymethyl-1,3-dioxane are suspended in 50 ml of toluene and with 2 g of thionyl chloride for 24 hours 80 ° C stirred. Then excess thionyl chloride and toluene are in the water jet vacuum distilled off.

The residue is taken up in 50 ml of toluene and with 0.9 g of potassium t-butoxide transferred. The reaction mixture is then under a thin layer chromatographic Control stirred at 50 ° C. After complete implementation, the Lö obtained solution washed with water and then the organic phase in water jet vacuum concentrated. The residue is on silica gel with cyclohexane / vinegar acid ethyl ester (vol. 2: 1) chromatographed.

1 g (31% of theory) of 8-phenyl-2- (2,6-dichlorophenyl) -1-aza-3,7,9-tri is obtained oxa-spiro [4.5] dec-1-en with melting point 158 ° C-160 ° C.  

Preparation of the starting compounds for Example 4 Example 4a

104 g (0.35 mol) of 2- (4-t-butylphenyl) -5-hydroxymethyl-5-nitro-1,3-dioxane in 1 liter of ethanol with 10 ml of triethylamine and 10 g of palladium / carbon and 3 Hydrogenated at 20 ° C and 30 bar for days. Then it is filtered, the filtrate in a water jet concentrated in vacuo, the residue digested with n-hexane and this crystalline product obtained isolated by suction.

43 g (47% of theory) of 2- (4-t-butylphenyl) -5-hydroxymethyl-5-amino are obtained. 1,3-dioxane with a melting point of 138 ° C-140 ° C.

Example 4b

5 g (20 mmol) of 2- (4-t-butylphenyl) -5-amino-5-hydroxymethyl-1,3-dioxane are in 80 ml of methylene chloride are mixed with 5 ml of triethylamine. Then one at 0 ° C Solution of 4.5 g (20 mmol) 2,6-dichlorobenzoyl chloride in 5 ml methylene chloride added dropwise and the mixture is stirred at 20 ° C. for 15 hours. Then will washed with 0.5 N sodium hydroxide solution, the organic phase with sodium sulfate dries and filtered. The filtrate is concentrated in a water jet vacuum, the back  was brought to crystallization by digestion with n-hexane and the product isolated by suction.

7.2 g (83% of theory) of 2- (4-t-butylphenyl) -5-hydroxymethyl-5- (2,6- dichlorobenzoylamino) -1,3-dioxane with a melting point of 178 ° C.-180 ° C.

Example 5

0.67 g (2 mmol) of N- (2-hydroxy-1 (3,4-difluoromethylenedioxy-phenyl) -ethyl) -2,6-di Fluorobenzamide are placed in 15 ml of toluene and 0.27 ml (4 mmol) of thionyl chloride is added at 20 ° C. The reaction mixture is then 3 hours heated to reflux. After cooling, the residue is concentrated in 15 ml of tetra Hydrofuran added and after the addition of 0.23 g (2 mmol) of potassium t-butoxide the mixture is stirred at 50 ° C for one hour. Then the back is narrowed was shaken with methylene chloride / water, the organic phase over Magnesium sulfate dried and filtered. The filtrate is concentrated and the back was recrystallized from methylene chloride / petroleum ether.

0.13 g (20% of theory) of 2- (2,6-difluorobenzoyl) -4- (3,4-difluoro) are obtained methylenedioxy-phenyl) -2-oxazoline, melting point 86 ° C.  

Preparation of the starting materials for Example 5 Example 5a

2.31 g (10 mmol) of α-amino-α- (3,4-difluoromethylenedioxy-phenyl) -acetic acid are introduced with 0.91 g (24 mmol) of sodium borohydride in 30 ml of tetrahydrofuran at 0 ° C and a solution of 3 .05 g (24 mmol) iodine in 10 ml tetrahydrofuran is then added dropwise. After the evolution of gas has subsided, the mixture is heated under reflux for 16 hours. Then, after cooling, dilute with methanol until a clear solution is obtained. It is concentrated, the residue is taken up in 20 ml of 20% 2N sodium hydroxide solution and extracted three times with 50 ml of methylene chloride. The combined organic phases are dried over magnesium sulfate and filtered. After evaporating the filtrate, the crude product obtained as a residue is reacted further without further purification.
Yield: 1.52 g (70% of theory),
Melting point: 70 ° C.

Example 5b

1.0 g (2 mmol) of N- [2- (2,6-difluorobenzoyloxy) -1- (3,4-difluoromethylenedioxy-phenyl) ethyl] -2,6-difluorobenzamide are placed in 2 ml of methanol at 20 ° C, 2 ml of 1N sodium hydroxide solution are added and the mixture is heated to reflux with stirring for one hour. After cooling, shake three times with 50 ml of methylene chloride. The combined organic phases are dried over magnesium sulfate and filtered. The filtrate is concentrated and the crude product obtained as a residue is reacted further without further purification.
Yield: 0.67 g (93% of theory),
Melting point: 158 ° C.

Claims (4)

1. Use of compounds of the formula (I) in which
B represents optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl,
A represents aryl, aryloxy, heteroaryl, heteroaryloxy which are optionally substituted and which are optionally bonded to the oxazoline ring via a divalent radical Z,
R stands for hydrogen or together with A and the adjacent C atom for a spirocyclic 3- to 6-membered ring which may optionally contain one or more heteroatoms of the group O, S, N and to which another ring may be fused, where the system is optionally substituted,
except
2- (2,6-difluorophenyl) -4- [4- (4-trifluoromethoxyphenyl) phenyl] -2-oxazoline, for controlling endoparasites in humans and animals. 2. Endoparasiticidal agents, characterized by a content of at least a compound of formula (I) according to claim 1. 3. Process for the preparation of endoparasiticidal agents, thereby characterized in that compounds of the formula (I) according to Claim 1 mixed with extenders and / or surfactants.   4. Use of compounds of formula (I) according to claim 1 for Manufacture of endoparasiticidal agents.