MXPA97002771A - Procedure for the sulfonilation, sulfenilation and phosphorilation of depsipeptides cicli - Google Patents

Abstract

The object of the present invention is a process for the sulfonylation, the sulfenylation, the thiocyanate and the aromatic phosphorylation of cyclic depsipeptides with 6 atoms to 24 atoms in the ring, which are constituted by alpha-hydroxycarboxylic acids and alpha-amino acids and which contain at least one phenyl residue, characterized in that these cyclic depsipeptides are reacted with sulfonylation, sulfenylation, thiocyanate or phosphorylation agents, if appropriate in the presence of catalysts, auxiliaries and / or diluents, as well as new asynaptic compounds and their use as endoparasiticide

Description

PROCEDURE FOR THE SULFONILATION, SULFENILATION AND PHOSPHORILATION OF CYCLIC DEP8IPEPTIDES DESCRIPTION OF THE INVENTION The present invention relates to a process for the sulfonylation, sulfenylation, thiocyanation and phosphorylation of cyclic depsipeptides as well as to the new compounds and their use as endoparasiticides. The cyclic depsipeptides and their effect as endoparasiticides are already known from EP 381 173, PCT WO 93/19 053. However, the effect of these compounds is not satisfactory in all cases. The object of the present invention are 1. Process for the aromatic sulfonylation, sulfenylation, thiocyanation and phosphorylation of cyclic depsipeptides with 6 to 24 ring atoms, which are constituted by a-hydroxycarboxylic acids and α-amino-acids and which they contain at least one phenyl residue, characterized in that these cyclic depsipeptides are reacted with sulfonylation, sulphenylation, thiocyanation or phosphorylation reagents, if appropriate in the presence of catalysts, auxiliaries and / or diluents. 2. Silylonized, sulfenylated, thiocyanated and / or aromatically phosphorylated cyclic peptides with 6 to 24 ring atoms, which are constituted from α-hydroxycarboxylic acids and -amino acids and which contain at least one phenyl radical. REF: 24398 The cyclic depsipeptides, which are used as starting materials for the process according to the invention, are natural products usually prepared by fermentation. From the structural point of view they are comparable with proteins. Therefore, they were expected to react sensitively to aggressive chemicals and to decompose totally or partially. Surprisingly it has been found that the process according to the invention can be carried out without destroying the basic body of the depsipeptides. In this way, compounds which are sulphonylated, sulfenylated, thiocyanated or phosphorylated in the phenyl ring and which are characterized by an excellent endoparasiticidal effect are obtained. Preferably, the process according to the invention will be used to obtain the new and preferred compounds of the formula (I), wherein at least one of the residues R3, R4, R5, R5, R6, R7, R8, R9, R10 means phenyl or benzyl, which is substituted by a sulfonyl, sulfenyl, thiocyano or phosphoryl moiety, and in which otherwise the radicals R.sup.1, R.sup.2, R.sup.11 and R.sup.12 are hydrogen, residues, optionally substituted, alkyl having 1 to 8 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, aralkyl, aryl, R.sup.3, R.sup.5, R.sup.7, R.sup.9 they mean hydrogen, straight chain or branched chain alkyl with 1 to 8 carbon atoms, which may be substituted, if appropriate, by hydroxy, by alkoxy with 1 to 4 carbon atoms, by aryloxy, by hetaryloxy, by carboxy, by OO II II (-COH), by carboxamide, by (-0-C-NH2), by imidazolyl, by indolyl, by guanidino by -SH or by alkylthio with 1 to 4 carbon atoms, furthermore they mean aryl, hetaryl or optionally substituted alkyl, R 4, R 6, R 8, R 10 mean hydrogen, alkyl with 1 to 8 carbon atoms, alkenyl with 2 to 6 carbon atoms rhono, straight or branched chain 3 to 7 carbon cycloalkyl, which may optionally be substituted by hydroxy, by alkoxy with 1 to 4 carbon atoms, by carboxy, by carboxamide, by imidazolyl , by indolyl, by guanidino, by SH or by alkylthio with 1 to 4 carbon atoms, as well as by aryl, hetaryl or aralkyl if substituted. Particularly preferred are compounds of the formula (I), in which at least one of the radicals R3 to R10 is benzyl, which is substituted by a sulfonyl, sulfenyl, thiocyano or phosphoryl radical and where the radicals have otherwise the meaning previously indicated. Particularly preferred are compounds of the formula (I) in which one or two radicals R 3 and R 7 are benzyl, which are substituted by a sulfonyl, sulfenyl, thiocyano or phosphoryl residue and in which, moreover, the radicals have the meaning above indicated. As sulphonyl, sulfenyl, thiocyano or phosphoryl radicals there may be mentioned: 0 0 II II II -S02-A; -SO-A, -S-A, -P (Hal) 