[go: up one dir, main page]

EP1115388A1 - Use of organophosphorous compounds for producing medicaments for the therapeutic and prophylactic treatment of infections or as a fungicide, bactericide or herbicide for plants - Google Patents

Use of organophosphorous compounds for producing medicaments for the therapeutic and prophylactic treatment of infections or as a fungicide, bactericide or herbicide for plants

Info

Publication number
EP1115388A1
EP1115388A1 EP99969332A EP99969332A EP1115388A1 EP 1115388 A1 EP1115388 A1 EP 1115388A1 EP 99969332 A EP99969332 A EP 99969332A EP 99969332 A EP99969332 A EP 99969332A EP 1115388 A1 EP1115388 A1 EP 1115388A1
Authority
EP
European Patent Office
Prior art keywords
substituted
viruses
unsubstituted
genus
quinone
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP99969332A
Other languages
German (de)
French (fr)
Inventor
Hassan Jomaa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bioagency AG
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP1115388A1 publication Critical patent/EP1115388A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A01N57/20—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds containing acyclic or cycloaliphatic radicals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P13/00—Herbicides; Algicides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P3/00—Fungicides
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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 manufacture of medicaments for the therapeutic and prophylactic treatment of infections or as a fungicide.
  • the invention relates to the use of organophosphorus compounds and their salts, esters and amides for the production of medicaments for the therapeutic and prophylactic treatment of infections in humans and animals which are caused by viruses, bacteria, fungi and parasites, and their use as a fungicide, bactericide and herbicide in plants.
  • the organophosphorus compounds comprise phosphinoyl derivatives and phosphinic 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 the group of substances defined in claim 1.
  • This group of substances shows both an anti-infectious effect against viruses, certain bacteria, fungi, single and multicellular parasites as well as a fungicidal, bactericidal and herbicidal activity in plants.
  • organophosphorus compounds used according to the invention correspond to the general formula (I):
  • Ri and R 2 are the same or different and are selected from the group consisting of Hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted, unsubstituted aralkyl, substituted, unsubstituted and unsubstituted OX !
  • Xi and X 2 may be the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl , substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical,
  • A is selected from the group consisting of an alkylene radical, an alkenylene radical and a hydroxyalkylene radical,
  • R 3 is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted Cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen,
  • R is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkyl, substituted and unsubstituted, substituted and unsubstituted heterocyclic radical, halogen, OX *, where XL »is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxylalkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted Alkenyl, substituted and unsubstituted alkynyl
  • X ⁇ is selected from the group consisting of hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic radical;
  • R 2 , R 3 , R4 and A have the same meaning as in formula (I).
  • A is particularly preferably a chain of three carbon atoms which connects the nitrogen atom to the phosphorus atom.
  • the three-link chain can be substituted.
  • R acyl, in particular formyl or acetyl
  • R 3 hydrogen, methyl or ethyl
  • A alkylene, alkenylene or hydroxyalkylene.
  • R 2 formyl or acetyl
  • A propylene, propenylene or hydroxypropylene.
  • Acyl is a substituent derived from an acid, such as from an organic carboxylic acid, carbonic acid, carbamic acid or the thioic acid or imidic acid corresponding to the individual acids above, or from an organic sulfonic acid, these acids each being aliphatic, aromatic and / or heterocyclic Include groups in the molecule as well as 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. mesyl, ethanesulfonyl, propanesulfonyl, etc.
  • Alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycar- bonyl, butoxycarbonyl, isobutoxycarbonyl etc.
  • Alkyl carbamoyl e.g. methyl carbamoyl etc.
  • N-alkyl thiocarbamoyl e.g. (N-methyl) thiocarbamoyl etc.
  • Alkyl carbamimidoyl e.g. methyl carbamimidoyl etc.
  • Alkoxalyl e.g. methoxalyl, ethoxalyl, propoxalyl etc.
  • the aliphatic hydrocarbon part in particular the alkyl group or the alkane radical, can optionally have one or more suitable substituents, such as amino, halogen (for example fluorine, chlorine, bromine, etc.), hydroxy, hydroxyimino, 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.
  • suitable substituents such as amino, halogen (for example fluorine, chlorine, bromine, etc.), hydroxy, hydroxyimino, Carboxy, alkoxy (e.g. methoxy,
  • 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. 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.
  • 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 substituted with hydroxy, hydroxyimino, dihalogenalkanoyloxyimino Aralkanoyl indicated as well
  • Arylthiocarbamoyl e.g. phenylthiocarbamoyl etc.
  • Arylcarbamimidoyl e.g. 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 groups the heterocycle and / or the aliphatic hydrocarbon portion may optionally have one or more suitable substituents, such as the same ones that have been stated to be suitable for alkyl and alkane groups.
  • Alkyl is a straight or branched chain alkyl radical having up to 9 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.
  • Hydroxylalkyl is a straight or branched chain alkyl radical with up to 9 carbons, which has at least one hydroxyl group, preferably one or two hydroxyl groups.
  • Alkenyl includes straight-chain or branched-chain alkenyl groups with up to 9 carbon atoms, such as, for example, vinyl, propenyl (for example 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl, hexenyl .
  • Alkynyl includes straight or branched chain alkynyl groups with up to 9 carbon atoms.
  • Cycloalkyl is preferably an optionally substituted C3-C7-cycloalkyl; possible substituents include Alkyl, alkenyl, alkynyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc.), nitro and the like are suitable.
  • 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.
  • Alkylene includes straight or branched chain alkylene groups which have up to 9 carbon atoms and by the formula
  • n is an integer from 1 to 9, such as methylene, ethylene, trimethylene, methylethylene, tetramethylene, 1-methyltrimethylene, 2-ethylethylene, pentamethylene, 2-methyltetramethylene, isopropylethylene, hexamethylene, and the like; preferred alkylene radicals have up to 4 carbon atoms and radicals with 3 carbon atoms such as e.g. Trimethylene.
  • the hydrogen atoms can be replaced by other substituents, such as halogen radicals.
  • Alkenylene includes straight or branched chain alkenylene groups with up to 9 carbon atoms, which are represented by the formula
  • n is an integer from 2 to 9, e.g. Vinylene, propenylene (e.g. 1-propenylene, 2-propenylene), 1-methyl propenylene, 2-methyl propenylene, butenylene, 2-ethyl propenylene, pentenylene, hexenylene and the like;
  • the alkenylene radical can particularly preferably have up to 5 carbon atoms and in particular 3 carbon atoms such as e.g. 1-propenylene.
  • the hydrogen atoms can be replaced by other substituents, such as halogen radicals.
  • Haldroxyalkylene can include straight or branched chain alkylene radicals which have up to 9 carbon atoms, at least one selected carbon atom being substituted by a hydroxyl group; these radicals can be represented by the formula
  • hydroxyalkylene groups include hy- droxymethylene, hydroxy ethylene (e.g. 1-hydroxyethylene and 2-hydroxyethylene), hydroxytrimethylene (e.g. 1-hydroxytrimethylene, 2-hydroxytrimethylene and 3-hydroxytrimethylene), hydroxytetramethylene (e.g. 2-hydroxytetramethylene), 2-hydroxy-2-methyltrimethylene , Hydroxypentamethylene (eg 2-hydroxy-pentamethylene), Hydroxyhexamethylene (eg 2-Hydroxyhexa-methylene) and the like.
  • a lower hydroxyalkylene with up to 4 carbon atoms and in particular one with 3 carbon atoms such as 2-hydroxytrimethylene is particularly preferred.
  • the hydrogen atoms can be replaced by other substituents, such as halogen radicals.
  • the radicals can preferably be chosen such that esters are formed on the phosphino group.
  • suitable examples of such esters according to formulas (I) and (II) include alkyl esters (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, hexyl ester, etc.);
  • Aralkyl esters (benziesters, phenethyl esters, benzhydryl esters, trityl esters, etc.);
  • Aryl esters e.g. phenyl esters, tolyl esters, naphthyl esters, etc.
  • Aroyl alkyl esters e.g. phenacyl esters etc.
  • silyl esters e.g. from 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 salt compounds of the organophosphorus compounds with organic or inorganic bases e.g. 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 e.g. arginine salt, aspartic acid salt, glutamic acid salt etc.
  • the compounds of the formulas (I) or (II) used according to the invention can be 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.
  • the compounds of the formulas (I) or (IT) used according to the invention allow, for example for double-containing or chiral groups R 1, R 2 , R 3 , Rt, Xi, X 2 or A, the occurrence of spatial isomers.
  • the use of the compounds according to the invention includes all spatial isomers both as pure substances and in the form of their mixtures.
  • 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
  • a combination 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 for combination preparations with other anti-infectives.
  • the active compounds according to the invention can also be used in particular for infections with the following viruses:
  • Parvoviridae Parvoviruses, Dependovire, Densoviruses, Adenoviridae: Adenoviruses, Mastadeviruses, Aviadenoviruses, Papovaviridae: Papovaviruses, in particular Papillomaviruses (so-called Wartsviruses), Polyomaviruses, in particular JC-Virus, Herpesviruses, and Herpesviruses, and Herpesviruses, and Herpesviruses, and Herpesviruses, and Herpesviruses, and 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: pox viruses, Orthopox, Parapox, Molluscum -Contagiosum virus, avivire,
  • organophosphorus compounds used according to the invention are therefore suitable for combating the following viral infections:
  • the connections described, i.e. the organophosphorus compounds of the formula (I) and (II) and esters and amides 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 used in the present invention are useful for the treatment of infectious diseases 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 used 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 those Administration can 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) and (II) used 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.
  • the salts which are formed by a suitable selection of L 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, are also particularly pharmaceutically suitable.
  • 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, fungi or plants in vitro.
  • test methods are used which are known to the person skilled in the art.
  • the inhibition of malaria parasite growth in blood cultures is determined to determine antimalaria 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.
  • 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, dragees, capsules, pills and granules latex can contain the active ingredient (s) in addition to the usual carriers, such as (a) bulking agents and extenders, e.g. B starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g.
  • cellulose carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, (c) humectants, e.g. B-Glyce ⁇ n, (d) disintegrant, eg agar-agar, calcium carbonate and sodium carbonate, (e) solution retarder, eg paraffin and (f) absorption accelerator, eg quaternary ammonium compounds, (g) wetting agent, eg cetyl alcohol, glycerol monostearate , (h) adsorbents, e.g. 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)
  • 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 compounds such as 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 carrier substances specified above
  • Suppositories can contain the usual water-soluble or water-insoluble carrier substances in addition to the active substance or substances, e.g. B polyethylene glycols, fats, e.g. B cocoa fat and higher esters (e.g. C 14 alcohol with C 16 fatty acid) or mixtures of these substances
  • ointments, pastes, creams and gels can contain the usual carrier substances, e.g. animal and vegetable fats, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances
  • carrier substances e.g. animal and vegetable fats, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances
  • powders and sprays can contain the usual carrier substances, e.g. milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances.
  • Sprays can additionally contain the usual blowing agents, e.g. chlorofluorocarbons
  • Solutions and emulsions can in addition to the active ingredient (s), 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, in particular cottonseedol, peanut oil, corn oil, olive oil, ricinusol and sesamol, glycerol, glyceryl formalin hol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances th.
  • solvents e.g. B water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, di
  • solutions and emulsions can also be in sterile and blood-isotonic 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) and (II) should be in the pharmaceutical preparations listed above, preferably in a concentration of about 0.1 to 99.5% by weight, preferably of 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: /www.customs.treas.gov/imp -exp / rulings / harmoniz / 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 be used in humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally, locally (powder, ointment, drops) and for the therapy 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 used 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) and (II) 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 single 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 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 used according to the invention can be used excellently as bactericides, fungicides and herbicides in plants.

