OA11718A

OA11718A - Use of phosphonoformic acid derivatives for treating infections.

Info

Publication number: OA11718A
Application number: OA1200100130A
Authority: OA
Inventors: Hassan Jomaa
Original assignee: Jomaa Pharmaka Gmbh
Priority date: 1998-11-25
Filing date: 1999-11-20
Publication date: 2005-01-26
Also published as: CZ20011819A3; EA200100585A1; IL142775A0; AP2001002164A0; JP2002530343A; WO2000030653A2; EP1133302A2; AU1859100A; NO20012540D0; CA2352511A1; BR9915605A; PL348354A1; WO2000030653A3; NO20012540L; CN1328464A; TR200101431T2; DE19854310A1

Abstract

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

Description

Use of phosphonoformic acid dérivatives for the treatment of infections

This invention relates to the use of phosphonoformic acid dérivatives for the therapeutic and prophylactic treatment of infections in humans and animais caused by bacteria, fungi and parasites, and to the use thereof as a fungicide, bactéricide and herbicide in plants. According to the invention, the phosphonoformic acid dérivatives comprise the physiologically5 y compatible salts, esters and amides.

Phosphonoformic acid dérivatives are already known for their antiviral properties.Pharmaceutical préparations for treating viral infections hâve already been described in USpatents 4 215 113,4 339, and 4 665 062 and 4 771 041.

In particular, the antiviral action of phosphonoformic acid dérivatives and the productionthereof hâve already been described in WO 98/16537 and WO 98/25938.

In order to widen the range of options for treating humans and animais and for protectingplants, there is an urgent requirement to provide agents which are not only highly active but,unlike other pharmaceutical préparations or phytosanitary agents, also exhibit reduced side- effects or reduced environmental impact and thus constitute a reduced risk to human health. 15

The object of the présent invention is accordingly to provide a substance which is universallyusable in infections by bacteria, fungi and parasites in humans and animais and as a fungicide,bactéricide and herbicide in plants and which meets the above-stated requirements.

This object is utterly surprisingly achieved by the group of substances defined in claim 1. Thisgroup of substances exhibits both an antiinfective action against bacteria, fungi and uni- and 20 multicellular parasites and a fungicidal, bactericidal and herbicidal action in plants.

The organophosphorus compounds used according to the invention are of the general formulaI -2-

117 1g in which Ri i is selected from the group which consists of C].26 alkyl residues, C2-26 alkenylresidues with 1 to 6 double bonds, C2.2e alkynyl residues with 1 to 6 triple bonds, Ci.26 acylresidues, Ar-Co-26-alkyl residues, C3.8-cycloalkyl-Co-26-alkyl residues, C3.8-heterocycloalkyl-Co-26-alkyl residues with one or two nitrogen, oxygen or sulfur atoms, halogen and OXn,wherein ail the above-stated residues may bè substituted with C1-9 alkyl, C1-9 alkoxy, hydroxy,amino, halogen or oxo groups, wherein Xn is selected from the group which consists of hydrogen, Ci.26 alkyl residues, C2.26alkenyl residues with 1 to 6 double bonds, C2.26 alkynyl residues with 1 to 6 triple bonds, Ar-Co-26-alkyl residues, C3.8 cycloalkyl residues, Ci-26 acyl residues, C3-8-heterocycloalkyl-Co-26-alkyl residues with one or two nitrogen, oxygen or sulfur atoms, Ci.26 silyl residues, whereinail the above-stated residues may be substituted with C1-9 alkyl, C4.9 alkoxy, hydroxy, amino,halogen or oxo groups and consists of a cation of an organic and inorganic base, in particulara métal of main groups I, II or III of the periodic System, ammonium, substituted ammoniumand ammonium compounds derived from ethylenediamine or amino acids, 15 20 25 in which Ri and R2 are each independently selected from the group which consists of Ci.24alkyl residues, C3-8 cycloalkyl residues, C3.8-cycloalkyl-Ci.24-alkyl residues, Ci.24 alkoxyresidues, Ci_24 alkylthio residues, Ci-24-alkoxy-Ci.24-alkyl residues and Ci.24-alkylthio-Ci-24-alkyl residues, acyl residues, Ar-(Ci.24)-alkyl residues, C3.8-heterocycloalkyl-Co-24-alkylresidues, halogen and hydrogen, and each Ci-24 alkyl residue and Ci.24 alkoxy residue may bebranched or unbranched and be saturated or unsaturated with 2 to 6 double bonds and mayoptionally be substituted with hydroxy, amino, mercapto, halogen, oxo groups or Cj.24 alkoxyresidues, Ci-24 alkylcarbonyloxy residues, Ci-24 alkoxycarbonyloxy residues, Ci.24 alkylthioresidues, Ci-24 alkylcarbonylthio residues, Ci-24 alkylamino residues, di-(Ci-24-alkyl)aminoresidues, Ci-24 alkylcarbonylamino residues, Ci-24-alkyl(Ci-24-alkylcarbonyl)amino residues,Ci.24-alkoxycarbonylamino residues or Ci.24-alkyl-(Ci.24-alkoxycarbonyl)amino residues,wherein each aralkyl residue, heterocy clic residue, Ci.24 alkyl residue and Ci_24 alkoxy residuemay be branched or unbranched and be saturated or unsaturated with 2 to 6 double bonds ortriple bonds, or in which Ri-CH-CH-R2 forms part of a C4.s carbon ring, which may optionally be substitutedwith hydroxy, mercapto, amino, halogen, oxo groups or with Ci.24 alkyl residues, Ci.24 alkoxy 30 -3- residues, Ci-24 alkylthio residues, C1.24 alkylamino residues, di-(Ci-24-alkyl)amino residues,Ci-24 alkylcarbonyl residues, C1.24 alkylcarbonyloxy residues, C1.24 alkoxycarbonyl residues,Ci-24 alkylcarbonylthio residues or Ci-24 alkylcarbonylamino residues, Ci.24-alkyl-(Ci.24-alkylcarbonyl)amino residues, wherein each Ci.24 alkyl residue may be branched orunbranched and be saturated or unsaturated with 1 to 6 double bonds, or wherein Rio is a branched or unbranched Cm alkyl residue, or in which R1-CH-CH-R2 forrns part of the furanose or pyranose ring of a sugar, for exampleD-ribose, D-arabinose, D-xylose, D-lyxose, D-glucose, D-galactose, D-mannose, D-talose, D-allose, D-altrose, D-gulose, D-idose or the corresponding L isomers, wherein the hydroxygroups may each optionally be substituted by hydrogen, amino, azido, oxo, mercapto residuesor Ci-24 alkoxy residues, C1.24 alkylthio residues, Ci-24 alkylamino residues, di-(Ci-24-alkyl)amino residues, C1.24 alkylcarbonyloxy residues, C1.24 alkylcarbonylthio residues, Ci-24alkylcarbonylamino residues, Ci-24-alkyl-(Ci-24-alkylcarbonyl)amino residues, wherein eachCj.24 alkyl residue may be branched or unbranched and be saturated or unsaturated with 1 to 6double bonds, and the pharmaceutically acceptable salts, esters and amides thereof and saltsof the esters and the optical isomers thereof.