2, -P (0R) 2, -P (NR «R ,,) 2, SCN, where Hal means halogen, A means halogen, hydroxy, -OR, -NH2, -NHR ', -NR'R ", R means alkyl, alkenyl, alkynyl, aryl or aralkyl if substituted, R' means alkyl, aryl or optionally substituted aralkyl, R "means optionally substituted alkyl, aryl or aralkyl, and the radicals R 'and R" signify, together with the boundary nitrogen atom, a substituted heterocyclic radical, which may also contain other heteroatoms such as N, O or S. Alkyl optionally substituted alone or as an integral part of a radical in the general formulas means straight-chain or branched-chain alkyl with preferably 1 to 8, especially 1 to 5, carbon atoms. By way of example and preferably, methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, optionally substituted, can be mentioned, if appropriate substituted alkenyl alone or as an integral part of a radical in the general formulas means alkenyl straight chain or branched chain with preferably 2 to 6, especially 2 to 4 carbon atoms. By way of example and preferably, ethenyl, propenyl- (1), propenyl- (2) and butenyl- (3), optionally substituted, may be mentioned. Cycloalkyl optionally substituted in the general formulas means mono-, bi- and tricyclic cycloalkyl with preferably 3 to 6, especially 3, 5 or 6 carbon atoms. By way of example and preferred embodiment, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted, may be mentioned. Alkoxy substituted, if appropriate, in the general formulas means straight-chain or branched-chain alkoxy with preferably 1 to 6, especially 1 to 4, carbon atoms. By way of example and preferably, methoxy, ethoxy, n- and i-propoxy and optionally substituted n-, o- and t-butoxy can be mentioned. Alkylthio optionally substituted in the general formulas means straight chain or branched chain alkylthio preferably with 1 to 6, especially 1 to 4, carbon atoms. By way of example and preferably, optionally substituted methylthio, ethylthio, n- or i-propylthio, n-, o- and t-butylthio can be mentioned. Halogenoalkyl in the general formulas contains from 1 to 4, in particular 1 or 2 carbon atoms and preferably 1 to 9, in particular 1 to 5 same or different halogen atoms, the halogen atoms preferably being fluorine, chlorine and bromine, especially fluorine and chlorine. Examples which may be mentioned are trifluoromethyl, chloro-di-fluoromethyl, 2,2,2-trifluoroethyl and pentafluoromethyl, perfluoro-t-butyl. Any substituted aryl in the general formulas preferably means phenyl or optionally substituted naphthyl, especially phenyl. Aralkyl optionally substituted in the general formulas means aralkyl optionally substituted on the aryl part and / or on the alkyl part with preferably 6 or 10, especially 6 carbon atoms on the aryl part (preferably phenyl or naphthyl, especially phenyl) and preferably 1 to 4, especially the 2 carbon atoms in the alkyl part, which may be the straight-chain or branched-chain alkyl part. By way of example and preferably, optionally substituted benzyl and phenylethyl can be mentioned. In the general formulas, substituted hetaryl which is substituted only as an integral part of a radical means rings with 5 to 7 members, preferably 1 to 3, especially 1 or 2 heteroatoms, which are the same or different. As heteroatoms, oxygen, sulfur or nitrogen may be mentioned. Exemplary and preferably, 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, oxetanyl, thiepinyl and 1,2,4-diazepinyl, optionally substituted. The radicals, if any substituted, of the general formulas can carry one or more, preferably one to three, in particular one to two identical or different substituents. Examples of substituents which may be mentioned are: Alkyl with preferably 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 with preferably 1 to 4, especially 1 or 2 carbon atoms, such as methoxy, ethoxy, n- and i-propyloxy and n-, i- and t-butyloxy; alkylthio with preferably 1 to 4, especially 1 or 2 carbon atoms, such as methylthio, ethylthio, n- or i-pro-pylthio and n-, i- and t-butylthio; haloalkyl with preferably 4, especially 1 or 2 carbon atoms and preferably 1 to 5, especially 1 to 3 halogen atoms, the halogen atoms being the same or different, and the halogen atoms preferably being fluorine, chlorine or bromine, especially fluorine, such as difluoromethyl, trifluoromethyl; hydroxy; halogen preferably fluorine, chlorine, bromine, especially fluorine, chlorine, cyano; nitro; Not me; monoalkyl- and dialkylamino with preferably 1 to 4, especially 1 or 2 carbon atoms for each alkyl group, such as methylamino, methylethylamino, n- and i-propylamino and methyl-n-butylamino; acyl moieties such as carboxyl; carboxy with preferably 2 to 4, especially 2 or 3 carbon atoms, such as carboxymethoxy and carboethoxy; alkylinyl