The present invention relates to a process for the aromatic sulfonylation, sulfenylation, thiocyanation and phosphorylation of cyclic depsipeptides having 6 to 24 ring atoms which are synthesized from .alpha.-hydroxycarboxylic acids and .alpha.-amino acids and contain at least one phenyl radical, characterized in that these cyclic depsipeptides are reacted with sulfonylating, sulfenylating, thiocyanating or phosphorylating agents, optionally in the presence of catalysts, auxiliaries and/or diluents, to novel thus-obtained compounds, and to their use as endoparasiticides.

This application is a 371 of PCT/EP95/03926 filed Oct. 5, 1995. 
The present invention relates to a process for the sulfonylation, 
sulfenylation, thiocyanation and phosphorylation of cyclic depsipeptides, 
to novel compounds and their use as endoparasiticides. 
Cyclic depsipeptides and their action as endoparasiticides are already 
known from EP 381 173, PCT WO 93/19 053. However, the activity of these 
compounds is not always satisfactory. 
The present invention relates to 
1. The process for the aromatic sulfonylation, sulfenylation, thiocyanation 
and phosphorylation of cyclic depsipeptides having 6 to 24 ring atoms 
which are synthesized from .alpha.-hydroxycarboxylic acids and 
.alpha.-amino acids and contain at least one phenyl radical, characterized 
in that these cyclic depsipeptides are reacted with sulfonylating, 
sulfenylating, thiocyanating or phosphorylating agents, optionally in the 
presence of catalysts, auxiliaries and/or diluents. 
2. Aromatically sulfonylated, sulfenylated, thiocyanated and/or 
phosphorylated cyclic depsipeptides having 6 to 24 ring atoms which are 
synthesized from .alpha.-hydroxycarboxylic acids and .alpha.-amino acids 
and contain at least one phenyl radical. 
Cyclic depsipeptides, which are employed as starting materials in the 
process according to the invention, are natural compounds usually prepared 
by fermentation. Structurally, they are similar to proteins. Therefore, 
they would be expected to be sensitive toward aggressive chemicals and to 
be destroyed entirely or at least partially. Surprisingly, it was found 
that the process according to the invention can be carried out without 
destroying the basic structure of the depsipeptides. Compounds are thus 
obtained which are sulfonylated, sulfenylated, thiocyanated or 
phosphorylated on the phenyl ring and which have outstanding 
endoparasiticidal activity. 
The process according to the invention is preferably employed for preparing 
the novel and preferred compounds of the formula (I) 
##STR1## 
as the core structure and in which at least one of the radicals 
R.sup.3,R.sup.4,R.sup.5,R.sup.6,R.sup.7,R.sup.8,R.sup.9 or R.sup.10 
represents phenyl or benzyl, each of which is substituted by a sulfonyl, 
sulfenyl, thiocyanato or phosphoryl radical 
and in which otherwise the radicals 
R.sup.1,R.sup.2,R.sup.11 and R.sup.12 each represent hydrogen or optionally 
substituted C.sub.1-8 -alkyl, C.sub.3-6 -cycloalkyl, aralkyl or aryl 
radicals, 
R.sup.3,R.sup.5,R.sup.7 and R.sup.9 each represent hydrogen, straight-chain 
or branched C.sub.1-8 -alkyl which is optionally substituted by hydroxyl, 
C.sub.1-4 -alkoxy, aryloxy, hetaryloxy, carboxyl, 
##STR2## 
carboxamide, 
##STR3## 
imidazolyl, indolyl, guanidino, --SH or C.sub.1-4 alkylthio, and further 
represent optionally substituted aryl, hetaryl or aralkyl, 
R.sup.4,R.sup.6,R.sup.8 and R.sup.10 each represent hydrogen, 
straight-chain or branched C.sub.1-8 -alkyl, C.sub.2-6 -alkenyl or 
C.sub.3-7 -cycloalkyl, each of which is optionally substituted by 
hydroxyl, C.sub.1-4 -alkoxy, carbonyl, carboxamide, imidazolyl, indolyl, 
guanidino, SH or C.sub.1-4 -alkylthio, or represent optionally substituted 
aryl, hetaryl or aralkyl. 
