CA2360661A1 - Use of phosphororganic compounds for the prophylactic and therapeutical treatment of infections - Google Patents
Use of phosphororganic compounds for the prophylactic and therapeutical treatment of infections Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
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- A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
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- A61P31/04—Antibacterial agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
The invention relates to the use of phosphororganic compounds of general formula (I), wherein X is a phosphor atom or a sulphur atom and A is a substituted or an unsubstituted C2-5-alkyl chain, for the therapeutical and prophylactic treatment of infections in humans and animals, whereby said infections are caused by viruses, bacteria, fungi and parasites. Said compounds can also be used in plants as fungicides, bactericides and herbicides.
Description
The invention relates to the use of organophosphorus compounds and the salts, esters and amides thereof for the therapeutic and prophylactic treatment of infections in humans and animals which are caused by viruses, bacteria, fungi and parasites and to the use thereof as a fungicide, bactericide and herbicide in plants. According to the invention, the organophosphorus compound comprise phosphinoyl derivatives, phosphinic acid derivatives and phosphoric acid derivatives.
to 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 and thus constitute a reduced risk to human health.
is The object of the present invention is accordingly to provide a substance which is universally usable in infections by viruses, bacteria, fungi and parasites in humans and animals and as a fungicide, bactericide and herbicide in plants and which meets the above-stated requirements.
2o This object is utterly surprisingly achieved by the use of the group of substances defined in claim 1. This group of substances exhibits antiinfective action against viruses, certain bacteria, fungi, uni- and multicellular parasites.
The organophosphorus compounds used according to the invention are of the general formula:
2s II II
Rl-X-A-P-R3 ( I ) I I
3o in which X is a phosphorus atom or a sulfur atom, wherein A is an unbranched C2_9 alkylene chain with substituents, which are identical or different and are selected from the group which consists of hydrogen, hydroxy, halogen, amino and oxo groups, C, _26 alkyl residues, C 1 _26 alkoxy residues, C 1 _26-alkoxy-C 1 _26-alkyl 3s residues or C3_8-cycloalkyl-(Co_9)-alkyl groups, wherein each C1_26 alkyl residue and each C1_26 alkoxy residue may be branched or unbranched and be saturated or unsaturated with one or more double bonds and may be substituted with hydroxy, amino, halogen and oxo groups and both the C3_$ cycloalkyl group and the Co_9 alkyl group of the C3_$-cycloalkyl-(Co_9)-alkyl group may comprise one or more double bonds and one or two carbon atoms of the cycloalkyl '; WO 00/44358 PCT/EP00/00542 group may be replaced by nitrogen, oxygen or sulfur atoms, and wherein both the cycloalkyl group and the alkyl group may be substituted with hydroxy, halogen, amino, oxo groups with branched or unbranched C1_9 alkyl groups and C2_9 alkenyl groups, wherein the C1_9 alkyl groups and C2_9 alkenyl groups may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups in which RI and RZ are identical or different and are selected from the group which consists of hydrogen, substituted and unsubstituted C1_9 alkyl, substituted and unsubstituted hydroxy-C1_ 9-alkyl, substituted and unsubstituted C1_9 alkenyl, substituted and unsubstituted C1_9 alkynyl, 1o substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic residue, halogen, OXl and OX2, wherein Xl and X2 are identical or different and are selected from the group which consists of 15 hydrogen, substituted and unsubstituted C1_9 alkyl, substituted and unsubstituted hydroxy-C1_ 9-alkyl, substituted and unsubstituted C1_9 alkenyl, substituted and unsubstituted C1_9 alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic residue, in which R3 and R4 are identical or different and are selected from the group which consists of substituted and unsubstituted Ci_26 alkyl, hydroxy-C1_26-alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C1_26 alkenyl, substituted and unsubstituted C1_26 alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic residue, halogen, OX3 and OX4, wherein X3 and X4 are identical or different and are selected from the group which consists of hydrogen, substituted and unsubstituted Ci_26 alkyl, substituted and unsubstituted hydroxy-C1_ 26-alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted C1_26 alkenyl, substituted and unsubstituted C1_26 alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic residue, a silyl; 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, and the pharmaceutically acceptable salts, esters and amides thereof and salts of the esters.
to 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 and thus constitute a reduced risk to human health.
is The object of the present invention is accordingly to provide a substance which is universally usable in infections by viruses, bacteria, fungi and parasites in humans and animals and as a fungicide, bactericide and herbicide in plants and which meets the above-stated requirements.
2o This object is utterly surprisingly achieved by the use of the group of substances defined in claim 1. This group of substances exhibits antiinfective action against viruses, certain bacteria, fungi, uni- and multicellular parasites.
The organophosphorus compounds used according to the invention are of the general formula:
2s II II
Rl-X-A-P-R3 ( I ) I I
3o in which X is a phosphorus atom or a sulfur atom, wherein A is an unbranched C2_9 alkylene chain with substituents, which are identical or different and are selected from the group which consists of hydrogen, hydroxy, halogen, amino and oxo groups, C, _26 alkyl residues, C 1 _26 alkoxy residues, C 1 _26-alkoxy-C 1 _26-alkyl 3s residues or C3_8-cycloalkyl-(Co_9)-alkyl groups, wherein each C1_26 alkyl residue and each C1_26 alkoxy residue may be branched or unbranched and be saturated or unsaturated with one or more double bonds and may be substituted with hydroxy, amino, halogen and oxo groups and both the C3_$ cycloalkyl group and the Co_9 alkyl group of the C3_$-cycloalkyl-(Co_9)-alkyl group may comprise one or more double bonds and one or two carbon atoms of the cycloalkyl '; WO 00/44358 PCT/EP00/00542 group may be replaced by nitrogen, oxygen or sulfur atoms, and wherein both the cycloalkyl group and the alkyl group may be substituted with hydroxy, halogen, amino, oxo groups with branched or unbranched C1_9 alkyl groups and C2_9 alkenyl groups, wherein the C1_9 alkyl groups and C2_9 alkenyl groups may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups in which RI and RZ are identical or different and are selected from the group which consists of hydrogen, substituted and unsubstituted C1_9 alkyl, substituted and unsubstituted hydroxy-C1_ 9-alkyl, substituted and unsubstituted C1_9 alkenyl, substituted and unsubstituted C1_9 alkynyl, 1o substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic residue, halogen, OXl and OX2, wherein Xl and X2 are identical or different and are selected from the group which consists of 15 hydrogen, substituted and unsubstituted C1_9 alkyl, substituted and unsubstituted hydroxy-C1_ 9-alkyl, substituted and unsubstituted C1_9 alkenyl, substituted and unsubstituted C1_9 alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic residue, in which R3 and R4 are identical or different and are selected from the group which consists of substituted and unsubstituted Ci_26 alkyl, hydroxy-C1_26-alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C1_26 alkenyl, substituted and unsubstituted C1_26 alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic residue, halogen, OX3 and OX4, wherein X3 and X4 are identical or different and are selected from the group which consists of hydrogen, substituted and unsubstituted Ci_26 alkyl, substituted and unsubstituted hydroxy-C1_ 26-alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted C1_26 alkenyl, substituted and unsubstituted C1_26 alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic residue, a silyl; 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, and the pharmaceutically acceptable salts, esters and amides thereof and salts of the esters.
X3 and X4 are preferably a metal of main groups I, II or III of the periodic system, ammonium, substituted ammonium or ammonium compounds derived from ethylenediamine or amino acids. In other words, the salt compounds of the organophosphorus compounds are formed with organic or inorganic bases (for example sodium salt, potassium salt, calcium salt, aluminium salt, ammonium salt, magnesium salt, triethylamine salt, ethanolamine salt, dicyclohexylamine salt, ethylenediamine salt, N,N'-dibenzylethylenediamine salts etc.) as well as salts with amino acids .(for example arginine salt, aspartic acid salt, glutamic acid salt etc.) and the like.
to X3 and X4 are particularly preferably identical or different and are selected from the group which consists of hydrogen, sodium, potassium, methyl, ethyl.
A is preferably a C3_5 alkyl chain.
Particularly preferred compounds are of the formula (II) II II
Rl-X-A-P-R3 ( I I ) , I I
wherein X, R1, R3, R4 are defined as above, wherein Ri is preferably substituted with a hydroxy group on the C atom adjacent to the heteroatom, and compounds of the formula (III) II II
Rl-X-A-P-R3 ( I I I ) I I
3o wherein X, Rl, R3, R4 are defined as above, wherein Rl is preferably an acyl group, particularly preferably a formyl, acetyl, propionyl or butyryl group.
Compounds having the following structures are likewise preferred:
II II II
R1-X-C-C-C-C-P-R3 (IV), I I .
to X3 and X4 are particularly preferably identical or different and are selected from the group which consists of hydrogen, sodium, potassium, methyl, ethyl.
A is preferably a C3_5 alkyl chain.
Particularly preferred compounds are of the formula (II) II II
Rl-X-A-P-R3 ( I I ) , I I
wherein X, R1, R3, R4 are defined as above, wherein Ri is preferably substituted with a hydroxy group on the C atom adjacent to the heteroatom, and compounds of the formula (III) II II
Rl-X-A-P-R3 ( I I I ) I I
3o wherein X, Rl, R3, R4 are defined as above, wherein Rl is preferably an acyl group, particularly preferably a formyl, acetyl, propionyl or butyryl group.