with 1 to 4, especially 1 to 2 carbon atoms, haloalkyl-inyl with 1 to 4, especially 1 to 2 carbon atoms and 1 to 5 halogen atoms such as trifluoromethyl-honyl with 1 to 4, especially 1 to 2 carbon atoms with 1 to 5 halogen atoms, such as trifluoromethylhinyl; onyl (-S03H); alkylonyl with preferably 1 to 4, especially 1 to 2 carbon atoms, such as methylonyl and ethylonyl; halogenalkylonyl with 1 to 4, especially 1 to 2 carbon atoms and 1 to 5 halogen atoms, such as trifluoromethyl onyl, perfluoro-t, n, s-butylonyl; arylonyl with preferably 6 or 10 carbon atoms in the aryl, such as phenylonyl; acyl, aryl, aryloxy, heteroaryl, heteroaryloxy, which in turn can carry one of the aforementioned substituents as well as the for-mimino moiety H I -C = N-0-alkyl.

Preferably, the compounds of the general formula (I), in which R 1, R 2, R 11 and R 12, independently of one another, are methyl, ethyl, propyl, butyl or phenyl, which is optionally substituted by halogen, 1 to 4 carbon atoms, OH, alkoxy with 4 carbon atoms, as well as benzyl or phenylethyl which may be substituted, if appropriate, by the indicated radicals in the case of phenyl; R3 to R10 have the meaning indicated above, meaning at least one of these benzyl radicals, the phenyl ring of which is sulphonylated, sulfonylated or phosphorylated. Particularly preferred are compounds of the formula (I), in which R1, R2, R11 and R12 independently of one another, mean methyl, ethyl, propyl, isopropyl or n-, s-, t-butyl, R3, R5, R7. R9 are hydrogen, straight chain alkyl or C5 alkyl or branched chain alkyl, especially methyl, ethyl, propyl, which may be substituted, if appropriate, by alkoxy with 1 to 4 atoms carbon, especially by methoxy, by ethoxy, by imidazolyl, by indolyl or by alkylthio with 1 to 4 carbon atoms, especially by methylthio, by ethylthio, as well as by isobutyl or s-butyl and also by phenyl, benzyl, phenethyl or hetarylmethyl, which may be substituted, if appropriate, by nitro, or by a radical -NR13R14, where R13 and R14 independently of one another, mean hydrogen or alkyl having 1 to 4 carbon atoms or R13 and R14 together with the N-boundary atom mean a ring with 5 , 6 or 7 members, which may be interrupted, if appropriate, by another heteroatom O, S and N, and which is optionally substituted by alkyl with 1 to 4 carbon atoms, or by halogen, especially chlorine. R4, R6, R8, R10 independently of one another, mean hydrogen, methyl, ethyl, n-propyl, n-butyl, vinyl, cyclohexyl, which may be substituted, if appropriate, by methoxy, by ethoxy, by imidazolyl, by indolyl in addition, for methylthio, for ethylthio, and also for isopropyl, s-butyl, they also mean halogen-substituted phenyl, benzyl, phenylethyl or hetarylmethyl, wherein at least one of the radicals R 3 or R 10 is benzyl, the phenyl residue of which is substituted by one of the above-mentioned sulfonyl, sulfenyl or phosphoryl radicals. The novel cyclic, aromatically sulfonylated, sulfenylated, thiocyanated and / or phosphorylated depsipeptides of the formula (I) as well as their acid addition salts and complexes with metal salts have very good anthelmintic properties and can be used preferably in the field of veterinary Medicine. Surprisingly, in the fight against dermicular diseases, they show a better activity than the compounds with the same direction of activity, previously known, similar from the point of view of their constitution. For carrying out the process according to the invention, halogen sulphonic acids (HalS03H), especially chlorosulfonic acid, as well as their derivatives, dihalogeno sulphides, especially dichlorosulphides, and their derivatives, halogensulfenic acids, especially chlorosulfenic acid, halides, are used as sulphonylation or sulfenylation reagents. of sulphonyl, in particular sulfenyl chlorides, disulfides, sulfuric acid (oleum), if appropriate in an inert diluent to the reactants, and, if appropriate, in the presence of Lewis acids. To carry out the process according to the invention, thiocyanate reagents will be used as rodanide salts, especially cupric stear (II) and ammonium or dirhanedium ((SCN) 2), optionally in a diluent inert to the reactants as well as in given case in the presence of Lewis acids. In order to carry out the process according to the invention, phosphorus halides, especially phosphorus trichloride, phosphorus pentachloride, optionally in a diluent inert to the reactants or, where appropriate, in the presence of Lewis acids, are used as phosphorylated reagents. As Lewis acids there may be mentioned: A1C13, TIC14, BF3-OEt2, SbCl5, SnCl4, CuCl2, FeCl3, SnCl2, AgBF4, AgSbF6, AgC104, LiC104, Br2. The reaction is carried out at temperatures of 0 to 150 ° C, preferably 0 to 80 ° C, particularly preferably 0 to 60 ° C.