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Plant Pathology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Environmental Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Epidemiology (AREA)
  • Dentistry (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Agronomy & Crop Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to the use of organophosphorous compounds of general formula (I) for producing medicaments for the therapeutic and prophylactic treatment of infections caused by viruses, bacteria, fungi and parasites, in humans and animals, and as a fungicide, bactericide and herbicide for plants.

Description

Verwendung von phosphororganischen Verbindungen zur Herstellung von Arzneimitteln zur therapeutischen und prophylaktischen Behandlung von Infektionen oder als Fungizid. Bakterizid oder Herbizid bei Pflanzen Use of organophosphorus compounds for the manufacture of medicaments for the therapeutic and prophylactic treatment of infections or as a fungicide. Bactericide or herbicide on plants
Die Erfindung betrifft die Verwendung von phosphororganischen Verbindungen und ihren Salzen, Estern und Amiden zur Herstellung von Arzneimitteln 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 und Phosphinsäurederivate.The invention relates to the use of organophosphorus compounds and their salts, esters and amides for the production of medicaments for the therapeutic and prophylactic treatment of infections in humans and animals which are caused by viruses, bacteria, fungi and parasites, and their use as a fungicide, bactericide and herbicide in plants. According to the invention, the organophosphorus compounds comprise phosphinoyl derivatives and phosphinic 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 in Anspruch 1 definierte Stoffgruppe gelöst. Diese Stoffgruppe zeigt sowohl eine antiinfektiöse Wirkung gegen Viren, bestimmte Bakterien, Pilze, ein- und mehrzellige Parasiten als auch eine fungizide, bakterizide und herbizide Wirkung bei Pflanzen.This object is achieved in a completely surprising manner by the group of substances defined in claim 1. This group of substances shows both an anti-infectious effect against viruses, certain bacteria, fungi, single and multicellular parasites as well as a fungicidal, bactericidal and herbicidal activity in plants.
Die erfindungsgemäß verwendeten phosphororganischen Verbindungen entsprechen der allgemeinen Formel (I):The organophosphorus compounds used according to the invention correspond to the general formula (I):
in der Ri und R2 gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsubstituiertem Hydroxyalkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen Rest, Halogen, OX! und OX2 besteht, wobei Xi und X2 gleich oder verschieden sein können und aus der Gruppe ausgewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsubstituiertem Hydroxyalkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen Rest besteht, A aus der Gruppe ausgewählt ist, die aus einem Alkylenrest, einem Alkenylenrest und einem Hydroxyalkylenrest besteht,in which Ri and R 2 are the same or different and are selected from the group consisting of Hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted, unsubstituted aralkyl, substituted, unsubstituted and unsubstituted OX ! and OX 2 , wherein Xi and X 2 may be the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl , substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, A is selected from the group consisting of an alkylene radical, an alkenylene radical and a hydroxyalkylene radical,
R3 aus der Gruppe ausgewählt ist, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsubstituiertem Hydroxyalkyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem he- terocyclischem Rest, Halogen besteht,R 3 is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted Cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen,
Rjaus der Gruppe ausgewählt ist, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsubstituiertem Hydroxyalkyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem he- terocyclischem Rest, Halogen, OX* besteht, wobei XL» aus der Gruppe ausgewählt ist, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsubstituiertem Hydroxylalkyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem heterocyclischem Rest, einem substituierten oder unsubstituierten 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 Ethylen- diamin oder Aminosäuren ableiten, besteht, und deren pharmazeutisch akzeptablen Salze, Ester und Amide und Salze der Ester.R is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkyl, substituted and unsubstituted, substituted and unsubstituted heterocyclic radical, halogen, OX *, where XL »is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxylalkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted Alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, a substituted or unsubstituted silyl, a kati on 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 ethylene diamine or amino acids, and their pharmaceutically acceptable salts, esters and amides and salts the ester.
Insbesondere eignen sich die Verbindungen, die der folgenden Formel (II): Particularly suitable are the compounds of the following formula (II):
entsprechen, wobeicorrespond with
Xι aus der Gruppe ausgewählt ist, die aus Wasserstoff, substituiertem oder unsubstituiertem Acyl, substituiertem oder unsubstituiertem Alkyl, substituiertem oder unsubstituiertem Aryl, substituiertem oder unsubstituiertem Aralkyl, substituiertem oder unsubstituiertem Cycloalkyl, substituiertem oder unsubstituiertem heterocyclischen Rest besteht; R2, R3, R4 und A die gleiche Bedeutung wie in Formel (I) haben.Xι is selected from the group consisting of hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic radical; R 2 , R 3 , R4 and A have the same meaning as in formula (I).
Besonders bevorzugt ist A eine Kette aus drei Kohlenstoffatomen, die das Stickstoffatom mit dem Phosphoratom verbindet. Die dreigliedrige Kette kann substituiert sein.A is particularly preferably a chain of three carbon atoms which connects the nitrogen atom to the phosphorus atom. The three-link chain can be substituted.
Insbesondere sind Verbindungen der Formel (II) bevorzugt, für die R = Acyl, insbesondere ein Formyl oder Acetyl, R3 = Wasserstoff, Methyl oder Ethyl, R» = Wasserstoff, Methyl, Ethyl oder OX* mit = Wasserstoff, Natrium, Kalium, Methyl, Ethyl, X] = H und A = Al- kylen, Alkenylen oder Hydroxyalkylen ist. Besonders gute Ergebnisse werden mit R2 = Formyl oder Acetyl und A = Propylen, Propenylen oder Hydroxypropylen erzielt.In particular, compounds of the formula (II) are preferred for which R = acyl, in particular formyl or acetyl, R 3 = hydrogen, methyl or ethyl, R »= hydrogen, methyl, ethyl or OX * with = hydrogen, sodium, potassium, Is methyl, ethyl, X] = H and A = alkylene, alkenylene or hydroxyalkylene. Particularly good results are achieved with R 2 = formyl or acetyl and A = propylene, propenylene or hydroxypropylene.
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 Carbonsäure, 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, carbonic acid, carbamic acid or the thioic acid or imidic acid corresponding to the individual acids above, or from an organic sulfonic acid, these acids each being aliphatic, aromatic and / or heterocyclic Include groups in the molecule as well as 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:Aliphatic acyl groups are acyl radicals derived from an aliphatic acid, which include the following:
Alkanoyl (z.B. Formyl, Acetyl, Propionyl, Butyryl, Isobutyryl, Valeryl, Isovaleryl, Pivaloyl etc.);Alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl etc.);
Alkenoyl (z. B. Acryloyl, Methacryloyl, Crotonoyl etc.);Alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl etc.);
Alkylthioalkanoyl (z.B. Methylthioacetyl, Ethylthioacetyl etc.)Alkylthioalkanoyl (e.g. methylthioacetyl, ethylthioacetyl etc.)
Alkansulfonyl (z.B. Mesyl, Ethansulfonyl, Propansulfonyl etc.);Alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, etc.);
Alkoxycarbonyl (z.B. Methoxycarbonyl, Ethoxycarbonyl, Propoxycarbonyl, Isopropoxycar- bonyl, Butoxycarbonyl, Isobutoxycarbonyl etc.);Alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycar- bonyl, butoxycarbonyl, isobutoxycarbonyl etc.);
Alkylcarbamoyl (z.B. Methylcarbamoyl etc.);Alkyl carbamoyl (e.g. methyl carbamoyl etc.);
(N-Alkyl)-thiocarbamoyl (z.B. (N-Methyl)-thiocarbamoyl etc.);(N-alkyl) thiocarbamoyl (e.g. (N-methyl) thiocarbamoyl etc.);
Alkylcarbamimidoyl (z.B. Methylcarbamimidoyl etc.);Alkyl carbamimidoyl (e.g. methyl carbamimidoyl etc.);
Oxalo;Oxalo;
Alkoxalyl (z.B. Methoxalyl, Ethoxalyl, Propoxalyl etc.).Alkoxalyl (e.g. methoxalyl, ethoxalyl, propoxalyl etc.).
Bei den obigen Beispielen für aliphatische Acylgruppen kann der aliphatische Kohlenwasserstoffteil, 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, Acy- lamino (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, can optionally have one or more suitable substituents, such as amino, halogen (for example fluorine, chlorine, bromine, etc.), hydroxy, hydroxyimino, 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. Phenylacetyl etc.); Aralkenoyl (z.B. Cinnamoyl etc.); Aryloxyalkanoyl (z.B. Phenoxyacetyl etc.); Arylthioalkanoyl (z.B. Phenylthioacetyl etc.); Arylaminoalkanoyl (z.B. N-Phenylglycyl, etc.);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.);
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.).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.).
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 sowieIn 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 substituted with hydroxy, hydroxyimino, dihalogenalkanoyloxyimino Aralkanoyl indicated as well
Arylthiocarbamoyl (z.B. Phenylthiocarbamoyl etc.);Arylthiocarbamoyl (e.g. phenylthiocarbamoyl etc.);
Arylcarbamimidoyl (z.B. Phenylcarbamimidoyl etc.).Arylcarbamimidoyl (e.g. 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 aufweisen, wie die gleichen, die als geeignet für Alkyl- und Alkangruppen angegeben wurden.In the above examples of heterocyclic acyl groups, the heterocycle and / or the aliphatic hydrocarbon portion may optionally have one or more suitable substituents, such as the same ones that have been stated to be suitable for alkyl and alkane groups.
„Alkyl" ist ein gerad- oder verzweigtkettiger Alkylrest mit bis zu 9 Kohlenstoffatomen, 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 9 carbon atoms, 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 9 Kohlenstoffen, der mindestens eine Hydroxylgruppe aufweist, bevorzugt ein oder zwei Hydroxylgruppen."Hydroxylalkyl" is a straight or branched chain alkyl radical with up to 9 carbons, which has at least one hydroxyl group, preferably one or two hydroxyl groups.
Zu „Alkenyl" gehören -gerad- oder verzweigtkettige Alkenylgruppen mit bis zu 9 Kohlenstoffatomen, wie z.B. Vinyl, Propenyl (z.B. 1-Propenyl, 2-Propenyl), 1-Methylpropenyl, 2- Methylpropenyl, Butenyl, 2-Ethylpropenyl, Pentenyl, Hexenyl."Alkenyl" includes straight-chain or branched-chain alkenyl groups with up to 9 carbon atoms, such as, for example, vinyl, propenyl (for example 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl, hexenyl .
Zu „Alkinyl" gehören gerad- oder verzweigtkettige Alkinylgruppen mit bis zu 9 Kohlenstoffatomen."Alkynyl" includes straight or branched chain alkynyl groups with up to 9 carbon atoms.
Cycloalkyl steht vorzugsweise für ein ggfs. substituiertes C3-C7-Cycloalkyl; als mögliche Substituenten sind u.a. Alkyl, Alkenyl, Alkinyl, Alkoxy (z.B. Methoxy, Ethoxy etc.), Halogen (z.B. Fluor, Chlor, Brom etc.), Nitro und dergleichen geeignet.Cycloalkyl is preferably an optionally substituted C3-C7-cycloalkyl; possible substituents include Alkyl, alkenyl, alkynyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc.), nitro and the like are suitable.
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.
Zu „ Alkylen" gehören gerad- oder verzweigtkettige Alkylengruppen, die bis zu 9 Kohlenstoffatome aufweisen und durch die Formel"Alkylene" includes straight or branched chain alkylene groups which have up to 9 carbon atoms and by the formula
wiedergegeben werden können, in der n eine ganze Zahl von 1 bis 9 ist, wie Methylen, Ethy- len, Trimethylen, Methylethylen, Tetramethylen, 1-Methyltrimethylen, 2-Ethylethylen, Pentamethylen, 2-Methyltetramethylen, Isopropylethylen, Hexamethylen, und dergleichen; bevorzugte Alkylenreste haben bis zu 4 Kohlenstoffatome und besonders bevorzugt werden Reste mit 3 Kohlenstoffatomen wie z.B. Trimethylen. Die Wasserstoffatome können durch andere Substituenten, wie zum Beispiel Halogenreste, ersetzt sein.in which n is an integer from 1 to 9, such as methylene, ethylene, trimethylene, methylethylene, tetramethylene, 1-methyltrimethylene, 2-ethylethylene, pentamethylene, 2-methyltetramethylene, isopropylethylene, hexamethylene, and the like; preferred alkylene radicals have up to 4 carbon atoms and radicals with 3 carbon atoms such as e.g. Trimethylene. The hydrogen atoms can be replaced by other substituents, such as halogen radicals.
Zu „Alkenylen" gehören gerad- oder verzweigtkettige Alkenylengruppen mit bis zu 9 Kohlenstoffatomen, die durch die Formel"Alkenylene" includes straight or branched chain alkenylene groups with up to 9 carbon atoms, which are represented by the formula
wiedergegeben werden können, in der n eine ganze Zahl von 2 bis 9 ist, wie z.B. Vinylen, Propenylen (z.B. 1 -Propenylen, 2-Propenylen), 1-Methylpropenylen, 2-Methylpropenylen, Butenylen, 2-Ethylpropenylen, Pentenylen, Hexenylen und dergleichen; besonders bevorzugt kann der Alkenylenrest bis zu 5 Kohlenstoffatome aufweisen und insbesondere 3 Kohlenstoffatome wie z.B. 1 -Propenylen. Die Wasserstoffatome können durch andere Substituenten, wie zum Beispiel Halogenreste, ersetzt sein.in which n is an integer from 2 to 9, e.g. Vinylene, propenylene (e.g. 1-propenylene, 2-propenylene), 1-methyl propenylene, 2-methyl propenylene, butenylene, 2-ethyl propenylene, pentenylene, hexenylene and the like; the alkenylene radical can particularly preferably have up to 5 carbon atoms and in particular 3 carbon atoms such as e.g. 1-propenylene. The hydrogen atoms can be replaced by other substituents, such as halogen radicals.
Zu „Hydroxyalkylen" können gerad- oder verzweigtkettige Alkylenreste gehören, die bis zu 9 Kohlenstoffatome aufweisen, wobei mindestens ein ausgewähltes Kohlenstoffatom mit einer Hydroxygruppe substituiert ist; diese Reste können durch die Formel"Hydroxyalkylene" can include straight or branched chain alkylene radicals which have up to 9 carbon atoms, at least one selected carbon atom being substituted by a hydroxyl group; these radicals can be represented by the formula
-(CnH2n.z)(OHV- (C n H 2n . Z ) (OHV
wiedergegeben werden, in der n eine ganze Zahl von 1 bis 9 ist und z eine ganze Zahl ist, für die 1 < z < n gilt. Zu geeigneten Beispielen für solche Hydroxyalkylengruppen gehören Hy- droxymethylen, Hydroxy ethylen (z.B. 1-Hydroxyethylen und 2-Hydroxyethylen), Hy- droxytrimethylen (z.B. 1-Hydroxy-trimethylen, 2-Hydroxytrimethylen und 3- Hydroxytrimethylen), Hydroxytetramethylen (z.B. 2-Hydroxytetramethylen), 2-Hydroxy-2- methyltrimethylen, Hydroxypentamethylen (z.B. 2-Hydroxy-pentamethylen), Hydroxyhexa- methylen (z.B. 2-Hydroxyhexa-methylen) und dergleichen. Besonders bevorzugt wird ein niederes Hydroxyalkylen mit bis zu 4 Kohlenstoffatomen und insbesondere ein solches mit 3 Kohlenstoffatomen wie z.B. 2-Hydroxytrimethylen. Die Wasserstoffatome können durch andere Substituenten, wie zum Beispiel Halogenreste, ersetzt sein.are reproduced in which n is an integer from 1 to 9 and z is an integer for which 1 <z <n. Suitable examples of such hydroxyalkylene groups include hy- droxymethylene, hydroxy ethylene (e.g. 1-hydroxyethylene and 2-hydroxyethylene), hydroxytrimethylene (e.g. 1-hydroxytrimethylene, 2-hydroxytrimethylene and 3-hydroxytrimethylene), hydroxytetramethylene (e.g. 2-hydroxytetramethylene), 2-hydroxy-2-methyltrimethylene , Hydroxypentamethylene (eg 2-hydroxy-pentamethylene), Hydroxyhexamethylene (eg 2-Hydroxyhexa-methylene) and the like. A lower hydroxyalkylene with up to 4 carbon atoms and in particular one with 3 carbon atoms such as 2-hydroxytrimethylene is particularly preferred. The hydrogen atoms can be replaced by other substituents, such as halogen radicals.
Vorzugsweise kann der Reste » so gewählt werden, daß Ester an der Phosphinogruppe gebildet werden. Zu geeigneten Beispielen für solche Ester gemäß der Formeln (I) und (II) zählen Alkylester (z.B. Methylester, Ethylester, Propylester, Isopropylester, Butylester, Isobu- tylester, Hexylester etc.);The radicals can preferably be chosen such that esters are formed on the phosphino group. Suitable examples of such esters according to formulas (I) and (II) include alkyl esters (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, hexyl ester, etc.);
Aralkylester (Benzyiester, Phenethylester, Benzhydrylester, Tritylester etc.);Aralkyl esters (benziesters, phenethyl esters, benzhydryl esters, trityl esters, 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.Aryl esters (e.g. phenyl esters, tolyl esters, naphthyl esters, etc.); Aroyl alkyl esters (e.g. 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.
Bevorzugt ist » ein Metall der ersten, zweiten oder dritten Hauptgruppe des Periodensystems, Ammonium, substituiertem 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, Triethylamin- salz, Ethanolaminsalz, Dicyclohexylaminsalz, Ethylendiaminsalz, N,N'- Dibenzylethylendiaminsalz etc.) sowie Salze mit Aminosäuren (z.B. Argininsalz, Asparagin- säuresalz, Glutaminsäuresalz etc.) und dergleichen gebildet.Preferred is 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. That The salt compounds of the organophosphorus compounds with organic or inorganic bases (e.g. 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 ( e.g. arginine salt, aspartic acid salt, glutamic acid salt etc.) and the like.
Die erfindungsgemäß verwendeten Verbindungen gemäß der Formeln (I) oder (II) 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. Die erfindungsgemäß verwendeten Verbindungen der Formeln (I) oder (IT) lassen beispielsweise für Doppelbindungen enthaltende oder chirale Gruppen Ri, R2, R3, Rt, Xi, X2, oder A das Auftreten räumlicher Isomerer zu. Die erfindungsgemäße Verwendung der Verbindungen umfaßt alle räumlichen Isomere sowohl als Reinstoffe als auch in Form ihrer Mischungen.The compounds of the formulas (I) or (II) used according to the invention can be 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. The compounds of the formulas (I) or (IT) used according to the invention allow, for example for double-containing or chiral groups R 1, R 2 , R 3 , Rt, Xi, X 2 or A, the occurrence of spatial isomers. The use of the compounds according to the invention includes all spatial isomers both as pure substances and in the form of their mixtures.
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 einsetzbar: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 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 Leptospiraceae, insbesondere der Gattungen Treponema, Borrelia und Leptospira, insbesondere Borrelia burgdorferi, Bakterien der Gattung Actinobacillus, Bakterien der Familie Legionellaceae, der Gattung Legiondia, Bakterien der Familie Rickettsiaceae und Familie Bartonellaceae, Bakterien der Gattungen Nocardia und Rhodococcus und Bakterien der Gattung Dermatophilus.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 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 Legionellaceae family, Legionellaceae bacteria the Rickettsiaceae family and the Bartonellaceae family, bacteria of the genera Nocardia and Rhodococcus and bacteria of the genus Dermatophilus.
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'Ma- gendarmtraktes.It is also useful in Helicobacter eradication therapy for ulcers of the gastrointestinal tract.
Es können auch Kombination mit einem weiteren Antibiotikum zur Behandlung der obengenannten Erkrankungen eingesetzt werden. Für Kombinationspräparate mit anderen Antiinfek- tiva eignen sich insbesondere Isoniazid, Rifampicin, Ethambutol, Pyrazinamid, Streptomycin, Protionamid und Dapson zur Behandlung der Tuberkulose.A combination 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 for combination preparations with other anti-infectives.