Particularly preferred are compounds of the formula (I) in which at least 
one of the radicals R.sup.3 to R.sup.10 represents benzyl which is 
substituted by a sulfonyl, sulfenyl, thiocyanato or phosphoryl radical and 
in which otherwise the radicals have the meanings stated above. 
Particularly preferred are compounds of the formula (I) in which one or 
both of the radicals R.sup.3 and R.sup.7 represent benzyl which is 
substituted by a sulfonyl, sulfenyl, thiocyanato or phosphoryl radical and 
in which otherwise the radicals have the meanings stated above. 
Suitable sulfonyl, sulfenyl, thiocyanato or phosphoryl radicals are: 
##STR4## 
--SO.sub.2 --A; --SO--A, --S--A SCN, wherein 
______________________________________ 
Hal represents halogen, 
A represents halogen, hydroxyl, --OR, --NH.sub.2, --NHR', --NR'R", 
R represents optionally substituted alkyl, alkenyl, alkinyl, aryl or 
aralkyl, 
R' represents optionally substituted alkyl, aryl or aralkyl, 
R" represents optionally substituted alkyl, aryl, or aralkyl, 
______________________________________ 
and the radicals R' and R" represent together with the nitrogen atom 
attached an optionally substituted heterocyclic radical which may contain 
further heteroatoms such as N, 0 or S. 
In the general formulae, optionally substituted alkyl on its own or as part 
of a radical is straight-chain or branched alkyl having preferably 1 to 8, 
in particular 1 to 5 carbon atoms. Preferred examples are optionally 
substituted methyl, ethyl, n- and i-propyl, n-, i- and t-butyl. 
In the general formulae, optionally substituted alkenyl on its own or as 
part of a radical is straight-chain or branched alkenyl having preferably 
2 to 6, in particular 2 to 4 carbon atoms. Preferred examples are 
optionally substituted ethenyl, 1-propenyl, 2-propenyl and 3-butenyl. 
In the general formulae, optionally substituted cycloalkyl is mono-, bi- 
and tricyclic cycloalkyl having preferably 3 to 6, in particular 3, 5 or 6 
carbon atoms. Preferred examples are optionally substituted cyclopropyl, 
cyclobutyl, cyclopentyl and cyclohexyl. 
In the general formulae, optionally substituted alkoxy is straight-chain or 
branched alkoxy having preferably 1 to 6, in particular 1 to 4 carbon 
atoms. Preferred examples are optionally substituted methoxy, ethoxy, n- 
and i-propoxy and n-, i- and t-butoxy. 
In the general formulae, optionally substituted alkylthio is straight-chain 
or branched alkylthio having preferably 1 to 6, in particular 1 to 4 
carbon atoms. Preferred examples are optionally substituted methylthio, 
ethylthio, n- and i-propylthio, n-, i- and t-butylthio. 
In the general formulae, halogenoalkyl contains 1 to 4, in particular 1 or 
2 carbon atoms and preferably 1 to 9, in particular 1 to 5 identical or 
different halogen atoms, preferred halogen atoms being fluorine, chlorine 
and bromine in particular fluorine and chlorine. Examples are 
trifluoromethyl, chloro-di-fluoromethyl, 2,2,2-trifluoroethyl and 
pentafluoroethyl, and perfluoro-t-butyl. 
In the general formulae, optionally substituted aryl is preferably 
optionally substituted phenyl or naphthyl, in particular phenyl. 
In the general formulae, optionally substituted aralkyl is aralkyl 
optionally substituted in the aryl moiety and/or alkyl moiety having 
preferably 6 or 10, in particular 6 carbon atoms in the aryl moiety 
(preferably phenyl or naphthyl, in particular phenyl) and preferably 1 to 
4, in particular 1 or 2 carbon atoms in the alkyl moiety, the alkyl moiety 
being straight-chain or branched. Preferred examples are optionally 
substituted benzyl and phenylethyl. 