Ri and R2 may in particular each independently be selected ffom the group which consists ofcarboxyl residues, carboxamido residues, aryl residues, aryloxycarbonyl residues, aryl-Ci.24-alkyl residues, C1.24 alkoxycarbonyloxy residues, C1.24 alkylaminocarbonyl residues, di-(Ci-24-alkyl)aminocarbonyl residues, aryl-Ci-24-alkoxycarbonyl residues, aryl-Ci-24-

alkylaminocarbonyl residues, Ci-24-alkylcarbonyloxy-(Ci.24)alkylmethoxycarbonyl residues,Ci-24 alkoxycarbonyloxymethoxycarbonyl residues, Ci-24-alkoxycarbonyloxy-(Ci-4-alkyl)methoxycarbonyl, wherein each C1.24 alkyl residue may be branched or unbranched andbe saturated or unsaturated with 2 to 6 double bonds, and each Cm alkyl residue and Cf-24alkoxy residue may be branched or unbranched and be saturated or unsaturated, and each arylresidue is of the formula II

(II) wherein R3 and R4 are identical or different and are each selected from the group whichconsists of hydrogen, halogen, Cm alkyl residues, Cm alkoxy residues, formyl, acetyl,

1 1 ? 4 P

; · 6 'V -4- propionyl, butÿryl residues, formyloxy, acetyloxy, propionyloxy, butyryloxy residues, Cmalkoxycarbonyl residues, ail of which may be branched or unbranched, orR3 and R4 together form an unbranched saturated alkylene chain with 3 to 4 carbon atoms,which is attached to adjacent positions of the phenyl ring, or R3 and R4 together form amethylenedioxy residue, a 1,1-ethylidenedioxy residue, 1,1-ethenylenedioxy residue, a 1,1- 5 ethylenedioxy residue or a 1,2-ethylenedioxy residue, which are attached to adjacent positionsof the phenyl ring.

It is preferred to use compounds in which Ri and R2 are each independently selected from thegroup which consists of hydrogen, hydroxy groups, formyl, acetyl and methyl, wherein themethyl group may optionally be substituted with a hydroxy group or mercapto group or with ’θ C]-24 alkoxy residues, Ci-24 alkylcarbonyloxy residues, C1.24 alkylthio residues or Ci-24 alkylcarbonylthio residues, wherein the Cj.24 alkyl groups and C1.24 alkoxy groups may bebranched or unbranched and be saturated or unsaturated with 1 to 6 double bonds.

Particularly preferably, Ri is a methyl residue, which may optionally be substituted with ahydroxy group or mercapto group or with Ci-24 alkoxy residues, C1.24 alkylcarbonyloxy ' residues, C1.24 alkylthio residues or C1.24 alkylcarbonylthio residues, wherein the C1.24 alkylgroups and the Ci.24 alkoxy groups may be branched or unbranched and be saturated orunsaturated with 1 to 6 double bonds, and R2 is a hydrogen residue.

Particularly good results are achieved with compounds in which Ri and R2 are eachindependently selected ffom the group which consists of hydrogen and an n-octadecylmethyl 20 residue, wherein Ri is preferably an n-octadecylmethyl residue and R2 a hydrogen residue.Particular advantages are achieved if the compound is of (R) configuration.

Ru preferably dénotés OH.

Spécial features of the above définitions and suitable examples thereof are given below: "Acyl" is a substituent which originates from an acid, such as from an organic carboxylic 25 acid, carbonic acid, carbamic acid or the thio acid or imidic acid corresponding to the aboveindividual acids, or from an organic sulfonic acid, wherein these acids in each case comprisealiphatic, aromatic and/or heterocyclic groups in the molécule together with carbamoyl orcarbamimidoyl.

