OA11655A

OA11655A - Use of organophosphorous compounds for producing medicaments for the therapeutic and prophylactic treatment of infections or as a fungicide, bactericide or herbicide for plants.

Info

Publication number: OA11655A
Application number: OA1200100073A
Authority: OA
Inventors: Hassan Jomaa
Original assignee: Jomaa Pharmaka Gmbh
Priority date: 1998-09-22
Filing date: 1999-09-22
Publication date: 2004-12-08
Also published as: CA2344867A1; NO20011430D0; SK3932001A3; DE19843222A1; AP2001002106A0; NO20011430L; WO2000016757A8; IL141887A0; ZA200101912B; PL353313A1; CN1319006A; JP2003520760A; WO2000016757A2; AU5981199A; EP1115388A1; KR20010075248A; BR9913990A

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

-1- 011655 ♦

This invention relates to the use of organophosphorus compounds and the salts, esters and amides thereof for the production of pharmaceutical préparations for the therapeutic and prophylactic treatment of infections in humans and animais caused by viruses, bacteria, fungi and parasites, and to the use thereof as a fungicide, bactéricide 5 and herbicide in plants. According to the invention, the organophosphorus compoundscomprise phosphinoyl dérivatives and phosphinic acid dérivatives.

In order to widen the range of options for treating humans and animais and forprotecting plants, there is an urgent requirement to provide agents which are not onlyhighly active but, unlike other pharmaceutical préparations or phytosanitary agents, 10 also exhibit reduced side-effects and thus constitute a reduced risk to human health.

The object of the présent invention is accordingly to provide a substance which isusable in infections by viruses, bacteria, fungi and parasites in humans and animaisand as a fungicide, bactéricide and herbicide in plants and which meets the above-stated requirements. 15 This object is utterly surprisingly achieved by the group of substances defined in claim 1. This group of substances exhibits both an antiinfective action against viruses,certain bacteria, fungi. uni- and multicellular parasites and a fungicidal, bactericidaland herbicidal action in plants.

The organophosphorus compounds used according to the invention are of the general 20 formula (I): -2- 011655 ο

R1 I

\ I N- A - P - R3 (I) r; r4 in which Ri and R2 are identical or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted andunsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstitutedacyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl,substituted and unsubstituted heterocyclic residue, halogen, OXi and OX2,wherein Xi and X2 may be identical or different and are selected from the groupconsisting of hydrogen, substituted and unsubstituted alkyl, substituted andunsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted andunsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstitutedacyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl,substituted and unsubstituted heterocyclic residue, A is selected from the group consisting of an alkylene residue, an alkenyl residue anda hydroxyalkylene residue, R3 is selected from the group consisting of hydrogen, substituted and unsubstitutedalkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl,substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substitutedand unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted andunsubstituted cycloalkyl, substituted and unsubstituted heterocyclic residue, halogen, R4 is selected from the group consisting of hydrogen, substituted and unsubstitutedalkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl,substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substitutedand unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted andunsubstituted cycloalkyl, substituted and unsubstituted heterocyclic residue, halogen, OX4, wherein X4 is selected from the group consisting of hydrogen, substituted andunsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and 011655 -3 - unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstitutedalkenyl, substituted and unsubstituted alkynyl, substituted and unsubstitutedcycloalkyl, substituted and unsubstituted heterocyclic residue, a substituted orunsubstituted silyl, a cation of an organic and inorganic base, in particular of a métalof main group I, II or III of the periodic System, ammonium, substituted ammoniumand ammonium compounds which are derived from ethylenediamine or amino acids,and pharmaceutically acceptable salts, esters and amides and salts of the esters.

Suitable compounds are in particular those of the formula (II) below:

O

wherein

Xi is selected from the group consisting of hydrogen, substituted or unsubstitutedacyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substitutedor unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclic residue;

Ri. R3, R4 and A hâve the same meaning as in formula (I).

Particularly preferably, A is a chain of three carbon atoms which joins the nitrogenatom to the phosphorus atom. The three-membered chain may be substituted.

In particular, preferred compounds of the formula (II) are those in which R2 = acyl, inparticular a formyl or acetvl, R3 = hydrogen, methyl or ethyl, R4 - hydrogen, methyl,ethyl or OX4 where X4 = hydrogen, sodium, potassium, methyl, ethyl, Xi = H and A =alkylene, alkenylene or hydroxyalkylene. Particularly good results are achieved withRi = formyl or acetyl and A - propylene, propenylene or hydroxypropylene.

Spécial features of the above définitions and suitable examples thereof are statedbelow: -4- 011655 "Acyl" is a substituent which originates from an acid, such as from an organiccarboxylic acid, carbonic acid, carbamic acid or the thioacid or imidic acid ·corresponding to the individual above-stated acids, or from an organic sulfonic acid,wherein these acids may in each case comprise aliphatic, aromatic and/or heterocyclicgroups in the molécule, as well as carbamoyl or carbamimidoyl.

Suitable examples of these acyl groups are stated below.

Aliphatic acyl groups are deemed to comprise acyl residues originating from analiphatic acid, such groups including the following: alkanoyl (for example formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaloyl etc.); alkenoyl (for example acryloyl, methacryloyl, crotonoyl etc.); alkylthioalkanoyl (for example methylthioacetyl, ethylthioacetyl etc.)·, alkanesulfonyl (for example mesyl, ethanesulfonyl, propanesulfonyl etc.)·,alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl etc.); alkylcarbamoyl (for example methylcarbamoyl etc.); (N-alkyl)thiocarbamoyl (for example (N-methyl)thiocarbamoyl etc.); alkylcarbamimidoyl (for example methylcarbamimidoyl etc.); oxalo; alkoxalyl (for example methoxalyl, ethoxalyl, propoxalyl etc.).

In the above examples of aliphatic acyl groups, the aliphatic hydrocarbon moiety, inparticular the alkyl group or alkane residue, may optionally comprise one or moresuitable substituents, such as amino, halogen (for example fluorine, chlorine, bromineetc.), hydroxy, hydroxyimino, carboxy, alkoxy (for example methoxy, ethoxy,propoxy etc.), alkoxycarbonyl, acylamino (for example benzyloxycarbonylaminoetc.), acyloxy (for example acetoxy, benzyloxy etc.) and the like; preferred aliphaticacyl residues having such substituents which may be mentioned are alkanoyls 011655 -5- substituted, for example, with amino, carboxy, amino and carboxy, halogen, acylamino or the like.