In the general formulae, optionally substituted hetaryl on its own or as 
part of a radical is a 5- to 7-membered ring having preferably 1 to 3, in 
particular 1 or 2 identical or different heteroatoms. Heteroatoms are 
oxygen, sulfur or nitrogen. Preferred examples are optionally substituted 
furyl, thiophenyl, pyrazolyl, imidazolyl, 1,2,3- and 1,2,4-triazolyl, 
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-, 1,3,4-, 1,2,4- and 
1,2,5-oxadiazolyl, azepinyl, pyrrolyl, isopyrrolyl, pyridyl, piperazinyl, 
pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-, 1,2,4- and 1,2,3-triazinyl, 
1,2,4-, 1,2,3-, 1,3,6- and 1,2,6-oxazinyl, oxepinyl, thiepinyl and 
1,2,4-diazepinyl. 
The optionally substituted radicals of the general formulae may carry one 
or more, preferably 1 to 3, in particular 1 to 2 identical or different 
substituents. Preferred examples of substituents are: 
alkyl preferably having 1 to 4, in particular 1 or 2 carbon atoms, such as 
methyl, ethyl, n- and i-propyl and n-, i- and. t-butyl; alkoxy having 
preferably 1 to 4, in particular 1 or 2 carbon atoms, such as methoxy, 
ethoxy, n- and i-propyloxy and n-, i- and t-butyloxy; alkylthio having 
preferably 1 to 4, in particular 1 or 2 carbon atoms, such as methylthio, 
ethylthio, n- and i-propylthio and n-, i- and t-butylthio; halogenoalkyl 
having preferably 1 to 4, in particular 1 or 2 carbon atoms and preferably 
1 to 5, in particular 1 to 3 halogen atoms, the halogen atoms being 
identical or different and preferably representing fluorine, chlorine or 
bromine, in particular fluorine, such as difluoromethyl and 
trifluoromethyl; hydroxyl; halogen, preferably fluorine, chlorine and 
bromine, in particular fluorine and chlorine; cyano; nitro; amino; 
monoalkyl- and dialkylamino having 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 carboxyl; 
carboxyl having preferably 2 to 4, in particular 2 or 3 carbon atoms, such 
as methoxycarbonyl and ethoxycarbonyl; alkylsulfinyl having 1 to 4, in 
particular 1 to 2 carbon atoms, halogenoalkylsulfinyl having 1 to 4, in 
particular 1 to 2 carbon atoms and 1 to 5 halogen atoms, such as 
trifluoromethylsulfinyl; sulfonyl (--SO.sub.3 H); alkylsulfonyl having 
preferably 1 to 4, in particular 1 or 2 carbon atoms, such as 
methylsulfonyl and ethylsulfonyl; halogenoalkylsulfonyl having 1 to 4, in 
particular 1 to 2 carbon atoms and 1 to 5 halogen atoms, such as 
trifluoromethylsulfonyl and perfluoro-t,n,s-butylsulfonyl; arylsulfonyl 
having preferably 6 or 10 aryl carbon atoms, such as phenylsulfonyl; acyl, 
aryl, aryloxy, hetaryl and hetaryloxy which may themselves carry one of 
the abovementioned substituents, and the formimino radical 
##STR5## 
Preferably used are compounds of the formula (I) in which 
R.sup.1,R.sup.2,R.sup.11 and R.sup.12 each represent independently of one 
another methyl, ethyl, propyl, butyl or phenyl which is optionally 
substituted by halogen, C.sub.1-4 -alkyl, OH or C.sub.1-4 -alkoxy, and 
represent benzyl or phenylethyl, each of which is optionally substituted 
by the radicals given for phenyl; 
R.sup.3 to R.sup.10 have the meanings stated above, at least one of these 
radicals representing benzyl whose phenyl radical is sulfenylated, 
sulfonylated or phosphorylated. 