Compounds having the following structures are likewise preferred:
II II II
R1-X-C-C-C-C-P-R3 (IV), I I .
II I II
Rl-X-C-C-C-C-P-R3 ( V ) , I I
II II II
Rl-X-C-C-C-C-P-R3 (VI) , I I
II I II
Rl-X-C-C-C-C-P-R3 (VII) , I I
RZ Rq II II II II
Rl-X-C-C-C-C-C-P-R3 ( VI I I ) , I I
OH OH
II I I II
Rl-X-C-C-C-C-C-P-R3 (IX), i I
RZ RQ
II I II II
Rl-X-C-C-C-C-C-P-R3 (X) and II II I II
Rl-X-C-C-C-C-C-P-R3 (XI).
i I
3o 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 thio 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.
Rl-X-C-C-C-C-P-R3 ( V ) , I I
II II II
Rl-X-C-C-C-C-P-R3 (VI) , I I
II I II
Rl-X-C-C-C-C-P-R3 (VII) , I I
RZ Rq II II II II
Rl-X-C-C-C-C-C-P-R3 ( VI I I ) , I I
OH OH
II I I II
Rl-X-C-C-C-C-C-P-R3 (IX), i I
RZ RQ
II I II II
Rl-X-C-C-C-C-C-P-R3 (X) and II II I II
Rl-X-C-C-C-C-C-P-R3 (XI).
i I
3o 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 thio 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.
Suitable examples of these acyl groups are given below.
Aliphatic acyl groups are defined as acyl 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.);
alkylthioa.lkanoyl (for example methylthioacetyl, ethylthioacetyl etc.);
alkanesulfonyl (for example mesyl, ethanesulfonyl, propanesulfonyl etc.); alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, 1o isobutoxycarbonyl etc.); alkylcarbamoyl (for example methylcarbamoyl etc.);
(N-alkyl)thiocarbamoyl (for example (N-methyl)thiocaxbamoyl etc.);
alkylcarbamimidoyl (for example methylcarbamimidoyl etc.); oxalo; alkoxalyl (for example methoxalyl, ethoxalyl, propoxalyl etc.).
15 In 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 as 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 2o the like; preferred aliphatic acyl residues with such substituents which may be mentioned are, for example, alkanoyls substituted with amino, carboxy, amino and carboxy, halogen, acylamino or the like.
Aromatic acyl residues are defined as those aryl residues which originate from an acid with a 25 substituted or unsubstituted aryl group, wherein the aryl group may comprise phenyl, toluyl, xylyl, naphthyl and the like; suitable examples are stated below:
amyl (for example benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl etc.);
aralkanoyl (for example phenylacetyl etc.); aralkenoyl (for example cinnamoyl etc.);
aryloxya.lkanoyl (for example phenoxyacetyl etc.); arylthioalkanoyl (for example phenylthioacetyl etc.);
3o arylaminoalkanoyl (for example N-phenylglycyl, etc.); arenesulfonyl (for example benzenesulfonyl, tosyl or toluenesulfonyl, naphthalenesulfonyl etc.);
aryloxycarbonyl (for example phenoxycarbonyl, naphthyloxycarbonyl etc.); axalkoxycarbonyl (for example benzyloxycarbonyl etc.); arylcarbamoyl (for example phenylcarbamoyl, naphthylcarbamoyl etc.); arylglyoxyloyl (for example phenylglyoxyloyl etc.).
In the above-stated Examples of aromatic aryl residues, the aromatic hydrocarbon moiety (in particular the aryl residue) and/or the aliphatic hydrocarbon moiety (in parkicular the alkane residue) may optionally have one or more suitable substituents, such as those which have akeady been stated as suitable substituents for the alkyl group or the alkane residue.
Examples of preferred aromatic acyl residues with specific substituents which may in particular be mentioned are amyl substituted with halogen and hydroxy or with halogen and acyloxy, and aralkanoyl substituted with hydroxy, hydroxyimino, dihaloalkanoyloxyimino, together with arylthiocarbamoyl (for example phenylthiocarbamoyl etc.);
arylcarbamimidoyl (for example phenylcarbamimidoyl 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, furoyl, pyrrolecarbonyl, nicotinyl etc.);
1 s 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 thiophenylacetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl etc.) and the like.
2o In 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.
"Alkyl" is a linear or branched alkyl residue with up to 26 carbon atoms, provided that it is 2s not otherwise defined, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl and the like.
"Hydroxya.lkyl" is a linear or branched alkyl residue with up to 26 carbon atoms, provided that it is not otherwise defined, which comprises at least one hydroxyl group, preferably one 30 or two hydroxyl groups.
"Alkenyl" includes linear or branched a.lkenyl groups with up to 26 carbon atoms, provided that it is not otherwise defined, such as for example vinyl, propenyl (for example 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl, 3 s hexenyl.
"Alkynyl" includes linear or branched alkynyl groups with up to 26 carbon atoms, provided that it is not otherwise defined.
-Cycloalkyl preferably denotes an optionally substituted C3.8 cycloallcyl;
possible substituents are inter alia alkyl, alkenyl, alkynyl, alkoxy (for example methoxy, ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.), vitro and the like.
Aryl is an aromatic hydrocarbon residue, such as phenyl, naphthyl etc., which may optionally comprise one or more suitable substituents, such as alkyl, alkenyl, alkynyl, alkoxy (for example methoxy, ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.), vitro and the like.
to "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 allcoxy (for example methoxy, ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.), vitro and the like.
The residues X3 and X4 may preferably be selected such that esters are formed on the phosphino group or phosphono group. Suitable examples of esters of the formulae (I) to (IX) include suitable mono- and diesters, and preferred examples of such esters are alkyl esters (for example hexadecanyl ester, octadecanyl ester etc.);
2o aralkyl esters (benzyl ester, phenethyl ester, benzhydryl ester, trityl ester etc.);
aryl esters (for example phenyl ester, tolyl ester, naphthyl ester etc.);
aroylalkyl esters (for example phenacyl ester etc.); and silyl esters (for example of trialkylhalosilyl, dialkyldihalosilyl, alkyltrihalosilyl, dialkylarylhalosilyl, trialkoxyhalosilyl, dialkylaralkylhalosilyl, dialkoxydihalosilyl, trialkoxyhalosilyl etc.) and the like.
2s In the above esters, the alkane and/or arene moiety may optionally comprise at least. one suitable substituent, such a.s halogen, alkoxy, hydroxy, vitro or the like.
The compounds used according to the invention according to the formulae (I) to (XI) may be 3o present in the protonated form thereof as an ammonium salt of organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, malefic acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid etc..
3s The compounds used according to the invention of the formulae (I) to (XI) permit, for example for groups Rl, R2, R3, R4, Xl, X2, X3, X4 or A which contain double bonds or are chiral, the occurrence of steric isomers. The use according to the invention of the compounds includes all steric isomers, both as pure substances and in the form of mixtures.
_g_ The organophosphorus compounds are in particular suitable for the therapeutic and prophylactic treatment of infections in humans and animals caused by viruses, bacteria, uni-and multicellular parasites and fungi.
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, acanthamoebosis, naeglerosis, coccidiosis, giardiasis and I o lambliasis.
They are accordingly in particular suitable for the prophylactic treatment of malaria and of sleeping sickness and of Chagas' disease, of toxoplasmosis, amoebic dysentery, leishmaniases, trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiosis, sarcocytosis, acanthamoebosis, naeglerosis, coccidiosis, giardiasis and lambliasis.
The active substances according to the invention may in particular be used against the following bacteria:
2o 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 3o 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, 3s 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 Treponemay 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 the genus Haemophilus, bacteria of the to 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.
Organophosphorus 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 animals, leprosy and further mycobacterioses in humans and animals, paratuberculosis in animals, plague, mesenterial lymphadenitis and pseudotuberculosis in humans and animals, cholera, legionnaires' disease, borreliosis in humans and animals, leptospiroses in humans and 2o animals, syphilis, Campylobacter enteritis infections in humans and animals, Moraxella keratoconjunctivitis and serositis in animals, brucellosis of animals and humans, anthrax in humans and animals, actinomycosis in humans and animals, streptotrichoses, psittacosis/ortnithosis in animals, Q fever, ehrlichiosis.
Use is furthermore effective in the eradication of Helicobacter in ulcers of the gastrointestinal tract.
Combinations with another antibiotic may also be used to treat the above-stated diseases.
Isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, protionamide and dapsone are 3o in particular suitable for combination preparations with other antiinfective agents for the treatment of tuberculosis.