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, Dependovire , 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, Avivire , 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, viskulares Stomatitisvirus, Coronaviridae: Coronaviren, Bunyaviridae: Bunyaviren, Nai- rovirus, Phlebovirus, Uukuvirus, Hantavirus, Hantaanvirus, Arenaviridae: Arenaviren, lym- phozytares Choriomeningitis- Virus, Retroviridae: Retroviren, alle HTL- Viren, humanes T- cell Leukamievirus, Oncornaviren, Spumaviren, Lentiviren, alle HI- Viren, Filoviridae: Marburg- und Ebolavirus, Slow-virus-Infektionen, Prionen, Onkoviren und Leukamieviren.Parvoviridae: Parvoviruses, Dependovire, Densoviruses, Adenoviridae: Adenoviruses, Mastadeviruses, Aviadenoviruses, Papovaviridae: Papovaviruses, in particular Papillomaviruses (so-called Wartsviruses), Polyomaviruses, in particular JC-Virus, Herpesviruses, and Herpesviruses, and Herpesviruses, and Herpesviruses, and 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: pox viruses, Orthopox, Parapox, Molluscum -Contagiosum virus, avivire, caprivirus, leporipox virus, all primarily hepatotropic virus, hepatitis virus: hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus Viruses, hepatitis F viruses, hepatits G viruses, hepadnaviruses: all hepatitis viruses, hepatitis B virus, hepatitis D viruses, Picornaviridae: Picornaviruses, all enteroviruses, all polioviruses, all Coxsackieviruses, all echo viruses, all rhino viruses, hepatitis A virus, aphthoviruses, Calciviridae: Hepatitis E virus, Reoviridae: reovirus, Orbi virus, rotavirus, Togaviridae: togaviruses, alphaviruses, Ru biviren, pestiviruses, rubella virus, Flaviviridae: flavivirus, TBE virus, hepatitis C virus, Orthomyxoviridae: All influenza viruses, Paramyxoviridae: paramyxovirus, morbillivirus, pneumovirus, measles virus, mumps virus, Rhabdoviridae: rhabdovirus, rabies virus, Lyssavi- rus, viskulares stomatitis, Coronaviridae: coronaviruses, Bunyaviridae: Bunya, NAI rovirus, Phlebovirus, uukuvirus, hantavirus, hantaan virus, arenaviridae: arena viruses, lymphocytic choriomeningitis virus, retroviridae: retroviruses, all HTL viruses, human T-cell leukemia virus, oncornaviruses, spumaviruses, lentiviruses, filenoviruses, all Ebola virus, slow virus infections, prions, oncoviruses and leukemia viruses.
Die erfindungsgemaß verwendeten phosphororganischen Verbindungen sind somit zur Bekämpfung folgender viraler Infekte geeignet:The organophosphorus compounds used 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 Epμstein- 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 Immunschwache- 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, progressive multifokale Leukoenzephalopathie, Lymphozytare 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 hamatopoeti- 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-Hamweg-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 hamorrhagisches 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 Epμstein-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 Coxsackieviren 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, progressive multifocal leukoencephalopathy, lymphocytic choriomeningitis), of the gastrointestinal tract (stomatitis, gingivostomatitis, oesophagitis, gastritis, gastroenteritis, diarrhea), of the liver and of the biliary system (hepatitis, cholangitis, hepatocellular carcinoma), the lymphatic tissue (mononucleosis, lymphadenitis), the hamatopoietic system, the genital organs (mumps orchitis), the skin (warts, dermatitis, herpes labialis, cold sores, herpes zoster, herpes zoster, herpes ), the mucous membranes (papillomas, connecting apapillomas, hyperplasias, dysplasias), the cardiovascular system (arteritis, myocarditis, endocarditis, pericarditis), the kidney-hamstring system, the genital organs (anogenital lesions, warts, genital warts, pointed) Condylomas, dysplasias, papillomas, cervical dysplasias, condylomata acuminata, epid ermodysplasia verruciformis), the organs of movement (myositis, myalgia), treatment of foot-and-mouth disease of the ungulates, Colorado tick fever, dengue syndrome, hamorrhagic fever, early Summer meningoencephalitis (TBE) and yellow fever.
Die beschriebenen Verbindungen, d.h. die phosphororganische Verbindungen nach Formel (I) und (II) und Ester und Amide 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 erfindungsgemäß verwendetenen Verbindungen für die Behandlung von Infektionskrankheiten brauchbar, 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 formula (I) and (II) and esters and amides 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 used in the present invention are useful for the treatment of infectious diseases 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 erfindungsgemäß verwendeten 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 wirkenden Mitteln (gemischt mit einem nicht toxischen pharmazeutisch akzeptablen Träger) zubereitet werden.The organophosphorus compounds used 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 those Administration can 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) und (II) 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) and (II) used 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 L gebildet werden, wie Natriumsalz, Kaliumsalz, Calciumsalz, Ammoniumsalz, Ethanolamin- salz, Triethylaminsalz, Dicyclohexylaminsalz und Salze einer Aminosäure wie Argininsalz, Asparaginsäuresalz, Glutaminsäuresalz.The salts which are formed by a suitable selection of L, 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, are also particularly pharmaceutically suitable.
Die Verwendung der oben angegebenen Substanzen ist insbesondere für die Herstellung von Arzneimitteln gegen Bakterienerkrankungen oder zu ihrer Vorbeugung oder für die Herstellung von Herbiziden geeignet.The use of the substances specified above is particularly suitable for the production of medicaments for bacterial diseases or for their prevention or for the production of herbicides.
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. Zum Beispiel wird zur Bestimmung der Antimalaria Aktivität die Inhibition des Wachstums von Malaria Parasiten in Blutkulturen bestimmt.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, fungi or plants in vitro. For this purpose, test methods are used which are known to the person skilled in the art. For example, the inhibition of malaria parasite growth in blood cultures is determined to determine antimalaria activity.
Die Bestimmung der antibakteriellen Aktivität beruht auf Messung der Hemmung von Bakterien Wachstum auf Nährböden und in Flüssigkulturen.The determination of the antibacterial activity is based on measuring the inhibition of bacterial growth on nutrient media and in liquid cultures.
Die Bestimmung der antiviralen Aktivität beruht auf Inhibition der Bildung von viralen Elementen in Zellkulturen.The determination of the antiviral activity is based on inhibition of the formation of viral elements in cell cultures.
Die Bestimmung der füngiziden Aktivität beruht auf Inhibition des Wachstums von Pilzen auf Nährböden und in Flüssigkulturen.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 wir dann die entsprechenden Modelle anwenden.Some of the microorganisms to be examined can only be examined in animal models. We will then apply the corresponding models here.
Substanzen, die eine Wirksamkeit in den in vitro Messsystemen zeigen, weiter in in vivo Modellen weiter untersucht.Substances that show an effectiveness in the in vitro measurement systems are further investigated in in vivo models.
Die antiparasitäre, antivirale, füngizide oder antibakterielle Aktivität wird in den entsprechenden Tiermodelle weiter evaluiert.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 Granu- late können den oder die Wirkstoffe neben den üblichen Tragerstoffen enthalten, wie (a) Full- und Streckmittel, z. B Starken, Milchzucker, Rohrzucker, Glukose, Mannit und Kieselsaure, (b) Bindemittel, z B Carboxymethylcellulose, Alginate, Gelatine, Polyvinylpyrrolidon, (c) Feuchthaltemittel, z. B- Glyceπn, (d) Sprengmittel, z B Agar-Agar, Calciumcarbonat und Natriumcarbonat, (e) Losungsverzogerer, z B Paraffin und (f) Resorptionsbeschleuniger, z B quarternare 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 StoffeTablets, 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, dragees, capsules, pills and granules latex can contain the active ingredient (s) in addition to the usual carriers, such as (a) bulking agents and extenders, e.g. B starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, (c) humectants, e.g. B-Glyceπn, (d) disintegrant, eg agar-agar, calcium carbonate and sodium carbonate, (e) solution retarder, eg paraffin and (f) absorption accelerator, eg quaternary ammonium compounds, (g) wetting agent, eg cetyl alcohol, glycerol monostearate , (h) adsorbents, e.g. 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 zusammengesetzt 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 könnenThe 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 compounds such as polymer substances and waxes can be used
Der oder die Wirkstoffe können gegebenenfalls mit einem oder mehreren der oben angegebenen Tragerstoffe auch in mikroverkapselter Form vorliegenThe active ingredient (s) can, if appropriate, also be present in microencapsulated form with one or more of the carrier substances specified above
Suppositorien können neben dem oder den Wirkstoffen die üblichen wasserlöslichen oder wasserunlöslichen Tragerstoffe enthalten, z. B Polyethylenglykole, Fette, z. B Kakaofett und höhere Ester (z. B C 14- Alkohol mit C16-Fettsaure) oder Gemische dieser StoffeSuppositories can contain the usual water-soluble or water-insoluble carrier substances in addition to the active substance or substances, e.g. B polyethylene glycols, fats, e.g. B cocoa fat and higher esters (e.g. C 14 alcohol with C 16 fatty acid) or mixtures of these substances
Salben, Pasten, Cremes und Gele können neben dem oder den Wirkstoffen die üblichen Tragerstoffe enthalten, z B tierische und pflanzliche Fette, Wachse, Paraffine, Starke, Tragant, Cellulosederivate, Polyethylenglykole, Silikone, Bentonite, Kieselsaure, Talkum und Zinkoxid oder Gemische dieser StoffeIn addition to the active ingredient (s), ointments, pastes, creams and gels can contain the usual carrier substances, e.g. animal and vegetable fats, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances
Puder und Sprays können neben dem oder den Wirkstoffen die üblichen Tragerstoffe enthalten, z B Milchzucker, Talkum, Kieselsaure, Aluminiumhydroxid, Calciumsilikat und Polyamidpulver oder Gemische dieser Stoffe Sprays können zusatzlich die üblichen Treibmittel, z B. Chlorfluorkohlenwasserstoffe, enthaltenIn addition to the active ingredient (s), powders and sprays can contain the usual carrier substances, e.g. milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can additionally contain the usual blowing agents, e.g. chlorofluorocarbons
Losungen und Emulsionen können neben dem oder den Wirkstoffen die üblichen Tragerstoffe wie Losungsmittel, Losungsvermittler und Emulgatoren, z. B Wasser, Ethylalkohol, Isopro- pylalkohol, Ethylcarbonat, Ethylacetat, Benzylalkohol, Benzylbenzoat, Propylenglykol, 1,3- Butylenglykol, Dimethylformamid, Ole, insbesondere Baumwollsaatol, Erdnußöl, Mais- keimol, Olivenöl, Ricinusol und Sesamol, Glycerin, Glycerinformal, Tetrahydrofürfurylalko- hol, Polyethylenglykole und Fettsaureester des Sorbitans oder Gemische dieser Stoffe enthal- ten.Solutions and emulsions can in addition to the active ingredient (s), 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, in particular cottonseedol, peanut oil, corn oil, olive oil, ricinusol and sesamol, glycerol, glyceryl formalin hol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances th.
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 in sterile and blood-isotonic 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) und (II) sollen in den oben aufgeführten pharmazeutischen Zubereitungen, vorzugsweise in einer Konzentration von etwa 0,1 bis 99,5 Gew.-%, vorzugsweise von etwa 0,5 bis 95 Gew.-%, der Gesamtmischung vorhanden sein.The active compounds of the formulas (I) and (II) should be in the pharmaceutical preparations listed above, preferably in a concentration of about 0.1 to 99.5% by weight, preferably of about 0.5 to 95% by weight, of the total mixture.
Die pharmazeutischen Zubereitungen können außer den Verbindungen der Formel (I) und (U) auch weitere pharmazeutische Wirkstoffe enthalten.In addition to the compounds of the formulas (I) and (U), 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:/www.customs.treas.gov/imp-exp/rulings/harmoniz/hrml29.html im Internet mitaufgeführt. Insbesondere können die Derivate mit Penicilline, Benzylpenicillin (Penicillin G), Phenoxypenicilline, Isoxazolylpenicilline, Aminopenicilline, Ampicillin, Amoxixillin, Bacampicillin, Carboxypenicillin, Ticarcillin, Temocillin, Acyalaminopenicilli- ne, Azlocillin, Mezlocillin, Piperacillin, Apalcillin, Mecillinam, Cephalosporine, Cefazolin- Gruppe, Cefüroxim-Gruppe, Cefoxitin-Gruppe, Cefoxitin, Cefotetan, Cefmetazol, Latamoxef, Flomoxef, Cefotaxim-Guppe, Cefozidim, Ceftazidim-Gruppe, Ceftazidim, Cefpirom, Cefe- pim, übrige Cephalosporine, Cefsulodin, Cefoperazon, Oralcephalosporine der Cefalexfn- Gruppe, Loracarbef, Cefprozil, neue Oralcephalosporine mit erweitertem Spektrum, Cefixim, Cefpodoxim-Proxetil, Cefüroxim-Axetil, Cefetamet, Cefotiam-Hexetil, Cefdinir, Ceftibuten, andere ß-Lactam- Antibiotika, Carbapenem, Imipenem /Cilastatin, Meropenem, Biapenem, Aztreonam, ß-Lactamase-Hemmer, Clavulansäure/Amoxicillin, Clavulansäure/Ticarcillin, Sulbactam/Ampicillin, Tazobactam/Piperacillin, Tetracycline, Oxytetracyclin, Rolitetraxyx- lin, Doxycyclin, Minocyclin, Chloramphenicol, Aminoglykoside, Gentamicin, Tobramycin, Netilmicin, Amikacin, Spectinomyxin, Makrolide, Erythromycin, Clarithromycin, Ro- xithromycin, Azithromycin, Dirithromycin, Spiramycin, Josamycin, Lincosamide, Clin- damycin, Fusidinsäure, Glykopeptid-Antibiotika, Vancomycin, Tecoplanin, Pristinamycin- Derivate, Fosfomycin, Antimikrobielle Folsäureantagonisten, Sulfonamide, Co-Trimoxazol, Trimethoprim, andere Diaminopyrimidin-Sulfonamid-Kombinationen, Nitrofürane, Nitrofü- 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, Griseofülvin, Ciclopiroxolamin, Tolnaftat, Naftifin, Terbinafin, Amorolfin, Antrachinone, Betulinic acid, Se ianthrachinone, 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, 10b artemether, Arteether, Atr- tesunat, Atovaquon, Suramin, Melarsoprol, Nifürtmox, 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: /www.customs.treas.gov/imp -exp / rulings / harmoniz / hrml29.html listed on the Internet. In particular, the derivatives with penicillins, benzylpenicillin (Penicillin G), phenoxypenicillins, isoxazolylpenicillins, aminopenicillins, ampicillins, amoxixillins, bacampicillins, carboxypenicillins, ticarcillins, temocillins, acyalaminopenicillins, aplocillinines, pezlocillinines, azlocillinines, azlocillininines, azlocillinines, azlocillinines , Cefüroxim group, cefoxitin group, cefoxitin, cefotetan, cefmetazole, latamoxef, flomoxef, cefotaxime Guppe, Cefozidim, ceftazidime group, ceftazidime, cefpirome, CEFE pim, other cephalosporins, cefsulodin, cefoperazone, Oralcephalosporine the Cefalexfn- group, Loracarbef, Cefprozil, new oral cephalosporins with an extended spectrum, Cefixim, Cefpodoxim-Proxetil, Cefüroxim-Axetil, Cefetamet, Cefotiam-Hexetil, Cefdinir, Ceftibuten, other ß-lactam antibiotics, Carbapenem, Biastem, Enipenememopen, C Lactamase inhibitors, clavulanic acid / amoxicillin, clavulanic acid / ticarcillin, Sulbactam / Ampicillin, Tazobactam / Piperacillin, Tetracycline, Oxytetracyclin, Rolitetraxyx- lin, Doxycyclin, Minocyclin, Chloramphenicol, Aminoglycoside, Gentamicin, Tobramycin, Netilmicin, Amikacin, Spectinomyxin, Makrolide, Dirithromycincinomycinomycinomycinomycinomycinomycinomycinomycinomycinomycinomycinomycinomycinomycinomycinomycinomycinomycinomycincinomycinomycinomycinomycincinomycinomycincinomycinomycincinomycinomycincinomycinomycincinomycinomycincinomycinomycincinomycinomycincinomycinomycincinomycinomycincinomycinomycincinomycinomycincinomycinomycinomycinomycin Josamycin, Lincosamide, Clindamycin, Fusidic Acid, Glycopeptide Antibiotics, Vancomycin, Tecoplanin, Pristinamycin Derivatives, Fosfomycin, Antimicrobial Folic Acid Antagonists, Sulfonamides, Co-Trimoxazole, Trimethoprim, Other Diaminopyrimidine-Sulfonamidofuron, Nitronitrone Combinations, Nitride Gyrase inhibitors (quinolones), norfloxacin, ciprofloxacin, ofloxacin, sparfloxacin, enoxacin, fleroxacin, pefloxacin, lomefloxacin, Bay Y3118, nitroimidazole, antimycobacterial agents, isoniazid, rifampicinidoin, rifampicinidoin, rifampicinidin, rifampicinidin, rifampicinid, rifampicinid, rifampicinid, rifampicinid, rifampicinid, rifampicinid, rifampicinid, rifampin, rifampin, rifampin, rifampin, rifampin, rifampin, rifampin, rifampin, rifampin, rifampin, rifampin, rifampin , Clofazimin, local antibiotics, bacitracin, tyrothricin, polymyxins, Neomycin, kanamycin, paromomycin, mupirocin, anti-viral agents, acyclovir, ganciclovir, azidothymidine, didanosine, zalcitabine, thiacytidine, stavudine, ribavirin, idoxuridine, trifluridine, foscarnet, amantadine, interferons, polyenotinotin, antigenic inhibitor, tibinotinotivate, tibinotinotinotinotinotivate , Amphothericin B, Nystatin, Natamycin, Azole, Azole for septic therapy, Miconazole, Ketoconazole, Itraconazole, Fluconazole, UK-109.496, Azole for topical use, Clotrimazole, Econazole, Isoconazole, Oxico-nazole, Bifonazinol, Flucynazole Griseofülvin, ciclopiroxolamine, tolnaftat, naftifin, terbinafine, amorolfin, antrachinone, betulinic acid, se ianthraquinone, xanthones, naphtoquinone, aryamino alcohols, quinine, quinidine, mefloquine, halofantrine, chloroquinidine, amodonone Sulfadoxin, Sulphene, Trimethoprim, Proguanil, Chlorproguanil, Diaminopyrimidine, Pyrimethamine, Primaquin, Aminoquinoline, WR 238,605, Tetracycline, Doxycycline , Clindamycin, norfloxacin, ciprofloxacin, ofloxacin, artemisinin, dihydroartemisinin, 10b artemether, arteether, atresunate, atovaquone, suramin, melarsoprol, nifürtmox, stibogluconate sodium, pentamidine, metronidazolobenzene, amphotericolazolebm , 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. Die genannten Zubereitungen können bei Mensch und Tier entweder oral, rektal, parenteral (intravenös, intramuskulär, subkutan), intracisternal, intravaginal, intraperitoneal, lokal (Puder, 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 Formulierungen, 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 erfindungsgemäß verwendeten Verbindungen in andere Trägermaterialien wie zum Beispiel Kunststoffe, (Kunststoffketten zur lokalen Therapie), Kollagen oder Knochenzement eingearbeitet werden.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 be used in humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally, locally (powder, ointment, drops) and for the therapy 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 used 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) und (II) in Gesamtmengen von- etwa 0,05 bis etwa 600, vorzugsweise 0,5 bis 200 mg/kg Körpergewicht je 24 Stunden, gegebenenfalls 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, it has proven to be advantageous in both human and veterinary medicine to use the active ingredient (s) of the formulas (I) and (II) 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 single 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.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.
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.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 erfindungsgemäß verwendeten Verbindungen hervorragend als Bakterizide, Fungizide und Herbizide bei Pflanzen eingesetzt werden. Furthermore, the compounds used according to the invention can be used excellently as bactericides, fungicides and herbicides in plants.

Claims

Patentansprüche claims
Verwendung von phosphororganischen Verbindungen der allgemeinen Formel (I)Use of organophosphorus compounds of the general formula (I)
R, 0R, 0
\ II\ II
N-A-P-R3 ( I )N-A-P-R3 (I)
/ I/ I
R2 R4 in der K\ und R2 gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsubstituiertem Hydroxyalkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen Rest, Halogen, und OX2 besteht, wobei Xi und X2 gleich oder verschieden sein können und aus der Gruppe ausgewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsubstituiertem Hydroxyalkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen Rest besteht,R 2 R 4 in which K \ and R 2 are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl , substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen, and OX 2 , wherein Xi and X 2 may be the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl , substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical,
A aus der Gruppe ausgewählt ist, die aus einem Alkylenrest, einem Alkenylenrest und einem Hydroxyalkylenrest besteht,A is selected from the group consisting of an alkylene radical, an alkenylene radical and a hydroxyalkylene radical,
R3 aus der Gruppe ausgewählt ist, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsubstituiertem Hydroxyalkyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem heterocyclischem Rest, Halogen besteht, R»aus der Gruppe ausgewählt ist, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsubstituiertem Hydroxyalkyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem heterocyclischem Rest, Halogen, OX-t besteht, wobei X» aus der Gruppe ausgewählt ist, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsubstituiertem Hydroxylalkyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und unsubstituiertem 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, Ammonium, substituiertem Ammonium und Ammoniumverbindungen, die sich von Ethylendiamin oder Aminosäuren ableiten, besteht, und deren pharmazeutisch akzeptablen Salze, Ester und Salze der Ester oder aber Verbindungen, die bei Applikation die erfindungsgemäß zu verwendenden Verbindungen als Stoffwechselprodukte oder Abbauprodukte bereitstellen, zur Herstellung von Arzneimitteln zur therapeutischen und prophylaktischen Behandlung von Infektionen bei Mensch und Tier, verursacht durch Parasiten, Pilze, Viren und Bakterien, ausgewählt aus der Gruppe, die aus Bakterien der Familie Propionibacteria- ceae, insbesondere der Gattung Propionibacterium, insbesondere die Art Propionibacterium acnes, Bakterien der Familie Actinomycetaceae, insbesondere der Gattung Acti- nomyces, Bakterien der Gattung Corynebacterium, insbesondere die Arten Corynebacterium diphteriae und Corynebacterium pseudotuberculosis, Bakterien der Familie My- cobacteriaceae, der Gattung Mycobacterium, insbesondere die Arten Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis und Mycobacterium 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 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 Bor- detella, 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 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 Rickettsia- ceae und Familie Bartonellaceae, Bakterien der Gattungen Nocardia und Rhodococcus, Bakterien der Gattung Dermatophilus besteht, und als Fungizid, Bakterizid und Herbizid bei Pflanzen.R 3 is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted Cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, R 'is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, OX-t, where X » is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxylalkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substituted 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 which are derived from ethylenediamine or amino acids, and their pharmaceutically acceptable salts, esters and salts of the esters or compounds which, when applied, provide the compounds to be used according to the invention as metabolites or degradation products, for the manufacture of medicaments for the therapeutic and prophylactic treatment of infections in humans and animals caused by parasites, fungi, viruses and bacteria, selected from the group consisting of bacteria n in the Propionibacteriaceae family, in particular the Propionibacterium genus, in particular the Propionibacterium acnes species, bacteria in the Actinomycetaceae family, in particular the Actonomyces genus, bacteria in the Corynebacterium genus, in particular the species Corynebacterium diphteriae and Corynebacterium pacteracteriaceae mycosis , the genus Mycobacterium, in particular 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, particularly the species Logenia, especially the species Logenia, particularly the species Logenia, the type Erogenysys , 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 Mycoplasmataceae family, of the genera Mycoplasma and Urea plasma, in particular the species Mycoplasma pneumoniae, bacteria of the genus Brucella, bacteria of the genus Bordetella, 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 Families Spirochaetaceae and Leptospiraceae, in particular of the genera Treponema, Borrelia and Leptospira, in particular Borrelia burgdorferi, bacteria of the genus Actinobacillus, bacteria of the family Legionellaceae, bacteria of the genus Legionella, bacteria of the family Rickettsia- ceae and family Bartonellattaceaoc, Bacteria deracattocaceae, Bacteria of the genus Dermatophilus exist, and as a fungicide, bactericide and herbicide in plants.
2. Verwendung nach Anspruch 1, dadurch gekennzeichnet, daß die phosphororganischen Verbindungen der Formel (U) XiO 02. Use according to claim 1, characterized in that the organophosphorus compounds of the formula (U) XiO 0
\ II\ II
N-A-P-R3 ( II )N-A-P-R3 (II)
//
R? R4 R? R 4
entsprechen, wobeicorrespond with
Xi aus der Gruppe ausgewählt ist, die aus Wasserstoff, substituiertem oder unsubstituiertem Acyl, substituiertem oder unsubstituiertem Alkyl, substituiertem oder unsubstituiertem Aryl, substituiertem oder unsubstituiertem Aralkyl, substituiertem oder unsubstituiertem Cycloalkyl, substituiertem oder unsubstituiertem heterocyclischen Rest besteht; R2, R3, * und A die gleiche Bedeutung wie in Formel (I) haben.Xi is selected from the group consisting of hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic radical; R 2 , R 3 , * and A have the same meaning as in formula (I).
3. Verwendung nach Anspruch 2, dadurch gekennzeichnet, daß3. Use according to claim 2, characterized in that
R2 ein Acylrest, insbesondere ein Formyl- oder Acetylrest, ist,R 2 is an acyl radical, in particular a formyl or acetyl radical,
R3 aus der Gruppe ausgewählt ist, die aus Wasserstoff, Methyl und Ethyl besteht,R 3 is selected from the group consisting of hydrogen, methyl and ethyl,
R* aus der Gruppe ausgewählt ist, die aus Wasserstoff, Methyl, Ethyl und OXt besteht,R * is selected from the group consisting of hydrogen, methyl, ethyl and OXt,
X4 aus der Gruppe ausgewählt ist, die aus Wasserstoff, Natrium, Kalium, Methyl undX4 is selected from the group consisting of hydrogen, sodium, potassium, methyl and
Ethyl besteht,There is ethyl,
Xi Wasserstoff ist, und A aus der Gruppe ausgewählt ist, die aus Alkylen, Alkenylen oder Hydroxyalkylen besteht.Xi is hydrogen and A is selected from the group consisting of alkylene, alkenylene, or hydroxyalkylene.
4. Verwendung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß A zwischen dem Phosphoratom und dem Stickstoffatom eine Kette aus drei Kohlenstoffatomen bildet.4. Use according to one of the preceding claims, characterized in that A forms a chain of three carbon atoms between the phosphorus atom and the nitrogen atom.
5. Verwendung nach Anspruch 2, dadurch gekennzeichnet, daß5. Use according to claim 2, characterized in that
X4 Gruppe ausgewählt ist, die aus Wasserstoff, Ammonium und Metallen der ersten und zweiten Hauptgruppe des Periodensystems, vorzugsweise Natrium, Kalium, Calcium oder Magnesium, Ammoniumverbindungen, die sich von Ethylendiamin oder Aminosäuren ableiten, vorzugsweise Ethanolamin, Ethylendiamin, N,N-Dibenzylethylen- diamin und Arginin, besteht.X 4 group is selected, which consists of hydrogen, ammonium and metals of the first and second main group of the periodic table, preferably sodium, potassium, calcium or magnesium, ammonium compounds derived from ethylenediamine or amino acids, preferably ethanolamine, ethylenediamine, N, N-dibenzylethylene - diamine and arginine.
6. Verwendung nach einem der Ansprüche 2 bis 5, dadurch gekennzeichnet, daß6. Use according to one of claims 2 to 5, characterized in that
R2 ein Acylrest und A ein Alkylenrest sind, wobei R2 vorzugsweise durch Formyl bzw. bzw. Acetyl und A vorzugsweise durch Propylen, Propenylen und Hydroxypropylen gebildet werden.R 2 is an acyl radical and A is an alkylene radical, where R 2 is preferably formyl or or acetyl and A are preferably formed by propylene, propenylene and hydroxypropylene.
7. Verwendung nach einem der vorhergehenden Ansprüche zur Herstellung von Arzneimitteln zur Behandlung von Infektionen, verursacht durch Bakterien, Viren, Pilze oder ein- oder mehrzellige Parasiten.7. Use according to one of the preceding claims for the manufacture of medicaments for the treatment of infections caused by bacteria, viruses, fungi or single or multicellular parasites.
8. Verwendung nach Anspruch 7 zur Herstellung von Arzneimitteln zur Behandlung von Infektionen verursacht durch Bakterien, ausgewählt aus der Gruppe, 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 Arten Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis und Mycobacterium avium, Bakterien der Familie Chlamydiaceae, insbesondere die Spezies Chlamydia trachomatis und Chlamydia psittaci, Bakterien der Gattung Listeria, insbesondere die Art Listeria monocytogenes besteht.8. Use according to claim 7 for the manufacture of medicaments 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 from the Actinomycetaceae family, in particular the Actinomyces genus , Bacteria of the genus Corynebacterium, in particular the species Corynebacterium diphteriae and Corynebacterium pseudotuberculosis, bacteria of the family Mycobacteriaceae, of the genus Mycobacterium, in particular the species Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bacterium and family bacteria, mycobacterium av Chlamydia psittaci, bacteria of the genus Listeria, in particular the species Listeria monocytogenes.
9. Verwendung nach Anspruch 7 zur Herstellung von Arzneimitteln zur Behandlung von Infektionen, die durch Viren hervorgerufen werden, die aus der Gruppe ausgewählt sind, die aus Viren der Gattung Parvoviridae, insbesondere Parvoviren, Dependoviren, Densoviren, Viren der Gattung Adenoviridae, insbesondere Adenoviren, Mastadenovi- ren, Aviadenoviren, Viren der Gattung Papovaviridae, insbesondere Papovaviren, insbesondere Papillomaviren (sogenannte Warzenviren), Polyomaviren, insbesondere JC- Virus, BK- Virus, und Miopapovaviren, Viren der Gattung Herpesviridae, insbesondere Herpes-Simplex- Viren, der Varizellen/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 hepato- tropen 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, alle Coxsackieviren, alle Echoviren, alle Rhinoviren, Hepatitis-A- Virus, Aphthoviren, Viren der Gattung Calciviridae, insbesondere Hepatitis-E- Viren, Viren der Gattung Reoviridae, insbesondere Reoviren, Orbiviren, Rotaviren, Viren der Gattung Togaviridae, insbesondere Togaviren, Alphaviren, Rubiviren, Pestivi- ren, Rubellavirus, Viren der Gattung Flaviviridae, insbesondere Flaviviren, FSME- Virus, Hepatitis-C- Virus, Viren der Gattung Orthomyxoviridae, insbesondere Influenzaviren, Viren der Gattung Paramyxoviridae, insbesondere Paramyxoviren, Morbillivi- rus, Pneumovirus, Masernvirus, Mumpsvirus, Viren der Gattung Rhabdoviridae, insbesondere Rhabdoviren, Rabiesvirus, Lyssavirus, viskuläres Stomatitisvirus, Viren der Gattung Coronaviridae, insbesondere Coronaviren, Viren der Gattung Bunyaviridae, insbesondere Bunyaviren, Nairovirus, Phlebovirus, Uukuvirus, Hantavirus, Hantaanvi- rus, Viren der Gattung Arenaviridae, 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.9. Use according to claim 7 for the manufacture of medicaments 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, the Var Zoster viruses, human cytomegalovirus, Epstein-Barr viruses, human herpes virus 6, human herpes virus 7, human herpes virus 8, viruses of the genus Poxviridae, in particular pox viruses, Orthopox parapox, molluscum contagiosum virus, aviviruses, caprivipiruses, caprivipiruses 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, hepatits G viruses, hepadnaviruses, in particular all hepatitis viruses such as hepatitis B virus, hepatitis D viruses, viruses of the genus Picornaviridae, in particular Picornaviruses, all enteroviruses, all polioviruses, all Coxsackieviruses, all echoviruses, all rhinoviruses, hepatitis A virus, aphthoviruses, viruses of the genus Calciviridae, in particular hepatitis E viruses, viruses of the genus Reoviridae, especially Reoviridae Orbiviruses, rotaviruses, viruses of the genus Togaviridae, in particular togaviruses, alphaviruses, rubiviruses, pestivizers, rubella virus, viruses of the genus Flaviviridae, in particular flaviviruses, TBE Virus, hepatitis C virus, viruses of the 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 Rhabvovirus virus, virus virus virus, rabies virus of the genus Coronaviridae, in particular Coronaviruses, viruses of the genus Bunyaviridae, in particular Bunyaviruses, Nairovirus, Phlebovirus, Uukuvirus, Hantavirus, Hantaanvirus, viruses of the genus Arenaviridae, in particular Arenaviruses, especially lymphocytic virus virus dermatitis, alleviral virus virus, dermatitis virus, dermatitis virus - Viruses, 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.
10. Verwendung nach Anspruch 7 zur Herstellung von Arzneimitteln 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, der Trichomoniasis, der Pneumozystose, der Balantidiose, der Kryptosporidiose, der Sarkozystose, der Akanthamöbose, der Naeglerose, der Kokzidiose, der Giardiose und der Lambliose.10. Use according to claim 7 for the manufacture of medicaments for the prevention and treatment of infections caused by unicellular parasites, namely pathogens of malaria, sleeping sickness, Chagas disease, toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis, pneumocystosis, the Balantidiosis, Cryptosporidiosis, Sarcocystosis, Acanthus Hobiosis, Naeglerosis, Coccidiosis, Giardiosis and Lambliosis.
11. Verwendung nach einem der Ansprüche 1 bis 10, dadurch gekennzeichnet, daß das Arzneimittel einen wirksamen Gehalt an zumindest einer phosphororganischen Verbindung und einen pharmazeutisch akzeptablen Träger aufweist.11. Use according to one of claims 1 to 10, characterized in that the medicament has an effective content of at least one organophosphorus compound and a pharmaceutically acceptable carrier.
12. Verwendung nach Anspruch 11, dadurch gekennzeichnet, daß das Arzneimittel mindestens einen weiteren pharmazeutischen Wirkstoff aufweist.12. Use according to claim 11, characterized in that the medicament has at least one further pharmaceutical active ingredient.
13. Verwendung nach Anspruch 12, dadurch gekennzeichnet, daß das Arzneimittel außerdem eines oder mehrere Bestandteile der Gruppe aufweist, die aus Sulfonamid, Sulfadoxin, Artemisinin, Atovaquon, Chinin, Chloroquin, Hydroxychloroquin, Mefloquin, Halofantrin, Pyrimethamin, Armesin, Tetracycline, Doxycyclin, Proguanil, Metronidazol, Praziquantil, Niclosamid, Mebendazol, Pyrantel, Tiabendazol, Diethylcarbazin, Piperazin, Pyrivinum, Metrifonat, Oxamniquin, Bithionol und Suramin besteht.13. Use according to claim 12, characterized in that the medicament also has one or more constituents of the group consisting of sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracycline, doxycycline, Proguanil, metronidazole, praziquantil, niclosamide, mebendazole, pyrantel, tiabendazole, diethylcarbazine, piperazine, pyrivinum, metrifonate, oxamniquin, bithionol and suramin.
14. Verwendung nach Anspruch 12, gekennzeichnet durch einen oder mehrere Bestandteile der Gruppe, die aus Penicilline, Benzylpenicillin (Penicillin G), Phenoxypenicilline, Isoxazolylpenicilline, Aminopenicilline, Ampicillin, Amoxixillin, Bacampicillin, Carboxypenicillin, Ticarcillin, Temocillin, Acyalaminope- nicilline, Azlocillin, Mezlocillin, Piperacillin, Apalcillin, Mecillinam, Cephalosporine, Cefazolin-Gruppe, Cefüroxim-Gruppe, Cefoxitin-Gruppe, Cefoxitin, Cefotetan, Cef- metazol, Latamoxef, Flomoxef, Cefotaxim-Guppe, Cefozidim, Ceftazidim-Gruppe, Ceftazidim, Cefpirom, Cefepim, übrige Cephalosporine, Cefsulodin, Cefoperazon, Oralcephalosporine der Cefalexin-Gruppe, Loracarbef, Cefprozil, neuen Oralcephalos- porinen mit erweitertem Spektrum, Cefixim, Cefpodoxim-Proxetil, Cefüroxim-Axetil, Cefetamet, Cefotiam-Hexetil, Cefdinir, Ceftibuten, andere ß-Lactam-Antibiotika, Car- bapenem, Imipenem /Cilastatin, Meropenem, Biapenem, Aztreonam, ß-Lactamase- Hemmer, Clavulansäure/Amoxicillin, Clavulansäure/Ticarcillin, Sulbactam/Ampicillin, Tazobactam/Piperacillin, Tetracycline, Oxytetracyclin, Rolitetraxyxlin, Doxycyclin, Minocyclin, Chloramphenicol, Aminoglykoside, Gentamicin, Tobramycin, Netilmicin, Amikacin, Spectinomyxin, Makrolide, Erythromycin, Clarithromycin, Roxithromycin, Azithromycin, Dirithromycin, Spiramycin, Josamycin, Lincosamide, Clindamycin, Fu- sidinsäure, Glykopeptid- Antibiotika, Vancomycin, Tecoplanin, Pristinamycin-Derivate, Fosfomycin, Antimikrobielle Folsäureantagonisten, Sulfonamide, Co-Trimoxazol, Trimethoprim, andere Diaminopyrimidin-Sulfonamid-Kombinationen, Nitrofürane, Nitro- fürantoin, Nitrofürazon, Gyrase-Hemmer (Chinolone), Norfloxacin, Ciprofloxacin, Ofloxacin, Sparfloxacin, Enoxacin, Fleroxacin, Pefloxacin, Lomefloxacin, Bay Y3118, Nitroimidazole, antimykobakterielle Mittel, Isoniazid, Rifampicin, Rifabutin, Etham- butol, Pyrazinamid, Streptomycin, Capreomycin, Prothionamid, Terizidon, Dapson, Clofazimin, Lokalantibiotika, Bacitracin, Tyrothricin, Polymyxine, Neomycin, Ka- namycin, Paromomycin, Mupirocin, antivirale Mittel, Acyclovir, Ganciclovir, Azido- thymidin, Didanosin, Zalcitabin, Thiacytidin, Stavudin, Ribavirin, Idoxuridin, Trifluri- din, Foscarnet, Amantadin, Interferone, Tibol-Derivate, Proteinase-Inhibitoren, An- timykotika, Polyene, Amphothericin B, Nystatin, Natamycin, Azole, Azole zur septischen Therapie, Miconazol, Ketoconazol, Itraconazol, Fluconazol, UK- 109.496, Azole für lokale Anwendung, Clotrimazol, Econazol, Isoconazol, Oxiconazol, Bifonazol, Flucytosin, Griseofulvin, Ciclopiroxolamin, Tolnaftat, Naftifm, Terbinafin, Amorolfin, Antrachinone, Betulinic acid, Semianthrachinone, Xanthone, Naphtoquinone, Aryami- noalkohole, Chinin, Quinidine, Mefloquin, Halofantrin, Chloroquin, Amodiaquin, Acri- din, Benzonaphthyridin, Mepacrin, Pyronaridin, Dapson, Sulfonamide, Sulfadoxin, Sul- falene, Trimethoprim, Proguanil, Chlorproguanil, Diaminopyrimidine, Pyrimethamin, Primaquin, Aminoquinoline, WR 238,605, Tetracyclin, Doxycyclin, Clindamycin, Norfloxacin, Ciprofloxacin, Ofloxacin, Artemisinin, Dihydroartemisinin, 10b artemether, Arteether, Atrtesunat, Atovaquon, Suramin, Melarsoprol, Nifurtmox, Stibogluconat- Natrium, Pentamidin, Amphotericin B, Metronidazol, clioquinol, Mebendazol, Niclosamid, Praziquantel, Pyrantel, Tiabendazol, Diethylcarbamazin, Ivermectin, Bithionol, Oxamniquin, Metrifonat, Piperazin, Embonat besteht. 14. Use according to claim 12, characterized by one or more constituents of the group consisting of penicillins, benzylpenicillin (penicillin G), phenoxypenicillins, isoxazolylpenicillins, aminopenicillins, ampicillin, amoxixillin, bacampicillin, carboxypenicillin, ticarcillin, temocillinicillin, acyalaminocillin, acylaline Mezlocillin, piperacillin, apalcillin, mecillinam, cephalosporins, cefazolin group, cefüroxim group, cefoxitin group, cefoxitin, cefotetan, cef- metazol, latamoxef, flomoxef, cefotaxim group, cefozidim, ceftazidim group, ceftazidim, cefpirom, cefepim, other cephalosporins, cefsulodin, cefoperazone, oralcephalosporins of the cefaleximef, cefalximalef, new, lor Prozacacim -Proxetil, Cefüroxim axetil, cefetamet, cefotiam hexetil, cefdinir, ceftibuten, other ß-lactam antibiotics, carboxylic bapenem, imipenem / cilastatin, meropenem, biapenem, aztreonam, ß-lactamase inhibitor, clavulanic acid / amoxicillin, clavulanic acid / ticarcillin, sulbactam / ampicillin, tazobactam / piperacillin, tetracycline, oxytetracycline, Rolitetraxyxlin, doxycycline, minocycline, chloramphenicol, aminoglycosides, gentamicin, tobramycin, netilmicin, amikacin, Spectinomyxin, macrolides, erythromycin, clarithromycin, roxithromycin, azithromycin, dirithromycin, spiramycin, josamycin, Lincosamides, clindamycin, fudic acid, glycopeptide antibiotics, vancomycin, tecoplanin, pristinamycin derivatives, fosfomycin, Antimicrobial folic acid antagonists, sulfonamides, co-trimoxazole, trimethoprim, other diaminopyrimidine-sulfonamide combinations, nitrofürans, nitro-forantoin, nitrofürazone, gyrase inhibitors (quinolones), norfloxacin, ciprofloxacin, ofloxacin, spoxoxacin, spoxoxacin Y3118, nitroimidazoles, antimycobacterial agents, isoniazid, rifampicin, rifabutin, Etham- Butol, pyrazinamide, streptomycin, capreomycin, prothionamide, terizidone, dapsone, clofazimine, local antibiotics, bacitracin, tyrothricin, polymyxins, neomycin, Ka namycin, paromomycin, mupirocin, antiviral, Agent, acyclovir, ganciclovir, azidothymidine, didanosine, zalcitabine, thiacytidine, stavudine, ribavirin, idoxuridine, trifluridine, foscarnet, amantadine, interferons, tibol derivatives, proteinase inhibitors, antimycotics, polyenes, amphotheratin , Natamycin, azoles, azoles for septic therapy, miconazole, ketoconazole, itraconazole, fluconazole, UK-109,496, azoles for local use endung, clotrimazole, econazole, isoconazole, oxiconazole, bifonazole, flucytosine, griseofulvin, ciclopiroxolamine, tolnaftat, naftifm, terbinafine, amorolfine, antrachinone, betulinic acid, semianthraquinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone, quinone , amodiaquine, din acridine, benzonaphthyridine, mepacrine, pyronaridine, dapsone, sulfonamides, sulfadoxine, sulfonic Falene, trimethoprim, proguanil, chlorproguanil, diaminopyrimidines, pyrimethamine, primaquine, aminoquinolines, WR 238,605, tetracycline, doxycycline, clindamycin, norfloxacin, ciprofloxacin, ofloxacin, artemisinin, dihydroartemisinin, 10b artemether, arteether, Atrtesunat, atovaquone, suramin, melarsoprol, Nifurtmox, Stibogluconat- sodium, pentamidine, amphotericin B, metronidazole, clioquinol, mebendazole, niclosamide, praziquantel, pyrantel, tiabendazole, diethylcarbamazine, ivermectin, bithionol, Oxamniquin, metrifonate, piperazine, embonate.
EP99969332A 1998-09-22 1999-09-22 Use of organophosphorous compounds for producing medicaments for the therapeutic and prophylactic treatment of infections or as a fungicide, bactericide or herbicide for plants Withdrawn EP1115388A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19843222 1998-09-22
DE19843222A DE19843222A1 (en) 1998-09-22 1998-09-22 Use of organophosphorus compounds for the therapeutic and prophylactic treatment of infections
PCT/EP1999/007054 WO2000016757A2 (en) 1998-09-22 1999-09-22 Use of organophosphorous compounds for producing medicaments for the therapeutic and prophylactic treatment of infections or as a fungicide, bactericide or herbicide for plants

Publications (1)

Publication Number Publication Date
EP1115388A1 true EP1115388A1 (en) 2001-07-18

Family

ID=7881691

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99969332A Withdrawn EP1115388A1 (en) 1998-09-22 1999-09-22 Use of organophosphorous compounds for producing medicaments for the therapeutic and prophylactic treatment of infections or as a fungicide, bactericide or herbicide for plants

Country Status (16)

Country Link
EP (1) EP1115388A1 (en)
JP (1) JP2003520760A (en)
KR (1) KR20010075248A (en)
CN (1) CN1319006A (en)
AP (1) AP2001002106A0 (en)
AU (1) AU5981199A (en)
BR (1) BR9913990A (en)
CA (1) CA2344867A1 (en)
DE (1) DE19843222A1 (en)
IL (1) IL141887A0 (en)
NO (1) NO20011430L (en)
OA (1) OA11655A (en)
PL (1) PL353313A1 (en)
SK (1) SK3932001A3 (en)
WO (1) WO2000016757A2 (en)
ZA (1) ZA200101912B (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002004002A2 (en) * 2000-07-11 2002-01-17 Bayer Aktiengesellschaft Use of strains of the parapox ovis virus for producing antiviral pharmaceuticals and anticancer pharmaceuticals
WO2002078714A1 (en) * 2001-03-30 2002-10-10 Jomaa Pharmaka Gmbh Formulations which are resistant to gastric juice and are used to apply anti-infective compounds inhibiting the 2-c-methylerythrose-4 metabolic pathway, and the salts and esters of the same
PL3010511T3 (en) 2014-09-12 2018-07-31 Antibiotx A/S Antibacterial use of halogenated salicylanilides
GB201509326D0 (en) 2015-05-29 2015-07-15 Antibio Tx Aps Novel use
CN105055431B (en) * 2015-08-11 2018-03-13 西南医科大学附属医院 A kind of medicine and its application with anti-tubercle bacillus
CN108853106B (en) * 2017-05-09 2021-02-02 中国食品药品检定研究院 Use of imine phenazine compound as rabies virus inhibitor
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
ES3040436T3 (en) * 2020-03-26 2025-10-30 Shin Poong Pharmaceutical Co Ltd Pharmaceutical composition comprising pyronaridine or a salt thereof, artemisinin or a derivative thereof or a combination of both for preventing or treating a respiratory disease caused by a coronavirus
CN112043707B (en) * 2020-09-09 2021-07-30 武汉珈创生物技术股份有限公司 Application of clofazimine and/or pharmaceutically acceptable derivatives thereof in preparation of anti-saxavirus medicine

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4216226A (en) * 1977-06-06 1980-08-05 Meiji Seika Kaisha, Ltd. Antiviral agent and treatment of viral infections
US4613355A (en) * 1983-08-02 1986-09-23 Satoshi Omura Antibiotic having herbicidal activity
US4693742A (en) * 1983-12-20 1987-09-15 Rohm And Hass Company Herbicidal hydroxyamino phosphonic acids and derivatives
US4846872A (en) * 1986-08-11 1989-07-11 Fujisawa Pharmaceutical Co., Ltd. Herbicide
EP0352508A1 (en) * 1988-07-05 1990-01-31 Sumitomo Chemical Company, Limited Herbicidal composition
WO1996016629A2 (en) * 1994-11-18 1996-06-06 Amira Inc Phosphinic creatine compounds having antiviral activity
WO1999052515A2 (en) * 1998-04-14 1999-10-21 Hassan Jomaa Use of organophosphoric compounds for the therapeutic and preventative treatment of infections

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4216226A (en) * 1977-06-06 1980-08-05 Meiji Seika Kaisha, Ltd. Antiviral agent and treatment of viral infections
US4613355A (en) * 1983-08-02 1986-09-23 Satoshi Omura Antibiotic having herbicidal activity
US4693742A (en) * 1983-12-20 1987-09-15 Rohm And Hass Company Herbicidal hydroxyamino phosphonic acids and derivatives
US4846872A (en) * 1986-08-11 1989-07-11 Fujisawa Pharmaceutical Co., Ltd. Herbicide
EP0352508A1 (en) * 1988-07-05 1990-01-31 Sumitomo Chemical Company, Limited Herbicidal composition
WO1996016629A2 (en) * 1994-11-18 1996-06-06 Amira Inc Phosphinic creatine compounds having antiviral activity
WO1999052515A2 (en) * 1998-04-14 1999-10-21 Hassan Jomaa Use of organophosphoric compounds for the therapeutic and preventative treatment of infections

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GREENWOOD D: "Fosfomycin and fosmidomycin", ANTIBIOTICS AND CHEMOTHERAPY, pages 357 - 359 *

Also Published As

Publication number Publication date
OA11655A (en) 2004-12-08
WO2000016757A8 (en) 2000-06-29
ZA200101912B (en) 2002-03-07
CN1319006A (en) 2001-10-24
IL141887A0 (en) 2002-03-10
KR20010075248A (en) 2001-08-09
AU5981199A (en) 2000-04-10
NO20011430L (en) 2001-05-09
WO2000016757A2 (en) 2000-03-30
BR9913990A (en) 2001-10-23
SK3932001A3 (en) 2001-08-06
NO20011430D0 (en) 2001-03-21
PL353313A1 (en) 2003-11-17
JP2003520760A (en) 2003-07-08
CA2344867A1 (en) 2000-03-30
DE19843222A1 (en) 2000-03-30
AP2001002106A0 (en) 2001-03-31

Similar Documents

Publication Publication Date Title
EP1071409B1 (en) Use of organophosphoric compounds for the therapeutic and preventative treatment of infections
DE19903398A1 (en) Use of thiadiazole derivatives for the prophylactic and therapeutic treatment of infections
EP1173183A2 (en) Use of compounds with a nitrogen-oxygen heterocycle
EP1095050A1 (en) Phosphorous organic compounds and their use
EP1140952B1 (en) Organo-phosphorus compounds and their utilization
EP1115388A1 (en) Use of organophosphorous compounds for producing medicaments for the therapeutic and prophylactic treatment of infections or as a fungicide, bactericide or herbicide for plants
EP1133500B1 (en) Organophosphorous compounds and the use thereof
EP1146880A2 (en) Use of phosphororganic compounds for the prophylactic and therapeutical treatment of infections
DE19843383A1 (en) New amino and imino substituted organo-phosphorus compounds useful in medicine against viral, bacterial, fungal and parasiticidal infections and as herbicides, plant fungicides and plant bactericides
WO2000017212A1 (en) Organophosphorous compounds and use thereof
EP1131075A2 (en) Use of phosphonoformic acid derivatives for treating infections
EP1255762A1 (en) Phosphororganic compounds and the use thereof
DE10014127A1 (en) Antibacterial, fungicidal, antiviral, antiparasitic and herbicidal agents for medicinal, veterinary or agricultural use, comprising amino- or imino-substituted organophosphorus compounds having nitrogen-containing spacer group
WO2001093872A1 (en) Use of organophosphorous hydroxamic acid derivatives for producing medicaments
DE19859668A1 (en) Treating or preventing viral, bacterial, fungal or parasitic infections using bis-phosphonic acid compounds, also having herbicidal activity
DE19843334A1 (en) New organosulfinic acid and organosulfonic acid derivatives useful in medicine against viral, bacterial, fungal and parasiticidal infections and as herbicides, plant fungicides and plant bactericides
EP1133302A2 (en) Use of phosphonoformic acid derivatives for treating infections
DE19843360A1 (en) New phosphororganic compounds; useful for treatment of bacterial, viral and parasitic infection, and as herbicides or for treating infections in plants
DE19903666A1 (en) Medicines containing 3-isoxazolidinones and hydroxylamic acids as an active ingredient and their use
CZ2001989A3 (en) Use of organophosphorous compounds for producing medicaments for the therapeutic and prophylactic treatment of infections or as a fungicide, bactericide or herbicide in plants
AU2003261554A1 (en) Organophosphorus containing preparations and applications therefor
WO2000003699A2 (en) Drugs containing phosphoric acid derivatives as active ingredient and their use

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20010403

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL;LT PAYMENT 20010403;LV;MK;RO;SI PAYMENT 20010403

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: JOMAA, HASSAN

RIN1 Information on inventor provided before grant (corrected)

Inventor name: JOMAA; HASSAN

17Q First examination report despatched

Effective date: 20010824

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BIOAGENCY AG

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20060331