Suitable examples of these acyl groups are given below.

Aliphatic acyl groups are defmed as acyl residues originating from an aliphatic acid andinclude the following: -5- 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, propanesulfonyi 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, in particularthe alkyl group or alkane residue, may optionally hâve one or more suitable substituents, suchas amino, halogen (for example fluorine, chlorine, bromine etc.), hydroxy, hydroxyimino,carboxy, alkoxy (for example methoxy, ethoxy, propoxy etc.), alkoxycarbonyl, acylamino (forexample benzyloxycarbonylamino etc.), acyloxy (for example acetoxy, benzoyloxy etc.) andthe like; preferred aliphatic acyl residues with such substituents which may be mentioned are,for example, alkanoyls substituted with amino, carboxy, amino and carboxy, halogen,acylamino or the like.

Aromatic acyl residues are defined as those acyl residues which originate from an acid with asubstituted or unsubstituted aryl group, wherein the aryl group may comprise phenyl, toluyl,xylyl, naphthyl and tire like; suitable examples are stated below: 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.); arylaminoalkanoyl (for example N-phenylglycyl, etc.); arenesulfonyl (for example benzenesulfonyl, tosyl or toluenesulfonyl, naphthalenesulfonyletc.); aryloxycarbonyl (for example phenoxycarbonyl, naphthyloxycarbonyl etc.); aralkoxycarbonyl (for example benzyloxycarbonyl etc.); arylcarbamoyl (for example phenylcarbamoyl, naphthylcarbamoyl etc.); arylglyoxyloyl (for example phenylglyoxyloyl etc.).

In the above-stated Examples of aromatic acyl residues, the aromatic hydrocarbon moiety (in -6- particular the aryl residue) and/or the aliphatic hydrocarbon moiety (in particular the alkaneresidue) may optionally hâve one or more suitable substituents, such as those which hâvealready been stated as suitable substituents for thé alkyl group or the alkane residue.

Examples of preferred aromatic acyl residues with spécifie substituents which may inparticular be mentioned are aroyl substituted with halogen and hydroxy or with halogen andaralkanoyl substituted with hydroxy, hydroxyimino, dihaloalkanoyloxyimino, together witharylthiocarbamoyl (for example phenylthiocarbamoyl etc.); arylcarbamimidoyl (for example phenylcarbamimidoyl etc.). A heterocyclic acyl residue is taken to mean an acyl residue which originates from an acidwith a heterocyclic group; such residues 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 nitrogen, oxygen andsulfur (for example thiophenyl, furoyl, pyrrolecarbonyl, nicotinyl etc.); heterocycle-alkanoyl, in which the heterocyclic residue is 5- to 6-membered and comprises atleast one heteroatom from the group nitrogen, oxygen and sulfur (for examplethiophenylacetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2-(2-amino-4-thiazolyl)- 2-methoxyiminoacetyl etc.) and the like.

In the above Examples of heterocyclic acyl residues, the heterocycle and/or the aliphatichydrocarbon moiety may optionally comprise one or more suitable substituents, such as thesame as were stated to be suitable for alkyl and alkane groups.

Aryl is an aromatic hydrocarbon residue, such as phenyl, naphthyl etc., which may optionallycomprise one or more suitable substituents, such as alkyl, alkenyl, alkynyl, alkoxy (forexample methoxy, ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.), nitroand the like. "Aralkyl" includes mono-, di-, triphenylalkyls such as benzoyl, phenethyl, benzhydryl, trityland the like, wherein the aromatic moiety may optionally comprise one or more suitablesubstituents, such as alkoxy (for example methoxy, ethoxy etc.), halogen (for example,fluorine, chlorine, bromine etc.), nitro and the like. *

The 5- and 6-membered heterocycles which may be denoted by Ri and R2 and which, apartfrom carbon, contain one or two nitrogen, oxygen or sulfur atoms as a ring member, may besaturated or unsaturated. 1 ο 4 q ί i £ Ο -7- WO 98/25938 provides a comprehensive description of a production process for thesecompounds.

The organophosphorus compounds are in particular suitable for the therapeutic andprophylactic treatment of infections in humans and animais caused by bacteria, uni- and multicellular parasites and fungi, 5

The compounds are active against unicellular parasites (protozoa), in particular against thecausative organisms of malaria and sleeping sickness and of Chagas' disease, toxoplasmosis,amoebic dysentery, leishmaniases, trichomoniasis, pneumocystosis, balantidiasis,cryptosporidiosis, sarcocytosis, acanthamoebosis, naeglerosis, coccidiosis, giardiasis andlambliasis. 10

They are accordingly in particular suitable for the prophylactic treatment of malaria and ofsleeping 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 the 15 following bacteria: bacteria of the family Propionibacteriaceae, in particular of the genus Propionibacterium, inparticular the species Propionibacterium acnés, bacteria of the family Actinomycetaceae, inparticular of the genus Actinomyces, bacteria of the genus Comynebacterium, in particularthe species Corynebacterium diphtheriae and Corynebacterium pseudotuberculosis, bacteria 20 of the family Mycobacteriaceae, of the genus Mycobacterium, in particular the species

Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and

Mycobacterium avium, bacteria of the family Chlamydiaceae, in particular the species