The active substances according to the invention are furthermore in particular usable in infections with the following viruses:
Parvoviridae: parvoviruses, dependoviruses, densoviruses, Adenoviridae:
adenoviruses, mastadenoviruses, aviadenoviruses, Papovaviridae: papovaviruses, in particular papillomaviruses ("wart" viruses), polyomaviruses, in particular JC virus, BK
virus and miopapovaviruses, Herpesviridae: all herpesviruses, in particular herpes simplex viruses, varicella-zoster viruses, human cytomegalovirus, Epstein-Barr viruses, all human herpesviruses, human herpesvirus 6, human herpesvirus 7, human herpesvirus 8, Poxiviridae:
poxviruses, orthopoxviruses, parapoxviruses, molluscum contagiosum virus, aviviruses, capriviruses, leporipoxviruses, all primarily hepatotropic viruses, hepatitisviruses: hepatitis A
viruses, hepatitis B viruses, hepatitis C viruses, hepatitis D viruses, hepatitis E viruses, hepatitis F viruses, hepatitis G viruses, hepadnaviruses: all hepatitisviruses, hepatitis B virus, hepatitis D viruses, Picornaviridae: picornaviruses, all enteroviruses, all polioviruses, all coxsackie-viruses, all echoviruses, all rhinoviruses, hepatitis A virus, aphthoviruses, Calciviridae: hepatitis E viruses, Reoviridae: reoviruses, orbiviruses, rotaviruses, Togaviridae:
1o togaviruses, alphaviruses, rubiviruses, pestiviruses, rubellavirus, Flaviviridae: flaviviruses, FSME virus, hepatitis C virus, Orthomyxoviridae: all influenza viruses, Paramyxoviridae:
paramyxoviruses, morbillivirus, pneumovirus, measles virus, mumps virus, Rhabdoviridae:
rhabdoviruses, rabies virus, lyssavirus, vascular stomatitisvirus, Coronaviridae: coronaviruses, Bunyaviridae: bunyaviruses, nairovirus, phlebovirus, uukuvirus, hantavirus, hantaan virus, Arenaviridae: arenaviruses, lymphocytic choriomeningitis virus, Retroviridae:
retroviruses, all HTL viruses, human T-cell leukaemia virus, oncornaviruses, spumaviruses, lentiviruses, all HI viruses, Filoviridae: Marburg and Ebola virus, slow-virus infections, prions, oncoviruses and leukaemia viruses.
2o The organophosphorus compounds used according to the invention are consequently suitable for combating the following viral infections:
eradication of papillomaviruses to prevent tumours, in particular tumours of the reproductive organs caused by papillomaviruses in humans, eradication of JC viruses and BK
viruses, eradication of herpesviruses, eradication of human herpesvirus 8 to treat Kaposi's sarcoma, eradication of cytomegaloviruses before transplantations, eradication of Epstein-Barr viruses before transplantation and to prevent tumours associated with Epstein-Barr viruses, eradication of hepatitis viruses to treat chronic liver disease and to prevent liver tumours and cirrhosis of the liver, eradication of coxsackie-viruses in cardiomyopathy, eradication of 3o coxsackie-viruses in diabetes mellitus patients, eradication of immunodeficiency viruses in humans and animals, treatment of accompanying infections in AIDS patients, treatment of respiratory tract inflammation of viral causation (laryngeal papilloma, hyperplasia, rhinitis, pharyngitis, bronchitis, pneumonia), of the sensory organs (keratoconjunctivitis), of the nervous system (poliomyelitis, meningoencephalitis, encephalitis, subacute sclerosing panencephalitis, SSPE, progressive multifocal leukoencephalopathy, lymphocytic choriomeningitis), of the gastrointestinal tract (stomatitis, gingivostomatitis, oesophagitis, gastritis, gastroenteritis, diarrhoea), of the liver and gall system (hepatitis, cholangitis, hepatocellular carcinoma), of the lymphatic tissue (mononucleosis, lymphadenitis), of the haemopoietic system, of the reproductive organs (mumps orchitis), of the skin (warts, dermatitis, herpes labialis, herpes febrilis, herpes zoster, shingles), of the mucous membranes (papillomas, conjunctiva) papillomas, hyperplasia, dysplasia), of the cardiovascular system (arteriitis, myocarditis, endocarditis, pericarditis), of the kidney/urinary system, of the reproductive organs (anogenital lesions, warts, genital warts, sharp condylomas, dysplasia, papillomas, cervical dysplasia, condyloma acuminatum, epidermodysplasia verruciformis), of the locomotory organs (myositis, myalgia), treatment of foot-and-mouth disease in cloven-hoofed animals, of Colorado tick fever, Dengue syndrome, of haemorrhagic fever, of early summer meningoencephalitis (FSME) and of yellow fever.
1o The described compounds, i.e. the organophosphorus compounds of the formulae (I) to (XI) and esters and amides thereof on the phosphino group 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 according to the invention are 15 accordingly usable for the treatment of infective diseases which are caused in humans and animals by viruses, bacteria, parasites and fungi. The compounds are also suitable for the prevention of diseases which are caused by viruses, bacteria, parasites and fungi, in particular for the prophylactic treatment of malaria and of sleeping sickness.
2o 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 25 antiinfective action (mixed with a non-toxic, pharmaceutically acceptable excipient).
Pharmaceutically acceptable salts of the compounds include salts which the compounds of the formulae (I) to (XI) according to the invention form in their protonated form as an ammonium salt of inorganic or organic acids, such as hydrochloric acid, sulfuric acid, citric acid, malefic 3o acid, fumaric acid, tartaric acid, p-toluenesulfonic acid.
Particularly pharmaceutically suitable salts are also those formed by suitable selection of X3 and X4, 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, 35 aspartic acid salt, glutamic acid salt.
The activity of the substances is determined using a test system. This system is based upon in vitro measurement of the inhibition of growth of bacteria, parasites, viruses, fungi or plants.
Test rnethods known to the person skilled in the art are in part used for this purpose.
For example, antimalarial activity is determined by measuring the inhibition of the growth of malaria parasites in blood cultures. Antibacterial activity is determined on the basis of measuring the inhibition of bacterial growth on nutrient media and in liquid cultures. Antiviral activity is determined on the basis of the formation of viral elements in cell cultures.
Fungicidal activity is determined on the basis of inhibition of fungal growth on nutrient media and in liquid cultures.
to 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.
Substances which exhibit activity in in vitro measurement systems are then further investigated in in vivo models. Antiparasitic, antiviral, fungicidal or antibacterial activity is 15 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.
2o The pharmaceutically active agents 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 l, 2, 3 or 4 individual doses or 1/2, 1/3 or 25 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-3o 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 35 and granules may contain the active substances together with conventional excipients, such as (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 (f j 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 and magnesium stearate and solid polyethylene glycols or mixtures of the substances stated in (a) to (i).
The tablets, coated tablets, capsules, pills and granules may be provided with conventional coatings and shells optionally containing opacifying agents and may also be composed such 1 o that they release the active substances only with a delay or preferably in a particular part of the intestinal tract, wherein polymeric substances and waxes may, for example, be used as the matrices.
The active substance or substances, optionally together with one or more of the above-stated 15 excipients, 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 esters (for example C14 alcohol with C16 fatty acid) or 2o 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, 25 silica, talcum and zinc oxide or mixtures 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 3o 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 alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl 35 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, tetrahydrofiu~furyl 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, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and gum tragacanth or mixtures of these substances.
io The stated formulations may also contain colorants, preservatives and odour-or flavour-enhancing additives, for example peppermint oil and eucalyptus oil, and sweeteners, for example saccharin.
15 The active substances of the formulae (I) to (XI) 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.
Apart from the compounds of the formulae (I) to {XI), the pharmaceutical preparations may 2o also contain fiuther pharmaceutical active substances.
The compounds may be used together with hitherto described substances having antibacterial, antiviral, antimycotic and antiparasitic properties. Such substances in particular include compounds which have akeady been used in therapeutic applications or are still used.
25 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, Schatuuer Verlag, or on the Internet at h://www.customs.treas.gov/imn-129.hti~. The derivatives may in particular be present with penicillin, benzylpenicillin (penicillin G), phenoxypenicillin, isoxazolylpenicillin, 3o aminopenicillin, ampicillin, amoxicillin, bacampicillin, carboxypenicillin, ticarcillin, temocillin, acylaminopenicillins, azlocillin, mezlocillin, piperacillin, apalcillin, mecillinam, cephalosporins, cefazolin group, cefuroxime group, cefoxitin group, cefoxitin, cefotetan, cefinetazole, latamoxef, flomoxef, cefotaxime group, cefozidime, ceftazidime group, ceftazidime, cefpirome, cefepime, conventional cephalosporins, cefsulodin, cefoperazone, 35 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/cilastatin, meropenem, biapenem, aztreonam, !3-lactamase inhibitors, clavulanic acid/amoxicillin, clavulanic acid/ticarcillin, sulbactam/ampicillin, tazobactam/piperacillin, tetracyclines, oxytetracycline, rolitetracycline, doxycycline, minocycline, chloramphenicol, aminoglycosides, gentamicin, tobramycin, netilmicin, amikacin, spectinomycin, macrolides, erythromycin, clarithromycin, roxithromycin, azithromycin, dirithromycin, spiramycin, josamycin, lincosamides, clindamycin, fusidic acid, glycopeptide antibiotics, vancomycin, teicoplanin, pristinamycin derivatives, fosfomycin, antimicrobial folic acid antagonists, sulfonamides, co-trimoxazole, trimethoprim, other diaminopyrimidine-sulfonamide combinations, nitrofurans, nitrofurantoin, nitrofurazone, gyrase inhibitors (quinolones), norfloxacin, ciprofloxacin, ofloxacin, sparfloxacin, enoxacin, fleroxacin, pefloxacin, lomefloxacin, Bay Y3118, nitroimidazoles, antimycobacterial agents, isoniazid, rifampicin, rifabutin, ethambutol, pyrazinamide, streptomycin, capreomycin, prothionamide, terizidone, dapsone, clofazimine, topical antibiotics, bacitracin, tyrothricin, polymyxins, neomycin, kanamycin, paromomycin, mupirocin, antiviral agents, acyclovir, ganciclovir, azidothymidine, didanosine, zalcitabine, thiacytidine, stavudine, ribavirin, idoxuridine, trifluridine, foscarnet, amantadine, interferons, tibol derivatives, proteinase inhibitors, antimycotics, polyenes, amphotericin B,'nystatin, natamycin, azoles, azoles for septic therapy, miconazole, ketoconazole, itraconazole, fluconazole, L1K-109,496, azoles for topical use, clotrimazole, econazole, isoconazole, oxiconazole, bifonazole, flucytosine, griseofulvin, ciclopirox olamine, tolnafnate, naftifine, terbinafine, amorolfine, anthraquinones, betulinic 2o acid, semianthraquinones, xanthones, naphthoquinones, arylamino alcohols, quinine, quinidines, mefloquine, halofantrine, chloroquine, amodiaquine, acridine, benzonaphthyridine, mepacrine, pyronaridine, dapsone, sulfonamides, sulfadoxine, sulfalenes, trimethoprim, proguanil, chlorproguanil, diaminopyrimidines, pyrimethamine, primaquine, aminoquinolines, WR 238,605, tetracycline, doxycycline, clindamycin, norfloxacin, ciprofloxacin, ofloxacin, artemisinin, dihydroartemisinin, lOb artemether, arteether, atresunate, atovaquone, suramin, melarsoprol, nifurtimox, stibogluconate sodium, pentamidine, amphotericin B, metronidazole, clioquinol, mebendazole, niclosamide, praziquantel, pyrantel, tiabendazole, diethylcarbamazine, ivermectin, bithionol, oxamniquine, metrifonate, piperazine, embonate.