Aromatic acyl residues are deemed to comprise those acyl residue which originatefrom an acid with a substituted or unsubstituted aryl group, wherein the aryl groupmay comprise phenyl, toluyl, xylyl, naphthyl and the like; suitable examples are statedbelow: aroyl (for example benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl etc.); aralkanoyl (for example phenylacetyl etc.); aralkenoyl (for example cinnamoyl etc.); aryloxyalkanoyl (for example phenoxyacetyl etc.); arylthioalkanoyl (for example phenylthioacetyl etc.); arvlaminoalkanoyl (for example N-phenylglycyl etc.); arenesulfonyl (for example benzenesulfonyl, tosyl or toluenesulfonyl, naphthalene-sulfonyl etc.); aryloxycarbonyl (for example phenoxycarbonyl, naphthyloxycarbonyl etc.);aralkoxycarbonyl (for example benzyloxycarbonyl etc. );arylcarbamoyl (for example phenylcarbamoyl, naphthylcarbamoyl etc.);arvlglyoxyloyl (for example phenylglyoxyloyl etc.).

In the above examples of acyl residues, the aromatic hydrocarbon moiety (inparticular the aryl residue) and/or the aliphatic hydrocarbon moiety (in particular thealkane residue) may optionally comprise one or more suitable substituents, such asthose which hâve already been stated as suitable substituents for the alkyl group or thealkane residue. Aromatic acyl residues having particular substituents which may inparticular be mentioned and constitute examples of preferred aromatic acyl residuesare aroyl substituted with halogen and hydroxy or with halogen and acyloxy, andaralkanoyl substituted with hydroxy, hydroxyimino, dihaloalkanoyloxyimino,together with arylthiocarbamoyl (for example phenylthiocarbamoyl etc.);arylcarbamimidoyl (for example phenylcarbamimidoyl etc.). -6- 011655 A heterocyclic acyl residue is taken to mean an acyl residue which originates from an acid with a heterocyclic group; these include: heterocyclic carbonyl, in which the heterocyclic residue is an aromatic or aliphatic 5-to 6-membered heterocycle with at least one heteroatom from the group comprisingnitrogen, oxygen and sulfur (for example thiophenyl, furoyl, pyrrolocarbonyl,nicotinoyl etc.); alkanoyl heterocycle, in which the heterocyclic residue is 5- to 6-membered andcomprises at least one heteroatom from the group comprising nitrogen, oxygen andsulfur (for example thiophenylacetyl, furylacetyl, imidazolylpropionyl, tetrazolyl-acetyl, 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl etc.) and the like.

In the above examples of heterocyclic acyl residues, the heterocycle and/or thealiphatic hydrocarbon moiety may optionally comprise one or more suitablesubstituents, such as those as hâve been stated to be suitable for alkyl and alkanegroups. "Alkyl" is a straight- or branched-chain alkyl residue with up to 9 carbon atoms, suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl and thelike. "Hydroxyalkyl" is a straight- or branched-chain alkyl residue with up to 9 carbonatoms which comprises at least one hydroxyl group, preferably one or two hydroxylgroups. "Alkenyl" includes straight- or branched-chain alkenyl groups with up to 9 carbonatoms, such as for example vinyl, propenyl (for example 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl, hexenyl. "Alkynyl" includes linear- or branched-chain alkynyl groups with up to 9 carbonatoms. -7- 011655

Cycloalkyl preferably dénotés an optionally substituted C3-C7 cycloalkyl; possiblysuitable substituents are inter alia alkyl, alkenyl, alkynyl, alkoxy (for examplemethoxy, ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.), nitroand the like.

Aryl is an aromatic hydrocarbon residue, such as phenyl, naphthyl etc., which mayoptionally comprise one or more suitable substituents, such as alkyl, alkenyl, alkynyl,alkoxy (for example methoxy, ethoxy etc.), halogen (for example fluorine, chlorine,bromine etc.), nitro and the like. "Aralkyl" includes mono-, di- and triphenylalkyls, such as benzyl, phenethyl,benzhydryl, trityl and the like, wherein the aromatic moiety may optionally compriseone or more suitable substituents, such as alkoxy (for example methoxy, ethoxy etc.),halogen (for example fluorine, chlorine, bromine etc. ), nitro and the like. "Alkylene" includes straight- or branched-chain alkylene groups which comprise upto 9 carbon atoms and may be represented by the formula -(CnH2n)- in which n is an integer from 1 to 9, such as methylene, ethylene, trimethylene,methylethylene, tetramethylene, 1 -methyltrimethylene, 2-ethylethylene, pentamethy-lene, 2-methyltetramethylene, isopropylethylene, hexamethylene and the like;preferred alkylene residues hâve up to 4 carbon atoms and particularly preferredresidues are those with 3 carbon atoms, such as for example trimethylene. Thehydrogen atoms may be replaced by other substituents, such as for example halogenresidues. "Alkenylene" includes straight- or branched-chain alkenylene groups with up to 9 carbon atoms, which may be represented by the formula -8- 011655 -(C„H2n.2)- in which n is an integer from 2 to 9, such as for example vinylene, propenylene (forexample 1-propenylene, 2-propenylene), 1-methylpropenylene, 2-methylpropenylene,butenylene, 2-ethylpropenylene, pentenylene, hexenylene and the like; the alkenyleneresidue may particularly preferably comprise up to 5 carbon atoms and, in particular, 3 carbon atoms, such as for example 1-propenylene. The hydrogen atoms may bereplaced by other substituents, such as for example halogen residues. "Hydroxyalkylene" may include straight- or branched-chain alkylene residues whichcomprise up to 9 carbon atoms, wherein at least one selected carbon atom issubstituted with a hydroxy group; these residues may be represented by the formula -(CnH2n.z)(OH)z- in which n is an integer from 1 to 9 and z is an integer to which the relation 1 < z < napplies. Suitable examples of such hydroxyalkylene groups include hydroxy-methylene, hydroxyethylene (for example 1 -hydroxyethylene and 2-hydroxy-ethylene), hydroxytrimethylene (for example 1-hydroxytrimethylene, 2-hydroxy-trimethylene and 3-hydroxytrimethylene), hydroxytetramethylene (for example 2-hydroxytetramethylene), 2-hydroxy-2-methyltrimethylene, hydroxypentamethylene(for example 2-hydroxypentamethylene), hydroxyhexamethylene (for example 2-hydroxyhexamethylene) and the like. A lower hydroxyalkylene comprising up to 4carbon atoms is particularly preferred and in particular such a compound comprising 3carbon atoms, such as for example 2-hydroxytrimethylene. The hydrogen atoms maybe replaced by other substituents, such as for example halogen residues.

