CA2352511A1 - Use of phosphonoformic acid derivatives for treating infections - Google Patents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/04—Amoebicides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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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~ho~honoformic acid derivatives for the treatment of infections This invention relates to the use of phosphonoformic acid derivatives for the therapeutic and prophylactic treatment of infections in humans and animals caused by bacteria, fungi and parasites, and to the use thereof as a fungicide, bactericide and herbicide in plants. According to the invention, the phosphonoformic acid derivatives comprise the physiologically compatible salts, esters and amides.
Phosphonoformic acid derivatives are already known for their antiviral properties.
Pharmaceutical preparations for treating viral infections have already been described in US
patents 4 215 113, 4 339, and 4 6Ei~ 062 and 4 771 041.
In particular, the antiviral action of phosphonoformic acid derivatives and the production thereof have already been described in WO 98/16537 and WO 98/25938.
In order to widen the range of options, for treating humans and animals and for protecting plants, there is an urgent requirement to provide agents which are not only highly active but, unlike other pharmaceutical preparations or phytosanitary agents, also exhibit reduced side-effects or reduced environmental impact and thus constitute a reduced risk to human health.
The object of the present invention is accordingly to provide a substance which is universally usable in infections by bacteria, fungi and parasites in humans and animals and as a fungicide, bactericide 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. This group of substances e;~hibits 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 _ F, in which R11 is selected from the group which consists of C~_26 alkyl residues, C2_26 alkenyl residues with 1 to 6 double bonds, C2_z6 alkynyl residues with 1 to 6 triple bonds, C~_26 aryl residues, Ar-Co_26-alkyl: residues, C3..s-cycloalkyl-Co_z6-alkyl residues, C3_8-heterocycloalkyl-C-o-26-alkyl residues with one or two nil~ogen, oxygen or sulfur atoms, halogen and OX11, wherein all the above-stated residues may be substituted with C~_9 al)tyl, C1_9 alkoxy, hydroxy, amino, halogen or oxo groups, wherein Xil is selected from the group which consists of hydrogen, C1_26 alkyl residues, C2_z6 alkenyl residues with 1 to 6 double bonds, C2_26 alkynyl residues with 1 to 6 triple bonds, Ar-~=o-z6-~Yl residues, C3_g cycloalkyl residues, C1_26 aryl residues, C3_8-heterocycloalkyl-Co_26-alkyl residues with one or two nitrogen, oxygen or sulfur atoms, C~_26 silyl residues, wherein all the above-stated residues may be substituted with C1_9 alkyl, C1_9 alkoxy, hydroxy, amino, halogen or oxo groups and consists. of a ration of an organic and inorganic base, in particular a metal of main groups. I, II or III of the periodic system, ammonium, substituted ammonium amd ammonium compounds derived from ethylenediamine or amino acids, in which Rl and RZ acre each independf:ntly selected from the group which consists of C1_2a alkyl residues, C3_g cyc;loalkyl residues, C;_g-cycloalkyl-C~_Z4-alkyl residues, C~_24 alkoxy residues, C~_24 alkylthio residues, Cr_24.-alkoxy-C1_24-alkyl residues and C~_24-alkylthio-C~_24-alkyl residues, aryl residues, Ar-(C1_24)-alkyl residues, C3_8-heterocycloalkyl-Co_z4-alkyl residues, halogen and hydrogen, and each C1_Z4 alkyl residue and Cl;za alkoxy residue may be branched or unbranched and be saturated or unsaturated with 2 to 6 double bonds and may optionally be substituted with hydroxy, amino, mercapto, halogen, oxo groups or C1_z4 alkoxy residues, C1_24 alkylcwbonyloxy reaidues, C1_24 alkoxycarbonyloxy residues, C1_2a alkylthio residues, C1_24 alkylcwbonylthio rfaidues, C1_24 alkylamino residues, di-(CI_24-alkyl)amino oesidues, C1_24 alkylca~-bonylamino residues, C1_24-alkyl(C~_24-alkylcarbonyl)amino residues, ~~~_24-alkoxycarbonylamino residues or C,_24-alkyl-(C1_24-alkoxycarbonyl)amino residues, 'wherein each aralkyl residue, hete:rocyclic residue, C~_24 all'yl residue and C~_24 alkoxy residue may be bramched or unbranched and be saturated or unsaturated with 2 to 6 double bonds or triple bonds, or in which Rl-CH-CH-R2 forms part of a C4_8 carbon ring, which may optionally be substituted with hydroxy, mercapto, amino, halogen, oxo groups or with C1_24 alkyl residues, C1_l4 alkoxy 'WO 00/30653 PCT/EP99/08964 residues, C,_24 alkylthio residues, C~_24 alkylarnino residues, di-(C1_24-alkyl)amino residues, (u-Za alkylcarbonyl residues, C1_2a alkylcarbonyloxy residues, C~_z4 alkoxycarbonyl residues, (u-Za alkylcarbonylthio residues or C.'I__>4 alkylcarbonylamino residues, Ci_24-alkyl-(Cl_2a-adkylcarbonyl)amino rf;sidues, wherein each C,_24 alkyl residue may be branched or imbranched and be saW rated or unsa.tu;rated with 1 to 6 double bonds, or wherein Rlo is a branched or unbranched C» alkyl residue, or in which RI-CH-CH-RZ forms part of the furanose or pyranose ring of a sugar, for example D-ribose, D-arabinose, D-xylose, L)-ly:xose, D-glucose, D-galactose, D-mannose, D-talose, D-a.llose, D-altrose, D-gu:lose, D-idose or the corresponding L isomers, wherein the hydroxy groups may each optionally be substituted by hydrogen, amino, azido, oxo, mercapto residues or C1_2a alkoxy residues, C1_24 alkyltllio residues, CI_z4 alkylamino residues, di-(C1_2a-alkyl)amino residues, C1_24 alkylcaJvor~yloxy residues, C1_24 alkylcarbonylthio residues, C1_2a alkylcarbonylamino residues, CI_24-alk;yl-(Cl_24-alkylcarbonyl)amino residues, wherein each C~_24 alkyl residue may be branched or unbranched and be saturated or unsaturated with 1 to 6 double bonds, and the pharmaceutically acceptable salts, esters and amides thereof and salts of the esters and the optical isomers thereof.
R'.1 and RZ may in particular each independently be selected from the group which consists of carboxyl residues, carboxamido residue°s, aryl residues, aryloxycarbonyl residues, aryl-C1_2a-alkyl residues, C1_z4 alkoxycarbonylox'r residues, C~_24 alkylaminocarbonyl residues, di-(C1_2a-alkyl)aminocarbonyl residues, aryl-C'.1_-,.4-alkoxycarbonyl residues, aryl-C1_2a-a:lkylaminocarbonyl residues, CI_24-alkylcarbonyloxy-(CI_24)alkylmethoxycarbonyl residues, ~'i-za alkoxycarbonyloxymethoxycarbo:nyl residues, C1_24-alkoxycarbonyloxy-(C1~-a;lkyl)methoxycarbonyl., wherein each C, _24 alkyl residue may be branched or.
unbranched and b~e saturated or unsaturated with 2 to 6 double bonds, and each C» alkyl residue and C~_2a al.koxy residue may be branched or unbranched and be saturated or unsaturated, and each aryl residue is of the formula II
(II) RQ
wherein R3 and R4 are identical or different and are each selected from the group which consists of hydrogen, hadogen, C1.~ alkyl residues, Cl~ alkoxy residues, formyl, acetyl, V~'O 00/30653 PCT/EP99/08964 propionyl, butyryl residues, formyloxy, acetyloxy, propionyloxy, butyryloxy residues, C»
alkoxycarbonyl residues, all of which rr~ay be branched or unbranched, or R3 and R4 together forrr.~ 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 a m~ethylenedioxy residue, a 1,1-ethylidenedioxy residue, 1,1-ethenylenedioxy residue, a l,l-ethylenedioxy residue or a 1,2-ethylenedioxy residue, which are attached to adjacent positions o:E the phenyl ring.
It is preferred to use compounds in which R~ and RZ are each independently selected from the group which consists of hydrogen, hydroxy groups, formyl, acetyl and methyl, wherein the rr~ethyl group may optionally be substituted with a hydroxy group or mercapto group or with Ci-as alkoxy residues, C 1_24 alkylcarbonyloxy residues, C1_24 alkylthio residues or CI_Za alkylcarbonylthio residues, wherein the C1_24 alkyl groups and C1_za alkoxy groups may be branched or unbranched and be saturated or unsaturated with 1 to 6 double bonds.
Particularly preferably, R1 is a methyl residue, which may optionally be substituted with a h;ydroxy group or mercapto group or with C1_24 alkoxy residues, C1_2a alkylcarbonyloxy residues, Ci_za alkylthio residues or C.'1_4 alkylcarbonylthio residues, wherein the C1_24 alkyl groups and the C1_24 alk;oxy groups rnay be branched or unbranched and be saturated or unsaturated with 1 to 6 double bonds, and RZ is a hydrogen residue.
Particularly good results are achieved with compounds in which Rl and RZ are each independently selected from the group which consists of hydrogen and an n-octadecylmethyl rcaidue, wherein Rl is preferably arm-octadecylmethyl residue and R2 a hydrogen residue.
Particular advantages are achieved if the compound is of (R) configuration.
R'.11 preferably denotes OH.
Special features of the above definitions and suitable examples thereof are given below:
"Acyl" is a substituent which originates from an acid, such as from an organic carboxylic acid, carbonic acid, carbamic acid or the thin acid or imidic acid corresponding to the above individual acids, or from an organic sulfonic acid, wherein these acids in each case comprise aliphatic, aromatic and/or heterocyclic groups in the molecule together with carbamoyl or carbamimidoyl.
~>uitable examples of these acyl groups are given below.
f~liphatic acyl groups are defined as ac;yl residues originating from an aliphatic acid and include the following:
alkanoyl (for example formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl etc.);
alkenoyl (for example acryloyl, methacryloyl, crotonoyl etc.);
alkylthioalkanoyl (for example me;thylthioacetyl, ethylthioacetyl etc.);
alkanesulfonyl (for example mesyl, ethanesulfonyl, propanesulfonyl etc.);
alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl etc.);
alkylcarbamoyl (for example methaylc;arbamoyl etc.);
(N-alkyl)thiocarbamoyl (for example (N-methyl)thiocarbamoyl etc.);
alkylcarbamimidoyl (for example methylcarbamimidoyl etc.);
~~xalo;
;alkoxalyl (for example methoxalyl, ethoxalyl, propoxalyl etc.).
:m the above examples of aliphatic acyl groups, the aliphatic hydrocarbon moiety, in particular the alkyl group or alkane residue, may optionally have one or more suitable substituents, such ~~s amino, halogen (for example fluorine, chlorine, bromine etc.), hydroxy, hydroxyimino, carboxy, alkoxy (for example methoxy, ethoxy, propoxy etc.), alkoxycarbonyl, acylamino (for example benzyloxycarbonylamino etc.), acyloxy (for example acetoxy, benzoyloxy etc.) and the like; preferred aliphatic acyl residues with such substituents which may be mentioned are, i:or example, allcanoyls substituted with amino, carboxy, amino and carboxy, halogen, acylamino or the like.
