WO2004019956A1 - Organophosphorous compounds for the treatment of helminthic infections - Google Patents

Abstract

The invention relates to a medicament comprising an active ingredient of an hydroxyaminoalkylphosphonic acid derivative of formula (I) for the therapeutic and prophylactic treatment of infections in animals and humans caused by parasitic helminthes, in particular filaria.

Description

Title: Use of organophosphorus compounds for the therapeutic and prophylactic treatment of infections caused by helminths

The invention relates to the use of organophosphorus compounds and their salts, esters and amides for the therapeutic and prophylactic treatment of infections in humans and animals which are caused by multicellular parasites (helminths). According to the invention, the organophosphorus compounds include phosphonic acid derivatives, phosphinoyl derivatives and phosphinic acid derivatives.

Helminths, especially filariae, cause a variety of serious diseases in humans and animals like that

"River blindness" and "elephantiasis", or "heartworm disease" in dogs and cats.

There are currently three groups of drugs against Filarial infections. On the one hand, these are active ingredients that kill "macrofilaria". These include, for example:

Surmarine (Antrypol):

This active ingredient has been known since 1920. It is very toxic and has a number of serious side effects such as nausea, anaphylactic shock, photophobia, nerve end neuritis, agranulocytosis and abscess formation. Use has declined dramatically in recent years.

A second group kills both macrofilaria and microfilariae. This includes:

Diethylcarbamazine (Heterazan, Banocide, Notezine): These active ingredients are mainly used against microfilariae, although they also have weak macrofilaria activity. Fever, nausea and headache are known as side effects.

The third group is used to combat microfilariae. The following are used:

Ivermectin (Mectizan [22, 23-dihydroavermectin Bl]) This active ingredient has few side effects. However, it has no effect against macrofilaria. Therefore, an infection can only be contained, but not cured.

Mebendazole (5-benzoyl-1H-benzimidazol-2-yl) -carbamic acid methyl ester) ./ Levamisole ((S) -2, 3, 5, 6-tetrahydro-6-phenyl-imidazo [2 1-6] thiazole ):

A combination of mebandazole / levamisole leads to a reduction in the number of microfilariae. Mebendazole is poorly absorbed by the body and must therefore be administered in high doses. However, this causes severe side effects. Levamisol also has side effects such as nausea, abdominal pain, dizziness, diarrhea and rashes. None of the remedies from the 3rd group is able to kill macrofilaria, therefore a filaria infection can only be contained. This means that the infected organism must be treated continuously over a long period of time.

There is currently no vaccine against filaria infections.

Due to the unsatisfactory effect of the existing drugs for combating parasitic helminths, especially nematodes, and the strong side effects, there is an acute need for new active substances or new areas of indication for known active substances, for the enrichment of the treatment of humans and animals.

It is therefore an object of the present invention to provide agents which have a strong activity against infections caused by parasitic helminths, where they can be used effectively against both microfilariae and macrofilariae and, in contrast to other medicaments, have reduced side effects and thus a lower health risk mean for humans.

Surprisingly, it has now been found that this object is achieved by the use of aminohydrocarbylphosphonic acid derivatives as defined in claim 1. They have an excellent effectiveness against both macrofilaria and microfilariae. It is also known from clinical studies that the compounds according to the invention have very few side effects.

The suitability of amino hydrocarbylphosphonic acid derivatives and some of their esters and salts in medicinal products is already known. However, so far only their antimicrobial activity against bacteria in humans and animals and against fungi in plants has been described (DE 27 33 658 AI, US 4 143 135, US 4 182 758 and US 4 206 156, US 4 994 447, US 4 888 330, US 4 210 635, US 3 955 958, US 4 196 193, US 4 268 503, US 4 330,529, U.S. 5,189,030, U.S. 3,764,677, U.S. 3,764,676). Substances of this group are furthermore as herbicides (US Pat. No. 4,693,742, US Pat. No. 5,002,602, US Pat. No. 4,131,448, US Pat. No. 3,977,860, US Pat. No. 4,062,669), as algaecides (US Pat. No. 3,887,353), as plant growth regulators (US Pat 127 401, US 4 120 688, US 3 961934, US 4 431438, US 3 853 530, US 4 205 977, US 4 025 332, US 3 894 861) and as reagents for dye production (US 4 051 175). DE 27 33 658 AI is the use of

Aminohydrocarbylphosphonic acid derivatives for the treatment of bacterial diseases have been described. In general, although this document speaks of a microbial activity against pathogenic microorganisms, it is clear from the overall context that the term is used synonymously for antibacterial activity.

From WO 99/52515 and WO 02/08235 are also antiparasitic, antiviral and fungicidal activities of

Aminohydrocarbylphosphonic acid derivatives known. An efficacy against single and multicellular parasites is generally reported in these publications. However, examples are only for unicellular parasites, i.e. Protozoa specified. The documents do not indicate any particular suitability for infections caused by helminths.

The organophosphorus compounds used according to the invention correspond to the general formula (I):

where Ri is selected from the group consisting of hydrogen, substituted and unsubstituted acyl,

Xi is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl and substituted and unsubstituted silyl,

A is selected from the group consisting of an alkylene radical, an alkenylene radical and a hydroxyalkylene radical,

R ₂ is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted Cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, and OX, where X ₂ and X _{3 are} independently selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted Cι- ₉ alkoxy-Cι- ₉ alkyl , substituted and unsubstituted Cι-9-acyloxy-Cι-9-alkyl, substituted and unsubstituted aryl, a silyl, a cation of an organic and inorganic base, in particular a metal of the first, second or third main group periodic table, ammonium, substituted ammonium and ammonium Compounds which are derived from ethylenediamine or amino acids, and their pharmaceutically acceptable salts, esters and arides and salts of the esters.

Compounds of the formula (I) are particularly preferred, wherein

Xi is selected from the group consisting of hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted silyl,

R ₂ = hydrogen, methyl, ethyl or OX ₂ and

Ri, X ₂ , X ₃ and A have the same meaning as above.

A is particularly preferably a chain, optionally substituted, of three carbon atoms which connects the nitrogen atom to the phosphorus atom, such as e.g. Propyl or trimethylene, hydroxypropyl.

In particular, compounds of formula (I) are preferred for which

Ri = acyl, especially a formyl or acetyl,

Xi = hydrogen, R ₂ = OX ₂ with X ₂ = hydrogen, sodium, potassium, substituted and unsubstituted Ci-g-alkoxy-Ci-g-alkyl, substituted and unsubstituted Cι-9-acyloxy-Cι-g-alkyl, in para position substituted phenyl,

X ₃ - H, sodium, potassium, substituted and unsubstituted Ci-g-alkoxy-Ci-g-alkyl, substituted and unsubstituted C ₁ -9-

Acyloxy-Cι-9-alkyl, phenyl substituted in para position and

A = alkylene, alkenylene or hydroxyalkylene.

Particularly good results were achieved with the following compounds:

Compounds 3-12 are so-called "prodrugs". These are converted into compounds 1 and 2 by metabolic processes. However, due to their higher lipophilicity, they are better absorbed by the body, which means that higher plasma levels can be achieved. Special features of the above definitions and suitable examples are given below:

"Acyl" is a substituent derived from an acid, such as an organic carboxylic acid, carbonic acid, or the thio acid corresponding to the individual acids above, these acids each comprising aliphatic, aromatic and / or heterocyclic groups in the molecule.

Suitable examples of these acyl groups are given below.

As aliphatic acyl groups are from an aliphatic

Acyl-derived acyl residues, which include the following:

Alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl,

Valeryl, isovaleryl, pivaloyl etc.);

Alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl etc.);

Alkylthioalkanoyl (e.g. methylthioacetyl, ethylthioacetyl etc.), alkanesulfonyl (e.g. mesyl, ethanesulfonyl,

Propanesulfonyl etc.);

Alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,

Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,

Isobutoxycarbonyl etc.); Alkyl carbamoyl (e.g. methyl carbamoyl etc.);

(N-alkyl) thiocarbamoyl (e.g. (N-methyl) thiocarbamoyl etc.);

Alkyl carbamimidoyl (e.g. methyl carbamimidoyl etc.);

oxalo;

Alkoxalyl (e.g. methoxalyl, ethoxalyl, propoxalyl etc.).

In the above examples of aliphatic acyl groups, the aliphatic hydrocarbon part, especially the

Alkyl group or the alkane radical, optionally have one or more suitable substituents, such as amino, halogen (e.g. fluorine, chlorine, bromine etc.), hydroxy, hydroxyimino, carboxy,

Alkoxy (e.g. methoxy, ethoxy, propoxy etc.), alkoxycarbonyl,

Acylamino (e.g. benzyloxycarbonylamino etc.), acyloxy (e.g. Acetoxy, benzoyloxy etc.) and the like; Examples of preferred aliphatic acyl radicals with such substituents are alkanyls substituted with amino, carboxy, amino and carboxy, halogen, acylamino or the like.

Aromatic acyl radicals are those acyl radicals which originate from an acid with a substituted or unsubstituted aryl group, where the aryl group can include phenyl, toluyl, xylyl, naphthyl and the like, suitable examples are given below:

Aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl etc.);

Aralkanoyl (e.g. phenylacetyl etc.); Aralkenoyl (e.g. cinnamoyl etc.);

Aryloxyalkanoyl (e.g. phenoxyacetyl etc.); Arylthioalkanoyl

(e.g. phenylthioacetyl etc.);

Arylaminoalkanoyl (e.g. N-phenylglycyl, etc.);

Arenesulfonyl (e.g. benzenesulfonyl, tosyl or toluenesulfonyl, naphthalenesulfonyl etc.);

Aryloxycarbonyl (e.g. phenoxycarbonyl, naphthyloxycarbonyl etc.);

Aralkoxycarbonyl (e.g. benzyloxycarbonyl etc.);

Arylcarbamoyl (e.g. phenylcarbamoyl, naphthylcarbamoyl etc.); Arylglyoxyloyl (e.g. phenylglyoxyloyl etc.).