Chlamydia trachomatis and Chlamydia psittaci, bacteria of the genus Listeria, in particular the species Listeria monocytogenes, bacteria of the species Erysipelthrix rhusiopathiae, bacteria25 of the genus Clostridium, bacteria of the genus Yersinia, the species Yersinia pestis, Yersiniapseudotuberculosis, Yersinia enterocolitica and Yersinia ruckeri, bacteria of the familyMycoplasmataceae, of the généra Mycoplasma and Ureaplasma, in particular the speciesMycoplasma pneumoniae, bacteria of the genus Brucella, bacteria of the genus Bordetella,bacteria of the family Neisseriaceae, in particular of the généra Neisseria and Moraxella, inparticular the species Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis,bacteria of the family Vibrionaceae, in particular of the généra Vibrio, Aeromonas,Plesiomonas and Photobacterium, in particular the species Vibrio cholerae, Vibrioanguillarum and Aeromonas salmonicidas, bacteria of the genus Campylobacter, in particular -8- the species Campylobacter jejuni, Campylobacter coli and Campylobacter fétus, bacteria of the genus Hélicobacter, in particular the species Hélicobacter pylori, bacteria of the families

Spirochaetaceae and Leptospiraceae, in particular of the généra Treponema, Borrelia and

Leptospira, in particular Borrelia burgdorferi, bacteria of the genus Actinobacillus, bacteria of the family Legionellaceae, of the genus Légionella, bacteria of the family Rickettsiaceae andg family Bartonellaceae, bacteria of the généra Nocardia and Rhodococcus, bacteria of thegenus Dermatophilus, bacteria of the family Pseudomonadaceae, in particular of the généraPseudomonas and Xanthomonas, bacteria of the family Enterobacteriaceae, in particular ofthe généra Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia and Shigella,bacteria of the family Pasteurellaceae, in particular of the genus Haemophilus, bacteria of the ' θ family Micrococcaceae, in particular of the généra Micrococcus and Staphylococcus, bacteria of the family Streptococcaceae, in particular of the généra Streptococcus and Enterococcusand bacteria of the family Bacillaceae, in particular of the généra Bacillus and Clostridium.

Organophosphorus compounds and the dérivatives thereof are consequently suitable fortreating diphtheria, acné vulgaris, listérioses, swine erysipelas in animais, gas gangrené inhumans and animais, malignant oedema in humans and animais, tuberculosis in humans andanimais, leprosy and further mycobacterioses in humans and animais, paratuberculosis inanimais, plague, mesenterial lymphadenitis and pseudotuberculosis in humans and animais,choiera, légionnaires' disease, borreliosis in humans and animais, leptospiroses in humans andanimais, syphilis, Campylobacter enteritis infections in humans and animais, Moraxellakeratoconjunctivitis and serositis in animais, brucellosis of animais and humans, anthrax inhumans 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 the gastrointestinaltract. 25

Combinations with another antibiotic may also be used to treat the above-stated diseases.Isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, protionamide and dapsone arein particular suitable for combination préparations with other antiinfective agents for thetreatment of tuberculosis.

The described compounds, i.e. the organophosphorus compounds of the formula I and estersand amides and salts thereof exhibit strong cytotoxic activity against uni- and multicellularparasites, in particular against the causative organisms of malaria and sleeping sickness. Thecompounds used according to the invention are accordingly usable for the treatment ofinfective diseases which are caused in humans and animais by bacteria, parasites and fungi.The compounds are also suitable for the prévention of diseases which are caused by bacteria,

8 -9- parasites and fungi.

The organophosphorus compounds used according to the invention, which generally includefor tliis purpose pharmaceutically acceptable salts, amides, esters, a sait of such an ester oralso compounds which, on administration, provide the compounds used according to theinvention as métabolites or breakdown products (also known as "prodrugs"), may beformulated for administration in any suitable manner analogous to known agents having anantiinfective action (mixed with a non-toxic, pharmaceutically acceptable excipient).

Pharmaceutically acceptable salts of the compounds include salts which the compounds of theformula I used according to the invention form in their protonated form as an ammonium saitof inorganic or organic acids, such as hydrochloric acid, sulfuric acid, citric acid, maleic acid,fumaric acid, tartaric acid, p-toluenesulfonic acid.

Salts are also particularly pharmaceutically suitable, such as sodium sait, potassium sait,calcium sait, ammonium sait, ethanolamine sait, triethylamine sait, dicyclohexylamine saitand salts of an amino acid, such as arginine sait, aspartic acid sait, glutamic acid sait.

The activity of the substances is determined using a test System. This System is based upon invitro measurement of the inhibition of growth of bacteria, parasites, fungi or plants. Testmethods known to the person skilled in the art are in part used for this purpose.

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

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

Fungicidal activity is determined on the basis of inhibition of fungal growth on nutrient mediaand in liquid cultures.

Some of the microorganisms which are to be investigated may only be investigated in animalmodels. In this case, the appropriate models will then be used.

Substances which exhibit activity in in vitro measurement Systems are further investigated inin vivo models.

Antiparasitic, fungicidal or antibacterial activity is further evaluated in the appropriate animalmodels.

I f -10-

Screening for herbicidal activity is determined by means of al gai Systems and measurement ofisoprene émissions from 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 of individualcomponents, for example tablets, coated tablets, capsules, pills, suppositories and ampoules, 5 the active substance content of which corresponds to a fraction or multiple of an individualdose. The dosage units may contain, for example 1,2,3 or 4 individual doses or 1/2,1/3 or1/4 of an individual dose. An individual dose preferably contains the quantity of activesubstance which is administered at one time and usually corresponds to a whole, half, third orquarter of a daily dose. 10

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

Preferred pharmaceutical préparations which may be mentioned are tablets, coated tablets,capsules, pills, granules, suppositories, solutions, suspensions and émulsions, pastes,ointments, gels, creams, lotions, powders and sprays. Tablets, coated tablets, capsules, pillsand granules may contains the active substances together with conventional excipients, suchas (a) fillers and extenders, for example starches, lactose, cane sugar, glucose, mannitol andsilica, (b) binders, for example carboxymethylcellulose, alginates, gélatine,polyvinylpyrrolidone, (c) humectants, for example glycerol, (d) suspending agents, forexample agar-agar, calcium carbonate and sodium carbonate, (e) dissolution retardants, for 20 example paraffm and (f) résorption accelerators, for example quatemary ammoniumcompounds, (g) wetting agents, for example cetyl alcohol, glycerol monostearate, (h)adsorbents, for example kaolin and bentonite and (i) lubricants, for example talcum, calciumand magnésium stéarate and solid polyethylene glycols or mixtures of the substances stated in (a)to(i). 25

The tablets, coated tablets, capsules, pills and granules may be provided with conventionalcoatings and shells optionally containing opacifying agents and may also be composed suchthat they release the active substances only with a delay or preferably in a particular part ofthe intestinal tract, wherein polymeric substances and waxes may, for example, be used as thematrices. 30

The active substance or substances, optionally together -with one or more of the above-statedexcipients, may also be présent in microencapsulated form. -11 -

In addition to the active substance or substances, suppositories may contain conventionalwater-soluble or water-insoluble excipients, for example polyethylene glycols, fats, forexample cocoa butter and higher esters (for example 04 alcohol with 06 fatty acid) ormixtures of these substances.

In addition to the active substance or substances, ointments, pastes, creams and gels maycontain conventional excipients, for example animal and vegetable fats, waxes, 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, calciumsilicate and polyamide powder or mixtures of these substances. Sprays may additionallycontain 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, for examplewater, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylène glycol, dimethylformamide, oils, inparticularcottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol, glycerolformai, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters ormixtures of these substances.

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

In addition to the active substance or substances, suspensions may contain conventionalexcipients, such as liquid diluents, for example water, ethyl alcohol, propylene glycol,suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol andsorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agarand gum tragacanth or mixtures of these substances.

The stated formulations may also contain colorants, preservatives and odour- or flavour-enhanced additives, for example peppermint oil and eucalyptus oil, and sweeteners, forexample saccharin.

The active substances of the formula I should preferably be présent in the pharmaceuticalpréparations listed above in a concentration of approx. 0.1 to 99.5 wt.%, preferably fromapprox. 0.5 to 95 wt.%, of the complété mixture. -12-

Apart from the compounds of the formula I, the pharmaceutical préparations may also containfurther pharmaceutical active substances. 15 20 25 30

The compounds may be used together with hitherto described substances having antibacterial,antimycotic and antiparasitic properties. Such substances in particular include compoundswhich hâve already been used in therapeutic applications or are still used. Substances whichare suitable for this purpose are in particular those Iisted in the Red List or in Simon/Stille,Antibiokia-Therapie in Klinik und Praxis, 9th édition, 1998, Schatauer Verlag, or on theInternet at http://www.customs.treas.gov/imp-exp/rulings/harmoniz/hrml29.html· Thedérivatives 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, cefazolin group, cefuroximegroup, cefoxitin group, cefoxitin, cefotetan, çefmetazole, latamoxef, flomoxef, cefotaximegroup, cefozidime, ceftazidime group, ceftazidime, cefpirome, cefepime, conventionalcephalosporins, 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 B-lactamantibiotics, carbapenem, imipenem/cilastatin, meropenem, biapenem, aztreonam, β-lactamaseinhibitors, 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 acid antagoniste, sulfonamides, co-trimoxazole, trimethoprim, otherdiaminopyrimidine-sulfonamide combinations, nitrofurans, nitrofurantoin, nitrofurazone,gyrase inhibitors (quinolones), norfloxacin, ciprofloxacin, ofloxacin, sparfloxacin, enoxacin,fleroxacin, pefloxacin, lomefloxacin, Bay Y3118, nitroimidazoles, antimycobacterial agents,isoniazid, rifampicin, 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 dérivatives, protéinaseinhibitors, antimycotics, polyenes, amphotericin B, nystatin, natamycin, azoles, azoles forseptic therapy, miconazole, kétoconazole, itraconazole, fluconazole, UK-109,496, azoles fortopical use, clotrimazole, econazole, isoconazole, oxiconazole, bifonazole, flucytosine,griseofulvin, ciclopirox olamine, tolna&ate, naftifine, terbinafïne, amorolfine, 35 -13-

anthraquinones, betulinic acid, semianthraquinones, xanlhones, naphthoquinones, arylaminoalcohols, 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,ciprofloxacin, ofloxacin, artemisinin, dihydroartemisinin, 10b artemether, arteether,atresunate, atovàquone, suramin, melarsoprol, nifurtimox, stibogluconate sodium,pentamidine, amphotericin B, metronidazole, clioquinol, mebendazole, niclosamide,praziquantel, pyrantel, tiabendazole, diethylcarbamazine, ivermectin, bithionol, oxamniquine, metrifonate, piperazine, embonate

ÎO

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, niclosamide, mebendazole,pyrantel, tiabendazole, diethylcarbazine, piperazine, pyrivinium, metrifonate, oxamniquine,bithionol or suramin or two or more of these substances.