Suitable diluents are all inert organic solvents with respect to the reactants. These include, in particular, aliphatic and aromatic hydrocarbons, if appropriate halogenated, such as pentane, hexane, heptane, cyclohexane, petroleum ether, benzene, ligroin, benzene, toluene, methylene chloride, ethyl chloride, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, furthermore ethers such as diethyl- and dibu-tyl ether, glycol dimethyl ether and diglycoldimethyl ether, tetrahydrofuran and dioxane, furthermore ketones, such as acetone, methylethyl-, methylisopropyl- and methyl isobutyl ketone, further esters such as methyl acetate and of ethyl, in addition nitriles, such as for example acetonitrile and propionitrile, benzonitrile, glutathionitrile, furthermore amides such as for example dimethylformamide, dimethylacetamide and N-methylpyrrolidone, as well as dimethylsulfoxide, tetramethylenesulphone and hexamethylphosphorotriamide. The depsipeptides are reacted with an excess of reagent (5 to 10 equivalents) and with an excess of Lewis acid (15 to 20 equivalents). After the reaction has been verified, the diluent is distilled off and the sulphonylated, sulphenylated, thiocyanated or phosphorylated compounds of the formula (I) are purified in the usual manner, for example by chromatography. The active products are suitable, with a toxicity favorable to mammals, for the control of pathogenic endoparasites in man and in the maintenance and breeding of useful animals, breeding, zoo, laboratory, testing and entertainment. In this case they are active against all stages of development or against individual stages of development of pests as well as against resistant and normally sensitive types. Through the fight against pathogenic endoparasites diseases, chaos of death and loss of yield are reduced (for example in the production of meat, milk, wool, skins, eggs, honey, etc.) as well as, if necessary, also the transmission to the human beings, in such a way that the use of the active products allows a maintenance of the animals more economic and simple. Pathogenic endoparasites belong to cestodes, trematodes, nematodes, especially: From the order of Pseudophyllidia, for example: Diphyllobothrium spp., Spirometra spp. , Schistocephalus spp. , Lígula spp., Bothridium spp., Diphlogonoorus spp. From the order of Cyclofilideos for example: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosmsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Anhyra spp., Bertiella spp. ., Taenia spp., Echinococcus spp., Hydratigera spp., Davainea spp., Raillietina spp., Hymenolepsis spp., Echinolepsis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp. From the subclass of the Monogeneous, for example: Cyrodactylus spp., Dactylogyrus spp., Polystoma spp. From the subclass of the Digéneos, 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., Typhloccelum spp., Paramphistomum spp., Calicophron 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., Chornornis spp., Metorchis spp., Heterophyes spp., Metagonimus spp. From the order of Enoplideans, for example: ris spp., Capillaria spp., Trichlomosoides spp., Trichinella spp. From the order of the Rhabditios, for example: Micro- nema spp., Strongyloides spp. From the order of the Strongylidae, for example: Stronylus spp., Triodontophorus spp. , Oesophagodontus spp. , Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Posteriostromum spp. , Cyclococercus spp. , Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus spp., Acrylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathosto spp., Metastrongylus spp., Dictyocaulus spp. ., Muellerius spp., Protostrongylus spp., Neostrongylus spp., Cystocaulus spp., Pneu- mostrongylus spp. , Spicocaulus spp. , Elaphostrongylus spp. , Parelaphostrongylus spp., Crenosa to spp., Paracrenosoma spp., Angiostrongylus spp. , Aelurostrongylus spp. , Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Haemonchus spp., Ostertagia spp. Marshallagia spp., Coopera- ria spp., Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp. From the order of the Oxyurids, for example: Oxyuris spp., Enterobius spp., Passalurus spp. ., Syphacia spp., As- • piculuris