Especially preferred are compounds of the formula (I) in which 
R.sup.1,R.sup.2,R.sup.11 and R.sup.12 each represent independently of one 
another methyl, ethyl, propyl, isopropyl or n-, s- or t-butyl, 
R.sup.3,R.sup.5,R.sup.7 and R.sup.9 each represent hydrogen, straight-chain 
C.sub.1-5 -alklyl or branched C.sub.4-5 -alkyl, in particular methyl, 
ethyl and propyl, which are optionally substituted by C.sub.1-4 -alkoxy, 
in particular methoxy, ethoxy, imidazolyl, indolyl or C.sub.1-4 
-alkylthio, in particular methylthio or ethylthio, and represent isobutyl 
or s-butyl and further represent phenyl, benzyl, phenylethyl or 
hetarylmethyl which are optionally substituted by nitro or by a radical 
--NR.sup.13 R.sup.14,R.sup.13 and R.sup.14 each representing independently 
of one another hydrogen or C.sub.1-4 -alkyl, or R.sup.13 and R.sup.14 
representing together with the N atom attached a 5-, 6- or 7-membered ring 
which is optionally interrupted by further O, S and N atoms and optionally 
substituted by C.sub.1-4 -alkyl or by halogen, in particular chlorine. 
R.sup.4,R.sup.6,R.sup.8 and R.sup.10 each represent independently of one 
another hydrogen, methyl, ethyl, n-propyl, n-butyl, vinyl and cyclohexyl 
which are optionally substituted by methoxy, ethoxy, imidazolyl, indolyl, 
methylthio or ethylthio and represent isopropyl or s-butyl and further 
represent optionally halogen-substituted phenyl, benzyl, phenylethyl or 
hetarylmethyl, 
at least one of the radicals R.sup.3 or R.sup.10 representing benzyl whose 
phenyl radical is substituted by one of the abovementioned sulfonyl, 
sulfenyl or phosphoryl radicals. 
The novel aromatic sulfonylated, sulfenylated, thiocyanated or 
phosphorylated cyclic depsipeptides of the formula (I) and their acid 
addition salts and metal salt complexes have very good anthelmintic 
properties and can be employed with preference in the veterinary sector. 
Surprisingly, they exhibit, in the control of worm diseases, better 
activity than the prior-art compounds having a similar constitution and 
used for the same purpose. 
The process according to the invention is carried out using 
halogenosulfonic acids (HalSO.sub.3 H), in particular chlorosulfonic acid, 
and their derivatives, sulfur dihalide, in particular sulfur dichloride 
and its derivatives, halogenosulfenic acid, in particular chlorosulfenic 
acid, sulfenyl halides, in particular sulfenyl chlorides, disulfides and 
sulfuric acid (oleum) as sulfonylating and sulfenylating agents, 
optionally in a diluent which is inert toward the reagents and optionally 
in the presence of Lewis acids. 
The process according to the invention is carried out using thiocyanate 
salts, in particular copper(II) thiocyanate and ammonium thiocyanate or 
thiocyanogen ((SCN).sub.2) as thiocyanating agents, optionally in a 
diluent which is inert toward the reagents and optionally in the presence 
of Lewis acids. 
The process according to the invention is carried out using phosphorus 
halides, in particular phosphorus trichloride and phosphorus pentachloride 
as phosphorylating agents, optionally in a diluent that is inert toward 
the reagents and optionally in the presence of Lewis acids. 
Examples of Lewis acids are: AlCl.sub.3, TiCl.sub.4, BF.sub.3, OEt.sub.2, 
SbCl.sub.5, SnCl.sub.4, CuCl.sub.2, FeCl.sub.3, SnCl.sub.2, AgBF.sub.4, 
AgSbF.sub.6, AgClO.sub.4, LiClO.sub.4, Br.sub.2. 
The reaction is carried out at temperatures from 0.degree. to 150.degree. 
