SK3932001A3 - USE OF ORGANOPHOSPHOROUS COMPOUNDS FOR PRODUCING MEDICAMENTS FORì (54) THE THERAPEUTIC AND PROPHYLACTIC TREATMENT OF INFECTIONS OR ASì (54) A FUNGICIDE, BACTERICIDE OR HERBICIDE FOR PLANTS - Google Patents

Abstract

The invention relates to the use of organophosphorous compounds of general formula (I) for producing medicaments for the therapeutic and prophylactic treatment of infections caused by viruses, bacteria, fungi and parasites, in humans and animals, and as a fungicide, bactericide and herbicide for plants.

Description

Technical field

The invention relates to the use of phosphororganic compounds, their salts, esters and amides for the manufacture of medicaments for the therapeutic and prophylactic treatment of infections caused by viruses, bacteria, fungi and parasites in humans and animals and their use as fungicide, bactericide and herbicide in plants. The phosphororganic compounds of the invention include phosphinoyl derivatives and phosphinic acid derivatives.

BACKGROUND OF THE INVENTION

There is a strong demand to enrich human and animal treatments, as well as to provide plant protection products that are not only potent, but versus other drugs, respectively. as a plant protection agent, they also exhibit fewer side effects and thus pose less of a health threat to humans.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION It is an object of the present invention to provide a substance which can be used universally in human, animal, viral, bacterial, fungal and parasitic infections and in plants such as fungicide, bactericide and herbicide and which satisfies the above conditions.

This task was surprisingly solved by a group of substances as defined in claim 1. This group of substances exhibits, as an anti-infective action against viruses, certain bacteria, fungi, 9 ··· Single and multicellular parasites as well as fungicidal, bactericidal and herbicidal activity in plants.

The phosphororganic compounds according to the invention correspond to the general formula I:

(D wherein R 1 and R 2 are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl , substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radicals, halogen, OX 1 and OX 2, wherein X 1 and X 2 may be the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted a heterocyclic radical,

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

R 3 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 · · · · · · · · · · · · · · · · · · · · · ·

9 9 9 • · · · · ·

9 9

9,9 and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic, halogen,

R 4 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, OX4, wherein X4 is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkyl, substituted and unsubstituted substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, substituted and unsubstituted silyl, organic cation and an inorganic base, in particular a metal of the first, second or third main group of the periodic system, ammonium, substituted ammonium and ammonium compounds, which are derived from ethylenediamine or amino acids, and their pharmaceutically acceptable salts, esters and amides and ester salts.

Particularly suitable are compounds which correspond to the following formula II:

OD taking

X1 is selected from the group consisting of hydrogen, substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radicals;

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ·

R ₂ , R-3, R 4 and A have the same meaning as in formula I.

A is particularly preferred as a chain of three carbon atoms that connects to the phosphorus atom with a nitrogen atom. The three-membered chain may be substituted.

Compounds of formula II are particularly preferred for R2 = acyl, especially formyl or acetyl, R3 = hydrogen, methyl or ethyl, R4 = hydrogen, methyl, ethyl or OX4 with X4 = hydrogen, sodium, potassium, methyl, ethyl, X1 = H and A = alkylene, alkenylene or hydroxyalkylene. Particularly good results are obtained when R2 = formyl or acetyl and A = propylene, propenylene or hydroxypropylene.

The following are specific features of the above definitions and suitable examples thereof:

Acyl is a substituent that is derived from an acid, such as an organic carboxylic acid, carbonic acid, carbamic acid, or an individual of the aforementioned corresponding thioacid or imidoacid, or an organic sulfonic acid, which acids include the corresponding aliphatic, aromatic and / or heterocyclic groups in molecule, as well as carbamoyl or carbamimidoyl. Suitable examples of these acyl groups are given below.

Aliphatic acyl groups are acyl residues derived from an aliphatic acid, including 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.);

Alkylcarbamoyl (e.g. methylcarbamoyl) Alkylcarbamoyl (e.g., methylcarbamoyl). etc.);

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

alkylcarbamimidoyl (e.g. methylcarbamimidoyl etc.);

oxalo;

alkoxalyl (e.g., methoxalyl, etoxalyl, propoxalyl, etc.).

In the above examples, for the aliphatic acyl groups, the aliphatic hydrocarbon moiety, in particular the alkyl group and the alkyl group, may be present. an alkane radical, in this case having 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 (acetoxy, benzoyloxy, etc.) and the like; preferred aliphatic acyl radicals with such substituents include alkanoyls substituted e.g. amino, carboxy, amino and carboxy, halogen, acylamino and the like.

Aromatic acyl radicals are those derived from an acid having a substituted or unsubstituted aryl group, wherein the aryl group may include phenyl, toluyl, xylyl, naphthyl, and the like; Suitable examples are as follows:

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

aralkanoyl (e.g. phenylacetyl, etc.);

aralkenoyl (e.g. cinnamoyl);

aryloxyalkanoyl (e.g. phenoxyacetyl etc.);

arylthioalkanoyl (e.g., phenylthioacetyl, etc.);

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

Arenesulfonyl (e.g., benzenesulfonyl, tosyl and benzenesulfonyl); 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 for aromatic acyl radicals, the aromatic hydrocarbon moiety (especially the aryl moiety) and / or the aliphatic hydrocarbon moiety (especially the alkane moiety) may optionally have one or more suitable substituents, such as have already been mentioned as suitable substituents for alkyl groups, respectively. alkane residue. Particularly and by way of example, preferred aromatic acyl radicals with particular substituents include halogen and hydroxy, or halogen and acyloxy substituted aroyl and hydroxy, hydroxyimino, dihaloalkanoyloxyimino substituted aralkanoyl such as arylthiocarbamoyl (e.g., phenylthiocarbamoyl, etc.);

arylcarbamimidoyl (e.g. phenylcarbamimidoyl, etc.).