~~romatic acyl residues are defined as those acyl residues which originate from an acid with a substituted or unsubstituted aryl group, wherein the aryl group may comprise phenyl, toluyl, :{ylyl, naphthyl and thf; like; suitable examples are stated below:
~rroyl (for example ber~zoyl, toluoyl, x;yloyl, naphthoyl, phthaloyl etc.);
~~ralkanoyl (for example phenylacetyl ~etc.);
~~ralkenoyl (for example cinnamoyl etc;. );
aryloxyalkanoyl (for example phenox~racetyl etc.);
~uylthioalkanoyl (for example phenyltlhioacetyl etc.);
arylaminoalkanoyl (for example N-phenylglycyl, etc.);
~~renesulfonyl (for example benzen.esulfonyl, tosyl or toluenesulfonyl, naphthalenesulfonyl E;tc.);
~~ryloxycarbonyl (for example phenoxycarbonyl, naphthyloxycarbonyl etc.);
~~ralkoxycarbonyl (for example benzyloxycarbonyl etc.);
arylcarbamoyl (for example phenylcarbamoyl, naphthylcarbamoyl etc.);
tn-ylglyoxyloyl (for example phenylglyoxyloyl etc.).
l.n the above-stated Examples of aromatic acyl residues, the aromatic hydrocarbon moiety (in particular the aryl residue) and/or the .aliphatic hydrocarbon moiety (in particular the alkane residue) may optionally have one or more suitable substituents, such as those which have already been stated as suitable substitizents for the alkyl group or the alkane residue.
Examples of preferred aromatic aryl residues with specific substituents which may in particular be mentioned are amyl substituted with halogen and hydroxy or with halogen and aralkanoyl substituted with hydroxy, hydroxyimino, dihaloalkanoyloxyimino, together with ~~-ylthiocarbamoyl (for example phen5~lthiocarbamoyl etc.);
~arylcarbamimidoyl (for example phenylcarbamimidovl etc.).
,A heterocyclic acyl residue is taken to mean an acyl residue which originates from an acid with 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 and sulfur (for example thiophenyl, fiwoyl, pyrrolecarbonyl, nicotinyl etc.);
heterocycle-alkanoyl, in which the heterocyclic residue is 5- to 6-membered and comprises at least one heteroatom from the group nitrogen, oxygen and sulfur (for example lhiophenylacetyl, furyl.acetyl, imidazolylpropionyl, tetrazolylacetyl, 2-(2-amino-4-thiazolyl)-;?-methoxyiminoacetyl etc.) and the like.
l:n the above Examples of heterocyclic acyl residues, the heterocycle and/or the aliphatic hydrocarbon moiety may optionally comprise one or more suitable substituents, such as the same as were stated to be suitable :for alkyl and alkane groups.
~~ryl is an aromatic hydrocarbon residue, such as phenyl, naphthyl etc., which may optionally comprise one or more suitable substiW ents, such as alkyl, alkenyl, alkynyl, alkoxy (for c;xample methoxy, ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.), vitro and the like.
"Aralkyl" includes mono-, di-, triphenylalkyls such as benzoyl, phenethyl, benzhydryl, trityl and the like, wherein the aromatic moiety may optionally comprise one or more suitable substituents, such as al.koxy (for example methoxy, ethoxy etc.), halogen (for example.
fluorine, chlorine, bromine etc.), vitro and the like.
~Che 5- and 6-membered heterocycles which may be denoted by Rl and RZ and which, apart from carbon, contain one or two nitrogen, oxygen or sulfur atoms as a ring member, may be saturated or unsaturated.
WO 00/30653 PCT/EP99/0$964 ~~VO 98/25938 provides a comprehensive description of a production process for these compounds.
The organophosphorus compounds are in particular suitable for the therapeutic and prophylactic treatment of infections in humans and animals caused by bacteria, uni- and multicellular parasites and fiwgi.
The compounds are active against unicellular parasites (protozoa), in particular against the causative organisms of malaria and sleeping sickness and of Chagas' disease, toxoplasmosis, amoebic dysentery, leishmaniases, trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiosis, sarcocytosis, acanth~~rnoebosis, naeglerosis, coccidiosis, giardiasis and l~~rnbliasis.
They are accordingly ire particular suitable for the prophylactic treatment of malaria and of sleeping sickness and of Chagas' disease, of toxoplasmosis, amoebic dysentery, le;ishmaniases, txichomoniasis, pneumocystosis, balantidiasis, cryptosporidiosis, sarcocytosis, acanthamoebosis, naeglerosis, coccidiosis, giardiasis and lambliasis.
T'he active substances according to the invention may in particular be used against the following bacteria:
bacteria of the family Propionibacteriac;eae, in particular of the genus Propionibacterium, in particular the species Propionibacteriurn acnes, bacteria of the family Actinomycetaceae, in particular of the genus .Actinomyces, b<~cteria of the genus Cornynebacterium, in particular the species Corynebacterium diphtheriae and Corynebacterium pseudotuberculosis, bacteria of the family Mycobacteriaceae, of the genus Mycobacterium, in particular the species Mycobacterium leprae, Mycobacteriurrc 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, bacteria of the genus Clostridium, bacteria of the genus Yersinia, the species Yersinia pestis, Yersinia pseudotuberculosis, Ye:rsinia enterocoliitica and Yersinia ruckeri, bacteria of the family Mycoplasmataceae, of the genera Mycoplasma and Ureaplasma, in particular the species Mycoplasma pneumoniae, bacteria of the genus Brucella, bacteria of the genus Bordetella, bacteria of the family Neisseriaceae, in particular of the genera Neisseria and Moraxella, in particular the species Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis, bacteria of the family V'ibrionaceae, in particular of the genera Vibrio, Aeromonas, Plesiomonas and Photobacterium, in particular the species Vibrio cholerae, Vibrio aJZguillarum and Aeromonas salmonicidas, bacteria of the genus Campylobacter, in particular _g_ the species Campylobacter jejuni, Carnpylobacter coli and Campylobacter fetus, bacteria of the genus Helicobacter, in particular tlae species Helicobacter pylori, bacteria of the families Spirochaetaceae and Leptospiraceae, in particular of the genera Treponema, Borrelia and :Leptospira, in particul~~r Borrelia burgdorferi, bacteria of the genus Actinobacillus, bacteria of i:he family Legionellaceae, of the genus Legionella, bacteria of the family Rickettsiaceae and :Family Bartonellaceae, bacteria of the genera Nocardia and Rhodococcus, bacteria of the genus Dermatophilus, bacteria of the family Pseudomonadaceae, in particular of the genera l?seudomonas and Xanthomonas, bacteria of the family Enterobacteriaceae, in particular of the genera Escherichia, Klebsiella, Prc>teus, Providencia, Salmonella, Serratia and Shigella, bacteria of the family Pasteurellaceae, in particular of the genus Haemophilus, bacteria of the i:amily Micrococcaceac:, in particular of the genera ~Micrococcus and Staphylococcus, bacteria of the family Streptococcaceae, in parl:icular of the genera Streptococcus and Enterococcus and bacteria of the family Bacillaceae, in particular of the genera Bacillus and Clostridium.
(~rganophosphorus compounds and the derivatives thereof are consequently suitable for treating diphtheria, acne vulgaris, listerioses, swine erysipelas in animals, gas gangrene in humans and animals, malignant oedema in humans and animals, tuberculosis in humans and mimals, leprosy and fru~ther mycobacterioses in humans and animals, paratuberculosis in mimals, plague, mesercterial lymphadc:nitis and pseudotuberculosis in humans and animals, cholera, legionnaires' disease, borreliosis in humans and animals, leptospiroses in humans and ~~nimals, syphilis, Campylobacter ente~:~itis infections in humans and animals, Moraxella l~;eratoconjunctivitis and serositis iti animals, brucellosis of animals and humans, anthrax in humans and animals, actinomycosis in humans and animals, streptotrichoses, psittacosis/ortnithosis in animals, Q fever, ehrlichiosis.
tJse is furthermore effective in the eradication of Helicobacter in ulcers of the gastrointestinal tract.
(:ombinations with another antibiotic may also be used to treat the above-stated diseases.
Isoniazid, rifampicin, a hambutol, pyrazinamide, streptomycin, protionamide and dapsone are i:n particular suitable for combination preparations with other antiinfective agents for the treatment of tuberculosis.
7'he described compounds, i.e. the organophosphorus compounds of the formula I
and esters and amides and salts thereof exhibit strong cytotoxic activity against uni-and multicellular parasites, in particular against the causative organisms of malaria and sleeping sickness. The compounds used according to the invention are accordingly usable for the treatment of i:nfective diseases which are caused in humans and animals by bacteria, parasites and fungi.
7'he compounds are also suitable for the prevention of diseases which are caused by bacteria, parasites and fungi.
The organophosphorus compounds used according to the invention, which generally include for this purpose pharmaceutically acceptable salts, amides, esters, a salt of such an ester or also compounds which, on administration, provide the compounds used according to the invention as metabolites or breakdown products (also known as "prodrugs"), may be formulated for administration in any suitable manner analogous to known agents having an antiinfective action (mixed with a non-toxic, pharmaceutically acceptable excipient).
Pharmaceutically acceptable salts of the compounds include salts which the compounds of the formula I used according to the inventian form in their protonated form as an ammonium salt of inorganic or organic acids, such as hydrochloric acid, sulfuric acid, citric acid, malefic acid, fumaric acid, tartaric acid, p-toluenesulfonic acid.
Salts are also particul~~rly pharmaceutically suitable, such as sodium salt, potassium salt, calcium salt, ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt and salts of an amino acid, such as arginine salt, aspartic acid salt, glutamic acid salt.
'The activity of the substances is dc;ten:nined using a test system. This system is based upon in vitro measurement of i:he inhibition of l,~rowth of bacteria, parasites, fungi or plants. Test methods known to the person skilled in the art are in part used for this purpose.
hor example, antimalarial activity is determined by measuring the inhibition of the growth of malaria parasites in blood cultures.
~4ntibacterial activity is determined on the basis of measuring the inhibition of bacterial growth on nutrient media and in liquid cultures.
Fungicidal activity is determined on tl°.ie basis of inhibition of fungal growth on nutrient media and in liquid cultures.
Some of the microorganisms which are to be investigated may only be investigated in animal models. In this case, the appropriate models will then be used.
~~ubstances which exhibit activity in in. vitro measurement systems are further investigated in in vivo models.
Elntiparasitic, fungicidal or antibacterial activity is further evaluated in the appropriate animal models.
Screening for herbicidal activity is determined by means of algal systems and measurement of isoprene emissions from plants under standard conditions.
The pharmaceutically active agenta may be prepared in dosage units in the form of pharmaceutical preparations. This means that the preparation is in the form of individual components, 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 dose. The dosage units may contain, for example 1, 2, 3 or 4 individual doses or 1/2, 1/3 or 1/4 of an individual dose. An individual dose preferably contains the quantity of active substance which is administered at one time and usually corresponds to a whole, half, third or quarter of a daily dose.
Non-toxic, inert, pharmaceutically suitable excipients should be taken to mean solid, semi-solid or liquid diluents;, fillers and formulation auxiliaries of all kinds.