C., preferably at 0.degree. to 80.degree. C., especially preferably at 
0.degree. to 60.degree. C. 
Suitable diluents are all organic solvents inert toward the reagents. These 
include in particular aliphatic and aromatic, optionally halogenated 
hydrocarbons, such as pentane, hexane, heptane, cyclohexane, petroleum 
ether, benzine, ligroin, benzene, toluene, methylene chloride, ethylene 
chloride, chloroform, carbon tetrachloride, chlorobenzene and 
o-dichlorobenzene, ethers, such as diethyl ether and dibutyl ether, glycol 
dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, 
ketones, such as acetone, methyl ethyl ketone, methyl isopropyl ketone and 
methyl isobutyl ketone, esters, such as methyl acetate and ethyl acetate, 
nitriles, such as for example acetonitrile and propionitrile, benzonitrile 
and glutaronitrile, amides, such as for example dimethylformamide, 
dimethylacetamide and N-methylpyrrolidone, and also dimethyl sulfoxide, 
tetramethylene sulfone and hexamethylphosphoric triamide. 
The depsipeptides are treated with an excess of reagent (5 to 10 
equivalents) and an excess of Lewis acid (15 to 20 equivalents). 
After the reaction has ended, the diluent is distilled off and the 
sulfonylated, sulfenylated, thiocyanated or phosphorylated compounds of 
the formula (I) are purified in a conventional manner, for example 
chromatographically. 
The active compounds are suitable for controlling pathogenic endoparasites 
encountered in humans and in animal husbandry and livestock breeding, in 
productive livestock, breeding stock, zoo animals, laboratory animals, 
animals used in experiments, and pets, and have low toxicity to 
warm-blooded animals. They are active against resistant and normally 
sensitive species and against all or some stages of development. By 
controlling the pathogenic endoparasites, it is intended to reduce 
disease, mortality and decreasing performance (for example in the 
production of meat,. milk, wool, hides, eggs, honey etc.), so that more 
economical and simpler animal keeping is possible by using the active 
compounds. The pathogenic endoparasites include Cestodes, Trematodes, 
Nematodes and Acantocephales in particular: 
From the order of the Pseudophyllidea, for example Diphyllobothrium spp., 
Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., 
Diplogonoporus Spp., 
From the order of the Cyclophyllidea, for example Mesocestoides spp., 
Anoplocephala spp., Paranoplocephala spp., Monieazia spp., Thysanosoma 
spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., 
Andyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hydatigera 
spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., 
Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., 
Diplopylidium spp.. 
From the subclass of the Monogenea, for example Gyrodactylus spp., 
Dactylogyrus spp., Polystoma spp.. 
From the subclass of the Digenea, for example 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., Typhlocoelum spp., 
Paramphistomum spp., Calicophoron spp., Cotylophoron spp., Gigantocotyle 
spp., Fischoederius spp., Gastrothylacus spp., Notocotylus spp., 
Catatropis spp., Plagiorchis spp., Prosthogonimus spp., Dicrocoelium spp., 
Eurytrema spp., Troglotrema spp., Paragonimus spp., Collyriclum spp., 
Nanophyetus spp., Opisthorchis spp., Clonorchis spp., Metorchis spp., 
Heterophyes spp., Metagonimus spp.. 
From the order of the Enoplida, for example Trichuris spp., Capillaria 
spp., Trichomosoides spp., Trichinella spp. 
From the order of the Rhabditida, for example Micronema spp., Strongyloides 
spp.. 
From the order of the Strongylida, for example Strongylus spp., 
Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus 
spp., Cylindropharynx spp., Poteriostomum spp., Cyclococercus spp., 
Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus 
spp., Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus 
spp., Syngamus spp., Cyathostoma spp., Metastrongylus spp., Dictyocaulus 
spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp., 
Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., 
Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., 
Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., 
Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Haemonchus 
spp., Ostertagia spp., Marshallagia spp., Cooperia spp., Nematodirus spp., 
Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp.. 