The organophosphorus compounds may furthermore be present in the pharmaceutical preparations in combination with sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimetharnixie, armesin, tetracyclines, doxycycline, proguanil, metronidazole, praziquantel, niclosamide, mebendazole, pyrantel, tiabendazole, diethylcarbazine, piperazine, pyrivinium, metrifonate, oxamniquine, bithionol or suramin or two or more of these substances.
The above-stated pharmaceutical preparations are produced in the conventional manner using known methods, for example by mixing the active substance or substances with the excipient or excipients.
The stated preparations may be administered to humans and animals orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally, 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. Gels, 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 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.
It has in general proved advantageous in both human and veterinary medicine to administer 2o the active substances of the formula (I) to (XI) in total quantities of approx. 0.05 to approx.
600, preferably of 0.5 to 200 mg/kg body weight per 24 hours, optionally in the form of two or more individual doses in order to achieve the desired results. An individual dose preferably contains the active substance or substances in quantities of approx. 1 to approx. 200, in particular of 1 to 60 mg/kg body weight. 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.
3o 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 the art will use his/her skill to determine the optimum dosage and route of administration required in each particular case. The compounds according to the invention may be given to animals in conventional concentrations and preparations together with feed or feed preparations or with drinking water.
The compounds according to the invention are furthermore ideally usable as bactericides, fungicides and herbicides in plants.
Aliphatic acyl groups are defined as acyl 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.);
alkylthioa.lkanoyl (for example methylthioacetyl, ethylthioacetyl etc.);
alkanesulfonyl (for example mesyl, ethanesulfonyl, propanesulfonyl etc.); alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, 1o isobutoxycarbonyl etc.); alkylcarbamoyl (for example methylcarbamoyl etc.);
(N-alkyl)thiocarbamoyl (for example (N-methyl)thiocaxbamoyl etc.);
alkylcarbamimidoyl (for example methylcarbamimidoyl etc.); oxalo; alkoxalyl (for example methoxalyl, ethoxalyl, propoxalyl etc.).
15 In 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 as 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 2o the like; preferred aliphatic acyl residues with such substituents which may be mentioned are, for example, alkanoyls substituted with amino, carboxy, amino and carboxy, halogen, acylamino or the like.
Aromatic acyl residues are defined as those aryl residues which originate from an acid with a 25 substituted or unsubstituted aryl group, wherein the aryl group may comprise phenyl, toluyl, xylyl, naphthyl and the like; suitable examples are stated below:
amyl (for example benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl etc.);
aralkanoyl (for example phenylacetyl etc.); aralkenoyl (for example cinnamoyl etc.);
aryloxya.lkanoyl (for example phenoxyacetyl etc.); arylthioalkanoyl (for example phenylthioacetyl etc.);
3o arylaminoalkanoyl (for example N-phenylglycyl, etc.); arenesulfonyl (for example benzenesulfonyl, tosyl or toluenesulfonyl, naphthalenesulfonyl etc.);
aryloxycarbonyl (for example phenoxycarbonyl, naphthyloxycarbonyl etc.); axalkoxycarbonyl (for example benzyloxycarbonyl etc.); arylcarbamoyl (for example phenylcarbamoyl, naphthylcarbamoyl etc.); arylglyoxyloyl (for example phenylglyoxyloyl etc.).
In the above-stated Examples of aromatic aryl residues, the aromatic hydrocarbon moiety (in particular the aryl residue) and/or the aliphatic hydrocarbon moiety (in parkicular the alkane residue) may optionally have one or more suitable substituents, such as those which have akeady been stated as suitable substituents for the alkyl group or the alkane residue.
Examples of preferred aromatic acyl residues with specific substituents which may in particular be mentioned are amyl substituted with halogen and hydroxy or with halogen and acyloxy, and aralkanoyl substituted with hydroxy, hydroxyimino, dihaloalkanoyloxyimino, together with arylthiocarbamoyl (for example phenylthiocarbamoyl etc.);
arylcarbamimidoyl (for example phenylcarbamimidoyl 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, furoyl, pyrrolecarbonyl, nicotinyl etc.);
1 s 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 thiophenylacetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl etc.) and the like.
2o In 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.
"Alkyl" is a linear or branched alkyl residue with up to 26 carbon atoms, provided that it is 2s not otherwise defined, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl and the like.
"Hydroxya.lkyl" is a linear or branched alkyl residue with up to 26 carbon atoms, provided that it is not otherwise defined, which comprises at least one hydroxyl group, preferably one 30 or two hydroxyl groups.
"Alkenyl" includes linear or branched a.lkenyl groups with up to 26 carbon atoms, provided that it is not otherwise defined, such as for example vinyl, propenyl (for example 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl, 3 s hexenyl.
"Alkynyl" includes linear or branched alkynyl groups with up to 26 carbon atoms, provided that it is not otherwise defined.
-Cycloalkyl preferably denotes an optionally substituted C3.8 cycloallcyl;
possible substituents are inter alia alkyl, alkenyl, alkynyl, alkoxy (for example methoxy, ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.), vitro and the like.
Aryl is an aromatic hydrocarbon residue, such as phenyl, naphthyl etc., which may optionally comprise one or more suitable substituents, such as alkyl, alkenyl, alkynyl, alkoxy (for example methoxy, ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.), vitro and the like.
to "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 allcoxy (for example methoxy, ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.), vitro and the like.
The residues X3 and X4 may preferably be selected such that esters are formed on the phosphino group or phosphono group. Suitable examples of esters of the formulae (I) to (IX) include suitable mono- and diesters, and preferred examples of such esters are alkyl esters (for example hexadecanyl ester, octadecanyl ester etc.);
2o aralkyl esters (benzyl ester, phenethyl ester, benzhydryl ester, trityl ester etc.);
aryl esters (for example phenyl ester, tolyl ester, naphthyl ester etc.);
aroylalkyl esters (for example phenacyl ester etc.); and silyl esters (for example of trialkylhalosilyl, dialkyldihalosilyl, alkyltrihalosilyl, dialkylarylhalosilyl, trialkoxyhalosilyl, dialkylaralkylhalosilyl, dialkoxydihalosilyl, trialkoxyhalosilyl etc.) and the like.
2s In the above esters, the alkane and/or arene moiety may optionally comprise at least. one suitable substituent, such a.s halogen, alkoxy, hydroxy, vitro or the like.
The compounds used according to the invention according to the formulae (I) to (XI) may be 3o present in the protonated form thereof as an ammonium salt of organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, malefic acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid etc..
3s The compounds used according to the invention of the formulae (I) to (XI) permit, for example for groups Rl, R2, R3, R4, Xl, X2, X3, X4 or A which contain double bonds or are chiral, the occurrence of steric isomers. The use according to the invention of the compounds includes all steric isomers, both as pure substances and in the form of mixtures.
_g_ The organophosphorus compounds are in particular suitable for the therapeutic and prophylactic treatment of infections in humans and animals caused by viruses, bacteria, uni-and multicellular parasites and fungi.
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, acanthamoebosis, naeglerosis, coccidiosis, giardiasis and I o lambliasis.
They are accordingly in particular suitable for the prophylactic treatment of malaria and of sleeping sickness and of Chagas' disease, of toxoplasmosis, amoebic dysentery, leishmaniases, trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiosis, sarcocytosis, acanthamoebosis, naeglerosis, coccidiosis, giardiasis and lambliasis.
The active substances according to the invention may in particular be used against the following bacteria:
2o 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 3o 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, 3s 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 Treponemay 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 the genus Haemophilus, bacteria of the to 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.
Organophosphorus 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 animals, leprosy and further mycobacterioses in humans and animals, paratuberculosis in animals, plague, mesenterial lymphadenitis and pseudotuberculosis in humans and animals, cholera, legionnaires' disease, borreliosis in humans and animals, leptospiroses in humans and 2o animals, syphilis, Campylobacter enteritis infections in humans and animals, Moraxella keratoconjunctivitis and serositis in animals, brucellosis of animals and humans, anthrax in humans and animals, actinomycosis in humans and animals, streptotrichoses, psittacosis/ortnithosis in animals, Q fever, ehrlichiosis.
Use is furthermore effective in the eradication of Helicobacter in ulcers of the gastrointestinal tract.
Combinations with another antibiotic may also be used to treat the above-stated diseases.
Isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, protionamide and dapsone are 3o in particular suitable for combination preparations with other antiinfective agents for the treatment of tuberculosis.
The active substances according to the invention are furthermore in particular usable in infections with the following viruses:
Parvoviridae: parvoviruses, dependoviruses, densoviruses, Adenoviridae:
adenoviruses, mastadenoviruses, aviadenoviruses, Papovaviridae: papovaviruses, in particular papillomaviruses ("wart" viruses), polyomaviruses, in particular JC virus, BK
virus and miopapovaviruses, Herpesviridae: all herpesviruses, in particular herpes simplex viruses, varicella-zoster viruses, human cytomegalovirus, Epstein-Barr viruses, all human herpesviruses, human herpesvirus 6, human herpesvirus 7, human herpesvirus 8, Poxiviridae:
poxviruses, orthopoxviruses, parapoxviruses, molluscum contagiosum virus, aviviruses, capriviruses, leporipoxviruses, all primarily hepatotropic viruses, hepatitisviruses: hepatitis A
viruses, hepatitis B viruses, hepatitis C viruses, hepatitis D viruses, hepatitis E viruses, hepatitis F viruses, hepatitis G viruses, hepadnaviruses: all hepatitisviruses, hepatitis B virus, hepatitis D viruses, Picornaviridae: picornaviruses, all enteroviruses, all polioviruses, all coxsackie-viruses, all echoviruses, all rhinoviruses, hepatitis A virus, aphthoviruses, Calciviridae: hepatitis E viruses, Reoviridae: reoviruses, orbiviruses, rotaviruses, Togaviridae:
1o togaviruses, alphaviruses, rubiviruses, pestiviruses, rubellavirus, Flaviviridae: flaviviruses, FSME virus, hepatitis C virus, Orthomyxoviridae: all influenza viruses, Paramyxoviridae:
paramyxoviruses, morbillivirus, pneumovirus, measles virus, mumps virus, Rhabdoviridae:
rhabdoviruses, rabies virus, lyssavirus, vascular stomatitisvirus, Coronaviridae: coronaviruses, Bunyaviridae: bunyaviruses, nairovirus, phlebovirus, uukuvirus, hantavirus, hantaan virus, Arenaviridae: arenaviruses, lymphocytic choriomeningitis virus, Retroviridae:
retroviruses, all HTL viruses, human T-cell leukaemia virus, oncornaviruses, spumaviruses, lentiviruses, all HI viruses, Filoviridae: Marburg and Ebola virus, slow-virus infections, prions, oncoviruses and leukaemia viruses.
2o The organophosphorus compounds used according to the invention are consequently suitable for combating the following viral infections:
eradication of papillomaviruses to prevent tumours, in particular tumours of the reproductive organs caused by papillomaviruses in humans, eradication of JC viruses and BK
viruses, eradication of herpesviruses, eradication of human herpesvirus 8 to treat Kaposi's sarcoma, eradication of cytomegaloviruses before transplantations, eradication of Epstein-Barr viruses before transplantation and to prevent tumours associated with Epstein-Barr viruses, eradication of hepatitis viruses to treat chronic liver disease and to prevent liver tumours and cirrhosis of the liver, eradication of coxsackie-viruses in cardiomyopathy, eradication of 3o coxsackie-viruses in diabetes mellitus patients, eradication of immunodeficiency viruses in humans and animals, treatment of accompanying infections in AIDS patients, treatment of respiratory tract inflammation of viral causation (laryngeal papilloma, hyperplasia, rhinitis, pharyngitis, bronchitis, pneumonia), of the sensory organs (keratoconjunctivitis), of the nervous system (poliomyelitis, meningoencephalitis, encephalitis, subacute sclerosing panencephalitis, SSPE, progressive multifocal leukoencephalopathy, lymphocytic choriomeningitis), of the gastrointestinal tract (stomatitis, gingivostomatitis, oesophagitis, gastritis, gastroenteritis, diarrhoea), of the liver and gall system (hepatitis, cholangitis, hepatocellular carcinoma), of the lymphatic tissue (mononucleosis, lymphadenitis), of the haemopoietic system, of the reproductive organs (mumps orchitis), of the skin (warts, dermatitis, herpes labialis, herpes febrilis, herpes zoster, shingles), of the mucous membranes (papillomas, conjunctiva) papillomas, hyperplasia, dysplasia), of the cardiovascular system (arteriitis, myocarditis, endocarditis, pericarditis), of the kidney/urinary system, of the reproductive organs (anogenital lesions, warts, genital warts, sharp condylomas, dysplasia, papillomas, cervical dysplasia, condyloma acuminatum, epidermodysplasia verruciformis), of the locomotory organs (myositis, myalgia), treatment of foot-and-mouth disease in cloven-hoofed animals, of Colorado tick fever, Dengue syndrome, of haemorrhagic fever, of early summer meningoencephalitis (FSME) and of yellow fever.
1o The described compounds, i.e. the organophosphorus compounds of the formulae (I) to (XI) and esters and amides thereof on the phosphino group 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 according to the invention are 15 accordingly usable for the treatment of infective diseases which are caused in humans and animals by viruses, bacteria, parasites and fungi. The compounds are also suitable for the prevention of diseases which are caused by viruses, bacteria, parasites and fungi, in particular for the prophylactic treatment of malaria and of sleeping sickness.
2o 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 25 antiinfective action (mixed with a non-toxic, pharmaceutically acceptable excipient).
Pharmaceutically acceptable salts of the compounds include salts which the compounds of the formulae (I) to (XI) according to the invention form in their protonated form as an ammonium salt of inorganic or organic acids, such as hydrochloric acid, sulfuric acid, citric acid, malefic 3o acid, fumaric acid, tartaric acid, p-toluenesulfonic acid.
Particularly pharmaceutically suitable salts are also those formed by suitable selection of X3 and X4, 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, 35 aspartic acid salt, glutamic acid salt.
The activity of the substances is determined using a test system. This system is based upon in vitro measurement of the inhibition of growth of bacteria, parasites, viruses, fungi or plants.
Test rnethods known to the person skilled in the art are in part used for this purpose.
For example, antimalarial activity is determined by measuring the inhibition of the growth of malaria parasites in blood cultures. Antibacterial activity is determined on the basis of measuring the inhibition of bacterial growth on nutrient media and in liquid cultures. Antiviral activity is determined on the basis of the formation of viral elements in cell cultures.
Fungicidal activity is determined on the basis of inhibition of fungal growth on nutrient media and in liquid cultures.
to 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.
Substances which exhibit activity in in vitro measurement systems are then further investigated in in vivo models. Antiparasitic, antiviral, fungicidal or antibacterial activity is 15 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.
2o The pharmaceutically active agents 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 l, 2, 3 or 4 individual doses or 1/2, 1/3 or 25 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-3o 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 35 and granules may contain the active substances together with conventional excipients, such as (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 (f j 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 and magnesium stearate and solid polyethylene glycols or mixtures of the substances stated in (a) to (i).
The tablets, coated tablets, capsules, pills and granules may be provided with conventional coatings and shells optionally containing opacifying agents and may also be composed such 1 o that they release the active substances only with a delay or preferably in a particular part of the intestinal tract, wherein polymeric substances and waxes may, for example, be used as the matrices.
The active substance or substances, optionally together with one or more of the above-stated 15 excipients, 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 esters (for example C14 alcohol with C16 fatty acid) or 2o 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, 25 silica, talcum and zinc oxide or mixtures 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 3o 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 alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl 35 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, tetrahydrofiu~furyl 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, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and gum tragacanth or mixtures of these substances.
io The stated formulations may also contain colorants, preservatives and odour-or flavour-enhancing additives, for example peppermint oil and eucalyptus oil, and sweeteners, for example saccharin.
15 The active substances of the formulae (I) to (XI) 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.
Apart from the compounds of the formulae (I) to {XI), the pharmaceutical preparations may 2o also contain fiuther pharmaceutical active substances.
The compounds may be used together with hitherto described substances having antibacterial, antiviral, antimycotic and antiparasitic properties. Such substances in particular include compounds which have akeady been used in therapeutic applications or are still used.
25 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, Schatuuer Verlag, or on the Internet at h://www.customs.treas.gov/imn-129.hti~. The derivatives may in particular be present with penicillin, benzylpenicillin (penicillin G), phenoxypenicillin, isoxazolylpenicillin, 3o aminopenicillin, ampicillin, amoxicillin, bacampicillin, carboxypenicillin, ticarcillin, temocillin, acylaminopenicillins, azlocillin, mezlocillin, piperacillin, apalcillin, mecillinam, cephalosporins, cefazolin group, cefuroxime group, cefoxitin group, cefoxitin, cefotetan, cefinetazole, latamoxef, flomoxef, cefotaxime group, cefozidime, ceftazidime group, ceftazidime, cefpirome, cefepime, conventional cephalosporins, cefsulodin, cefoperazone, 35 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/cilastatin, meropenem, biapenem, aztreonam, !3-lactamase inhibitors, clavulanic acid/amoxicillin, clavulanic acid/ticarcillin, sulbactam/ampicillin, tazobactam/piperacillin, tetracyclines, oxytetracycline, rolitetracycline, doxycycline, minocycline, chloramphenicol, aminoglycosides, gentamicin, tobramycin, netilmicin, amikacin, spectinomycin, macrolides, erythromycin, clarithromycin, roxithromycin, azithromycin, dirithromycin, spiramycin, josamycin, lincosamides, clindamycin, fusidic acid, glycopeptide antibiotics, vancomycin, teicoplanin, pristinamycin derivatives, fosfomycin, antimicrobial folic acid antagonists, sulfonamides, co-trimoxazole, trimethoprim, other diaminopyrimidine-sulfonamide combinations, nitrofurans, nitrofurantoin, nitrofurazone, gyrase inhibitors (quinolones), norfloxacin, ciprofloxacin, ofloxacin, sparfloxacin, enoxacin, fleroxacin, pefloxacin, lomefloxacin, Bay Y3118, nitroimidazoles, antimycobacterial agents, isoniazid, rifampicin, rifabutin, ethambutol, pyrazinamide, streptomycin, capreomycin, prothionamide, terizidone, dapsone, clofazimine, topical antibiotics, bacitracin, tyrothricin, polymyxins, neomycin, kanamycin, paromomycin, mupirocin, antiviral agents, acyclovir, ganciclovir, azidothymidine, didanosine, zalcitabine, thiacytidine, stavudine, ribavirin, idoxuridine, trifluridine, foscarnet, amantadine, interferons, tibol derivatives, proteinase inhibitors, antimycotics, polyenes, amphotericin B,'nystatin, natamycin, azoles, azoles for septic therapy, miconazole, ketoconazole, itraconazole, fluconazole, L1K-109,496, azoles for topical use, clotrimazole, econazole, isoconazole, oxiconazole, bifonazole, flucytosine, griseofulvin, ciclopirox olamine, tolnafnate, naftifine, terbinafine, amorolfine, anthraquinones, betulinic 2o acid, semianthraquinones, xanthones, naphthoquinones, arylamino alcohols, quinine, quinidines, mefloquine, halofantrine, chloroquine, amodiaquine, acridine, benzonaphthyridine, mepacrine, pyronaridine, dapsone, sulfonamides, sulfadoxine, sulfalenes, trimethoprim, proguanil, chlorproguanil, diaminopyrimidines, pyrimethamine, primaquine, aminoquinolines, WR 238,605, tetracycline, doxycycline, clindamycin, norfloxacin, ciprofloxacin, ofloxacin, artemisinin, dihydroartemisinin, lOb artemether, arteether, atresunate, atovaquone, suramin, melarsoprol, nifurtimox, stibogluconate sodium, pentamidine, amphotericin B, metronidazole, clioquinol, mebendazole, niclosamide, praziquantel, pyrantel, tiabendazole, diethylcarbamazine, ivermectin, bithionol, oxamniquine, metrifonate, piperazine, embonate.
The organophosphorus compounds may furthermore be present in the pharmaceutical preparations in combination with sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimetharnixie, armesin, tetracyclines, doxycycline, proguanil, metronidazole, praziquantel, niclosamide, mebendazole, pyrantel, tiabendazole, diethylcarbazine, piperazine, pyrivinium, metrifonate, oxamniquine, bithionol or suramin or two or more of these substances.
The above-stated pharmaceutical preparations are produced in the conventional manner using known methods, for example by mixing the active substance or substances with the excipient or excipients.
The stated preparations may be administered to humans and animals orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally, 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. Gels, 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 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.
It has in general proved advantageous in both human and veterinary medicine to administer 2o the active substances of the formula (I) to (XI) in total quantities of approx. 0.05 to approx.
600, preferably of 0.5 to 200 mg/kg body weight per 24 hours, optionally in the form of two or more individual doses in order to achieve the desired results. An individual dose preferably contains the active substance or substances in quantities of approx. 1 to approx. 200, in particular of 1 to 60 mg/kg body weight. 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.
3o 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 the art will use his/her skill to determine the optimum dosage and route of administration required in each particular case. The compounds according to the invention may be given to animals in conventional concentrations and preparations together with feed or feed preparations or with drinking water.
The compounds according to the invention are furthermore ideally usable as bactericides, fungicides and herbicides in plants.
Claims (13)
1. Use of organophosphorus compounds of the general formula in which X is a phosphorus atom or a sulfur atom, wherein A is an unbranched C2-9 alkylene chain with substituents, which are identical or different and are selected from the group which consists of hydrogen, hydroxy, halogen, amino and oxo groups, C1-26 alkyl residues, C1-26 alkoxy residues, C1-26-alkoxy-C1-26-alkyl residues or C3-8-cycloalkyl-(C0-9)-alkyl groups, wherein each C1-26 alkyl residue and each C1-26 alkoxy residue may be branched or unbranched and be saturated or unsaturated with one or more double bonds and may be substituted with hydroxy, amino, halogen and oxo groups and both the C3-8 cycloalkyl group and the C0-9 alkyl group of the C3-8-cycloalkyl-(C0-9)-alkyl group may comprise one or more double bonds and one or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur atoms, and wherein both the cycloalkyl group and the alkyl group may be substituted with hydroxy, halogen, amino, oxo groups with branched or unbranched C1-9 alkyl groups and C2-9 alkenyl groups, wherein the C1-9 alkyl groups and C2-9 alkenyl groups may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups in which R1 and R2 are identical or different and are selected from the group which consists of hydrogen, substituted and unsubstituted C1-9 alkyl, substituted and unsubstituted hydroxy-C1-9-alkyl, substituted and unsubstituted C1-9 alkenyl, substituted and unsubstituted C1-9 alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic residue, halogen, OX1 and OX2, wherein X1 and X2 are identical or different and are selected from the group which consists of hydrogen, substituted and unsubstituted C1-9 alkyl, substituted and unsubstituted hydroxy-C1-9-alkyl, substituted and unsubstituted C1-9 alkenyl, substituted and unsubstituted C1-9 alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic residue, in which R3 and R4 are identical or different and are selected from the group which consists of substituted and unsubstituted C1-26 alkyl, hydroxy-C1-26-alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C1-26 alkenyl, substituted and unsubstituted C1-26 alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic residue, halogen, OX3 and OX4, wherein X3 and X4 are identical or different and are selected from the group which consists of hydrogen, substituted and unsubstituted C1-26 alkyl, substituted and unsubstituted hydroxy-C1-26-alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted C1-26 alkenyl, substituted and unsubstituted C1-26 alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic residue, a silyl, 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.
and the pharmaceutically acceptable salts, esters and amides thereof and salts of the esters for the treatment of infectious processes in humans and animals which are caused by viruses, bacteria, fungi or parasites and as a fungicide, bactericide or herbicide in plants.
and the pharmaceutically acceptable salts, esters and amides thereof and salts of the esters for the treatment of infectious processes in humans and animals which are caused by viruses, bacteria, fungi or parasites and as a fungicide, bactericide or herbicide in plants.
2. Use according to claim 1, characterised in that A is a C3-5 alkyl group with substituents, which are identical or different and are selected from the group which consists of hydrogen, hydroxy, halogen, amino and oxo groups, C1-26 alkyl residues, C1-26 alkoxy residues, C1-26-alkoxy-C0-9-alkyl residues or C3-8-cycloalkyl-(C0-9)-alkyl groups, wherein each C1-26 alkyl residue and each C1-26 alkoxy residue may be branched or unbranched and be saturated or unsaturated with one or more double bonds and may be substituted with hydroxy, amino, halogen and oxo groups and both the C3-8 cycloalkyl group and the C0-9 alkyl group of the C3-8-cycloalkyl-(C0-9)-alkyl group may comprise one or more double bonds and one or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur atoms, and wherein both the cycloalkyl group and the alkyl group may be substituted with hydroxy, halogen, amino, oxo groups with branched or unbranched C1-9 alkyl groups and C2-9 alkenyl groups, wherein the alkyl groups and C2-9 alkenyl groups may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups.
3. Use according to claim 1 or claim 2, characterised in that the organophosphorus compounds are of the formula (II) wherein X, R1, R3, R4 are defined as in claim 1, wherein R1 is preferably substituted with a hydroxy group on the C atom adjacent to the heteroatom.
4. Use according to claim 1 or claim 2, characterised in that the organophosphorus compounds are of the formula (III) wherein X, R1, R3, R4 are defined as in claim 1, wherein R1 is preferably an acyl group, particularly preferably a formyl, acetyl, propionyl or butyryl group.
5. Use according to claim 1 or claim 2, characterised in that the organophosphorus compounds are selected from the group which consists of wherein X, R1, R2, R3 and R4 have the meaning defined in claim 1 and the undefined valencies of the carbon atoms may be substituted as defined in claim 1.
6. Use according to one of claims 1 to 5 for the treatment of infections caused by bacteria, viruses, fungi or uni- or multicellular parasites.
7. Use according to claim 6 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 the 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.