spp., Heterakis spp. From the order of the Asearids, for example: Asearis spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp. , Ascaridia spp. From the order of the Spirurids, for example: Gnathos- toma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp. Order of the Filiarids, for example: Stephanophilaria spp., Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp., Onchocerca spp. of the Gigantohinquídeos for example: Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp .. To the useful and breeding animals belong mammals such as for example cows, horses, goats, pigs, goats, camels, hippos , asses, rabbits, deer, reindeer, animals for the production of fur such as for example mink, chinchillas, raccoons, birds such as for example chickens, geese, ducks, turkeys, freshwater and water fish such as, for example trout, carps, eels, reptiles, insects such as for example bees d and honey and silkworms. Laboratory and test animals belong to mice, rats, guinea pigs, golden hamsters, dogs and cats. The animals of entertainment include dogs and cats. The application can be carried out both prophylactically and therapeutically. The application of the active ingredients is carried out directly or in the form of suitable preparations in an enteral, parenteral, dermal or nasal manner, by treatment of the environment or with the aid of moldings containing the active compound, such as, for example, strips, plates, bands, collars, marks for ears, bands for limbs, marking devices. The enteral application of the active compounds is carried out, for example orally, in the form of powders, tablets, capsules, pastes, beverages, granules, orally applicable solutions, suspensions and emulsions, boluses, feed or medicated drinking water. The dermal application is carried out for example in the form of immersion (Dippen), spraying, bathing, washing, pouring (pour-on and spot-on) and dusting. Parenteral administration is carried out, for example, in the form of an injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or by implantation. Suitable preparations are: Solutions such as injectable solutions, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in the body cavities, spray formulations, gels; emulsions and suspensions for oral or dermal application as well as for injection; semi-solid preparations; formulations in which the active product is administered in an ointment base or in an oil-in-water or water-in-oil emulsion base; solid preparations such as powders, premixes or concentrates, granulates, pellets, tablets, boluses, capsules; aerosols and inhaled, molded bodies containing the active product. The solutions for injection are administered intravenously, intramuscularly and subcutaneously. Injectable solutions are prepared by dissolving the active compound in a suitable solvent and optionally additives such as solubilizers, base acids, buffer salts, antioxidants, preservatives. The solutions are sterile filtered and packaged. Solvents which may be mentioned are physiologically compatible solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerin, propylene glycol, polyethylene glycols, N-methyl pyrrolidone, and mixtures thereof. The active compounds can also be dissolved, if appropriate, in physiologically compatible vegetable or synthetic oils which are suitable for injection. Solubilizers which may be mentioned are: solvents which favor the solution of the active compound in the main solvent or prevent its precipitation. Examples are polyvinylpyrrolidone, castor oil, polyoxyethylene, polyoxyethylenated sorbitan esters. The preservatives are: benzyl alcohol, trichlorobutanol, esters of p-hydroxybenzoic acid, n-butanol. The oral solutions are used directly. The concentrates are used orally after previous dilution up to the concentration of application. Oral solutions and concentrates are prepared in the manner described above in the case of injectable solutions, and can be desisted to work in a sterile manner. The solutions for use on the skin are smeared, spread, rubbed, splashed or injected. These solutions are prepared in the manner described above in the case of injectable solutions.