:Preferred pharmaceutical preparations which may be mentioned are tablets, coated tablets, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays. Tablets, coated tablets, capsules, pills ;end granules may contains the active substances together with conventional excipients, such His (a) fillers and extenders, for example starches, lactose, cane sugar, glucose, mannitol and silica, (b) binders, for example carboxymethylcellulose, alginates, gelatine, polyvinylpyrrolidone, (c) humectants, for example glycerol, (d) suspending agents, for example agar-agar, calcium carbonate and sodium carbonate, (e) dissolution retardants, for example paraffin and (fj resorption accelerators, for example quaternary ammonium compounds, (g) wetting agents, for example cetyl alcohol, glycerol monostearate, (h) adsorbents, for example kaolin and bentonite and (i) lubricants, for example talcum, calcium a.nd magnesium stearate and solid polyethylene glycols or mixtures of the substances stated in I;a) to (i).
'hhe tablets, coated tablets, capsules, pills and granules may be provided with conventional coatings and shells optionally containing opacifying agents and may also be composed such that they release the active substances only with a delay or preferably in a particular part of t:he intestinal tract, wherein polymeric substances and waxes may, for example, be used as the matrices.
'hhe active substance or substances, optionally together with one or more of the above-stated c:xcipients, may also be present in microencapsulated form.
In addition to the active substance or substances, suppositories may contain conventional water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cocoa butter and higher este~.rs (for example C 14 alcohol with C 16 fatty acid) or mixtures of these substances.
In addition to the active substance or substances, ointments, pastes, creams and gels may contain conventional excipients, for example animal and vegetable fats, waxes, paraffins, starch, gum tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talcum and zinc oxide or rnixfilres of these substances.
In addition to the active substance or substances, powders and sprays may contain conventional excipients, for example lactose, talcum, silica, aluminium hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays may additionally contain conventional propellants, for example chlorofluorocarbons.
In addition to the active substance or substances, solutions and emulsions may contain conventional excipients, such as solvents, solubilising agents and emulsifiers, for example water, ethyl alcohol, isopropyl alc:ohc>l, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters or mixtures of these substances.
For parenteral administration, the solutions and emulsions may also be present in sterile, isotonic form.
In addition to the active substance or substances, suspensions may contain conventional excipients, such as liquid diluents, for example water, ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microc;rystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and 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, for example saccharin.
'The active substances of the formula l should preferably be present in the pharmaceutical ;preparations listed above in a concentration of approx. 0.1 to 99.5 wt.%, preferably from approx. 0.5 to 95 wt.°/~, of the complete mixture.
WO 00/30653 PCTlEP99/08964 Apart from the compounds of the formula I, the pharmaceutical preparations may also contain further pharmaceutical active substances.
The compounds may be used togethesr with hitherto described substances having antibacterial, antimycotic and antiparasitic properties. Such substances in particular include compounds which have already been used in therapeutic applications or are still used.
Substances which are suitable for this purpose are in particular those listed in the Red List or in Simon/Stille, Antibiokia-Therapie :in Klinik and Praxis, 9th edition, 1998, Schatauer Verlag, or on the Internet at http://wvvwv.customs.treas.gov/imp-exp/rulings/harmoniz/hrm129 html. The derivatives may in particular be present with penicillins, benzylpenicillin (penicillin G), phenoxypenicillins, isoxazolylpencillins, aminopenicillins, ampicillin, amoxicillin, bacampicillin, carbox:ypenicillin, ticarcillin, temocillin, acylaminopenicillins, azlocillin, mezlocillin, piperacil:(in, apalcillin, mecillinam, cephalosporins, cefazolin group, cefuroxime group, cefoxitin group, cefoxitin, cef~tetan, cefmetazole, latamoxef, flomoxef, cefotaxime group, cefozidime, ceftazidime group, ceftazidime, cefpirome, cefepime, conventional cephalosporins, cefsulodin, cefoperal:ane, oral cephalosporins of the cephalexin group, loracarbef, cefprozil, new broad-spectrum oral cephalosporins, cefixime, cefpodoxime-proxetil, cefuroxime-axetil, cefetamet , cefotiam-hexetil, cefdinir, ceftibuten, other 13-lactam antibiotics, carbapenem, imipenem/ci.lastatin, meropenem, biapenem, aztreonam,13-lactamase inhibitors, clavulanic acid/amoxicillill, clavulanic acid/ticarcillin, sulbactam/ampicillin, tazobactam/piperacillin, tetracyclines, oxytetracycline, rolitetracycline, doxycycline, minocycline, chloramphenicol, arninoglycosides, gentamicin, tobramycin, netilmicin, amikacin, spectinomycin, macrolides, erythromycin, clarithromycin, roxithromycin, azithromycin, dirithromycin, spir~~rnycin, josamycin, lincosamides, clindamycin, fusidic acid, glycopeptide antibiotics, vancomycin, teicoplanin, pristinamycin derivatives, fosfomycin, antimicrobial folic acid antagonists, sulfonamides, ca-trimoxazole, trimethoprim, other diaminopyrimidine-sulfonamide corribinations, nitrofilrans, nitrofurantoin, nitrofurazone, gyrase inhibitors (quinolones), nori~oxacin, ciprofloxacin, ofloxacin, sparfloxacin, enoxacin, fleroxacin, pefloxacin, lomefloxacin, Bay Y3118, nitroimidazoles, antimycobacterial agents, isoniazid, rifampicin, rifabutin, etharr~butol, 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, foscarnet, amantadine, interferons, tibol derivatives, proteinase inhibitors, antimycotica, polyenes, arnphotericin B, nystatin, natamycin, azoles, azoles for septic therapy, miconazole, ketoconaa:ole, itraconazole, fluconazole, UK-109,496, azoles for topical use, clotrimazole, econazole, isoconazole, oxiconazole, bifonazole, flucytosine, griseofulvin, ciclopirox olamine, tolnafnate, naftifine, terbinafme, amorolfine, 'WO 00/30653 PCT/EP99/08964 anthraquinones, betulinic acid, semianthraquinones, xanthones, naphthoquinones, arylamino acohols, quinine, quinidines, mefloquine, halofantrine, chloroquine, amodiaquine, acridine, benzonaphthyridine, n-~epacrine, pyron.aridine, dapsone, sulfonamides, sulfadoxine, sulfalenes, lximethoprim, proguanil, chlorproguan.il, diaminopyrimidines, pyrimethamine, primaquine, ~uninoquinolines, WR 238,605, tetracycline, doxycycline, clindamycin, norfloxacin, c;iprofloxacin, ofloxacin, artemisinin, dihydroartemisinin, lOb artemether, arteether, atresunate, atovaquone, suramin, rnelarsoprol, nifurtimox, stibogluconate sodium, pentamidine, amphotericin B, rnetronidazole, clioquinol, mebendazole, niclosamide, praziquantel, pyrantel, tiabendazole, diiethylcarbamazine, ivermectin, bithionol, oxamniquine, rnetrifonate, piperazine, embonate 7'he organophosphorus compounds rna.y furthermore be present in the pharmaceutical yreparations in combination with sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, rnefloquine, halofantrine, pyrimethamine, armesin, tetracyclines, doxycycline, proguanil, metronidazole, praziquantel, niclosamide, mebendazole, pyrantel, tiabendazole, diethylcarb~~:ine, piperazine, pyrivinium, metrifonate, oxamniquine, k~ithionol or suramin or two or more of these substances.
'fhe above-stated pharmaceutical prep~~rations are produced in the conventional manner using known methods, for example by mixing the active substance or substances with the excipient or excipients.
'fhe stated preparations may be administered to humans and animals orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, vitraperitoneally, topically (powders, ointments, drops) and for the treatment of infections in cavities, body cavities. Suitable preparations which may be considered are solutions for injections, solutions and suspensions for oral therapy, gels, infusion formulations, emulsions, ointments or drops. Topical treatment may be performed using ophthalmological and dermatological formulations, silver and other salts, ear drops, eye ointments, powders or solutions. Administration to animals may also be achieved via the feed or drinking water in suitable formulations. <iels, pulverulent formulations, powders, tablets, controlled-release tablets, premixes, concentrates, granules, pellets, tablets, boli, capsules, aerosols, sprays, inhalation formulations may also be used in humans and animals. The compounds used according to the invention may also be incorporated into other supports, such as for example plastics (plastic chains for topical treatment), collagen or bone cement.
I1: has in general proved advantageous in both human and veterinary medicine to administer t1e 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 'WO 00/30653 PCT/EP99/08964 more individual doses in order to achic°ve the desired results. An individual dose preferably contains the active substance or substances in quantities of approx. 0.25 to approx. 2000 mg, ~,vhich are administered, for example, 1 to 4 times daily. It may, however, be necessary to deviate from the stated. dosages, in particular as a function of the nature and body weight of the patient to be treated, the nature and severity of the disease, the nature of the preparations and the route of administration of the pharmaceutical preparation and the period of time over which administration is performed.
lJiquid preparations may be administered in the form of solutions, syrups, emulsions or suspensions, which, for oral administration, contain for example 0.1 to 50 wt.% of active substance. In the case of topical adminustration in the form of solutions, gels, suspension or the like, the active substance preferably amounts to between =.OS and 20 wt.%
of the preparation.
In some cases, it may accordingly be sufficient to use less than the above-stated quantity of active substance, while; in other cases more than the above-stated quantity of active substance must be used. The person skilled in thc: art will use his/her skill to determine the optimum dosage and route of administration required in each particular case.
'Che compounds used according to the invention may be given to animals in conventional concentrations and preparations together with feed or feed preparations or with drinking water.
'.Che compounds used according to the invention are furthermore ideally usable as bactericides, fungicides and herbicides in plants.
_1!:xample ~~ntiprotozoal action ~Che following substances are tested for their antiprotozoal activity:
.W bstance l: 2-[(2-Ethoxycarbonylphenoxy)carbonyl]-1,3,2-dioxaphospholane 2-oxide ;substance 2: 2-[(2-Ethoxycarbonylphenoxy)carbonyl]-4-dodecanoyloxymethyl-1,3,2-dioxaphospholane 2-oxide ~~ubstance 3: 2-[(2-Ethoxycarbonylphenoxy)carbonyl]-4-octanoylthiomethyl-1,3,2-dioxaphospholane 2-~axide ',3ubstance 4: 2-[(2-Ethoxycarbonylphenoxy)carbonyl]-4-dodecanoylthiomethyl-1,3,2-dioxaphospholane 2-oxide ,W bstance 5: 2-Hydroxyethyl-[(2-ethoxycarbonylphenoxy)carbonyl] sodium phosphonate ',substance 6: 2-Dodecanoylox;y-2-hydroxypropyl-[(2-ethoxycarbonylphenoxy)carbonyl]
sodium phosphonate Substance 7: 2-C>ctanoylthio-2-hydroxypropyl[(2-ethoxycarbonyl Substance 8: 2-Dodecanoylttlio-2-hydroxypropyl-[(2-ethoxycaxbonylphenoxy)carbonyl]
sodium phosphonate Substance 9: Sodium 2-hydroxy-1,4,2-dioxaphosphorinane 2,3-dioxide Substance 10: Sodium 2-hydroxy-s-dodecanoyloxvmethyl-1,4,2-dioxaphosphorinane 2,3-dio;Ki de Substance 1 l: Sodium 2-hydroxy-5-octanoylthiomethyl-1,4,2-dioxaphosphorinane 2,3-dioxide Substance 12: Sodium 2-hydroxy-5-dodecanoylthiomethyl-1,4,2-dioxaphosphorinane 2,3-dioxide The antimalarial activity of substances 1 to 12 was determined using in vitro cultures of the causative organism of malaria, Plasmodium falciparum. 200 pl of an asynchronous Plasmodium 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 series of the compounds was then :prepared in steps of three between concentrations of 100 and 0.14 pmol 1-1. The plates are incubated at 37"C:, :3'% C02 and 5% 02 over a period of 48 hours. 30 pl of medium supplemented with 27 pCi rr~l~~ of [3H]-hypoxanthine were then added to each well.