8. Use according to claim 6 for the treatment of infections which are caused by viruses which are selected from the group which consists of viruses of the genus Parvoviridae, in particular parvoviruses, dependoviruses, densoviruses, viruses of the genus Adenoviridae, in particular adenoviruses, mastadenoviruses, aviadenoviruses, viruses of the genus Papovaviridae, in particular papovaviruses, in particular papillomaviruses ("wart" viruses), polyomaviruses, in particular JC virus, BK virus and miopapovaviruses, viruses of the genus Herpesviridae in particular herpes simplex viruses, varicella-zoster viruses, human cytomegalovirus, Epstein-Barr viruses, human herpesvirus 6, human herpesvirus 7, human herpesvirus 8, viruses of the genus Poxiviridae, in particular poxviruses, orthopoxviruses, parapoxviruses, molluscum contagiosum virus, aviviruses, capriviruses, leporipoxviruses, primarily hepatotropic viruses, in particular hepatitisviruses, such as hepatitis A viruses, hepatitis B viruses, hepatitis C viruses, hepatitis D viruses, hepatitis E viruses, hepatitis F
viruses, hepatitis G viruses, hepadnaviruses, in particular all hepatitisviruses, such as hepatitis B virus, hepatitis D viruses, viruses of the genus Picornaviridae, in particular picornaviruses, all enteroviruses, all polioviruses, all coxsackie-viruses, all echoviruses, all rhinoviruses, hepatitis A virus, aphthoviruses, viruses of the genus Calciviridae, in particular hepatitis E viruses, viruses of the genus Reoviridae, in particular reoviruses, orbiviruses, rotaviruses, viruses of the genus Togaviridae, in particular togaviruses, alphaviruses, rubiviruses, pestiviruses, rubellavirus, viruses of the genus Flaviviridae, in particular flaviviruses, FSME virus, hepatitis C virus, viruses of the genus Orthomyxoviridae, in particular all influenza viruses, viruses of the genus Paramyxoviridae, in particular paramyxoviruses, morbillivirus, pneumovirus, measles virus, mumps virus, viruses of the genus Rhabdoviridae, in particular rhabdoviruses, rabies virus, lyssavirus, vascular stomatitisvirus, viruses of the genus Coronaviridae, in particular coronaviruses, viruses of the genus Bunyaviridae, in particular bunyaviruses, nairovirus, phlebovirus, uukuvirus, hantavirus, hantaan virus, viruses of the genus Arenaviridae, in particular arenaviruses, lymphocytic choriomeningitis virus, viruses of the genus Retroviridae, in particular retroviruses, all HTL viruses, human T-cell leukaemia virus, oncornaviruses, spumaviruses, lentiviruses, all HI viruses, viruses of the genus Filoviridae, in particular Marburg and Ebola virus, slow-viruses, prions, oncoviruses and leukaemia viruses.
viruses, hepatitis G viruses, hepadnaviruses, in particular all hepatitisviruses, such as hepatitis B virus, hepatitis D viruses, viruses of the genus Picornaviridae, in particular picornaviruses, all enteroviruses, all polioviruses, all coxsackie-viruses, all echoviruses, all rhinoviruses, hepatitis A virus, aphthoviruses, viruses of the genus Calciviridae, in particular hepatitis E viruses, viruses of the genus Reoviridae, in particular reoviruses, orbiviruses, rotaviruses, viruses of the genus Togaviridae, in particular togaviruses, alphaviruses, rubiviruses, pestiviruses, rubellavirus, viruses of the genus Flaviviridae, in particular flaviviruses, FSME virus, hepatitis C virus, viruses of the genus Orthomyxoviridae, in particular all influenza viruses, viruses of the genus Paramyxoviridae, in particular paramyxoviruses, morbillivirus, pneumovirus, measles virus, mumps virus, viruses of the genus Rhabdoviridae, in particular rhabdoviruses, rabies virus, lyssavirus, vascular stomatitisvirus, viruses of the genus Coronaviridae, in particular coronaviruses, viruses of the genus Bunyaviridae, in particular bunyaviruses, nairovirus, phlebovirus, uukuvirus, hantavirus, hantaan virus, viruses of the genus Arenaviridae, in particular arenaviruses, lymphocytic choriomeningitis virus, viruses of the genus Retroviridae, in particular retroviruses, all HTL viruses, human T-cell leukaemia virus, oncornaviruses, spumaviruses, lentiviruses, all HI viruses, viruses of the genus Filoviridae, in particular Marburg and Ebola virus, slow-viruses, prions, oncoviruses and leukaemia viruses.
9. Use according to claim 6 for the prevention and treatment of infections caused by unicellular parasites, namely the causative organisms of malaria, sleeping sickness, Chagas' disease, toxoplasmosis, amoebic dysentery, leishmaniases, trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiosis, sarcocytosis, acanthamoebosis, naeglerosis, coccidiosis, giardiasis and lambliasis.
10. Use according to one of claims 1 to 9 in a pharmaceutical preparation, characterised in that the preparation contains an active content of at least one organophosphorus compound according to one of claims 1 to 5 together with a pharmaceutically acceptable excipient.
11. Use according to claim 10, characterised in that the pharmaceutical preparation contains another pharmaceutical active substance.
12. Use according to one of claims 10 or 11, characterised in that the pharmaceutical preparation [comprises] one or more constituents from the group which consists of sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracyclines, doxycycline, proguanil, metronidazole, praziquantel, niclosamide, mebendazole, pyrantel, tiabendazole, diethylcarbazine, piperazine, pyrivinium, metrifonate, oxamniquine, bithionol and suramin.
13. Use according to one of claims 11 to 12, characterised in that the pharmaceutical preparation [comprises] one or constituents from the group which consists of penicillin, benzylpenicillin (penicillin G), phenoxypenicillin, isoxazolylpenicillin, aminopenicillin, ampicillin, amoxicillin, bacampicillin, carboxypenicillin, ticarcillin, temocillin, acylaminopenicillins, azlocillin, mezlocillin, piperacillin, apalcillin, mecillinam, cephalosporins, cefazolin group, cefuroxime group, cefoxitin group, cefoxitin, cefotetan, cefmetazole, latamoxef, flomoxef, cefotaxime group, cefozidime, ceftazidime group, ceftazidime, cefpirome, cefepime, conventional cephalosporins, cefsulodin, cefoperazone, oral cephalosporins of the cephalexin group, loracarbef, cefprozil, new broad-spectrum oral cephalosporins, cefixime, cefpodoxime-proxetil, cefuroxime-axetil, cefetamet, cefotiam-hexetil, cefdinir, ceftibuten, other .beta.-lactam antibiotics, carbapenem, imipenem/cilastatin, meropenem, biapenem, aztreonam, .beta.-lactamase inhibitors, clavulanic acid/amoxicillin, clavulanic acid/ticarcillin, sulbactam/ampicillin, tazobactam/piperacillin, tetracyclines, oxytetracycline, rolitetracycline, doxycycline, minocycline, chloramphenicol, aminoglycosides, gentamicin, tobramycin, netilmicin, amikacin, spectinomycin, macrolides, erythromycin, clarithromycin, roxithromycin, azithromycin, dirithromycin, spiramycin, josamycin, lincosamides, clindamycin, fusidic acid, glycopeptide antibiotics, vancomycin, teicoplanin, pristinamycin derivatives, fosfomycin, antimicrobial folic acid antagonists, sulfonamides, co-trimoxazole, trimethoprim, other diaminopyrimidine-sulfonamide combinations, nitrofurans, nitrofurantoin, nitrofurazone, gyrase inhibitors (quinolones), norfloxacin, ciprofloxacin, ofloxacin, sparfloxacin, enoxacin, fleroxacin, pefloxacin, lomefloxacin, Bay Y3118, nitroimidazoles, antimycobacterial agents, isoniazid, rifampicin, rifabutin, ethambutol, pyrazinamide, streptomycin, capreomycin, prothionamide, terizidone, dapsone, clofazimine, topical antibiotics, bacitracin, tyrothricin, polymyxins, neomycin, kanamycin, paromomycin, mupirocin, antiviral agents, acyclovir, ganciclovir, azidothymidine, didanosine, zalcitabine, thiacytidine, stavudine, ribavirin, idoxuridine, trifluridine, foscarnet, amantadine, interferons, tibol derivatives, proteinase inhibitors, antimycotics, polyenes, amphotericin B, nystatin, natamycin, azoles, azoles for septic therapy, miconazole, ketoconazole, itraconazole, fluconazole, UK-109,496, azoles for topical use, clotrimazole, econazole, isoconazole, oxiconazole, bifonazole, flucytosine, griseofulvin, ciclopirox olamine, tolnafnate, naftifine, terbinafine, amorolfine, anthraquinones, betulinic acid, semianthraquinones, xanthones, naphthoquinones, arylamino alcohols, quinine, quinidines, mefloquine, halofantrine, chloroquine, amodiaquine, acridine, benzonaphthyridine, mepacrine, pyronaridine, dapsone, sulfonamides, sulfadoxine, sulfalenes, trimethoprim, proguanil, chlorproguanil, diaminopyrimidines, pyrimethamine, primaquine, aminoquinolines, WR 238,605, tetracycline, doxycycline, clindamycin, norfloxacin, ciprofloxacin, ofloxacin, artemisinin, dihydroartemisinin, 10b artemether, arteether, atresunate, atovaquone, suramin, melarsoprol, nifurtimox, stibogluconate sodium, pentamidine, amphotericin B, metronidazole, clioquinol, mebendazole, niclosamide, praziquantel, pyrantel, tiabendazole, diethylcarbamazine, ivermectin, bithionol, oxamniquine, metrifonate, piperazine, embonate.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19902924.5 | 1999-01-26 | ||
| DE19902924A DE19902924A1 (en) | 1999-01-26 | 1999-01-26 | Use of organophosphorus compounds for the prophylactic and therapeutic treatment of infections |
| PCT/EP2000/000542 WO2000044358A2 (en) | 1999-01-26 | 2000-01-25 | Use of phosphororganic compounds for the prophylactic and therapeutical treatment of infections |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2360661A1 true CA2360661A1 (en) | 2000-08-03 |
Family
ID=7895365
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002360661A Abandoned CA2360661A1 (en) | 1999-01-26 | 2000-01-25 | Use of phosphororganic compounds for the prophylactic and therapeutical treatment of infections |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP1146880A2 (en) |
| JP (1) | JP2002535354A (en) |
| CN (1) | CN1337881A (en) |
| AU (1) | AU2439900A (en) |
| CA (1) | CA2360661A1 (en) |
| CZ (1) | CZ20012584A3 (en) |
| DE (1) | DE19902924A1 (en) |
| HU (1) | HUP0105310A3 (en) |
| IL (1) | IL144115A0 (en) |
| NO (1) | NO20013651L (en) |
| PL (1) | PL349910A1 (en) |
| SK (1) | SK10552001A3 (en) |
| TR (1) | TR200102151T2 (en) |
| WO (1) | WO2000044358A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9949988B2 (en) | 2014-09-12 | 2018-04-24 | Antibiotx A/S | Antibacterial use of halogenated salicylanilides |
| US10463680B2 (en) | 2015-05-29 | 2019-11-05 | UNION therapeutics A/S | Halogenated salicylanilides for treating clostridium infections |
| US11419834B2 (en) | 2019-02-25 | 2022-08-23 | Rhode Island Hospital | Methods for treating diseases or infections caused by or associated with H. pylori using a halogenated salicylanilide |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7842719B2 (en) | 2002-10-31 | 2010-11-30 | Kemin Foods, L.C. | Use of endoperoxides for the treatment of infections caused by flaviviridae, including hepatitis C, bovine viral diarrhea and classical swine fever virus |
| WO2004085448A2 (en) * | 2003-03-19 | 2004-10-07 | Genzyme Corporation | Unsaturated phosphinyl-phosphonate phosphate transport inhibitors |
| JP2012521365A (en) * | 2009-03-20 | 2012-09-13 | ユニバーシティー オブ アイオワ リサーチ ファウンデーション | Prenylated bisphosphonates as antituberculous agents |
| CN104026151A (en) * | 2014-06-19 | 2014-09-10 | 南京麦思德餐饮管理有限公司 | Alfalfa seed soaking agent |
| CN105403221B (en) * | 2015-10-27 | 2018-01-23 | 广东欧珀移动通信有限公司 | The generation method and mobile terminal of a kind of navigation way |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3170944A (en) * | 1962-11-20 | 1965-02-23 | Stauffer Chemical Co | Haloacetonyl phosphonates and a method of preparing them |
| US3372209A (en) * | 1964-08-24 | 1968-03-05 | Monsanto Co | Diphosphorus ester hydrocarbon diols |
| BE687874A (en) * | 1965-10-06 | 1967-04-06 | ||
| US3532774A (en) * | 1966-09-29 | 1970-10-06 | Monsanto Co | Phosphinites,phosphine oxides and process for preparing |
| JPS4861259A (en) * | 1971-12-02 | 1973-08-28 | ||
| US4254114A (en) * | 1979-01-02 | 1981-03-03 | The Proctor & Gamble Company | Control of pyrophosphate microorganisms with organophosphonates |
| JPS5655394A (en) * | 1979-10-12 | 1981-05-15 | Otsuka Chem Co Ltd | 1,2-di alkoxycarbonylmethylamino ethylene-1,2-disulfonic acid phenyl ester derivative, its preparation, and herbicide containing said compound |
| DE3208600A1 (en) * | 1982-03-10 | 1983-09-22 | Henkel KGaA, 4000 Düsseldorf | AMIDINODIPHOSPHONIC ACIDS |
| CH664158A5 (en) * | 1984-07-18 | 1988-02-15 | Symphar Sa | DERIVATIVES PROPYLIDENEDIPHOSPHONATES-1,3 SUBSTITUTED IN POSITION 2, THEIR PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| US4820698A (en) * | 1985-11-04 | 1989-04-11 | The Procter & Gamble Company | Antimicrobial agents and process for their manufacture |
| US5196409A (en) * | 1989-08-20 | 1993-03-23 | Yissum, Research Development Company Of The Hebrew University Of Jerusalem | Bisphosphonates, pharmaceutical compositions, and process for the treatment of irregularities in calcium metabolism |
| DE4336099A1 (en) * | 1993-10-22 | 1995-04-27 | Boehringer Mannheim Gmbh | New 2,4-diphosphonoglutaric acid derivatives, processes for their preparation and medicaments containing these compounds |
| WO1996016629A2 (en) * | 1994-11-18 | 1996-06-06 | Amira Inc | Phosphinic creatine compounds having antiviral activity |
| DE19532235A1 (en) * | 1995-08-31 | 1997-03-06 | Keppler Bernhard K Priv Doz Dr | New antibacterial contg. osteotropic mol. fragments |
| GB9613637D0 (en) * | 1996-06-28 | 1996-08-28 | Agrevo Uk Ltd | Fungicidal compositions |
| EP0944635A4 (en) * | 1996-10-09 | 2000-07-05 | Elizanor Biopharmaceuticals In | Diphosphonate therapeutic compounds |
-
1999
- 1999-01-26 DE DE19902924A patent/DE19902924A1/en not_active Ceased
-
2000
- 2000-01-25 CN CN00803129A patent/CN1337881A/en active Pending
- 2000-01-25 SK SK1055-2001A patent/SK10552001A3/en unknown
- 2000-01-25 PL PL00349910A patent/PL349910A1/en not_active Application Discontinuation
- 2000-01-25 JP JP2000595662A patent/JP2002535354A/en active Pending
- 2000-01-25 CA CA002360661A patent/CA2360661A1/en not_active Abandoned
- 2000-01-25 HU HU0105310A patent/HUP0105310A3/en unknown
- 2000-01-25 EP EP00902630A patent/EP1146880A2/en not_active Withdrawn
- 2000-01-25 TR TR2001/02151T patent/TR200102151T2/en unknown
- 2000-01-25 WO PCT/EP2000/000542 patent/WO2000044358A2/en not_active Application Discontinuation
- 2000-01-25 IL IL14411500A patent/IL144115A0/en unknown
- 2000-01-25 CZ CZ20012584A patent/CZ20012584A3/en unknown
- 2000-01-25 AU AU24399/00A patent/AU2439900A/en not_active Abandoned
-
2001
- 2001-07-25 NO NO20013651A patent/NO20013651L/en not_active Application Discontinuation
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9949988B2 (en) | 2014-09-12 | 2018-04-24 | Antibiotx A/S | Antibacterial use of halogenated salicylanilides |
| US10758553B2 (en) | 2014-09-12 | 2020-09-01 | UNION therapeutics A/S | Antibacterial use of halogenated salicylanilides |
| US11285164B2 (en) | 2014-09-12 | 2022-03-29 | UNION therapeutics A/S | Antibacterial use of halogenated salicylanilides |
| US11324761B2 (en) | 2014-09-12 | 2022-05-10 | UNION therapeutics A/S | Antibacterial use of halogenated salicylanilides |
| US11331327B2 (en) | 2014-09-12 | 2022-05-17 | UNION therapeutics A/S | Antibacterial use of halogenated salicylanilides |
| US10463680B2 (en) | 2015-05-29 | 2019-11-05 | UNION therapeutics A/S | Halogenated salicylanilides for treating clostridium infections |
| US10857164B2 (en) | 2015-05-29 | 2020-12-08 | UNION therapeutics A/S | Halogenated salicylanilides for treating Clostridium infections |
| US11529361B2 (en) | 2015-05-29 | 2022-12-20 | UNION therapeutics A/S | Halogenated salicylanilides for treating Clostridium infections |
| US11419834B2 (en) | 2019-02-25 | 2022-08-23 | Rhode Island Hospital | Methods for treating diseases or infections caused by or associated with H. pylori using a halogenated salicylanilide |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0105310A3 (en) | 2002-08-28 |
| HUP0105310A2 (en) | 2002-06-29 |
| IL144115A0 (en) | 2002-05-23 |
| EP1146880A2 (en) | 2001-10-24 |
| PL349910A1 (en) | 2002-10-07 |
| WO2000044358A2 (en) | 2000-08-03 |
| CZ20012584A3 (en) | 2002-01-16 |
| SK10552001A3 (en) | 2001-12-03 |
| TR200102151T2 (en) | 2002-05-21 |
| NO20013651D0 (en) | 2001-07-25 |
| CN1337881A (en) | 2002-02-27 |
| WO2000044358A3 (en) | 2001-03-15 |
| DE19902924A1 (en) | 2000-08-03 |
| NO20013651L (en) | 2001-09-18 |
| JP2002535354A (en) | 2002-10-22 |
| AU2439900A (en) | 2000-08-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |