OA11717A - Use of phosphonoformic acid derivatives for treating infections. - Google Patents

Abstract

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

Description

-1- U 7 î 7

Use of phosphonoformic acid dérivatives for the treatment of infections

This invention relates to the use of phosphonoformic acid dérivatives for the therapeutic andprophylactic treatment of infections in humans and animais caused by bacteria, fungi andparasites, and to the use thereof as a fungicide, bactéricide and herbicide in plants. According 5 to the invention, the phosphonoformic acid dérivatives comprise the physiologicallycompatible 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, 4 665 062 and 4 771 041. 10 In particular, the antiviral action of phosphonoformic acid dérivatives and the productionthereof hâve already been described in WO 98/16537.

In order to widen the range of options for treating humans and animais and for protecting• plants, 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-15 effects or reduced environmental impact and thus constitute a reduced risk to human health.

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 defîned in claim 1. This20 group of substances exhibits both an antiinfective action against bacteria, fungi and uni- and multicellular parasites and a fungicidal, bactericidal and herbicidal action in plants.

The organophosphorus compounds used according to the invention are of the general formula(I): -2- 117 17

in which the zigzag line represents a bond which has either a- or β-configuration, n is 0 or 1, in winch Ru is selected from the group which consists of Ci.26 alkyl residues, C2-26 alkenylresidues with 1 to 6 double bonds, C2-26 alkynyl residues with 1 to 6 triple bonds, Cj_26 acyl 5 residues, Ar-Co-26-alkyl residues, Ca.g-cycloalkyl-Co^ô-alkyl residues, Ca.g-heterocycloalkyl-Co-26-alkyl residues with one or two nitrogen, oxygen or sulfur atoms, halogen and OXj 1,wherein ail the above-stated residues may be 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, C1.26 alkyl residues, C2-26 10 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, Ci_26 acyl residues, C3.8-heterocycloalkyl-C0.26-alkyl residues with one or two nitrogen, oxygen or sulfur atoms, Cj.26 silyl residues, whereinail the above-stated residues may be substituted with Ci-9 alkyl, Ci.9 alkoxy, hydroxy, amino,halogen or oxo groups and consists of a cation of an organic and inorganic base, in particular , 15 a métal of main groups I, II or III of the periodic System, ammonium, substituted ammoniumand ammonium compounds derived from ethylenediamine or amino acids, in which Ri is selected from the group which consists of C1.24 alkyl residues, C2-24 alkenylresidues with 1 to 6 double bonds, C2-24 alkynyl residues with 1 to 6 triple bonds, C3.8cycloalkyl residues, C3-8-cycloalkyl-Ci.24-alkyl residues and Ci.i2-alkoxy-Ci.i2-alkyl residues, 20 wherein ail the residues may be branched or unbranched and may optionally be substitutedwith C1.9 alkyl, C1.9 alkoxy, hydroxy, amino, halogen or oxo groups,

in which R2, R3 and R4 are each independently selected from the group which consists ofhydrogen, halogen, amino, acetylamino, azido and XRg groups, wherein X is O or S and R$ isselected from the group which [consists] of a hydrogen residue, branched or unbranched CM 25 alkyl residues and C2-4 alkenyl residues, wherein both the Cm <4 ' ί 7 -3- alkenyl residues may optionally be substituted with hydrogen, amino, halogen or oxo groups,or R2, R-3 and R4 together with the particular geminal hydrogen group dénoté an oxo group,

Rs is selected from the group which consists of hydrogen, Ci.24 alkyl residues, C3-8 cycloalkyl5 groups, Ar-(Co.24-alkyl) residues, C3.8-heterocycloalkyl-C0-24-alkyl residues with one or two nitrogen, oxygen or sulfur atoms, halogen, wherein ail the residues may be branched orunbranched and may optionally be substituted with hydroxy, amino, halogen, oxo groups, C1.4alkyl groups, C1-4 alkoxy groups, formyl, acetyl, propionyl, butyryl groups and C2-5alkoxycarbonyl groups or may contain 1-6 double or triple bonds, wherein, if R5 is an Ar-(Ci.24-alkyl) group, two adjacent alkyl residues or alkoxy residues may also form a 5-6-memberedcyclic ring, or R5 is selected from the group which consists of R9COOCHR10 and R9OCOOCHR10,wherein R9 is selected from the group which consists of Ci.6 alkyl residues, C2-6 alkenylresidues, C2-6 alkynyl residues, C3-8 cycloalkyl residues, C3.8-cycloalkyl-Ci.6-alkyl residues *5 and Ci-6-alkoxy-Ci_6-alkyl residues, wherein ail the residues may be branched or unbranchedand may optionally be substituted with hydroxy, amino, halogen or oxo groups, andRio is a branched or unbranched Ch alkyl residue, and wherein the configurations of the substituents R2, R3, R4 and R5OOCPO(OH)OCH2 in Iare independently from among D-gluco, L-gluco, D-galacto, L-galacto, D-manno, L-manno, 20 D-talo, L-talo, D-allo, L-allo, D-altro, L-altro, D-gulo, L-gulo, D-ido or L-ido, if n is 1, or theconfigurations of the substituents R2, R3 and R5OOCPO(OH)OCH2 in I are independentlyfrom among D-ribo, L-ribo, D-arabino, L-arabino, D-xylo, L-xylo, D-lyxo or L-lyxo, if n is 0.

The glycosidic bond in the compounds according to the invention is preferably in a. configuration.lt is furthermore preferred that R5 is a phenyl residue of the formula II or III,

(II) -4- 117)7 (III)

wherein R7 and Rs are identical or different and are attached to the phenyl ring at any twopositions and are each independently selected from the group which consists of hydrogen,halogen, Cm alkyl residues, Cm alkoxy residues, formyl, acetyl, propionyl, butyryl residues,formyloxy, acetyloxy, propionyloxy, butyryloxy residues, C2.5 alkoxycarbonyl residues, ail of 5 which may be branched or unbranched, or R7 and Rs together forai an unbranched saturated alkylene chain with 3 to 4 carbon atoms,which is attached to adjacent positions, for example the 2,3 positions or 3,4 positions of thephenyl ring or R7 and Re together form a methylenedioxy residue, a 1,1 -ethylidenedioxy residue, 1,1- 10 ethenylenedioxy residue, a 1,1-ethylenedioxy residue or a 1,2-ethylenedioxy residue, whichare attached to the 2,3 or 3,4 positions of the phenyl ring.

Preferred compounds of the formula I are moreover those in which R] is selected from thegroup which consists of C9.24 alkyl residues, C9-24 alkenyl residues with 1 to 6 double bonds,C9-24 alkynyl residues with 1 to 6 triple bonds, C3.g-cycloalkyl-C6-24-alkyl residues and Ci.2- 15 aIkoxy-Cg.M-alkyl residues, each of which may optionally be branched or unbranched andmay be substituted with hydrogen, amino, halogen or oxo residues.

In particular, it is preferred to use those compounds in which Ri is selected from the groupwhich consists of an n-tetradecyl residue, n-octadecyl residue, a Zzww-9-octadecen-l-ylresidue and a c/j-9-octadecen-l-yl residue. R2, R3, R4 are preferably each a hydroxy group. R5 20 is preferably a hydrogen. Moreover, n is preferably 1 and the configuration of the substituentsR2, R3, Ra and R5OOCPO(OH)OCH2 is D-gluco.

Ri 1 preferably dénotés OXn where Xn = hydrogen. -5- example mesyl, ethanesulfonyl, propanesulfonyl etc.); alkoxycarbonyl (for examplemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl etc.); alkylcarbamoyl (for example methylcarbamoyl etc.); (N-alkyl)thiocarbamoyl (for example (N-methyl)thiocarbamoyl etc.); alkylcarbamimidoyl (for 5 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, 1° 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. 15 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 the like; suitable examples are stated below: aroyl (for example benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl etc.); aralkanoyl (forexample 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,naphthalenesulfonyl etc.); aryloxycarbonyl (for example phenoxycarbonyl, naphthyloxycarbonyl etc.); aralkoxycarbonyl (for example benzyloxycarbonyl etc.); 25 arylcarbamoyl (for example phenylcarbamoyl, naphthylcarbamoyl etc.); arylglyoxyloyl (forexample phenylglyoxyloyl etc.).

In the above-stated Examples of aromatic acyl residues, the aromatic hydrocarbon moiety (inparticular 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 the 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.); ^5 arylcarbamimidoyl (for example phenylcarbamimidoyl etc.). 11/17 -6- WO 98/16537 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 5 multicellular parasites and fungi.

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 and Λ lambliasis.

They are accordingly in particular suitable for the prophylactic treatment of malaria and ofsleeping sickness -Ί -

They aie 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. 5 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 Propionibacterium, inparticular the species Propionibacterium acnés, bacteria of the family Actinomycetaceae, inparticular of the genus Actinomyces, bacteria of the genus Cornynebacterium, in particular W the species Corynebacterium diphtheriae and Corynebacterium pseudotuberculosis, bacteriaof the family Mycobacteriaceae, of the genus Mycobacterium, in particular the speciesMycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis andMycobacterium avium, bacteria of the family Chlamydiaceae, in particular the speciesChlamydia trachomatis and Chlamydia psittaci, bacteria of the genus Listeria, in particular the 15 species Listeria monocytogenes, bacteria of the species Erysipelthrix rhusiopathiae, bacteriaof 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 25 the species Campylobacter jejuni, Campylobacter coli and Campylobacter fétus, bacteria ofthe genus Hélicobacter, in particular the species Hélicobacter pylori, bacteria of the familiesSpirochaetaceae and Leptospiraceae, in particular of the généra Treponema, Borrelia andLeptospira, in particular Borrelia burgdorferi, bacteria of the genus Actinobacillus, bacteria ofthe family Legionellaceae, of the genus Légionella, bacteria of the family Rickettsiaceae and 3° family Bartonellaceae, bacteria of the généra Nocardia and Rhodococcus, bacteria of the genus 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 35 family Micrococcaceae, in particular of the généra Micrococcus and Staphylococcus, bacteriaof the family Streptococcaceae, in particular of the généra Streptococcus and Enterococcusand bacteria of the family Bacillaceae, in particular of the généra Bacillus and Clostridium. 7 -8 -

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 in 5 animais, 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, 10 psittacosis/ortnithosis in animais, Q fever, ehrlichiosis.

Use is furthermore effective in the éradication of Hélicobacter in ulcers of the gastrointestinaltract.

Combinations with another antibiotic may also be used to treat the above-stated diseases.Isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, protionamide and dapsone are 15 in particular suitable for combination préparations with other antiinfective agents for thetreatment of tuberculosis.

The described compounds, i.e. the organophosphorus compounds of the formulae 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. The 20 compounds used according to the invention are accordingly usable for the treatment of infective 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,parasites and fungi.

The organophosphorus compounds used according to the invention, which generally include 25 for this 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 suitablemanner analogous to known agents having anantiinfective action (mixed with a non-toxic, pharmaceutically acceptable excipient). 30 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. ........1 ‘ -9-

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 in5 vitro measurement of the inhibition of growth of bacteria, parasites, fungi or plants. Test methods 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 be used.

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

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

Screening for herbicidal activity is determined by means of algal Systems and measurement of 2® isoprene 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,the active substance content of which corresponds to a fraction or multiple of an individual 25 dose. 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.