After 24 hours' incubation, the parasil:es were harvested by filtration through glass fibre filters and the incorporated radioactivity was measured. Inhibition of parasite growth was measured as the percentage inhibition of tritium incorporation. Inhibition of parasite growth was measured as the percentage inhibition of tritium incorporation relative to a comparison without the substance. The median inhibitory concentration (IC50) of the substance was determined by extrapolating the values.
The results, i.e. the IC50 values, are listed in the following table:
Phosphonoformic acid derivatives are already known for their antiviral properties.
Pharmaceutical preparations for treating viral infections have already been described in US
patents 4 215 113, 4 339, and 4 6Ei~ 062 and 4 771 041.
In particular, the antiviral action of phosphonoformic acid derivatives and the production thereof have already been described in WO 98/16537 and WO 98/25938.
In order to widen the range of options, for treating humans and animals and for protecting plants, there is an urgent requirement to provide agents which are not only highly active but, unlike other pharmaceutical preparations or phytosanitary agents, also exhibit reduced side-effects or reduced environmental impact and thus constitute a reduced risk to human health.
The object of the present invention is accordingly to provide a substance which is universally usable in infections by bacteria, fungi and parasites in humans and animals and as a fungicide, bactericide 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. This group of substances e;~hibits 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 _ F, in which R11 is selected from the group which consists of C~_26 alkyl residues, C2_26 alkenyl residues with 1 to 6 double bonds, C2_z6 alkynyl residues with 1 to 6 triple bonds, C~_26 aryl residues, Ar-Co_26-alkyl: residues, C3..s-cycloalkyl-Co_z6-alkyl residues, C3_8-heterocycloalkyl-C-o-26-alkyl residues with one or two nil~ogen, oxygen or sulfur atoms, halogen and OX11, wherein all the above-stated residues may be substituted with C~_9 al)tyl, C1_9 alkoxy, hydroxy, amino, halogen or oxo groups, wherein Xil is selected from the group which consists of hydrogen, C1_26 alkyl residues, C2_z6 alkenyl residues with 1 to 6 double bonds, C2_26 alkynyl residues with 1 to 6 triple bonds, Ar-~=o-z6-~Yl residues, C3_g cycloalkyl residues, C1_26 aryl residues, C3_8-heterocycloalkyl-Co_26-alkyl residues with one or two nitrogen, oxygen or sulfur atoms, C~_26 silyl residues, wherein all the above-stated residues may be substituted with C1_9 alkyl, C1_9 alkoxy, hydroxy, amino, halogen or oxo groups and consists. of a ration of an organic and inorganic base, in particular a metal of main groups. I, II or III of the periodic system, ammonium, substituted ammonium amd ammonium compounds derived from ethylenediamine or amino acids, in which Rl and RZ acre each independf:ntly selected from the group which consists of C1_2a alkyl residues, C3_g cyc;loalkyl residues, C;_g-cycloalkyl-C~_Z4-alkyl residues, C~_24 alkoxy residues, C~_24 alkylthio residues, Cr_24.-alkoxy-C1_24-alkyl residues and C~_24-alkylthio-C~_24-alkyl residues, aryl residues, Ar-(C1_24)-alkyl residues, C3_8-heterocycloalkyl-Co_z4-alkyl residues, halogen and hydrogen, and each C1_Z4 alkyl residue and Cl;za alkoxy residue may be branched or unbranched and be saturated or unsaturated with 2 to 6 double bonds and may optionally be substituted with hydroxy, amino, mercapto, halogen, oxo groups or C1_z4 alkoxy residues, C1_24 alkylcwbonyloxy reaidues, C1_24 alkoxycarbonyloxy residues, C1_2a alkylthio residues, C1_24 alkylcwbonylthio rfaidues, C1_24 alkylamino residues, di-(CI_24-alkyl)amino oesidues, C1_24 alkylca~-bonylamino residues, C1_24-alkyl(C~_24-alkylcarbonyl)amino residues, ~~~_24-alkoxycarbonylamino residues or C,_24-alkyl-(C1_24-alkoxycarbonyl)amino residues, 'wherein each aralkyl residue, hete:rocyclic residue, C~_24 all'yl residue and C~_24 alkoxy residue may be bramched or unbranched and be saturated or unsaturated with 2 to 6 double bonds or triple bonds, or in which Rl-CH-CH-R2 forms part of a C4_8 carbon ring, which may optionally be substituted with hydroxy, mercapto, amino, halogen, oxo groups or with C1_24 alkyl residues, C1_l4 alkoxy 'WO 00/30653 PCT/EP99/08964 residues, C,_24 alkylthio residues, C~_24 alkylarnino residues, di-(C1_24-alkyl)amino residues, (u-Za alkylcarbonyl residues, C1_2a alkylcarbonyloxy residues, C~_z4 alkoxycarbonyl residues, (u-Za alkylcarbonylthio residues or C.'I__>4 alkylcarbonylamino residues, Ci_24-alkyl-(Cl_2a-adkylcarbonyl)amino rf;sidues, wherein each C,_24 alkyl residue may be branched or imbranched and be saW rated or unsa.tu;rated with 1 to 6 double bonds, or wherein Rlo is a branched or unbranched C» alkyl residue, or in which RI-CH-CH-RZ forms part of the furanose or pyranose ring of a sugar, for example D-ribose, D-arabinose, D-xylose, L)-ly:xose, D-glucose, D-galactose, D-mannose, D-talose, D-a.llose, D-altrose, D-gu:lose, D-idose or the corresponding L isomers, wherein the hydroxy groups may each optionally be substituted by hydrogen, amino, azido, oxo, mercapto residues or C1_2a alkoxy residues, C1_24 alkyltllio residues, CI_z4 alkylamino residues, di-(C1_2a-alkyl)amino residues, C1_24 alkylcaJvor~yloxy residues, C1_24 alkylcarbonylthio residues, C1_2a alkylcarbonylamino residues, CI_24-alk;yl-(Cl_24-alkylcarbonyl)amino residues, wherein each C~_24 alkyl residue may be branched or unbranched and be saturated or unsaturated with 1 to 6 double bonds, and the pharmaceutically acceptable salts, esters and amides thereof and salts of the esters and the optical isomers thereof.
R'.1 and RZ may in particular each independently be selected from the group which consists of carboxyl residues, carboxamido residue°s, aryl residues, aryloxycarbonyl residues, aryl-C1_2a-alkyl residues, C1_z4 alkoxycarbonylox'r residues, C~_24 alkylaminocarbonyl residues, di-(C1_2a-alkyl)aminocarbonyl residues, aryl-C'.1_-,.4-alkoxycarbonyl residues, aryl-C1_2a-a:lkylaminocarbonyl residues, CI_24-alkylcarbonyloxy-(CI_24)alkylmethoxycarbonyl residues, ~'i-za alkoxycarbonyloxymethoxycarbo:nyl residues, C1_24-alkoxycarbonyloxy-(C1~-a;lkyl)methoxycarbonyl., wherein each C, _24 alkyl residue may be branched or.
unbranched and b~e saturated or unsaturated with 2 to 6 double bonds, and each C» alkyl residue and C~_2a al.koxy residue may be branched or unbranched and be saturated or unsaturated, and each aryl residue is of the formula II
(II) RQ
wherein R3 and R4 are identical or different and are each selected from the group which consists of hydrogen, hadogen, C1.~ alkyl residues, Cl~ alkoxy residues, formyl, acetyl, V~'O 00/30653 PCT/EP99/08964 propionyl, butyryl residues, formyloxy, acetyloxy, propionyloxy, butyryloxy residues, C»
alkoxycarbonyl residues, all of which rr~ay be branched or unbranched, or R3 and R4 together forrr.~ 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 a m~ethylenedioxy residue, a 1,1-ethylidenedioxy residue, 1,1-ethenylenedioxy residue, a l,l-ethylenedioxy residue or a 1,2-ethylenedioxy residue, which are attached to adjacent positions o:E the phenyl ring.
It is preferred to use compounds in which R~ and RZ are each independently selected from the group which consists of hydrogen, hydroxy groups, formyl, acetyl and methyl, wherein the rr~ethyl group may optionally be substituted with a hydroxy group or mercapto group or with Ci-as alkoxy residues, C 1_24 alkylcarbonyloxy residues, C1_24 alkylthio residues or CI_Za alkylcarbonylthio residues, wherein the C1_24 alkyl groups and C1_za alkoxy groups may be branched or unbranched and be saturated or unsaturated with 1 to 6 double bonds.
Particularly preferably, R1 is a methyl residue, which may optionally be substituted with a h;ydroxy group or mercapto group or with C1_24 alkoxy residues, C1_2a alkylcarbonyloxy residues, Ci_za alkylthio residues or C.'1_4 alkylcarbonylthio residues, wherein the C1_24 alkyl groups and the C1_24 alk;oxy groups rnay be branched or unbranched and be saturated or unsaturated with 1 to 6 double bonds, and RZ is a hydrogen residue.
Particularly good results are achieved with compounds in which Rl and RZ are each independently selected from the group which consists of hydrogen and an n-octadecylmethyl rcaidue, wherein Rl is preferably arm-octadecylmethyl residue and R2 a hydrogen residue.
Particular advantages are achieved if the compound is of (R) configuration.
R'.11 preferably denotes OH.
Special features of the above definitions and suitable examples thereof are given below:
"Acyl" is a substituent which originates from an acid, such as from an organic carboxylic acid, carbonic acid, carbamic acid or the thin acid or imidic acid corresponding to the above individual acids, or from an organic sulfonic acid, wherein these acids in each case comprise aliphatic, aromatic and/or heterocyclic groups in the molecule together with carbamoyl or carbamimidoyl.
~>uitable examples of these acyl groups are given below.
f~liphatic acyl groups are defined as ac;yl residues originating from an aliphatic acid and include the following:
alkanoyl (for example formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl etc.);
alkenoyl (for example acryloyl, methacryloyl, crotonoyl etc.);
alkylthioalkanoyl (for example me;thylthioacetyl, ethylthioacetyl etc.);
alkanesulfonyl (for example mesyl, ethanesulfonyl, propanesulfonyl etc.);
alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl etc.);
alkylcarbamoyl (for example methaylc;arbamoyl etc.);
(N-alkyl)thiocarbamoyl (for example (N-methyl)thiocarbamoyl etc.);
alkylcarbamimidoyl (for example methylcarbamimidoyl etc.);
~~xalo;
;alkoxalyl (for example methoxalyl, ethoxalyl, propoxalyl etc.).