In the above examples of aromatic acyl radicals, the aromatic hydrocarbon part (in particular the aryl radical) and / or the aliphatic hydrocarbon part (in particular the alkane radical) may optionally have one or more suitable substituents, such as those which are suitable substituents for the alkyl group or the alkane radical have already been specified.

In particular and as an example of preferred aromatic

Acyl radicals with special substituents are substituted with halogen and hydroxy or with halogen and acyloxy and aroyl aralkanoyl indicated with hydroxy, hydroxyimino, dihalogenalkanoyloxyimino and arylthiocarbamoyl (eg phenylthiocarbamoyl etc.); Arylcarbamidoyl (e.g. phenylcarbamidoyl etc.).

A heterocyclic acyl radical is understood to mean an acyl radical which comes from an acid with a heterocyclic group; this includes:

Heterocyclic carbonyl, in which the heterocyclic radical is an aromatic or aliphatic 5 to 6-membered heterocycle with at least one heteroatom from the group consisting of nitrogen, oxygen and sulfur (e.g. thiophenyl, furoyl, pyrrolocarbonyl, nicotinoyl etc.); Heterocycle alkanoyl in which the heterocyclic radical is 5- to 6-membered and has at least one heteroatom from the group consisting of nitrogen, oxygen and sulfur (for example thiophenyl acetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino-4- thiazolyl) -2-methoxyiminoacetyl etc.) and the like.

In the above examples of heterocyclic acyl groups, the heterocycle and / or the aliphatic hydrocarbon portion may optionally have one or more suitable substituents, such as the same ones that have been indicated as being suitable for alkyl and alkane groups.

"Alkyl" is a straight or branched chain alkyl radical with up to 9 carbon atoms, unless otherwise defined, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.

"Hydroxyalkyl" is a straight or branched chain alkyl radical with up to 9 carbons, unless otherwise defined, which has at least one hydroxyl group, preferably one or two hydroxyl groups. "Alkenyl" includes straight or branched chain, alkenyl groups with up to 9 carbon atoms, unless otherwise defined, such as vinyl, propenyl (e.g. 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2- Ethyl propenyl, pentenyl, hexenyl.

"Alkynyl" includes straight or branched chain alkynyl groups with up to 9 carbon atoms, unless otherwise defined.

Any alkyl, hydroxyalkyl, alkenyl and alkynyl group can be substituted with oxo, hydroxy and aryl groups.

Cycloalkyl preferably represents an optionally substituted C ₃ -C cycloalkyl; possible substituents include alkyl,

Alkenyl, alkynyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc.), nitro and the like are suitable.

Aryl is an aromatic hydrocarbon radical, such as phenyl, naphthyl, etc., which may optionally have one or more suitable substituents, such as alkyl, alkenyl, alkynyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc .), Nitro and the like.

"Aralkyl" includes mono-, di-, triphenylalkyls such as benzyl, phenethyl, benzhydryl, trityl and the like, where the aromatic part may have one or more suitable substituents such as alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. Fluorine, chlorine, bromine, etc.), nitro and the like.

"Alkylene" includes straight or branched chain alkylene groups which have up to 9 carbon atoms and can be represented by the formula: (C _n H _2n ), in which n is an integer from 1 to 9, such as methylene, ethylene, trimethylene Methylethylene Tetramethylene, 1-methyltrimethylene, 2-ethylethylene, pentamethylene, 2-methyltetramethylene, isopropylethylene, hexamethylene, and the like; preferred alkylene radicals have up to 4 carbon atoms and radicals with 3 carbon atoms such as trimethylene are particularly preferred. The

Hydrogen atoms can be replaced by other substituents, such as halogen radicals.

"Alkenylene" includes straight or branched chain alkenylene groups with up to 9 carbon atoms, which are characterized by the

Formula: (C _n H _2n - ₂ ) can be reproduced (in which n is an integer from 2 to 9, such as vinylene, propenylene (e.g. 1-propenylene, 2-propenylene), 1-methylpropenylene, 2-methylpropenylene, Butenylene, 2-ethylpropenylene, pentenylene, hexenylene and the like, with particular preference the alkenylene radical can have up to 5 carbon atoms and in particular 3 carbon atoms such as 1-propenylene The hydrogen atoms can be replaced by other substituents such as halogen radicals.