A heterocyclic acyl radical is an acyl radical derived from an acid having a heterocyclic radical; here belongs:

heterocyclic carbonyl wherein the heterocyclic moiety is an aromatic or aliphatic 5- to 6-membered heterocycle having at least one heteroatom selected from nitrogen, oxygen and sulfur (e.g., thiophenyl, furoyl, pyrrolecarbonyl, nicotinoyl, etc.);

a heterocycle-alkanoyl in which the heterocyclic radical is 5- to 6-membered and has at least one nitrogen, oxygen and sulfur heteroatom (e.g.

thiophenylacetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetyl, etc.) and the like.

• · · · · · · · · · · · · · · · · · · ·

Ί · · · · · • • • • • • •

In the previous examples of heterocyclic acyl radicals, the heterocycle and / or the aliphatic hydrocarbon moiety may optionally have one or more suitable substituents, as previously described, as being suitable for the alkyl and alkyl groups respectively. alkane groups.

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

Hydroxyalkyl is a straight or branched chain alkyl radical of up to 9 carbon atoms having at least one hydroxyl group, preferably one or two hydroxy groups.

Alkenyl includes straight or branched chain alkenyl groups of up to 9 carbon atoms such as e.g. vinyl, propenyl, (e.g., 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl, hexenyl.

Alkynyl includes straight-chain or branched alkynyl groups of up to 9 carbon atoms.

Cycloalkyl is especially optionally substituted C 3 -C 7 cycloalkyl; as possible substituents are, inter alia, alkyl, alkenyl, alkynyl, alkoxy (e.g. methoxy, ethoxy, etc.), halogen (e.g. fluorine, chlorine, bromine, etc.), nitro and the like.

Aryl is an aromatic hydrocarbon residue such as phenyl, naphthyl, etc., which may optionally have one or more 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, wherein the aromatic moiety may optionally 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.

··········· · f · 9 · · ···· · · ···· · · ····

Alkylene includes straight or branched chain alkylene groups of up to 9 carbon atoms, which may be represented by the formula

- ( _Cn 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 and hexamethylene; preferred alkylene radicals have up to 4 carbon atoms, and especially those having 3 carbon atoms such as e.g. trimethylene. Hydrogen atoms can also be replaced by substituents such as halogen radicals.

Alkenylene includes straight or branched chain alkenyl groups of up to 9 carbon atoms, which may be represented by the formula

- ( _Cn H _2n . ₂ ) -, wherein n is an integer from 2 to 9, such as e.g. vinylene, propenylene (e.g., 1-propenylene, 2-propenylene), 1-methylpropenylene, 2-methylpropenylene, butenylene, 2-ethylpropenylene, pentenylene, hexenylene and the like; preferably, the alkenylene radical may preferably have up to 5 carbon atoms and in particular 3 carbon atoms such as e.g. 1-propenylene. Hydrogen atoms can also be replaced by substituents such as halogen radicals.

Hydroxyalkylene includes straight-chain or branched alkylene groups of up to 9 carbon atoms, wherein at least one selected hydrocarbon atom is substituted with hydroxy; these residues may be represented by the formula

- (C _n H _{2n. Z) (OH)} -, wherein n is an integer from 1 to 9 and z is an integer which benefit 1 <z <L. Suitable examples for such hydroxyalkylene groups include hydroxymethylene, hydroxyethylene (e.g., 1-hydroxyethylene and 2-hydroxyethylene), hydroxytrimethylene (e.g., 1-hydroxytrimethylene, 2-hydroxytrimethylene and 3-hydroxy-trimethylene), hydroxytetramethylene (e.g., 2-hydroxyytetramethylene). , 2-hydroxy-2-methyltri ·· ·

A 9a aa aa aa aa aa aa aa aa aa a a a a a a methylene, hydroxypentamethylene (2-hydroxypentamethylene), hydroxyhexamethylene (2-hydroxyhexamethylene) and the like. Particular preference is given to lower hydroxyalkylene of up to 4 carbon atoms and in particular to those having 3 carbon atoms such as e.g. 2-hydroxytrimetyIén. Hydrogen atoms can also be replaced by other substituents such as halogen radicals.

In particular, the X 4 moieties may be selected such that esters are formed on the phosphine moiety. Suitable examples for such esters of formulas I and II include alkyl esters (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hexyl, etc.);

aralkyl esters (benzyl, phenethyl, benzhydryl, trityl, etc.);

aryl esters (e.g., phenyl ester, tolyl ester, naphthyl ester, etc.);

aroylalkyl esters (e.g., phenacyl ester, etc.) and silyl esters (e.g., trialkyl halosilyl ester, dialkyldihalosilyl ester, alkyltrihalosilyl ester, dialkylarylhalo-silyl ester, trialkoxyhalo-silyl ester, dialkylaralkylhalo-silyl ester, dialkoxydisilyl ester, dialkoxydisilyl ester, dialkoxydisilyl ester, dialkoxydisilyl ester, dialkoxydisilyl ester).

In the above esters, the alkane and / or arene moiety may optionally have at least one suitable substituent such as halogen, alkoxy, hydroxy, nitro or the like.