The residue X4 may preferably be selected such that esters are formed on thephosphino group. Suitable examples of such esters of the formulae (I) and (II) includealkyl esters (for example methyl esters, ethyl esters, propyl esters, isopropyl esters,butyl esters, isobutyl esters, hexyl esters etc.y, -9- 011655 aralkyl esters (benzyl esters, phenylethyl esters, benzhydryl esters, trityl esters etc.); aryl esters (for example phenyl esters, tolyl esters, naphthyl esters etc.); aroylalkylesters (for example phenacyl esters etc.); and silyl esters (for example oftrialkylhalosilyl, dialkyldihalosilyl, alkyltrihalosilyl, dialkylarylhalosilyl,trialkoxyhalosilyl, dialkylaralkylhalosilyl, dialkoxydihalosilyl, trialkoxyhalosilyl etc.)and the like.

In the above esters, the alkane and/or arene moiety may optionally comprise at leastone suitable substituent, such as halogen, alkoxy, hydroxy, nitro or the like. X4 is preferably a métal of main group I, II or III of the periodic System, ammonium,substituted ammonium or ammonium compounds which are derived firomethylenediamine or amino acids. In other words, the sait compounds of theorganophosphorus compounds are formed with organic or inorganic bases (forexample sodium sait, potassium sait, calcium sait, aluminium sait, ammonium sait,magnésium sait, triethylamine sait, ethanolamine sait, dicyclohexylamine sait,eihvlenediamine sait, N.N'-dibenzylethylenediamine sait etc.) as are salts with aminoacids (for example arginine sait, aspartic acid sait, glutamic acid sait etc.) and the like.

The compounds of the formula (I) or (II) used according to the invention may assumethe protonated form thereof as an ammonium sait of organic or inorganic acids, suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonicacid, p-toluenesulfonic acid, acetic acid, lactic acid, maleic acid, fumaric acid, oxalicacid, tartaric acid, benzoic acid etc..

The compounds of the formula (I) or (II) used according to the invention permit theoccurrence spatial isomers, for example for double bond-containing or chiral groupsRi, R2, R3, R4, Xi, X2, Xa or A. The use according to the invention of the compoundsincludes ail spatial isomers, both as pure substances and in the form of mixturesthereof. - 10- 011655

The organophosphorus compounds are in particular suitable for the therapeutic andprophylactic treatment of human and animal infections which are caused by viruses,bacteria, uni- and multicellular parasites and fungi.

The compounds are active against unicellular parasites (protozoa), in particularagainst the causative organisms of malaria and sleeping sickness and of Chagas'disease, toxoplasmosis, amoebic dysentery, leishmaniases, trichomoniasis,pneumocystosis, balantidiasis, cryptosporidiosis, sarcocytosis, acanthamoebosis,naeglerosis, coccidiosis, giardiasis and lambliasis.

They are accordingly in particular suitable for the prophylactic treatment of malariaand of sleeping sickness and of Chagas' disease, of toxoplasmosis, amoebic dysentery,leishmaniases, trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiosis,sarcocytosis, acanthamoebosis, naeglerosis, coccidiosis, giardiasis and lambliasis.

The active substances according to the invention may in particular be used against thefollowing bacteria: bacteria of the family Propionibacteriaceae, in particular of the genus Propioni-bacterium, in particular the species Propionibacterium acnés, bacteria of the familyActinomycetaceae, in particular of the gémis Actinomyces, bacteria of the genusCornynebacterium, in particular the species Corynebacterium diphtheriae andCorynebacterium pseudotuberculosis, bacteria of the family Mycobacteriaceae, of thegenus Mycobacterium, in particular the species Mycobacterium leprüe,Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium,bacteria of the family Chlamydiaceae, in particular the species Chlamydiatrachomatis and Chlamydia psittaci, bacteria of the genus Listeria, in particular thespecies Listeria monocytogenes, bacteria of the species Erysipelthrix rhusiopathiae,bacteria of the genus Clostridium, bacteria of the genus Yersinia, the species Yersiniapestis, Yersinia pseudotuberculosis, Yersinia enterocolitica and Yersinia ruckeri,bacteria of the family Mycoplasmataceae, of the généra Mycoplasma andUreaplasma, in particular the species Mycoplasma pneumoniae, bacteria of the genus - 11 - 011655

Brucella, bacteria of the genus Bordetella, bacteria of the genus Campylobacter, inparticular the species Campylobacter jejuni, Campylobacter coli and Campylobacterfétus, bacteria of the genus Hélicobacter, in particular the species Hélicobacter pylori,bacteria of the families Spirochaetaceae and Leptospiraceae, in particular the généraTreponema, Borrelia and Leptospira, in particular Borrelia burgdorferi, bacteria ofthe genus Actinobacillus, bacteria of the family Legionellaceae, of the genusLégionella, bacteria of the family Rickettsiaceae and the family Bartonellaceae,bacteria of the généra Nocardia and Rhodococcus and bacteria of the genusDermatophilus.

Organophosphorus compounds and the dérivatives thereof are consequently suitablefor treating diphtheria, acné vulgaris, listérioses, swine erysipelas in animais, gasgangrené in humans and animais, malignant oedema in humans and animais,tuberculosis in humans and animais, leprosy and further mycobacterioses in humansand animais, paratuberculosis in animais, plague, mesenterial lymphadenitis andpseudotuberculosis in humans and animais, choiera, légionnaires' disease, borreliosisin humans and animais, leptospiroses in humans and animais, syphilis,

Campylobacter enteritis infections in humans and animais, Moraxellakeratoconjunctivitis and serositis in animais, brucellosis of animais and humans,anthrax in humans and animais, actinomycosis in humans and animais,streptotrichoses, psittacosis/ortnithosis in animais, Q fever, ehrlichiosis.

Use is furthermore effective in the éradication of Hélicobacter in ulcers of thesastrointestinal tract.

Combinations with another antibiotic may also be used to treat the above-stateddiseases. Isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, protionamideand dapsone are in particular suitable for combination préparations with otherantiinfective agents for the treatment of tuberculosis.