Non-toxic, inert, pharmaceutically suitable excipients should be taken to mean sùlid, semi-solid or liquid diluents, fillers and formulation auxiliaries of ail kinds. A-.. - 10-

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, such 5 as (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, forexample paraffîn and (f) résorption accelerators, for example quaternary ammonium 10 compounds, (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).

The tablets, coated tablets, capsules, pills and granules may be provided with conventional 15 coatings 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 oftire intestinal tract, wherein polymeric substances and waxes may, for example, be used as thematrices.

The active substance or substances, optionally together with one or more of the above-stated 20 excipients, may also be présent in microencapsulated form.

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 C14 alcohol with Cl6 fatty acid) ormixtures of these substances. 25 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 contain 30 conventional excipients, for example lactose, talcum, silica, aluminium hydroxide, calciumsilicate and polyamide powder or mixtures of these substances. Sprays may additionallycontain conventional propellants, for example chlorofluôrocarbons. 1 i 7 4 η - Il -

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, in particular 5 cottonseed 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. 0 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. 5 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 from 5 approx. 0.5 to 95 wt.%, of the complété mixture.

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

The compounds may be used together with hitherto described substances having antibacterial,antimycotic and antiparasitic properties. Such substances in particular include compounds * which hâve already been used in therapeutic applications or are still used. Substances whichare suitable for this purpose are in particular tliose listed 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 grôup, cefuroximè"group, cefoxitin group, cefoxitin, cefotetan, cefmetazole, latamoxef, flomoxef, cefotaxime i 4 ~7 4 “γ -12- group, 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-lactam 5 antibiotics, carbapenem, imipenem/cilastatin, meropenem, biapenem, aztreonam, B-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, 10 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, 15 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, 20 idoxuridine, trifluridine, foscarnet, 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, tolnafnate, naftifîne, terbinafine, amorolfîne, 25 anthraquinones, betulinic acid, semianthraquinones, xanthones, 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, 30 ciprofloxacin, ofloxacin, artemisinin, dihydroartemisinin, 10b artemether, arteether,atresunate, atovaquone, suramin, melarsoprol, nifurtimox, stibogluconate sodium,pentamidine, amphotericin B, metronidazole, clioquinol, mebendazole, niclosamide,praziquantel, pyrantel, tiabendazole, diethylcarbamazine, ivermectin, bithionol, oxamniquine,metrifonate, piperazine, embonate. 35 The organophosphorus compounds may furthermore be présent in the pharmaceutical préparations in combination with sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine,chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamirié, afmesin,tetracyclines, doxycycline, proguanil, metronidazole, praziquantel, niclosamide, mebendazole,

*· “Ί A -13 - 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 excipient 5 or excipients.

The stated préparations may be administered to humans and animais orally, rectally,parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally,intraperitoneally, topically (powders, ointments, drops) and for the treatment of infections incavities, body cavities. Suitable préparations which may be considered are solutions for 10 injections, solutions and suspensions for oral therapy, gels, infusion formulations, émulsions,ointments or drops. Topical treatment may be performed using ophthalmological anddermatological 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-release 15 tablets, 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 administer 20 the active substances of the formula I in total quantifies 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 ormore individual doses in order to achieve the desired results. An individual dose preferablycontains the active substance or substances in quantifies of approx. 0.25 to approx. 2000 mg,which are administered, for example, 1 to 4 times daily. It may, however, be necessary to 25 deviate 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 or 30 suspensions, 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 =0.05 and 20 wt.% of thepréparation.

11 7 P -14- Ιη some cases, it may accordingly be sufficient to use less 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 ail will use his/her skill to détermine the optimumdosage and route of administration required in each particular case. 5 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.

Substance 4Substance 5Substance 6Substance 7

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

Example

The following substances are tested for antimalarial activity:

Disodium n-octadecyl-cc-D-glycopyranosid-6-yl carboxyphosphonate Substance 1

Disodium cz\-9-octadecen-l-yl-a-D-glycopyranosid-6-yl carboxyphosphonate Substance 2Disodium frans-9-octadecen-l-yl-a-D-glycopyranosid-6-yl carboxyphosphonate Substance 315 Disodium n-tetradecyl-oc-D-glycopyranosid-6-yl carboxyphosphonate

Disodium n-tetradecyl-P-D-glycopyranosid-6-yl carboxyphosphonateDisodium n-dodecyl-a-D-glycopyranosid-6-yl carboxyphosphonateDisodium n-eicosyl-p-D-galactopyranosid-6-yl carboxyphosphonate

The antimalarial activity of substances 1 to 7 was tested on mice which had been infected 20 with the murine malaria pathogen Plasmodium vinckei. The test was performed in accordancewith a modified Peters protocol [W. Peters, Malaria, J.P. Kreier, Ed., Academie Press, NewYork 1980, Vol. 1, pages 160-161]. To this end, mice were each infected on day 0 with 107infected érythrocytes by intraperitoneal (i.p.) injection. Successfol infection was confirmed onday 1 by Giemsa-stained blood smears. Treatment was performed on days 1 to 4 by twice 25 daily i.p. injections of various doses of the substances. Three to four mice were treated at eachdose. On day 5, the blood parasite contents of the treated mice and untreated Controls weredetermined by blood smears. The percentage decrease in blood parasite contents of the treatedanimais relative to the Controls was calculated. These data were used to extrapolate to theconcentration of the drug at which the blood parasite content falls to 50% (ED50). 30 The results, i.e. ED50 values, are listed in the following table:

-15-Table

Substance no. ED50/(mg/kg) 1 240 2 320 3 570 4 180 5 280 6 370 7 420

Claims (14)

1. « ï f

   -16- Patent Claims

   1. Use of a compound of the formula I

   in which the zigzag line represents a bond which has either a- or β-configuration, in which n is 0 or 1, 5 in which Ri i is selected from the group which consists of Ci .26 alkyl residues, C2-26 alkenyl residues with 1 to 6 double bonds, C2-26 alkynyl residues with 1 to 6 triple bonds,Ci-26 acyl residues, Ar-C0-26-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 be substituted with C1.9 tO alkyl, C1.9 alkoxy, hydroxy, amino, halogen or oxo groups, wherein Xn is selected from the group which consists of hydrogen, C1-26 alkyl residues,C2-26 alkenyl residues with 1 to 6 double bonds, C2-26 alkynyl residues with 1 to 6 triplebonds, 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, 15 Ci-26 silyl residues, wherein ail the above-stated residues may be substituted with C1-9 alkyl, C1.9 alkoxy, hydroxy, amino, halogen or oxo groups and consists of a cation of anorganic and inorganic base, in particular a métal of main groups I, II or III of the periodicSystem, ammonium, substituted ammonium and ammonium compounds derived fromethylenediamine or amino acids, 20 in which Ri is selected from the group which consists of Ci.24 alkyl residues, C2.24 alkenyl residues with 1 to 6 double bonds, C2-24 alkynyl residues with 1 to 6 triple bonds,C3-8 cycloalkyl residues, C3-8-cycloalkyl-Ci-24-alkyl residues and Ci.n-alkoxy-Cj-n-alkylresidues, wherein ail the residues may be branched or unbranched and may optionally besubstituted with Ci I ! ί ί 7 -17- .9 alkyl, Ci-9 alkoxy, hydroxy, amino, halogen or oxy groups, in which R2, R3 and R4 are each independently selected from the group which consists ofhydrogen, halogen, amino, acetylamino, azido and XRô groups, wherein X is O or S and is selected from the group which consists of a hydrogen residue, branched or5 unbranched Cm alkyl residues and C2-4 alkenyl residues, wherein both the Ci.4 alkyl residues and the C2-4 alkenyl residues may optionally be substituted with hydrogen,amino, halogen or oxo groups, or R2, R3 and R4 together with the particular geminal hydrogen group dénoté an oxo group, Rs is selected from the group which consists of hydrogen, C1.24 alkyl residues, C3.8cycloalkyl residues, Ar-(Co-24-alkyl) residues, C3.8-heterocycloalkyl-C0-24-alkyl residueswith one or two nitrogen, oxygen or sulfur atoms, halogen, wherein ail the residues maybe branched or unbranched and may optionally be substituted with hydroxy, amino,halogen, oxo groups, Cm alkyl groups, Cm alkoxy groups, formyl, acetyl, propionyl,butyryl groups and C2-5 alkoxycarbonyl groups or may contain 1-6 double or triple bonds, 15 wherein, if R5 is an Ar-(Ci_24-alkyl) group, two adjacent alkyl residues or alkoxy residuesmay also form a 5-6-membered cyclic ring, or Rs is selected from the group which consists of R9COOCHR10 and R9OCOOCHR10,wherein R9 is selected from the group which consists of Cm alkyl residues, C2-6 alkenylresidues, C2-6 alkynyl residues, C3.8 cycloalkyl residues, C3-8-cycloalkyl-Ci.6-alkyl 20 residues and CM-alkoxy-CM-alkyl residues, wherein ail the residues may be branched orunbranched and may optionally be substituted with hydroxy, amino, halogen or oxogroups, and Rio is a branched or unbranched Cm alkyl residue, and in which the configurations of the substituents R2, R3, R4 and R5OOCPO(OH)OCH2 25 in I are independently from among D-gluco, L-gluco, D-galacto, L-galacto, D-manno, L-manno, D-talo, L-talo, D-allo, L-allo, D-altro, L-altro, D-gulo, L-gulo, D-ido or L-ido, ifn is 1, or the configurations of the substituents R2, R3 and RsOOCPO(OH)OCH2 in I areindependently from among D-ribo, L-ribo, D-arabino, L-arabino, D-xylo, L-xylo, D-lyxoor L-lyxo, if n is 0. and the pharmaceutically acceptable salts, esters and amides thereof and salts of the estersand the optical isomers thereof

   -18- for the production of a pharmaceutical préparation for the prophylactic and therapeutictreatment of infectious processes in humans and animais which are caused by bacteria,fungi or parasites and as a fungicide, bactéricide or herbicide in plants.
2. 2. Use according to claim 1, characterised in that R5 is a phenyl residue of the formula II orIII, :n:

   (III) wherein R7 and R8 are identical or different and are attached to the phenyl ring at any twopositions and are each independently selected from the group which consists of hydrogen,halogen, Cm alkyl residues, Cm alkoxy residues, formyl, acetyl, propionyl, butyrylresidues, formyloxy, acetyloxy, propionyloxy, butyryloxy residues, C2-s alkoxycarbonyl 10 residues, ail of which may be branched or unbranched, or R7 and R8 together form an unbranched saturated alkylene chain with 3 to 4 carbonatoms, which is attached to adjacent positions, for example the 2,3 positions or 3,4positions of the phenyl ring or R7 and R8 together form a methylenedioxy residue, a 1,1-ethenylenedioxy residue, a 1,1- 15 ethylidenedioxy residue, a 1,1 -ethylenedioxy residue or a 1,2-ethylenedioxy residue, which are attached to the 2,3 or 3,4 positions of the phenyl ring.
3. 3. Use according to claim 1, characterised in that R5 is a hydrogen.
4. 4. Use according to one of daims 1 to 3, wherein Ri is selected from the group whichconsists of C9-24 alkyl residues, C9.24 alkenyl residues with 1 to 6 double bonds, C9.24 20 alkynyl residues, C3.8-cycloalkyl6.24-alkyl residues and Ci.i2-alkoxy8-i2-alkyl residues. 4 4 ~7 4 if ϊ ' -19-
5. 5. Use according to claim 4, wherein Ri is selected from the group which consists of an n-tetradecyl residue, n-octadecyl residue, a irans-9-octadecen-l-yl residue and a cis-9-octadecen-l-yl residue.
6. 6. Use according to one of the preceding daims, wherein R2, R3, R4 are each a hydroxy5 group.
7. 7. Use according to one of the preceding daims, wherein the glycosidic bond is in occonfiguration.
8. 8. Use according to one of daims 1 to 6, wherein the glycosidic bond is in β configuration.
9. 9. Use according to one of daims 1 to 8, wherein n is 1.
10. 10. Use according to one of daims 1 to 9, wherein the configuration of the substituents R2, R3, Rt and R5OOCPO(OH)OCH2 is D-gluco.
11. 11. Use according to one of the preceding daims for the treatment of infections caused bybacteria, ftmgi or uni- or multicellular parasites.
12. 12. Use according to claim 11 for the treatment of infections which are caused by bacteria 15 which are selected from the group which consists of bacteria of the family Propionibacteriaceae, in particular of the genus Propionibacterium, in particular thespecies Propionibacterium acnés, bacteria of the family Actinomycetaceae, in particularof the genus Actinomyces, bacteria of the genus Comynebacterium, in particular thespecies 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 andMycobacterium avium, bacteria of the family Chlamydiaceae, in particular the speciesChlamydia trachomatis and Chlamydia psittaci, bacteria of the genus Listeria, inparticular the species Listeria monocytogenes, bacteria of the species Erysipelthrix 25 rhusiopathiae, bacteria of the genus Clostridium, bacteria of the genus Yersinia, the species Yersinia pestis, Yersinia pseudotuberculosis, Yersinia enterocolitica and Yersiniaruckeri, bacteria of the family Mycoplasmataceae, of the généra 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 généra Neisseria and Moraxella, in particular the species Neisseriameningitides, Neisseria gonorrhoeae and Moraxella bovis, bacteria of the familyVibrionaceae, in particular of the généra i [/17 -20- Vibrio, Aeromonas, Plesiomonas and Photobacterium, in particular the species Vibriocholerae, Vibrio anguillarum and Aeromonas salmonicidas, bacteria of the genusCampylobacter, in particular the species Campylobacter jejuni, Campylobacter coli andCampylobacter fétus, bacteria of the genus Hélicobacter, in particular the speciesHélicobacter pylori, bacteria of the families Spirochaetaceae and Leptospiraceae, inparticular of the généra Treponema, Borrelia and Leptospira, in particular Borreliaburgdorferi, bacteria of the genus Actinobacillus, bacteria of the family Legionellaceae,of the genus Légionella, bacteria of the family Rickettsiaceae and family Bartonellaceae,bacteria of the généra Nocardia and Rhodococcus, bacteria of the genus Dermatophilus,bacteria of the family Pseudomonadaceae, in particular of the généra Pseudomonas andXanthomonas, bacteria of the family Enterobacteriaceae, in particular of the généraEscherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia and Shigella, bacteriaof the family Pasteurellaceae, in particular of the genus Haemophilus, bacteria of thefamily Micrococcaceae, in particular of the généra Micrococcus and Staphylococcus,bacteria of the family Streptococcaceae, in particular of the généra Streptococcus andEnterococcus and bacteria of the family Bacillaceae, in particular of the généra Bacillusand Clostridium, and in the éradication of Hélicobacter in ulcers of the gastrointestinaltract.
13. 13. Use according to claim 11 for the prévention and treatment of infections caused byunicellular parasites which are selected from the group winch consists of tire causativeorganisms of malaria, sleeping sickness, Chagas' disease, toxoplasmosis, amoebicdysentery, leishmaniases, trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiosis, sarcocytosis, acanthamoebosis, naeglerosis, coccidiosis, giardiasis andlambliasis.
14. 14. Process for the treatment of infectious diseases caused by bacteria, fungi or parasites inwhich a therapeutically effective quantity of a compound according to one of daims 1 to11 is administered to a patient suffering from an infection caused by bacteria, fungi orparasites.