WO2000030653A2 - Use of phosphonoformic acid derivatives for treating infections - Google Patents

Abstract

The invention relates to the use of a compound of formula (I) for the prophylaxis and therapy of infectious processes in humans and animals, which processes are induced by bacteria, fungi or parasites. The inventive compound is also used as fungicidal, bactericidal or herbicidal agent in plants.

Description

 Use of phosphonoformic acid derivatives for the treatment of infections

The invention relates to the use of phosphonoformic acid derivatives for the therapeutic and prophylactic treatment of infections in humans and animals which are caused by bacteria, fungi and parasites, and their use as a fungicide, bactericide and herbicide in plants. According to the invention, the phosphonoformic acid derivatives comprise the physiologically tolerable salts, esters and amides.

Phosphonoformic acids are already known for their antiviral properties. Pharmaceutical preparations for the treatment of viral infections are already in the US patents

No. 4215 113, 4,339, 4,665,062 and 4,771,041.

In particular, the antiviral effect of phosphonoformic acid derivatives and their preparation have been described in WO 98/16537 and WO 98/25938.

There is a strong need to provide means for the enrichment of the treatment of humans and animals and the protection of plants which not only have a potent activity, but also, in contrast to other medicinal products or crop protection agents, have reduced side effects or cause less environmental pollution and thus mean a lower health risk for humans.

The object of the present invention is therefore to provide a substance which can be used universally in infections by bacteria, fungi and parasites in humans and animals and as a fungicide, bactericide and herbicide in plants and which fulfills the conditions specified above.

This object is achieved in a completely surprising manner by the group of substances defined in claim 1. This group of substances shows both an anti-infectious effect against bacteria, fungi and single and multicellular parasites as well as a fungicidal, bactericidal and herbicidal effect on plants.

The organophosphorus compounds used according to the invention correspond to the general formula I.

in which Rπ is selected from the group consisting of d- ₂ 6-alkyl radicals, C2.26-alkenyl radicals. with 1 to 6 double bonds, C ₂ -26-alkynyl radicals with 1 to 6 triple bonds, C _1-26 -acyl radicals, Ar _-co-26 alkyl, _C3-8 cycloalkyl-Co-6 alkyl radicals _-2, C _3-8 heterocycloalkyl-co- ₂₆ alkyl radicals having one or two nitrogen, oxygen or sulfur atoms, halogen and consists OXπ , where all the aforementioned radicals can be substituted with d-9-alkyl, d-9-alkoxy, hydroxyl, amino, halogen or oxo groups, where Xu is selected from the group consisting of hydrogen, d-26- alkyl radicals, C ₂ - ₂ 6- alkenyl group having 1 to 6 double bonds, C2 ₂₆ alkynyl radicals having 1 to 6 triple bonds, Ar-Co-26 alkyl groups, C _3-8 cycloalkyl, d-26-acyl, C _{3- 8-} Heterocycloalkyl-Co- ₂₆ -alkyl radicals with one or two nitrogen, oxygen or sulfur atoms, C _1-26 -silyl radicals, all the above radicals with d-9-alkyl, C _1-9 alkoxy, hydroxy -, Amino-, Halogen- or Oxogr groups can be substituted, and consists of 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 derived from ethylenediamine or amino acids,

in which Ri and R _{2 are} each independently selected from the group consisting of d-2 alkyl radicals, C ₃ . -Cycloalkyl residues, C ₃ . -Cycloalkyl-C ₁ . ₂₄ -alkyl radicals, d ^ -alkoxy radicals, Cι- ₂₄ - alkylthio radicals, C _1-24 -alkoxy-Cι- ₂₄ -alkyl radicals and C _1-24 -alkylthio-C ₁ .2 ₄ -alkyl radicals, acyl radicals, Ar- ( d- ₂₄ ) alkyl, C _3-8 heterocyloalkyl-Co- ₂₄ alkyl, halogen and hydrogen, and each d. ₂₄ -alkyl radical and -CC-24-alkoxy radical may be branched or unbranched and saturated or unsaturated with 2 to 6 double bonds and optionally with hydroxyl, amino, mercapto, halogen, oxo groups or d. ₂₄ -alkoxy radicals, d ^ -alkylcarbonyloxy radicals, Cι- ₂₄ -alkoxycarbonyloxy radicals, d- ₂₄ -alkylthio radicals, d- ₂ 4-alkylcarbonylthio radicals, Amino residues ₂₄ -Alkylaminoresten, di- (C _{1. 24,} alkyl), amino radicals Cι- ₂₄ -Alkylcabonyl-, amino radicals Cι _-2 alkyl (C _1-2 alkylcarbonyl), d-24-alkoxycarbonylamino radicals or d ^ -Alkyl- Ci ^ -alkoxycarbonyl amino radicals can be substituted, wherein each aralkyl radical, heterocyclic radical,

and Cι.2 -alkoxy radical may be branched or unbranched and saturated or unsaturated with 2 to 6 double bonds or triple bonds, or in the R ₁ -CH-CH-R ₂ part of a

form, the optionally substituted with hydroxy, mercapto, amino, halogen, oxo groups or with Cι-24 alkyl groups, C ₁ - ₂₄ - alkoxy, d- ₂ 4-alkylthio, d- ₂ 4-alkylamino, di- ( C ₁ -2 ₄ -alkyl) amino residues, C _1-24 -alkylcarbonyl residues, d-2 ₄ -alkylcarbonyloxy residues,

Cι- ₂ - Alkylcarbonylthioresten or d ^ -Alkylcarbonylaminoresten, C 1-24 alkyl (C ₁ - ₂₄ - alkyl carbonyl) amino radicals may be substituted, each Cι- ₂₄ branched alkyl, or unbranched and saturated or having 1 to 6 Double bonds may be unsaturated, or where R _{10 is} a branched or unbranched C _1-4 alkyl radical, or in the

form part of the furanose or pyranose ring of a sugar, for example D-ribose, D-arabinose, D-xylose, D-lyxose, D-glucose, D-galactose, D-mannose, D-talose, D-allose, D-altrose , D-gulose, D-idose or the corresponding L-isomers, the hydroxyl groups in each case optionally by hydrogen, amino, azido, oxo, mercapto or C _1- 2 ₄ -alkoxy, Cι-2 ₄ -alkylthio , d ^ -alkylamino residues, di- (d. ₂₄ -alkyl) amino residues, d ^ -alkylcarbonyloxy residues, d ^ -alkylcarbonylthio residues, d-2 ₄ -alkylcarbonylamino residues, C _1- 2 ₄ -alkyl- (C _1- 2 ₄ -Alkylcarbonyl) amino radicals can be substituted, each d. ₂₄ -alkyl radical can be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds, and their pharmaceutically acceptable salts, esters and amides and salts of the esters and their optical isomers.

R _t and R ₂ can in particular each be independently selected from the group consisting of carboxyl residues, carboxamido residues, aryl residues, aryloxycarbonyl residues, aryl-d- ₂ 4-alkyl residues, C _1-24 alkoxycarbonyloxy residues, i.e. ₂₄ -alkylaminocarbonyl residues, di- (-Cι. ₂₄ -alkyl) - aminocarbonyl residues, aryl-C _1-24 -alkoxycarbonyl residues, aryl-C _1-24 -alkylaminocarbonyl-residues, C _1-24 -alkylcabonyloxy- (Ci ^ alkylmethoxycarbonyl residues, C _{1 24} -alkoxycarbonyloxy-methoxycarbonyl radicals, Ci ^ - ^ - alkoxycarbonyloxy-Cd ^ -alky-methoxycarbonyl, where each C _{1, 24} -alkyl radical may be branched or unbranched and saturated or unsaturated with 2 to 6 double bonds, and each C -alkyl radical and d. ₂₄ alkoxy radical can be branched or unbranched and saturated or unsaturated, and any aryl radical of the formula II

R ₃ and _{Λ are the} same or different and are each selected from the group consisting of hydrogen, halogen, C.-4-alkyl radicals, C _M alkoxy radicals, formyl, acetyl, pro pionyl, butyryl, formyl, acetyl, propionyl, butyryloxy, C _1- alkoxycarbonyl, which can all be branched or unbranched, or R ₃ and t together form an unbranched saturated alkylene chain with 3 to 4 carbon atoms, which is bonded to adjacent positions of the phenyl ring, or R ₃ and t together form a methylenedioxy radical, a 1,1-ethylenedioxy radical, a 1,1-ethylenedioxy radical, a 1,1-ethylenedioxy radical or a 1,2-ethylenedioxy radical which are attached to adjacent positions of the phenyl ring.

Preferred is the use of compounds in which R 1 and R 2 are each independently selected from the group consisting of hydrogen, hydroxyl groups, formyl, acetyl and methyl, the methyl radical optionally having a hydroxyl group or mercapto group or having d- ₂₄ alkoxy radicals, C _1- 2 alkylcarbonyloxy radicals.

or C1-24 alkylcarbonylthio radicals can be substituted, the d. ₂₄ alkyl groups and the d. ₂₄ - alkoxy groups can be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds.

Ri is particularly preferably a methyl radical, optionally with a hydroxyl group or mercapto group or with

Cι- ₂₄ alkylcarbonyloxy radicals, d-2 ₄ - alkylthio radicals or d- ₂₄ -alkylcarbonylthio radicals can be substituted, the C1. ₂ 4- alkyl groups and the Cι- ₂ 4-alkoxy groups can be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds, and R _{2 is} a hydrogen radical.

Particularly good results are achieved with compounds in which Ri and R. are each independently selected from the group consisting of hydrogen and a w-octadecylmethyl radical, where

preferably a «octadecylmethyl radical and R2 is a hydrogen radical. Special advantages are achieved if the connection has the configuration (R).

Rπ is preferably OH.

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 heterocyclic Include groups in the molecule as well as carbamoyl or carbamimidoyl.

Suitable examples of these acyl groups are given below. 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, 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, in particular the alkyl group or the alkane radical, can optionally have one or more suitable substituents, such as amino, halogen (for example 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; as preferred aliphatic acyl radicals with such substituents are e.g. alkanoyl substituted with amino, carboxy, amino and carboxy, halogen, acylamino or the like.

Aromatic acyl radicals are those acyl radicals which derive 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 as substituents for the alkyl group or the In particular and as an example of preferred aromatic acyl radicals with special substituents, arylanoyl substituted with halogen and hydroxyl or with halogen and acyloxy and arroyl substituted with hydroxyl, hydroxyimino, dihalogenalkanoyloxyimino and arylthiocarbamoyl (eg phenylthiocarbamoylimidamidl) (arylcarb) (arylcarb) (arylcarb) (arylcarbamoylimid) 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, furoyl, 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 (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 stated to be suitable for alkyl and alkane groups.

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. The 5- and 6-membered heterocycles, which R 1 and R _{2 can} stand for, and which contain one or two nitrogen, oxygen or sulfur atoms as the ring member in addition to carbon, can be saturated or unsaturated.

A production process for these compounds is described in detail in WO 98/25938.

The organophosphorus compounds are particularly suitable for the therapeutic and prophylactic treatment of infections in humans and animals which are caused by bacteria, unicellular and multicellular parasites and fungi.

The compounds are active against unicellular parasites (protozoa), in particular against pathogens of malaria and sleeping sickness as well as Chagas disease, toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis, pneumocystosis, balantidosis, cryptosporidiosis, and sarcolocystosis , Akanthamöbose, Naeglerose, Coccidiosis, Giardiosis and Lambliosis.

They are therefore particularly useful as malaria prophylaxis and as prophylaxis of sleeping sickness and Chagas disease, toxoplasmosis, amoebic dysentery, Leishmaniasis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcolocystosis, acanthamoebosis, cocoonosis, naeglerosis Giardiosis and Lambliosis.

The active substances according to the invention can be used in particular against the following bacteria:

Bacteria of the Propionibacteriaceae family, in particular the Propionibacterium genus, in particular the Propionibacterium acnes species, Actinomycetaceae bacteria, in particular the Actinomyces genus, Corynebacterium bacteria, in particular the Corynebacterium diphteriae and Corynebacterium pseudote family mycobacteria, bacteria the species Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium, bacteria of the family Chlamydiaceae, in particular the species Chlamydia trachoήiatis and Chlamydia psittaci, bacteria of the genus Listeria, in particular the species Listeria mondhrixysnixytocytosis , Bacteria of the genus Clostridium, bacteria of the genus Yersinia, of the species Yersinia pestis, Yersinia pseudotuberculosis, Yersinia enterocolitica and Yersinia ruckeri, bacteria of the family Mycoplasmataceae, of the genera Mycopla sma and ureaplasma, especially the species Mycoplasma pneumoniae, bacteria of the genus Brucella, bacteria of the genus Bordetella, bacteria of the family Nei- sseriaceae, in particular of the genera Neisseria and Moraxella, in particular the species Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis, bacteria of the family Vibrionaceae, in particular of the genera Vibrio, Aeromonas, Plesiomonas and Photobacterium, in particular the species Vibrio cholerae, Vibrio anguillarum and Aeromonas salmonici- das, bacteria of the genus Campylobacter, in particular the species Campylobacter jejuni, Campylobacter coli and Campylobacter fetus, bacteria of the genus Helicobacter, in particular the species Helicobacter pylori, bacteria of the Spirochaetaceae and Leptospiraceae families, in particular the genus , Borrelia and Leptospira, in particular Borrelia burgdorferi, bacteria of the genus Actinobacillus, bacteria of the family Legioneüaceae, of the genus Legionella, bacteria of the family Rickettsiaceae and family Bartonellaceae, bacteria of the genera Nocardia and Rhodococcus, bacteria of the genus Dermatophamus, " ilie Pseudomonadaceae, in particular of the genera Pseudomonas and Xanthomonas, bacteria of the Enterobacteriaceae family, in particular of the genera Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia and Shigella, bacteria of the Pasteurellaceae family, in particular of the genus Haemophilus, bacteria of the Micro- family , in particular the genera Micrococcus and Staphylococcus, bacteria of the Streptococcaceae family, in particular the genera Streptococcus and Enterococcus and bacteria of the Bacillaceae family, in particular the genera Bacillus and Clostridium.

Organophosphorus compounds and their derivatives are therefore suitable for the treatment of diphtheria, acne vulgaris, listeriosis, erysipelas in animals, gas burns in humans and animals, para-noise burns in humans and animals, tuberculosis in humans and animals, leprosy and a wide variety of mycobacteriosis in humans and animals, paratuberculosis in animals, plague, mesenteric lymphadenitis and pseudotuberculosis in humans and animals, cholera, legionnaires' disease, Lyme disease in humans and animals, leptospirosis in humans and animals, syphilis, Campylobacter enteritis in humans and animals, Moraxella keratoconjunc -tivitis and serositis of animals, brucellosis of animals and humans, anthrax in humans and animals, actinomycosis in humans and animals, streptotrichoses, psittacosis / ornithosis in animals, Q fever, Ehrlichiosis.

The use is also useful in Helicobacter eradication therapy for ulcers of the gastrointestinal tract.

Combinations with another antibiotic can also be used to treat the above-mentioned diseases. For combination preparations with other anti-infectives, isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, protionamide and dapsone are particularly suitable for the treatment of tuberculosis.

The compounds described, ie the organophosphorus compounds according to the mel I and esters and amides and salts thereof show a strong cytotoxic activity against single and multicellular parasites, especially against the pathogens of malaria and sleeping sickness. Accordingly, the organophosphorus compounds are useful for the treatment of infectious diseases caused by bacteria, parasites and fungi in humans and animals. The compounds are also used for the prevention of diseases caused by bacteria, parasites and fungi.

The organophosphorus compounds, these generally include pharmaceutically acceptable salts, amides, esters, a salt of such an ester, or compounds which, when applied, provide the organophosphorus compounds as metabolites or degradation products, also called "prodrugs", for administration in any of them be prepared in a suitable manner analogous 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 formula I 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.

The salts, 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, are also particularly pharmaceutically suitable.

The activity of the substances is determined in a test system. This system is based on the measurement of the inhibition of the growth of bacteria, parasites, fungi or plants in vitro. For this purpose, test methods are used which are known to the person skilled in the art.

For example, to determine antimalarial activity, the inhibition of malaria parasite growth in blood cultures is determined.

The determination of the antibacterial activity is based on measuring the inhibition of bacterial growth on nutrient media and in liquid cultures.

The determination of the fungicidal activity is based on the inhibition of the growth of fungi on nutrient media and in liquid cultures. Some of the microorganisms to be examined can only be examined in animal models. The corresponding models are then applied here.

Substances that show an effectiveness in the in vitro measuring systems are further investigated in in vivo models.

The antiparasitic, fungicidal or antibacterial activity is further evaluated in the corresponding animal models.

The screening for herbicidal activity is determined by means of algae systems and measurement of the isoprene emission from plants under standard conditions.

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. B. tablets, dragees, capsules, pills, suppositories and ampoules are present, the active ingredient content of which corresponds to a fraction or a multiple of a single dose. The dosage units can e.g. B. 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.

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. B. starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. B. carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, (c) humectants, e.g. B. glycerin, (d) disintegrant, e.g. B. agar-agar, calcium carbonate and sodium carbonate, (e) solution retarders, e.g. B. paraffin and (f) absorption accelerator, e.g. B. quaternary 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 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, and can also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, possibly with a delay, where as Embedding compounds e.g. B. 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 carriers.

Suppositories can contain the usual water-soluble or water-insoluble excipients in addition to the active ingredient (s), e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat and higher esters (z. B. C 14 alcohol with C16 fatty acid) or mixtures of these substances.

Ointments, pastes, creams and gels can contain the usual excipients in addition to the active ingredient (s), e.g. B. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.

Powder and sprays can contain the usual excipients in addition to the active ingredient (s), e.g. B. milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also use the usual blowing agents, e.g. B. chlorofluorocarbons.

In addition to the active ingredient (s), solutions and emulsions can contain 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, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol, glycerol formaldehyde - hol, polyethylene glycols and fatty acid esters 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. B. water, ethyl alcohol, propylene glycol, suspending agents, e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth or mixtures of these substances. 12

The formulation forms mentioned can also contain colorants, preservatives and odor and taste-improved additives, e.g. B. peppermint oil and eucalyptus oil and sweeteners, e.g. B. saccharin.

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 addition to the compounds of the formula I, the pharmaceutical preparations can also contain further active pharmaceutical ingredients.

The compounds can be used with previously described substances with antibacterial, antimyctoic and antiparasitic properties. These include in particular compounds that have already been used in therapy or are still being used. Substances are particularly suitable for this purpose, which are listed in the Red List or in Simon / Stille, Antibiotic Therapy in Clinic and Practice, 9th Edition 1998 Schattauer Verlag, or at http: /www.customs.treas.gov/imp-exp /rulings/harmoniz/hrml29.html listed on the Internet. In particular, the derivatives with penicillin, benzylpenicillin (Penicillin G), phenoxypenicillins, isoxazolylpenicillin, aminopenicillin, ampicillin, amoxixillin, bacampicillin, carboxypenicillin, ticarcillin, temocillin, acyalaminopenicillin, pezlocillin, azlocillin, azlocillin, azlocillin , Cefüroxim group, Cefoxitin group, Cefoxitin, Cefotetan, Cefmetazol, Latamoxef, Flomoxef, Cefaxaxim group, Cefozidim, Ceftazidim group, Ceftazidim, Ce irom, Cefepim, other Cephaloperazalone, Cefaloperazaline, Cefsoperulosaline, Cefoxulosporin the Cefalexin group, Loracar- bef, Cefprozil, new oral cephalosporins with extended spectrum, Cefixim, Cefpodoxim-Proxetil, Cefüroxim-Axetil, Cefetamet, Cefotiam-Hexetil, Cefdinir, Ceftibuten, other ß-lactam / antibiotics, Carbap Meropenem, biapenem, aztreonam, ß-lactamase inhibitor, clavulanic acid / amoxicillin, clavulanic acid / ticarcillin, sulbactam / ampicillin, tazobactam / pi pera cillin, tetracycline, oxytetracycline, Rolitetraxyxlin, doxycycline, minocycline, chloramphenicol, aminoglycosides, gentamicin, tobramycin, Ne tilmicin, amikacin, xithromycin Spectinomyxin, macrolides, erythromycin, clarithromycin, Ro, azithromycin, dirithromycin, spiramycin, josamycin, lincosamides, Clin- damycin, fusidic acid, glycopeptide antibiotics, vancomycin, tecoplanin, pristinamycin derivatives, fosfomycin, antimicrobial folic acid antagonists, sulfonamide, co-trimoxazole, trimethoprim, other diaminopyrimidine-sulfonamide combinations, nitrofüran, nitrofitrone, nitrofuronoin (nitrofurone), nitrofluoronu , Norfloxacin, Ciprofloxacin, Ofloxacin, Sparfloxacin, Enoxacin, Fleroxacin, Pefloxacin, Lomefloxacin, Bay Y3118, Nitroimidazole, Antifungal Agents, Isoniazid, Rifampicin, Rifabutin, Ethambamidol, Pyamb Streptomycin, capreomycin, prothionamide, terizidone, dapsone, clofazimin, local antibiotics, bacitracin, tyrothricin, polymyxins, neomycin, kanamycin, paromomycin, mupirocin, anti-viral agents, acyclovir, ganciclovir, azidothymidine, didanoxinidine, didanoxinidine , Trifluridine, foscarnet, amantadine, interferons, tibol derivatives, proteinase inhibitors, antifungals, polyenes, amphothericin B, nystatin, natamycin, azoles, azoles for septic therapy, miconazole, ketoconazole, itraconazole, flucononazole, UK- 109.496 , azoles for topical application, clotrimazole, econazole, isoconazole, Oxico- Nazole, bifonazole, flucytosine, griseofulvin, ciclopiroxolamine, tolnaftate, naftifine, terbinafine, amorolfine, anthraquinones, Betulinic acid, Semianthrachinone, xanthones, Naphtoquinone, Aryaminoalkohole, quinine, quinidine, mefloquine , Halofantrine, chloroquine, amodiaquine, acridine, benzonaphthyridine, mepacrine, pyronaridine, dapsone, sulfonamides, sulfadoxine, sulphene, trimethoprim , Proguanil, chlorproguanil, diaminopyrimidines, pyrimethamine, primary maquin, aminoquinolines, WR 238,605, tetracycline, doxycycline, clindamycin, norfloxacin, ciprofloxacin, ofloxacin, artemisinin, dihydroartemisinin, 10b artemether, arteether, Atr- tesunat, atovaquone, suramin, melarsoprol, Nifürtmox , Stibogluconate sodium, pentamidine, amphotericin B, metronidazole, clioquinol, mebendazole, niclosamide, praziquantel, pyrantel, tiabendazole, diethylcarbamazine, ivermectin, bithionol, oxamniquin, metrifonate, piperazine, embonate.

Furthermore, the organophosphorus compounds in the pharmaceutical compositions can be used in combination with sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine, chloroquine, hydroxylchloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracycline, doxycycline, proguanil, metronidazole, nicazolantil, prazoliquilil, praziquantilil Pyrantel, tiabendazole, diethyl carbazine, piperazine, pyrivinum, metrifonate, oxamniquin, bithionol or suramin or more of these substances are present.

The pharmaceutical preparations listed above are prepared in a conventional manner by known methods, e.g. B. by mixing the active ingredient (s) with the carrier (s).

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 therapy of infections in cavities, body cavities. Suitable preparations are injection solutions, solutions and suspensions for oral therapy, gels, pour-on formulations, emulsions, ointments or drops. 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. Furthermore, gels, powders, powders, tablets, slow-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 plastics, (plastic chains for local therapy), collagen or bone cement.

In general, it has proven to be advantageous in both human and veterinary medicine to use the active ingredient (s) of the formula I in total amounts of about 0.05 to about 2000, preferably 5 to 1000 mg, body weight per 24 hours, optionally in the form multiple doses to achieve the desired results. A single dose contains the active ingredient (s) preferably in amounts from about 0.25 to about 2000 mg, e.g. 1 to 4 times a day. 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.

Liquid preparations can be administered in the form of solutions, syrups, emulsions or suspensions which are suitable for oral applications e.g. Contain 0.1 to 50 wt .-% of active ingredient. In topical applications in the form of solutions, gels, suspensions or the like, the active ingredient is preferably between 0.05 and 20% by weight of the preparation.

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 has to 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 used according to the invention can be given in the usual concentrations and preparations in animals together with the feed or with feed preparations or with the drinking water.

Furthermore, the compounds used according to the invention can be used excellently as bactericides, fungicides and herbicides in plants.

example

Antiprotozoal effect

The following substances are checked for their antiprotozoal activity: Substance 1: 2 - [(2-ethoxycarbonylphenoxy) carbonyl] - 1, 3, 2-dioxaphospholan-2-oxide Substance 2: 2 - [(2-ethoxycarbonylphenoxy) carbonyl] -4-dodecanoyloxymethyl-l, 3,2-dioxaphospholan-2-oxide

Substance 3: 2 - [(2-ethoxycarbonylphenoxy) carbonyl] -4-octanoylthiomethyl-l, 3,2-dioxaphospholan-2-oxide

Substance 4: 2 - [(2-ethoxycarbonylphenoxy) carbonyl] -4-dodecanoylthiomethyl-l, 3 ^* , 2-dioxaphospholan-2-oxide

Substance 5: 2-hydroxyethyl - [(2-ethoxycarbonylphenoxy) carbonyl] sodium phosphonate Substance 6: 2-dodecanoyloxy-2-hydroxypropyl [(2-ethoxycarbonylphenoxy) carbonyl] sodium phosphonate

Substance 7: 2-octanoylthio-2-hydroxypropyl [(2-ethoxycarbonyl Substance 8: 2-dodecanoylthio-2-hydroxypropyl [(2-ethoxycarbonylphenoxy) carbonyl] sodium phosphonate

Substance 9: sodium 2-hydroxy-l, 4,2-dioxaphosphorinane-2,3-dioxide Substance 10: sodium 2-hydroxy-5-dodecanoyloxymethyl-l, 4,2-dioxaphosphorinane-2,3-dioxide

Substance 11: Sodium 2-hydroxy-5-octanoylthiomethyl-l, 4,2-dioxaphosphorinane-2,3-dioxide

Substance 12: Sodium 2-hydroxy-5-dodecanoylthiomethyl-l, 4,2-dioxaphosphorinane-2,3-dioxide

The antimalarial activity of substances 1 to 12 was determined on in vitro cultures of the malaria pathogen Plasmodium falciparum. The wells of a 96-well microtiter plate were each loaded with 200 μl of an asynchronous Plasmodium falciparum culture with 0.4% parasitemia and 2% hematocrit. A serial dilution series of the compounds was then prepared in triplicate between concentrations of 100 to 0.14 μmol l ^"1. The plates are incubated at 37 ° C., 3% CO ₂ and 5% O ₂ for a period of 48 hours 30 μl of medium supplemented with 27 μCi ml of ^“1 [ ³ H] hypoxanthine were added to each well. After 24 hours of incubation, the parasites were harvested by filtration on glass fiber filters and the incorporated radioactivity was measured. Inhibition of parasite growth was measured as a percentage inhibition of tritium corporation. The inhibition of parasite growth was expressed as a percentage inhibition of tritium corporation based on a comparison without substance. The half-maximum inhibitory concentration (IC50) of the substance was determined by extrapolation of the values.

The results, ie the IC50 values, are shown in the table below: table

Claims

claims

1. Use of a compound of formula I.

in which Rπ is selected from the group consisting of C _1-2 6 alkyl residues, C _2- 26 alkenyl residues with 1 to 6 double bonds, C _2- 26 alkynyl residues with 1 to 6 triple bonds, d- ₂₆ - acyl residues, Ar -Co- ₂ 6-alkyl radicals, C _3- 8 -cycloalkyl-Co- ₂₆ -alkyl radicals, C _3-8 - heterocycloalkyl-C _0-2 6-alkyl radicals with one or two nitrogen, oxygen or sulfur atoms, halogen and OX _and exists, where all the aforementioned radicals can be substituted with C _1-9 alkyl, Ci ₉ alkoxy, hydroxy, amino, halogen or oxo groups, where Xπ is selected from the group consisting of hydrogen, d- 26- alkyl residues, C2-26- alkenyl residues with 1 to 6 double bonds, d ^ _ö alkynyl residues with 1 to 6 triple bonds, Ar-Co- ₂₆ alkyl residues, C _3-8 cycloalkyl residues, Cι- ₂ 6-acyl residues, C ₃ . ₈ - Heterocycloalkyl-Co- ₂ 6-alkyl radicals with one or two nitrogen, oxygen or sulfur atoms, Cι- ₂₆ silyl radicals, all the above radicals with C _1-9 alkyl, d-9 alkoxy, hydroxy, Amino, halogen or oxo groups can be substituted, and consists of 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 derived from ethylenediamine or amino acids ,

in which R _\ and R _{2 are} each independently selected from the group consisting of d-24-alkyl radicals, C _3-8 -cycloalkyl radicals, C _3-8 -cycloalkyl-d-2 ₄ -alkyl radicals, d-24-alkoxy radicals, d. ₂₄ alkylthio radicals, C ₁ . ₂₄ alkoxy-C ₁ . ₂₄ -alkyl radicals and C _1- 2 ₄ -alkylthio-C ₁ -2 ₄ -alkyl radicals, acyl radicals, Ar- (C _1-24 ) alkyl radicals, C ₃ . _8- Heterocyloalkyl- Co-24-alkyl radicals, halogen and hydrogen, and each d- ₂ 4-alkyl radical and d- ₂₄ -alkoxy radical may be branched or unbranched and saturated or unsaturated with 2 to 6 double bonds and optionally with hydroxy, amino -, mercapto, halogen, oxo groups or Ci- ₂₄ alkoxy, C _1-24 alkylcarbonyloxy, i. ₂₄ -alkoxycarbonyloxy radicals, C1-24- alkylthio radicals, C _1-24 -alkylcarbonylthio radicals, d- ₂₄ -alkylamino radicals, di- (C ₁ .2 - Alkyl) amino residues, d ^ -alkyl-carbonylamino residues, C _1- 2 ₄ -alkyl- (C _1-24 -alkylcarbonyl) - amino residues, C _1-24 -alkoxycarbonylamino residues or C ₁ .2 -alkyl- (C _{1. 24} -alkoxy- carbonyl) amino radicals may be substituted, each aralkyl radical, heterocyclic radical, d- _24- alkyl radical and d-2 ₄ -alkoxy radical being branched or unbranched and saturated or unsaturated with 2 to 6 double bonds or triple bonds, or in the Rj-CH -CH-R2 form part of a C ^ s carbon ring, which can be optionally with hydroxy, mercapto, amino, halogen, oxo groups or with C1-24 alkyl radicals, C ₁ - ₂ 4-alkoxy radicals,

C _1- 2 ₄ -alkylamino residues, di- (C _1-24 -alkyl) amino residues, Cι _-24 -alkylcarbonyl residues, C ₁ . ₂₄ -alkylcarbonyloxy, Cι _-24 -alkoxycarbonyl-, Cι _-24 -alkylcarbonylthioresten or Ci _-24 -alkylcarbonylamino, d- ₂₄ -alkyl- (d ^ -Alkylcarbony ^ amino radicals may be substituted, each C _1-24 -alkyl radical being branched or unbranched and may be saturated or unsaturated with 1 to 6 double bonds, or wherein R _{10. 4,} alkyl is a branched or unbranched d, and wherein R1-CH-CH-R2 part of the furanose or pyranose ring form of a sugar, for example D -Ribose, D-arabinose, D-xylose, D-lyxose, D-glucose, D-galactose, D-mannose, D-talose, D-allose, D-old rose, D-gulose, D-idose or the corresponding L - Isomers, the hydroxyl groups each optionally by hydrogen, amino, azido, oxo, mercapto or Cι-2 ₄ -alkoxy, d-2 ₄ -alkylthio, C ₁ .24- alkylamino, di- (C _1- 2 _4- alkyl) amino residues, C _1- 2 ₄ -alkylcarbonyloxy residues, C1.24-alkylcarbonylthio residues, C 1 _-2 -alkylcarbonylamino residues, C 1-24-alkyl- (C. _2Λ -alkylcarbonyl) am may be substituted, each d. ₂₄ -alkyl radical can be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds, and their pharmaceutically acceptable salts, esters and amides and salts of the esters and their optical isomers, for the prophylactic and therapeutic treatment of infectious processes in humans and animals, the caused by bacteria, fungi or parasites and as a fungicide, bactericide or herbicide in plants.

2. Use according to claim 1, characterized in that R 1 and R 2 are each independently selected from the group consisting of carboxyl radicals, carboxamido radicals, aryl radicals, aryloxycarbonyl radicals, aryl -CC-24-alkyl radicals, d-24-alkoxycarbonyloxy radicals, Ci. ₂₄ -alkylaminocarbonyl residues, di- (C ₁ -24-alkyl) -aminocarbonyl residues, aryl-d-24-alkoxycarbonyl residues, aryl-d- ₂ 4-alkylaminocarbonyl residues, d- ₂₄ -alkylcabonyloxy- (Cι- ₄ ) alkylmethoxycarbonyl residues, d ^ - Alkoxycarbonyloxymethoxycarbonylreste, Ci ₂₄ alkoxycarbonyloxy (C _1- alkyl) methoxycarbonyl, where each C ₁ -2 ₄ alkyl radical is branched or unbranched and saturated or unsaturated with 2 to 6 double bonds may be, and each C _1-4 alkyl and Cι-2 ₄ alkoxy group is branched or unbranched and may be saturated or unsaturated, and each aryl radical of the formula II

R ₃ and R »are identical or different and are each selected from the group consisting of hydrogen, halogen, C _1- alkyl radicals, d ^ alkoxy radicals, formyl, acetyl, propionyl, butyryl radicals, Formyl, acetyl, propionyl, butyryloxy, d-4-alkoxy carbonyl radicals, which can all be branched or unbranched, or R ₃ and R »together form an unbranched saturated alkylene chain with 3 to 4 carbon atoms, which are attached to neighboring Positions of the phenyl ring is bonded, or R ₃ and i together form a methylenedioxy radical, a 1,1-ethylenedioxy radical, a 1,1-ethylenedioxy radical, a 1,1-ethylenedioxy radical or a 1,2-ethylenedioxy radical which are located at adjacent positions of the phenyl ring are bound, or

3. Use according to claim 1, wherein R 1 and R _{2 are} each independently selected from the group consisting of hydrogen groups, acetyl groups, formyl groups, hydroxyl groups and methyl groups, the methyl radical optionally having a hydroxyl group or mercapto group or having C _1-24 alkoxy radicals , d.2 ₄ - alkylcarbonyloxy radicals,

or

may be substituted, wherein the d ^ alkyl groups and the d. ₂₄ alkoxy groups can be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds.

4. Use according to claim 3, wherein Ri is a methyl radical which can optionally be substituted by a hydroxyl group or mercapto group or by d- ₂₄ -alkoxy radicals, C1-24-alkylcarbonyloxy radicals, d ^ -alkylthio radicals or d- _24- alkylcarbonylthio radicals, wherein the d ^ alkyl groups and the d- ₂ alkoxy groups can be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds, and R2 is a hydrogen radical.

5. Use according to claim 1, wherein R 1 and R _{2 are} each independently selected from the group consisting of hydrogen and a “octadecylmethyl radical.

6. Use according to claim 5, wherein Ri is a w-octadecylmethyl radical and R _{2 is} a hydrogen radical.

7. Use according to any one of claim 6, wherein the compound has the (R) configuration.

8. Use according to one of the preceding claims for the treatment of infections caused by bacteria, fungi or single or multicellular parasites.

9. Use according to claim 8 for the treatment of infections caused by bacteria selected from the group consisting of bacteria from the Propionibacteriaceae family, in particular the Propionibacterium genus, in particular the Propionibacterium acnes species, bacteria from the Actinomycetaceae family, in particular the genus Actinomyces, bacteria of the genus Corynebacterium, in particular the species Corynebacterium diphteriae and Corynebacterium pseudotuberculosis, bacteria of the family Mycobacteriaceae, of the genus Mycobacterium, in particular the species Mycobacterium leprae, Mycobacterium tuberculiaium, mycobacteriaceae, Mycobacteria bamea, Mycobacteria bam - chomatis and Chlamydia psittaci, bacteria of the genus Listeria, in particular the species Listeria monocytogenes, bacteria of the species Erysipelthrix rhusiopathiae, bacteria of the genus Clostridium, bacteria of the genus Yersinia, of the species Yersinia pes tis, Yersinia pseudotuberculosis, Yersinia enterocolitica and Yersinia ruckeri, bacteria of the family Mycoplasmataceae, of the genera Mycoplasma and Ureaplasma, in particular the species Mycoplasma pneumoniae, bacteria of the genus Brucella, bacteria of the genus Bordetella, bacteria of the family Neisseriacellae, especially the Gattia in particular the species Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis, bacteria of the Vibrionaceae family, in particular the genera Vibrio, Aeromonas, Plesiomonas and Photobacterium, in particular the species Vibrio cholerae, Vibrio anguillarum and Aeromonas salmonicidas, bacteria of the genus Campylobacter, in particular the species Campylobacter, in particular the species Campylobacter , Campylobacter coli and Campylobacter fetus, bacteria of the genus Helicobacter, in particular the species Helicobacter pylori, bacteria of the families Spirochaetaceae and the Leptospiraceae, in particular the genera Treponema, Borrelia and Leptospira, in particular Borrel ia burgdorferi, bacteria of the genus Actinobacillus, bacteria of the family Legioneüaceae, of the genus Legionella, bacteria of the family Rickettsiaceae and family Bartonellaceae, bacteria of the genera Nocardia and Rhodococcus, bacteria of the genus Dermatophilus, bacteria of the family Pseudomonasattacungen, in particular der Pseudomonasattacungen and Xanthomonas. Bacteria of the Enterobacteriaceae family, particularly of the genera Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia and Shi- gella, bacteria of the Pasteurellaceae family, in particular of the genus Haemophilus, bacteria of the Micrococcaceae family, in particular of the genera Micrococcus and Staphylococcus, bacteria of the Streptococcaceae family, in particular of the Streptococcus and Enterococcus genera, and bacteria of the Bacillaceae family, in particular and the Bacillacium and genus species in Helicobacter eradication therapy for ulcers of the gastrointestinal tract.

10. Use according to claim 8 for the prevention and treatment of infections caused by unicellular parasites which are selected from the group consisting of pathogens of malaria, sleeping sickness, Chagas disease, toxoplasmosis, amoeba stirring, leishmaniasis, the Trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcolocystosis, acanthamoebosis, nail disease, coccidiosis, giardiosis and lambliosis.

11. A method for the treatment of infectious diseases caused by bacteria, fungi or parasites, in which a therapeutically effective amount of a compound according to any one of claims 1 to 7 is administered to a patient suffering from an infection caused by bacteria, fungi or parasites.