The active substances according to the invention are furthermore usable in infectionswith the following viruses: - 12- 011655

Parvoviridae·. parvoviruses, dependoviruses, densoviruses, Adenoviridae·.adenoviruses, mastadenoviruses, aviadenoviruses, Papovaviridae·. papovaviruses, inparticular papillomaviruses ("wart" viruses), polyomaviruses, in particular JC virus,BK virus and miopapovaviruses, Herpesviridae·. ail herpesviruses, in particular herpessimplex viruses, varicella-zoster viruses, human cytomégalovirus, Epstein-Barrviruses, ail human herpesviruses, human herpesvirus 6, human herpesvirus 7, humanherpesvirus 8, Poxiviridae·. poxviruses, orthopoxviruses, parapoxviruses, molluscumcontagiosum virus, aviviruses, capriviruses, leporipoxviruses, ail primarilyhepatotropic viruses, hepatitisviruses: hepatitis A viruses, hepatitis B viruses, hepatitisC viruses, hepatitis D viruses, hepatitis E viruses, hepatitis F viruses, hepatitis Gviruses, hepadnaviruses: ail hepatitisviruses, hepatitis B virus, hepatitis D viruses,Picornaviridae'. picomaviruses, ail enteroviruses, ail polio viruses, ail coxsackie-viruses, ail echoviruses, ail rhinoviruses, hepatitis A virus, aphthoviruses,Calciviridae: hepatitis E viruses, Reoviridae·. reoviruses, orbiviruses, rotaviruses,Togaviridae: togaviruses, alphaviruses, rubiviruses, pestiviruses, rubellavirus,Flaviviridae·. flaviviruses, FSME virus, hepatitis C virus, Orthomyxoviridae'. ailinfluenza viruses, Paramyxoviridae·. paramyxoviruses, morbillivirus, pneumovirus,measles virus, mumps virus, Rhabdoviridae·. rhabdoviruses, rabies virus, lyssavirus,vascular stomatitisvirus, Coronaviridae·. coronaviruses, Bunyaviridae·. bunyaviruses,nairovirus, phlebovirus, uukuvirus, hantavirus, hantaan virus, Arenaviridae·.arenaviruses, lymphocytic choriomeningitis virus, Retroviridae·. retroviruses, ail HTLviruses, human T-cell leukaemia virus, oncomaviruses, spumaviruses, lentiviruses, ailHI viruses, Filoviridae·. Marburg and Ebola virus, slow-virus infections, prions,oncoviruses and leukaemia viruses.

The organophosphorus compounds used according to the invention are consequentlysuitable for combating the following viral infections: éradication of papillomaviruses to prevent tumours, in particular tumours of thereproductive organs caused by papillomaviruses in humans, éradication of JC virusesand BK viruses, éradication of herpesviruses, éradication of human herpesvirus 8 totreat Kaposi's sarcoma, éradication of cytomegaloviruses before transplantations, -13- 011655 éradication of Epstein-Barr viruses before transplantation and to prevent tumoursassociated with Epstein-Barr viruses, éradication of hepatitis viruses to treat chronicliver disease and to prevent liver tumours and cirrhosis of the liver, éradication ofcoxsackieviruses in cardiomyopathy, éradication of coxsackieviruses in diabètesmellitus patients, éradication of immunodeficiency viruses in humans and animais,treatment of accompanying infections in AIDS patients, treatment of respiratory tractinflammation of viral causation (laryngeal papilloma, hyperplasia, rhinitis,pharyngitis, bronchitis, pneumonia), of the sensory organs (keratoconjunctivitis), ofthe nervous System (poliomyelitis, meningoencephalitis, encephalitis, subacutesclerosing panencephalitis, SSPE, progressive multifocal leukoencephalopathy,lymphocytic choriomeningitis), of the gastrointestinal tract (stomatitis,gingivostomatitis, oesophagitis, gastritis, gastroenteritis, diarrhoea), of the liver andgall System (hepatitis, cholangitis, hepatocellular carcinoma), of the lymphatic tissue(mononucleosis, lymphadenitis), of the haemopoietic System, of the reproductiveorgans (mumps orchitis), of the skin (warts, dermatitis, herpes labialis, herpes febrilis,herpes zoster, shingles), of the mucous membranes (papillomas, conjunctivalpapillomas, hyperplasia, dysplasia), of the cardiovascular System (arteriitis,myocarditis, endocarditis, pericarditis), of the kidney/urinary System, of thereproductive organs (anogenital lésions, warts, génital warts, sharp condylomas,dysplasia, papillomas, cervical dysplasia, condyloma acuminatum, epidermodysplasiaverruciformis), of the locomotory organs (myositis, myalgia), treatment of foot-and-mouth disease in cloven-hoofed animais, of Colorado tick fever, Dengue syndrome, ofhaemorrhagic fever, of early summer meningoencephalitis (FSME) and of yellowfever.

The described compounds, i.e. the organophosphorus compounds of the formula (I)and (II) and esters and amides thereof on the phosphino group and salts thereofexhibit strong cytotoxic activity against uni- and multicellular parasites, in particularagainst the causative organisms of malaria and sleeping sickness. The compoundsused according to the invention are accordingly usable for the treatment of infectivediseases which are caused in humans and animais by viruses, bacteria, parasites andfungi. The compounds are also suitable for the prévention of diseases which are -14- 011655 caused by viruses, bacteria, parasites and fungi, in particular for the prophylactic treatment of malaria and of sleeping sickness.

The organophosphorus compounds used according to the invention, which generallyinclude for this purpose pharmaceutically acceptable salts, amides, esters, a sait ofsuch an ester or also compounds which, on administration, provide the compoundsused according to the invention as métabolites or breakdown products (also known as"prodrugs"), may be formulated for administration in any suitable manner analogousto known agents having an antiinfective action (mixed with a non-toxic,pharmaceutically acceptable excipient).

Pharmaceutically acceptable salts of the compounds include salts which thecompounds of the formulae (I) and (II) used according to the invention form in theirprotonated form as an ammonium sait of inorganic or organic acids, such ashydrochloric acid, sulfuric acid, citric acid, maleic acid, fumaric acid, tartaric acid,p-toluenesulfonic acid.

Particularly pharmaceutically suitable salts are also those formed by suitable sélectionof X4, such as sodium sait, potassium sait, calcium sait, ammonium sait, ethanolaminesait, triethylamine sait, dicyclohexylamine sait and salts of an amino acid such asarginine sait, aspartic acid sait, glutamic acid sait.

Use of the above-stated substances is in particular suitable for the production ofpharmaceutical préparations against bacterial diseases or for the prévention thereof orfor the production of herbicides.

The activity of the substances is determined using a test System. This System is basedupon in vitro measurement of the inhibition of growth of bacteria, parasites, viruses,fungi or plants. Test methods known to the person skilled in the art are in part used forthis purpose. - 15 - 011655

For example, antimalarial activity is determined by measuring the inhibition of thegrowth of malaria parasites in blood cultures.

Antibacterial activity is determined on the basis of measuring the inhibition ofbacterial growth on nutrient media and in liquid cultures.

Antiviral activity is determined on the basis of the formation of viral éléments in cellcultures.

Some of the microorganisms which are to be investigated may only be investigated inanimal models. In this case, we will then use the appropriate models.

Substances which exhibit activity in in vitro measurement Systems are then furtherinvestigated in in vivo models.

The antiparasitic, antiviral, fungicidal or antibacterial activity is further evaluated inthe appropriate animal models.

Screening for herbicidal activity is determined by means of algal Systems andmeasurement of isoprene émissions ffom plants under standard conditions.

The pharmaceutically active agents may be prepared in dosage units in the form ofpharmaceutical préparations. This means that the préparation is in the form ofindividual components, for example tablets, coated tablets, capsules, pills,suppositories and ampoules, the active substance content of which corresponds to afraction or multiple of an individual dose. The dosage units may contain, for example1. 2, 3 or 4 individual doses or 1/2, 1/3 or 1/4 of an individual dose. An individualdose preferably contains the quantity of active substance which is administered at onetime and usually corresponds to a whole, half, third or quarter of a daily dose.

Non-toxic, inert, pharmaceutically suitable excipients should be taken to mean solid,semi-solid or liquid diluents, fillers and formulation auxiliaries of ail kinds. -16- 011655

Preferred pharmaceutical préparations which may be mentioned are tablets, coatedtablets, capsules, pills, granules, suppositories, solutions, suspensions and émulsions,pastes, ointments, gels, creams, lotions, powders and sprays. Tablets, coated tablets,capsules, pills and granules may contains the active substances together withconventional excipients, such as (a) fillers and extenders, for example starches,lactose, cane sugar, glucose, mannitol and silica, (b) binders, for example carboxy-methylcellulose, alginates, gélatine, polyvinylpyrrolidone, (c) humectants, forexample glycerol, (d) suspending agents, for example agar-agar, calcium carbonateand sodium carbonate, (e) dissolution retardants, for example paraffin and (f)résorption accelerators, for example quatemary ammonium compounds, (g) wettingagents, for example cetyl alcohol, glycerol monostearate, (h) adsorbents, for examplekaolin and bentonite and (i) lubricants, for example talcum, calcium and magnésiumstéarate and solid polyethylene glycols or mixtures of the substances stated in (a)to (i).

The tablets, coated tablets, capsules, pills and granules may be provided withconventional coatings and shells optionally containing opacifying agents and may alsobe composed such that they release the active substances only with a delay orpreferably in a particular part of the intestinal tract, wherein polymeric substances andwaxes may, for example, be used as the matrices.

The active substance or substances, optionally together with one or more of theabove-stated excipients, may also be présent in microencapsulated form.

In addition to the active substance or substances, suppositories may containconventional water-soluble or water-insoluble excipients, for example polyethyleneglycols, fats, for example cocoa butter and higher esters (for example 04 alcoholwith 06 fatty acid) or mixtures of these substances.

In addition to the active substance or substances, ointments, pastes, creams and gelsmay contain conventional excipients, for example animal and vegetable fats, waxes, - 17- 011655 paraffins, starch, gum tragacanth, cellulose dérivatives, polyethylene glycols, silicones, bentonites, silica, talcum and zinc oxide or mixtures of these substances.

In addition to the active substance or substances, powders and sprays may containconventional excipients, for example lactose, talcum, silica, aluminium hydroxide,calcium silicate and polyamide powder or mixtures of these substances. Sprays mayadditionally contain conventional propellants, for example chlorofluorocarbons.

In addition to the active substance or substances, solutions and émulsions may containconventional excipients, such as solvents, solubilising agents and emulsifiers, forexample water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylène glycol, dimethylformamide,oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesameoil, glycerol, glycerol formai, tetrahydrofurfuryl alcohol, polyethylene glycols andsorbitan fatty acid esters or mixtures of these substances.

For parentéral administration, the solutions and émulsions may also be présent instérile, isotonie form.

In addition to the active substance or substances, suspensions may containconventional excipients, such as liquid diluents, for example water, ethyl alcohol,propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminiummetahydroxide, bentonite, agar-agar and gum tragacanth or mixtures of thesesubstances.

The stated formulations may also contain colorants, preservatives and odour- orflavour-enhancing additives, for example peppermint oil and eucalyptus oil, andsweeteners, for example saccharin. - 18 - 011655

The active substances of the formulae (I) and (II) should preferably be présent in thepharmaceutical préparations listed above in a concentration of approx. 0.1 to99.5 wt.%, preferably from approx. 0.5 to 95 wt.%, of the complété mixture.

Apart from the compounds of the formulae (I) and (II), the pharmaceuticalpréparations may also contain further pharmaceutical active substances.

The compounds may be used together with hitherto described substances havingantibacterial, antiviral, antimycotic and antiparasitic properties. Such substances inparticular include compounds which hâve already been used in therapeuticapplications or are still used. Substances which are suitable for this purpose are inparticular those listed in the Red List or in Simon/Stille, Antibiokia-Therapie in Klinikund Praxis, 9th édition, 1998, Schatauer Verlag, or on the Internet at http.7/www.customs.treas.gov/imp-exp/rulings/harmoniz/hrml29.html. The dériv-atives may in particular be présent with penicillins, benzylpenicillin (penicillin G),phenoxypenicillins, isoxazolylpenicillins, aminopenicillins, ampicillin, amoxicillin,bacampicillin, carboxypenicillin, ticarcillin, temocillin, acylaminopenicillins,azlocillin, mezlocillin, piperacillin, apalcillin, mecillinam, cephalosporins, cefazolingroup, cefuroxime group, cefoxitin group, cefoxitin, cefotetan, cefmetazole,latamoxef, flomoxef, cefotaxime group, cefozidime, ceftazidime group, ceftazidime,cefpirome, cefepime, conventional cephalosporins, cefsulodin, cefoperazone, oralcephalosporins of the cephalexin group, loracarbef, cefprozil, new broad-spectrumoral cephalosporins, cefixime, cefpodoxime-proxetil, cefuroxime-axetil, cefetamet,cefotiam-hexetil, cefdinir. ceftibuten, other β-lactam antibiotics, carbapenem,imipenem/cilastatin, meropenem. biapenem, aztreonam, β-lactamase inhibitors,clavulanic acid/amoxicillin. clavulanic acid/ticarcillin, sulbactam/ampicillin,tazobactam/piperacillin. tetracyclines, oxytetracycline, rolitetracycline, doxycycline,minocycline, chloramphenicol, aminoglycosides, gentamicin, tobramycin, netilmicin,amikacin, spectinomycin. macrolides, erythromycin, clarithromycin, roxithromycin,azithromycin, dirithromycin, spiramycin, josamycin, lincosamides, clindamycin,fusidic acid, glycopeptide antibiotics, vancomycin, teicoplanin, pristinamycindérivatives, fosfomycin, antimicrobial folie acid antagonists, sulfonamides, - 19- 011655 co-trimoxazole, trimethoprim, other diaminopyrimidine-sulfonamide combinations,nitrofurans, nitrofurantoin, nitrofurazone, gyrase inhibitors (quinolones), norfloxacin,ciprofloxacin, ofloxacin, sparfloxacin, enoxacin, fleroxacin, pefloxacin, lomefloxacin,Bay Y3118, nitroimidazoles, antimycobacterial agents, isoniazid, rifampicin, 5 rifabutin, ethambutol, pyrazinamide, streptomycin, capreomycin, prothionamide,terizidone, dapsone, clofazimine, topical antibiotics, bacitracin, tyrothricin,polymyxins, neomycin, kanamycin, paromomycin, mupirocin, antiviral agents,acyclovir, ganciclovir, azidothymidine, didanosine, zalcitabine, thiacytidine,stavudine, ribavirin, idoxuridine, trifluridine, foscamet, amantadine, interferons, tibol 10 dérivatives, protéinase inhibitors, antimycotics, polyenes, amphotericin B, nystatin,natamycin, azoles, azoles for septic therapy, miconazole, kétoconazole, itraconazole,fluconazole, UK-109,496, azoles for topical use, clotrimazoie, econazole, isoconazole,oxiconazole, bifonazole, flucytosine, griseofulvin, ciclopirox olamine, tolnafnate,naftifme, terbinafine. amorolfîne, anthraquinones, betulinic acid, semianthraquinones, 15 xanthones, naphthoquinones, arylamino alcohols, quinine, quinidines, mefloquine,halofantrine, chloroquine, amodiaquine, acridine, benzonaphthyridine, mepacrine,pyronaridine, dapsone, sulfonamides, sulfadoxine, sulfalenes, trimethoprim,proguanil, chlorproguanil. diaminopyrimidines, pyrimethamine, primaquine,aminoquinolines, WR 238.605, tétracycline, doxycycline, clindamycin, norfloxacin, 20 ciprofloxacin, ofloxacin, artemisinin, dihydroartemisinin, 10b artemether, arteether,atresunate, atovaquone. suramin, melarsoprol, nifurtimox, stibogluconate sodium,pentamidine, amphotericin B, metronidazole, clioquinol, mebendazole, niclosamide,praziquantel. pyrantel, tiabenzazole, diethylcarbamazine, ivermectin, bithionol,oxamniquine, metrifonate. piperazine, embonate. 25

The organophosphorus compounds may furthermore be présent in the pharmaceuticalpréparations in combination with sulfonamide, sulfadoxine, artemisinin, atovaquone,quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine,armesin, tetracyclines, doxycycline, proguanil, metronidazole, praziquantel, 30 niclosamide. mebendazole, pyrantel, tiabendazole, diethylcarbazine, piperazine, pyrivinium, metrifonate, oxamniquine, bithionol or suramin or two or more of thesesubstances. -20- 011655

The above-stated pharmaceutical préparations are produced in the conventional manner using known methods, for example by mixing the active substance or substances with the excipient or excipients.

The stated préparations may be administered to humans and animais orally, rectally,parenterally (intravenously, intramuscularly, subcutaneously), intracistemally,intravaginally, intraperitoneally, topically (powders, ointments, drops) and for thetreatment of infections in cavities, body cavities. Suitable préparations which may beconsidered are solutions for injections, solutions and suspensions for oral therapy,gels, infusion formulations, émulsions, ointments or drops. Topical treatment may beperformed using ophthalmological and dermatological formulations, silver and othersalts. ear drops, eye ointments, powders or solutions. Administration to animais mayalso be achieved via the feed or drinking water in suitable formulations. Gels,pulvérulent formulations, powders, tablets, controlled-release tablets, premixes,concentrâtes, granules, pellets, tablets, boli, capsules, aérosols, sprays, inhalationformulations may also be used in humans and animais. The compounds usedaccording to the invention may also be incorporated into other supports, such as forexample plastics (plastic chains for topical treatment), collagen or bone cernent.

It has in general proved advantageous in both human and veterinary medicine toadminister the active substances of the formulae (I) and (II) in total quantifies ofapprox. 0.05 to approx. 600, preferably of 0.5 to 200 mg/kg body weight per 24 hours,optionally in the form of two or more individual doses in order to achieve the desiredresults. An individual dose preferably contains the active substance or substances inquantities of approx. 1 to approx. 200, in particular of 1 to 60 mg/kg body weight. Itmay, however, be necessary to deviate from the stated dosages, in particular as afunction of the nature and body weight of the patient to be treated, the nature andseverity of the disease, the nature of the préparations and the route of administrationof the drug and the period of time over which administration is performed. -21 - 011655

In some cases, it may be sufficient to use less than the above-stated quantity of activesubstance, while in other cases more than the above-stated quantity of activesubstance must be used. The person skilled in the art will use his/her skill todétermine the optimum dosage and route of administration required in each particular 5 case.

The compounds according to the invention may be given to animais in conventionalconcentrations and préparations together with feed or feed préparations or withdrinking water. 10

The compounds used according to the invention are furthermore ideally usable asbactéricides, fungicides and herbicides in plants.

Claims

- 22 - 011655 Claims

1. Use of organophosphorus compounds of the general formula (I) O \ r2 r4 in which Ri and R2 are identical or different and are selected from the groupconsisting of hydrogen, substituted and unsubstituted alkyl, substituted andunsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substitutedand unsubstituted alkynyl, substituted and unsubstituted aryl, substituted andunsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted andunsubstituted aralkyl, substituted and unsubstituted heterocyclic residue,halogen, OXi and OX2, wherein Xi and X2 may be identical or different and are selected from thegroup consisting of hydrogen, substituted and unsubstituted alkyl, substitutedand 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 unsubstitutedheterocyclic residue, A is selected from the group consisting of an alkylene residue, an alkenylresidue and a hydroxyalkylene residue, R3 is selected from the group consisting of hydrogen, substituted andunsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substitutedand unsubstituted aryl, substituted and unsubstituted acyl, substituted andunsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted andunsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substitutedand unsubstituted heterocyclic residue, halogen, R4 is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted -23- 011655 and unsubstituted aryl, substituted and unsubstituted acyl, substituted andunsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted andunsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substitutedand unsubstituted heterocyclic residue, halogen, OX4, wherein X4 is selected from the group consisting of hydrogen, substituted andunsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substitutedand unsubstituted aryl, substituted and unsubstituted aralkyl, substituted andunsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted andunsubstituted cycloalkyl, substituted and unsubstituted heterocyclic residue, asilyl, a cation of an organic and inorganic base, in particular of a métal of maingroup I, II or III of the periodic System, ammonium, substituted ammoniumand ammonium compounds which are derived from ethylenediamine or aminoacids, and pharmaceutically acceptable salts, esters and amides and salts of theesters, or altemativelv compounds which, on administration, provide thecompounds to be used according to the invention as métabolites or breakdownproducts. for the production of pharmaceutical préparations for the therapeutic andprophylactic treatment of infections in humans and animais caused byparasites, fungi, viruses and bacteria selected from the group consisting ofbacteria of the family Propionibacteriaceae, in particular of the genusPropionibacterium. in particular the species Propionibacterium acnés, bacteriaof the family Actinomycetaceae. in particular of the genus Actinomyces,bacteria of the genus Cornynebacteriam, in particular the speciesCorynebacterium dîphtheriae and Corynebacterium pseudotuberculosis,bacteria of the family Mycobacteriaceae, of the genus Mycobacterium, inparticular the species Mycobacterium leprae, Mycobacterium tuberculosis,Mycobacterium bovis and Mycobacterium avium, bacteria of the familyChlamydiaceae, in particular the species Chlamydia trachomatis andChlamydia psittaci, bacteria of the genus Listeria, in particular the speciesListeria monocytogenes, bacteria of the species Erysipelthrix rhusiopathiae,bacteria of the genus Clostridium, bacteria of the genus Yerpinia, the species -24- 011655 Yersinia pestis, Yersinia pseudotuberculosis, Yersinia enterocolitica andYersinia ruckeri, bacteria of the family Mycoplasmataceae, of the généraMycoplasma and Ureaplasma, in particular the species Mycoplasmepneumoniae, bacteria of the genus Brucella, bacteria of the genus Bordetella,bacteria of the genus Campylobacter. in particular the species Campylobacterjejuni, Campylobacter coli and Campylobacter fétus, bacteria of the genusHélicobacter, in particular the species Hélicobacter pylori, bacteria of thefamilies Spirochaetaceae and Leptospiraceae, in particular the généraTreponema, Borrelia and Leptospira, in particular Borrelia burgdorferi,bacteria of the genus Actinobacillus, bacteria of the family Legionellaceae, ofthe genus Légionella, bacteria of the family Rickettsiaceae and the familyBartonellaceae, bacteria of the généra Nocardia and Rhodococcus,.bacteria ofthe genus Dermatophilus, and as a fungicide. bactéricide and herbicide inplants. Use according to claim 1. characterised in that the organophosphoruscompounds are of the formula (II) Xi .N R, (II) R2 r4 wherein Xi is selected from the group consisting of hydrogen, substituted orunsubstituted acyl. substituted or unsubstituted alkyl, substituted orunsubstituted aryl. substituted or unsubstituted aralkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclic residue;R-2, R-3, R4 and A hâve the same meaning as in formula (I). Use according to claim 2, characterised in that R2 is an acyl residue, in particular a formyl or acetyl residue, -25 - 011655 R-3 is selected from the group consisting of hydrogen, methyl and ethyl, R4 is selected from the group consisting of hydrogen, methyl, ethyl and OX4,X4 is selected from the group consisting of hydrogen, sodium, potassium,methyl and ethyl, X, isH and A is selected from the group consisting of alkylene, alkenylene orhydroxyalkylene.
4. Use according to one of the preceding claims, characterised in that A forms achain of three carbon atoms between the phosphorus atom and the nitrogenatom.
5. Use according to claim 2,characterised in that X4 is selected from the group consisting of hydrogen, ammonium and metalsof main groups I and II of the periodic svstem. preferably sodium, potassium,calcium or magnésium, ammonium compounds, which are derived fromethylenediamine or amino acids, preferably ethanolamine, ethylenediamine,Ν,Ν-dibenzylethylenediamine and arginine.
6. Use according to one of claims 2 to 5,characterised in that R? is an acyl residue and A an alkylene residue, wherein R2 is preferablyformed by formyl or acetyl and A preferably by propylene, propenylene andhydroxvpropylene.
7. Use according to one of the preceding claims for the production ofpharmaceutical préparations for the treatment of infections caused by bacteria,viruses. fungi or uni- or multicellular parasites.
8. Use according to claim 7 for the production of pharmaceutical préparations forthe treatment of infections caused by bacteria selected from the group -26- 011655 consisting of bacteria of the family Propionibacteriaceae, in particular of thegenus Propionibacterium, in particular the species Propionibacterium acnés,bacteria of the family Actinomycetaceae, in particular of the genusActinomyces, bacteria of the genus Cornynebacterium, in particular the speciesCorynebacterium diphtheriae and Corynebacterium pseudotuberculosis,bacteria of the family Mycobacteriaceae, ofthe genus Mycobacterium, inparticular the species Mycobacterium leprae, Mycobacterium tuberculosis,Mycobacterium bovis and Mycobacterium avium, bacteria of the familyChlamydiaceae, in particular the species Chlamydia trachomatis andChlamydia psittaci, bacteria of the genus Listeria, in particular the speciesListeria monocytogenes.
9. Use according to claim 7 for the production of pharmaceutical préparations forthe treatment of infections caused by viruses selected from the groupconsisting of Parvoviridae, in particular parvoviruses, dependoviruses,densoviruses, Adenoviridae, in particular adenoviruses, mastadenoviruses,aviadenoviruses, viruses of the genus Papovaviridae, in particularpapovaviruses, in particular papillomaviruses ("wart" viruses),polyomaviruses, in particular JC virus, BK virus and miopapovaviruses,viruses of the genus Herpesviridae, in particular herpes simplex viruses,varicella-zoster viruses, human cytomégalovirus, Epstein-Barr viruses, humanherpesvirus 6, human herpesvirus 7, human herpesvirus 8, viruses of the genusPoxiviridae, in particular poxviruses, orthopoxviruses, parapoxviruses,molluscum contagiosum virus, aviviruses, capriviruses, leporipoxviruses,primarily hepatotropic viruses. in particular hepatitisviruses, such ashepatitis A viruses, hepatitis B viruses, hepatitis C viruses, hepatitis D viruses,hepatitis E viruses, hepatitis F viruses, hepatitis G viruses, hepadnaviruses, inparticular ail hepatitisviruses, such as hepatitis B virus, hepatitis D viruses,viruses of the genus Picornaviridae, in particular picomaviruses, ailenteroviruses, ail polioviruses, ail coxsackieviruses, ail echoviruses, ailrhinoviruses, hepatitis A virus, aphthoviruses, viruses of the genusCalciviridae, in particular hepatitis E viruses, viruses of the genus Reoviridae, -27- 011655 orbiviruses, rotaviruses, viruses of the genus Togaviridae, in particulartogaviruses, alphaviruses, rubiviruses, pestiviruses, rubellavirus, viruses of thegenus Flaviviridae, in particular flaviviruses, FSME virus, hepatitis C virus,viruses of the genus Orthomyxoviridae, in particular influenza viruses, virusesof the genus Paramyxoviridae, in particular paramyxoviruses, morbillivirus,pneumovirus, measles virus, mumps virus, viruses of the genus Rhabdoviridae, in particular rhabdoviruses, rabies virus, lyssavirus, vascularstomatitisvirus, viruses of the genus Coronaviridae, in particularcoronaviruses, viruses of the genus Bunyaviridae, in particular bunyaviruses,nairovirus, phlebovirus, uukuvirus, hantavirus, hantaan virus, viruses of thegenus Arenaviridae, in particular arenaviruses, lymphocytic choriomeningitisvirus, viruses of the genus Retroviridae, in particular retroviruses, ail HTLviruses, human T-cell leukaemia virus, oncomaviruses, spumaviruses,lentiviruses, ail HI viruses, viruses of the genus Filoviridae, in particularMarburg and Ebola virus, slow viruses, prions, oncoviruses and leukaemiaviruses.
10. Use according to claim 7 for the production.of pharmaceutical préparations forthe prévention and treatment of infections caused by unicellular parasites,namely the causative organisms of malaria and sleeping sickness and ofChagas' disease, toxoplasmosis, amoebic dysentery, leishmaniases,trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiosis, sarcocytosis,acanthamoebosis, naeglerosis, coccidiosis, giardiasis and lambliasis.
11. Use according to one of daims 1 to 10, characterised in that thepharmaceutical préparation comprises an effective content of at least oneorganophosphorus compound and a pharmaceutically acceptable excipient.
12. Use according to claim 11, characterised in that the pharmaceuticalpréparation comprises at least one further pharmaceutical active substance. -28- 011655
13. Use according to claim 12, characterised in that the pharmaceuticalpréparation moreover comprises one or more constituents of the groupconsisting of sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine,chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine,armesin, tetracyclines, doxycycline, proguanil, metronidazole, praziquantel,niclosamide, mebendazole, pyrantel, tiabendazole, diethylcarbazine,piperazine, pyrivinium, metrifonate, oxamniquine, bithionol and suramin.
14. Use according to claim 12, characterised by one or more constituents of the group consisting of penicillins,benzylpenicillin (penicillin G), phenoxypenicillins, isoxazolylpenicillins,aminopenicillins, ampicillin, amoxicillin, bacampicillin, carboxypenicillin,ticarcillin, temocillin, acylaminopenicillins, azlocillin, mezlocillin,piperacillin, apalcillin, mecillinam, cephalosporins, cefazolin group,cefuroxime group, cefoxitin group, cefoxitin, cefotetan, cefmetazole,latamoxef, flomoxef, cefotaxime group, cefozidime, ceftazidime group,ceftazidime, cefpirome, cefepime, conventional cephalosporins, cefsulodin,cefoperazone, oral cephalosporins of the cephalexin group, loracarbef,cefprozil, new broad-spectrum oral cephalosporins, cefixime, cefpodoxime-proxetil, cefuroxime-axetil, cefetamet, cefotiam-hexetil, cefdinir, ceftibuten,other β-lactam antibiotics, carbapenem, imipenem/cilastatin, meropenem,biapenem, aztreonam, β-lactamase inhibitors, clavulanic acid/amoxicillin,clavulanic acid/ticarcillin, sulbactam/ampicillin, tazobactam/piperacillin,tetracyclines, oxytetracycline, rolitetracycline, doxycycline, minocycline,chloramphenicol, aminoglycosides, gentamicin, tobramycin, netilmicin,amikacin, spectinomycin, macrolides, erythromycin, clarithromycin,roxithromycin, azithromycin, dirithromycin, spiramycin, josamycin,lincosamides, clindamycin, fusidic acid, glycopeptide antibiotics, vancomycin,teicoplanin, pristinamycin dérivatives, fosfomycin, antimicrobial folie acidantagonists, sulfonamides, co-trimoxazole, trimethoprim, otherdiaminopyrimidine-sulfonamide combinations, nitrofurans, nitroforantoin,nitroforazone, gyrase inhibitors (quinolones), norfloxacin, ciprofloxacin, -29- 011655 ofloxacin, sparfloxacin, enoxacin, fleroxacin, pefloxacin, lomefloxacin, Bay¥3118- nitroimidazoles, antimycobacterial agents, isoniazid, rifampicin,rifabutin, ethambutol, pyrazinamide, streptomycin, capreomycin,prothionamide, terizidone, dapsone, clofazimine, topical antibiotics, 5 bacitracin, tyrothricin, polymyxins, neomycin, kanamycin, paromomycin, mupirocin, antiviral agents, acyclovir, ganciclovir, azidothymidine,didanosine, zalcitabine, thiacytidine, stavudine, ribavirin, idoxuridine,trifluridine, foscamet, amantadine, interferons, tibol dérivatives, protéinaseinhibitors, antimycotics, polyenes, amphotericin B, nystatin, natamycin, 10 azoles, azoles for septic therapy, miconazole, kétoconazole, itraconazole, fluconazole, UK-109,496, azoles for topical use, clotrimazole, econazole,isoconazole, oxiconazole, bifonazole, flucytosine, griseofulvin, ciclopiroxolamine, tolnafnate, naftifine, terbinafine, amorolfine, anthraquinones,betulinic acid, semianthraquinones, xanthones, naphthoquinones, arylamino 15 alcohols, quinine, quinidines, mefloquine, halofantrine, chloroquine, amodiaquine, acridine, benzonaphthyridine, mepacrine, pyronaridine, dapsone,sulfonamides, sulfadoxine, sulfalenes, trimethoprim, proguanil, chlorproguanil. diaminopyrimidines, pyrimethamine, primaquine,aminoquinolines, WR 238,605, tétracycline, doxycycline, clindamycin, 20 norfloxacin, ciprofloxacin, ofloxacin, artemisinin, dihydroartemisinin, 10b artemether, arteether, atresunate, atovaquone, suramin, melarsoprol,nifurtimox, stibogluconate sodium, pentamidine, amphotericin B,metronidazole, clioquinol. mebendazole, niclosamide, praziquantel, pyrantel,tiabenzazole, diethylcarbamazine, ivermectin, bithionol, oxamniquine, 25 metrifonate, piperazine, embonate. -30- 011655 Translatons comments: p.14, final para.-p.15, para.l: "vorliegen" has been assumed to hâve been omittedfrom after the list of antibiotics etc. and "be présent" has accordingly been inserted inthe translation. p.19, claim 5: "aus der" has been assumed to hâve been omitted from before"Gruppe" and the phrase has accordingly been translated as "from the group", c.f.p.19, claim 3.