"Hydroxyalkylene" may include straight or branched chain alkylene radicals that have up to 9 carbon atoms where at least one selected carbon atom is substituted with a hydroxy group; these residues can be removed by the

Formula: (C _n H _2n _ _z ) (0H) _{Z are} reproduced in which n is an integer from 1 to 9 and z is an integer for which 1 ≤ z ≤ n. Suitable examples of such hydroxyalkylene groups include hydroxymethylene, hydroxyethylene (e.g. 1-hydroxyethylene and 2-hydroxyethylene), hydroxytrimethylene (e.g. 1-hydroxytrimethylene 2-hydroxytrimethylene and 3-hydroxytrimethylene), hydroxytetramethylene ethylene (e.g. 2-hydroxyhexamethylene), 2-hydroxy- 2- methyltrimethylene), hydroxypentamylene (eg 2-hydroxyhexamethylene), hydroxyhexamethylene (eg 2-hydroxyhexamethylene) and the like. A lower hydroxyalkylene with up to 4 carbon atoms and is particularly preferred especially with 3 carbon atoms such as hydroxytrimethylene. The hydrogen atoms can be replaced by other substituents such as halogen radicals.

The radicals X ₂ and X ₃ can preferably be chosen such that esters are formed on the phosphino group or phosphono group. Suitable examples of such esters according to formulas (I) include:

Alkyl esters (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, hexyl ester,

Hexadecanyl ester, octadecanyl ester, etc.);

Aralkyl esters (benzyl esters, phenethyl esters, benzhydryl esters

Tritylester etc.);

Aryl esters (e.g. phenyl esters, tolyl esters, naphthyl esters, etc.); Aroyl alkyl esters (e.g. phenacyl esters etc.); and

Silyl esters (e.g. from trialkylhalosilyl,

Dialkyldihalosilyl, alkyltrihalosilyl,

Dialkylarylhalosilyl, trialkoxyhalosilyl,

Dialkylaralkyl alogensilyl, dialkoxydihalosilyl, trialkoxyhalosilyl etc.) and the like;

-C-g-alkoxy--C-g-alkyl ester (e.g. ethoxyethyl ester);

Cι- ₉ -acyloxy-Cι-9-alkyl esters (eg acetoxyethyl ester).

In the above ester, the alkyl, alkoxy, acyloxy and / or arene portion can optionally have at least one suitable substituent such as oxo, alkyl, halogen, alkoxy, hydroxy, nitro or the like.

X ₂ and X ₃ are preferably a metal from the first, second or third main group of the periodic table, ammonium, substituted ammonium, or ammonium compounds which are derived from ethylenediamine or amino acids. Ie there are the salt compounds of organophosphorus compounds with organic or inorganic bases (e.g. sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylamine salt, ethanolamine salt, dicyclohexylamine salt, ethylenediamine salt, N, N-dibenzylethylenediamine salt etc.) and salts with amino acids (e.g. arginine salt, aspartic acid salt, glutamic acid salt etc.) and the like.

The compounds of the formula (I) used according to the invention can, in their protonated form, as the ammonium salt of organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc. are available.

The compounds of the formulas (I) used according to the invention permit, for example, the occurrence of spatial isomers for double or chiral groups R 1, R ₂ , Xi, X ₂ , X ₃ or A. The use of the compounds according to the invention includes all spatial isomers both as pure substances and in the form of their mixtures.

In the context of this invention, helminths are understood to mean multicellular, endoparasitic organisms (worms) which belong to two different animal strains: 1. Plathelminthes (flatworms) with the classes trematodes (suction worms) and cestodes (tapeworms); 2. Nemathelminthes (nematodes) with the classes Nematodes and Acanthocephala (scratches). According to the invention, the pentastomidae (tongue worms) belonging to the arthropods are also subsumed as helminths as endoparasites.

The active substances mentioned with the organophosphorus formula. (I) are suitable for the prophylaxis and treatment of diseases (infections) caused by helminths.

The invention therefore relates to a medicament comprising at least one organophosphorus compound of the formula (I) for the prophylaxis and treatment of diseases (infections) which are caused by helminths. Particularly preferred is the treatment of diseases caused by nematodes, in particular of the filaria genus, as thread-like, highly specialized representatives of the nematodes from the Filariidae and Onchocercidae families; with the most famous genera: Wuchereria, Brugia, Loa, Mansonella, ^• Onchocerca, Dirofilaria. A distinction is made between adult worms (macrofilariae) in the lymphatic system or in the subcutaneous or peritoneal connective tissue; 2. female-female live-bearing; Larvae (microfilariae, divorced or non-divorced) enter the blood or migrate to the dermis; 3. Further development in blood-sucking insects (Diptera), which serve as intermediate hosts and transmitters; 4. Infectable larvae (3rd stage) actively penetrate the end host through the sting channel created by the insect; 5. Development to adult filaria in the specific organ systems within months or years.

The prophylaxis or treatment according to the invention with a medicament containing at least one organophosphorus compound of the formula (I) of the diseases (filariasis) caused by filaria can be carried out at any time during the infectious stages of the above life cycle.