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

The stated préparations may be administered to humans and animais orally, rectally, 20 parenterally (intravenously, intramuscularly, subcutaneously), intracistemally, intravaginally, intraperitoneally, topically (powders, ointments, drops) and for the treatment of infections in cavities, body cavities. Suitable préparations which may be considered are solutions for injections, solutions and suspensions for oral therapy, gels, infusion formulations, émulsions, ointments or drops. Topical treatment may be performed using ophthalmological and25 dermatological formulations, silver and other salts, ear drops, eye ointments, powders orsolutions. Administration to animais may also be achieved via the feed or drinking water insuitable formulations. Gels, pulvérulent formulations, powders, tablets, controlled-releasetablets, premixes, concentrâtes, granules, pellets, tablets, boli, capsules, aérosols, sprays,inhalation formulations may also be used in humans and animais. The compounds usedaccording to the invention may also be incorporated into other supports, such as for exampleplastics (plastic chains for topical treatment), collagen or bone cernent.

It has in general proved advantageous in both human and veterinary medicine to administerthe active substances of the formula I in total quantities of approx. 0.05 to approx. 2000,preferably of 5 to 1000 mg/kg body weight per 24 hours, optionally in the form of two or 35 -14- X “7 Σ I /'

more individual doses in order to achieve the desired results. An individual dose preferablycontains the active substance or substances in quantities of approx. 0.25 to approx. 2000 mg,which are administered, for example, 1 to 4 times daily. It may, however, be necessary todeviate from the stated dosages, in particular as a function of the nature and body weight ofthe patient to be treated, the nature and severity of the disease, the nature of the préparationsand the route of administration of the pharmaceutical préparation and the period of time overwhich administration is performed.

Liquid préparations may be administered in the form of solutions, syrups, émulsions orsuspensions, which, for oral administration, contain for example 0.1 to 50 wt.% of activesubstance. In the case of topical administration in the form of solutions, gels, suspension orthe like, the active substance preferably amounts to between =.05 and 20 wt.% of thepréparation.

In some cases, it may accordingly be sufficient to use Iess than the above-stated quantity ofactive substance, while in other cases more than the above-stated quantity of active substancemust be used. The person skilled in the art will use his/her skill to détermine the optimumdosage and route of administration required in each particular case.

The compounds used according to the invention may be given to animais in conventionalconcentrations and préparations together with feed or feed préparations or with drinkingwater.

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

Example

Antiprotozoal action

The following substances are tested for their antiprotozoal activity:

Substance 1: 2-[(2-Ethoxycarbonylphenoxy)carbonyl]-l,3,2-dioxaphospholane 2-oxide

Substance 2: 2-[(2-Ethoxycarbonylphenoxy)carbonyl]-4-dodecanoyloxymethyl-l ,3,2- dioxaphospholane 2-oxide

Substance 3: 2-[(2-Ethoxycarbonylphenoxy)carbonyl]-4-octanoylthiomethyl-l ,3,2- dioxaphospholane 2-oxide

Substance 4: 2-[(2-EthoxycarbonyIphenoxy)carbonyl]-4-dodecanoylthiomethyl-l ,3,2- dioxaphospholane 2-oxide

Substance 5: 2-Hydroxyethyl-[(2-ethoxycarbonylphenoxy)carbonyl] sodium phosphonate

Substance 6: 2-Dodecanoyloxy-2-hy droxypropyl- [(2-ethoxycarbonylphenoxy)carbonyl]

-15- sodium phosphonate

Substance 7: 2-Octanoylthio-2-hydroxypropyl[(2-ethoxycarbonyl

Substance 8: 2-Dodecanoylthio-2-hydroxypropyl-[(2-ethoxycarbonylphenoxy)carbonyl] sodium phosphonate

Substance 9: Sodium 2-hydroxy-1,4,2-dioxaphosphorinane 2,3-dioxide

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

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

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

The antimalarial activity of substances 1 to 12 was determined using in vitro cultures of thecausative organism of malaria, Plasmodium falciparum. 200 μΐ of an asynchronousPlasmodium falciparum culture with a 0.4% blood parasite content and a haematocrit of 2%were loaded into each of the wells of a 96 well microtitre plate. A serial dilution sériés of thecompounds was then prepared in steps of three between concentrations of 100 and 0.14 pmolΓ1. The plates are incubated at 37°C, 3% CO2 and 5% O2 over a period of 48 hours. 30 μΐ ofmedium supplemented with 27 pCi ml'1 of [3H]-hypoxanthine were then added to each well.After 24 hours' incubation, the parasites were harvested by filtration through glass fibre filtersand the incorporated radioactivity was measured. Inhibition of parasite growth was measuredas the percentage inhibition of tritium incorporation. Inhibition of parasite growth wasmeasured as the percentage inhibition of tritium incorporation relative to a comparisonwithout the substance. The médian inhibitory concentration (IC50) of the substance wasdetermined by extrapolating the values.

The results, i.e. the IC50 values, are listed in the following table:

1 8 -16-

Table

Substance no. IC50/(nM) 1 415 2 357 3 518 4 653 5 215 6 640 7 517 8 387 9 946 10 384 11 862 12 751

Claims

-17-

T * · »Claims of a compound of the formula I O O

Wherein C1-26 alkyl residues, C2-26alkenyl residues with 1 to 6 double bonds, C2-26 alkynyl residues with 1 to 6 triple bonds, Ci-26 acyl residues , Ar-Co-26-alkyl residues, C3-8-cycloalkyl-Co-26-alkyl residues, C3-8-heterocycloalkyl-Co-26-alkyl residues with one or two nitrogen, oxygen or sulfur atoms, halogen and OXn, C1-9alkyl, C1-9 alkoxy, hydroxy, amino, halogen or oxo groups, wherein Cj.26 alkyl residues, C2-26, are selected from the group consisting of alkenyl residues with 1 to 6 double bonds, C2-26 alkynyl residues with 1 to 6 triple bonds, Ar-Co-26-alkyl residues, C3.8 cycloalkyl residues, C1.26 acyl residues, C3.8-heterocycloalkyl-Co-26 Alkyl residues with one or two nitrogen, oxygen or sulfur atoms, cis-silyl residues, wherein the above-mentioned residues may be substituted with C1-9alkyl, C1-9alkoxy, hydroxy, amino, halogen or oxo groups. CIPO - Patent - 254803 Canadian Intellectual Property Office Symbol of the Government of Canada CA 2371897 AMORINATION OF ANTIMICALLY ORGANIC ORAL PHARMACEUTICES, AMMUNITION OF AMMONIUM OR AMINO ACID AMINO ACIDS AMMUNITIONED FROM C, -C3.8 cycloalkyl residues, C3-8-cycloalkyl-C1-24-alkyl residues, C1-24alkoxy residues, C1-24 alkylthio residues, C1-24-alkoxy-C1-24-alkyl residues. and C1.24-alkylthio-C1-24-alkyl residues, acyl residues, Ar- (C1-24) -alkyl residues, C3.8-heterocycloalkyl-Co-24-alkyl residues, halogen and hydrogen, and each C1-24 Alkyl residues may be branched or substituted with 2 to 6 double bonds and may be substituted with hydroxy, amino, mercapto, halogen, oxo groups or C1-24 alkoxy residues, C1-24 alkylcarbonyloxy residues. , C1-24alkoxycarbonyloxy residues, C1.24 alkylthio residues, C1.24 alkylcarbonylthioresidu Es, C1.24 alkylamino residues, di- (C1-24alkyl) amino residues, C1.24-alkylcarbonylamino residues, C1-24-alkyl (C1-24alkylcarbonyl) amino residues, C1-24alkoxycarbonylamino residues. or C1-24-alkyl- (C1-24alkoxycarbonyl) amino residues, each aralkyl residue, heterocyclic residue, C1-24 alkyl residue and C1-24 alkoxyresidue may be branched or unbranched and be saturated or unsaturated with 2 to 6double bonds gold triple bonds, or in which R1-CH-CH-R2 forms part of a C4.8 carbon ring, which may optionally besubstituted with hydroxy, mercapto, amino, halogen, oxo groups or with C1.24 alkylresidues, C1-24 alkoxy residues, C1.24 alkylthio residues, C1.24 alkylamino residues, di- (C1-24alkyl) aniino residues, C1-24alkylcarbonyl residues, C1-24alkylcarbonyloxy residues, C1-24alkoxycarbonyl residues, C1-24 alkylcarbonylthio residues gold C1.24 alkylcarbonylaminoresidues, C1-24-alkyl- (C1-24alkylcarbonyl) amino residues, each C1.24 alkylresidue may be branched or unbranched and A single branch of the ring or a branch of the ring or a branch of the ring or a ring of a sugar, forexample D-ribose, D-arabinose, and R1-CH-CH-R2 forms , D-xylose, D-lyxose, D-glucose, D-galactose, D-mannose, D-Talose, D-allose, D-altrose, D-gulose, D-idose or the corresponding C1.24 alkoxy residues, C1.24 alkylthio residues, C1-24 alkylamino residues, di- (C1-24alkyl) amino residues, C1.24 alkylcarbonyloxyresidues, , C1.24 alkylcarbonylthio residues, C1-24 alkylcarbonylamino residues, C1-24alkyl- (C1-24alkylcarbonyl) amino residues, each C1-24 alkyl residue may be branched orunbranched and be saturated or unsaturated with 1 to 6 double esters, and the pharmaceutically acceptable salts, esters and amides thereof and salts of the esters and the optical isomers thereof, for the prophylactic These bacteria are caused by bacteria, fungi or parasites and have a fungicide, bactericidal orherbicide in plants.

2. wherein according to claim 1, characterized in that R 1 and R 2 are each independently selected from the group consisting of carboxyl residues, carboxamido residues, aryl residues, aryloxycarbonyl residues, aryl-Ci.24-alkyl residues, C1-24 alkoxycarbonyloxy residues, C1-24 alkylaminocarbonyl residues, di- (C1-24-alkyl) aminocarbonyl residues, aryl-C1-24-alkoxycarbonyl residues, aryl-C1-24-alkylaminocarbonyl residues, C1-24-alkylcarbonyloxy- (C1-24) alkylmethoxycarbonyl residues, C1-24alkoxycarbonyloxymethoxycarbonyl residues, C1-24alkoxycarbonyloxy- (CM-alkyl) methoxycarbonyl, C1-24 alkyl residues may be branched or unbranchedand be saturated or unsaturated with 2 to 6 double bonds, and each

-19- Alkyl residue may be branched or unbranched and saturated or unsaturated, andeach aryl residue is of formula II

(II) wherein R3 and R4 are selected from the group consisting of hydrogen, halogen, C1-alkyl residues, C1-alkoxy residues, formyl, acetyl, propionyl, butyryl residues, formyloxy, acetyloxy, propionyloxy, butyryloxy residues, As alkoxycarbonyl residues, unbranched gold, or R3 and R4together forms an unbranched saturated alkylene chain with 3 to 4 carbon atoms, which is attached to adjacent positions on the phenyl ring, or R3 and R4 together form amethylenedioxy residue, 1,1-ethylidenedioxy residue, 1,1-ethenylenedioxy residue, 1,1,1-ethylenedioxy residue or 1,2-ethylenedioxy residue, which are attached to adjacentpositions of the phenyl ring, gold

Reactions in which R 1 and R 2 are each independently selected from the group consisting of hydrogen groups, acetyl groups, formyl groups, hydroxy groups and methyl groups, and wherein the group may be substituted with a hydroxy group or a mercapto group. with C1-24 alkoxy residues, C1.24 alkylcarbonyloxyresidues, C1.24 alkylthio residues or C1.24 alkylcarbonylthio residues, wherein the C1.24alkyl groups and C1.24 alkoxy groups may be branched or unbranched and be saturated orunsaturated with 1 to 6 double leaps.

4. Where it is a methyl residue, which may be substituted with a hydroxy group or a mercapto group with C1.24 alkoxy residues, C1-24 alkylcarbonyloxy residues, C1.24 alkylthio residues or C1-24 alkylcarbonylthio residues C1.24 alkyl groups and C1.24 alkoxy groups may be branched or unbranched and may be saturated or unsaturated with 1 to 6 double bonds, and R2 is a hydrogenated residue.

.5. R and R2 are each independently selected from the group consisting of hydrogen and n-octadecylmethyl residue. 117 18 10 15 20 25 30 -20-

6. Use according to claim 5, which is a n-octadecylmethyl residue and R2 a hydrogenresidue.

7. Use according to claim 6, the compound is in (R) configuration.

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

9. Propagation of bacteria in the family of Propionibacterium acnes, in particular of the genus Propionibacterium, in particular thespecies Propionibacterium acnes, bacteria of the family Actinomycetaceae particularof the genus Actinomyces, bacteria of the genus Comynebacterium, in particular thespecies Corynebacterium diphtheriae and Corynebacterium pseudotuberculosis, bacteria of the family Mycobacteriaceae, of the genus Mycobacterium, in particular speciesMycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium, bacteria of the family Chlamydiaceae, in particular the speciesChlamydia trachomatis and Chlamydia psittaci, bacteria of the genus Listeria, in particular species Listeria monocytogenes, bacteria of the species Erysipelthrixrhusiopathiae, bacteria of the genus Clostridium, bacteria of the genus Yersinia, thespecia Yersinia pestis, Yersinia pseudotuberculosis, Yersinia enterocolitica and Yersiniaruckeri, bacteria of the family Mycoplasmataceae, of the genus Mycoplasma andUreaplasma, in particular the species Mycoplasma pneumoniae, bacteria of the genusBrucella, bacteria of the genus Bordetella, bacteria of the family Neisseriaceae, inparticular of The genera Neisseria and Moraxella, in particular the species Neisseriameningitides, Neisseria gonorrhoeae and Moraxella bovis, bacteria of the familyVibrionaceae, in particular of the genera Vibrio, Aeromonas, Plesiomonas andPhotobacterium, in particular the species Vibrio cholerae, Vibrio anguillarum andAeromonas salmonicidas, bacteria of the genus Campylobacter, in particular the speciesCampylobacter jejuni, Campylobacter coli and Campylobacter fetus, bacteria of the genus Helicobacter, in particular the species Helicobacter pylori, bacteria of the familySpirochaetaceae and Leptospiraceae, in particular of the genus Treponema, Borreli andLeptospira, in particular Borrelia burgdorferi, bacteria of the genus Actinobacillus, bacteria of the family Legionellaceae, of the genus Legionella, bacteria of the familyRickettsiaceae and family Bartonellaceae, bacteria of the genus Nocardia andRhodococcus, bacteria of the genus Dermatophilus, bacteria of the familyPseudomonadaceae , in particular of the genus Pseudomonas and Xanthomonas, bacteria of the family Enterobacteriaceae, in particular of the genus Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia and Shigella, bacteria of the family 35 -21 - 117 18 Pasteurellaceae, in particular of the genus Haemophilus, bacteria of the familyMicrococcaceae, in particular of the genus Micrococcus and Staphylococcus, bacteria of the family Streptococcaceae, in particular of the genus Streptococcus and Enterococcusand bacteria of the family Bacillaceae, in particular of the genera Bacillus andClostridium, and in the eradication of Helicobacter in ulcers of the gastrointestinal tract.

10. The use of the disease is one of the causes of the causative organism of malaria, sleeping sickness, Chagas' disease, toxoplasmosis, amoebicdysentery, leishmaniasis, trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiosis, sarcocytosis, acanthamoebosis, naeglerosis, coccidiosis, giardiasis andlambliasis.

11. Process for the treatment of infectious diseases caused by bacteria, fungi or parasites inwhich a therapeutically effective amount of a compound according to one of suedes 1 to 7 is administered to a patient suffering from an infection caused by bacteria, fungi orparasites. 15