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WO2000044358A2 - 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

Info

Publication number
WO2000044358A2
WO2000044358A2 PCT/EP2000/000542 EP0000542W WO0044358A2 WO 2000044358 A2 WO2000044358 A2 WO 2000044358A2 EP 0000542 W EP0000542 W EP 0000542W WO 0044358 A2 WO0044358 A2 WO 0044358A2
Authority
WO
WIPO (PCT)
Prior art keywords
viruses
substituted
virus
bacteria
unsubstituted
Prior art date
Application number
PCT/EP2000/000542
Other languages
German (de)
French (fr)
Other versions
WO2000044358A3 (en
Inventor
Hassan Jomaa
Original Assignee
Jomaa Pharmaka Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jomaa Pharmaka Gmbh filed Critical Jomaa Pharmaka Gmbh
Priority to JP2000595662A priority Critical patent/JP2002535354A/en
Priority to AU24399/00A priority patent/AU2439900A/en
Priority to PL00349910A priority patent/PL349910A1/en
Priority to EP00902630A priority patent/EP1146880A2/en
Priority to CA002360661A priority patent/CA2360661A1/en
Priority to SK1055-2001A priority patent/SK10552001A3/en
Priority to IL14411500A priority patent/IL144115A0/en
Publication of WO2000044358A2 publication Critical patent/WO2000044358A2/en
Publication of WO2000044358A3 publication Critical patent/WO2000044358A3/en
Priority to NO20013651A priority patent/NO20013651L/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
    • A01N57/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • organophosphorus compounds for the prophylactic and therapeutic treatment of infections
  • the invention relates to the use of organophosphorus compounds and their salts, esters and amides for the therapeutic and prophylactic treatment of infections in humans and animals caused by viruses, bacteria, fungi and parasites, and their use as fungicides, bactericides and herbicides in plants .
  • the organophosphorus compounds include phosphinoyl derivatives, phosphinic acid derivatives and phosphonic acid derivatives.
  • the object of the present invention is therefore to provide a substance which can be used in infections by viruses, bacteria, fungi and parasites in humans and animals and as a fungicide, bactericide and herbicide in plants and which fulfills the conditions specified above.
  • This object is achieved in a completely surprising manner by using the substance group defined in claim 1.
  • This group of substances shows an anti-infectious effect against viruses, certain bacteria, fungi, single and multicellular parasites.
  • organophosphorus compounds used according to the invention correspond to the general formula (I):
  • X is a phosphorus atom or a sulfur atom
  • A is an unbranched C 2 - alkylene chain with substituents which are the same or different and are selected from the group consisting of hydrogen, hydroxyl, halogen, amino and oxo groups, C. 2 6 -alkyl radicals, C 1 -2 6-alkoxy radicals, C_.26-alkoxy-C1.26- alkyl radicals or C 3 -8-cycloalkyl- (Co-9) alkyl groups, each C ⁇ - 2 6-alkyl radical and
  • each C 1-26 alkoxy radical may be branched or unbranched and saturated or unsaturated with one or more double bonds and may be substituted with hydroxyl, amino, halogen and oxo groups and both the C 3-8 cycloalkyl group and that C0.9 alkyl group of C 3 .
  • Cycloalkyl- (C 0 -9) -alkyl group can have one or more double bonds and one or two carbon atoms of the cycloalkyl group can be replaced by nitrogen, oxygen or sulfur atoms, and both the cycloalkyl group and the alkyl group with hydroxy -, Halogen, amino, oxo groups with branched or unbranched C 9 alkyl groups and C 2-9 alkenyl groups can be substituted, the Ci.g-alkyl groups and C -9 alkenyl groups with hydrogen, hydroxyl, amino -, Halogen and oxo groups can be substituted
  • R ⁇ and R 2 are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted C 1 . 9 -Al.cyl, substituted and unsubstituted hydroxy-9 C ⁇ - alkyl, substituted and unsubstituted C ⁇ -9 alkenyl, substituted and unsubstituted C ⁇ - 9 alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen, OXi and OX 2 ,
  • Xi and X 2 are the same or different and is selected from the group consisting of hydrogen, substituted and unsubstituted C ⁇ - 9 alkyl, substituted and unsubstituted hydroxy-C ⁇ - 9 alkyl, substituted and unsubstituted C ⁇ -9 alkenyl, substituted and unsubstituted C ⁇ -9 alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical is,
  • R 3 and j are the same or different and are selected from the group consisting of substituted and unsubstituted C ⁇ alkyl, hydroxy-C .. 26 alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C ⁇ . 26 alkenyl, substituted and unsubstituted C ⁇ . 26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, OX 3 and OX t ,
  • X 3 and 4 are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted C ⁇ . 26 alkyl, substituted and unsubstituted hydroxy-d- 26 alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted C ⁇ .
  • X 3 and 4 are preferably a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium, or ammonium compounds which are derived from ethylenediamine or amino acids.
  • salt compounds of the organophosphorus compounds with organic or inorganic bases for example sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylamine salt, ethanolamine salt, dicyclohexylamine salt, ethylenediamine salt, N, N'-dibenzylethylenediamine salt etc.
  • salts with amino acids for example arginine salt, aspartic acid salt, glutamic acid salt etc.
  • X 3 and X 4 are particularly preferably the same or different and selected from the group consisting of hydrogen, sodium, potassium, methyl, ethyl.
  • A is preferably a C 3 . 5 alkyl chain.
  • R ⁇ is preferably an acyl group, particularly preferably a formyl, acetyl, propionyl or butyryl group.
  • Acyl is a substituent derived from an acid, such as from an organic carboxylic acid. re, carbonic acid, carbamic acid or the thioic acid or imidic acid corresponding to the individual above acids, or from an organic sulfonic acid, these acids each comprising aliphatic, aromatic and / or heterocyclic groups in the molecule and carbamoyl or carbamimidoyl.
  • Aliphatic acyl groups are acyl radicals derived from an aliphatic acid, which include the following: alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.); Alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl etc.); Alkylthioalkanoyl (e.g. methylthioacetyl, ethylthioacetyl etc.); Alkanesulfonyl (e.g.
  • alkanoyl e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.
  • Alkenoyl e.g. acryloyl, methacryloyl, crotonoyl etc.
  • Alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.
  • Alkyl carbamoyl e.g. methyl carbamoyl etc.
  • N-alkyl thiocarbamoyl
  • Alkylcarbamimidoyl e.g. methylcarbamimidoyl etc.
  • Oxalo Alkoxalyl (e.g. methoxalyl, ethoxalyl, propoxalyl etc.).
  • the aliphatic hydrocarbon part in particular the alkyl group or the alkane radical, may optionally have one or more suitable substituents, such as amino, halogen (for example fluorine, chlorine, bromine etc.), hydroxy, hy- droxyimino.
  • suitable substituents such as amino, halogen (for example fluorine, chlorine, bromine etc.), hydroxy, hy- droxyimino.
  • suitable substituents such as amino, halogen (for example fluorine, chlorine, bromine etc.), hydroxy, hy- droxyimino.
  • Aromatic acyl radicals are those acyl radicals which derive from an acid with a substituted or unsubstituted aryl group, where the aryl group can include phenyl, toluyl, xylyl, naphthyl and the like; suitable examples are given below:
  • Aroyl e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl etc.
  • Aralkanoyl e.g phenylacetyl etc.
  • Aralkenoyl e.g. cinnamoyl etc.
  • Aryloxyalkanoyl e.g. phenoxyacetyl etc.
  • Arylthioalkanoyl e.g. phenylthioacetyl etc.
  • Arylaminoalkanoyl e.g. N-phenylglycyl, etc.
  • Arenesulfonyl e.g.
  • Aryloxycarbonyl e.g. phenoxycarbonyl, naphthyloxycarbonyl etc.
  • Aralkoxycarbonyl e.g. benzyloxycarbonyl etc.
  • Arylcarbamoyl e.g. phenylcarbamoyl, naphthylcarbamoyl etc
  • aromatic hydrocarbon part in particular the aryl radical
  • aliphatic hydrocarbon part in particular the alkane radical
  • suitable substituents such as those which are suitable substituents for the alkyl group or the alkane radical have already been specified.
  • aromatic acyl radicals with special substituents aroyl substituted with halogen and hydroxy or with halogen and acyloxy and aralkanoyl substituted with hydroxy, hydroxyimino, dihalogenalkanoyloxyimino and arylthiocarbamoyl (eg phenylthiocarbamoyl etc.); Arylcarbamimidoyl (eg phenylcarbamimidoyl etc.).
  • a heterocyclic acyl radical is understood to mean an acyl radical which comes from an acid with a heterocyclic group; this includes:
  • Heterocyclic carbonyl in which the heterocyclic radical is an aromatic or aliphatic 5- to 6-membered heterocycle with at least one heteroatom from the group consisting of nitrogen, oxygen and sulfur (e.g. thiophenyl, furoyl, pyrrole carbonyl, nicotinoyl etc.);
  • Heterocycle alkanoyl in which the heterocyclic radical is 5- to 6-membered and has at least one heteroatom from the group consisting of nitrogen, oxygen and sulfur (for example thiophenyl-acetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino- 4-thiazolyl) -2-methoxyiminoacetyl etc.) and the like.
  • nitrogen, oxygen and sulfur for example thiophenyl-acetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino- 4-thiazolyl) -2-methoxyiminoacetyl etc.
  • heterocyclic acyl radicals the heterocycle and / or the aliphatic hydrocarbon part may optionally have one or more suitable substituents, such as the same ones which have been stated to be suitable for alkyl and alkane groups.
  • Alkyl is a straight or branched chain alkyl radical having up to 26 carbon atoms, unless otherwise defined, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.
  • Hydroxylalkyl is a straight or branched chain alkyl radical having up to 26 carbon atoms, unless defined otherwise, which has at least one hydroxyl group, preferably one or two hydroxyl groups.
  • Alkenyl includes straight or branched chain alkenyl groups with up to 26 carbon atoms, unless defined otherwise, such as vinyl, propenyl (e.g. 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2 -Ethylpropenyl, pentenyl, hexenyl.
  • Alkynyl includes straight or branched chain alkynyl groups with up to 26 carbon atoms, unless it is defined otherwise.
  • Cycloalkyl preferably represents an optionally substituted C 3 . 8- cycloalkyl; Possible substituents include alkyl, alkenyl, alkynyl, alkoxy (eg methoxy, ethoxy etc.), halogen (eg fluorine, chlorine, bromine etc.), nitro and the like.
  • Aryl is an aromatic hydrocarbon radical, such as phenyl naphthyl etc., which may optionally have one or more suitable substituents, such as alkyl, alkenyl, alkynyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc. ), Nitro and the like.
  • suitable substituents such as alkyl, alkenyl, alkynyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc. ), Nitro and the like.
  • Alkyl includes mono-, di-, triphenylalkyls such as benzyl, phenethyl, benzhydryl, trityl and the like, where the aromatic part may have one or more suitable substituents such as alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. Fluorine, chlorine, bromine, etc.), nitro and the like.
  • alkoxy e.g. methoxy, ethoxy etc.
  • halogen e.g. Fluorine, chlorine, bromine, etc.
  • the radicals X 3 and j can preferably be chosen such that esters are formed on the phosphino group or phosphono group.
  • suitable examples of such esters according to formulas (I) to (XI) include suitable mono- and diesters, and preferred examples of such esters include alkyl esters (for example hexadecanyl ester, octadecanyl ester, etc.); Aralkyl esters (benzyl esters, phenethyl esters, benzhydryl esters, trityl esters, etc.); Aryl esters (for example phenyl esters, tolyl esters, naphthyl esters etc.); Aroyl alkyl esters (eg phenacyl esters etc.); and silyl esters (e.g.
  • trialkylhalosilyl dialkyldihalosilyl, alkyltrihalosilyl, dialkylarylhalosilyl, trialkoxyhalosilyl, dialkylaralkylhalosilyl, dialkoxydihalosilyl, trialkoxyhalosilyl, etc.
  • the alkane and / or arene portion can optionally have at least one suitable substituent such as halogen, alkoxy, hydroxy, nitro or the like.
  • the compounds of the formulas (I) to (XI) used according to the invention can, in their protonated form, as the 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, maleic acid, fumaric acid, oxalic acid , Tartaric acid, benzoic acid, etc. are present.
  • organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, maleic acid, fumaric acid, oxalic acid , Tartaric acid, benzoic acid, etc. are present.
  • the compounds used in the invention of the formulas (I) to (XI) can, for example, containing double bonds or chiral groups Ri, R 2, R 3, R, X ls X 2, X 3, X t or A, the occurrence of spatial isomers for.
  • the use of the compounds according to the invention includes all spatial isomers both as pure substances and in the form of their loop.
  • organophosphorus compounds are particularly suitable for the therapeutic and prophylactic treatment of infections in humans and animals which are caused by viruses, bacteria, single and multicellular parasites and fungi.
  • the compounds are active against unicellular parasites (protozoa), in particular against pathogens of malaria and sleeping sickness as well as Chagas disease, toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis, pneumocystosis, balantidosis, cryptosporidiosis, and sarcolocystosis , Akanthamöbose, Naeglerose, Coccidiosis, Giardiosis and Lambliosis.
  • malaria prophylaxis and as prophylaxis of sleeping sickness and Chagas disease, toxoplasmosis, amoebic dysentery, Leishmaniasis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcolocystosis, acanthamoebosis, cocoonosis, naeglerosis Giardiosis and Lambliosis.
  • the active compounds according to the invention can be used in particular against the following bacteria:
  • Bacteria of the Propionibacteriaceae family in particular the Propionibacterium genus, in particular the Propionibacterium acnes species, Actinomycetaceae bacteria, in particular the Actinomyces genus, Corynebacterium bacteria, in particular the Corynebacterium diphteriae and Corynebacterium pseudote family mycobacteria, bacteria the species Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium, bacteria of the Chlamydiaceae family, in particular the species Chlamydia trachomatis and Chlamydia psittaci, bacteria of the genus Listeria, in particular the species Listeria mon- derhrixysiophysiophythropia , Bacteria of the genus Clostridium, bacteria of the genus Yersinia, of the species Yersinia pestis, Yersinia
  • Organophosphorus compounds and their derivatives are therefore suitable for the treatment of diphtheria, acne vulgaris, listeriosis, erysipelas in animals, gas fires in humans and animals, para-noise burns in humans and animals, tuberculosis in humans and animals, leprosy and other mycobacteriosis in humans and animals, paratuberculosis in animals, plague, mesenteric lymphadenitis and pseudotuberculosis in humans and animals, cholera, legionnaires' disease, Lyme disease in humans and animals, leptospirosis in humans and animals, syphilis, Campylobacter enteritis in humans and animals, Moraxella keratoconjunc -tivitis and serositis of animals, brucellosis of animals and humans, anthrax in humans and animals, actinomycosis in humans and animals, streptotrichoses, psittacosis / ornithosis in animals, Q fever, Ehr
  • the use is also useful in Helicobacter eradication therapy for ulcers of the gastrointestinal tract.
  • Combinations with another antibiotic can also be used to treat the above-mentioned diseases.
  • isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, protionamide and dapsone are particularly suitable for the treatment of tuberculosis.
  • the active compounds according to the invention can also be used in particular for infections with the following viruses:
  • Parvoviridae Parvoviruses, Dependoviruses, Densoviruses, Adenoviridae: Adenoviruses, Mastadenoviruses, Aviadenoviruses, Papovaviridae: Papovaviruses, in particular Papillomaviruses (so-called Wartsviruses), Polyomaviruses, in particular JC and Viruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesvirus
  • organophosphorus compounds according to the invention are therefore suitable for combating the following viral infections:
  • the organophosphorus compounds of the formulas (I) to (XI) and esters and A ide thereof on the phosphino group and salts thereof show a strong cytotoxic activity against single and multicellular parasites, in particular against the pathogens of malaria and sleeping sickness.
  • the compounds according to the invention can be used for the treatment of infectious diseases which are caused by viruses, bacteria, parasites and fungi in humans and animals.
  • the compounds are also suitable for use in preventing diseases caused by viruses, bacteria, parasites and fungi, in particular as malaria prophylaxis and as sleeping sickness prophylaxis.
  • organophosphorus compounds according to the invention generally include pharmaceutically acceptable salts, amides, esters, a salt of such an ester, or compounds which, when applied, provide the compounds used according to the invention as metabolites or degradation products, also called “prodrugs", for administration be prepared in any suitable manner analogous to known anti-infectious agents (mixed with a non-toxic pharmaceutically acceptable carrier).
  • Pharmaceutically acceptable salts of the compounds include salts which the compounds of the formulas (I) to (XI) used according to the invention in their protonated form as the ammonium salt of inorganic or organic acids, such as hydrochloric acid, sulfuric acid, citric acid, maleic acid, fumaric acid, tartaric acid, p-toluenesulfonic acid , form.
  • inorganic or organic acids such as hydrochloric acid, sulfuric acid, citric acid, maleic acid, fumaric acid, tartaric acid, p-toluenesulfonic acid , form.
  • salts which are formed by suitable selection of X 3 and, such as sodium salt, potassium salt, calcium salt, ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt and salts of an amino acid such as arginine salt, aspartic acid salt, glutamic acid salt.
  • test system The activity of the substances is determined in a test system. This system is based on the measurement of the inhibition of the growth of bacteria, parasites, viruses, or fungi Plants in vitro. For this purpose, test methods are used which are known to the person skilled in the art.
  • the inhibition of the growth of malaria parasites in blood cultures is determined to determine the antimalarial activity.
  • the determination of the antibacterial activity is based on measuring the inhibition of bacterial growth on nutrient media and in liquid cultures.
  • the determination of the antiviral activity is based on inhibition of the formation of viral elements in cell cultures.
  • the determination of the fungicidal activity is based on the inhibition of the growth of fungi on nutrient media and in liquid cultures.
  • microorganisms to be examined can only be examined in animal models.
  • the corresponding models are used here.
  • Substances that show efficacy in the in vitro measurement systems are further investigated in in vivo models.
  • the antiparasitic, antiviral, fungicidal or antibacterial activity is further evaluated in the corresponding animal models.
  • the screening for herbicidal activity is determined by means of algae systems and measurement of the isoprene emission from plants under standard conditions.
  • the pharmaceutically active agents can be prepared in the form of pharmaceutical preparations in dosage units. This means that the preparation in the form of individual parts, e.g. B. tablets, dragees, capsules, pills, suppositories and ampoules are present, the active ingredient content of which corresponds to a fraction or a multiple of a single dose.
  • the dosage units can e.g. B. 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose.
  • a single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.
  • Non-toxic, inert pharmaceutically suitable carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.
  • Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations.
  • Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. B. starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. B. carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, (c) Humectants, e.g.
  • B. glycerin B. glycerin
  • disintegrant e.g. B. agar-agar, calcium carbonate and sodium carbonate
  • solution retarders e.g. B. paraffin
  • absorption accelerator e.g. B. quaternary ammonium compounds
  • wetting agents e.g. B. cetyl alcohol, glycerol monostearate
  • adsorbent for. B. kaolin and bentonite
  • lubricants e.g. B. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).
  • the tablets, dragees, capsules, pills and granules can be provided with the customary coatings and casings, optionally containing opacifying agents, and can also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, possibly with a delay, where as embedding z.
  • B. polymer substances and waxes can be used.
  • the active ingredient (s) can, if appropriate, also be present in microencapsulated form with one or more of the above-mentioned carriers.
  • Suppositories can contain the usual water-soluble or water-insoluble excipients in addition to the active ingredient (s), e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat and higher esters (z. B. C 14 alcohol with Ci 6 fatty acid) or mixtures of these substances.
  • active ingredient e.g. B. polyethylene glycols
  • fats e.g. B. cocoa fat and higher esters (z. B. C 14 alcohol with Ci 6 fatty acid) or mixtures of these substances.
  • Ointments, pastes, creams and gels can contain the usual excipients in addition to the active ingredient (s), e.g. B. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.
  • active ingredient e.g. B. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.
  • Powder and sprays can contain the usual excipients in addition to the active ingredient (s), e.g. B. milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances.
  • Sprays can also use the usual blowing agents, e.g. B. chlorofluorocarbons.
  • solutions and emulsions can contain the usual carriers such as solvents, solubilizers and emulsifiers, e.g. B. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol, glycerol formalin - hol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.
  • solvents e.g. B. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottons
  • solutions and emulsions can also be used in sterile and blood sotonic form.
  • suspensions can contain the usual carriers such as liquid diluents, e.g. B. water, ethyl alcohol, propylene glycol, suspending agents, e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth or mixtures of these substances.
  • liquid diluents e.g. B. water, ethyl alcohol, propylene glycol
  • suspending agents e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth or mixtures of these substances.
  • the formulation forms mentioned can also contain colorants, preservatives and odor and taste-improving additives, e.g. B. peppermint oil and eucalyptus oil and sweeteners, e.g. B. saccharin.
  • the active compounds of the formulas (I) to (XI) should be present in the pharmaceutical preparations listed above, preferably in a concentration of about 0.1 to 99.5% by weight, preferably about 0.5 to 95% by weight. % of the total mixture.
  • the pharmaceutical preparations can also contain further active pharmaceutical ingredients.
  • the compounds can be used with previously described substances with antibacterial, antiviral, antimyctoic and antiparasitic properties. These include in particular compounds that have already been used in therapy or are still being used. Substances are particularly suitable for this purpose, which are listed in the Red List or in Simon / Stille, Antibiotic Therapy in Clinic and Practice, 9th Edition 1998 Schattauer Verlag, or at http: /w ⁇ vw.customs.treas.gov/imp -exp / lings / narmoniz / hrml29.html listed on the Internet.
  • organophosphorus compounds in the pharmaceutical compositions can be used in combination with sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine, chloroquine, hydroxylchloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracycline, doxycycline, proguanil, metronidazole, nicazolantil, prazoliquilil, praziquantilil Pyrantel, tiabendazole, diethyl carbazine, piperazine, pyrivinum, metrifonate, oxamniquin, bithionol or suramin or more of these substances are present.
  • the pharmaceutical preparations listed above are prepared in a conventional manner by known methods, e.g. B. by mixing the active ingredient (s) with the carrier (s).
  • the preparations mentioned can either be oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, local (PU der, ointment, drops) and for the treatment of infections in cavities, body cavities.
  • Suitable preparations are injection solutions, solutions and suspensions for oral therapy, gels, pour-on formulations, emulsions, ointments or drops.
  • ophthalmic and dermatological formulations silver and other salts, ear drops, eye ointments, powder or solutions can be used.
  • suitable formulations can also be ingested through feed or drinking water.
  • Gels, powders, powders, tablets, prolonged-release tablets, premixes, concentrates, granules, pellets, tablets, boluses, capsules, aerosols, sprays, inhalants can also be used in humans and animals.
  • the compounds according to the invention can be incorporated into other carrier materials such as plastics, (plastic chains for local therapy), collagen or bone cement.
  • the active ingredient (s) of the formulas (I) to (XI) in total amounts of from about 0.05 to about 600, preferably 0.5 to 200 mg / kg Body weight per 24 hours, _ if necessary in the form of several individual doses, to achieve the desired results.
  • a single dose contains the active ingredient (s) preferably in amounts of about 1 to about 200, in particular 1 to 60 mg / kg body weight.
  • the above-mentioned amount of active ingredient In some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient has to be exceeded.
  • the person skilled in the art can determine the optimum dosage and type of application of the active ingredients required on the basis of his specialist knowledge.
  • the compounds according to the invention can be given in the usual concentrations and preparations in animals together with the feed or with feed preparations or with the drinking water.
  • the compounds according to the invention can be used outstandingly as bactericides, fungicides and herbicides in plants.

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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

Verwendung von phosphororganischen Verbindungen zur prophylaktischen und therapeutischen Behandlung von Infektionen Use of organophosphorus compounds for the prophylactic and therapeutic treatment of infections
Die Erfindung betrifft die Verwendung von phosphororganischen Verbindungen sowie ihren Salzen, Estern und Amiden zur therapeutischen und prophylaktischen Behandlung von Infektionen bei Mensch und Tier, die durch Viren, Bakterien, Pilze und Parasiten hervorgerufen werden, und ihre Verwendung als Fungizid, Bakterizid und Herbizid bei Pflanzen. Erfindungsgemäß umfassen die phosphororganischen Verbindungen Phosphinoylderivate, Phos- phinsäurederivate und Phosphonsäurederivate.The invention relates to the use of organophosphorus compounds and their salts, esters and amides for the therapeutic and prophylactic treatment of infections in humans and animals caused by viruses, bacteria, fungi and parasites, and their use as fungicides, bactericides and herbicides in plants . According to the invention, the organophosphorus compounds include phosphinoyl derivatives, phosphinic acid derivatives and phosphonic acid derivatives.
Es besteht ein starker Bedarf, für die Bereicherung der Behandlung von Mensch und Tier sowie den Schutz von Pflanzen Mittel bereitzustellen, die nicht nur eine starke Wirksamkeit besitzen, sondern auch im Gegensatz zu anderen Arzneimitteln bzw. Pflanzenschutzmitteln verringerte Nebenwirkungen zeigen und damit eine geringere Gesundheitsgefahr für den Menschen bedeuten.There is a strong need to provide means for the enrichment of the treatment of humans and animals and the protection of plants which are not only highly effective but also, in contrast to other medicinal products or crop protection agents, have reduced side effects and thus a lower health risk for mean to people.
Aufgabe der vorliegenden Erfindung ist es daher, eine Substanz bereitzustellen, die bei Infektionen durch Viren, Bakterien, Pilze und Parasiten bei Menschen und Tieren und als Fungizid, Bakterizid und Herbizid bei Pflanzen einsetzbar ist und die oben angegebenen Bedingungen erfüllt.The object of the present invention is therefore to provide a substance which can be used in infections by viruses, bacteria, fungi and parasites in humans and animals and as a fungicide, bactericide and herbicide in plants and which fulfills the conditions specified above.
Diese Aufgabe wird in völlig überraschender Weise durch die Verwendung der in Anspruch 1 definierte StofFgruppe gelöst. Diese StofFgruppe zeigt eine antiinfektiöse Wirkung gegen Viren, bestimmte Bakterien, Pilze, ein- und mehrzellige Parasiten.This object is achieved in a completely surprising manner by using the substance group defined in claim 1. This group of substances shows an anti-infectious effect against viruses, certain bacteria, fungi, single and multicellular parasites.
Die erfindungsgemäß verwendeten phosphororganischen Verbindungen entsprechen der allgemeinen Formel (I):The organophosphorus compounds used according to the invention correspond to the general formula (I):
0 00 0
II II R1-X-A-P-R3 ( I )II II R1-X-A-P-R3 (I)
1 I1 I
R2 R4 R 2 R 4
in der X ein Phosphoratom oder ein Schwefelatom ist,in which X is a phosphorus atom or a sulfur atom,
wobei A eine unverzweigte C2- -Alkylenkette ist mit Substituenten, die gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, Hydroxy-, Halogen-, Amino- und Oxogruppen, C.-26-Alkylresten, C1-26-Alkoxyresten, C_.26-Alkoxy-C1.26- Alkylresten oder C3-8-Cycloalkyl-(Co-9)-alkylgruppen besteht, wobei jeder Cι-26-Alkylrest undwherein A is an unbranched C 2 - alkylene chain with substituents which are the same or different and are selected from the group consisting of hydrogen, hydroxyl, halogen, amino and oxo groups, C. 2 6 -alkyl radicals, C 1 -2 6-alkoxy radicals, C_.26-alkoxy-C1.26- alkyl radicals or C 3 -8-cycloalkyl- (Co-9) alkyl groups, each Cι- 2 6-alkyl radical and
ERSATZBLAπ (REGEL 26) jeder C1-26-Alkoxyrest verzweigt oder unverzweigt und gesättigt oder mit ein oder mehreren Doppelbindungen ungesättigt sein kann und mit Hydroxy-, Amino-, Halogen- und Oxogrup- pen substituiert sein kann und sowohl die C3-8-Cycloalkylgruppe als auch die C0.9- Alkylgruppe der C3.8-Cycloalkyl-(C0-9)-alkylgruppe ein oder mehrere Doppelbindungen auf- weisen können und ein oder zwei Kohlenstoffatome der Cycloalkylgruppe durch Stickstoff-, Sauerstoff- oder Schwefelatome ersetzt sein können, und wobei sowohl die Cycloalkylgruppe als auch die Alkylgruppe mit Hydroxy-, Halogen-, Amino-, Oxogruppen mit verzweigten oder unverzweigten Cι-9-Alkylgruppen und C2-9-Alkenylgruppen substituiert sein können, wobei die Ci.g-Alkylgruppen und C -9-Alkenylgruppen mit Wasserstoff-, Hydroxy-, Amino-, Halogen- und Oxogruppen substituiert sein könnenREPLACEMENT BLAπ (RULE 26) each C 1-26 alkoxy radical may be branched or unbranched and saturated or unsaturated with one or more double bonds and may be substituted with hydroxyl, amino, halogen and oxo groups and both the C 3-8 cycloalkyl group and that C0.9 alkyl group of C 3 . 8- Cycloalkyl- (C 0 -9) -alkyl group can have one or more double bonds and one or two carbon atoms of the cycloalkyl group can be replaced by nitrogen, oxygen or sulfur atoms, and both the cycloalkyl group and the alkyl group with hydroxy -, Halogen, amino, oxo groups with branched or unbranched C 9 alkyl groups and C 2-9 alkenyl groups can be substituted, the Ci.g-alkyl groups and C -9 alkenyl groups with hydrogen, hydroxyl, amino -, Halogen and oxo groups can be substituted
in der R\ und R2 gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem C1.9-Al.cyl, substituiertem und unsubstituiertem Hydroxy-Cι-9-alkyl, substituiertem und unsubstituiertem Cι-9-Alkenyl, substituiertem und unsubstituiertem Cι-9-Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen Rest, Halogen, OXi und OX2 besteht,in which R \ and R 2 are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted C 1 . 9 -Al.cyl, substituted and unsubstituted hydroxy-9 Cι- alkyl, substituted and unsubstituted Cι -9 alkenyl, substituted and unsubstituted Cι- 9 alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen, OXi and OX 2 ,
wobei Xi und X2 gleich oder verschieden sind und aus der Gruppe ausgewählt ist, die aus Wasserstoff, substituiertem und unsubstituiertem Cι-9-Alkyl, substituiertem und unsubstituiertem Hydroxy-Cι-9-alkyl, substituiertem und unsubstituiertem Cι-9-Alkenyl, substituiertem und unsubstituiertem Cι-9-Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen Rest besteht,where Xi and X 2 are the same or different and is selected from the group consisting of hydrogen, substituted and unsubstituted Cι- 9 alkyl, substituted and unsubstituted hydroxy-Cι- 9 alkyl, substituted and unsubstituted Cι -9 alkenyl, substituted and unsubstituted Cι -9 alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical is,
in der R3 und j gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus substituiertem und unsubstituiertem C^-Alkyl, Hydroxy-C..26-alkyl, substituiertem und un- substituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem Cι.26-Alkenyl, substituiertem und unsubstituiertem Cι.26-Alkinyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem heterocyclischem Rest, Halogen, OX3 und OXt besteht,in which R 3 and j are the same or different and are selected from the group consisting of substituted and unsubstituted C ^ alkyl, hydroxy-C .. 26 alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted Cι. 26 alkenyl, substituted and unsubstituted Cι. 26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, OX 3 and OX t ,
wobei X3 und 4 gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem Cι.26-Alkyl, substituiertem und unsubstituiertem Hydroxy-d-26-alkyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem Cι.26-Alkenyl, substituiertem und unsubstituiertem C.-26-Alkinyl, substituiertem und unsubstituiertem Cycloalkyl, substituier- tem und unsubstituiertem heterocyclischem Rest, einem Silyl, einem Kation einer organischen und anorganischen Base, insbesondere einem Metall der ersten, zweiten oder dritten Hauptgruppe des Periodensystems, Ammonium, substituiertem Ammonium und Ammoniumverbindungen, die sich von Ethylendiamin oder Aminosäuren ableiten, besteht, und deren pharmazeutisch akzeptablen Salze, Ester und Amide und Salze der Ester.where X 3 and 4 are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted Cι. 26 alkyl, substituted and unsubstituted hydroxy-d- 26 alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted Cι. 26 -alkenyl, substituted and unsubstituted C.-26-alkynyl, substituted and unsubstituted cycloalkyl, substituted- tem and unsubstituted heterocyclic radical, a silyl, a cation of an organic and inorganic base, in particular a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids, and their pharmaceutical acceptable salts, esters and amides and salts of the esters.
Bevorzugt sind X3 und 4 ein Metall der ersten, zweiten oder dritten Hauptgruppe des Periodensystems, Ammomum, substituiertes Ammonium, oder Ammoniumverbindungen, die sich von Ethylendiamin oder Aminosäuren ableiten. D.h. es werden die Salzverbindungen der phosphororganischen Verbindungen mit organischen oder anorganischen Basen (z.B. Natriumsalz, Kaliumsalz, Calciumsalz, Aluminiumsalz, Ammoniumsalz, Magnesiumsalz, Trie- thylaminsalz, Ethanolaminsalz, Dicyclohexylaminsalz, Ethylendiaminsalz, N,N'- Dibenzylethylen-diaminsalz etc.) sowie Salze mit Aminosäuren (z.B. Arginin-salz, Aspa- raginsäuresalz, Glutaminsäuresalz etc.) und dergleichen gebildet.X 3 and 4 are preferably a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium, or ammonium compounds which are derived from ethylenediamine or amino acids. Ie there are the salt compounds of the organophosphorus compounds with organic or inorganic bases (for example sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylamine salt, ethanolamine salt, dicyclohexylamine salt, ethylenediamine salt, N, N'-dibenzylethylenediamine salt etc.) and salts with amino acids (for example arginine salt, aspartic acid salt, glutamic acid salt etc.) and the like.
Besonders bevorzugt sind X3 und X4 gleich oder verschieden und aus der Gruppe ausgewählt, die aus Wasserstoff, Natrium, Kalium, Methyl, Ethyl besteht.X 3 and X 4 are particularly preferably the same or different and selected from the group consisting of hydrogen, sodium, potassium, methyl, ethyl.
Bevorzugt ist A eine C3.5-Alkylkette.A is preferably a C 3 . 5 alkyl chain.
Besonders bevorzugt sind Verbindungen der Formel (II)Compounds of the formula (II) are particularly preferred
0 0 II II R1-X-A- P-R3 ( I I ) ,0 0 II II R1-X-A-P-R3 (I I),
1 1 CH3 R4 1 1 CH 3 R 4
wobei X, Rj, R3, » wie oben definiert sind, wobei Rj bevorzugt an dem dem Heteroatom benachbarten C-Atom mit einer Hydroxygruppe substituiert ist,where X, Rj, R 3 , »are as defined above, where Rj is preferably substituted by a hydroxyl group on the C atom adjacent to the heteroatom,
und Verbindungen der Formel (III)and compounds of the formula (III)
0 00 0
R1-X-A-P-R3 ( I I I ) , I IR1-X-A-P-R3 (I I I), I I
OH R4 OH R 4
wobei X, Ri, R3, ι wie oben definiert sind, wobei R\ bevorzugt eine Acylgruppe, besonders bevorzugt eine Formyl-, Acetyl-, Propionyl- oder Butyrylgruppe ist. Ebenfalls sind Verbindungen mit den folgenden Strukturen bevorzugt:where X, Ri, R 3 , ι are as defined above, wherein R \ is preferably an acyl group, particularly preferably a formyl, acetyl, propionyl or butyryl group. Compounds with the following structures are also preferred:
0 0 0 II II II0 0 0 II II II
R1-X-C-C-C-C-P-R3 (IV) ,R 1 -XCCCCPR 3 (IV),
1 I1 I
OH ROH R
0 OH 0 II I II0 OH 0 II I II
R1-X-C-C-C-C-P-R3 (V) ,R1-X-C-C-C-C-P-R3 (V),
1 I R2 4 1 IR 2 4
0 0 00 0 0
II 11 IIII 11 II
Ri -X-C-C-C-C-P-R3 (vi:Ri -XCCCCPR 3 (vi:
R7 OHR 7 OH
0 HO 00 HO 0
R1-X-C-C-C-C-P-R3 ;vn),R 1 -XCCCCPR 3 ; vn),
I II I
R2 R4 R 2 R 4
0 0 0 00 0 0 0
II II II IIII II II II
R1-X-C-C-C-C-C-P-R3 (VIII) ,R1-X-C-C-C-C-C-P-R3 (VIII),
OH OHOH OH
0 OH HO 00 OH HO 0
II I 1 11II I 1 11
R1-X-C-C-C-C-C-P-R3 (IX) ,R1-X-C-C-C-C-C-P-R3 (IX),
I I R2 R4 IIR 2 R 4
0 OH 0 00 OH 0 0
II I II IIII I II II
R1-X-C-C-C-C-C-P-R3 (X) undR 1 -XCCCCCPR 3 (X) and
R2 OHR 2 OH
0 0 HO 0 II II I II0 0 HO 0 II II I II
R1-X-C-C-C-C-C-P-R3 (XI) .R1-XCCCCCPR 3 (XI).
1 I1 I
OH R 4OH R 4
Besonderheiten der obigen Definitionen und geeignete Beispiele dafür werden nachfolgend angegeben:Special features of the above definitions and suitable examples are given below:
„Acyl" ist ein Substituent, der von einer Säure stammt, wie von einer organischen Carbonsäu- re, Kohlensäure, Carbaminsäure oder der den einzelnen vorstehenden Säuren entsprechenden Thiosäure oder Imidsäure, oder von einer organischen Sulfonsäure, wobei diese Säuren jeweils aliphatische, aromatische und/oder heterocyclische Gruppen im Molekül umfassen sowie Carbamoyl oder Carbamimidoyl."Acyl" is a substituent derived from an acid, such as from an organic carboxylic acid. re, carbonic acid, carbamic acid or the thioic acid or imidic acid corresponding to the individual above acids, or from an organic sulfonic acid, these acids each comprising aliphatic, aromatic and / or heterocyclic groups in the molecule and carbamoyl or carbamimidoyl.
Geeignete Beispiele für diese Acylgruppen werden nachfolgend angegeben.Suitable examples of these acyl groups are given below.
Als aliphatische Acylgruppen werden von einer aliphatischen Säure stammende Acylreste bezeichnet, zu denen die folgenden gehören: Alkanoyl (z.B. Formyl, Acetyl, Propionyl, Butyryl, Isobutyryl, Valeryl, Isovaleryl, Pivaloyl etc.); Alkenoyl (z. B. Acryloyl, Methacryloyl, Crotonoyl etc.); Alkylthioalkanoyl (z.B. Me- thylthioacetyl, Ethylthioacetyl etc.); Alkansulfonyl (z.B. Mesyl, Ethansulfonyl, Propansul- fonyl etc.); Alkoxycarbonyl (z.B. Methoxycarbonyl, Ethoxycarbonyl, Propoxycarbonyl, Iso- propoxycarbonyl, Butoxycarbonyl, Isobutoxycarbonyl etc.); Alkylcarbamoyl (z.B. Me- thylcarbamoyl etc.); (N-Alkyl)-thiocarbamoyl (z.B. (N-Methyl)-thiocarbamoyl etc.); Al- kylcarbamimidoyl (z.B. Methylcarbamimidoyl etc.); Oxalo; Alkoxalyl (z.B. Methoxalyl, Ethoxalyl, Propoxalyl etc.).Aliphatic acyl groups are acyl radicals derived from an aliphatic acid, which include the following: alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.); Alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl etc.); Alkylthioalkanoyl (e.g. methylthioacetyl, ethylthioacetyl etc.); Alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, etc.); Alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.); Alkyl carbamoyl (e.g. methyl carbamoyl etc.); (N-alkyl) thiocarbamoyl (e.g. (N-methyl) thiocarbamoyl etc.); Alkylcarbamimidoyl (e.g. methylcarbamimidoyl etc.); Oxalo; Alkoxalyl (e.g. methoxalyl, ethoxalyl, propoxalyl etc.).
Bei den obigen Beispielen für aliphatische Acylgruppen kann der aliphatische Kohlenwasser- stoffteil, insbesondere die Alkylgruppe bzw. der Alkanrest, ggf. einen oder mehrere geeignete Substituenten aufweisen, wie Amino, Halogen (z.B. Fluor, Chlor, Brom etc.), Hydroxy, Hy- droxyimino. Carboxy, Alkoxy (z.B. Methoxy, Ethoxy, Propoxy etc.), Alkoxycarbonyl, Acylamino (z.B. Benzyloxycarbonylamino etc.), Acyloxy (z.B. Acetoxy, Benzoyloxy etc.) und dergleichen; als bevorzugte aliphatische Acylreste mit solchen Substituenten sind z.B. mit Amino, Carboxy, Amino und Carboxy, Halogen, Acylamino oder dergleichen substituierte Alkanoyle zu nennen.In the above examples of aliphatic acyl groups, the aliphatic hydrocarbon part, in particular the alkyl group or the alkane radical, may optionally have one or more suitable substituents, such as amino, halogen (for example fluorine, chlorine, bromine etc.), hydroxy, hy- droxyimino. Carboxy, alkoxy (e.g. methoxy, ethoxy, propoxy etc.), alkoxycarbonyl, acylamino (e.g. benzyloxycarbonylamino etc.), acyloxy (e.g. acetoxy, benzoyloxy etc.) and the like; as preferred aliphatic acyl radicals with such substituents are e.g. alkanoyl substituted with amino, carboxy, amino and carboxy, halogen, acylamino or the like.
Als aromatische Acylreste werden solche Acylreste bezeichnet, die von einer Säure mit substituierter oder nicht substituierter Arylgruppe stammen, wobei die Arylgruppe Phenyl, To- luyl, Xylyl, Naphthyl und dergleichen umfassen kann; geeignete Beispiele werden nachfolgend angegeben:Aromatic acyl radicals are those acyl radicals which derive from an acid with a substituted or unsubstituted aryl group, where the aryl group can include phenyl, toluyl, xylyl, naphthyl and the like; suitable examples are given below:
Aroyl (z.B. Benzoyl, Toluoyl, Xyloyl, Naphthoyl, Phthaloyl etc.); Aralkanoyl (z.B. Phenyla- cetyl etc.); Aralkenoyl (z.B. Cinnamoyl etc.); Aryloxyalkanoyl (z.B. Phenoxyacetyl etc.); Arylthioalkanoyl (z.B. Phenylthioacetyl etc.); Arylaminoalkanoyl (z.B. N-Phenylglycyl, etc.); Arensulfonyl (z.B.Benzolsulfonyl, Tosyl bzw. Toluolsulfonyl, Naphthalinsulfonyl etc.); Aryloxycarbonyl (z.B. Phenoxycarbonyl, Naphthyl-oxycarbonyl etc.); Aralkoxycarbonyl (z.B. Benzyloxycarbonyl etc.); Arylcarbamoyl (z.B. Phenylcarbamoyl, Naphthylcarbamoyl etc.); Arylglyoxyloyl (z.B. Phenylglyoxyloyl etc.). Bei den vorstehenden Beispielen für aromatische Acylreste kann der aromatische Kohlenwasserstoffteil (insbesondere der Arylrest) und/oder der aliphatische Kohlenwasserstoffteil (insbesondere der Alkanrest) ggf. ein oder mehrere geeignete Substituenten aufweisen, wie solche, die als geeignete Substituenten für die Alkylgruppe bzw. den Alkanrest bereits angegeben wurden. Insbesondere und als Beispiel für bevorzugte aromatische Acylreste mit besonderen Substituenten werden mit Halogen und Hydroxy oder mit Halogen und Acyloxy substituiertes Aroyl und mit Hydroxy, Hydroxyimino, Dihalogenalkanoyloxyimino substituiertes Aralkanoyl angegeben sowie Arylthiocarbamoyl (z.B. Phenylthiocarbamoyl etc.); Arylcarba- mimidoyl (z.B. Phenylcarbamimidoyl etc.).Aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl etc.); Aralkanoyl (eg phenylacetyl etc.); Aralkenoyl (e.g. cinnamoyl etc.); Aryloxyalkanoyl (e.g. phenoxyacetyl etc.); Arylthioalkanoyl (e.g. phenylthioacetyl etc.); Arylaminoalkanoyl (e.g. N-phenylglycyl, etc.); Arenesulfonyl (e.g. benzenesulfonyl, tosyl or toluenesulfonyl, naphthalenesulfonyl etc.); Aryloxycarbonyl (e.g. phenoxycarbonyl, naphthyloxycarbonyl etc.); Aralkoxycarbonyl (e.g. benzyloxycarbonyl etc.); Arylcarbamoyl (e.g. phenylcarbamoyl, naphthylcarbamoyl etc.); Arylglyoxyloyl (e.g. phenylglyoxyloyl etc.). In the above examples of aromatic acyl radicals, the aromatic hydrocarbon part (in particular the aryl radical) and / or the aliphatic hydrocarbon part (in particular the alkane radical) may optionally have one or more suitable substituents, such as those which are suitable substituents for the alkyl group or the alkane radical have already been specified. In particular and as an example of preferred aromatic acyl radicals with special substituents, aroyl substituted with halogen and hydroxy or with halogen and acyloxy and aralkanoyl substituted with hydroxy, hydroxyimino, dihalogenalkanoyloxyimino and arylthiocarbamoyl (eg phenylthiocarbamoyl etc.); Arylcarbamimidoyl (eg phenylcarbamimidoyl etc.).
Als heterocyclischer Acylrest wird ein Acylrest verstanden, der von einer Säure mit heterocy- clischer Gruppe stammt; dazu gehören:A heterocyclic acyl radical is understood to mean an acyl radical which comes from an acid with a heterocyclic group; this includes:
Heterocyclisches Carbonyl, bei dem der heterocyclische Rest ein aromatischer oder aliphati- scher 5-bis 6-gliedriger Heterocyclus mit zumindest einem Heteroatom aus der Gruppe Stickstoff, Sauerstoff und Schwefel ist (z.B. Thiophenyl, Furoyl, Pyrrolcarbonyl, Nicotinoyl etc.);Heterocyclic carbonyl, in which the heterocyclic radical is an aromatic or aliphatic 5- to 6-membered heterocycle with at least one heteroatom from the group consisting of nitrogen, oxygen and sulfur (e.g. thiophenyl, furoyl, pyrrole carbonyl, nicotinoyl etc.);
Heterocyclus-Alkanoyl, bei dem der heterocyclische Rest 5- bis 6-gliedrig ist und zumindest ein Heteroatom aus der Gruppe Stickstoff, Sauerstoff und Schwefel aufweist (z.B. Thiophen- yl-acetyl, Furylacetyl, Imidazolylpropionyl, Tetrazolylacetyl, 2-(2-Amino-4-thiazolyl)-2- methoxyiminoacetyl etc.) und dergleichen.Heterocycle alkanoyl, in which the heterocyclic radical is 5- to 6-membered and has at least one heteroatom from the group consisting of nitrogen, oxygen and sulfur (for example thiophenyl-acetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino- 4-thiazolyl) -2-methoxyiminoacetyl etc.) and the like.
Bei den obigen Beispielen für heterocyclische Acylreste kann der Heterocyclus und/oder der aliphatische Kohlenwasserstoffteil ggf. einen oder mehrere geeignete Substituenten aufwei- sen, wie die gleichen, die als geeignet für Alkyl- und Alkangruppen angegeben wurden.In the above examples of heterocyclic acyl radicals, the heterocycle and / or the aliphatic hydrocarbon part may optionally have one or more suitable substituents, such as the same ones which have been stated to be suitable for alkyl and alkane groups.
„Alkyl" ist ein gerad- oder verzweigtkettiger Alkylrest mit bis zu 26 Kohlenstoffatomen, soweit er nicht anders definiert ist, wie Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.- Butyl, Pentyl, Hexyl und dergleichen."Alkyl" is a straight or branched chain alkyl radical having up to 26 carbon atoms, unless otherwise defined, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.
„Hydroxylalkyl" ist ein gerad- oder verzweigtkettiger Alkylrest mit bis zu 26 Kohlenstoffatomen, soweit er nicht anders definiert ist,, der mindestens eine Hydroxylgruppe aufweist, bevorzugt ein oder zwei Hydroxylgruppen."Hydroxylalkyl" is a straight or branched chain alkyl radical having up to 26 carbon atoms, unless defined otherwise, which has at least one hydroxyl group, preferably one or two hydroxyl groups.
Zu „Alkenyl" gehören gerad- oder verzweigtkettige Alkenylgruppen mit bis zu 26 Kohlenstoffatomen, soweit er nicht anders definiert ist, wie z.B. Vinyl, Propenyl (z.B. 1-Propenyl, 2- Propenyl), 1-Methylpropenyl, 2-Methylpropenyl, Butenyl, 2-Ethylpropenyl, Pentenyl, Hexe- nyl. Zu „Alkinyl" gehören gerad- oder verzweigtkettige Alkinylgruppen mit bis zu 26 Kohlenstoffatomen, soweit er nicht anders definiert ist."Alkenyl" includes straight or branched chain alkenyl groups with up to 26 carbon atoms, unless defined otherwise, such as vinyl, propenyl (e.g. 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2 -Ethylpropenyl, pentenyl, hexenyl. "Alkynyl" includes straight or branched chain alkynyl groups with up to 26 carbon atoms, unless it is defined otherwise.
Cycloalkyl steht vorzugsweise für ein ggfs. substituiertes C3.8-Cycloalkyl; als mögliche Sub- stituenten sind u.a. Alkyl, Alkenyl, Alkinyl, Alkoxy (z.B. Methoxy, Ethoxy etc.), Halogen (z.B. Fluor, Chlor, Brom etc.), Nitro und dergleichen geeignet.Cycloalkyl preferably represents an optionally substituted C 3 . 8- cycloalkyl; Possible substituents include alkyl, alkenyl, alkynyl, alkoxy (eg methoxy, ethoxy etc.), halogen (eg fluorine, chlorine, bromine etc.), nitro and the like.
Aryl ist ein aromatischer Kohlenwasserstoffrest, wie Phenyl Naphthyl usw., der ggf. einen oder mehrere geeignete Substituenten aufweisen kann, wie Alkyl, Alkenyl, Alkinyl, Alkoxy (z.B. Methoxy, Ethoxy etc.), Halogen (z.B. Fluor, Chlor, Brom etc.), Nitro und dergleichen.Aryl is an aromatic hydrocarbon radical, such as phenyl naphthyl etc., which may optionally have one or more suitable substituents, such as alkyl, alkenyl, alkynyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc. ), Nitro and the like.
Zu „Aralkyl" gehören Mono-, Di-, Triphenylalkyle wie Benzyl, Phenethyl, Benzhydryl, Trityl und dergleichen, wobei der aromatische Teil ggf. ein oder mehrere geeignete Substituenten aufweisen kann wie Alkoxy (z.B. Methoxy, Ethoxy etc.), Halogen (z.B. Fluor, Chlor, Brom etc.), Nitro und dergleichen."Aralkyl" includes mono-, di-, triphenylalkyls such as benzyl, phenethyl, benzhydryl, trityl and the like, where the aromatic part may have one or more suitable substituents such as alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. Fluorine, chlorine, bromine, etc.), nitro and the like.
Vorzugsweise können die Reste X3 und j so gewählt werden, daß Ester an der Phosphino- gruppe oder Phosphonogruppe gebildet werden. Zu geeigneten Beispielen für solche Ester gemäß der Formeln (I) bis (XI) zählen geeignete Mono- und Diester, und zu bevorzugten Bei- spielen für solche Ester gehören Alkylester (z.B. Hexadecanylester, Octadecanylester etc.); Aralkylester (Benzylester, Phenethylester, Benzhydrylester, Tritylester etc.); Arylester (z.B. Phenylester, Tolylester, Naphthylester etc.); Aroylalkylester (z.B. Phenacyle- ster etc.); und Silylester (z.B. von Trialkylhalogensilyl, Dialkyldihalogensilyl, Alkyltrihalo- gensilyl, Dialkylarylhalogensilyl, Trialkoxyhalogensilyl, Dialkylaralkylhalogensilyl, Dial- koxydihalogensilyl, Trialkoxyhalogensilyl etc.) und dergleichen.The radicals X 3 and j can preferably be chosen such that esters are formed on the phosphino group or phosphono group. Suitable examples of such esters according to formulas (I) to (XI) include suitable mono- and diesters, and preferred examples of such esters include alkyl esters (for example hexadecanyl ester, octadecanyl ester, etc.); Aralkyl esters (benzyl esters, phenethyl esters, benzhydryl esters, trityl esters, etc.); Aryl esters (for example phenyl esters, tolyl esters, naphthyl esters etc.); Aroyl alkyl esters (eg phenacyl esters etc.); and silyl esters (e.g. from trialkylhalosilyl, dialkyldihalosilyl, alkyltrihalosilyl, dialkylarylhalosilyl, trialkoxyhalosilyl, dialkylaralkylhalosilyl, dialkoxydihalosilyl, trialkoxyhalosilyl, etc.) and the like.
Beim obigen Ester kann der Alkan- und/oder Arenteil wahlweise zumindest einen geeigneten Substituenten aufweisen wie Halogen, Alkoxy, Hydroxy, Nitro oder dergleichen.In the above ester, the alkane and / or arene portion can optionally have at least one suitable substituent such as halogen, alkoxy, hydroxy, nitro or the like.
Die erfindungsgemäß verwendeten Verbindungen gemäß der Formeln (I) bis (XI) können in ihrer protonierten Form als Ammoniumsalz organischer oder anorganischer Säuren, wie Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Salpetersäure, Methansulfonsäure, p- Toluolsulfonsäure, Essigsäure, Milchsäure, Maleinsäure, Fumarsäure, Oxalsäure, Weinsäure, Benzoesäure, etc. vorliegen.The compounds of the formulas (I) to (XI) used according to the invention can, in their protonated form, as the 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, maleic acid, fumaric acid, oxalic acid , Tartaric acid, benzoic acid, etc. are present.
Die erfindungsgemäß verwendeten Verbindungen der Formeln (I) bis (XI) lassen beispielsweise für Doppelbindungen enthaltende oder chirale Gruppen Ri, R2, R3, R-, Xls X2, X3, Xt oder A das Auftreten räumlicher Isomerer zu. Die erfindungsgemäße Verwendung der Verbindungen umfaßt alle räumlichen Isomere sowohl als Reinstoffe als auch in Form ihrer Mi- schlingen.The compounds used in the invention of the formulas (I) to (XI) can, for example, containing double bonds or chiral groups Ri, R 2, R 3, R, X ls X 2, X 3, X t or A, the occurrence of spatial isomers for. The use of the compounds according to the invention includes all spatial isomers both as pure substances and in the form of their loop.
Die phosphororganischen Verbindungen sind insbesondere für die therapeutische und prophylaktischen Behandlung von Infektionen bei Mensch und Tier geeignet, die durch Viren, Bakterien, ein- und mehrzellige Parasiten und Pilze hervorgerufen werden.The organophosphorus compounds are particularly suitable for the therapeutic and prophylactic treatment of infections in humans and animals which are caused by viruses, bacteria, single and multicellular parasites and fungi.
Die Verbindungen sind gegen einzellige Parasiten (Protozoen) wirksam, insbesondere gegen Erreger der Malaria und der Schlafkrankheit sowie der Chagas-Krankheit, der Toxoplasmose, der Amöbenruhr, der Leishmaniosen, der Trichomoniasis, der Pneumozystose, der Balanti- diose, der Kryptosporidiose, der Sarkozystose, der Akanthamöbose, der Naeglerose, der Kokzidiose, der Giardiose und der Lambliose.The compounds are active against unicellular parasites (protozoa), in particular against pathogens of malaria and sleeping sickness as well as Chagas disease, toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis, pneumocystosis, balantidosis, cryptosporidiosis, and sarcolocystosis , Akanthamöbose, Naeglerose, Coccidiosis, Giardiosis and Lambliosis.
Sie sind daher insbesondere als Malariaprophylaxe und als Prophylaxe der Schlafkrankheit sowie der Chagas-Krankheit, der Toxoplasmose, der Amöbenruhr, der Leishmaniosen, der Trichomoniasis, der Pneumozystose, der Balantidiose, der Kryptosporidiose, der Sarkozystose, der Akanthamöbose, der Naeglerose, der Kokzidiose, der Giardiose und der Lambliose geeignet.They are therefore particularly useful as malaria prophylaxis and as prophylaxis of sleeping sickness and Chagas disease, toxoplasmosis, amoebic dysentery, Leishmaniasis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcolocystosis, acanthamoebosis, cocoonosis, naeglerosis Giardiosis and Lambliosis.
Die erfindungsgemäßen Wirkstoffe sind insbesondere gegen die folgenden Bakterien einsetz- bar:The active compounds according to the invention can be used in particular against the following bacteria:
Bakterien der Familie Propionibacteriaceae, insbesondere der Gattung Propionibacterium, insbesondere die Art Propionibacterium acnes, Bakterien der Familie Actinomycetaceae, insbesondere der Gattung Actinomyces, Bakterien der Gattung Corynebacterium, insbesondere die Arten Corynebacterium diphteriae und Corynebacterium pseudotuberculosis, Bakterien der Familie Mycobacteriaceae, der Gattung Mycobacterium, insbesondere die Arten Mycob- acterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis und Mycobacterium avi- um, Bakterien der Familie Chlamydiaceae, insbesondere die Spezies Chlamydia trachomatis und Chlamydia psittaci, Bakterien der Gattung Listeria, insbesondere die Art Listeria mo- nocytogenes, Bakterien der Art Erysipelthrix rhusiopathiae, Bakterien der Gattung Clostridi- um, Bakterien der Gattung Yersinia, der Spezies Yersinia pestis, Yersinia pseudotuberculosis, Yersinia enterocolitica und Yersinia ruckeri, Bakterien der Familie Mycoplasmataceae, der Gattungen Mycoplasma und Ureaplasma, insbesondere die Art Mycoplasma pneumoniae, Bakterien der Gattung Brucella, Bakterien der Gattung Bordetella, Bakterien der Familie Nei- sseriaceae, insbesondere der Gattungen Neisseria und Moraxella, insbesondere die Arten Neisseria meningitides, Neisseria gonorrhoeae und Moraxella bovis, Bakterien der Familie Vi- brionaceae, insbesondere der Gattungen Vibrio, Aeromonas, Plesiomonas und Photobacteri- um, insbesondere die Arten Vibrio cholerae, Vibrio anguillarum und Aeromonas salmonici- das, Bakterien der Gattung Campylobacter, insbesondere die Arten Campylobacter jejuni, Campylobacter coli und Campylobacter fetus, Bakterien der Gattung Helicobacter, insbesondere die Art Helicobacter pylori, Bakterien der Familien Spirochaetaceae und der Leptospira- ceae, insbesondere der Gattungen Treponema, Borrelia und Leptospira, insbesondere Borrelia burgdorferi, Bakterien der Gattung Actinobacillus, Bakterien der Familie Legionellaceae, der Gattung Legionella, Bakterien der Familie Rickettsiaceae und Familie Bartonellaceae, Bakterien der Gattungen Nocardia und Rhodococcus, Bakterien der Gattung Dermatophilus, Bakterien der Familie Pseudomonadaceae, insbesondere der Gattungen Pseudomonas und Xantho- monas, Bakterien der Familie Enterobacteriaceae, insbesondere der Gattungen Escherichia, Klebsieila, Proteus, Providencia, Salmonella, Serratia und Shigella, Bakterien der Familie Pasteurellaceae, insbesondere der Gattung Haemophilus, Bakterien der Familie Micrococca- ceae, insbesondere der Gattungen Micrococcus und Staphylococcus, Bakterien der Familie Streptococcaceae, insbesondere der Gattungen Streptococcus und Enterococcus und Bakterien der Familie Bacillaceae, insbesondere der Gattungen Bacillus und Clostridium.Bacteria of the Propionibacteriaceae family, in particular the Propionibacterium genus, in particular the Propionibacterium acnes species, Actinomycetaceae bacteria, in particular the Actinomyces genus, Corynebacterium bacteria, in particular the Corynebacterium diphteriae and Corynebacterium pseudote family mycobacteria, bacteria the species Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium, bacteria of the Chlamydiaceae family, in particular the species Chlamydia trachomatis and Chlamydia psittaci, bacteria of the genus Listeria, in particular the species Listeria mon- derhrixysiophysiophythropia , Bacteria of the genus Clostridium, bacteria of the genus Yersinia, of the species Yersinia pestis, Yersinia pseudotuberculosis, Yersinia enterocolitica and Yersinia ruckeri, bacteria of the family Mycoplasmataceae, of the genera Mycoplasm a and ureaplasma, in particular the species Mycoplasma pneumoniae, bacteria of the genus Brucella, bacteria of the genus Bordetella, bacteria of the Neisseria family, in particular the Neisseria and Moraxella species, in particular the Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis species, bacteria of the Vi family brionaceae, in particular of the genera Vibrio, Aeromonas, Plesiomonas and Photobacterium, in particular the species Vibrio cholerae, Vibrio anguillarum and Aeromonas salmonici- das, 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 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 the genera Pseudomonas and Xanthomonas, bacteria of the family Enterobacteriaceae, especially the genus Escherbsila Proteus, Providencia, Salmonella, Serratia and Shigella, bacteria of the Pasteurellaceae family, in particular of the genus Haemophilus, bacteria of the Micrococceae family, especially of the genera Micrococcus and Staphylococcus, bacteria of the Streptococcaceae family , in particular the genera Streptococcus and Enterococcus and bacteria of the family Bacillaceae, in particular the genera Bacillus and Clostridium.
Damit eignen sich phosphororganischen Verbindungen und ihre Derivate zur Behandlung der Diphterie, der Acne vulgaris, der Listeriosen, des Rotlaufs bei Tieren, der Gasbrand beim Mensch und beim Tier, Pararauschbrand bei Mensch und Tier, Tuberkulose bei Mensch und Tier, Lepra, und weitere Mykobacteriosen bei Mensch und Tier, der Paratuberkulose der Tiere, Pest, mesenterialen Lymphadenitis und Pseudotuberkulose bei Mensch und Tier, Cholera, Legionärskrankheit, Borreliose bei Mensch und Tier, Leptospirosen bei Mensch und Tier, Syphilis, Campylobacter-Enteritiden bei Mensch und Tier, Moraxella-Keratokonjunc-tivitis und Serositis der Tiere, Brucellosen der Tiere und des Menschen, Milzbrand bei Mensch und Tier, Aktinomykose bei Mensch und Tier, Streptotrichosen, Psittakose/Ornithose bei Tieren, Q-Fieber, Ehrlichiose.Organophosphorus compounds and their derivatives are therefore suitable for the treatment of diphtheria, acne vulgaris, listeriosis, erysipelas in animals, gas fires in humans and animals, para-noise burns in humans and animals, tuberculosis in humans and animals, leprosy and other mycobacteriosis in humans and animals, paratuberculosis in animals, plague, mesenteric lymphadenitis and pseudotuberculosis in humans and animals, cholera, legionnaires' disease, Lyme disease in humans and animals, leptospirosis in humans and animals, syphilis, Campylobacter enteritis in humans and animals, Moraxella keratoconjunc -tivitis and serositis of animals, brucellosis of animals and humans, anthrax in humans and animals, actinomycosis in humans and animals, streptotrichoses, psittacosis / ornithosis in animals, Q fever, Ehrlichiosis.
Weiter ist der Einsatz nützlich bei der Helicobacter-Eradikationstherapie bei Ulcera des Magendarmtraktes.The use is also useful in Helicobacter eradication therapy for ulcers of the gastrointestinal tract.
Es können auch Kombinationen mit einem weiteren Antibiotikum zur Behandlung der oben- genannten Erkrankungen eingesetzt werden. Für Kombinationspräparate mit anderen Antiin- fektiva eignen sich insbesondere Isoniazid, Rifampicin, Ethambutol, Pyrazinamid, Strep- tomycin, Protionamid und Dapson zur Behandlung der Tuberkulose.Combinations with another antibiotic can also be used to treat the above-mentioned diseases. For combination preparations with other anti-infectives, isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, protionamide and dapsone are particularly suitable for the treatment of tuberculosis.
Die erfindungsgemäßen Wirkstoffe sind ferner insbesondere bei Infektionen mit folgenden Viren einsetzbar:The active compounds according to the invention can also be used in particular for infections with the following viruses:
Parvoviridae: Parvoviren, Dependoviren, Densoviren, Adenoviridae: Adenoviren, Mastade- noviren, Aviadenoviren, Papovaviridae: Papovaviren, insbesondere Papillomaviren (sogenannte Warzenviren), Polyomaviren, insbesondere JC -Virus, BK- Virus, und Miopapovaviren, Herpesviridae: Alle Herpesviren, insbesondere Herpes-Simplex-Viren, der Varizellen/Zoster- Viren, menschlicher Zytomegalievirus, Epstein-Barr- Viren, alle humanen Herpesviren, humanes Herpesvirus 6, Humanes Herpesvirus 7, humanes Herpesvirus 8, Poxviri- dae:Pockenviren, Orthopox-, Parapox-, Molluscum-Contagiosum- Virus, Aviviren, Caprivi- ren, Leporipoxviren, alle primär hepatotropen Viren, Hepatitisviren: Hepatitis- A- Viren, He- patitis-B-Viren, Hepatitis-C-Viren, Hepatitis-D- Viren, Hepatitis-E- Viren, Hepatitis-F- Viren, Hepatits-G- Viren, Hepadnaviren: sämtliche Hepatitisviren, Hepatitis-B-Virus, Hepatitis-D- Viren, Picornaviridae: Picornaviren, alle Enteroviren, alle Polioviren, alle Coxsackieviren, alle Echoviren, alle Rhinoviren, Hepatitis-A- Virus, Aphthoviren, Calciviridae: Hepatitis-E- Viren, Reoviridae: Reoviren, Orbiviren, Rotaviren, Togaviridae: Togaviren, Alphaviren, Ru- biviren, Pestiviren, Rubellavirus, Flaviviridae: Flaviviren, FSME- Virus, Hepatitis-C-Virus, Orthomyxoviridae: Alle Influenzaviren, Paramyxoviridae: Paramyxoviren, Morbillivirus, Pneumovirus, Masernvirus, Mumpsvirus, Rhabdoviridae: Rhabdoviren, Rabiesvirus, Lyssavi- rus, viskuläres Stomatitisvirus, Coronaviridae: Coronaviren, Bunyaviridae: Bunyaviren, Nai- rovirus, Phlebovirus, Uukuvirus, Hantavirus, Hantaanvirus, Arenaviridae: Arenaviren, lym- phozytäres Choriomeningitis- Virus, Retroviridae: Retroviren, alle HTL- Viren, humanes T- cell Leukämievirus, Oncornaviren, Spumaviren, Lentiviren, alle HI-Viren, Filoviridae: Marburg- und Ebolavirus, Slow-virus-Infektionen, Prionen, Onkoviren und Leukämieviren.Parvoviridae: Parvoviruses, Dependoviruses, Densoviruses, Adenoviridae: Adenoviruses, Mastadenoviruses, Aviadenoviruses, Papovaviridae: Papovaviruses, in particular Papillomaviruses (so-called Wartsviruses), Polyomaviruses, in particular JC and Viruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses, Herpesviruses -Simplex viruses, the varicella / zoster- Viruses, human cytomegalovirus, Epstein-Barr viruses, all human herpes viruses, human herpes virus 6, human herpes virus 7, human herpes virus 8, poxviridae: poxviruses, orthopox, parapox, molluscum contagiosum virus, aviviruses, capriviruses , Leporipox viruses, all primarily hepatotropic viruses, hepatitis viruses: hepatitis A viruses, hepatitis B viruses, hepatitis C viruses, hepatitis D viruses, hepatitis E viruses, hepatitis F viruses, hepatitis viruses G viruses, hepadnaviruses: all hepatitis viruses, hepatitis B virus, hepatitis D viruses, Picornaviridae: Picornaviruses, all enteroviruses, all polioviruses, all Coxsackieviruses, all echoviruses, all rhinoviruses, hepatitis A virus, aphthiroviruses, calc. Hepatitis E viruses, reoviridae: reoviruses, orbiviruses, rotaviruses, Togaviridae: togaviruses, alphaviruses, rabiviruses, pestiviruses, rubella virus, flaviviridae: flaviviruses, TBE virus, hepatitis C virus, orthomyxoviroviriruses: alleomyxovirus viruses , Morbillivirus, pneumovirus , Measles virus, mumps virus, rhabdoviridae: rhabdoviruses, rabies virus, lyssavirus, viscous stomatitis virus, coronaviridae: coronaviruses, bunyaviridae: bunyaviruses, nanoviruses, arviraviruses, arviraviruses, virus virus, hanavirus virus, hanavirus virus, hanavirus virus virus : Retroviruses, all HTL viruses, human T-cell leukemia virus, oncornaviruses, spuma viruses, lentiviruses, all HI viruses, Filoviridae: Marburg and Ebola viruses, slow virus infections, prions, oncoviruses and leukemia viruses.
Die erfindungsgemäßen phosphororganischen Verbindungen sind somit zur Bekämpfung fol- gender viraler Infekte geeignet:The organophosphorus compounds according to the invention are therefore suitable for combating the following viral infections:
Eradikation von Papillomaviren zur Vorbeugung von Tumoren, insbesondere von Tumoren der Geschlechtsorgane verursacht durch Papillomaviren beim Menschen, Eradikation von JC- Viren und BK- Viren, Eradikation von Herpesviren, Eradikation humaner Herpesviren 8 zur Behandlung der Kaposi-Sarkoma, Eradikation von Zytomegalie- Viren vor Transplantationen, Eradikation von Eppstein-Barr- Viren vor Transplantation und zur Vorbeugung von Eppstein- Barr-Viren-assozierten Tumoren, Eradikation von Hepatitisviren zur Behandlung von chronischen Leber-Erkrankungen und zur Vorbeugung von Lebertumoren und Leberzirrhosen, Eradikation von Coxsackieviren bei Kardiomyopathien, Eradikation von Coxsackieviren bei Dia- betes-mellitus-Patienten, Eradikation von Immunschwäche- Viren in Mensch und Tier, Behandlung von Begleitinfektionen in AIDS-Patienten, Behandlung von Entzündungen viraler Genese des Respirationstraktes (Larynxpapillome, Hyperplasien, Rhinitis, Pharyngitis, Bronchitis, Pneumonien), der Sinnesorgane (Keratokonjunktivitis), des Nervensystems (Poliomyelitis, Meningoenzephalitis, Enzephalitis, subakute sklerosierende Panenzephalitis, SSPE, pro- gressive multifokale Leukoenzephalopathie, Lymphozytäre Choriomeningitis), des Magen- Darm-Traktes (Stomatitis, Gingivostomatitis, Ösophagitis, Gastritis, Gastroenteritis, Durchfallerkrankungen), der Leber und des Gallensystems (Hepatitis, Cholangitis, hepatozelluläres Karzinom), des lymphatischen Gewebes (Mononukleose, Lymphadenitis), des hämatopoeti- schen Systems, der Geschlechtsorgane (Mumpsorchitis), der Haut (Warzen, Dermatitis, Her- pes labialis, Fieberbläschen, Herpes Zoster, Gürtelrose), der Schleimhäute (Papillome, Kon- junktivapapillome, Hyperplasien, Dysplasien), des Herz-Blutgefäß-Systems (Arteriitis, Myokarditis, Endokarditis, Perikarditis), des Nieren-Harnweg-Systems, der Geschlechtsorgane (Anogenitale Läsionen, Warzen, Genitalwarzen, spitzen Kondylome, Dysplasien, Papillome, Zervixdysplasien, Condylomata acuminata, Epidermodysplasia verruciformis), der Bewegungsorgane (Myositis, Myalgien), Behandlung der Maul- und Klauenseuche der Paarhufer, des Colorado-Zeckenfiebers, des Dengue-Syndroms, des hämorrhagisches Fiebers, der Früh- sommermeningoenzephalitis (FSME) und des Gelbfiebers.Eradication of papillomaviruses for the prevention of tumors, in particular tumors of the genital organs caused by papillomaviruses in humans, eradication of JC viruses and BK viruses, eradication of herpes viruses, eradication of human herpes viruses 8 for the treatment of Kaposi's sarcoma, eradication of cytomegaloviruses Transplants, eradication of Eppstein-Barr viruses before transplantation and for the prevention of Eppstein-Barr virus-associated tumors, eradication of hepatitis viruses for the treatment of chronic liver diseases and for the prevention of liver tumors and liver cirrhosis, eradication of Coxsackieviruses in cardiomyopathies, eradication Coxsackieviruses in diabetes mellitus patients, eradication of immunodeficiency viruses in humans and animals, treatment of concomitant infections in AIDS patients, treatment of inflammation of the viral genesis of the respiratory tract (laryngeal papillomas, hyperplasia, rhinitis, pharyngitis, bronchitis, pneumonia), the Sensory care ane (keratoconjunctivitis), of the nervous system (poliomyelitis, meningoencephalitis, encephalitis, subacute sclerosing panencephalitis, SSPE, pro- sive multifocal leukoencephalopathy, lymphocytic choriomeningitis), of the gastrointestinal tract (stomatitis, gingivostomatitis, oesophagitis, gastritis, gastroenteritis, diarrhea), the liver and the biliary system (hepatitis, cholangitis, hepatocellular carcinoma), the lymphatic tissue (mononucleosis, lymphadenitis), the hematopoietic system, the genital organs (mumps orchitis), the skin (warts, dermatitis, pes labialis, cold sores, herpes zoster, shingles), the mucous membranes (papillomas, connecting apapillomas, hyperplasias, dysplasias), the cardiovascular system (arteritis, myocarditis, endocarditis, pericarditis), the kidney-urinary system, the genital organs (Anogenital lesions, warts, genital warts, pointed condylomas, dysplasias, papillomas, cervical dysplasias, condylomata acuminata, epidermodysplasia verruciformis), the movement organs (myositis, myalgias), treatment of foot and mouth disease of the cloven-hoofed animals, the Colorado syndrome tick, the Colorado syndrome tick , hemorrhagic fever, early summer meningoencephalitis (TBE) and yellow fever.
Die beschriebenen Verbindungen, d.h. die phosphororganische Verbindungen nach den Formeln (I) bis (XI) und Ester und A ide derselben an der Phosphinogruppe sowie Salze derselben zeigen eine starke zytotoxische Wirksamkeit gegenüber ein- und mehrzelligen Parasiten, insbesondere gegenüber den Erregern der Malaria und der Schlafkrankheit. Demgemäß sind die erfindungsgemäßen Verbindungen für die Behandlung von Infektionskrankheiten brauch- bar, die durch Viren, Bakterien, Parasiten und Pilze bei Mensch und Tier verursacht werden. Die Verbindungen sind auch für den Einsatz zur Vorbeugung von Erkrankungen, die durch Viren, Bakterien, Parasiten und Pilze hervorgerufen werden, insbesondere als Malariaprophylaxe und als Schlafkrankheitsprophylaxe geeignet.The connections described, i.e. The organophosphorus compounds of the formulas (I) to (XI) and esters and A ide thereof on the phosphino group and salts thereof show a strong cytotoxic activity against single and multicellular parasites, in particular against the pathogens of malaria and sleeping sickness. Accordingly, the compounds according to the invention can be used for the treatment of infectious diseases which are caused by viruses, bacteria, parasites and fungi in humans and animals. The compounds are also suitable for use in preventing diseases caused by viruses, bacteria, parasites and fungi, in particular as malaria prophylaxis and as sleeping sickness prophylaxis.
Die erfindungsgemäßen phosphororganischen Verbindungen, hierzu gehören im allgemeinen pharmazeutisch verträgliche Salze, Amide, Ester, ein Salz eines solchen Esters, oder aber Verbindungen, die bei Applikation die erfindungsgemäß verwendeten Verbindungen als Stoffwechselprodukte oder Abbauprodukte bereitstellen, auch "Prodrugs" genannt, können für die Verabreichung in irgendeiner geeigneten Weise analog zu bekannten antiinfektiös wir- kenden Mitteln (gemischt mit einem nicht toxischen pharmazeutisch akzeptablen Träger) zubereitet werden.The organophosphorus compounds according to the invention, these generally include pharmaceutically acceptable salts, amides, esters, a salt of such an ester, or compounds which, when applied, provide the compounds used according to the invention as metabolites or degradation products, also called "prodrugs", for administration be prepared in any suitable manner analogous to known anti-infectious agents (mixed with a non-toxic pharmaceutically acceptable carrier).
Zu pharmazeutisch akzeptablen Salzen der Verbindungen gehören Salze, die die erfindungsgemäß verwendeten Verbindungen der Formeln (I) bis (XI) in ihrer protonierten Form als Ammoniumsalz anorganischer oder organischer Säuren, wie Salzsäure, Schwefelsäure, Zitronensäure, Maleinsäure, Fumarsäure, Weinsäure, p-Toluolsulfonsäure, bilden.Pharmaceutically acceptable salts of the compounds include salts which the compounds of the formulas (I) to (XI) used according to the invention in their protonated form as the ammonium salt of inorganic or organic acids, such as hydrochloric acid, sulfuric acid, citric acid, maleic acid, fumaric acid, tartaric acid, p-toluenesulfonic acid , form.
Pharmazeutisch besonders geeignet sind auch die Salze, die durch geeignete Auswahl von X3 und gebildet werden, wie Natriumsalz, Kaliumsalz, Calciumsalz, Ammoniumsalz, Etha- nolaminsalz, Triethylaminsalz, Dicyclohexylaminsalz und Salze einer Aminosäure wie Argi- ninsalz, Asparaginsäuresalz, Glutaminsäuresalz.Also particularly pharmaceutically suitable are the salts which are formed by suitable selection of X 3 and, such as sodium salt, potassium salt, calcium salt, ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt and salts of an amino acid such as arginine salt, aspartic acid salt, glutamic acid salt.
Die Aktivität der Substanzen wird in einem Versuchssystem bestimmt. Dieses System beruht auf die Messung der Inhibition des Wachstums von Bakterien, Parasiten, Viren, Pilze oder Pflanzen in vitro. Hierzu werden zum Teil Versuchsverfahren verwendet, die dem Fachmann bekannt sind.The activity of the substances is determined in a test system. This system is based on the measurement of the inhibition of the growth of bacteria, parasites, viruses, or fungi Plants in vitro. For this purpose, test methods are used which are known to the person skilled in the art.
Zum Beispiel wird zur Bestimmung der Antimalaria- Aktivität die Inhibition des Wachstums von Malaria-Parasiten in Blutkulturen bestimmt. Die Bestimmung der antibakteriellen Aktivität beruht auf Messung der Hemmung von Bakterienwachstum auf Nährböden und in Flüssigkulturen. Die Bestimmung der antiviralen Aktivität beruht auf Inhibition der Bildung von viralen Elementen in Zellkulturen. Die Bestimmung der fungiziden Aktivität beruht auf Inhibition des Wachstums von Pilzen auf Nährböden und in Flüssigkulturen.For example, the inhibition of the growth of malaria parasites in blood cultures is determined to determine the antimalarial activity. The determination of the antibacterial activity is based on measuring the inhibition of bacterial growth on nutrient media and in liquid cultures. The determination of the antiviral activity is based on inhibition of the formation of viral elements in cell cultures. The determination of the fungicidal activity is based on the inhibition of the growth of fungi on nutrient media and in liquid cultures.
Einige der Mikroorganismen, die untersucht werden sollen, können nur in Tiermodellen untersucht werden. Hier werden die entsprechenden Modelle angewendet.Some of the microorganisms to be examined can only be examined in animal models. The corresponding models are used here.
Substanzen, die eine Wirksamkeit in den In-vitro-Meßsystemen zeigen, werden in In-vivo- Modellen weiter untersucht. Die antiparasitäre, antivirale, fungizide oder antibakterielle Aktivität wird in den entsprechenden Tiermodelle weiter evaluiert.Substances that show efficacy in the in vitro measurement systems are further investigated in in vivo models. The antiparasitic, antiviral, fungicidal or antibacterial activity is further evaluated in the corresponding animal models.
Das Screening nach herbizider Aktivität wird mittels Algensystemen und Messung der Isoprenemission von Pflanzen unter Standardbedingungen bestimmt.The screening for herbicidal activity is determined by means of algae systems and measurement of the isoprene emission from plants under standard conditions.
Die pharmazeutisch wirksamen Mittel können in Form von pharmazeutischen Zubereitungen in Dosierungseinheiten zubereitet werden. Dies bedeutet, daß die Zubereitung in Form einzelner Teile, z. B. Tabletten, Dragees, Kapseln, Pillen, Suppositorien und Ampullen vorliegen, deren Wirkstoffgehalt einem Bruchteil oder einem Vielfachen einer Einzeldosis entsprechen. Die Dosierungseinheiten können z. B. 1, 2, 3 oder 4 Einzeldosen oder 1/2, 1/3 oder 1/4 einer Einzeldosis enthalten. Eine Einzeldosis enthält vorzugsweise die Menge Wirkstoff, die bei einer Applikation verabreicht wird und die gewöhnlich einer ganzen, einer halben oder einem Drittel oder einem Viertel einer Tagesdosis entspricht.The pharmaceutically active agents can be prepared in the form of pharmaceutical preparations in dosage units. This means that the preparation in the form of individual parts, e.g. B. tablets, dragees, capsules, pills, suppositories and ampoules are present, the active ingredient content of which corresponds to a fraction or a multiple of a single dose. The dosage units can e.g. B. 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.
Unter nicht-toxischen, inerten pharmazeutisch geeigneten Trägerstoffen sind feste, halbfeste oder flüssige Verdünnungsmittel, Füllstoffe und Formulierungshilfsmittel jeder Art zu verstehen.Non-toxic, inert pharmaceutically suitable carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.
Als bevorzugte pharmazeutische Zubereitungen seien Tabletten, Dragees, Kapseln, Pillen, Granulate, Suppositorien, Lösungen, Suspensionen und Emulsionen, Pasten, Salben, Gele, Cremes, Lotions, Puder und Sprays genannt. Tabletten, Dragees, Kapseln, Pillen und Granulate können den oder die Wirkstoffe neben den üblichen Trägerstoffen enthalten, wie (a) Füll- und Streckmittel, z. B. Stärken, Milchzucker, Rohrzucker, Glukose, Mannit und Kieselsäure, (b) Bindemittel, z. B. Carboxymethylcellulose, Alginate, Gelatine, Polyvinylpyrrolidon, (c) Feuchthaltemittel, z. B. Glycerin, (d) Sprengmittel, z. B. Agar-Agar, Calciumcarbonat und Natriumcarbonat, (e) Lösungsverzögerer, z. B. Paraffin und (f) Resorptionsbeschleuniger, z. B. quarternäre Ammoniumverbindungen, (g) Netzmittel, z. B. Cetylalkohol, Glycerinmono- stearat, (h) Adsorptionsmittel, z. B. Kaolin und Bentonit und (i) Gleitmittel, z. B. Talkum, Calcium- und Magnesiumstearat und feste Polyethylenglykole oder Gemische der unter (a) bis (i) aufgeführten Stoffe.Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations. Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. B. starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. B. carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, (c) Humectants, e.g. B. glycerin, (d) disintegrant, e.g. B. agar-agar, calcium carbonate and sodium carbonate, (e) solution retarders, e.g. B. paraffin and (f) absorption accelerator, e.g. B. quaternary ammonium compounds, (g) wetting agents, e.g. B. cetyl alcohol, glycerol monostearate, (h) adsorbent, for. B. kaolin and bentonite and (i) lubricants, e.g. B. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).
Die Tabletten, Dragees, Kapseln, Pillen und Granulate können mit den üblichen, gegebenenfalls Opakisierungsmittel enthaltenden Überzügen und Hüllen versehen sein und auch so zu- sammengesetzt sein, daß sie den oder die Wirkstoffe nur oder bevorzugt in einem bestimmten Teil des Intestinaltraktes gegebenenfalls verzögert abgeben, wobei als Einbettungsmassen z. B. Polymersubstanzen und Wachse verwendet werden können.The tablets, dragees, capsules, pills and granules can be provided with the customary coatings and casings, optionally containing opacifying agents, and can also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, possibly with a delay, where as embedding z. B. polymer substances and waxes can be used.
Der oder die Wirkstoffe können gegebenenfalls mit einem oder mehreren der oben angegebe- nen Trägerstoffe auch in mikroverkapselter Form vorliegen.The active ingredient (s) can, if appropriate, also be present in microencapsulated form with one or more of the above-mentioned carriers.
Suppositorien können neben dem oder den Wirkstoffen die üblichen wasserlöslichen oder wasserunlöslichen Trägerstoffe enthalten, z. B. Polyethylenglykole, Fette, z. B. Kakaofett und höhere Ester (z. B. C14-Alkohol mit Ci6-Fettsäure) oder Gemische dieser Stoffe.Suppositories can contain the usual water-soluble or water-insoluble excipients in addition to the active ingredient (s), e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat and higher esters (z. B. C 14 alcohol with Ci 6 fatty acid) or mixtures of these substances.
Salben, Pasten, Cremes und Gele können neben dem oder den Wirkstoffen die üblichen Trägerstoffe enthalten, z. B. tierische und pflanzliche Fette, Wachse, Paraffine, Stärke, Tragant, Cellulosederivate, Polyethylenglykole, Silikone, Bentonite, Kieselsäure, Talkum und Zinkoxid oder Gemische dieser Stoffe.Ointments, pastes, creams and gels can contain the usual excipients in addition to the active ingredient (s), e.g. B. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.
Puder und Sprays können neben dem oder den Wirkstoffen die üblichen Trägerstoffe enthalten, z. B. Milchzucker, Talkum, Kieselsäure, Alumimumhydroxid, Calciumsilikat und Polyamidpulver oder Gemische dieser Stoffe. Sprays können zusätzlich die üblichen Treibmittel, z. B. Chlorfluorkohlenwasserstoffe, enthalten.Powder and sprays can contain the usual excipients in addition to the active ingredient (s), e.g. B. milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also use the usual blowing agents, e.g. B. chlorofluorocarbons.
Lösungen und Emulsionen können neben dem oder den Wirkstoffen die üblichen Trägerstoffe wie Lösungsmittel, Lösungsvermittler und Emulgatoren, z. B. Wasser, Ethylalkohol, Isopro- pylalkohol, Ethylcarbonat, Ethylacetat, Benzylalkohol, Benzylbenzoat, Propylenglykol, 1,3- Butylenglykol, Dimethylformamid, Öle, insbesondere Baumwollsaatöl, Erdnußöl, Mais- keimöl, Olivenöl, Ricinusöl und Sesamöl, Glycerin, Glycerinformal, Tetrahydrofurfürylalko- hol, Polyethylenglykole und Fettsäureester des Sorbitans oder Gemische dieser Stoffe enthalten.In addition to the active ingredient (s), solutions and emulsions can contain the usual carriers such as solvents, solubilizers and emulsifiers, e.g. B. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol, glycerol formalin - hol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.
Zur parenteralen Applikation können die Lösungen und Emulsionen auch in steriler und bluti- sotonischer Form vorliegen.For parenteral administration, the solutions and emulsions can also be used in sterile and blood sotonic form.
Suspensionen können neben dem oder den Wirkstoffen die üblichen Trägerstoffe wie flüssige Verdünnungsmittel, z. B. Wasser, Ethylalkohol, Propylenglykol, Suspendiermittel, z. B. ethoxylierte Isostearylalkohole, Polyoxyethylensorbit- und Sorbitan-Ester, mikrokristalline Cellulose, Aluminiummetahydroxid, Bentonit, Agar-Agar und Tragant oder Gemische dieser Stoffe enthalten.In addition to the active ingredient (s), suspensions can contain the usual carriers such as liquid diluents, e.g. B. water, ethyl alcohol, propylene glycol, suspending agents, e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth or mixtures of these substances.
Die genannten Formulierungsformen können auch Färbemittel, Konservierungsstoffe sowie geruchs- und geschmacksverbessernde Zusätze, z. B. Pfefferminzöl und Eukalyptusöl und Süßmittel, z. B. Saccharin, enthalten.The formulation forms mentioned can also contain colorants, preservatives and odor and taste-improving additives, e.g. B. peppermint oil and eucalyptus oil and sweeteners, e.g. B. saccharin.
Die Wirkstoffe der Formeln (I) bis (XI) sollen in den oben aufgeführten pharmazeutischen Zubereitungen, vorzugsweise in einer Konzentration von etwa 0,1 bis 99,5 Gew.-%, vorzugs- weise von etwa 0,5 bis 95 Gew.-%, der Gesamtmischung vorhanden sein.The active compounds of the formulas (I) to (XI) should be present in the pharmaceutical preparations listed above, preferably in a concentration of about 0.1 to 99.5% by weight, preferably about 0.5 to 95% by weight. % of the total mixture.
Die pharmazeutischen Zubereitungen können außer den Verbindungen der Formeln (I) bis (XI) auch weitere pharmazeutische Wirkstoffe enthalten.In addition to the compounds of the formulas (I) to (XI), the pharmaceutical preparations can also contain further active pharmaceutical ingredients.
Die Verbindungen können mit bisher beschriebenen Substanzen mit antibakterieller, antivi- raler, antimyktoischer und antiparasitärer Eigenschaften verwendet werden. Hierzu gehören insbesondere Verbindungen, die bereits in der Therapie Anwendung gefunden haben oder noch angewendet werden. Hierzu sind insbesondere geeignet Stoffe, die in der in der Roten Liste oder in Simon/Stille, Antibiotika-Therapie in Klinik und Praxis, 9. Auflage 1998 Schat- tauer Verlag, oder unter http:/wΛvw.customs.treas.gov/imp-exp/ lings/narmoniz/hrml29.html im Internet mitaufgeführt. Insbesondere können die Derivate mit Penicillin, Benzylpenicillin (Penicillin G), Phenoxypenicillin, Isoxazolylpenicillin, Aminopenicillin, Ampicillin, Amoxi- xillin, Bacampicillin, Carboxypenicillin, Ticarcillin, Temocillin, Acyalaminopenicilline, Az- locillin, Mezlocillin, Piperacillin, Apalcillin, Mecillinam, Cephalosporine, Cefazolin-Gruppe, Cefuroxim-Gruppe, Cefoxitin-Gruppe, Cefoxitin, Cefotetan, Cefmetazol, Latamoxef, Flomo- xef, Cefotaxim-Guppe, Cefozidim, Ceftazidim-Gruppe, Ceftazidim, Cefpirom, Cefepim, übrige Cephalosporine, Cefsulodin, Cefoperazon, Oralcephalosporine der Cefalexin-Gruppe, Loracarbef, Cefprozil, neue Oralcephalosporine mit erweitertem Spektrum, Cefixim, Cefpo- doxim-Proxetil, Cefuroxim-Axetil, Cefetamet, Cefotiam-Hexetil, Cefdinir, Ceftibuten, andere ß-Lactam- Antibiotika, Carbapenem, Imipenem /Cilastatin, Meropenem, Biapenem, Aztreo- nam, ß-Lactamase-Hemmer, Clavulansäure/Amoxicillin, Clavulansäure/Ticarcillin, Sulbac- tam/ Ampicillin, Tazobactam/Piperacillin, Tetracycline, Oxytetracyclin, Rolitetraxyxlin, Doxycyclin, Minocyclin, Chloramphenicol, Aminoglykoside, Gentamicin, Tobramycin, Ne- tilmicin, Amikacin, Spectinomyxin, Makrolide, Erythromycin, Clarithromycin, Ro- xithromycin, Azithromycin, Dirithromycin, Spiramycin, Josamycin, Lincosamide, Clindamycin, Fusidinsäure, Glykopeptid-Antibiotika, Vancomycin, Tecoplanin, Pristinamycin- Derivate, Fosfomycin, Antimikrobielle Folsäureantagonisten, Sulfonamide, Co-Trimoxazol, Trimethoprim, andere Diaminopyrimidin-Sulfonamid-Kombinationen, Nitrofurane, Nitrofu- rantoin, Nitrofurazon, Gyrase-Hemmer (Chinolone), Norfloxacin, Ciprofloxacin, Ofloxacin, Sparfloxacin, Enoxacin, Fleroxacin, Pefloxacin, Lomefloxacin, Bay Y3118, Nitroimidazole, antimykobakterielle Mittel, Isoniazid, Rifampicin, Rifabutin, Ethambutol, Pyrazinamid, Streptomycin, Capreomycin, Prothionamid, Terizidon, Dapson, Clofazimin, Lokalantibiotika, Bacitracin, Tyrothricin, Polymyxine, Neomycin, Kanamycin, Paromomycin, Mupirocin, anti- virale Mittel, Acyclovir, Ganciclovir, Azidothymidin, Didanosin, Zalcitabin, Thiacytidin, Stavudin, Ribavirin, Idoxuridin, Trifluridin, Foscarnet, Amantadin, Interferone, Tibol- Derivate, Proteinase-Inhibitoren, Antimykotika, Polyene, Amphothericin B, Nystatin, Na- tamycin, Azole, Azole zur septischen Therapie, Miconazol, Ketoconazol, Itraconazol, Fluco- nazol, UK- 109.496, Azole für lokale Anwendung, Clotrimazol, Econazol, Isoconazol, Oxico- nazol, Bifonazol, Flucytosin, Griseofulvin, Ciclopiroxolamin, Tolnaftat, Naftifin, Terbinafin, Amorolfin, Antrachinone, Betulinic acid, Semianthrachinone, Xanthone, Naphtoquinone, Aryaminoalkohole, Chinin, Quinidine, Mefloquin, Halofantrin, Chloroquin, Amodiaquin, Acridin, Benzonaphthyridin, Mepacrin, Pyronaridin, Dapson, Sulfonamide, Sulfadoxin, Sul- falene, Trimethoprim, Proguanil, Chlorproguanil, Diaminopyrimidine, Pyrimethamin, Pri- maquin, Aminoquinoline, WR 238,605, Tetracyclin, Doxycyclin, Clindamycin, Norfloxacin, Ciprofloxacin, Ofloxacin, Artemisinin, Dihydroartemisinin, 1 Ob artemether, Arteether, Atr- tesunat, Atovaquon, Suramin, Melarsoprol, Nifurtmox, Stibogluconat-Natrium, Pentamidin, Amphotericin B, Metronidazol, clioquinol, Mebendazol, Niclosamid, Praziquantel, Pyrantel, Tiabendazol, Diethylcarbamazin, Ivermectin, Bithionol, Oxamniquin, Metrifonat, Piperazin, Embonat.The compounds can be used with previously described substances with antibacterial, antiviral, antimyctoic and antiparasitic properties. These include in particular compounds that have already been used in therapy or are still being used. Substances are particularly suitable for this purpose, which are listed in the Red List or in Simon / Stille, Antibiotic Therapy in Clinic and Practice, 9th Edition 1998 Schattauer Verlag, or at http: /wΛvw.customs.treas.gov/imp -exp / lings / narmoniz / hrml29.html listed on the Internet. In particular, the derivatives with penicillin, benzylpenicillin (Penicillin G), phenoxypenicillin, isoxazolylpenicillin, aminopenicillin, ampicillin, amoxixillin, bacampicillin, carboxypenicillin, ticarcillin, temocillin, acyalaminopenicillin, apezlillillin, pezlocillin, azizillillin, azecillinillin - group, cefuroxime group, cefoxitin group, cefoxitin, cefotetan, cefmetazole, latamoxef, flomoxef, cefotaxim group, cefozidim, ceftazidim group, ceftazidim, cefpirom, cefepim, other cefalosporinos, cefalodinosine cefalosine cefalosporin cefalosporin Gruppe, Loracarbef, Cefprozil, new oral cephalosporins with extended spectrum, Cefixim, Cefpodoxim-Proxetil, Cefuroxim-Axetil, Cefetamet, Cefotiam-Hexetil, Cefdinir, Ceftibuten, other ß-Lactam antibiotics, Carbapenememilil, Imipenemil , Aztreonam, ß-lactamase inhibitor, clavulanic acid / amoxicillin, clavulanic acid / ticarcillin, sulbactam / ampicillin, tazobactam / pipe racillin, tetracycline, oxytetracycline, rolitetraxyxlin, doxycycline, minocycline, chloramphenicol, aminoglycosides, gentamicin, tobramycin, netilmicin, amikacin, spectinomyxin, macrolides, erythromycin, clarithromycin, ro- xithromycin, azithromycin, dirithromycin, spiramycin, josamycin, lincosamides, clindamycin, fusidic acid, glycopeptide antibiotics, vancomycin, tecoplanin, pristinamycin derivatives, fosfomycin, antimicrobial folic acid antagonists, sulfonamides, di-trimopyrimidonimone, n-trimopyrimidoximidone combinations, other trimimidopyrimidone, sulfonamides, trimidopyrimidoximidone combinations, trimidopyrimidoximidone combinations, other tri-trimopyrimidoximidone combinations, trimidopyrimidoximidone combinations Nitrofurantoin, nitrofurazone, gyrase inhibitors (quinolones), norfloxacin, ciprofloxacin, ofloxacin, sparfloxacin, enoxacin, fleroxacin, pefloxacin, lomefloxacin, Bay Y3118, nitroimidazole, antimycomycinidine, antimycomycinidin, antimycobidin, rimimobinobenzirin, antimycobidin, antimycobinamine, antimycobin, rimimobinocytin , Prothionamide, terizidone, dapsone, clofazimin, local antibiotics, bacitracin, tyrothricin, polymyxins, neomycin, kanamycin, paromomycin, mupirocin, anti-viral agents, acyclovir, ganciclovir, azidothymidine, didanosine, zalcitidine, thidifinurin, thioditinurin, thiocitidine, ribocinidine, thiidocinidine, thiidocinidine, thiidocinidine, thiocinidine, thiocinidine, thiocinidine, thiocinidine, thiocinidine, thiocinidine, thiocytidine, thiocinidine, thiocinidine, thiocinidine, thiocinidine, thiocinidine, thiocididine, thi, Foscarnet, amantadine, interferons, tibol derivatives, proteinase inhibitors, Antifungals, polyenes, amphothericin B, nystatin, natamycin, azoles, azoles for septic therapy, miconazole, ketoconazole, itraconazole, fluconazole, UK-109,496, azoles for topical use, clotrimazole, econazole, isoconazole, biconazole , Flucytosine, griseofulvin, ciclopiroxolamine, tolnaftat, naftifin, terbinafine, amorolfine, antrachinones, betulinic acid, semianthraquinones, xanthones, naphthoquinones, aryamino alcohols, quinine, quinidines, mefloquine, halofanidinodonone, halofantrinone, chlorine Sulfonamides, sulfadoxin, sulphene, trimethoprim, proguanil, chlorproguanil, diaminopyrimidines, pyrimethamine, primaquine, aminoquinolines, WR 238,605, tetracycline, doxycycline, clindamycin, norfloxacin, ciprofloxacin, ofloxacin, dihydroartinisemin, artemisartininem - tesunate, atovaquone, suramin, melarsoprol, nifurtmox, stibogluconate sodium, pentamidine, amphotericin B, metronidazole, clioquinol, mebendazole, Ni closamid, praziquantel, pyrantel, tiabendazole, diethylcarbamazine, ivermectin, bithionol, oxamniquin, metrifonate, piperazine, embonate.
Ferner können die phosphororganischen Verbindungen in den pharmazeutischen Mitteln in Kombination mit Sulfonamid, Sulfadoxin, Artemisinin, Atovaquon, Chinin, Chloroquin, Hy- droxychloroquin, Mefloquin, Halofantrin, Pyrimethamin, Armesin, Tetracycline, Doxycyclin, Proguanil, Metronidazol, Praziquantil, Niclosamid, Mebendazol, Pyrantel, Tiabendazol, Die- thylcarbazin, Piperazin, Pyrivinum, Metrifonat, Oxamniquin, Bithionol oder Suramin oder mehreren dieser Substanzen vorliegen.Furthermore, the organophosphorus compounds in the pharmaceutical compositions can be used in combination with sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine, chloroquine, hydroxylchloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracycline, doxycycline, proguanil, metronidazole, nicazolantil, prazoliquilil, praziquantilil Pyrantel, tiabendazole, diethyl carbazine, piperazine, pyrivinum, metrifonate, oxamniquin, bithionol or suramin or more of these substances are present.
Die Herstellung der oben aufgeführten pharmazeutischen Zubereitungen erfolgt in üblicher Weise nach bekannten Methoden, z. B. durch Mischen des oder der Wirkstoffe mit dem oder den Trägerstoffen.The pharmaceutical preparations listed above are prepared in a conventional manner by known methods, e.g. B. by mixing the active ingredient (s) with the carrier (s).
Die genannten Zubereitungen können bei Mensch und Tier entweder oral, rektal, parenteral (intravenös, intramuskulär, subkutan), intracisternal, intravaginal, intraperitoneal, lokal (Pu- der, Salbe, Tropfen) und zur Therapie von Infektionen in Hohlräumen, Körperhöhlen angewendet werden. Als geeignete Zubereitungen kommen Injektionslösungen, Lösungen und Suspensionen für die orale Therapie, Gele, Aufgußformulierungen, Emulsionen, Salben oder Tropfen in Frage. Zur lokalen Therapie können ophtalmologische und dermatologische For- mulierungen, Silber- und andere Salze, Ohrentropfen, Augensalben, Puder oder Lösungen verwendet werden. Bei Tieren kann die Aufnahme auch über das Futter oder Trinkwasser in geeigneten Formulierungen erfolgen. Ferner können Gele, Pulver, Puder, Tabletten, Retard- Tabletten, Premixe, Konzentrate, Granulate, Pellets, Tabletten, Boli, Kapseln, Aerosole, Sprays, Inhalate bei Mensch und Tier angewendet werden. Ferner können die erfindungsge- mäßen Verbindungen in andere Trägermaterialien wie zum Beispiel Kunststoffe, (Kunststoffketten zur lokalen Therapie), Kollagen oder Knochenzement eingearbeitet werden.In humans and animals, the preparations mentioned can either be oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, local (PU der, ointment, drops) and for the treatment of infections in cavities, body cavities. Suitable preparations are injection solutions, solutions and suspensions for oral therapy, gels, pour-on formulations, emulsions, ointments or drops. For local therapy, ophthalmic and dermatological formulations, silver and other salts, ear drops, eye ointments, powder or solutions can be used. In animals, suitable formulations can also be ingested through feed or drinking water. Gels, powders, powders, tablets, prolonged-release tablets, premixes, concentrates, granules, pellets, tablets, boluses, capsules, aerosols, sprays, inhalants can also be used in humans and animals. Furthermore, the compounds according to the invention can be incorporated into other carrier materials such as plastics, (plastic chains for local therapy), collagen or bone cement.
Im allgemeinen hat es sich sowohl in der Human- als auch in der Veterinärmedizin als vorteilhaft erwiesen, den oder die Wirkstoffe der Formel (I) bis (XI) in Gesamtmengen von etwa 0,05 bis etwa 600, vorzugsweise 0.5 bis 200 mg/kg Körpergewicht je 24 Stunden,_gegebenen- falls in Form mehrerer Einzelgaben, zur Erzielung der gewünschten Ergebnisse zu verabreichen. Eine Einzelgabe enthält den oder die Wirkstoffe vorzugsweise in Mengen von etwa 1 bis etwa 200, insbesondere 1 bis 60 mg/kg Körpergewicht. Es kann jedoch erforderlich sein, von den genannten Dosierungen abzuweichen, und zwar in Abhängigkeit von der Art und dem Körpergewicht des zu behandelnden Patienten, der Art und der Schwere der Erkrankung, der Art der Zubereitung und der Applikation des Arzneimittels sowie dem Zeitraum bzw. Intervall, innerhalb welchem die Verabreichung erfolgt.In general, both in human and in veterinary medicine, it has proven to be advantageous to use the active ingredient (s) of the formulas (I) to (XI) in total amounts of from about 0.05 to about 600, preferably 0.5 to 200 mg / kg Body weight per 24 hours, _ if necessary in the form of several individual doses, to achieve the desired results. A single dose contains the active ingredient (s) preferably in amounts of about 1 to about 200, in particular 1 to 60 mg / kg body weight. However, it may be necessary to deviate from the doses mentioned, depending on the type and body weight of the patient to be treated, the type and severity of the disease, the type of preparation and administration of the drug, and the period or interval within which the administration takes place.
So kann es in einigen Fällen ausreichend sein, mit weniger als der obengenannten Menge Wirkstoff auszukommen, während in anderen Fällen die oben angeführte Wirkstoffmenge überschritten werden muß. Die Festlegung der jeweils erforderlichen optimalen Dosierung und Applikationsart der Wirkstoffe kann durch den Fachmann aufgrund seines Fachwissens erfolgen. Die erfindungsgemäßen Verbindungen können in den üblichen Konzentrationen und Zubereitungen bei Tieren zusammen mit dem Futter bzw. mit Futterzubereitungen oder mit dem Trinkwasser gegeben werden.In some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient has to be exceeded. The person skilled in the art can determine the optimum dosage and type of application of the active ingredients required on the basis of his specialist knowledge. The compounds according to the invention can be given in the usual concentrations and preparations in animals together with the feed or with feed preparations or with the drinking water.
Ferner können die erfindungsgemäßen Verbindungen hervorragend als Bakterizide, Fungizide und Herbizide bei Pflanzen eingesetzt werden. Furthermore, the compounds according to the invention can be used outstandingly as bactericides, fungicides and herbicides in plants.

Claims

Patentansprüche claims
1. Verwendung von phosphororganischen Verbindungen der allgemeinen Formel (I)1. Use of organophosphorus compounds of the general formula (I)
0 0 ιι n0 0 ιι n
R1-X-A-P-R3 ( I )R1-X-A-P-R3 (I)
I II I
R2 R4 R 2 R 4
in der X ein Phosphoratom oder ein Schwefelatom ist,in which X is a phosphorus atom or a sulfur atom,
wobei A eine C2-9-Alkylenkette ist mit Substituenten, die gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, Hydroxy-, Halogen-, Amino- und Oxogruppen, Cι.26-Alkylresten, Cι. 6-Alkoxyresten, Cι.26-Alkoxy-Cι.26-Alkylresten oder C3.8-Cycloalkyl-(Co-9)-alkylgruppen besteht, wobei jeder Cι.26- Alkylrest und jeder C 1.26- Alkoxyrest verzweigt oder unverzweigt und gesättigt oder mit ein oder mehrerenwherein A is a C 2-9 alkylene chain with substituents that are the same or different and are selected from the group consisting of hydrogen, hydroxyl, halogen, amino and oxo groups, Cι. 26 -alkyl radicals, Cι. 6-alkoxy radicals, Cι. 26 -alkoxy-Cι. 26 -alkyl radicals or C 3 . 8 -Cycloalkyl- (Co- 9 ) alkyl groups, each Cι. 26 - alkyl radical and each C 1 . 26 - Alkoxy radical branched or unbranched and saturated or with one or more
Doppelbindungen ungesättigt sein kann und mit Hydroxy-, Amino-, Halogen- und Oxogruppen substituiert sein kann und sowohl die C3.8-Cycloalkylgruppe als auch die C0.9- Alkylgruppe der C3.8-Cycloalkyl-(C0.9)-alkyl-gruppe ein oder mehrere Doppelbindungen aufweisen können und ein oder zwei Kohlenstoffatome der Cycloalkylgruppe durch Stickstoff-, Sauerstoff- oder Schwefelatome ersetzt sein können, und wobei sowohl dieDouble bonds can be unsaturated and can be substituted with hydroxyl, amino, halogen and oxo groups and both the C 3 . 8- cycloalkyl group as well as the C 0 . 9 - C 3 alkyl group. 8 cycloalkyl (C 0. 9,) alkyl group may have one or more double bonds and one or two carbon atoms of the cycloalkyl group by nitrogen, oxygen or sulfur atoms may be replaced, and both the
Cycloalkylgruppe als auch die Alkylgruppe mit Hydroxy-, Halogen-, Amino-, Oxogruppen mit verzweigten oder unverzweigten Cj.g-Alkylgruppen und C2-9- Alkenylgruppen substituiert sein können, wobei die Ci.g-Alkylgruppen und C2.9- Alkenylgruppen mit Wasserstoff-, Hydroxy-, Amino-, Halogen- und Oxogruppen sub- stituiert sein könnenCycloalkyl group and the alkyl group of hydroxy, halo, amino, oxo groups with branched or unbranched Cj.g alkyl groups and C 2 - 9 - alkenyl groups may be substituted, said Ci.g alkyl groups and C. 2 9 - Alkenyl groups can be substituted with hydrogen, hydroxyl, amino, halogen and oxo groups
in der Ri und R2 gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem C 1.9- Alkyl, substituiertem und unsubstituiertem Hydroxy-Cι-9-alkyl, substituiertem und unsubstituiertem C.-9-Alkenyl, substituiertem und unsubstituiertem .9- Alkinyl, substituiertem und unsubstituiertemin which Ri and R 2 are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted C 1 . 9 - alkyl, substituted and unsubstituted hydroxy- 9 -C alkyl, substituted and unsubstituted C.- 9 alkenyl, substituted and unsubstituted. 9 - alkynyl, substituted and unsubstituted
Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen Rest, Halogen, OXi und OX2 besteht,Aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen, OXi and OX 2 ,
wobei Xi und X2 gleich oder verschieden sind und aus der Gruppe ausgewählt ist, die aus Wasserstoff, substituiertem und unsubstituiertem .9- Alkyl, substituiertem und unsubstituiertem Hydroxy-C.^-alkyl, substituiertem und unsubstituiertem C1-9- Alkenyl, substituiertem und unsubstituiertem .9- Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen Rest besteht,wherein Xi and X 2 are the same or different and is selected from the group consisting of hydrogen, substituted and unsubstituted. 9 - alkyl, substituted and unsubstituted hydroxy-C ^ -. Alkyl, substituted and unsubstituted C 1 - 9 - alkenyl, substituted and unsubstituted. 9 - alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted Cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical,
in der R3 und R4 gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus substituiertem und unsubstituiertem C 1-20- Alkyl, Hydroxy-Cι-26-alkyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem Cι-26-Alkenyl, substituiertem und unsubstituiertem C 1-20- Alkinyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem heterocyclischem Rest, Halogen, OX3 und OX4 besteht,in which R 3 and R 4 are the same or different and are selected from the group consisting of substituted and unsubstituted C 1 -, hydroxy-Cι- 26 alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted alkyl, and - 20 unsubstituted aralkyl, substituted and unsubstituted Cι- 26 alkenyl, substituted and unsubstituted C 1 - 20 - alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, OX 3 and OX4 consists,
wobei X3 und gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem Cι.26- Alkyl, substituiertem und unsubstituiertem Hydroxy-Cι-26-alkyl, substituiertem und unsubstituiertem Aryl, sub- stituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem d-26-where X 3 and are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted Cι. 26 - alkyl, substituted and unsubstituted hydroxy-Cι-6 alkyl 2, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted d- 26 -
Alkenyl, substituiertem und unsubstituiertem C 1-26- Alkinyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem heterocyclischem Rest, einem Silyl, einem Kation einer organischen und anorganischen Base, insbesondere einem Metall der ersten, zweiten oder dritten Hauptgruppe des Periodensystems, Ammo- nium, substituiertem Ammonium und Ammoniumverbindungen, die sich von Ethylendiamin oder Aminosäuren ableiten, besteht. und deren pharmazeutisch akzeptablen Salze, Ester und Amide und Salze der Ester zur Behandlung von infektiösen Prozessen bei Mensch und Tier, die durch Viren, Bakterien, Pilze oder Parasiten hervorgerufen werden und als Fungizid, Bakterizid oder Herbizid bei Pflanzen.Alkenyl, substituted and unsubstituted C 1 - 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 the first, second or third main group of the periodic system, ammonium nium , substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids. and their pharmaceutically acceptable salts, esters and amides 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. Verwendung nach Anspruch 1 , dadurch gekennzeichnet, daß A C3.5-Alkylgruppe ist mit Substituenten, die gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, Hydroxy-, Halogen-, Amino- und Oxogruppen, C.-26-Alkylresten, Ci. 26-Alkoxyresten, Cι.26-Alkoxy-Cι- 6-Alkylresten oder C3-8-Cycloalkyl-(C0-9)- alkylgruppen besteht, wobei jeder C..26- Alkylrest und jeder C.-26-Alkoxyrest verzweigt oder unverzweigt und gesättigt oder mit ein oder mehreren Doppelbindungen ungesättigt sein kann und mit Hydroxy-, Amino-, Halogen- und Oxogruppen substituiert sein kann und sowohl die C3.8-Cycloalkylgruppe als auch die Co-9-Alkylgruppe der C3.8- Cycloalkyl-(C0-9)-alkylgruppe ein oder mehrere Doppelbindungen aufweisen können und ein oder zwei Kohlenstoffatome der Cycloalkylgruppe durch Stickstoff-, Sauerstoff- oder Schwefelatome ersetzt sein können, und wobei sowohl die Cycloalkylgruppe als auch die Alkylgruppe mit Hydroxy-, Halogen-, Amino-, Oxogruppen mit verzweigten oder unverzweigten Cι-9-Alkylgruppen und C2-9- Alkenylgruppen substituiert sein können, wobei die -9-Alkylgruppen und C2-9- Alkenylgruppen mit Wasserstoff-, Hydroxy-, Amino-, Halogen- und Oxogruppen substituiert sein können.2. Use according to claim 1, characterized in that AC 3rd 5 -alkyl group is substituted by substituents which are the same or different and are selected from the group consisting of hydrogen, hydroxyl, halogen, amino and oxo groups, C.- 26 -alkyl radicals, Ci. 26 -alkoxy radicals, Cι.26-alkoxy-Cι- 6 alkyl radicals or C 3-8 cycloalkyl- (C 0 - 9 ) - alkyl groups, each C .. 26 - alkyl radical and each C.- 26 alkoxy radical branched or unbranched and saturated or unsaturated with one or more double bonds and can be substituted with hydroxyl, amino, halogen and oxo groups and both the C 3 . 8- cycloalkyl group as well as the Co- 9- alkyl group of C 3 . 8 - cycloalkyl (C 0 - 9 ) alkyl group can have one or more double bonds and one or two carbon atoms of the cycloalkyl group can be replaced by nitrogen, oxygen or sulfur atoms, and where both the cycloalkyl group and the alkyl group with hydroxy, Halogen, amino, oxo groups can be substituted with branched or unbranched C 9 alkyl groups and C 2 - 9 alkenyl groups can, wherein the 9-alkyl groups and C 2 - 9 - alkenyl groups having from hydrogen, hydroxy, amino, halogen and oxo groups may be substituted.
3. Verwendung nach Anspruch 1 oder Anspruch 2, dadurch gekennzeichnet, daß die phos- phororganischen Verbindungen der Formel (II)3. Use according to claim 1 or claim 2, characterized in that the organophosphorus compounds of the formula (II)
0 0 II II R1-X-A-P-R3 ( I I )0 0 II II R1-X-A-P-R3 (I I)
I 1I 1
CH3 RCH 3 R
entspricht, wobei X, Ri, R3, i wie in Anspruch 1 definiert sind, wobei Ri bevorzugt an dem dem Heteroatom benachbarten C-Atom mit einer Hydroxygruppe substituiert ist.corresponds, wherein X, Ri, R 3 , i are as defined in claim 1, wherein Ri is preferably substituted on the C atom adjacent to the hetero atom with a hydroxyl group.
4. Verwendung nach Anspruch 1 oder Anspruch 2, dadurch gekennzeichnet, daß die phos- phororganischen Verbindungen der Formel (III)4. Use according to claim 1 or claim 2, characterized in that the organophosphorus compounds of the formula (III)
0 00 0
II 11II 11
R1-X-A-P-R3 ( I II )R1-X-A-P-R3 (I II)
1 I OH R4 1 I OH R 4
entspricht, wobei X, Rj, R , * wie in Anspruch 1 definiert sind, wobei Ri bevorzugt eine Acylgruppe, besonders bevorzugt eine Formyl, Acetyl, Propionyl oder Butyryl- gruppe ist.corresponds, where X, Rj, R, * are as defined in claim 1, wherein Ri is preferably an acyl group, particularly preferably a formyl, acetyl, propionyl or butyryl group.
5. Verwendung nach Anspruch 1 oder Anspruch 2, dadurch gekennzeichnet, daß die phosphororganischen Verbindungen aus der Gruppe ausgewählt sind, die aus5. Use according to claim 1 or claim 2, characterized in that the organophosphorus compounds are selected from the group consisting of
0 0 00 0 0
II II 11II II 11
R1-X-C-C-C-C-P-R3 ( IV) ,R1-X-C-C-C-C-P-R3 (IV),
1 I OH R4 1 I OH R 4
0 OH 0 II I II0 OH 0 II I II
R1-X-C-C-C-C-P-R3 (V) ,R1-X-C-C-C-C-P-R3 (V),
1 I R2 R4 1 IR 2 R 4
O O OO O O
R1-X-C-C-C-C- P-R3 (VI ) , I IR 1 -XCCCC- P-R3 (VI), II
R2 OH 0 HO 0R 2 OH 0 HO 0
II I IIII I II
R1-X-C-C-C-C-P-R3 :VIDR1-X-C-C-C-C-P-R3: VID
R2 R4 R 2 R 4
0 0 0 00 0 0 0
II II II IIII II II II
R1-X-C-C-C-C-C- P-R3 (vin ;R1-X-C-C-C-C-C-P-R3 (vin;
I II I
OH OHOH OH
0 OH HO 0 I II0 OH HO 0 I II
Ri-X-C-C-C-C-C-P-R. ( IX)
Figure imgf000022_0001
Ri-XCCCCCPR. (IX)
Figure imgf000022_0001
0 OH 0 00 OH 0 0
II I II II R1-X-C-C-C-C-C-P-R3 (X) undII I II II R1-X-C-C-C-C-C-P-R3 (X) and
R2 OHR 2 OH
0 0 HO 0 II II I II0 0 HO 0 II II I II
Rι-x-c-c-c-c-c-p-R3 (xi :R ι -xcccccpR 3 (xi:
1 I OH R4 1 I OH R 4
besteht, wobei X, Ri, R2, R3 und Rj die in Anspruch 1 definierte Bedeutung haben und die nicht definierten Valenzen der Kohlenstoffatome substituiert sein können, wie es in Anspruch 1 definiert ist.exists, wherein X, Ri, R 2 , R 3 and Rj have the meaning defined in claim 1 and the undefined valences of the carbon atoms can be substituted, as defined in claim 1.
6. Verwendung nach einem der Ansprüche 1 bis 5 zur Behandlung von Infektionen, verursacht durch Bakterien, Viren, Pilze oder ein- oder mehrzellige Parasiten.6. Use according to one of claims 1 to 5 for the treatment of infections caused by bacteria, viruses, fungi or single or multicellular parasites.
7. Verwendung nach Anspruch 6 zur Behandlung von Infektionen, die durch Bakterien hervorgerufen werden, die aus der Gruppe ausgewählt sind, die aus Bakterien der Familie Propionibacteriaceae, insbesondere der Gattung Propionibacterium, insbesondere die Art Propionibacterium acnes. Bakterien der Familie Actinomycetaceae, insbesondere der Gattung Actinomyces, Bakterien der Gattung Corynebacterium, insbesondere die Arten Corynebacterium diphteriae und Corynebacterium pseudotuberculosis, Bakterien der Familie Mycobacteriaceae, der Gattung Mycobacterium, insbesondere die Arten7. Use according to claim 6 for the treatment of infections caused by bacteria selected from the group consisting of bacteria from the Propionibacteriaceae family, in particular the Propionibacterium genus, in particular the Propionibacterium acnes species. Bacteria of the Actinomycetaceae family, in particular of the Actinomyces genus, bacteria of the Corynebacterium genus, in particular the Corynebacterium diphteriae and Corynebacterium pseudotuberculosis species, bacteria of the Mycobacteriaceae family of the Mycobacterium genus, in particular the species
Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis und My- cobacterium avium, Bakterien der Familie Chlamydiaceae, insbesondere die Spezies Chlamydia trachomatis und Chlamydia psittaci, Bakterien der Gattung Listeria, insbesondere die Art Listeria monocytogenes, Bakterien der Art Erysipelthrix rhusiopathiae, Bakterien der Gattung Clostridium, Bakterien der Gattung Yersinia, der Spezies Yersi- nia pestis, Yersinia pseudotuberculosis, Yersinia enterocolitica und Yersinia ruckeri,Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and My- cobacterium avium, bacteria of the Chlamydiaceae family, 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 nia piesestia species , Yersinia pseudotuberculosis, Yersinia enterocolitica and Yersinia ruckeri,
Bakterien der Familie Mycoplasmataceae, der Gattungen Mycoplasma und Ureaplasma, insbesondere die Art Mycoplasma pneumoniae, Bakterien der Gattung Brucella, Bakterien der Gattung Bordetella, Bakterien der Familie Neisseriaceae, insbesondere der Gattungen Neisseria und Moraxella, insbesondere die Arten Neisseria meningitides, Neisseria gonorrhoeae und Moraxella bovis, Bakterien der Familie Vibrionaceae, insbesondere der Gattungen Vibrio, Aeromonas, Plesiomonas und Photobacterium, insbesondere die Arten Vibrio cholerae, Vibrio anguillarum und Aeromonas salmonicidas, Bakterien der Gattung Campylobacter, insbesondere die Arten Campylobacter jejuni, Campylobacter coli und Campylobacter fetus, Bakterien der Gattung Helicobacter, ins- besondere die Art Helicobacter pylori, Bakterien der Familien Spirochaetaeeae und derBacteria of the Mycoplasmataceae family, 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 gaxorrellaeae Bacteria of the Vibrionaceae family, in particular the Vibrio, Aeromonas, Plesiomonas and Photobacterium genera, in particular the Vibrio cholerae, Vibrio anguillarum and Aeromonas salmonicidas species, Campylobacter bacteria, in particular the Campylobacter jejuni species, Campylobacter coli and Campylobacter fetus, bacteria of the genus , especially the Helicobacter pylori species, bacteria of the Spirochaetaeeae and
Leptospiraceae, insbesondere der Gattungen Treponema, Borrelia und Leptospira, insbesondere Borrelia burgdorferi, Bakterien der Gattung Actinobacillus, Bakterien der Familie Legionellaceae, der Gattung Legionella, Bakterien der Familie Rickettsiaceae und Familie Bartonellaceae, Bakterien der Gattungen Nocardia und Rhodococcus, Bakterien der Gattung Dermatophilus, Bakterien der Familie Pseudomonadaceae, insbesondere der Gattungen Pseudomonas und Xanthomonas, Bakterien der Familie Enter- obacteriaceae, insbesondere der Gattungen Escherichia, Klebsiella, Proteus, Providen- cia, Salmonella, Serratia und Shigella, Bakterien der Familie Pasteurellaceae, insbesondere der Gattung Haemophilus, Bakterien der Familie Micrococcaceae, insbesondere der Gattungen Micrococcus und Staphylococcus, Bakterien der Familie Streptococca- ceae, insbesondere der Gattungen Streptococcus und Enterococcus und Bakterien der Familie Bacillaceae, insbesondere der Gattungen Bacillus und Clostridium besteht, und bei der Helicobacter-Eradikationstherapie bei Ulcera des Magendarmtraktes.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, Bacteria, and Rhodilungus deratocungia and Rhodocungia and Rhodocungia the family Pseudomonadaceae, in particular the genera Pseudomonas and Xanthomonas, bacteria of the family Enterobacteriaceae, in particular the genera Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia and Shigella, bacteria of the family Pasteurellaceae, in particular the genus Haemophilus, bacteria of the family Micrococcaceae, in particular of the genera Micrococcus and Staphylococcus, bacteria of the Streptococceae family, in particular of the genera Streptococcus and Enterococcus and bacteria of the Bacillaceae family, in particular of the genera Bacillus and Clostridium, and in d he Helicobacter eradication therapy for ulcers of the gastrointestinal tract.
Verwendung nach Anspruch 6 zur Behandlung von Infektionen, die durch Viren hervorgerufen werden, die aus der Gruppe ausgewählt sind, die aus Viren der Gattung Par- voviridae, insbesondere Parvoviren, Dependoviren, Densoviren, Viren der Gattung Adenoviridae, insbesondere Adenoviren, Mastadenoviren, Aviadenoviren, Viren der Gattung Papovaviridae, insbesondere Papovaviren, insbesondere Papillomaviren (soge- nannte Warzenviren), Polyomaviren, insbesondere JC-Virus, BK-Virus, und Miopapo- vaviren, Viren der Gattung Herpesviridae, insbesondere Herpes-Simplex- Viren, der Va- rizellen/Zoster-Viren, menschlicher Zytomegalievirus, Epstein-Barr- Viren, humanes Herpesvirus 6, humanes Herpesvirus 7, humanes Herpesvirus 8, Viren der Gattung Poxviridae, insbesondere Pockenviren, Orthopox- Parapox-, Molluscum-Contagiosum- Virus, Aviviren, Capriviren, Leporipoxviren, primär hepatotropen Viren, insbesondere Hepatitisviren, wie Hepatitis-A- Viren, Hepatitis-B-Viren, Hepatitis-C-Viren, Hepatitis- D-Viren, Hepatitis-E-Viren, Hepatitis-F- Viren, Hepatits-G- Viren, Hepadnaviren, insbesondere sämtliche Hepatitisviren, wie Hepatitis-B -Virus, Hepatitis-D- Viren, Viren der Gattung Picornaviridae, insbeondere Picornaviren, alle Enteroviren, alle Polioviren, alleUse according to claim 6 for the treatment of infections caused by viruses selected from the group consisting 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 (so-called wart viruses), polyomaviruses, in particular JC virus, BK virus, and miopapovaviruses, viruses of the genus Herpesviridae, in particular herpes simplex virus, of the varicella / Zoster viruses, human cytomegalovirus, Epstein-Barr viruses, human herpes virus 6, human herpes virus 7, human herpes virus 8, viruses of the genus Poxviridae, especially smallpox viruses, Orthopox- Parapox-, Molluscum-Contagiosum- Virus, aviviruses, capriviruses, leporipox viruses, primarily hepatotropic viruses, especially hepatitis viruses, such as hepatitis A viruses, hepatitis B viruses, hepatitis C viruses, hepatitis D viruses, hepatitis E viruses, hepatitis F viruses Viruses, hepatits G viruses, hepadnaviruses, in particular all hepatitis viruses, such as hepatitis B virus, hepatitis D viruses, viruses of the Picornaviridae genus, in particular Picornaviruses, all enteroviruses, all polioviruses, all
Coxsackieviren, alle Echoviren, alle Rhinoviren, Hepatitis-A- Virus, Aphthoviren, Viren der Gattung Calciviridae, insbesondere Hepatitis-E-Viren, Viren der Gattung Reoviri- dae, insbesondere Reoviren, Orbiviren, Rotaviren, Viren der Gattung Togaviridae, insbesondere Togaviren, Alphaviren, Rubiviren, Pestiviren, Rubellavirus, Viren der Gat- tung Flaviviridae, insbesondere Flaviviren, FSME -Virus, Hepatitis-C-Virus, Viren derCoxsackieviruses, 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 Togaviren, in particular Togaviridae Alphaviruses, rubiviruses, pestiviruses, rubella virus, viruses of the genus Flaviviridae, in particular flaviviruses, TBE virus, hepatitis C virus, viruses of the
Gattung Orthomyxoviridae, insbesondere Influenzaviren, Viren der Gattung Paramyxo- viridae, insbesondere Paramyxoviren, Morbillivirus, Pneumovirus, Masernvirus, Mumpsvirus, Viren der Gattung Rhabdoviridae, insbesondere Rhabdoviren, Rabiesvi- rus, Lyssavirus, viskuläres Stomatitisvirus, Viren der Gattung Coronaviridae, insbeson- dere Coronaviren, Viren der Gattung Bunyaviridae, insbesondere Bunyaviren, Nairovi- rus, Phlebovirus, Uukuvirus, Hantavirus, Hantaanvirus, Viren der Gattung Arenaviri- dae, insbesondere Arenaviren, lymphozytäres Choriomeningitis- Virus, Viren der Gattung Retroviridae, insbesondere Retroviren, alle HTL-Viren, humanes T-cell Leukämievirus, Oncornaviren, Spumaviren, Lentiviren, alle HI- Viren, Viren der Gattung Filoviridae, insbesondere Marburg- und Ebolavirus, Slow- Viren, Prionen, Onkoviren und Leukämieviren besteht.Genus Orthomyxoviridae, in particular influenza viruses, viruses of the genus Paramyxoviridae, in particular Paramyxoviruses, morbillivirus, pneumovirus, measles virus, mumps virus, viruses of the genus Rhabdoviridae, in particular Rhabdoviruses, Rabiesvirus, Styrenon virus virus, virus virus, virus virus, virus virus, virus virus, virus virus, virus virus, virus virus, virus virus, virus virus, virus virus virus, viscous virus virus Viruses of the genus Bunyaviridae, in particular Bunyaviruses, Nairovirus, phlebovirus, uukuvirus, Hantavirus, Hantaan virus, viruses of the genus Arenaviridae, in particular Arena viruses, lymphocytic choriomeningitis virus, viruses of the genus Retroviridae, in particular human T-cell leukemia virus, oncornaviruses, spuma viruses, lentiviruses, all HI viruses, viruses of the Filoviridae genus, in particular Marburg and Ebola viruses, slow viruses, prions, oncoviruses and leukemia viruses.
9. Verwendung nach Anspruch 6 zur Vorbeugung und Behandlung von Infektionen verursacht durch einzellige Parasiten, nämlich Erreger der Malaria, der Schlafkrankheit, der Chagas-Krankheit, der Toxoplasmose, der Amöbenruhr, der Leishmaniosen, der9. Use according to claim 6 for the prevention and treatment of infections caused by unicellular parasites, namely pathogens of malaria, sleeping sickness, Chagas disease, toxoplasmosis, amoebic dysentery, and leishmaniasis
Trichomoniasis, der Pneumozystose, der Balantidiose, der Kryptosporidiose, der Sarko- zystose, der Akantha-möbose, der Naeglerose, der Kokzidiose, der Giardiose und der Lambliose.Trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcomocystosis, Akantha-Möbose, Naeglerose, coccidiosis, giardiosis and lambliosis.
10. Verwendung nach einem der Ansprüche 1 bis 9 in einem pharmazeutischen Präparat, dadurch gekennzeichnet, daß das pharmazeutische Präparat einen wirksamen Gehalt an zumindest einer phosphororganischen Verbindung nach einem der Ansprüche 1 bis 5 zusammen mit einem pharmazeutisch akzeptablen Träger.10. Use according to one of claims 1 to 9 in a pharmaceutical preparation, characterized in that the pharmaceutical preparation has an effective content of at least one organophosphorus compound according to one of claims 1 to 5 together with a pharmaceutically acceptable carrier.
11. Verwendung nach Anspruch 10, dadurch gekennzeichnet, daß das pharmazeutische Präparat mindestens einen weiteren pharmazeutischen Wirkstoff enthält.11. Use according to claim 10, characterized in that the pharmaceutical preparation contains at least one further pharmaceutical active ingredient.
12. Verwendung nach einem der Ansprüche 10 oder 11, dadurch gekennzeichnet, daß das pharmazeutische Präparat einen oder mehrere Bestandteile der Gruppe, die aus Sulfo- namid, Sulfadoxin, Artemisinin, Atovaquon, Chinin, Chloroquin, Hydroxychloroquin, Mefloquin, Halofantrin, Pyrimethamin, Armesin, Tetracycline, Doxycyclin, Proguanil, Metronidazol, Praziquantil, Niclosamid, Mebendazol, Pyrantel, Tiabendazol, Die- thylcarbazin, Piperazin, Pyrivinum, Metrifonat, Oxamniquin, Bithionol und Suramin besteht.12. Use according to one of claims 10 or 11, characterized in that the pharmaceutical preparation comprises one or more constituents of the group consisting of sulfo- namid, sulfadoxin, artemisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracycline, doxycycline, proguanil, metronidazole, praziquantil, niclosamide, mebendazole, pyrantel, mifloinazonifone, pyrantel, tiabendazonazine, Oxamniquin, Bithionol and Suramin exist.
13. Verwendung nach einem der Ansprüche 1 1 bis 12, dadurch gekennzeichnet, daß das pharmazeutische Präparat einen oder mehrere Bestandteile der Gruppe, die aus Penicillin, Benzylpenicillin (Penicillin G), Phenoxypenicillin, Isoxazolylpenicillin, Aminope- nicillin, Ampicillin, Amoxixillin, Bacampicillin, Carboxypenicillin, Ticarcillin, Temo- cillin, Acyalaminopenicilline, Azlocillin, Mezlocillin, Piperacillin, Apalcillin, Mecilli- nam, Cephalosporine, Cefazolin-Gruppe, Cefuroxim-Gruppe, Cefoxitin-Gruppe, Cefo- xitin, Cefotetan, Cefmetazol, Latamoxef, Flomoxef, Cefotaxim-Gruppe, Cefozidim, Ceftazidim-Gruppe, Ceftazidim, Cefpirom, Cefepim, übrige Cephalosporine, Cefsulo- din, Cefoperazon, Oralcephalosporine der Cefalexin-Gruppe, Loracarbef, Cefprozil, neuen Oralcephalosporinen mit erweitertem Spektrum, Cefixim, Cefpodoxim-Proxetil, Cefuroxim-Axetil, Cefetamet, Cefotiam-Hexetil, Cefdinir, Ceftibuten, andere ß-Lactam- Antibiotika, Carbapenem, Imipenem /Cilastatin, Meropenem, Biapenem, Aztreonam, ß- Lactamase-Hemmer, Clavulansäure/Amoxicillin, Clavulansäure/Ticarcillin, Sulbac- tarn/ Ampicillin, Tazobactam/Piperacillin, Tetracycline, Oxytetracyclin, Rolitetraxyxlin,13. Use according to one of claims 1 1 to 12, characterized in that the pharmaceutical preparation comprises one or more constituents from the group consisting of penicillin, benzylpenicillin (penicillin G), phenoxypenicillin, isoxazolylpenicillin, aminopenicillin, ampicillin, amoxixillin, bacampicillin, Carboxypenicillin, Ticarcillin, Temocillin, Acyalaminopenicilline, Azlocillin, Mezlocillin, Piperacillin, Apalcillin, Mecillinam, Cephalosporine, Cefazolin Group, Cefuroxim Group, Cefoxitin Group, Cefoxetefoxoxinin, Cefotoxefanoxoxinin, Cefotoxefinoxoxinin, Cefotoxefinoxoxinin, Cefotoxefinoxoxinin, Cefotoxefinoxoxinin, Cefotoxefinoxoxininoxoxininoxoxininoxoxinoxoxinin group Cefozidim, ceftazidime group, ceftazidime, cefpirome, cefepime, other cephalosporins, Cefsulo- din, cefoperazone, Oralcephalosporine the cephalexin group, loracarbef, cefprozil, new Oralcephalosporinen extended spectrum, cefixime, cefpodoxime proxetil, cefuroxime axetil, cefetamet , Cefotiam-hexetil, cefdinir, ceftibutene, other ß-lactam antibiotics, carbapenem, imipenem / cilastatin, meropenem, biapenem, Aztreonam, ß-lactamase inhibitor, clavulanic acid / amoxicillin, clavulanic acid / ticarcillin, sulbacarne / ampicillin, tazobactam / piperacillin, tetracycline, oxytetracycline, rolitetraxyxlin,
Doxycyclin, Minocyclin, Chloramphenicol, Aminoglykoside, Gentamicin, Tobramycin, Netilmicin, Amikacin, Spectinomyxin, Makrolide, Erythromycin, Clarithromycin, Ro- xithromycin, Azithromycin, Dirithromycin, Spiramycin, Josamycin, Lincosamide, Clindamycin, Fusidinsäure, Glykopeptid-Antibiotika, Vancomycin, Tecoplanin, Pristi- namycin-Derivate, Fosfomycin, Antimikrobielle Folsäureantagonisten, Sulfonamide,Doxycycline, xithromycin minocycline, chloramphenicol, aminoglycosides, gentamicin, tobramycin, netilmicin, amikacin, Spectinomyxin, macrolides, erythromycin, clarithromycin, Ro, azithromycin, dirithromycin, spiramycin, josamycin, lincosamides, clindamycin, fusidic acid, glycopeptide antibiotics, vancomycin, Tecoplanin, Pristaminomycin derivatives, fosfomycin, antimicrobial folic acid antagonists, sulfonamides,
Co-Trimoxazol, Trimethoprim, andere Diaminopyrimidin-Sulfonamid-Kombinationen, Nitrofurane, Nitrofurantoin, Nitrofurazon, Gyrase-Hemmer (Chinolone), Norfloxacin, Ciprofloxacin, Ofloxacin, Sparfloxacin, Enoxacin, Fleroxacin, Pefloxacin, Lomeflox- acin, Bay Y3118, Nitroimidazole, antimykobakterielle Mittel, Isoniazid, Rifampicin, Rifabutin, Ethambutol, Pyrazinamid, Streptomycin, Capreomycin, Prothionamid, Teri- zidon, Dapson, Clofazimin, Lokalantibiotika, Bacitracin, Tyrothricin, Polymyxine, Neomycin, Kanamycin, Paromomycin, Mupirocin, antivirale Mittel, Acyclovir, Gan- ciclovir, Azidothymidin, Didanosin, Zalcitabin, Thiacytidin, Stavudin, Ribavirin, Idoxu- ridin, Trifluridin, Foscarnet, Amantadin, Interferone, Tibol-Derivate, Proteinase- Inhibitoren, Antimykotika, Polyene, Amphothericin B, Nystatin, Natamycin, Azole,Co-trimoxazole, trimethoprim, other diaminopyrimidine-sulfonamide combinations, nitrofurans, nitrofurantoin, nitrofurazone, gyrase inhibitors (quinolones), norfloxacin, ciprofloxacin, ofloxacin, sparfloxacin, enoxacin, fleroxacinimidolimidominoximine, lefloxacoxin, pef Medium, isoniazid, rifampicin, rifabutin, ethambutol, pyrazinamide, streptomycin, capreomycin, prothionamide, terizidon, dapson, clofazimin, local antibiotics, bacitracin, tyrothricin, polymyxine, neomycin, kanamycin, parominomycine, antiririr, mir , Azidothymidine, didanosine, zalcitabine, thiacytidine, stavudine, ribavirin, idoxuridine, trifluridine, foscarnet, amantadine, interferons, tibol derivatives, proteinase inhibitors, antifungals, polyenes, amphothericin B, nystole, natamycin, azamycin
Azole zur septischen Therapie, Miconazol, Ketoconazol, Itraconazol, Fluconazol, UK- 109.496, Azole für lokale Anwendung, Clotrimazol, Econazol, Isoconazol, Oxiconazol, Bifonazol, Flucytosin, Griseofulvin, Ciclopiroxolamin, Tolnaftat, Naftifin, Terbinafin, Amorolfin, Antrachinone, Betulinic acid, Semianthrachinone, Xanthone, Naphtoquino- ne, Aryaminoalkohole, Chinin, Quinidine, Mefloquin, Halofantrin, Chloroquin, Amo- diaquin, Acridin, Benzonaphthyridin, Mepacrin, Pyronaridin, Dapson, Sulfonamide, Sulfadoxin, Sulfalene, Trimethoprim, Proguanil, Chlorproguanil, Diaminopyrimidine, Pyrimethamin, Primaquin, Aminoquinoline, WR 238,605, Tetracyclin, Doxycyclin, Clindamycin, Norfloxacin, Ciprofloxacin, Ofloxacin, Artemisinin, Dihydroartemisinin, 1 Ob Artemether, Arteether, Artesunat, Atovaquon, Suramin, Melarsoprol, Nifürtmox, Stibogluconat-Natrium, Pentamidin, Amphotericin B, Metronidazol, clioquinol, Mebendazol, Niclosamid, Praziquantel, Pyrantel, Tiabendazol, Diethylcarbamazin, Iver- mectin, Bithionol, Oxamniquin, Metrifonat, Piperazin, Embonat besteht. Azoles for septic therapy, miconazole, ketoconazole, itraconazole, fluconazole, UK-109,496, azoles for topical application, clotrimazole, econazole, isoconazole, oxiconazole, bifonazole, flucytosine, griseofulvin, ciclopiroxolamine, tolnaftate, naftifine, terbinafine, amorolfine, anthraquinones, Betulinic acid , Semianthraquinones, xanthones, naphtoquino ne, aryamino alcohols, quinine, quinidines, mefloquine, halofantrine, chloroquine, amodiaquine, acridine, benzonaphthyridine, mepacrine, pyronaridine, dapsone, sulfonamides, sulfadoxine, sulfalene, trimethoprim, proguanil, chlorproguanil, diaminopethinoquinoline, pyraminarimine, diaminopyrinoquinoline, pyraminarimine, pyraminimine, pyraminimine, 23, aminopyrimine, prinimine, aminopyrimine , tetracycline, doxycycline, clindamycin, norfloxacin, ciprofloxacin, ofloxacin, artemisinin, dihydroartemisinin, 1 Whether artemether, arteether, artesunate, atovaquone, suramin, melarsoprol, Nifürtmox, stibogluconate-sodium, pentamidine, amphotericin B, metronidazole, clioquinol, mebendazole, niclosamide, Praziquantel, pyrantel, tiabendazole, diethylcarbamazine, ivermectin, bithionol, oxamniquin, metrifonate, piperazine, embonate.
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US10463680B2 (en) 2015-05-29 2019-11-05 UNION therapeutics A/S Halogenated salicylanilides for treating clostridium infections
US10758553B2 (en) 2014-09-12 2020-09-01 UNION therapeutics A/S Antibacterial use of halogenated salicylanilides
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

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WO2004085448A2 (en) * 2003-03-19 2004-10-07 Genzyme Corporation Unsaturated phosphinyl-phosphonate phosphate transport inhibitors
WO2010108190A1 (en) * 2009-03-20 2010-09-23 University Of Iowa Research Foundation Prenylated bisphosphonates as anti-tuberculosis 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

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10758553B2 (en) 2014-09-12 2020-09-01 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

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HUP0105310A2 (en) 2002-06-29
WO2000044358A3 (en) 2001-03-15
EP1146880A2 (en) 2001-10-24
CN1337881A (en) 2002-02-27
DE19902924A1 (en) 2000-08-03
IL144115A0 (en) 2002-05-23
CA2360661A1 (en) 2000-08-03
CZ20012584A3 (en) 2002-01-16
PL349910A1 (en) 2002-10-07
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AU2439900A (en) 2000-08-18
HUP0105310A3 (en) 2002-08-28
NO20013651D0 (en) 2001-07-25

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