From the order of the Oxyurida, for example Oxyuris spp., Enterobius spp., 
Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp.. 
From the order of the Ascaridia, for example Ascaris spp., Toxascaris spp., 
Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp.. 
From the order of the Spirurida, for example Gnathostoma spp., Physaloptera 
spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., 
Draschia spp., Dracunculus spp.. 
From the order of the Filariida, for example Stephanofilaria spp., 
Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides 
spp., Brugia spp., Wuchereria spp., Onchocerca spp.. 
From the order of the Gigantorhynchida, for example Filicollis spp., 
Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp.. 
The livestock and breeding stock include mammals, such as, for example, 
cattle,. horses, sheep, pigs, goats, camels, water buffalo, donkeys, 
rabbits, fallow deer, reindeer, fur-bearing animals, such as, for example, 
minks, chinchilla or racoon, birds, such as, for example chickens, geese, 
turkeys or ducks, freshwater fish and sea fish, such as, for example, 
trout, carp and eels, reptiles and insects, such as, for example, honey 
bee and silkworm. 
The laboratory and test animals include mice, rats, guinea pigs, golden 
hamsters, dogs and cats. 
The pets include dogs and cats. 
Administration can be effected prophylactically as well as therapeutically. 
The active substances are administered, either directly or in the form of 
suitable preparations, enterally, parenterally, dermally, nasally, by 
treating the habitat or with the aid of shaped articles containing the 
active compound, such as, for example, strips, plates, tapes, collars, ear 
tags, limb bands or marking devices. 
Enteral administration of the active compounds is effected for example 
orally in the form of powders, tablets, capsules, pastes, drinks, 
granules, solutions, suspensions and emulsions which can be applied 
orally, boluses, medicated feed or drinking water. 
Dermal application is effected, for example, in the form of dipping, 
spraying, or pouring-on and spotting-on. Parenteral administration is 
effected, for example, in the form of injection (intramuscular, 
subcutaneous, intravenous or intraperitoneal) or by implants. 
Suitable preparations include: 
Solutions, such as solutions for injection, oral solutions, concentrates 
for oral administration after dilution, solutions for use on the skin or 
in body cavities, pour-on formulations, gels; 
Emulsions and suspension for oral or dermal administration and for 
injection; semi-solid preparations; 
Formulations in which the active compound is incorporated in a cream base 
or in an oil-in-water or water-in-oil emulsion base; 
Solid preparations, such as powders, premixes or concentrates, granules, 
pellets, tablets, boluses, capsules; aerosols and inhalants, shaped 
articles containing the active compound. 
Solutions for injection are administered intravenously, intramuscularly and 
subcutaneously. 
Solutions for injection are prepared by dissolving the active compound in a 
suitable solvent and, if desired, adding additives, such as solubilizers, 
acids, bases, buffer salts, antioxidants, or preservatives. The solutions 
are sterile-filtered and decanted into containers. 
Suitable solvents include: physiologically acceptable solvents, such as 
water, alcohols, such as ethanol, butanol, benzyl alcohol, glycerol, 
propylene glycol, polyethylene glycols and N-methyl-pyrrolidone, and their 
mixtures. 
If appropriate, the active compounds can also be dissolved in 
physiologically acceptable vegetable or synthetic oils which are suitable 
for injection. 
Suitable solubilizers include: solvents which facilitate the dissolution of 
the active compound in the main solvent or which prevent precipitation of 
the active compound. Examples of solubilizers are polyvinylpyrrolidone, 
polyethoxylated castor oil and polyethoxylated sorbitan esters. 
The following are preservatives: benzyl alcohol, trichlorobutanol, 
p-hydroxybenzoic esters or n-butanol. 
Oral solutions are administered directly. Concentrates are first diluted to 
the administration concentration and then administered orally. Oral 
solutions and concentrates are prepared as described above in the case of 
the solutions for injection, sterile procedures not being necessary. 