X ₄ is preferably a metal of the first, second or third main group of the periodic system, ammonium, substituted ammonium and ammonium compounds which are derived from ethylenediamine or amino acids. That is, the salt compounds of the phosphororganic compounds with organic and inorganic bases (e.g., sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylamine salt, ethanolamine salt, dicyclohexylamine salt, ethylene salt) are formed. , a salt with Ν, Ν'-dibenzylethylenediamine, etc.) as well as salts with amino acids (e.g., arginine salt, aspartic acid salt, glutamic acid salt, etc.) and the like.

······························ · t · ·

The compounds according to the invention of formula I or II may exist in their protonated form as an 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.

The compounds used according to the invention of formulas I, II admit the existence of spatial isomers for example, containing double bonds or chiral groups R _t, R _2, R 3, R 4, X, X 2, X 4, and A use of a compound of the invention includes all spatial isomers both pure Individuals in the form of mixtures thereof.

In particular, the phosphororganic compounds are useful in humans and animals for the therapeutic and prophylactic treatment of infections caused by viruses, bacteria, single-cell and multi-cell parasites and fungi.

The compounds are effective against unicellular parasites (protozoa), in particular against agents of malaria and sleeping sickness, as well as Chagas disease, toxoplasmosis, amoebic dysentery, leishmaniases, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcocystosis, acantamebioscosis, laccamcellosis, naantamebosis, naantamebosis, naantamebosis, naegamcosis.

They are therefore particularly suitable for the prophylaxis of malaria and for the prophylaxis of sleeping sickness as well as Chagas' disease, toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcocystosis, acantamebosis, naeglerosis, coccidiosis, coccidiosis, coccidiosis, coccidiosis.

The active compounds according to the invention are particularly useful against the following bacteria;

bacteria of the family Propionibacteriaceae, in particular of the genus Propionibacterium, in particular of the species Propionibacterium acnes, bacteria of the family Actinomycetaceae, in particular of the genus Actinomyces, bacteria of the genus Corynebacterium, in particular the species Corynebacterium diphteriae and Corynebacterium · · · · · ·

II • Pseudotuberculosis, Mycobacteriaceae, Mycobacterium spp. Chlamydiaceae, in particular Chlamydia trachomatis and Chlamydia psiltaci, Listeria in particular Listeria monocytogenes, Erysipelthrix rhusiopathiae, Clostridium, Yersinia, Yersinia, Yersinia, Yersinia, Yersinia, Yersinia, Yersinia, Yersinia, Yersinia of the genera Mycoplasma and Ureoplasma, in particular Mycoplasma pneumoniae, Brucella, Bordetella, Campylobacter, in particular Campylobacter jejuni, Campylobacter coli and Campylobacter fetus, Helicobacter, in particular Heli cobacter pylori, Spirochaetaceae and Leptospiraceae, in particular Treponema, Borrelia and Leptospira, in particular Borrelia burgdorferi, Actinobacillus, Legionellaceae, Legionella, and Noctilia bacteria, Ricketiae family, Ricketiae, Ricketiae family.

Thus, phosphororganic compounds and derivatives thereof are useful in the treatment of diphtheria, Acne vulgaris, listeriosis, animal robins, gaseous sores in man and animal, human and animal paragonimosis, human and animal tuberculosis, leprosy and other mycobacteria in human and animal paraphernalia, animal, plague, mesentrial lymphadenitis and pseudotuberculosis in man and animal, cholera, legionnaires disease, human and animal borreliosis, human and animal leptospirosis, syphilis, Campylobacter enteritis in human and animal, Moraxella and animal conjunctivitis, animal and animal conjunctivitis, human, animal spleen, human and animal actinomycosis, streptotrichosis, psittacosis / ornithosis in animals, Q-fever and Ehrlichiosis.

It is also beneficial to use Helicobacter in the ulcer of the stomach and intestinal tract.

Combinations with another antibiotic may also be employed in the treatment of the above diseases. For combination preparations with the other e anti-infectives are suitable for use with antiinfectives. in particular isoniazid, rifampicin, etambutol, pyrazinamide, streptomycin, protonamide and dapson for the treatment of tuberculosis

The active compounds according to the invention can be used further in particular in infections with the following viruses:

Parvoviridae '. parvoviruses, dependoviruses, densoviruses, Adenoviridae. adenoviruses, mastadenoviruses, aviadenoviruses, Papovaviridae. papovaviruses, in particular papillomaviruses (so-called wart viruses), polyomaviruses, in particular JC-virus, BK-virus and miopapovaviruses, Herpesviridae '. all herpesviruses, especially Herpes-simplex-viruses, varicela / zoster-viruses, human cytomegalovirus, Epstein-Barr viruses, all human herpesviruses, human herpesvirus 6, human herpesvirus 7, human herpesvirus 8, Poxviridae ·. poxviruses, orthopox-, parapox-, molluscum-contagiosum-virus, aviviruses, capriviruses, leporipoxviruses; all primary hepatotropic viruses, hepatitis-viruses: hepatitis-A-viruses, hepatitis-B-viruses, hepatitis-C-viruses, hepatitis-D-viruses, hepatitis-E-viruses, hepatitis-F-viruses, hepatitis-G-viruses, Hepadnaviruses : all hepatitis viruses. Hepatitis-B-virus, hepatitis-D-viruses, Picornaviridae. picornaviruses, all enteroviruses, all polioviruses, all coxsackieviruses, all echoviruses, all rhinoviruses, hepatitis-A-virus, aftoviruses, Calciviridae. hepatitis-D-viruses, Reoviridae: reoviruses, orbiviruses, rotaviruses, Togaviridae '. togaviruses, alphaviruses, rubiviruses, pestiviruses, Rubellavirus, Flaviridae. flaviviruses, FSME-virus, hepatitis-C-virus, Orthomyxoviridae. all influenza viruses, Paramyxoviridae: paramyxoviruses, morbillivirus, pneumovirus, masernvirus, mumpsvirus, Rhabdoviridae: rhabdoviruses, rabiesvirus, lyssavirus, viscular stomatitisvirus, Coronaviridae '. coronaviruses, Bunyaviridae. bunyaviruses, nairovirus, phlebovirus, uucvirus, hantavirus, hantaanvirus, Arenaviridae '. arenaviruses, lymphocytic choriomeningitis-virus, Retrovindae: retroviruses, all HTL-viruses, human Tcell leukemia virus, oncornaviruses, spumaviruses, lentiviruses, all HI-viruses, Filoviridae. Marburg- and Ebola virus, slow virus infections, prions; oncoviruses, leukemia-viruses.

···························································· · · · · · · · Β ·

The phosphororganic compounds are thus suitable for preventing the following viral infections:

eradication of papilloma viruses for the prophylaxis of tumors, particularly genital tumors caused by papillomaviruses in humans. Eradication of JC-and BK-viruses, eradication of herpesviruses, eradication of human herpesviruses 8 for the treatment of Kaposi-sarcoma, eradication of cytomegalitic viruses prior to transplantation, eradication of Eppstein-Barr viruses prior to transplantation, and for the prophylaxis of tumor eruptions by hepatitis B diseases and for the prophylaxis of liver tumors and liver cirrhoses, eradication of coxsackieviruses in cardiomyopathies, eradication of coxsackieviruses in patients with diabetes mellitus, eradication of immunodeficiency viruses in humans and animals, treatment of concomitant infections in lapses , rhinitis, pharyngitis, bronchitis, pneumonia), sensory organs (keratoconjunctivitis), nervous system (poliomyelitis, meningoencephalitis, ence falitis, subacute sclerosing panencephalitis SSPE, progressive multifocal leukoencephalopathy, lymphocytic choriomeningitis of the stomach and intestinal tract (stomatitis, gingivostomatitis, esophagitis, gastritis, gastroenteritis, hepatocelitis, gastroenteritis) lymphadenitis), hematopoietic system, genital organs (mumpsorchitis), skin (warts, dermatitis, Herpes labialis, fever blisters, Herpes zoster, shingles), mucous membranes (papillomas, conjunctivapapilomas, artery, hyperplasia, dysplasia, dysplasia, dysplasia, dysplasia) myocarditis, endocarditis, pericarditis), kidney and urinary tract system, genital organs (anogenital lesions, warts, genital warts, congenital condylomas, dysplasias, papillomas, cervical dysplasias, condylomodys vilas, epidermis acuminata uciformis), locomotive organs (myositis, myalgia), treated foot-and-mouth fluids, Colorado-tick fever, Dengue-syndrome, hemorrhagic fever, early summer meningoencephalitis (FSME) and yellow fever.

······································ ·

The disclosed compounds, i. the phosphororganic compounds of the formulas I and II and their esters and amides on the phosphono- or phosphino group, as well as their salts, show potent cytotoxic activity against bacteria, fungi, viruses, monocellular and multicellular parasites, in particular malaria and sleeping sickness. Accordingly, the compounds of the invention are useful for the treatment of infectious diseases caused by viruses, bacteria, parasites and fungi in humans and animals. The compounds are also suitable for use in the prophylaxis of diseases caused by viruses, bacteria, parasites and fungi, in particular as a prophylaxis of malaria and a prophylaxis of sleeping sickness.

The phosphororganic compounds of the present invention, which generally include pharmaceutically acceptable salts, amides, esters, salts of such an ester, or even compounds which, when administered, provide the compounds of the present invention as metabolic or degradation products, also called prodrugs, can be prepared for administration by any suitable route. , analogous to a known anti-infectious agent (mixed with a non-toxic, pharmaceutically acceptable carrier).

Pharmaceutically acceptable salts of the compounds include those which the compounds of the formulas I and II form in their protonated form as an ammonium salt of inorganic or organic acids such as hydrochloric acid, sulfuric acid, citric acid, maleic acid, fumaric acid, tartaric acid, p acid. toluenesulfonic.

Pharmaceutically suitable are those salts formed by a suitable selection of X ₄ , such as sodium salt, potassium salt, calcium salt, ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt, and amino acid salts such as arginine salt, acid salt aspartic acid, glutamic acid salt.

The use of the above-mentioned substances is particularly suitable for the manufacture of medicaments against bacterial diseases or for their prophylaxis or for the production of herbicides.

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The activity of the substances is determined by a system of experiments. This system is based on measuring the inhibition of the growth of bacteria, parasites, viruses, fungi or plants in vitro. Experimental procedures are known to those skilled in the art.

For example, inhibition of malaria parasite growth in blood cultures is determined to determine anti-malarial activity.

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

The determination of antiviral activity consists in inhibiting the production of viral elements in cell cultures.

The determination of fungicidal activity consists in inhibiting the growth of fungi on the culture medium and in liquid cultures.

Some micro-organisms to be studied can only be studied in animal models. Then we will use the corresponding models here.

Substances exhibiting efficacy in in vitro measurement systems are studied further in in vivo models.

Antiparasitic, antiviral, fungicidal or antibacterial activities are further evaluated in animal models.

Screening of herbicidal activity is determined using an algae system and measuring isoprene emission of plants under standard conditions.

Pharmaceutically active compositions may be presented in unit dosage form. That is, the composition is available in the form of individual particles, e.g. coated tablets, capsules, pills, suppositories and ampoules, in which the active substance content corresponds to a fraction or more of a single dose. Dosage units may contain e.g. 1

2, 3 or 4 single doses or 1/2, 1/3 or 1/4 single dose.

A single dose contains, in particular, an amount of the active ingredient which, in turn, is administered in a single dose. It is given when administered, which usually corresponds to half or a third or a quarter of the daily dose.

Non-toxic, inert, pharmaceutically acceptable carrier materials are solid, semi-solid or liquid diluents, fillers, and formulation aids of any kind.

Tablets, dragees, capsules, pills, granules, lace, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays will also be mentioned as pharmaceutical preparations. Tablets, dragees, capsules, pills, and granules may contain the active ingredients in conventional carriers such as (a) fillers and extenders, e.g. starches, milk sugar, raw sugar, glucose, mannitol and silicic acid, (b) binders, e.g. carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, (c) humectants, e.g. (d) blowing agents e.g. agarcar, calcium carbonate, sodium carbonate, (e) solution retarders e.g. (f) resorption accelerators e.g. quaternary ammonium compounds; (g) wetting agents, e.g. cetyl alcohol, glycerol monostearate, (h) adsorbents, e.g. kaolin and bentonite; and (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethylene glycols, or mixtures of the substances mentioned under (a) to (i).

Tablets, dragees, capsules, pills, and granules may optionally be provided with coatings and shells containing opacifying agents, and may also be formulated to deliver the active ingredients only or preferentially in a certain part of the intestinal tract, optionally elongated, where polymeric materials may be used. substances and waxes.

F

Alternatively, the active ingredient (s) may also exist in microencapsulated form with one or more of the above carriers.

in

The suppositories may contain, in addition to the active ingredients, conventional, water-soluble or water-insoluble carriers, e.g. polyethylene glycols, fats, e.g. cocoa butter and higher esters (eg Cu-alcohol with Cie-fatty acid) or mixtures of these substances · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Ointments, pastes, creams and gels may contain, in addition to the active ingredients, conventional carriers, e.g. animal and vegetable fats, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays may contain, in addition to the active ingredient (s), conventional carriers, e.g. milk sugar, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures thereof. The sprays may additionally comprise conventional spray propellants e.g. chlorofluorocarbons.

The solutions and emulsions may contain, in addition to the active ingredients, conventional 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, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glyceral, glycerol, , tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters or mixtures thereof.

For parenteral administration, solutions and emulsions may also be available in sterile and blood-isotonic form.

The suspensions may contain, in addition to the active compounds, customary carriers such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, suspending agents e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitan esters and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures thereof.

Said formulation forms may also contain coloring agents, preservatives as well as flavor enhancers, e.g. peppermint oil and eucalyptus oil and sweeteners such as e.g. saccharin.

······························································· I · · · · · · ·

The active compounds of the formulas I and II are preferably to be present in the abovementioned pharmaceutical preparations in a concentration of from about 0.1 to 99.5% by weight, in particular from about 0.5 to 95% by weight of the total mixture.

In addition to the compounds of formulas I and II, the pharmaceutical preparations may also contain other pharmaceutically active substances.

The compounds can be used with the substances described to date with antibacterial, antiviral, antifungal and antiparasitic properties. These include in particular compounds which have already found use in therapy or are still in use. Particularly suitable for this are the substances which are mentioned together in Rote Liste or in Simon / Stille, Antibiotics-Therapy in Klinik und Praxis, 9th Ed. 1998, Schattauer Verlag or under httpVwww.customs.treas.gov/imp-exp/ruling/harmoniz/hrm 129.html on the Internet. In particular, they may be penicillin derivatives, benzylpenicillin (penicillin G), phenoxypenicillin, isoxazolylpenicillin, aminopenicillin, ampicillin, amoxixillin, bacampicillin, carboxypenicillin, ticarcillin, temocillin, acyalaminopenicillin, cephalecillin, cilecillin, , cefoxitin, cefoxitin, cefotethane, cefmetazole, latamoxef, flomoxef, cefotaxime, cefozidime, ceftazidime, ceftazidime, cefpirome, cefepime, other cephalosporins, cefsulodine, cefphorosporexes, oral cefoperorospine, oral , cefpodoxime-proxetil, cefuroxime-axetil, cefetamet, cefotiam-hexetil, cefdinir, ceftibuten, other blactam antibiotics, carbapenem, imipenem (cilastatin, meropenem, biapenem, aztreonam, b-lactulic acid / tlavicillinic acid / tlavicillinic acid / tlavicillinic acid / tlavicillinic acid / tlavicillin) They are l of Bacto / ampicillin, tazobactam / piperacillin, tetracycline, oxytetracycline, rolitetracycline, doxycycline, minocycline, chloramphenicol, aminoglycosides, gentamicin, tobramycin, netilmicin, amikacin, spektinomyxín, macrolides, erythromycin, clarithromycin, roxithromycin, azithromycin, dirithromycin, spiramycin, jozamycín, lincozamide, Clindamycin, Fusidinic Acid, Glycopeptide Antibiotics, Vancomycin, Ticoplanin, pristinamycin Derivatives, fosfomycin, Antimicrobial Folic Acid Antagonists, Sulphonamides, Co · Trimoxazole, trimethoprim, other combinations of diaminopyridine sulfonamide, nitrofurans, nitrofurantoin, nitrofurazone, gyrase inhibitors (quinolones), norfloxacin, ciprofloxacin, ofloxacin, sparfloxacin, enoxacin, fleroxacin, fleroxacin, pefoxacin, pefoxacin, pefoxacin, pefoxacin, pefoxacin, pefoxoxin , rifabutin, etambutol, pyrazines d, streptomycin, capreomycin, protonamide, terizidone, dapson, clofazimine, topical antibiotics, bacitracin, tyrotricin, polymyxins, neomycin, kanamycin, paromomycin, mupirocin, antiviral agents, acyclovir, gancicin, stavitabine, tidabitin, azitotyin, azitotyin, azitotyin, azitotyin, azidotyin, azidotyin idoxuridine, trifluridine, foscarnet, amantadine, interferons, tibol derivatives, proteinase inhibitors, antifungals, polyenes, amphotericin B, nystatin, natamycin, azoles, azoles for septic therapy, miconazole, ketoconazole, itraconazole, fluconazole, UK-109.496 administration, clotrimazole, econazole, isoconazole, oxiconazole, bifonazole, flucytosine, grizeofulvin, ciclopiroxolamine, tolnaphthate, naphthifine, terbinafine, amorolfine, anthraquinones, betulinic acid, semianthraquinones, xanthones, naphthoquinines, quinochine, choline, quinoline acridine, benzonaphthyridine, mepacrine, pyronaridine, daps he, sulfonamides, sulfadoxin, sulfalene, trimethoprim, proguanil, chloroproguanil, diaminopyrimidines, pyrimethamine, primaquine, aminoquinoline, WR 238,605, tetracycline, doxycycline, clindamycin, norfloxacin, ariprofloxinine, artemisone, artemisone, artemisone, artemisone, artemisone, artemisone, artemisone, artemisone, suramine, melarzoprol, nifurtmox, sodium stibogluconate, pentamidine, amphotericin B, metronidazole, clioquinol, mebendazole, niclozamide, praziquantel, pyrantel, tiabendazole, diethylcarbamazine, ivermectin, bitionol, oxamnichate, metrifinate, metrif.

Furthermore, the phosphororganic compounds in the pharmaceutical compositions may exist in combination with sulfonamide, sulfadoxin, artemizinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracycline, methoxylcyclazine, doxycyclilide, proxycyclazine, , diethylcarbazine, piperazine, pyrivine, fl 9 9 9 9 9 9 9 9 9 9 9 9 Metrifonate, oxamnichine, bitionol or suramine, or in combination with a plurality of such substances.

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

Said preparations can be used in humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally, locally (powders, ointments, drops) and for the treatment of infections in cavities and body cavities. Injectable solutions, solutions and suspensions for oral therapy, gels, poured formulations, emulsions, ointments or drops are suitable preparations. Ophthalmic and dermatological formulations, silver and other salts, ear drops, eye ointments, powders or solutions can be used for topical therapy. In animals, intake may also take place in suitable formulations in feed or drinking water. Gels, powders, powders, tablets, prolonged-action tablets, premixes, concentrates, granules, pellets, tablets, boluses, capsules, aerosols, sprays, inhalants can also be used in humans and animals. The compounds used according to the invention can be further incorporated into other carrier materials such as e.g. Synthetic materials (plastic chains for local therapy), collagen or bone cement.

In general, in both human and veterinary medicine, it has proven advantageous to administer the active compound (s) I and II in total amounts of from about 0.05 to about 600, in particular 0.5 to 200 mg / kg body weight, to achieve the desired results. for 24 hours, optionally in the form of multiple individual doses. A single dose contains the active compound (s) in particular in amounts of from about 1 to about 200, in particular from 1 to 60 mg / kg of body weight. However, it may be desirable to deviate from the indicated dosage, 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 drug being administered, as well as the time span and time. the interval within which administration takes place.

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Thus, in some cases it may be sufficient to suffice with less than the amount of active ingredient given above, while in other cases the amount of active ingredient must be exceeded. The precise determination of the optimum dosage just required and the method of application of the active ingredients can be made by the skilled person on the basis of his expert knowledge.

The compounds of the invention may be administered to animals in the usual concentrations and formulations together with feeding and / or feeding. feedingstuffs or drinking water.

Furthermore, the compounds of the invention can be used in an excellent manner as bactericides, fungicides and herbicides in plants.

Claims (14)

PATENT CLAIMS Use of phosphororganic compounds of formula I wherein R 1 and R ₂ are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted a. unsubstituted heterocyclic radical, halogen, OX ₁ and OX ₂ , wherein X 1 and X ₂ may be the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl , substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radicals, A is selected from the group consisting of alkylene, alkenylene and hydroxyalkylene, R? is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl, substituted and unsubstituted aryl, substituted and unsubstituted aryl, and substituted and unsubstituted aryl; Unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, R 4 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, OX ₄ , wherein X 4 is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted , substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radicals, silyl, cations of organic and inorganic bases, in particular 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 their pharmaceutically acceptable salts, esters and amides and ester salts, or even compounds which are used according to the invention provide as metabolic or degradation products for the manufacture of medicaments for the therapeutic and prophylactic treatment of infections caused by humans and animals caused by parasites, fungi, viruses and bacteria selected from the group consisting of bacteria of the family Propionibacteriaceae, in particular of the genus ·· · ··························································· I · Propionibacterium, in particular the species Propionibacterium acnes, bacteria of the family Actinomyceíaceae, especially the genus Actinomyces, bacteria of the genus Corynebacterium, particularly Corynebacterium diphtheriae and Corynebacterium pseudotuberculosis, bacteria of the family Mycobacteriaceae, genus Mycobacterium, in particular the second Mycobaclerium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium, bacteria Chlamydiaceae , in particular Chlamydia trachomatis and Chlamydia psittaci, Listeria in particular Listeria monocytogenes, Erysipelthrix rhusiopathiae, Clostridium, Yersinia, Yersinia pestis, Yersinia pseudotuberciaeriascia, Ureoplasma, especially Mycoplasma pneumoniae, Brucella, Bordetella, Campylobacter, especially Cam pylobacter jejuni, Campylobacter coli and Campylobacter fetus, Helicobacter spp., in particular Helicobacter pylori spp., Spirochaetaceae and Leptospiraceae spp., especially Treponema, Borrelia and Leptospira spp., especially Borrelia burgdorferi, Legion spp. and the family Bartonellaceae, bacteria of the genera Nocardia and Rhodococcus, bacteria of the genus Dermatophilus and as fungicide, bactericide and herbicide in plants. Use according to claim 1, characterized in that the phosphororganic compounds correspond to the formula II: · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ΧιΟ \ -Α R ₂ ^Z r ₃ FROM R4 taking X is selected from the group consisting of hydrogen, substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radicals; R 2, R 3, R a and A have the same meaning as in formula I. Use according to claim 2, characterized in that: R 2 is acyl, especially formyl or acetyl, R 3 is selected from the group consisting of hydrogen, methyl or ethyl, R 4 is selected from the group consisting of hydrogen, methyl, ethyl or OX ₄ , X 4 is selected from the group consisting of hydrogen, sodium, potassium, methyl and ethyl, X 1 is hydrogen and A is selected from the group consisting of alkylene, alkenylene or hydroxyalkylene. The use according to any one of the preceding claims, characterized in that the use is carried out in accordance with one of the preceding claims. ··· · · · ··· 9 · · 99 99 99 99 99 A forms a chain of three carbon atoms between the phosphorus atom and the nitrogen atom. Use according to claim 2, characterized in that X 4 is selected from the group consisting of hydrogen, ammonium and metals of the first and second main groups of the periodic system, in particular sodium, potassium, calcium or magnesium, ammonium compounds derived from ethylenediamine or amino acids, in particular ethanolamine, ethylenediamine, NN-dibenzylethylenediamine and arginine . Use according to any one of claims 2 to 5, characterized in that R ₂ is an acyl radical and A is an alkylene radical, wherein R ₂ is composed mainly of formyl and / or formyl. acetyl and A especially propylene, propenylene and hydroxypropylene. Use according to any one of the preceding claims for the manufacture of medicaments for the treatment of infections caused by bacteria, viruses, fungi or single-cell or multi-cell parasites. Use according to claim 7 for the manufacture of a medicament for the treatment of infections caused by bacteria selected from the group consisting of bacteria of the family Propionibacteriaceae, in particular of the genus Propionibacterium, in particular of the species Propionibacterium acnes, bacteria of the family Actinomycetaceae, in particular of the genus Actinomyces, pseudotuberculosis, bacteria of the family Mycobacteriaceae, of the genus Mycobacterium, in particular of the species Mycobacterium leprae, ··· · ··· · · · · · ··· · · · · · · ··· · 27 · Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium, bacteria of the family Chlamydiaceae, in particular Chlamydia trachomatis and Chlamydia psittaci, bacteria of the genus Listeria, in particular of the species Listeria monocytogenes. Use according to claim 7 for the manufacture of medicaments for the treatment of infections caused by viruses selected from the group consisting of viruses of the genus Parvoviridae, in particular parvoviruses, dependoviruses, densoviruses, viruses of the genus Adenoviridae, in particular adenoviruses, mastadenoviruses, especially aviadenoviruses, papillomaviruses (so-called wart viruses), polyomaviruses, in particular JC-virus, BK-virus and miopapovaviruses, viruses of the genus Herpesviridae, in particular Herpessimplex-viruses, varicela / zoster-viruses, human cytomegalovirus, human viruses 7, Epstein-Barr