It can be advantageous to add thickeners in the obtainment. Thickeners are: inorganic thickeners such as bentonite, colloidal silicic acid, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates. The gels are applied to the skin or smeared or inserted into the body cavities. The gels are prepared by combining solutions, which have been prepared as described in the case of injectable solutions, with an amount of thickener such that a clear mass with ointment-like consistency is formed. The thickeners indicated above are used as thickeners. The formulations for watering are irrigated or sprayed on limited areas of the skin, the active product penetrating the skin and acting systemically. The watering formulations are prepared by dissolving, suspending or emulsifying the active product in suitable solvents compatible with the skin or solvent mixtures. If necessary, other auxiliary products are added, such as dyes, resorption promoting agents, antioxidants, light stabilizers, adhesives. As solvents there may be mentioned: alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerin, aromatic alcohols such as benzyl alcohol, phenyl ethanol, phenoxyethanol, esters such as acetates, butylates, benzylbenzoates, ethers such as alkylene glycol alkylether, carboxypropylene glycol monomethyl ether, diethylene glycol monobutyl ether, ketones such as acetone, methylethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, N-methylpi-rolidone, 2,2-dimethyl-4-oxy-methylene-3. -oxiolane. The dyes are all dyes admitted to be used with animals, which can be dissolved or suspended. The resorption promoting products are for example DMSO, extender oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols. The antioxidants are sulphites or metabisulfites such as potassium bisulfite, ascorbic acid, butylhydtoluene, butylhydroanisole, tocopherol. The light-protecting agents are, for example, novantisolic acid. The adhesives are, for example, cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatins. The emulsions can be used orally, dermally or as injections. The emulsions are of the water-in-oil type or the oil-in-water type. They are prepared by dissolving the active compound either in hydrophobic phase or in hydrophilic phase and homogenizing it with the solvent of the other phase with the aid of suitable emulsifiers and, if necessary, other auxiliary products such as dyes, products which promote resorption, preservatives, antioxidants, light protection products, products to increase viscosity. As the hydrophobic phase (oils) there may be mentioned: paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic acid glyceride / capric acid, mixed • triglycerides with vegetable fatty acids having a chain length of 8 to 12 carbon atoms or with other specially selected natural fatty acids, mixtures of partial glycerides of saturated or unsaturated fatty acids, optionally also containing hydl groups, mono-, and diglycerides of fatty acids with 8/10 carbon atoms. Esters of fatty acids such as ethyl stearate, di-n-butyryl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid having an average chain length with saturated fatty alcohols having a chain length of 16 to 18 carbon atoms, isopropyl myristate, isopropyl palmitate, esters of the caprylic / capric acids of saturated fatty alcohols with a chain length of 12-18 carbon atoms, isopropyl stearate, oleiyl oleate, decyl oleate, ethyl oleate, ethyl lactate, acid esters fatty waxy type, such as synthetic fat of the uropigial gland of the añades, dibutyl phthalate, diisopropyl adipate, mixtures of esters related to the former and others. Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol. Fatty acids such as, for example, oleic acid and mixtures thereof. As the hydrophobic phase, there can be mentioned: water, alcohols such as for example propylene glycol, glycerin, sorbitol and their mixtures. The following may be mentioned as emulsifiers: nonionic surfactants, for example polyoxyethylenated castor oil, polyoxyethylenated sorbitan monooleate, sorbitan monostearate, glycerin monostearate, polyoxyethylstearylate, alkylphenol polyglycol ether; ampholytic surfactants such as disodium N-lauryl-β-iminodipropionate or lecithin; anionic surfactants such as sodium lauryl sulfate, fatty alcohol ether sulfate, mono / dialkyl-polyol ether ortho-orthophosphate salts of monoethanolamine; cationic surfactants such as cetyltrimethylammonium chloride. Other auxiliaries which may be mentioned are: viscosity-increasing products and emulsion stabilizing products such as carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatins, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycol, waxes, colloidal silicic acid or mixtures of the indicated products. The suspensions can be used orally, dermally, or as an injection. They are prepared by suspending the active compound in an excipient liquid, if appropriate, with the addition of other auxiliary agents such as humectants, dyes, absorption-promoting products, preservatives, antioxidants, light-protection agents. Suitable excipient liquids are all solvents and homogeneous solvent mixtures. As humectants (dispersants), the surfactants mentioned above can be mentioned. As additional auxiliary products, those mentioned above may be mentioned. Semi-solid preparations can be administered orally or dermally. They differ from the suspensions and emulsions described above only because of their higher viscosity. In order to obtain solid preparations, the active compound is mixed with suitable excipients, optionally with the addition of auxiliary products, and brought to the desired shape.

Suitable excipients are all physiologically acceptable solid inert products. As such they serve inorganic and organic products. Inorganic products are for example common salt, carbonates such as calcium carbonate, bicarbonates, aluminum oxide, silicic acids, clays, precipitated or colloidal silicon dioxide, phosphates. Organic products are for example sugars, celluloses, food and feed such as sugar powder, animal flour, cereal flours and starches, starches. Auxiliary products are preservatives, antioxidants, dyes, which have already been indicated above. Other suitable auxiliary products are lubricants and fatliquors, such as for example magnesium stearate, stearic acid, talc, bentonite, decomposition promoting substances such as starches or crosslinked polyvinylpyrrolidone, binders such as for example starches, gelatins or linear polyvinylpyrrolidone as well as binders. dry, such as microcrystalline cellulose. The active products can also be present in the preparations in a mixture with synergists or with other active products which act against the pathogenic endoparasites. Such active compounds are, for example, L-2,3,5,6-tetrahydro-6-phenyl-imidazothiazole, benzimidazole carbamate, Praziquantel, Pyrantel, Febantel. Preparations ready for application contain the active compound in concentrations of 10 ppm to 20% by weight, preferably 0.1 to 10% by weight. Preparations that are diluted before application contain the active compound in concentrations of 0.5 to 90% by weight, preferably 5 to 50% by weight. In general, it has been found to be advantageous to administer amounts of about 1 to about 100 mg of active compound per kg of body weight per day in order to achieve effective results. Example A. In vivo test against nematodes. Haßmonchus contortus / cor ero. Lambs experimentally infected with Haemonchus contortus were treated, once the prepotency time of the parasites had elapsed. The active compounds were applied orally (p.o.) in the form of a pure active ingredient in gelatin capsules or as an injectable solution (i.v.). The degree of activity is determined by quantitative counting of the eggs of earthworms detached with the excrements before and after the treatment. A complete interruption of the egg shed after treatment means that the worms were expelled or have been so damaged that they no longer produce eggs (effective dose).

The active products tested and the active doses (effective dose) can be seen in the following table.

The preparation of the active compounds according to the invention is apparent from the following examples. Preparation examples »1. General procedure routine for chlorosulfonation. A solution of a depsipeptide (0.523 mmol) in dichloromethane at 0 ° C is combined with chlorosulfonic acid (37.3 mmol), stirred for 2 hours at 0 ° C and for 2 hours at room temperature. The reaction mixture is added, dropwise, at 0 ° C, in acetone (50 ml). Then, at 0 ° C, morpholine (79.4 mmol) is combined and the mixture is stirred for 12 hours at 60 ° C. After this time, it is concentrated by evaporation, taken up in water and extracted with dichloromethane (three times). The combined organic extracts are dried over Na 2 SO 4 and concentrated by evaporation. The residue is purified by column chromatography with the eluent consisting of tert-butylmethyl ether-cyclohexane-methanol = 10: 1: 0.4. Depytypes of the formula (I) are obtained, in which the substituents have the following meaning. 2. General routine for sulfonation. The corresponding depsipeptide (1.05 mmol) in oleum cooled to 0 ° C (20%, 25 ml) is introduced and stirred for 1 to 2 hours at this temperature. It is then poured onto 250 ml of ice and neutralized with Ba (OH) 2. The residue is filtered off and washed three times with water. The filtrate is concentrated by evaporation to 5 to 10 ml and chromatographed through a strong acid ion exchanger (50 g) with water. After concentration by evaporation of the solvent, the peptides of the formula (I) are obtained. 3. General routine for phosphorylation. It is added, dropwise, sulfonyl chloride (3 equivalents) to a suspension cooled to -10 ° C of PC13 (3 equivalents), A1C13 (3 equivalents) and of the depsipeptide in tetrachloromethane. Stirring is continued for 1 minute at 70 ° C and excess S02C12 is distilled off under vacuum. The residue is taken up in tetrachloromethane and combined, under cooling, slowly with an excess of an alcohol or an amine. The reaction mixture is washed several times with a little water, dried over Na 2 SO 4, and concentrated by evaporation. Column chromatography of the residue on silica gel provides the depsipeptide of the formula (I). 4. General routine for sulfenylation. SbCl 5 (0.15 mmol) and AgSbF 6 (0.15 mmol) are placed in 2 ml of 1,2-dichloroethane at room temperature, then a solution of dimethyl disulfide (0.5 mmol) is added dropwise. ) in dichloromethane (2 ml) and finally a solution of the depsipeptide (1.0 mmol) in 1,2-dichloroethane is added dropwise. The reaction mixture is refluxed for 3 to 6 hours and, after cooling, neutralized with saturated aqueous NaHCO 3 solution. It is washed three times with water, dried over Na 2 SO 4 and concentrated by evaporation. Column chromatography of the residue on silica gel provides the depsipeptide of the formula (I). 5. General routine for thiocyanate. A solution of the depsipeptide (1.0 mmol) in glacial acetic acid (5 ml) is reacted with Ca (SCN) 2 (2 to 5 mmol) and stirred at 60 ° C. After cooling and filtration, it is diluted with water, neutralized with NaHCO 3 solution and extracted with ethyl acetate. Column chromatography of the residue on silica gel provides the depsipeptide of the formula (I).

? It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property:

Claims (8)

1. CLAIMS 1. Process for the aromatic sulfonylation, sulfenylation, thiocyanation and phosphorylation of cyclic depsipeptides with 6 to 24 ring atoms, which are constituted by α-hydroxycarboxylic acids and α-amino acids and which contain at least one phenyl residue, characterized in that these cyclic depsipeptides are reacted with sulfonylation, sulfenylation, thiocyanation or phosphorylation reagents, if appropriate in the presence of catalysts, auxiliaries and / or diluents.
2. 2.- Silylonized, sulfenylated, thiocyanated and / or aromatically phosphorylated cyclic peptides having 6 to 24 ring atoms, characterized in that they are constituted from α-hydroxycarboxylic acids and α-amino acids and contain at least one residue phenyl, which are sulphonylated, sulphenylated, thiocyanated or phosphorylated.
3. 3.- Compounds of the general formula (I) characterized in that R3, R4, R5, R5, R6, R7, R8, R9, R10 means phenyl or benzyl, which is substituted by a sulfonyl, sulfenyl, thiocyano or phosphoryl moiety, and in which otherwise the residues R1, R2 , R 11 and R 12 signify hydrogen, optionally substituted radicals, alkyl having 1 to 8 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, aralkyl, aryl, R 3, R 5, R 7, R 9 are hydrogen, - neal or branched chain with 1 to 8 carbon atoms, which may be substituted, if appropriate, by hydroxy, by alkoxy with 1 to 4 carbon atoms, by aryloxy, by hetaryloxy, by carboxy, by 0 O II II (-C0H), by carboxamide, by (-0-C-NH2), by imidazolyl, by indolyl, by guanidino by -SH or by alkylthio with 1 to 4 carbon atoms, also mean aryl, hetaryl or alkyl, if appropriate substituted, R 4, R 6, R 8, R 10 mean hydrogen, alkyl having 1 to 8 carbon atoms, alkenyl with 2 to 6 carbon atoms, cycloal straight-chain or branched-chain carbon atoms, which may be substituted, if appropriate, by hydroxy, by alkoxy with 1 to 4 carbon atoms, by carboxy, by carboxamide, by imidazolyl, by indolyl, by guanidino, by SH or by alkylthio with 1 to 4 carbon atoms, as well as substituted aryl or aralkyl, if appropriate.
4. 4. Compounds of the formula (I) according to claim 3, characterized in that at least one of the radicals R to R means benzyl, which are substituted by a sulfonyl, sulfenyl, thiocyano or phosphoryl radical and in which the radicals have the meaning indicated in the claim. 3.
5. 5.- Compounds of the. formula (I), according to claim 3, characterized in that one or both radicals R and R represent benzyl, which is substituted by a sulfonyl, sulfenyl, thiocyano or phosphoryl radical of the formulas -S02-A; -SO-A, -S-A, -P (Hal) 2, -P (OR) 2, -P (NR'R ") 2, where Hal means halogen, A means halogen, hydroxy, -OR, -NH2, -NHR ', -NR'R ", R means alkyl, alkenyl, alkynyl, aryl or aralkyl if substituted, R' means alkyl, aryl or optionally substituted aralkyl, R "means optionally substituted alkyl, aryl or aralkyl, and the radicals R 'and R" signify, together with the boundary nitrogen atom, a substituted heterocyclic radical, which may contain in addition other heteroatoms such as N, O or S, and in which otherwise the moieties have the meaning indicated in claim 3.
6. 6. Endoparasiticidal agents characterized in that they have a content of at least one sulphonylated, sulfonylated cyclic depsipeptide. , thiocyanated and / or aromatically phosphorylated with 6 to 24 ring atoms, which consists of α-hydroxycarboxylic acids and α-amino acids and which contains at least one phenyl residue, which is sulfonylated, sulfenylated, thiocyanated and phosphorylated according to claim 2.
7. 7.- Use of cyclic sulfonyl, sulfenylated, thiocyanated and / or aromatically phosphorylated depsipeptides with 6 to 24 ring atoms, which are constituted by α-hydroxycarboxylic acids and α-amino acids and which contain at least one phenyl residue, which is sulfonylated, sulfenylated, thiocyanated and / or phosphorylated according to claim 2 for the control against endoparasites.
8. 8. Use of cyclic sulfonyl, sulfenylated, thiocyanated and / or aromatically phosphorylated depsipeptides having 6 to 24 ring atoms, which are constituted by α-hydroxycarboxylic acids and α-amino acids and which contain at least one phenyl residue, which is sulfonylated, sulfenylated, thiocyanated and / or phosphorylated according to claim 2, for the preparation of endoparasitic agents.