Solutions for use on the skin are applied drop by drop, smoothed on, rubbed 
in, splashed on or sprayed on. These solutions are prepared as described 
above in the case of the solutions for injection. 
It may be advantageous to add thickeners in the preparation process. The 
following are thickeners: inorganic thickeners, such as bentonites, 
colloidal silica, aluminum monostearate, or organic thickeners, such as 
cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates 
and methacrylates. 
Gels are applied to the skin or smoothed on or introduced into body 
cavities. Gels are prepared by adding such an amount of thickener to 
solutions which have been prepared as described in the solutions for 
injection that a clear composition is formed which has an ointment-like 
consistency. The thickeners used are the thickeners indicated further 
above. 
Pour-on and spot-on formulations are poured or splashed onto limited areas 
of the skin, the active compound penetrating the skin and acting 
systemically. 
Pour-on and spot-on formulations are prepared by dissolving, suspending or 
emulsifying the active compound in suitable solvents or solvent mixtures 
which are tolerated by the skin. If appropriate, other auxiliaries, such 
as colorants, absorption promoters, antioxidants, photostabilizers or 
tackifiers. 
Suitable solvents include: water, alkanols, glycols, polyethylene glycols, 
polypropylene glycols, glycerol, aromatic alcohols, such as benzyl 
alcohol, phenylethanol or phenoxyethanol, esters, such as ethyl acetate, 
butyl acetate or benzyl benzoate, ethers, such as alkylene glycol alkyl 
ethers, such as dipropylene glycol monomethyl ether or diethylene glycol 
mono-butyl ether, ketones, such as acetone or methyl ethyl ketone, 
aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, 
dimethylacetamide, N-methylpyrrolidone, or 
2,2-dimethyl-4-oxy-methylene-1,3-dioxolane. 
Colorants are all colorants which can be dissolved or suspended and which 
are approved for use in animals. 
Examples of absorption promoters are DMSO, spreading oils, such as 
isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty 
acid esters, triglycerides or fatty alcohols. 
The following are antioxidants: sulfites or metabisulfites, such as 
potassium metabisulfite, ascorbic acid, butylhydroxytoluene, 
butylhydroxyanisole or tocopherol. 
Example of photostabilizers are novantisolic acid. 
Tackifiers are, for example, cellulose derivatives, starch derivatives, 
polyacrylates or natural polymers such as alginates or gelatin. 
Emulsions can be administered orally, dermally or as injections. 
Emulsions are either the water-in-oil type or the oil-in-water type. 
They are prepared by dissolving the active compound either in the 
hydrophobic or in the hydrophilic phase and by homogenizing this phase 
with the solvent of the other phase, with the aid of suitable emulsifiers 
and, if appropriate, other auxiliaries, such as colorants, absorption 
promoters, preservatives, antioxidants, photostabilizers, and 
viscosity-increasing substances. 
Suitable hydrophobic phases (oils) include: paraffin oils, silicone oils, 
natural vegetable oils such as sesame seed oil, almond oil or castor oil, 
synthetic triglycerides, such as caprylic/capric acid biglyceride, a 
triglyceride mixture with vegetable fatty acids of chain length C.sub.8-12 
or other specifically selected natural fatty acids, mixtures of partial 
glycerides of saturated or unsaturated fatty acids which may also contain 
hydroxyl groups, and mono- and diglycerides of the C.sub.8 /C.sub.10 
-fatty acids. 
Fatty acid esters, such as ethyl stearate, di-n-butyladipate, hexyl 
laurate, dipropylene glycol pelargonate, esters of a branched fatty acid 
having a medium chain length with saturated fatty alcohols of chain length 
C.sub.16 -C.sub.18, isopropyl myristate, isopropyl palmitate, 
caprylic/capric esters of saturated fatty alcohols of chain length 
C.sub.12 -C.sub.18, isopropyl stearate, oleyl oleate, decyl oleate, ethyl 
oleate, ethyl lactate, waxy fatty acid esters such as artificial duck 
uropygial fat, dibutyl phthalate, diisopropyl adipate, ester mixtures 
related to the latter, etc. 
Fatty alcohols, such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl 
alcohol or oleyl alcohol. 
Fatty acids, such as, for example, oleic acid and its mixtures. 
Suitable hydrophilic phases include: water, alcohols, such as, for example, 
propylene glycol, glycerol, sorbitol and their mixtures. 
Suitable emulsifiers include: non-ionic surfactants, for example 
polyethoxylated castor oil, polyethoxylated sorbitan monooleate, sorbitan 
monostearate, glycerol monostearate, polyoxyethyl stearate or alkylphenol 
polyglycol ethers; 
Ampholytic surfactants, such as disodium N-lauryl-.beta.-iminodipropionate 
or lecithin; 
Anionic surfactants, such as Na lauryl sulfate, fatty alcohol ether 
sulfates, and the monoethanolamine salt of mono/dialkylpolyglycol ether 
orthophosphoric ester; 
Cationic surfactants, such as cetyltrimethylammonium chloride. 
Suitable other auxiliaries include: substances which increase the viscosity 
and stabilize the emulsion, such as carboxymethylcellulose, 
methylcellulose and other cellulose and starch derivatives, polyacrylates, 
alginates, gelatin, gum arabic, polyvinylpyrrolidone, polyvinylalcohol, 
methylvinyl ether/maleic anhydride copolymers, polyethylene glycols, 
waxes, colloidal silica, or mixtures of the listed substances. 
Suspensions can be administered orally, dermally or as an injection. They 
are prepared by suspending the active compound in a liquid excipient, if 
appropriate with the addition of other auxiliaries, such as wetting 
agents, colorants, absorption promoters, preservatives, antioxidants and 
photostabilizers. 
Suitable liquid excipients include all homogeneous solvents and solvent 
mixtures. 
Suitable wetting agents (dispersants) include the surfactants indicated 
further above. 
Suitable other auxiliaries include those indicated further above. 
Semi-solid preparations can be administered orally or dermally. They are 
only distinguished from the above-described suspensions and emulsions by 
their higher viscosity. 
To prepare solid preparations, the active compound is mixed with suitable 
excipients, if appropriate with the addition of auxiliaries, and the 
mixture is formulated as desired. 
Suitable excipients include all physiologically acceptable solid inert 
substances. Suitable for this purpose are inorganic and organic 
substances. Inorganic substances are, for example, common salt, 
carbonates, such as calcium carbonate, hydrogencarbonates, aluminum 
oxides, silicas, clays, precipitated or colloidal silica, and phosphates. 
Organic substances are, for example, sugars, cellulose, foodstuffs and 
animal feeds, such as powdered milk, animal meals, cereal meals, coarse 
cereal meals and starches. 
Auxiliaries are preservatives, antioxidants and colorants which have 
already been mentioned further above. 
Other suitable auxiliaries are lubricants and gliding agents, such as, for 
example, magnesium stearate, stearic acid, talc, bentonites, 
disintegrants, such as starch or crosslinked polyvinylpyrrolidone, 
binders, such as, for example, starch, gelatin or linear 
polyvinylpyrrolidone, and dry binders, such as microcrystalline cellulose. 
In the preparations, the active compounds can also be present in mixtures 
with synergists or other active compounds which are active against 
pathogenic endoparasites. Examples of such active compounds are 
L-2,3,5,6-tetrahydro-6-phenylimidazothiazole, benzimidazole carbamates, 
praziquantel, pyrantel or febantel. 
Ready-to-use preparations contain the active compound in concentrations of 
10 ppm to 20 percent by weight, preferably from 0.1 to 10 percent by 
weight. 
Preparations which are diluted before use contain the active compound in 
concentrations of 0.5 to 90 per cent by weight, preferably from 5 to 50 
percent by weight. 
In general, it has proved advantageous to administer amounts of about 1 to 
about 100 mg of active compound per kg of body weight per day, to achieve 
effective results.