virus human herpesvirus 8, viruses of the genus Poxviridae, smallpox viruses, orthopox-, parapox-, molluscum-contagiosum-virus, aviviruses, capriviruses, leporipoxviruses; primary hepatotropic viruses, in particular hepatitis viruses such as hepatitis-A-viruses, hepatitis-B viruses, hepatitis-C-viruses, hepatitis-D-viruses, hepatitis-E-viruses, hepatitis-F-viruses, hepatitis-G-viruses, Hepadnaviruses, in particular all hepatitis viruses. Hepatitis-B-virus, hepatitis-D-viruses, viruses of the genus Picornaviridae, in particular picornaviruses, all enteroviruses, all polioviruses, all coxsackieviruses, all echoviruses, all rhinoviruses, hepatitis-A-virus, hepatitis-A-virus, aftoviruses, viritis virus, viruses, viruses of the genus Reoviridae, in particular reoviruses, orbiviruses, rotaviruses, viruses of the genus Togaviridae, in particular togaviruses, alphaviruses, rubiviruses, pestiviruses, Rubellaviruses, viruses of the genus Flaviridae, in particular flaviviruses, hepatitis viruses, FSME viruses, FSME viruses especially influenza viruses, genera viruses B · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Paramyxoviridae, especially paramyxoviruses, morbillivirus, pneumovirus, masernvírusu, mumps virus family Rhabdoviridae, rhabdo rabiesvírusov, Iyssavírusu, viskulárneho stomatitisvírusu, virus genus Coronaviridae, coronaviruses, viral family Bunyaviridae, especially Bunyavirus, Nairovirus, phleboviruses, Uukuvirus, hantavirus, hantanvírusu, viruses Arenaviridae, in particular arenaviruses, lymphocytic choriomeningitis virus, Retroviridae viruses, in particular retroviruses, all human T-cell leukemia virus, oncornaviruses, lentiviruses, all HI viruses, Filoviridae virus, Marburg and Ebo virus, Marburg and Ebo virus, ; oncoviruses and leukemia-viruses. HTL-viruses, spumaviruses, Use according to claim 7 for the manufacture of medicaments for the prophylaxis and treatment of infections caused by unicellular parasites, namely agents of malaria, sleeping sickness, Chagas' disease, toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis, pneumocystosis, balantidiosis, acantamosporebiosis, sptamosporebiosis , coccidiosis, giradiosis and lambliosis. Use according to any one of claims 1 to 10, characterized in that the medicament has an effective content of at least one phosphororganic compound and one pharmaceutically acceptable carrier. Use according to claim 11, characterized in that the medicament comprises at least one further pharmaceutical active substance. Use according to claim 12, characterized in that the medicament further comprises one or more of sulfonamide, one or more of the group consisting of a sulphonamide. Sulfadoxin, artemizinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracyclines, doxycycline, proguanil, metronidazole, praziquantil, niclozamide, mebendazole, pyrantel, thiabendazole, diethylcarbazine, piperazine, pyrivine, metrifonate, oxamnichine, bitionol or suram. Use according to claim 12, characterized by one or more of penicillins, benzylpenicillin (penicillin G), phenoxypenicillin, isoxazolylpenicillin, aminopenicillin, ampicillin, amoxixillin, bacampicillin, carboxypenicillin, ticarcillin, azinloilliniline, temocilliniline, temocloilliniline, temocloilliniline, temocloilliniline, temocloilliniline. piperacillin, apalcillin, mecillin, cephalosporins, cefazoline group, ceftaosporins, ceftaosporins, ceftaosporins, ceftaosporins, ceftaosporins, ceftaosporins, ceftaosporins, cefalexin, loracarbef, cefprozil, the new extended spectrum oralcephalosporins, cefixime, cefpodoxime-proxetil, cefuroxime-axetil, cefetamet, cefotiam-hexetil, cefdinir, ceftibuten, other b-lactam antibiotics, impenem, a β-lactamase inhibitor , clavulanic acid / amoxicillin, clavulanic acid / ticarcillin, sulbactam / ampicillin, tazobactam / piperacillin, tetracyclines, oxytetracycline, rolitetracycline, doxycycline, minocycline, chloramphenicol, aminoglycine, nincinine, gentamicin, nicotinicin, gentamicin, , azithromycin, dirithromycin, spiramycin, josamycin, lincozamide, clindamycin, fusidinic acid, glycopeptide antibiotics, vancomycin, ticoplanin, pristinamycin derivatives, fosfomycin, antimicrobial folic acid antagonists, nitrophosphinamides, sulfonamide oxides, sulfonamide oxides, sulfonamide, others , nitrofurazone, gyrase inhibitors (quinolones), norfloxacin, ciprofloxacin, ofloxacin, sparfloxacin, enoxacin, fleroxacin, pefloxacin, ··· ··· · · · · · · · · · • · ···· · · ···· · · · · Lomefloxacin, Bay ¥ 3118, nitroimidazoles, antimycobacterial agents, isoniazid, rifampicin, rifabutin, etambutol, pyrazinamide, streptomycin, capreomycin, protonamide, terizidone, dapson, local, clofazimine, clofazimine, clofazimine, clofazimine, clofazimine, clofazimine polymyxins, neomycin, kanamycin, paromomycin, mupirocin, antiviral agents, acyclovir, ganciclovir, azidothymidine, didanosine, zalcitabine, tiacytidine, stavudine, ribavirin, idoxuridine, trifluridine, antifungal agents, amphibine, amantibine, amantibine, amantadine, amantadine, , nystatin, natamycin, azoles, azoles for septic therapy, miconazole, ketoconazole, itraconazole, fluconazole, UK-109,496, topical azoles, clotrimazole, econazole, isoconazole, oxiconazole, bifonazole, flucytosine, grizeofulvinine, ciclopi tinbine, ticlopi tinbine, ticlopiroxine , amorolfine, anthraquinones, betulinic acid, semi-anthraquinones, xanthones, naphtha quinones, arylaminoalcohols, quinine, quinidines, mefloquine, halofantrine, chloroquine, amodiaquine, acridine, benzonaphthyridine, mepacrine, pyronaridine, dapson, sulfonamides, sulfadoxin, sulfalene, trimethoprim, proguanil, priminimine, chloropropoline, quinopyridine, chloropropamine, quinoline , doxycycline, clindamycin, norfloxacin, ciprofloxacin, ofloxacin, artemizinin, dihydroartemizinin, 10b artemeter, arteether, atreszunate, atovaquone, suramine, melarzoprol, nifurtmox, sodium stibogluconine, propyl stinogluconin, pentamidine, pentamidine, thiabendazole, diethylcarbamazine, ivermectin, bitionol, oxamnichine, metrifonate, piperazine, embonate.