:m the above examples of aliphatic acyl groups, the aliphatic hydrocarbon moiety, in particular the alkyl group or alkane residue, may optionally have one or more suitable substituents, such ~~s amino, halogen (for example fluorine, chlorine, bromine etc.), hydroxy, hydroxyimino, carboxy, alkoxy (for example methoxy, ethoxy, propoxy etc.), alkoxycarbonyl, acylamino (for example benzyloxycarbonylamino etc.), acyloxy (for example acetoxy, benzoyloxy etc.) and the like; preferred aliphatic acyl residues with such substituents which may be mentioned are, i:or example, allcanoyls substituted with amino, carboxy, amino and carboxy, halogen, acylamino or the like.
~~romatic acyl residues are defined as those acyl residues which originate from an acid with a substituted or unsubstituted aryl group, wherein the aryl group may comprise phenyl, toluyl, :{ylyl, naphthyl and thf; like; suitable examples are stated below:
~rroyl (for example ber~zoyl, toluoyl, x;yloyl, naphthoyl, phthaloyl etc.);
~~ralkanoyl (for example phenylacetyl ~etc.);
~~ralkenoyl (for example cinnamoyl etc;. );
aryloxyalkanoyl (for example phenox~racetyl etc.);
~uylthioalkanoyl (for example phenyltlhioacetyl etc.);
arylaminoalkanoyl (for example N-phenylglycyl, etc.);
~~renesulfonyl (for example benzen.esulfonyl, tosyl or toluenesulfonyl, naphthalenesulfonyl E;tc.);
~~ryloxycarbonyl (for example phenoxycarbonyl, naphthyloxycarbonyl etc.);
~~ralkoxycarbonyl (for example benzyloxycarbonyl etc.);
arylcarbamoyl (for example phenylcarbamoyl, naphthylcarbamoyl etc.);
tn-ylglyoxyloyl (for example phenylglyoxyloyl etc.).
l.n the above-stated Examples of aromatic acyl residues, the aromatic hydrocarbon moiety (in particular the aryl residue) and/or the .aliphatic hydrocarbon moiety (in particular the alkane residue) may optionally have one or more suitable substituents, such as those which have already been stated as suitable substitizents for the alkyl group or the alkane residue.
Examples of preferred aromatic aryl residues with specific substituents which may in particular be mentioned are amyl substituted with halogen and hydroxy or with halogen and aralkanoyl substituted with hydroxy, hydroxyimino, dihaloalkanoyloxyimino, together with ~~-ylthiocarbamoyl (for example phen5~lthiocarbamoyl etc.);
~arylcarbamimidoyl (for example phenylcarbamimidovl etc.).
,A heterocyclic acyl residue is taken to mean an acyl residue which originates from an acid with 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 and sulfur (for example thiophenyl, fiwoyl, pyrrolecarbonyl, nicotinyl etc.);
heterocycle-alkanoyl, in which the heterocyclic residue is 5- to 6-membered and comprises at least one heteroatom from the group nitrogen, oxygen and sulfur (for example lhiophenylacetyl, furyl.acetyl, imidazolylpropionyl, tetrazolylacetyl, 2-(2-amino-4-thiazolyl)-;?-methoxyiminoacetyl etc.) and the like.
l:n the above Examples of heterocyclic acyl residues, the heterocycle and/or the aliphatic hydrocarbon moiety may optionally comprise one or more suitable substituents, such as the same as were stated to be suitable :for alkyl and alkane groups.
~~ryl is an aromatic hydrocarbon residue, such as phenyl, naphthyl etc., which may optionally comprise one or more suitable substiW ents, such as alkyl, alkenyl, alkynyl, alkoxy (for c;xample methoxy, ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.), vitro and the like.
"Aralkyl" includes mono-, di-, triphenylalkyls such as benzoyl, phenethyl, benzhydryl, trityl and the like, wherein the aromatic moiety may optionally comprise one or more suitable substituents, such as al.koxy (for example methoxy, ethoxy etc.), halogen (for example.
fluorine, chlorine, bromine etc.), vitro and the like.
~Che 5- and 6-membered heterocycles which may be denoted by Rl and RZ and which, apart from carbon, contain one or two nitrogen, oxygen or sulfur atoms as a ring member, may be saturated or unsaturated.
WO 00/30653 PCT/EP99/0$964 ~~VO 98/25938 provides a comprehensive description of a production process for these compounds.
The organophosphorus compounds are in particular suitable for the therapeutic and prophylactic treatment of infections in humans and animals caused by bacteria, uni- and multicellular parasites and fiwgi.
The compounds are active against unicellular parasites (protozoa), in particular against the causative organisms of malaria and sleeping sickness and of Chagas' disease, toxoplasmosis, amoebic dysentery, leishmaniases, trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiosis, sarcocytosis, acanth~~rnoebosis, naeglerosis, coccidiosis, giardiasis and l~~rnbliasis.
They are accordingly ire particular suitable for the prophylactic treatment of malaria and of sleeping sickness and of Chagas' disease, of toxoplasmosis, amoebic dysentery, le;ishmaniases, txichomoniasis, pneumocystosis, balantidiasis, cryptosporidiosis, sarcocytosis, acanthamoebosis, naeglerosis, coccidiosis, giardiasis and lambliasis.
T'he active substances according to the invention may in particular be used against the following bacteria:
bacteria of the family Propionibacteriac;eae, in particular of the genus Propionibacterium, in particular the species Propionibacteriurn acnes, bacteria of the family Actinomycetaceae, in particular of the genus .Actinomyces, b<~cteria of the genus Cornynebacterium, in particular the species Corynebacterium diphtheriae and Corynebacterium pseudotuberculosis, bacteria of the family Mycobacteriaceae, of the genus Mycobacterium, in particular the species Mycobacterium leprae, Mycobacteriurrc 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, bacteria of the genus Clostridium, bacteria of the genus Yersinia, the species Yersinia pestis, Yersinia pseudotuberculosis, Ye:rsinia enterocoliitica and Yersinia ruckeri, bacteria of the family Mycoplasmataceae, of the genera Mycoplasma and Ureaplasma, in particular the species Mycoplasma pneumoniae, bacteria of the genus Brucella, bacteria of the genus Bordetella, bacteria of the family Neisseriaceae, in particular of the genera Neisseria and Moraxella, in particular the species Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis, bacteria of the family V'ibrionaceae, in particular of the genera Vibrio, Aeromonas, Plesiomonas and Photobacterium, in particular the species Vibrio cholerae, Vibrio aJZguillarum and Aeromonas salmonicidas, bacteria of the genus Campylobacter, in particular _g_ the species Campylobacter jejuni, Carnpylobacter coli and Campylobacter fetus, bacteria of the genus Helicobacter, in particular tlae species Helicobacter pylori, bacteria of the families Spirochaetaceae and Leptospiraceae, in particular of the genera Treponema, Borrelia and :Leptospira, in particul~~r Borrelia burgdorferi, bacteria of the genus Actinobacillus, bacteria of i:he family Legionellaceae, of the genus Legionella, bacteria of the family Rickettsiaceae and :Family Bartonellaceae, bacteria of the genera Nocardia and Rhodococcus, bacteria of the genus Dermatophilus, bacteria of the family Pseudomonadaceae, in particular of the genera l?seudomonas and Xanthomonas, bacteria of the family Enterobacteriaceae, in particular of the genera Escherichia, Klebsiella, Prc>teus, Providencia, Salmonella, Serratia and Shigella, bacteria of the family Pasteurellaceae, in particular of the genus Haemophilus, bacteria of the i:amily Micrococcaceac:, in particular of the genera ~Micrococcus and Staphylococcus, bacteria of the family Streptococcaceae, in parl:icular of the genera Streptococcus and Enterococcus and bacteria of the family Bacillaceae, in particular of the genera Bacillus and Clostridium.
(~rganophosphorus compounds and the derivatives thereof are consequently suitable for treating diphtheria, acne vulgaris, listerioses, swine erysipelas in animals, gas gangrene in humans and animals, malignant oedema in humans and animals, tuberculosis in humans and mimals, leprosy and fru~ther mycobacterioses in humans and animals, paratuberculosis in mimals, plague, mesercterial lymphadc:nitis and pseudotuberculosis in humans and animals, cholera, legionnaires' disease, borreliosis in humans and animals, leptospiroses in humans and ~~nimals, syphilis, Campylobacter ente~:~itis infections in humans and animals, Moraxella l~;eratoconjunctivitis and serositis iti animals, brucellosis of animals and humans, anthrax in humans and animals, actinomycosis in humans and animals, streptotrichoses, psittacosis/ortnithosis in animals, Q fever, ehrlichiosis.
tJse is furthermore effective in the eradication of Helicobacter in ulcers of the gastrointestinal tract.
(:ombinations with another antibiotic may also be used to treat the above-stated diseases.
Isoniazid, rifampicin, a hambutol, pyrazinamide, streptomycin, protionamide and dapsone are i:n particular suitable for combination preparations with other antiinfective agents for the treatment of tuberculosis.
7'he described compounds, i.e. the organophosphorus compounds of the formula I
and esters and amides and salts thereof exhibit strong cytotoxic activity against uni-and multicellular parasites, in particular against the causative organisms of malaria and sleeping sickness. The compounds used according to the invention are accordingly usable for the treatment of i:nfective diseases which are caused in humans and animals by bacteria, parasites and fungi.
7'he compounds are also suitable for the prevention of diseases which are caused by bacteria, parasites and fungi.
The organophosphorus compounds used according to the invention, which generally include for this purpose pharmaceutically acceptable salts, amides, esters, a salt of such an ester or also compounds which, on administration, provide the compounds used according to the invention as metabolites or breakdown products (also known as "prodrugs"), may be formulated for administration in any suitable manner analogous to known agents having an antiinfective action (mixed with a non-toxic, pharmaceutically acceptable excipient).
Pharmaceutically acceptable salts of the compounds include salts which the compounds of the formula I used according to the inventian form in their protonated form as an ammonium salt of inorganic or organic acids, such as hydrochloric acid, sulfuric acid, citric acid, malefic acid, fumaric acid, tartaric acid, p-toluenesulfonic acid.
Salts are also particul~~rly pharmaceutically suitable, such as sodium salt, potassium salt, calcium salt, ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt and salts of an amino acid, such as arginine salt, aspartic acid salt, glutamic acid salt.
'The activity of the substances is dc;ten:nined using a test system. This system is based upon in vitro measurement of i:he inhibition of l,~rowth of bacteria, parasites, fungi or plants. Test methods known to the person skilled in the art are in part used for this purpose.
hor example, antimalarial activity is determined by measuring the inhibition of the growth of malaria parasites in blood cultures.
~4ntibacterial activity is determined on the basis of measuring the inhibition of bacterial growth on nutrient media and in liquid cultures.
Fungicidal activity is determined on tl°.ie basis of inhibition of fungal growth on nutrient media and in liquid cultures.
Some of the microorganisms which are to be investigated may only be investigated in animal models. In this case, the appropriate models will then be used.
~~ubstances which exhibit activity in in. vitro measurement systems are further investigated in in vivo models.
Elntiparasitic, fungicidal or antibacterial activity is further evaluated in the appropriate animal models.
Screening for herbicidal activity is determined by means of algal systems and measurement of isoprene emissions from plants under standard conditions.
The pharmaceutically active agenta may be prepared in dosage units in the form of pharmaceutical preparations. This means that the preparation is in the form of individual components, 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 dose. The dosage units may contain, for example 1, 2, 3 or 4 individual doses or 1/2, 1/3 or 1/4 of an individual dose. An individual dose preferably contains the quantity of active substance which is administered at one time and usually corresponds to a whole, half, third or quarter of a daily dose.
Non-toxic, inert, pharmaceutically suitable excipients should be taken to mean solid, semi-solid or liquid diluents;, fillers and formulation auxiliaries of all kinds.
:Preferred pharmaceutical preparations which may be mentioned are tablets, coated tablets, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays. Tablets, coated tablets, capsules, pills ;end granules may contains the active substances together with conventional excipients, such His (a) fillers and extenders, for example starches, lactose, cane sugar, glucose, mannitol and silica, (b) binders, for example carboxymethylcellulose, alginates, gelatine, polyvinylpyrrolidone, (c) humectants, for example glycerol, (d) suspending agents, for example agar-agar, calcium carbonate and sodium carbonate, (e) dissolution retardants, for example paraffin and (fj resorption accelerators, for example quaternary ammonium compounds, (g) wetting agents, for example cetyl alcohol, glycerol monostearate, (h) adsorbents, for example kaolin and bentonite and (i) lubricants, for example talcum, calcium a.nd magnesium stearate and solid polyethylene glycols or mixtures of the substances stated in I;a) to (i).
'hhe tablets, coated tablets, capsules, pills and granules may be provided with conventional coatings and shells optionally containing opacifying agents and may also be composed such that they release the active substances only with a delay or preferably in a particular part of t:he intestinal tract, wherein polymeric substances and waxes may, for example, be used as the matrices.
'hhe active substance or substances, optionally together with one or more of the above-stated c:xcipients, may also be present in microencapsulated form.
In addition to the active substance or substances, suppositories may contain conventional water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cocoa butter and higher este~.rs (for example C 14 alcohol with C 16 fatty acid) or mixtures of these substances.
In addition to the active substance or substances, ointments, pastes, creams and gels may contain conventional excipients, for example animal and vegetable fats, waxes, paraffins, starch, gum tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talcum and zinc oxide or rnixfilres of these substances.
In addition to the active substance or substances, powders and sprays may contain conventional excipients, for example lactose, talcum, silica, aluminium hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays may additionally contain conventional propellants, for example chlorofluorocarbons.
In addition to the active substance or substances, solutions and emulsions may contain conventional excipients, such as solvents, solubilising agents and emulsifiers, for example water, ethyl alcohol, isopropyl alc:ohc>l, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters or mixtures of these substances.
For parenteral administration, the solutions and emulsions may also be present in sterile, isotonic form.
In addition to the active substance or substances, suspensions may contain conventional excipients, such as liquid diluents, for example water, ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microc;rystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and 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, for example saccharin.
'The active substances of the formula l should preferably be present in the pharmaceutical ;preparations listed above in a concentration of approx. 0.1 to 99.5 wt.%, preferably from approx. 0.5 to 95 wt.°/~, of the complete mixture.
WO 00/30653 PCTlEP99/08964 Apart from the compounds of the formula I, the pharmaceutical preparations may also contain further pharmaceutical active substances.
The compounds may be used togethesr with hitherto described substances having antibacterial, antimycotic and antiparasitic properties. Such substances in particular include compounds which have already been used in therapeutic applications or are still used.
Substances which are suitable for this purpose are in particular those listed in the Red List or in Simon/Stille, Antibiokia-Therapie :in Klinik and Praxis, 9th edition, 1998, Schatauer Verlag, or on the Internet at http://wvvwv.customs.treas.gov/imp-exp/rulings/harmoniz/hrm129 html. The derivatives may in particular be present with penicillins, benzylpenicillin (penicillin G), phenoxypenicillins, isoxazolylpencillins, aminopenicillins, ampicillin, amoxicillin, bacampicillin, carbox:ypenicillin, ticarcillin, temocillin, acylaminopenicillins, azlocillin, mezlocillin, piperacil:(in, apalcillin, mecillinam, cephalosporins, cefazolin group, cefuroxime group, cefoxitin group, cefoxitin, cef~tetan, cefmetazole, latamoxef, flomoxef, cefotaxime group, cefozidime, ceftazidime group, ceftazidime, cefpirome, cefepime, conventional cephalosporins, cefsulodin, cefoperal:ane, oral cephalosporins of the cephalexin group, loracarbef, cefprozil, new broad-spectrum oral cephalosporins, cefixime, cefpodoxime-proxetil, cefuroxime-axetil, cefetamet , cefotiam-hexetil, cefdinir, ceftibuten, other 13-lactam antibiotics, carbapenem, imipenem/ci.lastatin, meropenem, biapenem, aztreonam,13-lactamase inhibitors, clavulanic acid/amoxicillill, clavulanic acid/ticarcillin, sulbactam/ampicillin, tazobactam/piperacillin, tetracyclines, oxytetracycline, rolitetracycline, doxycycline, minocycline, chloramphenicol, arninoglycosides, gentamicin, tobramycin, netilmicin, amikacin, spectinomycin, macrolides, erythromycin, clarithromycin, roxithromycin, azithromycin, dirithromycin, spir~~rnycin, josamycin, lincosamides, clindamycin, fusidic acid, glycopeptide antibiotics, vancomycin, teicoplanin, pristinamycin derivatives, fosfomycin, antimicrobial folic acid antagonists, sulfonamides, ca-trimoxazole, trimethoprim, other diaminopyrimidine-sulfonamide corribinations, nitrofilrans, nitrofurantoin, nitrofurazone, gyrase inhibitors (quinolones), nori~oxacin, ciprofloxacin, ofloxacin, sparfloxacin, enoxacin, fleroxacin, pefloxacin, lomefloxacin, Bay Y3118, nitroimidazoles, antimycobacterial agents, isoniazid, rifampicin, rifabutin, etharr~butol, 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, foscarnet, amantadine, interferons, tibol derivatives, proteinase inhibitors, antimycotica, polyenes, arnphotericin B, nystatin, natamycin, azoles, azoles for septic therapy, miconazole, ketoconaa:ole, itraconazole, fluconazole, UK-109,496, azoles for topical use, clotrimazole, econazole, isoconazole, oxiconazole, bifonazole, flucytosine, griseofulvin, ciclopirox olamine, tolnafnate, naftifine, terbinafme, amorolfine, 'WO 00/30653 PCT/EP99/08964 anthraquinones, betulinic acid, semianthraquinones, xanthones, naphthoquinones, arylamino acohols, quinine, quinidines, mefloquine, halofantrine, chloroquine, amodiaquine, acridine, benzonaphthyridine, n-~epacrine, pyron.aridine, dapsone, sulfonamides, sulfadoxine, sulfalenes, lximethoprim, proguanil, chlorproguan.il, diaminopyrimidines, pyrimethamine, primaquine, ~uninoquinolines, WR 238,605, tetracycline, doxycycline, clindamycin, norfloxacin, c;iprofloxacin, ofloxacin, artemisinin, dihydroartemisinin, lOb artemether, arteether, atresunate, atovaquone, suramin, rnelarsoprol, nifurtimox, stibogluconate sodium, pentamidine, amphotericin B, rnetronidazole, clioquinol, mebendazole, niclosamide, praziquantel, pyrantel, tiabendazole, diiethylcarbamazine, ivermectin, bithionol, oxamniquine, rnetrifonate, piperazine, embonate 7'he organophosphorus compounds rna.y furthermore be present in the pharmaceutical yreparations in combination with sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, rnefloquine, halofantrine, pyrimethamine, armesin, tetracyclines, doxycycline, proguanil, metronidazole, praziquantel, niclosamide, mebendazole, pyrantel, tiabendazole, diethylcarb~~:ine, piperazine, pyrivinium, metrifonate, oxamniquine, k~ithionol or suramin or two or more of these substances.
'fhe above-stated pharmaceutical prep~~rations are produced in the conventional manner using known methods, for example by mixing the active substance or substances with the excipient or excipients.
'fhe stated preparations may be administered to humans and animals orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, vitraperitoneally, topically (powders, ointments, drops) and for the treatment of infections in cavities, body cavities. Suitable preparations which may be considered are solutions for injections, solutions and suspensions for oral therapy, gels, infusion formulations, emulsions, ointments or drops. Topical treatment may be performed using ophthalmological and dermatological formulations, silver and other salts, ear drops, eye ointments, powders or solutions. Administration to animals may also be achieved via the feed or drinking water in suitable formulations. <iels, pulverulent formulations, powders, tablets, controlled-release tablets, premixes, concentrates, granules, pellets, tablets, boli, capsules, aerosols, sprays, inhalation formulations may also be used in humans and animals. The compounds used according to the invention may also be incorporated into other supports, such as for example plastics (plastic chains for topical treatment), collagen or bone cement.
I1: has in general proved advantageous in both human and veterinary medicine to administer t1e 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 'WO 00/30653 PCT/EP99/08964 more individual doses in order to achic°ve the desired results. An individual dose preferably contains the active substance or substances in quantities of approx. 0.25 to approx. 2000 mg, ~,vhich are administered, for example, 1 to 4 times daily. It may, however, be necessary to deviate from the stated. dosages, in particular as a function of the nature and body weight of the patient to be treated, the nature and severity of the disease, the nature of the preparations and the route of administration of the pharmaceutical preparation and the period of time over which administration is performed.
lJiquid preparations may be administered in the form of solutions, syrups, emulsions or suspensions, which, for oral administration, contain for example 0.1 to 50 wt.% of active substance. In the case of topical adminustration in the form of solutions, gels, suspension or the like, the active substance preferably amounts to between =.OS and 20 wt.%
of the preparation.
In some cases, it may accordingly be sufficient to use less than the above-stated quantity of active substance, while; in other cases more than the above-stated quantity of active substance must be used. The person skilled in thc: art will use his/her skill to determine the optimum dosage and route of administration required in each particular case.
'Che compounds used according to the invention may be given to animals in conventional concentrations and preparations together with feed or feed preparations or with drinking water.
'.Che compounds used according to the invention are furthermore ideally usable as bactericides, fungicides and herbicides in plants.
_1!:xample ~~ntiprotozoal action ~Che following substances are tested for their antiprotozoal activity:
.W bstance l: 2-[(2-Ethoxycarbonylphenoxy)carbonyl]-1,3,2-dioxaphospholane 2-oxide ;substance 2: 2-[(2-Ethoxycarbonylphenoxy)carbonyl]-4-dodecanoyloxymethyl-1,3,2-dioxaphospholane 2-oxide ~~ubstance 3: 2-[(2-Ethoxycarbonylphenoxy)carbonyl]-4-octanoylthiomethyl-1,3,2-dioxaphospholane 2-~axide ',3ubstance 4: 2-[(2-Ethoxycarbonylphenoxy)carbonyl]-4-dodecanoylthiomethyl-1,3,2-dioxaphospholane 2-oxide ,W bstance 5: 2-Hydroxyethyl-[(2-ethoxycarbonylphenoxy)carbonyl] sodium phosphonate ',substance 6: 2-Dodecanoylox;y-2-hydroxypropyl-[(2-ethoxycarbonylphenoxy)carbonyl]
sodium phosphonate Substance 7: 2-C>ctanoylthio-2-hydroxypropyl[(2-ethoxycarbonyl Substance 8: 2-Dodecanoylttlio-2-hydroxypropyl-[(2-ethoxycaxbonylphenoxy)carbonyl]
sodium phosphonate Substance 9: Sodium 2-hydroxy-1,4,2-dioxaphosphorinane 2,3-dioxide Substance 10: Sodium 2-hydroxy-s-dodecanoyloxvmethyl-1,4,2-dioxaphosphorinane 2,3-dio;Ki de Substance 1 l: Sodium 2-hydroxy-5-octanoylthiomethyl-1,4,2-dioxaphosphorinane 2,3-dioxide Substance 12: Sodium 2-hydroxy-5-dodecanoylthiomethyl-1,4,2-dioxaphosphorinane 2,3-dioxide The antimalarial activity of substances 1 to 12 was determined using in vitro cultures of the causative organism of malaria, Plasmodium falciparum. 200 pl of an asynchronous Plasmodium 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 series of the compounds was then :prepared in steps of three between concentrations of 100 and 0.14 pmol 1-1. The plates are incubated at 37"C:, :3'% C02 and 5% 02 over a period of 48 hours. 30 pl of medium supplemented with 27 pCi rr~l~~ of [3H]-hypoxanthine were then added to each well.
After 24 hours' incubation, the parasil:es were harvested by filtration through glass fibre filters and the incorporated radioactivity was measured. Inhibition of parasite growth was measured as the percentage inhibition of tritium incorporation. Inhibition of parasite growth was measured as the percentage inhibition of tritium incorporation relative to a comparison without the substance. The median inhibitory concentration (IC50) of the substance was determined by extrapolating the values.
The results, i.e. the IC50 values, are listed in the following table:
Table Substance no. r ICSO/(nM) 9 ___ 946 _ _ ~ 384 ~
11 _ ___ ~ 862 12 ' 7S1
11 _ ___ ~ 862 12 ' 7S1
Claims (11)
1. Use of a compound of the formula I
in which R11 is selected from the group which consists of C1-26 alkyl residues, C2-26 alkenyl residues with 1 to 6 double, bonds, C2-26 alkynyl residues with 1 to 6 triple bonds, C1-26 acyl residues, Ar-C0-26-alkyl residues, C3-8-cycloalkyl-C0-26-alkyl residues, C3-8-heterocycloalkyl-C0-26-alkyl residues with one or two nitrogen, oxygen or sulfur atoms, halogen and OX11, wherein all the above-stated residues may be substituted with C1-9 alkyl, C1-9 alkoxy, hydroxy, amino, halogen or oxo groups, wherein X11 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 triple bonds, Ar-C0-26-alkyl residues, C3-8 cycloalkyl residues, C1-26 acyl residues, heterocycloalkyl-C0-26-alkyl residues with one or two nitrogen, oxygen or sulfur atoms, C1-26 silyl residues, wherein all 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 an organic and inorganic base, in particular a metal of main groups I, II or III
of the periodic system, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids, in which R1 and R2 are each independently selected from the group which consists of C1-24 alkyl residues, C3-8 cycloalkyl residues, C3-8-cycloalkyl-C1-24-alkyl residues, C1-24 alkoxy 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-C0-24-alkyl residues, halogen and hydrogen, and each C1-24 alkyl residue and C1-24 alkoxy residue may be branched or unbranched and be saturated or unsaturated with 2 to 6 double bonds and may optionally be substituted with hydroxy, amino, mercapto, halogen, oxo groups or C1-24 alkoxy residues, C1-24 alkylcarbonyloxy residues, C1-24 alkoxycarbonyloxy residues, C1-24 alkylthio residues, C1-24 alkylcarbonylthio residues, C1-24 alkylamino residues, di-(C1-24-alkyl)amino residues, C1-24 alkylcarbonylamino residues, C1-24-alkyl(C1-24-alkylcarbonyl)amino residues, alkoxycarbonylamino residues or C1-24-alkyl-(C1-24-alkoxycarbonyl)amino residues, wherein each aralkyl residue, heterocyclic residue, C1-24 alkyl residue and C1-24 alkoxy residue may be branched or unbranched and be saturated or unsaturated with 2 to 6 double bonds or triple bonds, or in which R1-CH-CH-R2 forms part of a C4-8 carbon ring, which may optionally be substituted with hydroxy, mercapto, amino, halogen, oxo groups or with C1-24 alkyl residues, C1-24 alkoxy residues, C1-24 alkylthio residues, C1-24 alkylamino residues, di-(C1-24-alkyl)amino residues, C1-24 alkylcarbonyl residues, C1-24 alkylcarbonyloxy residues, C1-24 alkoxycarbonyl residues, C1-24 alkylcarbonylthio residues or C1-24 alkylcarbonylamino residues, C1-24-alkyl-(C1-24-alkylcarbonyl)amino residues, wherein each C1-24 alkyl residue may be branched or unbranched and be saturated or unsaturated with 1 to 6 double bonds, or wherein R10 is a branched or unbranched C1-4 alkyl residue, and wherein R1-CH-CH-R2 forms part of the furanose or pyranose ring of a sugar, for example D-ribose. D-arabinose, D-xylose, D-lyxose, D-glucose, D-galactose, D-mannose, D-talose, D-allow, D-altrose, D-gulose, D-idose or the corresponding L
isomers, wherein the hydroxy groups may each optionally be substituted by hydrogen, amino, azido, oxo, mercapto residues or C1-24 alkoxy residues, C1-24 alkylthio residues, C1-24 alkylamino residues, di-(C1-24-alkyl)amino residues, C1-24 alkylcarbonyloxy residues, C1-24 alkylcarbonyl)amino residues, C1-24 alkylcarbonylamino residues, C1-24-alkyl-(C1-24-alkylcarbonyl)amino residues, wherein each C1-24 alkyl residue may be branched or unbranched and be saturated or unsaturated with 1 to 6 double bonds, and the pharmaceutically acceptable salts, esters and amides thereof and salts of the esters and the optical isomers thereof.
for the prophylactic and therapeutic treatment of infectious processes in humans and animals which are: caused by bacteria, fungi or parasites and as a fungicide, bactericide or herbicide in plants.
in which R11 is selected from the group which consists of C1-26 alkyl residues, C2-26 alkenyl residues with 1 to 6 double, bonds, C2-26 alkynyl residues with 1 to 6 triple bonds, C1-26 acyl residues, Ar-C0-26-alkyl residues, C3-8-cycloalkyl-C0-26-alkyl residues, C3-8-heterocycloalkyl-C0-26-alkyl residues with one or two nitrogen, oxygen or sulfur atoms, halogen and OX11, wherein all the above-stated residues may be substituted with C1-9 alkyl, C1-9 alkoxy, hydroxy, amino, halogen or oxo groups, wherein X11 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 triple bonds, Ar-C0-26-alkyl residues, C3-8 cycloalkyl residues, C1-26 acyl residues, heterocycloalkyl-C0-26-alkyl residues with one or two nitrogen, oxygen or sulfur atoms, C1-26 silyl residues, wherein all 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 an organic and inorganic base, in particular a metal of main groups I, II or III
of the periodic system, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids, in which R1 and R2 are each independently selected from the group which consists of C1-24 alkyl residues, C3-8 cycloalkyl residues, C3-8-cycloalkyl-C1-24-alkyl residues, C1-24 alkoxy 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-C0-24-alkyl residues, halogen and hydrogen, and each C1-24 alkyl residue and C1-24 alkoxy residue may be branched or unbranched and be saturated or unsaturated with 2 to 6 double bonds and may optionally be substituted with hydroxy, amino, mercapto, halogen, oxo groups or C1-24 alkoxy residues, C1-24 alkylcarbonyloxy residues, C1-24 alkoxycarbonyloxy residues, C1-24 alkylthio residues, C1-24 alkylcarbonylthio residues, C1-24 alkylamino residues, di-(C1-24-alkyl)amino residues, C1-24 alkylcarbonylamino residues, C1-24-alkyl(C1-24-alkylcarbonyl)amino residues, alkoxycarbonylamino residues or C1-24-alkyl-(C1-24-alkoxycarbonyl)amino residues, wherein each aralkyl residue, heterocyclic residue, C1-24 alkyl residue and C1-24 alkoxy residue may be branched or unbranched and be saturated or unsaturated with 2 to 6 double bonds or triple bonds, or in which R1-CH-CH-R2 forms part of a C4-8 carbon ring, which may optionally be substituted with hydroxy, mercapto, amino, halogen, oxo groups or with C1-24 alkyl residues, C1-24 alkoxy residues, C1-24 alkylthio residues, C1-24 alkylamino residues, di-(C1-24-alkyl)amino residues, C1-24 alkylcarbonyl residues, C1-24 alkylcarbonyloxy residues, C1-24 alkoxycarbonyl residues, C1-24 alkylcarbonylthio residues or C1-24 alkylcarbonylamino residues, C1-24-alkyl-(C1-24-alkylcarbonyl)amino residues, wherein each C1-24 alkyl residue may be branched or unbranched and be saturated or unsaturated with 1 to 6 double bonds, or wherein R10 is a branched or unbranched C1-4 alkyl residue, and wherein R1-CH-CH-R2 forms part of the furanose or pyranose ring of a sugar, for example D-ribose. D-arabinose, D-xylose, D-lyxose, D-glucose, D-galactose, D-mannose, D-talose, D-allow, D-altrose, D-gulose, D-idose or the corresponding L
isomers, wherein the hydroxy groups may each optionally be substituted by hydrogen, amino, azido, oxo, mercapto residues or C1-24 alkoxy residues, C1-24 alkylthio residues, C1-24 alkylamino residues, di-(C1-24-alkyl)amino residues, C1-24 alkylcarbonyloxy residues, C1-24 alkylcarbonyl)amino residues, C1-24 alkylcarbonylamino residues, C1-24-alkyl-(C1-24-alkylcarbonyl)amino residues, wherein each C1-24 alkyl residue may be branched or unbranched and be saturated or unsaturated with 1 to 6 double bonds, and the pharmaceutically acceptable salts, esters and amides thereof and salts of the esters and the optical isomers thereof.
for the prophylactic and therapeutic treatment of infectious processes in humans and animals which are: caused by bacteria, fungi or parasites and as a fungicide, bactericide or herbicide in plants.
