DE19831637A1 - Identifying antiparasitic agents used to treat or prevent parasitic infections, especially malaria, sleeping sickness and leishmaniosis - Google Patents

Abstract

Identification of agents (A) suitable for treatment of infections caused by mono- or poly-cellular parasites comprises (i) treating a test compound with a protein (I) that is involved in the 1-deoxy-D-xylulose-5-phosphate (dDXP) metabolic pathway (or its derivatives with equivalent activity) and (ii) selecting compounds that inhibit (I) or its derivatives. Independent claims are also included for the following: (a) proteins (II) encoded by approximately 3.8 kb (1b) or 3.7 kb (2b) sequences or by sequences that hybridize to (1b) or (2b), or their fragments that encode the mature protein; (b) proteins (III) encoded by approximately 1.5 kb (1a) or 1.5 kb (2a) sequences or by sequences that hybridize to (1a) or (2a) or their fragments that encode the mature protein; (c) (II), (III) and other proteins (IV) involved in the dDXP metabolic pathway isolated from parasite culture media or lysate by chromatography and electrophoresis; (d) (1a), (1b), (2a) and (2b) and sequences that hybridize with them or that would do so but for the degeneracy of the genetic code; (e) recombinant expression vector containing DNA (V) that encodes (II)-(IV) and expresses them in a transformed microorganism or eukaryotic cell, animal or plant; (f) host cells transformed with (V) and able to express (II)-(IV); (g) antibodies (Ab) raised against (II)-(IV); and (h) (A), or herbicides, identified using (I).

Description

The invention relates to the use of organophosphorus Compounds and their salts and esters for therapeutic and prophylactic treatment of infections caused by Pa rasiten be caused. According to the invention include organophosphorus compounds phosphinoyl derivatives, Phos phinic acid derivatives and phosphonic acid derivatives.

The suitability of some of these organophosphorus compounds as well as some of their esters and salts in medicinal products already known. This is the antimicrobial for fosfonochlorin Efficacy against bacteria and an effect for Foscarnet compared to viruses. Furthermore, the property of fosamine ammonium and N, N-dimethyl- (hydroxy-2-oxo-2- methoxy-ethyl) phosphonamide has been reported as a herbicide.

Surprisingly, this group of substances shows an antiparasitic we against single and multicellular parasites, especially against unicellular parasites (protozoa), especially against pathogens malaria and sleeping sickness as well as Chagas Disease, toxoplasmosis, amoebic dysentery, leishmanio sen, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcocystosis, acanthamoebosis, the Naeglerose, Coccidiosis, Giardiosis and Lambliosis.

The compounds are for therapeutic and prophylactic  suitable treatment of infections in humans and animals, which are caused by parasites. The connections are especially as malaria prophylaxis and as prophylaxis of the Sleeping sickness as well as Chagas disease, toxoplasmosis, the amoebic dysentery, the leishmaniasis, the trichomoniasis, the Pneumocystosis, balantidiosis, cryptosporidiosis, Sarcocystosis, Acanthoma, Naeglerosis, Coccidio se, Giardiosis and Lambliosis.

Furthermore, all of the compounds described here are also available as Her can be used bicide.

The invention relates to the use of these compounds as Agents against infections by parasites and compounds, which are used to prepare anti-parasitic substances. The pharmaceutical compositions according to the invention can or several active substances from the group of organophosphorus Compounds, the phosphinoyl derivatives, phosphonic acid derivatives and phosphinic acid derivatives and their esters and salts sen, included. These generally include pharmaceuticals compatible salts, amides, esters, a salt of such Esters, or compounds that invent the inventions compounds to be used according to the invention as metabolic pro Provide products or degradation products, including "prodrugs" called.

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

R ₁ is selected from the group consisting of H, a substituted and unsubstituted acyl, a substituted and unsubstituted alkyl, a substituted and unsubstituted hydroxyalkyl, a substituted and unsubstituted alkenyl, a substituted and unsubstituted alkynyl, a substituted and unsubstituted aryl , a substituted and unsubstituted cycloalkyl, a substituted and unsubstituted aralkyl, a substituted and unsubstituted heterocyclic radical, halogen and OX ₁ , where X ₁ is selected from the group consisting of hydrogen, a substituted and unsubstituted acyl, a substituted and unsubstituted alkyl, a substituted and unsubstituted hydroxyalkyl, a substituted and unsubstituted alkenyl, a substituted and unsubstituted alkynyl, a substituted and unsubstituted aryl, a substituted and unsubstituted cycloalkyl, a substituted and unsubstituted aralkyl, a silyl, substituted and unsubstituted heterocyclic radical, a cation of an organic and inorganic base, in particular a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium and ammonium compounds,
R ₂ and R ₃ may be the same or different and are selected from the group consisting of hydrogen, a substituted and unsubstituted acyl, a substituted and unsubstituted alkyl, a substituted and unsubstituted hydroxyalkyl, a substituted and unsubstituted alkenyl, a substituted and unsubstituted alkynyl, a substituted and unsubstituted aryl, a substituted and unsubstituted cycloalkyl, a substituted and unsubstituted aralkyl, a substituted and unsubstituted heterocyclic radical, halogen and OX ₂ and OX ₃ , where X ₂ and X _{3 are} selected from the group are made of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted cycloalkyl, a silyl, substituted and unsubstituted heterocyclic radical, a cation of an organic and inorganic base e, in particular a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids, and
A ₁ and A ₂ , one or both of which can be omitted, are the same or different and represent an alkylene radical, an alkenylene radical, an oxo radical, a hydroxyl radical or oxo hydroxyalkylene radical, with A ₂ preferably being eliminated.

The invention also includes pharmaceutically acceptable blen salts, amides, esters and salts of the esters.

The phosphonic acid derivatives of the present invention prove to be particularly suitable. They are represented by the following formula (II)

wherein R ₁ , X ₂ , X ₃ , A ₁ and A _{2 have the} same meaning as in formula (I).

Chlorine is a particularly preferred phosphonic acid derivative acetylphosphonic acid (fosfonochlorin), phosphonoformic acid (Foscarnet), phosphonoacetic acid, N, N-dimethyl (1-hydroxy-2- oxo-2-methoxy-ethyl) -phosphonamide and 2-hydroxy-2-hydroxy methyl-3-oxo-butylphosphonic acid (phosphonothrixin) and ammoni um-ethylcarbamoylphosphonate (fosamine ammonium).

Special features of the above definitions and suitable examples are given below:
"Acyl" is a substituent derived from an acid, such as from an organic carboxylic acid, carbonic acid, carbamic acid or the thioic acid or imidic acid corresponding to the individual acids above, or from an organic sulfonic acid, these acids each being aliphatic, aromatic and / or include heterocyclic groups in the molecule as well as carbamoyl or carbamimidoyl.

Suitable examples of these acyl groups are shown below specified.

Aliphatic acyl groups are acyl radicals derived from an aliphatic acid, 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, propoxy carbonyl, 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 Al kylgruppe or the alkane radical, optionally one or more suitable have substituents such as amino, halogen (e.g. fluorine, Chlorine, bromine etc.), hydroxy, hydroxyimino, carboxy, alkoxy (e.g. methoxy, ethoxy, propoxy etc.), alkoxycarbonyl, acylami no (e.g. benzyloxycarbonylamino etc.), acyloxy (e.g. acetoxy, Benzoyloxy etc.) and the like; as the preferred aliphatic Acyl radicals with such substituents are e.g. B. with amino, car boxy, amino and carboxy, halogen, acylamino or the like to name substituted alkanoyle.

Aromatic acyl radicals are those acyl radicals which derive from an acid having a substituted or unsubstituted aryl group, where the aryl group can include phenyl, tolyl, 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) can optionally have one or more suitable substituents, such as those which are suitable substituents for the alkyl group or the alkane residue has already been given. In particular and as an example of preferred aromatic acyl radicals with special substituents, arylanoyl substituted with halogen and hydroxy or with halogen and acyloxy and aralkanoyl substituted with hydroxy, hydroxyimino, dihalogenalkanoyloxyimino are also given
Arylthiocarbamoyl (e.g. phenylthiocarbamoyl etc.);
Arylcarbamimidoyl (e.g. phenylcarbamimidoyl 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, fuoyl, pyrrole carbonyl, 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 (e.g. thiophene yl-acetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2- Amino-4-thiazolyl) -2-methoxyiminoacetyl etc.) and the like.

In the above examples of heterocyclic acyl residues the heterocycle and / or the aliphatic hydrocarbon some may have one or more suitable substituents sen, like the same ones that are suitable for alkyl and alkane groups were specified.

"Alkyl" is a straight or branched chain alkyl group with up to 9 carbon atoms, such as methyl, ethyl, propyl, isopro pyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like chen.

"Hydroxyalkyl" is a straight or branched chain alkyl radical with up to 9 carbon atoms, the at least one hydroxyl group, preferably has one or two hydroxyl groups.

"Alkenyl" includes straight or branched chain alkenyls groups with up to 9 carbon atoms, such as. B. Vinyl, prope nyl (e.g. 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl, hexenyl.

"Alkynyl" includes straight or branched chain alkenylene groups with up to 9 carbon atoms.

Cycloalkyl preferably represents an optionally substituted C3-  C7 cycloalkyl; as possible substituents are u. a. Alkyl, Al kenyl, alkynyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc.), nitro and the like net.

Aryl is an aromatic hydrocarbon residue, such as phenyl Naphthyl, etc., which optionally one or more suitable substituents ducks 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, the aro Matic part optionally one or more suitable substituents may have 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 are represented by the formula

- (C _n H _2n ) -

can be reproduced in which n is an integer of 1 to 9, such as methylene, ethylene, trimethylene, methylethylene, Tetramethylene, 1-methyltrimethylene, 2-ethylethylene, pentame ethylene, 2-methyltetramethylene, isopropylethylene, hexamethylene, and the same; preferred alkylene radicals have up to 4 Koh lenstoffatome and particularly preferred are residues with 3 Koh lenstoffatomen such as. B. Trimethylene.

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

- (C _n H _2n-2 ) -

can be reproduced in which n is an integer of 2 to 9, such as B. vinylene, propenylene (e.g. 1-propenylene, 2- Propenylene), 1-methylpropenylene, 2-methylpropenylene, buteny len, 2-ethylpropenylene, pentenylene, hexenylene and the like; the alkenylene radical can particularly preferably contain up to 5 carbons Have substance atoms and in particular 3 carbon atoms such as e.g. B. 1-propenylene.

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

- (C _n H _2n-z ) (OH) _z -

are reproduced in which n is an integer from 1 to 9 and z is an integer to which 1 ≦ z ≦ n applies. Too suitable Examples of such hydroxyalkylene groups include Hy droxymethylene, hydroxyethylene (e.g. 1-hydroxyethylene and 2-hydroxyethylene), hydroxytrimethylene (e.g. 1-hydroxy trimethylene, 2-hydroxytrimethylene and 3-hydroxytrimethylene), Hydroxytetramethylene (e.g. 2-hydroxytetramethylene), 2-hydroxy 2-methyltrimethylene, hydroxypentamethylene (e.g. 2-hydroxy pentamethylene), hydroxyhexamethylene (e.g. 2-hydroxyhexa methylene) and the like. A low is particularly preferred res hydroxyalkylene with up to 4 carbon atoms and esp special one with 3 carbon atoms such. B. 2-hydroxytrimethylene.

"Oxoalkylene" can include straight or branched chain alkylene radicals which have up to 9 carbon atoms, at least one selected carbon atom being substituted by an oxo group; these residues can be represented by the formula

- (CH ₂ ) _n (CO) _y -

are reproduced in which n is an integer from 1 to 8 and y is an integer between I and 8, where n + y ≦ 9 applies.

"Oxo-hydroxyalkylene" includes straight or branched chain alkylene radicals which have up to 9 carbon atoms, at least one selected carbon atom being substituted with a hydroxyl group and at least one selected carbon atom being substituted with an oxo group; these residues can be represented by the formula

- (C _n H _2n-z ) (OH) _z (CO) _y

are reproduced in which n is an integer from 1 to 8 and z is an integer for which 1 ≦ z ≦ n, and y is one is an integer between 1 and 8 for which n + Y ≦ 9 applies.

The radicals X ₁ and X ₂ can preferably be chosen such that esters are formed on the phosphono group or phosphino group. Suitable examples of such esters according to formulas (I) and (II) include suitable mono- and diesters, and preferred examples of such esters include alkyl esters (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, hexyl ester) Etc.);
Aralkyl esters (benzyl esters, phenethyl esters, benzhydryl esters, trityl esters, 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, alkyl trihalosilyl, dialkylarylhalosilyl, trialkoxyhalosilyl, dialkylaralkylhalosilyl, dialkoxydihalosilyl, trialkoxyhalosilyl, etc.) and the like.

In the above ester, the alkane and / or arene part can be optional have at least one suitable substituent such as halo gene, 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. That is, the salt compounds of the 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, ethylene diamine 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 used according to the invention according to the formulas (I), (II) or (III) in their protonated form as Am monium salt of organic or inorganic acids, such as hydrochloric acid re, hydrobromic acid, sulfuric acid, nitric acid, Methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid re, maleic acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid re, etc. are available.

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

The compounds described, i. H. the organophosphorus  Compounds of formula (I), (II) and (III) and esters and Amides thereof on the phosphono or phosphino group and Salts thereof show strong cytotoxic activity against single and multicellular parasites, especially against over the pathogens of malaria and sleeping sickness. Demge The compounds used according to the invention are for the Treatment of infectious diseases usable by Pa races are caused in humans and animals. The connection are also for use in the prevention of diseases, which are caused by parasites, especially as Ma laria prophylaxis and suitable as sleep sickness prophylaxis.

The organophosphorus compounds according to the invention generally include pharmaceutically acceptable salts, ami de, ester, a salt of such an ester, or compound gene, those to be used according to the invention when applied Compounds as metabolites or degradation products Equestrian sites, also called "prodrugs", can be used for administration in any suitable manner analogous to known ones tiparasitic agents (mixed with a non-toxic pharmaceutically acceptable carrier).

Pharmaceutically acceptable salts of the compounds include Salts which the compounds of the invention used Formulas (I) and (II) in their protonated form as ammonium salt of inorganic or organic acids, such as hydrochloric acid, Sulfuric acid, citric acid, maleic acid, fumaric acid, wine acid, p-toluenesulfonic acid.

Also particularly pharmaceutically suitable are the salts which are formed by a suitable selection of X ₂ and X ₃ , such as sodium salt, potassium salt, calcium salt, ammonium salt, ethanolamine 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 in the form of pharma deutical preparations in dosage units the. This means that the preparation in the form of individual parts le, z. B. tablets, dragees, capsules, pills, suppositories and ampoules are present, the active ingredient content of which is a fraction or a multiple of a single dose. Thu Sation units can, for. B. 1, 2, 3 or 4 single doses or Contain 1/2, 1/3 or 1/4 of a single dose. A single do sis preferably contains the amount of active ingredient that is present in a Application is administered and usually an entire, a half or a third or a quarter of a day dose corresponds.

Taking non-toxic, inert pharmaceutically acceptable drugs materials are solid, semi-solid or liquid diluents tel, fillers and formulation auxiliaries of all kinds stand.

The preferred pharmaceutical preparations are tablets, Coated tablets, capsules, pills, granules, suppositories, solutions, Suspensions and emulsions, pastes, ointments, gels, creams, lo tion, powder and sprays called. Tablets, coated tablets, capsules, Pills and granules can be the active ingredient or ingredients in addition to the contain conventional carriers, such as (a) filling and stretching tel, e.g. B. starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. B. Carboxymethyl cellulo se, alginates, gelatin, polyvinylpyrrolidone, (c) damp means, e.g. B. glycerin, (d) disintegrant, e.g. B. agar, Calcium carbonate and sodium carbonate, (e) solution retarders, e.g. B. Paraffin and (f) absorption accelerators, e.g. B. quaternary re ammonium compounds, (g) wetting agents, e.g. B. cetyl alcohol, Glycerol monostearate, (h) adsorbent, e.g. B. kaolin and Bentonite and (i) lubricants, e.g. B. talc, calcium and Ma magnesium stearate and solid polyethylene glycols or mixtures of  substances listed under (a) to (i).

The tablets, dragees, capsules, pills and granules can with the usual, optionally containing opacifiers tendency coatings and covers and so together be set that they only or be the active ingredients preferably in a certain part of the intestinal tract If necessary, deliver with a delay, with z. B. Polymer substances and waxes can be used.

The active ingredient (s) can optionally be combined with an or several of the above-mentioned carriers also in microver encapsulated form.

Suppositories can besides the active ingredient (s) the usual Chen water-soluble or water-insoluble carriers hold, e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat and higher esters (e.g. C14 alcohol with C16 fatty acid) or Gemi of these substances.

Ointments, pastes, creams and gels can next to the or Active substances contain the usual carriers, e.g. B. tieri vegetable and vegetable fats, waxes, paraffins, starch, tra gant, cellulose derivatives, polyethylene glycols, silicones, bento nite, silica, talc and zinc oxide or mixtures of these Fabrics.

Powders and sprays can in addition to the active ingredient (s) Lichen carriers included, for. B. milk sugar, talc, Kie silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also be used union blowing agents, e.g. B. chlorofluorocarbons, ent hold.

Solutions and emulsions can be added to the active ingredient (s)  the usual carriers such as solvents, solubilizers and emulsifiers, e.g. B. water, ethyl alcohol, isopropyl alcohol, Ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, Pro pylene glycol, 1,3-butylene glycol, dimethylformamide, oils, esp special cottonseed oil, peanut oil, corn oil, olive oil, Castor oil and sesame oil, glycerin, glycerin formal, tetrahydro furfuryl alcohol, polyethylene glycols and fatty acid esters of Contain sorbitans or mixtures of these substances.

The solutions and emulsions can be used for parenteral administration are also available in sterile and blood isotonic form.

Suspensions can besides the active ingredient (s) the usual Chen carriers such as liquid diluents, e.g. B. What water, ethyl alcohol, propylene glycol, suspending agents, e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and Sorbitan esters, microcrystalline cellulose, aluminum metal hydroxide, bentonite, agar and tragacanth or mixtures of these Contain substances.

The formulation forms mentioned can also contain colorants, Preservatives as well as smell and taste-improved Additives, e.g. B. peppermint oil and eucalyptus oil and sweeteners, e.g. B. saccharin.

The active ingredients of the formulas (I) and (II) are intended in the above listed pharmaceutical preparations, preferably in a concentration of about 0.1 to 99.5% by weight, preferably from about 0.5 to 95% by weight of the total mixture.

The pharmaceutical preparations listed above can in addition to the compounds of formula (I) and (II) also others contain active pharmaceutical ingredients.

Furthermore, the organophosphorus compounds in the  pharmaceutical agents in combination with sulfonamide, sulfa doxin, artemisinin, atovaquone, quinine, chloroquine, hydroxy chloroquine, mefloquine, halofantrine, pyrimethamine, armesin, Te tracycline, doxycycline, proguanil, metronidazole, praziquantil, Niclosamide, mebendazole, pyrantel, tiabendazole, diethylcarba zin, piperazine, pyrivinum, metrifonate, oxamniquin, bithionol or suramin or more of these substances.

The manufacture of the pharmaceutical accessories listed above Horse riding is done in the usual way according to known methods, e.g. B. by mixing the active ingredient or ingredients with the or Carriers.

The preparations mentioned can be used in humans and animals the oral, rectal, parenteral (intravenous, intramuscular, sub cutaneous), intracisternal, intravaginal, intraperitoneal, local (Powder, ointment, drops) and for the treatment of infections in Cavities, body cavities are applied. As a suitable addition Preparations come with injection solutions, solutions and suspensions NEN for oral therapy, gels, infusion formulations, emul ions, ointments or drops. For local therapy ophthalmic and dermatological formulations, Silver and other salts, ear drops, eye ointments, powder or solutions are used. In animals, the intake also in suitable form via the feed or drinking water take place. Gels, powders, powders, tablets, Prolonged-release tablets, premixes, concentrates, granules, pellets, Tablets, boluses, capsules, aerosols, sprays, inhalants Humans and animals can be used. Furthermore, the inventions compounds according to the invention in other carrier materials such as Example plastics, (plastic chains for local therapy), Collagen or bone cement can be incorporated.

In general, it has been in both human and of veterinary medicine has been shown to be advantageous  Active ingredients of the formula (I) and (II) in total amounts of about 0.5 to about 1000, preferably 5 to 500 mg / kg body weight 24 hours each, possibly in the form of several individual doses, to achieve the desired results. A Single dose preferably contains the active ingredient (s) in Amounts from about 1 to about 200, especially 3 to 100 mg / kg Body weight. However, it may be necessary from the ge named doses vary, 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 the application of the drug and the period or interval within which the administration takes place.

So in some cases it may be sufficient with less than the above amount of active ingredient to get by while in at whose cases exceeded the amount of active ingredient mentioned above must become. The determination of the optima required in each case len dosage and type of application of the active ingredients can by the specialist on the basis of his specialist knowledge.

The compounds to be used according to the invention can be found in the usual concentrations and preparations in animals with the feed or with feed preparations or with the Be given drinking water.

example 1 Test of the effectiveness of the substances against malaria in vivo

The various derivatives were based on the modified Pe ters test tested. The substances were in one Quarter of the half-lethal dose (LD50) applied. When ver ten mice with Plasmodium vinckeii, the Er mouse malaria, infected. After confirmation of the infect blood test, treatment was performed in four Mice. Six mice that were not treated served as controls were. Treatment with 1000 mg / kg / d formic acid phosphonate  (Foscarnet) over 4 days led to the parasites being killed in the blood of mice. The treated group was already after egg a day free from live parasites. The control mice had to on day 5 after infection with a parasitemia of <80% be tested. Further experiments showed an effectiveness of 400 mg / kg / d phosphonoacetates in mice with parasitemia of 80%. These mice were also free of live after 1 day Parasites.

Claims (9)

1. Use of organophosphorus compounds of the general formula (I)
wherein R ₁ is selected from the group consisting of H, a substituted and unsubstituted acyl, a substituted and unsubstituted alkyl, a substituted and unsubstituted hydroxyalkyl, a substituted and unsubstituted alkenyl, a substituted and unsubstituted alkynyl, a substituted and unsubstituted Aryl, a substituted and unsubstituted cycloalkyl, a substituted and unsubstituted aralkyl, a substituted and unsubstituted heterocyclic radical, halogen and OX ₁ ,
wherein X ₁ is selected from the group consisting of hydrogen, a substituted and unsubstituted acyl, a substituted and unsubstituted alkyl, a substituted and unsubstituted hydroxyalkyl, a substituted and unsubstituted alkenyl, a substituted and unsubstituted alkynyl, a substituted and unsubstituted aryl, a substituted and unsubstituted cycloalkyl, a substituted and unsubstituted aralkyl, a silyl, substituted and unsubstituted heterocyclic radical, a cation of an organic and inorganic base, in particular a metal of the first, second or third main group of the Pe periodic system, ammonium, substituted ammonium and ammonium compounds,
R ₂ and R _{3 may be the} same or different and are selected from the group consisting of hydrogen, a substituted and unsubstituted acyl, a substituted and unsubstituted alkyl, a substituted and unsubstituted hydroxyalkyl, a substituted and unsubstituted alkenyl, one substituted and unsubstituted alkynyl, a substituted and unsubstituted aryl, a substituted and unsubstituted cycloalkyl, a substituted and unsubstituted aralkyl, a substituted and unsubstituted heterocyclic radical, halogen and OX ₂ and OX ₃ ,
wherein X ₂ and X ₃ are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted cycloalkyl, a silyl, substituted and unsubstituted heterocyclic radical, a cation of a organic and inorganic base, in particular a metal of the first, second or third main group of the periodic system, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids, and
A ₁ and A ₂ , one or both of which can be omitted, are the same or different and are selected from the group consisting of an alkylene radical, alkenylene radical, an oxoalkylene radical, a hydroxyalkylene radical and an oxo-hydroxyalkylene radical ,
and their pharmaceutically acceptable salts, esters and amides and salts of the esters or compounds which, when applied, provide the compounds to be used according to the invention as metabolic products or degradation products,
for the therapeutic and prophylactic treatment of infections caused by single or multicellular parasites in humans and animals. 2. Use of organophosphorus compounds of the general my formula (I) according to claim 1 for the treatment of Infek ions caused by unicellular parasites. 3. Use of organophosphorus compounds of the general my formula (I) according to claim 1 for prevention and Be act of infections caused by pathogens of mala ria, sleeping sickness, Chagas disease, the Toxoplasmosis, the amoebic dysentery, the leishmaniasis, the Trichomoniasis, pneumocystosis, balantidiosis, the Cryptosporidiosis, Sarcocystosis, Acanthoma, Naeglerose, Coccidiosis, Giardiosis and Lamblio se. 4. Use of organophosphorus compounds of the general my formula (I) according to claim 1 for prevention and Be malaria, sleeping sickness, Chagas Illness, the amoebic dysentery, the leishmaniasis, the trichomo niasis, pneumocystosis, balantidiosis, cryptospo Ridiosis, Sarcocystosis, Acanthoma, Naeglero se, coccidiosis, giardiosis and lambliosis. 5. Use according to one of claims 1 to 4, characterized in that the compound is represented by the fol lowing formula (II)
wherein R ₁ , X ₂ , X ₃ , A ₁ and A _{2 have the} same meaning as in formula (I). 6. Use according to claim 5, characterized in that it  chlorine in the case of the phosphonic acid derivatives acetylphosphonic acid (fosfonochlorin), phosphonoformic acid (Foscarnet), phosphonoacetic acid, N, N-dimethyl (1-hydroxy-2- oxo-2-methoxy-ethyl) -phosphonamide, 2-hydroxy-2-hydroxy methyl-3-oxo-butylphosphonic acid (phosphonothrixin) or Am monium ethyl carbamoyl phosphonate (fosamine ammonium). 7. Use according to one of claims 1 to 6 in a phar pharmaceutical agents for the treatment of parasitic infections, the effective content of at least one phosphororga African compound and a pharmaceutically acceptable Carrier has. 8. Use according to claim 7, characterized in that the pharmaceutical agent at least one other phar contains active pharmaceutical ingredient. 9. Use according to one of claims 7 or 8, characterized in that the pharmaceutical agent also one or more Be Components of the group that consists of sulfonamide, sulfa doxin, artemisinin, atovaquone, quinine, chloroquine, hydroxy chloroquine, mefloguin, halofantrine, pyrimethamine, armesin, Tetracycline, doxycycline, proguanil, metronidazole, prazi quantile, niclosamide, mebendazole, pyrantel, tiabendazole, Diethylcarbazin, Piperazin, Pyrivinum, Metrifonat, Oxamni quin, bithionol and suramin.