The organophosphorus compounds according to formula (I) and their esters and amides on the phosphino group or phosphono group and salts thereof show a strong cytotoxic activity against helminths, i.e. the multicellular, endoparasitic organisms (worms), preferably against filariae.

Use against human and animal pathogenic filariae of the species is also preferred:

Acanthocheilonema spp., Especially the species: A. dracunculoides, A. vitae (Dipetalonema vitae)

Brugia spp. , especially the types:

B. malayi, B. timori, B. pahangi, B. malati, B. baveri, B. guyanesis

Cardiofilaria spp., Cercopithifilaria spp., Chandlerella spp.,

Dipetalonema spp., Especially the species:

D. reconditum, D. grassi, D. dracunculoides, D. setariosum, D. arbuta, D. sprenti

Dirofilaria spp., Especially the species:

D. immitis, D. repens, D. spectans, D. striata, D. tenuis, D. ursi

Dracunculus spp., Especially the species:

D. medinensis, D. insignis

Elaeophora spp., Especially the species:

E. schneideri, E. poeli

Litosomoides spp., Especially the species: L. sig odontis

Loa spp., Especially the species: L. loa

Mansonella spp., Especially the species:

M. ozzardi, M. perstans (Dipetalonema perstans), M. leopoldi,

M. lopeensis, M. streptocera, M. semiclarum

Meningonema spp., Especially the species: Meningonema peruzzi

Microfilaria spp., Especially the species: Microfilaria rodhaini

Monanema spp., Especially the species: Monanema martini Onchocerca spp., Especially the species: 0. volvulus, O. lienalis, 0. gutturosa, O. gibboni, 0. jakutensis, 0. stilesi, 0. ochengi, 0. garmsi, 0. dewittei japonica, 0. fasciata, 0 .cervicalis, 0. armillata, 0. lupi, 0. tarsicola, 0. skrjabini

Parafilaria spp., Especially the species: P. bassoni, P. bovicola

Pelecitus spp.

Setaria spp., Especially the species: S. digitata, S. equina, S. cervi

Stephanofilaria spp., Especially the species: Stephanofilaria zaheeri

Wuchereria spp., Especially the species: W. bancrofti, W. kalimantani

The substances according to the invention are outstandingly suitable for the treatment of filiarioses, in particular lymphatic filariasis (lymphatic filariasis), subcutaneous filariasis (subcutaneous filariasis) and serum cavity filariasis (serous cavity filariasis).

They are particularly suitable for the treatment of elephantiasis, onchocerciasis (onchocerciasis, river blindness), loiasis (African eye worm disease, Kalabar swelling), dracunculiasis (dracunculose, medina worm infection), mansonelliasis, canine and feline dirofilarioses (heartworm disease).

In the context of the invention, filiarosis is understood to mean infections with filaria, which affect the lymphatic system and the superficial or deep connective tissue of humans or animals colonize and their infectious larvae are transmitted by an intermediate host (mostly insects); in particular the microfilariae of the above filaria species produced by the sexually mature females. They cause a similar clinic after mostly early childhood infection; poss.

Course forms: 1. Inapparent infection with microfilariaemia which may persist for years; 2. Symptomatic acute infection usually early stages of infection with eosinophilia, fever, intermittent lymphangitis, increasing microfilariaemia with circadian periodicity, later funiculitis, orchitis, epididymitis, hydrocele, so-called lymphatic scrotum (lymphedema of the scrotum); 3. Symptomatic chronic infection after several years of continuous exposure can lead to obstruction u. Sclerotherapy of the lymphatic vessels by dying filaria

Lymphatic varicose veins, elephantiasis, chyluria, chylothorax come. 4. Tropical eosinophilia as an allergic reaction to filaria antigens.

The medicament according to the invention is preferably administered for the prophylaxis and treatment of filariasis in the case of an inapparent infection or symptomatic acute infection or symptomatic chronic infection.

Areas of application of the substances according to the invention include the prophylaxis and therapy of animals, such as pets / hobby animals, such as dogs, cats, etc., and of farm animals, such as ruminants (e.g. cattle), pigs, camels, sheep, goats, racing pigeons, chickens, geese , Ducks etc.

The activity of the substances is determined in a test system. This system is based on measuring the filaria kill in vivo. For this purpose, test methods are used which are known to the person skilled in the art. The corresponding animal models were applied.

The organophosphorus used according to the invention Compounds, which generally include pharmaceutically acceptable salts, amides, esters, a salt of such an ester, or compounds which, when applied, provide the compounds used according to the invention as metabolites or degradation products, also called "prodrugs", can be administered in any suitable manner Be prepared analogously to known anti-infectious agents (mixed with a non-toxic pharmaceutically acceptable carrier).

Pharmaceutically acceptable salts of the compounds include salts which form the compounds of the formulas (I) used according to the invention in their protonated form as the ammonium salt of inorganic or organic acids, such as hydrochloric acid, sulfuric acid, citric acid, maleic acid, fumaric acid, tartaric acid, p-toluenesulfonic acid. Also particularly pharmaceutically suitable are the salts which are formed by suitable selection of X ₂ and X ₃ , such as sodium salt, potassium salt, calcium salt, ammonium salt, ethanalamine salt, triethylamine salt, dicyclohexylamine salt and salts of an amino acid such as arginine salt, aspartic acid salt, glutamic acid salt.

The pharmaceutically active agents can be prepared in the form of pharmaceutical preparations in dosage units. This means that the preparation in the form of individual parts, e.g. Tablets, coated tablets, capsules, pills, suppositories and ampoules are available, the active ingredient content of which corresponds to a fraction or a multiple of a single dose. The dosage units can e.g. 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.

Among non-toxic, inert pharmaceutically suitable Carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.

Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations. Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. Starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. Carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, (c) humectants, e.g. Glycerin, (d) disintegrant, e.g. Agar-agar, calcium carbonate and

Sodium carbonate, (e) solution retarder e.g. Paraffin and (f) absorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents, e.g. Cetyl alcohol, glycerol monostearate, (h) adsorbent e.g. Kaolin and bentonite and (i) lubricants, e.g. Talc, calcium and

Magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

The tablets, dragees, capsules, pills and granules can be provided with the customary coatings and casings, optionally containing opacifying agents, gastric acid-resistant coatings, and can also be composed in such a way that they only or preferably delay the active ingredient (s) in a certain part of the intestinal tract deliver, where as embedding compounds, for example Polymer substances and waxes can be used.

The active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned excipients. In addition to the active ingredient or ingredients, suppositories can contain the usual water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cocoa fat and higher esters (e.g. C14 alcohol with Cl6 fatty acid) or mixtures of these substances.

In addition to the active ingredient (s), ointments, pastes, creams and gels can contain the usual carriers, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances. Powders and sprays can contain the usual excipients in addition to the active ingredient (s), e.g. Milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also contain the usual propellants, e.g. Chlorofluorocarbons. In addition to the active ingredient (s), solutions and emulsions can contain the usual carriers such as solvents, solubilizers and emulsifiers, e.g. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glycerol alcohol and fatty acid, fatty acid, fatty acid, tetrahydrofuran of sorbitan or mixtures of these substances. For parenteral administration, the solutions and emulsions can also be in sterile and blood isotonic form.

In addition to the active ingredient (s), suspensions can contain the usual carriers such as liquid diluents, e.g.

Water, ethyl alcohol, propylene glycol, suspending agents e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and

Sorbitan esters, microcrystalline cellulose,

Aluminum metahydroxide, bentonite, agar and tragacanth or

Mixtures of these substances contain.

The formulation forms mentioned can also contain colorants, preservatives and odor and taste-improving agents

Additives, such as peppermint oil and eucalyptus oil and sweeteners, such as saccharin. In addition to the compounds of the formula (I), the pharmaceutical preparations can also contain further active pharmaceutical ingredients.

The compounds can be used in combination with previously described substances with antibacterial, antiviral, antifungal and antiparasitic properties and with medicaments for the treatment of worm diseases. This includes, in particular, compounds that have already been used in therapy or are still being used. Substances that are listed in the Rote Liste or in Simon / Stille, Antibiotic Therapy in Clinic and Practice, 9th edition 1998 Schattauer Verlag, are particularly suitable for this purpose.

Particularly preferred are combinations with antibacterial agents selected from the group consisting of β-lactam antibiotics, combinations of β-lactam antibiotics and β-lactamase inhibitors e.g. Clavulanic acid / amoxicillin,

Cephalosporins, tetracyclines e.g. Doxycycline, aminoglycosides e.g. Gentamycin, streptomycin, macrolides e.g. Clarithromycin, azithromycin, lincosamides e.g. Clindamycin, gyrase inhibitors e.g. Ciprofloxacin, antimicrobial folic acid antagonists (especially sulfonamides, co-trimoxazole, 15 trimethoprim, pyrimethamine, dapsone), glycopeptide antibiotics e.g. Vancomycin, nitrofurans, nitroimidazoles, rifampicin, pyrazinamide, ethambutol, pyrazinamide, and agents for the treatment of worm diseases in humans and animals (anthelmintics), which are selected from the group consisting of:

Agents against cestodes (tapeworms) such as arecoline, aspidine, aspidinol, dichlorophen (s), embelin, cosine, naphthalenes, niclosamides, pelletierins, quinacrine, agents against roundworms (nematodes), for example alantolactones, amorcarzins, amoscanates, ascaridols, bephenium, bitoscanates Carbon, tetrachloride, carvacrol, cyclobendazole, diethylcarbamazine, Diphenane, dithiazanine, iodide, doramectin, dymanthine, gentian violet, 4-hexylresorcinol, iver ectin, kainic acid, levamisole, mebendazole, moxidectin, 2-naphthol, oxantel, papain, piperazine, pyrantel, pyrvinium pamoate, stilbazineodinide, alpha- santinodin , Suramin Sodium,

Tetrachloroethylene, thiabendazole, thymol, thymyl N-isoamylcarbamate, triclofenol, piperazines, urea stibamine, anti-platinum minerals (flatworms) e.g. Amoscanate, Amphotalide, Antimony Potassium Tartrate, Antimony Sodium Tartrate, Antimony Sodium Thioglycollate, Antimony

Thioglycollamide, Anthiolimine, Becanthone, Hycanthone, Lucanthone Hydrochloride, Niridazole, Oxamniquine, Praziquantel, Stibocaptate, Stibophen, Sodium Antimonylgluconate, Tetrachloroethylene, Urea Stibamine.

Combinations of several of the active ingredients mentioned are also part of the present application. The pharmaceutical preparations listed above are prepared in a conventional manner according to known methods

Methods, e.g. by mixing the active substance or substances with the carrier substance or substances.

The preparations mentioned can be used in humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally, locally (powder, ointment drops) and for the treatment of infections in cavities, body cavities. Injection solutions, solutions and suspensions for oral therapy, gels,

Infusion formulations, emulsions, ointments or drops in question. For local therapy, ophthalmic and dermatological formulations, silver and other salts, ear drops, eye ointments, powder or solutions can be used. In animals, suitable formulations can also be ingested through feed or drinking water. Gels, powders, powders, tablets, prolonged-release tablets, Premixes, concentrates, granules, pellets, tablets, boluses, capsules, aerosols, sprays, inhalants, can be used in humans and animals. Furthermore, the compounds used according to the invention can be incorporated into other carrier materials such as, for example, plastics (plastic chains for local therapy), collagen or bone cement.

The active compounds of the formula (I) should be present in the pharmaceutical preparations listed above, preferably in a concentration of about 0.1 to 99.5% by weight, preferably of about 0.5 to 95% by weight, of the total mixture.

In general, it has proven advantageous in both human and veterinary medicine to use the active compound (s) of the formula (I) in total amounts of from about 0.05 to about 600 mg / kg, preferably from 0.15 to 200 mg / kg Body weight per 24 hours, if necessary in the form of several individual doses, to achieve the desired results. A single dose contains the active ingredient (s) preferably in amounts of about 1 to about 200, in particular 1 to 60 mg / kg body weight. However, it may be necessary to deviate from the doses mentioned, depending on the type and body weight of the patient to be treated, the type and severity of the disease, the type of preparation and administration of the drug, and the period or interval within which the administration takes place.

In some cases, it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient must be exceeded. The person skilled in the art can determine the optimum dosage and type of application of the active ingredients required on the basis of his specialist knowledge. The compounds according to the invention can be used in the usual concentrations and preparations in animals together with the feed or with feed preparations or with the Be given drinking water.

The preparation of the substances according to the invention was described in DE 27 33 658 AI and WO 02/08235. The person skilled in the art is able to produce the substances according to the regulations contained therein.

Example: Efficiency of fosmidomycin against filaria in the mouse model.

The efficiency of fosmidomycin against filaria was tested using the rodent ilarie Litomosoides sigmodontis in the mouse model. First, mites of the species Ornithonyssus bacoti were set up for a blood meal on South American cotton rats (Sigmodon hispidus) infected with Litomosoides sigmodontis. The mites were then used to infect BALB / c mice. The infected mice were treated with 100 mg / kg fosmidomycin daily by i.p. injection for 4 weeks. Half of the animals were killed 42 and 63 days after the infection.

To check the effectiveness, the number and length of the worms were determined in comparison to an untreated control group. The worms were also examined histologically. The microfilaraemia was determined in EDTA-treated peripheral blood after staining with Hinkelmann's solution. Adult worms were obtained by perfusing the pleural and peritoneal cavities with PBS-1% FCS. After the length was determined, the worms were examined under the stereomicroscope. The number of adult worms was reduced to 62% on day 42 and 58% on day 63. In addition, no microfilariae were detectable in the blood of the treated animals on day 63. The length of the worms was reduced to 16% on day 42 and to 21% on day 63. The histological analysis on day 63 showed that embryonic development into microfilariae was disturbed in the uteri of the female worms. A similar result was obtained when the infected mice were treated with a combination of 100 mg / kg fosmidomycin and 30 mg / kg doxycycline for two weeks. The number of adult worms was reduced to 66% on day 42 and to 62% on day 63. On day 63, no microfilariae were also detectable in the blood of the treated animals. The length of the worms was reduced to 14% on day 42 and 17% on day 63. The histological analysis on day 63 also revealed a fertility disorder.

Claims

claims 1. Use of at least one organophosphorus compound according to the general formula (I): * ι ° x ff ^ NAPR ₂ ^R <0X where Ri is selected from the group consisting of hydrogen, substituted and unsubstituted acyl, Xi is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl and substituted and unsubstituted silyl, A is selected from the group consisting of an alkylene radical, an alkenylene radical and a hydroxyalkylene radical, R is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkyl , substituted and unsubstituted heterocyclic radical, halogen, and 0X ₂ , where X ₂ and X _{3 are} independently selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted Ci-g-alkoxy-Ci-g- alkyl, substituted and unsubstituted Cι-acyloxy-Cι-g-alkyl, substituted and unsubstituted aryl, a silyl, a cation of an organic and inorganic base, in particular a metal of the first, second or third main group periodic table, ammonium, substituted ammonium and There are ammonium compounds derived from ethylenediamine or amino acids and their pharmaceutically acceptable salts, esters and arides and salts of the esters, for the manufacture of a medicament for the therapeutic and prophylactic treatment of infections in humans and animals caused by parasitic helminths. 2. Use according to claim 1, characterized in that Xi is selected from the group consisting of hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted silyl, R ₂ = hydrogen, methyl, ethyl or OX ₂ and Ri, X ₂ , X ₃ and A have the same meaning as in claim 1. 3. Use according to claim 1 or 2, characterized in that A is a chain of three carbon atoms that connects the nitrogen atom with the phosphorus atom. 4. Use according to one of claims 1 to 3, characterized in that Rι = acyl, especially formyl or acetyl, Xι = hydrogen, R ₂ = OX ₂ with X ₂ = hydrogen, sodium, potassium substituted and unsubstituted Ci-g-alkoxy -Ci-g-alkyl, substituted 10 and unsubstituted Ci-g-acyloxy-Ci-g-alkyl, phenyl substituted in the para position, X ₃ = H, sodium, potassium, substituted and unsubstituted Ci-g-alkoxy-Ci-g -alkyl, substituted and unsubstituted Cι-acyloxy-Cι-9-alkyl, phenyl substituted in the para position and A = alkylene, alkenylene or hydroxyalkylene. 5. Use according to claim 4, characterized in that the active ingredient is selected from the following group:

6. Use according to one of claims 1 to 5 for the treatment and prophylaxis of infections in humans and animals, caused by filaria. 7. Use according to claim 6, characterized in that the infection is triggered by one or more organisms selected from the group consisting of Acanthocheilonema spp., Especially the species: A. dracunculoides, A. vitae (Dipetalonema vitae); Brugia spp., Especially the species: B. malayi, B. timori, B. pahangi, B. malati, B. baveri, B. guyanesis; Cardiofilaria spp .; Cercopithifilaria spp .; Chandlerella spp .; Dipetalonema spp., Especially the species: D. reconditum, D. grassi, D. dracunculoides, D. setariosum, D. arbuta, D. sprenti; Dirofilaria spp., In particular the species: D. immitis, D. repens, D. spectans, D. striata, D. tenuis, D. ursi; Dracunculus spp., Especially the species: D. medinensis, D. insignis; Elaeophora spp., Especially the species: E. schneideri, E. poeli; Litosomoides spp., Especially the species: L. sigmodontis; Loa spp., Especially the species: L.loa; Mansonella spp., In particular the species: M. ozzardi, M. perstans (Dipetalonema perstans), M. leopoldi, M. lopeensis, M. streptocera, M. semiclarum; Meningonema spp., Especially the species: Meningonema peruzzi; Microfilaria spp., In particular the species: Microfilaria rodhaini; Monanema spp., Especially the species: Monanema martini; Onchocerca spp., Especially the species: 0. volvulus, 0. lienalis, 0. gutturosa, 0. gibboni, 0. jakutensis, 0. stilesi, 0. ochengi, 0. 15garmsi, 0. dewittei japonica, 0. fasciata, 0 . cervicalis, 0. armillata, 0. lupi, 0. tarsicola, 0. skrjabini; Parafilaria spp., Especially the species: P. bassoni, P. bovicola Pelecitus spp. ; Setaria spp., Especially the species: S. digitata, S. equina, S. cervi; Stephanofilaria spp., Especially the species: Stephanofilaria zaheeri; Wuchereria spp., In particular the species: W. bancrofti, W. kalimantani; consists . 8. Use according to claim 6 for the treatment of filariasis, in particular lymphatic filariasis (lymphatic filariasis), subcutaneous filariasis (subcutaneous filariasis) and serum cavity filariasis (serous cavity filariasis). 9. Use according to claim 8 for the treatment of elephantiasis, onchocerciasis (onchocerciasis, river blindness), loiasis (African eye worm disease, Kalabar swelling), dracunculose (medina worm infection), mansonelliasis, canine and feline dirofilarioses (heartworm disease). 10. Use according to claim 9, characterized in that the active ingredient in combination with a further active ingredient selected from the group consisting of antibacterial agents, agents against cestodes (tapeworms), agents against roundworms (nematodes) and agents against platinum mints (flatworms), is used. 11. Pharmaceutical preparation containing an active ingredient according to any one of claims 1-10.