2. Use according to claim 1, characterised in that R1 and R2 are each independently selected from the group which consists of carboxyl residues, carboxamido residues, aryl residues, aryloxycarbonyl residues, aryl-C1-24-alkyl residues, C1-24 alkoxycarbonyloxy residues, C1-24 alkylaminocarbonyl residues, di-(C1-24-alkyl)aminocarbonyl residues, aryl-alkoxycarbonyl residues, aryl-C1-24-alkylaminocarbonyl residues, C1-24-alkylcarbonyloxy-(C1-24)alkylmethoxycarbonyl residues, C1-24 alkoxycarbonyloxymethoxycarbonyl residues, C1-24-alkoxycarbonyloxy-(C1-4 alkyl)methoxycarbonyl, wherein each C1-24 alkyl residue may be branched or unbranched and be saturated or unsaturated with 2 to 6 double bonds, and each C1-4 alkyl residue and C1-24 alkoxy residue may be branched or unbranched and be saturated or unsaturated, and each aryl residue is of the formula II
wherein R3 and R4 are identical or different and are each selected from the group which consists of hydrogen, halogen, C1-4 alkyl residues, C1-4 alkoxy residues, formyl, acetyl, propionyl, butyryl residues, formyloxy, acetyloxy, propionyloxy, butyryloxy residues, C1-4 alkoxycarbonyl residues, all of which may be branched or unbranched, or R3 and R4 together form 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 a methylenedioxy residue, a 1,1-ethylidenedioxy residue, L,1-ethenylenedioxy residue, a 1,1-ethylenedioxy residue or a 1,2-ethylenedioxy residue, which are attached to adjacent positions of the phenyl ring, or
wherein R3 and R4 are identical or different and are each selected from the group which consists of hydrogen, halogen, C1-4 alkyl residues, C1-4 alkoxy residues, formyl, acetyl, propionyl, butyryl residues, formyloxy, acetyloxy, propionyloxy, butyryloxy residues, C1-4 alkoxycarbonyl residues, all of which may be branched or unbranched, or R3 and R4 together form 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 a methylenedioxy residue, a 1,1-ethylidenedioxy residue, L,1-ethenylenedioxy residue, a 1,1-ethylenedioxy residue or a 1,2-ethylenedioxy residue, which are attached to adjacent positions of the phenyl ring, or
3. Use according to claim 1, wherein R1 and R2 are each independently selected from the group which consists of hydrogen groups, acetyl groups, formyl groups, hydroxy groups and methyl groups, wherein the methyl group may optionally be substituted with a hydroxy group or mercapto group or with C1-24 alkoxy residues, C1-24 alkylcarbonyloxy residues, C1-24 alkylthio residues or C1-24 alkylcarbonylthio residues, wherein the C1-24 alkyl groups and C1-24 alkoxy groups may be branched or unbranched and be saturated or unsaturated with 1 to 6 double bonds.
4. Use according to claim 3, wherein, R1 is a methyl residue, which may optionally be substituted with a hydroxy group or mercapto group or with C1-24 alkoxy residues, C1-24 alkylcarbonyloxy residues, C1-24 alkylthio residues or C1-24 alkylcarbonylthio residues, wherein the C1-24 alkyl groups and. the C1-24 alkoxy groups may be branched or unbranched and be saturated or unsaturated with 1 to 6 double bonds, and R2 is a hydrogen residue.
5. Use according to claim 1, wherein R1 and R2 are each independently selected from the group which consists of hydrogen and an ~-octadecylmethyl residue.
6. Use according to claim 5, wherein R1 is an ~-octadecylmethyl residue and R2 a hydrogen residue.
7. Use according to claim 6, wherein the compound is in (R) configuration.
8. Use according to one of the preceding claims for the treatment of infections caused by bacteria, fungi or uni- or multicellular-parasites.
9. Use according to claim 8 for the treatment of infections which are caused by bacteria which are selected from the group which consists of bacteria of the family Propionibacteriaceae, in particular of the genus Propionibacterium, in particular the species Propionibacterium acnes, bacteria of the family Actinomycetaceae, in particular of the genus Actinomyces, bacteria of the genus Cornynebacterium, in particular the species Corynebacterium diphtheriae and Corynebacterium pseudotuberculosis, bacteria 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, bacteria of the genus Clostridium, bacteria of the genus Yersinia, the species Yersinia pestis, Yersinia pseudotuberculosis, Yersinia enterocolitica and Yersinia ruckeri, bacteria of the family Mycoplasmataceae, of the genera Mycoplasma and Ureaplasma, in particular the species Mycoplasma pneumoniae, bacteria of the genus Brucella, bacteria of the genus Bordetella, bacteria of the family Neisseriaceae, in particular of the genera Neisseria and Moraxella, in particular the species Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis, bacteria of the family Vibrionaceae, in particular of the genera Vibrio, Aeromonas, Plesiomonas and Photobacterium, in particular the species Vibrio cholerae, Vibrio anguillarum and Aeromonas salmonicidas, bacteria of the genus Campylobacter, in particular the species Campylobacter jejuni, Campylobacter coli and Campylobacter fetus, bacteria of the genus Helicobacter, in particular the species Helicobacter pylori, bacteria of the families Spirochaetaceae and Leptospiraceae, in particular of the genera Treponema, Borrelia and Leptospira, in particular Borrelia burgdorferi, bacteria of the genus Actinobacillus, bacteria of the family Legionellaceae, of the genus Legionella, bacteria of the family Rickettsiaceae and family Bartonellaceae, bacteria of the genera Nocardia and Rhodococcus, bacteria of the genus Dermatophilus, bacteria of the family Pseudomonadaceae, in particular of the genera Pseudomonas and Xanthomonas, bacteria of the family Enterobacteriaceae, in particular of the genera Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia and Shigella, bacteria of the family Pasteurellaceae, in particular of tine genus Haemophilus, bacteria of the family Micrococcaceae, in particular of the genera Micrococcus and Staphylococcus, bacteria of the family Streptococcaceae, in particular of the genera Streptococcus and Enterococcus and bacteria of the family Bacillaceae, in particular of the genera Bacillus and Clostridium, and in the eradication of Helicobacter in ulcers of the gastrointestinal tract.
10. Use according to claim 8 for the prevention and treatment of infections caused by unicellular parasites which are selected from the group which consists of the causative organisms of malaria, sleeping sickness, Chagas' disease, toxoplasmosis, amoebic dysentery, leishmaniases, trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiosis, sarcocytosis, acanthamoebosis, naeglerosis, coccidiosis, giardiasis and lambliasis.
11. Process for the treatment of infectious diseases caused by bacteria, fungi or parasites in which a therapeutically effective quantity of a compound according to one of claims 1 to 7 is administered to a patient suffering from an infection caused by bacteria, fungi or parasites.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19854310.7 | 1998-11-25 | ||
| DE19854310A DE19854310A1 (en) | 1998-11-25 | 1998-11-25 | Use of phosphonoformic acid derivatives for the therapeutic and prophylactic treatment of infections |
| PCT/EP1999/008964 WO2000030653A2 (en) | 1998-11-25 | 1999-11-20 | Use of phosphonoformic acid derivatives for treating infections |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2352511A1 true CA2352511A1 (en) | 2000-06-02 |
Family
ID=7888924
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002352511A Abandoned CA2352511A1 (en) | 1998-11-25 | 1999-11-20 | Use of phosphonoformic acid derivatives for treating infections |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP1133302A2 (en) |
| JP (1) | JP2002530343A (en) |
| CN (1) | CN1328464A (en) |
| AP (1) | AP2001002164A0 (en) |
| AU (1) | AU1859100A (en) |
| BR (1) | BR9915605A (en) |
| CA (1) | CA2352511A1 (en) |
| CZ (1) | CZ20011819A3 (en) |
| DE (1) | DE19854310A1 (en) |
| EA (1) | EA200100585A1 (en) |
| IL (1) | IL142775A0 (en) |
| NO (1) | NO20012540L (en) |
| OA (1) | OA11718A (en) |
| PL (1) | PL348354A1 (en) |
| TR (1) | TR200101431T2 (en) |
| WO (1) | WO2000030653A2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT1408984E (en) | 2001-07-20 | 2008-12-26 | Bioagency Ag | Organo-phosphorous compounds for activating gamma/delta t cells |
| CA2518763A1 (en) * | 2003-03-14 | 2004-09-23 | Epistem Limited | Treatment and/or prevention of non-viral epithelial damage |
| US20050171063A1 (en) * | 2003-10-20 | 2005-08-04 | Pawan Malhotra | Use of phosphono derivatives as anti-malarials |
| CN104940211B (en) * | 2015-06-08 | 2018-06-19 | 广州万粤知识产权运营有限公司 | Application of the betulic acid in antimycotic biofilm drug is prepared |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995012604A1 (en) * | 1993-11-05 | 1995-05-11 | Aktiebolaget Astra | Novel amino acid derivatives |
| SE9604582D0 (en) * | 1996-12-13 | 1996-12-13 | Astra Ab | Novel compounds |
| RU2116790C1 (en) * | 1997-07-02 | 1998-08-10 | Закрытое акционерное общество "Рефарм" | Antiinfectious agent "repharm" for external using |
| DE19859668A1 (en) * | 1998-06-24 | 1999-12-30 | Hassan Jomaa | Treating or preventing viral, bacterial, fungal or parasitic infections using bis-phosphonic acid compounds, also having herbicidal activity |
-
1998
- 1998-11-25 DE DE19854310A patent/DE19854310A1/en not_active Withdrawn
-
1999
- 1999-11-20 CA CA002352511A patent/CA2352511A1/en not_active Abandoned
- 1999-11-20 EP EP99962147A patent/EP1133302A2/en not_active Withdrawn
- 1999-11-20 CN CN99813747A patent/CN1328464A/en active Pending
- 1999-11-20 OA OA1200100130A patent/OA11718A/en unknown
- 1999-11-20 AU AU18591/00A patent/AU1859100A/en not_active Abandoned
- 1999-11-20 CZ CZ20011819A patent/CZ20011819A3/en unknown
- 1999-11-20 WO PCT/EP1999/008964 patent/WO2000030653A2/en not_active Application Discontinuation
- 1999-11-20 PL PL99348354A patent/PL348354A1/en unknown
- 1999-11-20 BR BR9915605-9A patent/BR9915605A/en not_active IP Right Cessation
- 1999-11-20 AP APAP/P/2001/002164A patent/AP2001002164A0/en unknown
- 1999-11-20 IL IL14277599A patent/IL142775A0/en unknown
- 1999-11-20 JP JP2000583536A patent/JP2002530343A/en active Pending
- 1999-11-20 EA EA200100585A patent/EA200100585A1/en unknown
- 1999-11-20 TR TR2001/01431T patent/TR200101431T2/en unknown
-
2001
- 2001-05-23 NO NO20012540A patent/NO20012540L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| CZ20011819A3 (en) | 2001-12-12 |
| EA200100585A1 (en) | 2002-04-25 |
| IL142775A0 (en) | 2002-03-10 |
| AP2001002164A0 (en) | 2001-06-30 |
| JP2002530343A (en) | 2002-09-17 |
| WO2000030653A2 (en) | 2000-06-02 |
| EP1133302A2 (en) | 2001-09-19 |
| AU1859100A (en) | 2000-06-13 |
| OA11718A (en) | 2005-01-26 |
| NO20012540D0 (en) | 2001-05-23 |
| BR9915605A (en) | 2001-08-14 |
| PL348354A1 (en) | 2002-05-20 |
| WO2000030653A3 (en) | 2000-11-16 |
| NO20012540L (en) | 2001-07-24 |
| CN1328464A (en) | 2001-12-26 |
| TR200101431T2 (en) | 2001-10-22 |
| DE19854310A1 (en) | 2000-06-29 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |