WO2000017212A1 - Organophosphorous compounds and use thereof - Google Patents

Organophosphorous compounds and use thereof Download PDF

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Publication number
WO2000017212A1
WO2000017212A1 PCT/EP1999/007053 EP9907053W WO0017212A1 WO 2000017212 A1 WO2000017212 A1 WO 2000017212A1 EP 9907053 W EP9907053 W EP 9907053W WO 0017212 A1 WO0017212 A1 WO 0017212A1
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Prior art keywords
substituted
viruses
unsubstituted
genus
bacteria
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PCT/EP1999/007053
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German (de)
French (fr)
Inventor
Hassan Jomaa
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Hassan Jomaa
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Priority to AU63287/99A priority Critical patent/AU6328799A/en
Publication of WO2000017212A1 publication Critical patent/WO2000017212A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • 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

  • the invention relates to organophosphorus compounds and their salts, esters and amides and their use for the manufacture of medicaments for the therapeutic and prophylactic treatment of infections in humans and animals caused by viruses, bacteria, fungi and parasites, and their use as a fungicide, bactericide and herbicide in plants.
  • the organophosphorus compounds include phosphinoyl derivatives, phosphinic acid derivatives and phosphonic acid derivatives.
  • the object of the present invention is therefore to provide a substance which can be used in infections by viruses, bacteria, fungi and parasites in humans and animals and as a fungicide, bactericide and herbicide in plants and which fulfills the conditions specified above.
  • This object is achieved in a completely surprising manner by the group of substances defined in claim 1.
  • This group of substances shows an anti-infectious effect against viruses, certain bacteria, fungi, single and multicellular parasites.
  • organophosphorus compounds according to the invention correspond to the general formula (I):
  • R 1 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, OXi and OX 2 , where 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
  • R 3 is selected from the group consisting of substituted and unsubstituted alkyl of 1 to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl of 1 to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl 1 to 26 carbon atoms, substituted and unsubstituted alkynyl having 1 to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen and OX 3 , where X 3 is hydrogen, substituted and unsubstituted alkyl having 1 to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl with 1 to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted aral
  • R » is selected from the group consisting of a substituted and unsubstituted alkyl having 10 to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having 10 to 26 carbon atoms, substituted and unsubstituted alkenyl having 10 to 26 carbon atoms, substituted and unsubstituted alkynyl having 10 to 26 carbon atoms and O is, wherein X4 is selected from the group consisting of a substituted and unsubstituted alkyl of 10 to 26 carbon atoms, substituted and unsubstituted hydroxylalkyl of 10 to 26 carbon atoms, substituted and unsubstituted alkenyl of 10 to 26 carbon atoms and a substituted and unsubstituted alkynyl with 10 to 26 ° carbon atoms, and their pharmaceutically acceptable salts, esters and amides and salts of the esters.
  • R $ is preferably an alkyl, hydroxyalkyl, alkynyl or alkenyl group with 16 or 18 carbon atoms or OX 3 , where X 3 is an alkyl, hydroxyalkyl, alkynyl or alkenyl group with 16 or 18 carbon atoms, R »is an alkyl , Hydroxyalkyl, alkynyl or alkenyl group with 16 or 18 carbon atoms or O, where X * is an alkyl, hydroxyalkyl, alkynyl or alkenyl group with 16 or 18 carbon atoms.
  • 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 , R »and A have the same meaning as in formula (I).
  • R 2 acyl
  • R 3 is an alkyl, hydroxyalkyl, alkynyl or alkenyl group with 16 or 18 carbon atoms or OX 3
  • X 3 is an alkyl, alkynyl, Is hydroxyalkyl or alkenyl group with 16 or 18 carbon atoms
  • R- t is an alkyl, alkynyl, hydroxyalkyl or alkenyl group with 16 or 18 carbon atoms or OX
  • 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. Suitable examples of these acyl groups are given below.
  • Aliphatic acyl groups are acyl radicals derived from an aliphatic acid, which include the following:
  • Alkanoyl e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl etc.
  • Alkenoyl e.g. acryloyl, methacryloyl, crotonoyl etc.
  • Alkylthioalkanoyl e.g. methylthioacetyl, ethylthioacetyl etc.
  • Alkanesulfonyl e.g. mesyl, ethanesulfonyl, propanesulfonyl, etc.
  • Alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.
  • Alkyl carbamoyl e.g. methyl carbamoyl etc.
  • N-alkyl thiocarbamoyl e.g. (N-methyl) thiocarbamoyl etc.
  • 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, may 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 residue have already been specified.
  • aroyl substituted with halogen and hydroxy or with halogen and acyloxy and aralkanoyl substituted with hydroxy, hydroxyimino, dihalogenalkanoyloxyimino and aryithiocarbamoyl e.g. phenylthiocarbamoyl etc.
  • Arylcarbamimidoyl e.g. phenylcarbamimidoyl etc.
  • a heteroeyclic acyl residue is understood to mean an acyl residue which comes from an acid with a heteroyclic 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.);
  • Heterocyclic alkanoyi 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, unless otherwise defined, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.
  • Hydroxylalkyl is a straight or branched chain alkyl radical with up to 9 carbons, unless defined otherwise, which has at least one hydroxyl group, preferably one or two hydroxyl groups.
  • Alkenyl includes straight or branched chain alkenyl groups with up to 9 carbon atoms, unless otherwise defined, such as vinyl, propenyl (e.g. 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2 -Ethylpropenyl, pentenyl, hexenyl.
  • Alkynyl includes straight or branched chain alkynyl groups with up to 9 carbon atoms, unless otherwise defined.
  • 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-chain or branched-chain alkylene groups which have up to 9 carbon atoms and can be represented by the formula - (C n H 2n ) -, in which n is an integer from 1 to 9, such as methylene, ethyl len, trimethylene, methylethylene, tetramethylene, 1-methyltrimethylene, 2-ethylene, 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 trimethylene are particularly preferred can also be replaced by 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 can be reproduced in which n is an integer from 2 to 9, such as vinylene, propenylene (e.g. 1-propenylene, 2-propenylene), 1-methylpropenylene, 2-methylpropenylene, butenylene, 2-ethylpropenylene, 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, for example, 1-propenylene.
  • the hydrogen atoms can also be substituted by substituents such as for example halogen residues.
  • 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 Hydroxymethylene, hydroxyethylene (e.g. 1-hydroxyethyl and 2-hydroxyethylene), hydroxytrimethylene (e.g. 1-hydroxytrimethylene, 2-hydroxytrimethylene and 3-hydroxytrimethylene), hydroxytetramethylene (e.g. 2-hydroxytetramethylene), 2-hydroxy-2- methyltrimethylene, hydroxypentamethylene (e.g. 2-hydroxy-pentamethylene), hydroxyhexamethylene (e.g.
  • 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 also be replaced by substituents, such as halogen radicals.
  • Suitable examples of such esters according to formulas (I) and (II) include suitable mono- and diesters, and preferred examples of such esters include alkyl esters (eg hexadecanyl ester, octadecanyl ester, etc.);
  • Aralkyl esters (benzyl esters, 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.
  • X 3 is preferably also a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium, or ammonium compounds which are derived from ethylenediamine or amino acids.
  • salt compounds of the organophosphorus compounds with organic or inorganic bases for example sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylamine salt, ethanolamine salt, dicyclohexylamine salt, ethylenediamine salt, N, N "- dibenzylethylenediamine salt, etc.
  • salts with amino acids e.g. arginine salt, asparagine o acid salt, glutamic acid salt etc.
  • the compounds according to formulas (I) or (II) used according to the invention can, in their protonated form, as the ammonium salt of organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, maleic acid, fumaric acid, oxalic acid , Tartaric acid, benzoic acid, etc. are present.
  • organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, maleic acid, fumaric acid, oxalic acid , Tartaric acid, benzoic acid, etc. are present.
  • the compounds of the formulas (I) or (II) according to the invention allow, for example for spatial groups containing chiral groups R 1, R 2 , R 3 , Rt, Xi, X 2 , X 'or A, to have 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 family Chlamydiaceae, especially the species Chlamydia trachomatis and Chlamydia psittaci, bacteria of the genus Listeria, especially the species Listeria mo- nocytogenes, bacteria of the species Erysipelthrix rhusiopathiae, bacteria of the genus Clostridium, bacteria of the genus Yersinia, of the species 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 keratoko ⁇ junc -tivitis and serositis of animals, brucellosis of animals and humans, anthrax in humans and animals, actinomycosis in humans and animals, streptotrichoses, psittacosis / orithosis in animals, Q fever, Ehrlich
  • the use is also useful in Helicobacter eradication therapy for ulcers of the gastrointestinal tract.
  • Combinations with another antibiotic can also be used to treat the above mentioned diseases are used.
  • isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, protionamide and dapsone are particularly suitable for the treatment of tuberculosis.
  • the active compounds according to the invention can also be used in particular for infections with the following viruses:
  • Parvoviridae Parvoviruses, Dependoviruses, Densoviruses, Adenoviridae: Adenoviruses, Mastadenoviruses, Aviadenovire, 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, aviviruses, capriviruses, leporipox viruses,
  • organophosphorus compounds used according to the invention are therefore suitable for combating the following viral infections:
  • the compounds described ie 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 the prevention of 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 (IT) used according to the invention in their protonated form Form ammonium salt of inorganic or organic acids, such as hydrochloric acid, sulfuric acid, citric acid, maleic acid, fumaric acid, tartaric acid, p-toluenesulfonic acid.
  • salts which are formed by suitable selection of X 3 , such as sodium salt, potassium salt, calcium salt, ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt and salts of an amino acid such as arginine salt, aspartic acid salt, glutamic acid salt.
  • test system The activity of the substances is determined in a test system. This system is based on the measurement of the inhibition of the growth of bacteria, parasites, viruses, fungi or plants in vitro. For this purpose, 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, coated tablets, capsules, pills, suppositories and ampoules are present, whose active ingredient content 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, nert pharmaceutically suitable carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.
  • Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations.
  • Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. B. starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. B.
  • humectants e.g. B. glycerin
  • disintegrant e.g. B. agar-agar, calcium
  • 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 e.g. B. polymer substances and waxes can be used.
  • Embedding compounds e.g. B. polymer substances and waxes can be used.
  • the active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned carriers.
  • Suppositories can contain the usual water-soluble or water-insoluble excipients in addition to the active ingredient (s), e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat and higher esters (z. B. C 14 alcohol with C16 fatty acid) or mixtures of these substances.
  • active ingredient e.g. B. polyethylene glycols
  • fats e.g. B. cocoa fat and higher esters (z. B. C 14 alcohol with C16 fatty acid) or mixtures of these substances.
  • Ointments, pastes, creams and gels can contain the usual excipients in addition to the active ingredient (s), e.g. B. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and Z i- koxid or mixtures of these substances.
  • active ingredient e.g. B. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and Z i- koxid or mixtures of these substances.
  • Powder and sprays can contain the usual excipients in addition to the active ingredient (s), e.g. B. milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances.
  • Sprays can also use the usual blowing agents, e.g. B. chlorofluorocarbons.
  • solutions and emulsions can contain the usual carriers such as solvents, solubilizers and emulsifiers, e.g. B. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol, glycerol formaldehyde - hol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.
  • solvents e.g. B. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils,
  • 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 antipa asitary properties. These include in particular compounds that have already been used in therapy or are still being used. For this purpose, particularly suitable substances are those 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 / hrm 129.html listed on the Internet.
  • the derivatives can be combined with known antibiotics: for example with penicillin, benzylpenicillin (penicillin G), phenoxypenicillin, isoxazolylpenicillin, aminopenicillin, ampicillin, amoxixillin, bacampicillin, carboxypenidillin, ticarcillin, temocillocinin, acyalinoclaminocillinaclinoclaminocillin, acyalaminocillin lin, mecillinam, cephalosporins, cefazolin group, cefuroxime group, cefoxitin group, cefoxitin, Cefatetan, cefmetazole, latamoxef, flomoxef, cefotaxime Guppe, Cefozidim, ceftazidime group, ceftazidime, cefpirome, cefepime, other cephalosporins, cefsulodin, Ce - foperazone, oral cephalosporins of the cef
  • organophosphorus compounds in the pharmaceutical compositions can be used in combination with sulfonamide, sulfadoxine, artemisinin and artemisinin derivatives, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracycline, doxycycline, proguanil, prazamidazolazole, metronidazolazole Pyrantel, Tiaben azole, diethyl carbazine, piperazine, pyrivinum, metrifonate, oxamniquin, bithionol, lumefantrine or suramin or several 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).
  • 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 treatment of infections in cavities, body cavities.
  • Suitable preparations are injection solutions, solutions and suspensions for oral therapy, gels, pour-on formulations, emulsions, ointments or drops.
  • ophthalmic and dermatological formulations silver and other salts, ear drops, eye ointments, powder or solutions can be used.
  • suitable formulations can also be ingested through feed or drinking water.
  • Gels, powders, powders, tablets, prolonged-release tablets, premixes, concentrates, granules, pellets, tablets, boluses, capsules, aerosols, sprays, inhalants can also be used in humans and animals.
  • the compounds 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 a total amount 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 outstandingly as bactericides, fungicides and herbicides in plants.
  • the monoesters can be prepared from fosmidomycin as well as from di-octadecyl ester 1.
  • Example 2 is

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Abstract

The invention relates to organophosphorous compounds of general formula (I) and to their use 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

Phosphororganische Verbindungen und ihre Verwendung Organophosphorus compounds and their use
Die Erfindung betrifft phosphororganische Verbindungen sowie ihre Salze, Ester und Amide und ihre Verwendung 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. Erfindungsgemaß umfassen die phosphororganischen Verbindungen Phosphinoylderivate, Phosphinsäurederivate und Phosphonsäurederivate.The invention relates to organophosphorus compounds and their salts, esters and amides and their use for the manufacture of medicaments for the therapeutic and prophylactic treatment of infections in humans and animals 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 include phosphinoyl derivatives, phosphinic acid derivatives and phosphonic acid derivatives.
Es besteht ein starker Bedarf, für die Bereicherung der Behandlung von Mensch und Tier sowie den Schutz von Pflanzen Mittel bereitzustellen, die nicht nur eine starke Wirksamkeit besitzen, sondern auch im Gegensatz zu anderen Arzneimitteln bzw. Pflanzenschutzmitteln verringerte Nebenwirkungen zeigen und damit eine geringere Gesundheitsgefahr für den Menschen bedeuten.There is a strong need to provide means for the enrichment of the treatment of humans and animals and the protection of plants which are not only highly effective but also, in contrast to other medicinal products or crop protection agents, have reduced side effects and thus a lower health risk for mean to people.
Aufgabe der vorliegenden Erfindung ist es daher, eine Substanz bereitzustellen, die bei Infektionen durch Viren, Bakterien, Pilze und Parasiten bei Menschen und Tieren und als Fungizid, Bakterizid und Herbizid bei Pflanzen einsetzbar ist und die oben angegebenen Bedingungen erfüllt.The object of the present invention is therefore to provide a substance which can be used in infections by viruses, bacteria, fungi and parasites in humans and animals and as a fungicide, bactericide and herbicide in plants and which fulfills the conditions specified above.
Diese Aufgabe wird in völlig überraschender Weise durch die in Anspruch 1 definierte Stoffgruppe gelöst. Diese Stoffgruppe zeigt eine antiinfektiöse Wirkung gegen Viren, bestimmte Bakterien, Pilze, ein- und mehrzellige Parasiten.This object is achieved in a completely surprising manner by the group of substances defined in claim 1. This group of substances shows an anti-infectious effect against viruses, certain bacteria, fungi, single and multicellular parasites.
Die erfindungsgemäßen phosphororganischen Verbindungen entsprechen der allgemeinen Formel (I):The organophosphorus compounds according to the invention correspond to the general formula (I):
Figure imgf000003_0001
Figure imgf000003_0001
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, OXi 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 un- substituiertern Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsub- stituiertem 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,wherein R 1 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, OXi and OX 2 , where 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 aralkyl, substituted and unsubstituted a heterocyclic radical 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 substituiertem und unsubstituiertem Alkyl mit 1 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Hydroxyalkyl mit 1 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem Alkenyl mit 1 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Alkinyl mit 1 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem heterocyclischem Rest, Halogen und OX3 besteht, wobei X3 aus Wasserstoff, substituiertem und unsubstituiertem Alkyl mit 1 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Hydroxyalkyl mit 1 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem Alkenyl mit 1 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Alkinyl mit 1 bis 26 Kohlenstoffatomen, 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, undR 3 is selected from the group consisting of substituted and unsubstituted alkyl of 1 to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl of 1 to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl 1 to 26 carbon atoms, substituted and unsubstituted alkynyl having 1 to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen and OX 3 , where X 3 is hydrogen, substituted and unsubstituted alkyl having 1 to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl with 1 to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl with 1 to 26 carbon atoms, substituted and unsubstituted alkiny l with 1 to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, a substituted or unsubstituted silyl, a cation of an organic and inorganic base, in particular a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium and Ammonium compounds derived from ethylenediamine or amino acids, and
R» aus der Gruppe ausgewählt ist, die aus einem substituiertem und unsubstituiertem Alkyl mit 10 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Hydroxyalkyl mit 10 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Alkenyl mit 10 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Alkinyl mit 10 bis 26 Kohlenstoffatomen und O besteht, wobei X4 aus der Gruppe ausgewählt ist, die aus einem substituiertem und unsubstituiertem Alkyl mit 10 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Hydroxylalkyl mit 10 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Alkenyl mit 10 bis 26 Kohlenstoffatomen und einem substituierten und unsubstituierten Alkinyl mit 10 bis 26°Koh- lenstoffatomen besteht, und deren pharmazeutisch akzeptablen Salze, Ester und Amide und Salze der Ester. Bevorzugt ist R$ eine Alkyl-, Hydroxyalkyl-, Alkinyl- oder Alkenylgruppe mit 16 oder 18 Kohlenstoffatomen oder OX3, wobei X3 eine Alkyl-, Hydroxyalkyl-, Alkinyl- oder Alkenylgruppe mit 16 oder 18 Kohlenstoffatomen ist, R» eine Alkyl-, Hydroxyalkyl-, Alkinyl- oder Alkenylgruppe mit 16 oder 18 Kohlenstoffatomen oder O ist, wobei X* eine Alkyl-, Hydroxyalkyl-, Alkinyl- oder Alkenylgruppe mit 16 oder 18 Kohlenstoffatomen ist.R »is selected from the group consisting of a substituted and unsubstituted alkyl having 10 to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having 10 to 26 carbon atoms, substituted and unsubstituted alkenyl having 10 to 26 carbon atoms, substituted and unsubstituted alkynyl having 10 to 26 carbon atoms and O is, wherein X4 is selected from the group consisting of a substituted and unsubstituted alkyl of 10 to 26 carbon atoms, substituted and unsubstituted hydroxylalkyl of 10 to 26 carbon atoms, substituted and unsubstituted alkenyl of 10 to 26 carbon atoms and a substituted and unsubstituted alkynyl with 10 to 26 ° carbon atoms, and their pharmaceutically acceptable salts, esters and amides and salts of the esters. R $ is preferably an alkyl, hydroxyalkyl, alkynyl or alkenyl group with 16 or 18 carbon atoms or OX 3 , where X 3 is an alkyl, hydroxyalkyl, alkynyl or alkenyl group with 16 or 18 carbon atoms, R »is an alkyl , Hydroxyalkyl, alkynyl or alkenyl group with 16 or 18 carbon atoms or O, where X * is an alkyl, hydroxyalkyl, alkynyl or alkenyl group with 16 or 18 carbon atoms.
Insbesondere eignen sich die Verbindungen, die die folgende Formel (II) haben:The compounds which have the following formula (II) are particularly suitable:
XiO 0XiO 0
\ II\ II
N-A-P-R3 ( II)NAPR 3 (II)
/ I/ I
R2 4 R 2 4
entsprechen, wobeicorrespond with
X\ 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, R» und A die gleiche Bedeutung wie in Formel (I) haben.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 , R »and A have the same meaning as in formula (I).
Insbesondere sind Verbindungen der Formel (II) bevorzugt, für die R2 = Acyl, R3 eine Alkyl-, Hydroxyalkyl-, Alkinyl- oder Alkenylgruppe mit 16 oder 18 Kohlenstoffatomen oder OX3 ist, wobei X3 eine Alkyl-, Alkinyl-, Hydroxyalkyl- oder Alkenylgruppe mit 16 oder 18 Kohlenstoffatomen ist, R-t eine Alkyl-, Alkinyl-, Hydroxyalkyl- oder Alkenylgruppe mit 16 oder 18 Kohlenstoffatomen oder OX ist, wobei eine Alkyl-, Alkinyl-, Hydroxyalkyl- oder Alkenylgruppe mit 16 oder 18 Kohlenstoffatomen ist und mit Xi = H und A = Alkylen, Alkenylen oder Hydroxyalkylen ist. Besonders gute Ergebnisse werden mit R2 = Formyl oder Acetyl und A = eine Gruppe, die das Phosphoratom und das Stickstoffatom mit einer Kette aus drei Kohlenstoffatomen verbindet, insbesondere Propylen, Propenylen oder Hydroxypropylen, erzielt.In particular, compounds of the formula (II) are preferred for which R 2 = acyl, R 3 is an alkyl, hydroxyalkyl, alkynyl or alkenyl group with 16 or 18 carbon atoms or OX 3 , where X 3 is an alkyl, alkynyl, Is hydroxyalkyl or alkenyl group with 16 or 18 carbon atoms, R- t is an alkyl, alkynyl, hydroxyalkyl or alkenyl group with 16 or 18 carbon atoms or OX, wherein an alkyl, alkynyl, hydroxyalkyl or alkenyl group with 16 or 18 Is carbon atoms and with Xi = H and A = alkylene, alkenylene or hydroxyalkylene. Particularly good results are obtained with R 2 = formyl or acetyl and A = a group which connects the phosphorus atom and the nitrogen atom with a chain of three carbon atoms, in particular 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. Geeignete Beispiele für diese Acylgruppen werden nachfolgend angegeben."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. 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. Bf 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, isopropoxycarbonyl, 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 A ino, 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, may 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 sol- ehe, die als geeignete Substituenten für die Alkylgruppe bzw. den Alkanrest bereits angegeben wurden. Insbesondere und als Beispiel für bevorzugte aromatische Acylreste mit besonderen Substituenten werden mit Halogen und Hydroxy oder mit Halogen und Acyloxy substituiertes Aroyl und mit Hydroxy, Hydroxyimino, Dihalogenalkanoyloxyimino substituiertes Aralkanoyl angegeben sowie Aryithiocarbamoyl (z.B. Phenylthiocarbamoyl etc.); Arylcarbamimidoyl (z.B. Phenylcarbamimidoyl etc.).In the above examples of aromatic acyl radicals, the aromatic hydrocarbon part (in particular the aryl radical) and / or the aliphatic hydrocarbon part (in particular the alkane radical) may optionally have one or more suitable substituents, such as those which are suitable substituents for the alkyl group or the alkane residue have already been specified. In particular and as an example of preferred aromatic acyl radicals with special substituents, aroyl substituted with halogen and hydroxy or with halogen and acyloxy and aralkanoyl substituted with hydroxy, hydroxyimino, dihalogenalkanoyloxyimino and aryithiocarbamoyl (e.g. phenylthiocarbamoyl etc.); Arylcarbamimidoyl (e.g. phenylcarbamimidoyl etc.).
Als heteroeyclischer Acylrest wird ein Acylrest verstanden, der von einer Säure mit heteroey- clischer Gruppe stammt; dazu gehören:A heteroeyclic acyl residue is understood to mean an acyl residue which comes from an acid with a heteroyclic 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-Alkanoyi, 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.Heterocyclic alkanoyi 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 Kohlenstoffatome , soweit es nicht anders definiert ist, wie Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.- Butyl, Pentyl, Hexyl und dergleichen."Alkyl" is a straight or branched chain alkyl radical having up to 9 carbon atoms, unless otherwise defined, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.
„Hydroxylalkyi" ist ein gerad- oder verzweigtkettiger Alkylrest mit bis zu 9 Kohlenstoffen, soweit es nicht anders definiert ist, der mindestens eine Hydroxylgruppe aufweist, bevorzugt ein oder zwei Hydroxylgruppen. Zu „Alkenyl" gehören gerad- oder verzweigtkettige Alkenylgruppen mit bis zu 9 Kohlenstoffatomen, soweit es nicht anders definiert ist, wie z.B. Vinyl, Propenyl (z.B. 1-Propenyl, 2- Propenyl), 1-Methylpropenyl, 2-Methylpropenyl, Butenyl, 2-Ethylpropenyl, Pentenyl, Hexe- nyl."Hydroxylalkyl" is a straight or branched chain alkyl radical with up to 9 carbons, unless defined otherwise, which has at least one hydroxyl group, preferably one or two hydroxyl groups. "Alkenyl" includes straight or branched chain alkenyl groups with up to 9 carbon atoms, unless otherwise defined, such as vinyl, propenyl (e.g. 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, soweit es nicht anders definiert ist."Alkynyl" includes straight or branched chain alkynyl groups with up to 9 carbon atoms, unless otherwise defined.
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 -(CnH2n)- wiedergegeben werden können, in der n eine ganze Zahl von 1 bis 9 ist, wie Methylen, Ethy- len, Trimethylen, Methylethylen, Tetramethylen, 1-Methyltrimethylen, 2-Efhylethylen, 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 auch durch Substituenten, wie zum Beispiel Halogenreste, ersetzt sein.“Alkylene” includes straight-chain or branched-chain alkylene groups which have up to 9 carbon atoms and can be represented by the formula - (C n H 2n ) -, in which n is an integer from 1 to 9, such as methylene, ethyl len, trimethylene, methylethylene, tetramethylene, 1-methyltrimethylene, 2-ethylene, 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 trimethylene are particularly preferred can also be replaced by substituents, such as halogen radicals.
Zu „Alkenylen" gehören gerad- oder verzweigtkettige Alkenylengruppen mit bis zu 9 Kohlenstoffatomen, die durch die Formel
Figure imgf000008_0001
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 auch durch Substituenten, wie zum Beispiel Halogenreste, ersetzt sein."Alkenylene" includes straight or branched chain alkenylene groups with up to 9 carbon atoms, which are represented by the formula
Figure imgf000008_0001
can be reproduced in which n is an integer from 2 to 9, such as vinylene, propenylene (e.g. 1-propenylene, 2-propenylene), 1-methylpropenylene, 2-methylpropenylene, butenylene, 2-ethylpropenylene, 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, for example, 1-propenylene. The hydrogen atoms can also be substituted by substituents such as for example halogen residues.
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
-(C„H2n-z)(OH)z- wiedergegeben werden, in der n eine ganze Zahl von 1 bis 9 ist und z eine ganze Zahl ist, für die 1 < z < n gϊlfc Zu geeigneten Beispielen für solche Hydroxyalkylengruppen gehören Hy- droxymethylen, Hydroxyethylen (z.B. 1-Hydroxyethyle 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 auch durch Substituenten, wie zum Beispiel Halogenreste, ersetzt sein.- (C "H 2n - z ) (OH) z - are reproduced, in which n is an integer from 1 to 9 and z is an integer for which 1 <z <n gclfc. Suitable examples of such hydroxyalkylene groups include Hydroxymethylene, hydroxyethylene (e.g. 1-hydroxyethyl and 2-hydroxyethylene), hydroxytrimethylene (e.g. 1-hydroxytrimethylene, 2-hydroxytrimethylene and 3-hydroxytrimethylene), hydroxytetramethylene (e.g. 2-hydroxytetramethylene), 2-hydroxy-2- methyltrimethylene, hydroxypentamethylene (e.g. 2-hydroxy-pentamethylene), hydroxyhexamethylene (e.g. 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 also be replaced by substituents, such as halogen radicals.
Vorzugsweise können die Reste X3 und X» so gewählt werden, daß Ester an der Phosphino- gruppe oder Phosphonogruppe gebildet werden. Zu geeigneten Beispielen für solche Ester gemäß der Formeln (I) und (II) zählen geeignete Mono- und Diester, und zu bevorzugten Beispielen für solche Ester gehören Alkylester (z.B. Hexadecanylester, Octadecanylester etc.);The radicals X 3 and X »can preferably be chosen such that esters are formed on the phosphino group or phosphono group. Suitable examples of such esters according to formulas (I) and (II) include suitable mono- and diesters, and preferred examples of such esters include alkyl esters (eg hexadecanyl ester, octadecanyl ester, etc.);
Aralkylester (Benzylester, Phenethylester, Benzhydrylester, Tritylester etc.);Aralkyl esters (benzyl esters, 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 X3 auch 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, Trie- thylaminsalz, Ethanolaminsalz, Dicyclohexylaminsalz, Ethylendiaminsalz, N,N"- Dibenzylethylendiaminsalz etc.) sowie Salze mit Aminosäuren (z.B. Argininsalz, Asparagin- o säuresalz, Glutaminsäuresalz etc.) und dergleichen gebildet.X 3 is preferably also a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium, or ammonium compounds which are derived from ethylenediamine or amino acids. Ie there are the salt compounds of the organophosphorus compounds with organic or inorganic bases (for example sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylamine salt, ethanolamine salt, dicyclohexylamine salt, ethylenediamine salt, N, N "- dibenzylethylenediamine salt, etc.) and salts with amino acids (e.g. arginine salt, asparagine o acid salt, glutamic acid salt etc.) and the like.
Die erfindungsgemäß verwendeten Verbindungen gemäß der Formeln (I) oder (II) könηen in ihrer protonierten Form als Ammoniumsalz organischer oder anorganischer Säuren, wie Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Salpetersäure, Methansulfonsäure, p- Toluolsulfonsäure, Essigsäure, Milchsäure, Maleinsäure, Fumarsäure, Oxalsäure, Weinsäure, Benzoesäure, etc. vorliegen.The compounds according to formulas (I) or (II) used according to the invention can, in their protonated form, as the ammonium salt of organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, maleic acid, fumaric acid, oxalic acid , Tartaric acid, benzoic acid, etc. are present.
Die erfindungsgemäßen Verbindungen der Formeln (I) oder (II) lassen beispielsweise für Doppelbindungen enthaltende oder chirale Gruppen Ri, R2, R3, Rt, Xi, X2, X» 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) according to the invention allow, for example for spatial groups containing chiral groups R 1, R 2 , R 3 , Rt, Xi, X 2 , X 'or A, to have 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 Behandlμng 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 Familie Nei- sseriaceae, insbesondere der Gattungen Neisseria und Moraxella, insbesondere die Arten Nei- sseria meningitides, Neisseria gonorrhoeae und Moraxella bovis, Bakterien der Familie Vi- brionaceae, insbesondere der Gattungen Vibrio, Aeromonas, Plesiomonas und Photobadteri- um, insbesondere die Arten Vibrio cholerae, Vibrio anguillarum und Aeromonas salmonici- das, Bakterien der Gattung Campylobacter, insbesondere die Arten Campylobacter jejuni, Campylobacter coli und Campylobacter fetus, Bakterien der Gattung Helicobacter, insbesondere die Art Helicobacter pylori, Bakterien der Familien Spirochaetaceae und der Leptospira- ceae, insbesondere der Gattungen Treponema, Borrelia und Leptospira, insbesondere Borrelia burgdorferi, Bakterien der Gattung Actinobacillus, Bakterien der Familie Legionellaceae, der Gattung Legionella, Bakterien der Familie Rickettsiaceae und Familie Bartonellaceae, Bakterien der Gattungen Nocardia und Rhodococcus, Bakterien der Gattung Dermatophilus, Bakterien der Familie Pseudomonadaceae, insbesondere der Gattungen Pseudomonas und Xantho- monas, Bakterien der Familie Enterobacteriaceae, insbesondere der Gattungen Escherichia, Klebsieila, Proteus, Providencia, Salmonella, Serratia und Shigella, Bakterien der Familie Pasteurellaceae, insbesondere der Gattung Haemophilus, Bakterien der Familie Micrococca- ceae, insbesondere der Gattungen Micrococcus und Staphylococcus, Bakterien der Familie Streptococcaceae, insbesondere der Gattungen Streptococcus und Enterococcus und Bakterien der Familie Bacillaceae, insbesondere der Gattungen Bacillus und Clostridium.Bacteria of the Propionibacteriaceae family, in particular the Propionibacterium genus, in particular the Propionibacterium acnes species, Actinomycetaceae bacteria, in particular the Actinomyces genus, Corynebacterium bacteria, in particular the Corynebacterium diphteriae and Corynebacterium pseudote family mycobacteria, bacteria the species Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium, bacteria of the family Chlamydiaceae, especially the species Chlamydia trachomatis and Chlamydia psittaci, bacteria of the genus Listeria, especially the species Listeria mo- nocytogenes, bacteria of the species Erysipelthrix rhusiopathiae, 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, especially the Mycoplasma genus and the Mycoplasma genus and the Mycoplasma genus , Bacteria of the genus Brucella, bacteria of the genus Bordetella, bacteria of the family Neiseriaeae, in particular of the genera Neisseria and Moraxella, in particular the species Neiseria meningitides, Neisseria gonorrhoeae and Moraxella bovis, bacteria of the family Vibrionaceae, particularly of the Vibrio genus , Aeromonas, Plesiomonas and Photobadterium, in particular the species Vibrio cholerae, Vibrio anguillarum and Aeromonas salmonici- das, bacteria of the genus Campylobacter, in particular the species Campylobacter jejuni, Campylobacter coli and Campylobacter fetus, bacteria of the genus Helicobacter, in particular the species Hel icobacter pylori, bacteria of the Spirochaetaceae and Leptospiraceae families, in particular the Treponema, Borrelia and Leptospira genera, in particular Borrelia burgdorferi, Actinobacillus bacteria, Legionellaceae family, Legionella family, Bartettoneaceae family and bacteria, the Rickettiacelleae family Genera Nocardia and Rhodococcus, bacteria of the genus Dermatophilus, bacteria of the family Pseudomonadaceae, especially of the genera Pseudomonas and Xanthomonas, bacteria of the family Enterobacteriaceae, especially of the genera Escherichia, Klebsieila, Proteus, Providencia, Salmonella, Serratia and der Pasteur family , in particular of the genus Haemophilus, bacteria of the Micrococceae family, especially of the genera Micrococcus and Staphylococcus, bacteria of the Streptococcaceae family, in particular of the Streptococcus and Enterococcus genus and bacteria of the Bacillaceae family, in particular especially of the genera Bacillus and Clostridium.
Damit eignen sich phosphororganischen Verbindungen und ihre Derivate zur Behandlung der Diphterie, der Acne vulgaris, der Listeriosen, des Rotlaufs bei Tieren, der Gasbrand beim Mensch und beim Tier, Pararauschbrand bei Mensch und Tier, Tuberkulose bei Mensch und Tier, Lepra, und weitere Mykobacteriosen bei Mensch und Tier, der Paratuberkulose der Tiere, Pest, mesenterialen Lymphadenitis und Pseudotuberkulose bei Mensch und Tier, Cholera, Legionärskrankheit, Borreliose bei Mensch und Tier, Leptospirosen bei Mensch und Tier, Syphilis, Campylobacter-Enteritiden bei Mensch und Tier, Moraxella-Keratokoηjunc-tivitis und Serositis der Tiere, Brucellosen der Tiere und des Menschen, Milzbrand bei Mensch und Tier, Aktinomykose bei Mensch und Tier, Streptotrichosen, Psittakose/Oraithose 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 keratokoηjunc -tivitis and serositis of animals, brucellosis of animals and humans, anthrax in humans and animals, actinomycosis in humans and animals, streptotrichoses, psittacosis / orithosis in animals, Q fever, Ehrlichiosis.
Weiter ist der Einsatz nützlich bei der Helicobacter-Eradikationstherapie bei Ulcera des Magendarmtraktes.The use is also useful in Helicobacter eradication therapy for ulcers of the gastrointestinal tract.
Es können auch Kombinationen mit einem weiteren Antibiotikum zur Behandlung der oben- genannten Erkrankungen eingesetzt werden. Für Kombinationspräparate mit anderen Antiin- fektiva eignen sich insbesondere Isoniazid, Rifampicin, Ethambutol, Pyrazinamid, Strep- tomycin, Protionamid und Dapson zur Behandlung der Tuberkulose.Combinations with another antibiotic can also be used to treat the above mentioned diseases are used. For combination preparations with other anti-infectives, isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, protionamide and dapsone are particularly suitable for the treatment of tuberculosis.
Die erfindungsgemäßen Wirkstoffe sind ferner insbesondere bei Infektionen mit folgenden Viren einsetzbar:The active compounds according to the invention can also be used in particular for infections with the following viruses:
Parvoviridae: Parvoviren, Dependoviren, Densoviren, Adenoviridae: Adenoviren, Mastade- noviren, Aviadenovire , Papovaviridae: Papovaviren, insbesondere Papillomaviren (sogenannte Warzenviren), Polyomaviren, insbesondere JC- Virus, BK- Virus, und Miopapovaviren, Herpesviridae: Alle Herpesviren, insbesondere Herpes-Simplex- Viren, der Varizellen/Zoster- Viren, menschlicher Zytomegalievirus, Epstein-Barr- Viren, alle humanen Herpesviren, humanes Herpesvirus 6, Humanes Herpesvirus 7, humanes Herpesvirus 8, Poxviri- dae:Pockenviren, Orthopox-, Parapox-, Molluscum-Contagiosum- Virus, Aviviren, Caprivi- ren, Leporipoxviren, alle primär hepatotropen Viren, Hepatitisviren: Hepatitis- A- Viren, He- patitis-B-Viren, Hepatkis-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: Hepatiti§-E- Viren, Reoviridae: Reoviren, Orbiviren, Rotaviren, Togaviridae: Togaviren, Alphaviren, Ru- biviren, Pestiviren, Rubellavirus, Flaviviridae: Flaviviren, FSME-Virus, Hepatitis-C-Virus, Orthomyxoviridae: Alle Influenzaviren, Paramyxoviridae: Paramyxoviren, Morbillivirus, Pneumovirus, Masernvirus, Mumpsvirus, Rhabdoviridae: Rhabdoviren, Rabiesvirus, Lyssavi- rus, viskuläres Stomatitisvirus, Coronaviridae: Coronavire , Bunyaviridae: Bunyaviren, Nai- rovirus, Phlebovirus, Uukuvirus, Hantavirus, Hantaanvirus, Arenaviridae: Arenaviren, lym- phozytäres Choriomeningitis- Virus, Retroviridae: Retrovire , alle HTL- Viren, humanes T- cell Leukämievirus, Oncornaviren, Spumaviren, Lentiviren, alle HI- Viren, Filoviridae: Marburg- und Ebolavirus, Slow-virus-Infektionen, Prionen, Onkoviren und Leukämieviren.Parvoviridae: Parvoviruses, Dependoviruses, Densoviruses, Adenoviridae: Adenoviruses, Mastadenoviruses, Aviadenovire, Papovaviridae: Papovaviruses, in particular Papillomaviruses (so-called Wartsviruses), Polyomaviruses, in particular JC Virus, 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, aviviruses, capriviruses, leporipox viruses, all primarily hepatotropic viruses, hepatitis viruses: hepatitis A viruses, hepatitis B viruses, hepatkis C viruses, hepatitis D viruses, hepatitis E viruses 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 echoviruses, all Rh inoviruses, hepatitis A virus, aphthoviruses, calciviridae: hepatitis E viruses, reoviridae: reoviruses, orbiviruses, rotaviruses, togaviridae: togaviruses, alphaviruses, riviviruses, pestiviruses, rubellavirus, flaviviridae FS: -C virus, Orthomyxoviridae: all influenza viruses, Paramyxoviridae: Paramyxoviruses, Morbillivirus, Pneumovirus, measles virus, Mumpsvirus, Rhabdoviridae: Rhabdoviruses, Rabies virus, Lyssavirus, Viscular Stomatitisvirus, Coronaviravirovir, Virus Coronaviravirovirus, Coronaviravirovirus, Coronaviraviravir , Hantavirus, Hantaanvirus, Arenaviridae: Arenaviruses, lymphocytic choriomeningitis virus, Retroviridae: Retrovire, all HTL viruses, human T-cell leukemia virus, Oncornaviruses, Spumaviruses, Lentiviruses, all HI viruses, Marburg virus, Filoviridae and Eboviridae viruses -virus infections, prions, oncoviruses and leukemia viruses.
Die erfindungsgemäß verwendeten phosphororganischen Verbindungen sind somit zur Bekämpfung folgender vi'raler 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 Eppstein- Barr-Viren-assozierten Tumoren, Eradikation von Hepatitisviren zur Behandlung von chronischen Leber-Erkrankungen und zur Vorbeugung von Lebertumoren und Leberzirrhosen, Eradikation von Coxsackieviren bei Kardiomyopathien, Eradikation von Coxsackieviren bei Dia- betes-mellitus-Patienten, Eradikation von Immunschwäche- Viren in Mensch und Tier, Behandlung von Begleitinfektionen in AIDS-Patienten, Behandlung von Entzündungen viraler Genese des Respirationstraktes (Larynxpapillome, Hyperplasien, Rhinitis, Pharyngitis, Bronchitis, Pneumonien), der Sinnesorgane (Keratokonjunktivitis), des Nervensystems (Poliomyelitis, Meningoenzephalitis, Enzephalitis, subakute sklerosierende Panenzephalitis, SSPE, progressive multifokale Leukoenzephalopathie, Lymphozytäre Choriomeningitis), des Magen- Darm-Traktes (Stomatitis, Gingivostomatitis, Ösophagitis, Gastritis, Gastroenteritis, Durch- fallerkrankungerL), der Leber und des Gallensystems (Hepatitis, Cholangitis, hepatozelluläres Karzinom), des lymphatischen Gewebes (Mononukleose, Lymphadenitis), des hämatopoeti- schen Systems, der Geschlechtsorgane (Mumpsorchitis), der Haut (Warzen, Dermatitis, Her- pes labialis, Fieberbläschen, Herpes Zoster, Gürtelrose), der Schleimhäute (Papillome, Kon- junktivapapillome, Hyperplasien, Dysplasien), des Herz-Blutgefäß-Systems (Arteriitis, Myokarditis, Endokarditis, Perikarditis), des Nieren-Harnweg- Systems, der Geschlechtsorgane (Anogenitale Läsionen, Warzen, Genitalwarzen, spitzen Kondylome, Dysplasien, Papillome, Zervixdysplasien, Condylomata acuminata, Epidermodysplasia verruciformis), der Bewegungsorgane (Myositis, Myalgien), Behandlung der Maul- und Klauenseuche der Paarhufer, des Colorado-Zeckenfiebers, des Dengue-Syndroms, des hämorrhagisches Fiebers, der Früh- sommermeningoenzephalitis (FSME) und des Gelbfiebers.Eradication of papillomaviruses for the prevention of tumors, in particular tumors of the genital organs caused by papillomaviruses in humans, eradication of JC viruses and BK viruses, eradication of herpes viruses, eradication of human herpes viruses 8 for the treatment of Kaposi's sarcoma, eradication of cytomegaloviruses Transplants, eradication of Eppstein-Barr viruses before transplantation and for the prevention of Eppstein-Barr virus-associated tumors, eradication of hepatitis viruses for the treatment of chronic liver diseases and for the prevention of liver tumors and liver cirrhosis, eradication of Coxsackieviruses in cardiomyopathies, eradication Coxsackie viruses in slide betes-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, hyperplasias, rhinitis, pharyngitis, bronchitis, pneumonia), the sensory organs (keratoconjunctivitis) , the nervous system (poliomyelitis, meningoencephalitis, encephalitis, subacute sclerosing panencephalitis, SSPE, progressive multifocal leukoencephalopathy, lymphocytic choriomeningitis), of the gastrointestinal tract (stomatitis, gingivostomatitis, oesophagitis, gastritis, gastroenteritis, transit fallerkrankungerL), the liver and the Biliary system (hepatitis, cholangitis, hepatocellular carcinoma), the lymphatic tissue (mononucleosis, lymphadenitis), the hematopoietic system, the genital organs (mumps orchitis), the skin (warts, dermatitis, herpes labialis, cold sores, herpes zoster, herpes zoster, herpes zoster , the mucous membranes (papillomas, conjunctival apillomas, hyperplasias, dysplasias), the cardiovascular system (arteritis, myocarditis, endocarditis, pericarditis), the kidney-urinary system, the genital organs (anogenital lesions, warts, genital warts, acute condylomas, dysplasias, papillomas, cervical dysplasia) acuminata, epidermodysplasia verruciformis), the locomotive organs (myositis, myalgia), treatment of foot and mouth disease in cloven hoofed animals, Colorado tick fever, dengue syndrome, hemorrhagic 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 compounds described, ie 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 the prevention of 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 (IT) 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 (IT) used according to the invention in their protonated form Form ammonium salt of inorganic or organic acids, such as hydrochloric acid, sulfuric acid, citric acid, maleic acid, fumaric acid, tartaric acid, p-toluenesulfonic acid.
Pharmazeutisch besonders geeignet sind auch die Salze, die durch geeignete Auswahl von X3 gebildet werden, wie Natriumsalz, Kaliumsalz, Calciumsalz, Ammoniumsalz, Ethanolamin- salz, Triethylaminsalz, Dicyclohexylaminsalz und Salze einer Aminosäure wie Argininsalz, Asparaginsäuresalz, Glutaminsäuresalz.Also particularly pharmaceutically suitable are the salts which are formed by suitable selection of X 3 , such as sodium salt, potassium salt, calcium salt, ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt and salts of an amino acid such as arginine salt, aspartic acid salt, glutamic acid salt.
Die Aktivität der Substanzen wird in einem Versuchssystem bestimmt. Dieses System beruht auf die Messung der Inhibition des Wachstums von Bakterien, Parasiten, Viren, Pilze oder Pflanzen in vitro. Hierzu werden zum Teil Versuchsverfahren verwendet, die dem Fachmann bekannt sind.The activity of the substances is determined in a test system. This system is based on the measurement of the inhibition of the growth of bacteria, parasites, viruses, fungi or plants in vitro. For this purpose, test methods are used which are known to the person skilled in the art.
Zum Beispiel wird zur Bestimmung der Antimalaria-Aktivität die Inhibition des Wachstums von Malaria-Parasiten in Blutkulturen bestimmt.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 fungiziden 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, fungizide 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, coated tablets, capsules, pills, suppositories and ampoules are present, whose active ingredient content 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, nerten pharmazeutisch geeigneten Trägerstoffen sind feste, halbfeste oder flüssige Vejdünnungsmittel, Füllstoffe und Formulierungshilfsmittel jeder Art zu verstehen.Non-toxic, nert pharmaceutically suitable carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.
Als bevorzugte pharmazeutische Zubereitungen seien Tabletten, Dragees, Kapseln, Pillen, Granulate, Suppositorien, Lösungen, Suspensionen und Emulsionen, Pasten, Salben, Gele, Cremes, Lotions, Puder und Sprays genannt. Tabletten, Dragees, Kapseln, Pillen und Granulate können den oder die Wirkstoffe neben den üblichen Trägerstoffen enthalten, wie (a) Füll- und Streckmittel, z. B. Stärken, Milchzucker, Rohrzucker, Glukose, Mannit und Kieselsäure, (b) Bindemittel, z. B. Carboxymethylcellulose, Alginate, Gelatine, Polyvinylpyrrolidon, (c) Feuchthaltemittel, z. B. Glycerin, (d) Sprengmittel, z. B. Agar-Agar, Calciumcarbonat und Natriumcarbonat, (e) Lösungsverzögerer, z. B. Paraffin und (f) Resorptionsbeschleuniger, z. B. quarternäre Ammoniumverbindungen, (g) Netzmittel, z. B. Cetylalkohol, Glycerinmono- stearat, (h) Adsorptionsmittel, z. B. Kaolin und Bentonit und (i) Gleitmittel, z. B. Talkum, Calcium- und Magnesiumstearat und feste Polyethyienglykole oder Gemische der unter (a) bis (i) aufgeführten Stoffe.Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations. Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. B. starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. B. carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, (c) humectants, e.g. B. glycerin, (d) disintegrant, e.g. B. agar-agar, calcium carbonate and sodium carbonate, (e) solution retarders, e.g. B. paraffin and (f) absorption accelerator, e.g. B. quaternary ammonium compounds, (g) wetting agents, e.g. B. cetyl alcohol, glycerol monostearate, (h) adsorbent, for. B. kaolin and bentonite and (i) lubricants, e.g. B. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).
Die Tabletten, Dragees, Kapseln, Pillen und Granulate können mit den üblichen, gegebenenfalls Opakisierungsmittel enthaltenden Überzügen und Hüllen versehen sein und auch so 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 können.The tablets, dragees, capsules, pills and granules can be provided with the customary coatings and casings, optionally containing opacifying agents, and can also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, possibly with a delay, where as Embedding compounds e.g. B. polymer substances and waxes can be used.
Der oder die Wirkstoffe können gegebenenfalls mit einem oder mehreren der oben angegebenen Trägerstoffe auch in mikroverkapselter Form vorliegen.The active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned carriers.
Suppositorien können neben dem oder den Wirkstoffen die üblichen wasserlöslichen oder wasserunlöslichen Trägerstoffe enthalten, z. B. Polyethyienglykole, Fette, z. B. Kakaofett und höhere Ester (z. B. C 14- Alkohol mit C16-Fettsäure) oder Gemische dieser Stoffe.Suppositories can contain the usual water-soluble or water-insoluble excipients in addition to the active ingredient (s), e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat and higher esters (z. B. C 14 alcohol with C16 fatty acid) or mixtures of these substances.
Salben, Pasten, Cremes und Gele können neben dem oder den Wirkstoffen die üblichen Trägerstoffe enthalten, z. B. tierische und pflanzliche Fette, Wachse, Paraffine, Stärke, Tragant, Cellulosederivate, Polyethyienglykole, Silikone, Bentonite, Kieselsäure, Talkum und Z i- koxid oder Gemische dieser Stoffe.Ointments, pastes, creams and gels can contain the usual excipients in addition to the active ingredient (s), e.g. B. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and Z i- koxid or mixtures of these substances.
Puder und Sprays können neben dem oder den Wirkstoffen die üblichen Trägerstoffe enthalten, z. B. Milchzucker, Talkum, Kieselsäure, Aluminiumhydroxid, Calciumsilikat und Polyamidpulver oder Gemische dieser Stoffe. Sprays können zusätzlich die üblichen Treibmittel, z. B. Chlorfluorkohlenwasserstoffe, enthalten.Powder and sprays can contain the usual excipients in addition to the active ingredient (s), e.g. B. milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also use the usual blowing agents, e.g. B. chlorofluorocarbons.
Lösungen und Emulsionen können neben dem oder den Wirkstoffen die üblichen Trägerstoffe wie Lösungsmittel, Lösungsvermittler und Emulgatoren, z. B. Wasser, Ethylalkohol, Isopro- pylalkohol, Ethylcarbonat, Ethylacetat, Benzylalkohol, Benzylbenzoat, Propylenglykol, 1,3- Butylenglykol, Dimethylformamid, Öle, insbesondere Baumwollsaatöl, Erdnußöl, Mais- keimöl, Olivenöl, Ricinusöl und Sesamöl, Glycerin, Glycerinformal, Tetrahydrofürfurylalko- hol, Polyethyienglykole und Fettsäureester des Sorbitans oder Gemische dieser Stoffe enthalten.In addition to the active ingredient (s), solutions and emulsions can contain the usual carriers such as solvents, solubilizers and emulsifiers, e.g. B. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol, glycerol formaldehyde - hol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.
Zur parenteralen Applikation können die Lösungen und Emulsionen auch in steriler und bluti- sotonischer Form vorliegen.For parenteral administration, the solutions and emulsions can also be 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 antipa asitärer 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/hrm 129.html im Internet mitaufgeführt. Insbesondere können die Derivate mit bekannten Antibiotika kombiniert werden: z.B. mit Penicillin, Benzylpenicillin (Penicillin G), Phenoxypenicillin, Isoxa- zolylpenicillin, Aminopenicillin, Ampicillin, Amoxixillin, Bacampicillin, Carboxypenidillin, Ticarcillin, Temocillin, Acyalaminopenicilline, Azlocillin, Mezlocillin, Piperacillin, Apalcil- lin, Mecillinam, Cephalosporine, Cefazolin-Gruppe, Cefuroxim-Gruppe, Cefoxitin-Gruppe, Cefoxitin, Cefatetan, Cefmetazol, Latamoxef, Flomoxef, Cefotaxim-Guppe, Cefozidim, Ceftazidim-Gruppe, Ceftazidim, Cefpirom, Cefepim, übrige Cephalosporine, Cefsulodin, Ce- foperazon, Oralcephalosporine der Cefalexin-Gruppe, Loracarbef, Cefprozil, neue Oralce- phalosporine mit erweitertem Spektrum, Cefixim, Cefpodoxim-Proxetil, Cefuroxim-Axetil, Cefetamet, Cefotiam-Hexetil, Cefdinir, Ceftibuten, andere ß-Lactam-Antibiotika, Carbape- nem, Imipenem /Cilastatin, Meropenem, Biapenem, Aztreonam, ß-Lactamase-Hemmer, Cla- vulansäure/Amoxicillin, Clavulansäure/Ticarcillin, Sulbactam/Ampicillin, Tazobac- tam/Piperacillin, Tetracycline, Oxytetracyclin, Rolitetraxyxlin, Doxycyclin, Minocyclin, Chloramphenicol, Aminoglykoside, Gentamicin, Tobramycin, Netilmicin, Amikacin, Specti- nomyxin, Makrolide, Erythromycin, Clarithromycin, Roxithromycin, Azithromycin, Di- rithromycin, Spiramyci , Josamycin, Lincosamide, Clindamycin, Fusidinsäure, Glykopeptid- Antibiotika, Vancomycin, Tecoplanin, Pristinamycin-Derivate, Fosfomycin, Antimikrobielle Folsäureantagonisten, Sulfonamide, Co-Trimoxazol, Trimethoprim, andere Diaminopyrimi- din-Sulfonamid-Kombinationen, Nitrofurane, Nitrofürantoin, Nitrofurazon, Gyrase-Hemmer (Chinolone), Norfloxacin, Ciprofloxacin, Ofloxacin, Sparfloxacin, Enoxacin, Fleroxacin, Pe- floxacin, 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, antivirale Mittel, Acyclovir, Ganciclovir, Azidothymidin, Didanosin, Zalcitabin, Thiacytidin, Stavudin, Ribavirin, Idoxuridin, Trifluri- din, Foscamet, Amantadin, Interferone, Tibol-Derivate, Proteinase-Inhibitoren, Antimykotika, Polyene, Amphothericin B, Nystatin, Natamycin, Azole, Azole zur septischen Therapie, Mi- conazol, Ketoconazol, Itraconazol, Fluconazol, UK- 109.496, Azole für lokale Anwendung, Clotrimazol, Econazol, Isoconazol, Oxiconazol, Bifonazol, Flucytosin, Griseofulvin, Ciclopi- roxolamin, Tolnaftat, Naftifin, Terbinafin, Amorolfin, Antrachinone, Betulinic acid, Semian- thrachinone, Xanthone, Naphtoquinone, Aryaminoalkohole, Chinin, Quinidine, Mefloquin, Halofantrin, Chloroquin, Amodiaquin, Acridin, Benzonaphthyridin, Mepacrin, Pyronaridin, Dapson, Sulfonamide, Sulfadoxin, Sulfalene, Trimethoprim, Proguanil, Chlorproguanil, Dia- minopyrimidine, Pyrimethamin, Primaquin, Aminoquinoline, WR 238,605, Tetracyclin, Doxycyclin, Clindamycin, Norfloxacin, Ciprofloxacin, Ofloxacin, Artemisinin, Dihydroar- temisinin, 10b artemether, Arteether, Atrtesunat, Atovaquon, Suramin, Melarsoprol, Nifurt- mox, Stibogluconat-Natrium, Pentamidin, Amphotericin B, Metronidazol, clioquinol, Meben- dazol, Niclosamid, Praziquantel, Pyrantel, Tiabendazol, Diethylcarbamazin, Ivermectin, Bit- hionol, Oxamniquin, Metrifonat, Piperazin, Embonat.The compounds can be used with previously described substances with antibacterial, antiviral, antimyctoic and antipa asitary properties. These include in particular compounds that have already been used in therapy or are still being used. For this purpose, particularly suitable substances are those 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 / hrm 129.html listed on the Internet. In particular, the derivatives can be combined with known antibiotics: for example with penicillin, benzylpenicillin (penicillin G), phenoxypenicillin, isoxazolylpenicillin, aminopenicillin, ampicillin, amoxixillin, bacampicillin, carboxypenidillin, ticarcillin, temocillocinin, acyalinoclaminocillinaclinoclaminocillin, acyalaminocillin lin, mecillinam, cephalosporins, cefazolin group, cefuroxime group, cefoxitin group, cefoxitin, Cefatetan, cefmetazole, latamoxef, flomoxef, cefotaxime Guppe, Cefozidim, ceftazidime group, ceftazidime, cefpirome, cefepime, other cephalosporins, cefsulodin, Ce - foperazone, oral cephalosporins of the cefalexin group, loracarbef, cefprozil, new oral chalphosporins with extended spectrum, cefixime, cefpodoxime proxetil, cefuroxime axetil, cefetamet, cefotiam hexetil, cefdinir, antibiotics, antibiotics, ceftibutene, antibiotic, ceftibutene, antibiotic, ceftibutene, antibiotics nem, imipenem / cilastatin, meropenem, biapenem, aztreonam, ß-lactamase inhibitor, cla-vulanoic acid / amoxicillin, clavulanic acid / tica rcillin, sulbactam / ampicillin, Tazobac- tam / piperacillin, tetracycline, oxytetracycline, Rolitetraxyxlin, doxycycline, minocycline, chloramphenicol, aminoglycosides, gentamicin, tobramycin, netilmicin, amikacin, nomyxin Specti-, macrolides, erythromycin, clarithromycin, roxithromycin, azithromycin, di- rithromycin, Spiramyci, Josamycin, Lincosamide, Clindamycin, Fusidic Acid, Glycopeptide Antibiotics, Vancomycin, Tecoplanin, Pristinamycin Derivatives, Fosfomycin, Antimicrobial Folic Acid Antagonists, Sulfonamides, Co-Trimoxazole, Trimethoprim, Combinations of Nino-Nitropyrimine, Other Naminitritronimurimine Nitrofurazon, gyrase inhibitors (quinolones), norfloxacin, ciprofloxacin, ofloxacin, sparfloxacin, enoxacin, fleroxacin, pefloxacin, lomefloxacin, Bay Y3118, nitroimidazole, antifungal agents, isoniaicidomycinid, rifinoxinidomycinid, rifampinidomycinidin, rifinocinidomycinid, rifinoxincinidin, rifinocinidomycinid, ronampicinocinidin, ronampicidinid, rifinocinidomycinid, ronampinocinidin, rifinocinidomycinid, ramampinocinidomycinid, ronampicidomycinid, ronampicidin, rifin , Terizidon, Dapson, Clofazimin, local antibiotics, Bacitracin, Tyrothricin, Po lymyxine, neomycin, kanamycin, paromomycin, mupirocin, antiviral agents, acyclovir, ganciclovir, azidothymidine, didanosine, zalcitabine, thiacytidine, stavudine, ribavirin, idoxuridine, Trifluri- din, foscarnet, amantadine, interferons, Tibol derivatives, proteinase inhibitors, antimycotics , Polyenes, amphothericin B, nystatin, natamycin, azoles, azoles for septic therapy, miconazole, ketoconazole, itraconazole, fluconazole, UK-109.496, azoles for local use, clotrimazole, econazole, isoconazole, oxiconazole, bifoninazole, grisecytosazole, flucytulosine Ciclopiroxolamine, tolnaftat, naftifin, terbinafine, amorolfine, antrachinone, betulinic acid, semanthrachinone, xanthones, naphtoquinone, aryamino alcohols, quinine, quinidine, mefloquine, halofantrine, chloroquine, amodonepinone, acridine , Sulfadoxin, Sulfalene, Trimethoprim, Proguanil, Chlorproguanil, Diaaminopyrimidine, Pyrimethamine, Primaquin, Aminoquinoline, WR 238,605, Tetracycline, Doxyc yclin, clindamycin, norfloxacin, ciprofloxacin, ofloxacin, artemisinin, dihydroartemisinin, 10b artemether, arteether, atresunate, atovaquon, suramin, melarsoprol, nifurtmox, stibogluconate sodium, pentamidine, metrotonicol, aminotrophonidol, aminotronicinol, aminotronicinol dazol, niclosamide, praziquantel, pyrantel, tiabendazole, diethylcarbamazine, ivermectin, bithionol, oxamniquin, metrifonate, piperazine, embonate.
Ferner können die phosphororganischen Verbindungen in den pharmazeutischen Mitteln in Kombination mit Sulfonamid, Sulfadoxin, Artemisinin und Artemisininderivaten, Atovaquon, Chinin, Chloroquin, Hydroxychloroquin, Mefloquin, Halofantrin, Pyrimethamin, Armesin, Tetracycline, Doxycyclin, Proguanil, Metronidazol, Praziquantil, Niclosamid, Mebendazol, Pyrantel, Tiaben azol, Diethylcarbazin, Piperazin, Pyrivinum, Metrifonat, Oxamniquin, Bit- hionol, Lumefantrin oder Suramin oder mehreren dieser Substanzen vorliegen.Furthermore, the organophosphorus compounds in the pharmaceutical compositions can be used in combination with sulfonamide, sulfadoxine, artemisinin and artemisinin derivatives, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracycline, doxycycline, proguanil, prazamidazolazole, metronidazolazole Pyrantel, Tiaben azole, diethyl carbazine, piperazine, pyrivinum, metrifonate, oxamniquin, bithionol, lumefantrine or suramin or several of these substances are present.
Die Herstellung der oben aufgeführten pharmazeutischen Zubereitungen erfolgt in üblicher Weise nach bekannten Methoden, z. B. durch Mischen des oder der Wirkstoffe mit dem oder den Trägerstoffen.The pharmaceutical preparations listed above are prepared in a conventional manner by known methods, e.g. B. by mixing the active ingredient (s) with the carrier (s).
Die genannten Zubereitungen können bei Mensch und Tier entweder oral, rektal, parenteral (intravenös, intramuskulär, subkutan), intracisternal, intravaginal, intraperitoneal, lokal (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 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 treatment of infections in cavities, body cavities. Suitable preparations are injection solutions, solutions and suspensions for oral therapy, gels, pour-on formulations, emulsions, ointments or drops. For local therapy, ophthalmic and dermatological formulations, silver and other salts, ear drops, eye ointments, powder or solutions can be used. In animals, suitable formulations can also be ingested through feed or drinking water. Gels, powders, powders, tablets, prolonged-release tablets, premixes, concentrates, granules, pellets, tablets, boluses, capsules, aerosols, sprays, inhalants can also be used in humans and animals. Furthermore, the compounds 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. 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 dej Wirkstoffe kann durch den Fachmann aufgrund seines Fachwissens erfolgen.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 a total amount 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. 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, on the basis of his specialist knowledge, can determine the optimum dosage and type of application of the active substances required in each case.
Die erfmdungsgemäßen 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 erfindungsgemaß verwendeten Verbindungen hervorragend als Bakterizide, Fungizide und Herbizide bei Pflanzen eingesetzt werden.Furthermore, the compounds used according to the invention can be used outstandingly as bactericides, fungicides and herbicides in plants.
Prinzipiell weiß der Fachmann, wie er die erfindungsgemäßen Stoffe zu synthetisieren hat. Im folgen werden einige Beispiele für Synthesen angegeben.In principle, the person skilled in the art knows how to synthesize the substances according to the invention. Some examples of syntheses are given below.
Beispiele für Synthesewege für Stoffe mit der folgenden Struktur;Examples of synthetic routes for substances with the following structure;
O OHO OH
IMIN THE
H-C-N-CH2CH2CH2-PO(OR1R2)2 mit Ri = R2 = C i8H37 1HCN-CH 2 CH 2 CH 2 -PO (OR 1 R 2 ) 2 with Ri = R 2 = C i8H 37 1
mit Ri = H oder Na4" und R2 = Ci8H37 2 mit Ri = H oder Na" und R2 = C16H33 3with Ri = H or Na 4 " and R 2 = Ci8H 37 2 with Ri = H or Na" and R 2 = C 16 H 33 3
Beispiel 1;Example 1;
3-(N-Formyl-N-hydroxylamino)propylphosphonsäuredioctadecyl-ester 1 1 Äquivalent Fosmidomycin (FR-31564) und 6 Äquivalente Tris(octadecyl)- orthoameisensäure werden unter reduziertem Druck und starkem Rühren 2 h unter Rückfluß erwärmt. Dann destilliert man - ebenfalls unter reduziertem Druck - Methanol sowie Amei- sensäureoctadecylester ab, wobei die Temperatur unterhalb der Zersetzungstemperatur des Produktes gehalten werden muß. Im Ölpumpenvakuum werden weitere flüchtige Nebenprodukte entfernt, um schließlich 1 als hochviskoses Öl zu erhalten.3- (N-Formyl-N-hydroxylamino) propylphosphonic acid dioctadecyl ester 1 1 equivalent of fosmidomycin (FR-31564) and 6 equivalents of tris (octadecyl) ortho formic acid are heated under reflux under reduced pressure and vigorous stirring for 2 h. Then, likewise under reduced pressure, methanol and octadecyl formate are distilled off, the temperature having to be kept below the decomposition temperature of the product. Further volatile by-products are removed in an oil pump vacuum in order to finally obtain 1 as a highly viscous oil.
(Zur Durchführung vgl.: D.A. Nicholson, W.A. Cilley, O.T. Quimby, J Org Chem. 1970, 35, 3149-50)(For implementation see: D.A. Nicholson, W.A. Cilley, O.T. Quimby, J Org Chem. 1970, 35, 3149-50)
Die Mono-Ester können sowohl ausgehend von Fosmidomycin als auch von Di- Octadecylester 1 dargestellt werden. Beispiel 2:The monoesters can be prepared from fosmidomycin as well as from di-octadecyl ester 1. Example 2:
3-fN-Formyl-N-hydroxylaminoVpropylphosphonsäure mono octadecylester 2 Synthese 1:3-fN-formyl-N-hydroxylamino-propylphosphonic acid mono octadecyl ester 2 synthesis 1:
0.21 mmol Fosmidomycin (Phosphonsäure) und 0.2 mmol n-Octadecanol werden in 1-2 ml trockenem Pyridin gelöst und 0.67 mmol Trichloracetonitril dazu getropft. Die Reaktionsmischung wird 16 h auf 80 °C erwärmt und dann im Vakuum eingeengt. Nach Aufnehmen in Wasser - zum Membranfiltrieren von Ungelöstem - wird erneut unter reduziertem Druck eingeengt und daSjProdukt an Silicagel mit Essigsäureethylester, Ethanol sowie Wasser als Laufmittel chromatographiert. Das Produkt 3 fällt dabei als zähe gummiartige bis glasartige Verbindung an. (Zur Durchführung vgl.: G.B.Brooks, D. Edwards, J.D.I. Hatto, T.C. Smale, R. Southgate, Tetrahedron 1995, 51, 7999-814)0.21 mmol of fosmidomycin (phosphonic acid) and 0.2 mmol of n-octadecanol are dissolved in 1-2 ml of dry pyridine and 0.67 mmol of trichloroacetonitrile are added dropwise. The reaction mixture is heated to 80 ° C. for 16 h and then concentrated in vacuo. After taking up in water - for membrane filtration of the insoluble - it is concentrated again under reduced pressure and the product is chromatographed on silica gel with ethyl acetate, ethanol and water as the eluent. The product 3 is obtained as a tough rubbery to glassy compound. (For implementation see: G.B.Brooks, D. Edwards, J.D.I. Hatto, T.C. Smale, R. Southgate, Tetrahedron 1995, 51, 7999-814)
Synthese 2:Synthesis 2:
0.2 mmol des Diesters 3-(N-Formyl-N-hydroxylamino)-propylphosphonsäuredioctadecylester0.2 mmol of the diester 3- (N-formyl-N-hydroxylamino) propylphosphonic acid dioctadecyl ester
2 gelöst in Ethanol wird mit 1 Äquivalent KOH (ethanolische Lösung) versetzt und 10 h unter Rückfluß gekocht. Durch Einleiten von CO2 lassen sich Kaliumsalze als Carbonate fällen und durch Filtrieren entfernen. Das Filtrat engt man bis zur Trockene ein, trocknet das Öl über P2O5 , wäscht mit Petrolether und'kann schließlich aus absolutem Ethanol durch Zugabe von Isopropanol das Produkt Umkristallisieren.2 dissolved in ethanol, 1 equivalent of KOH (ethanolic solution) is added and the mixture is boiled under reflux for 10 h. By introducing CO 2 , potassium salts can be precipitated as carbonates and removed by filtration. The filtrate is concentrated to dryness, drying the oil over P2O5, washed with petroleum ether and 'can eventually from absolute ethanol by the addition of isopropanol, the product recrystallization.
(Zur Durchführung vgl.: V. Jagodic, Chem Ber 1960, 93, 2308-13)(For implementation see: V. Jagodic, Chem Ber 1960, 93, 2308-13)
Beispiel 3:Example 3:
3-(N-Formyl-N-hydroxyamino)-propylphosphonsäure mono hexadecylester 33- (N-Formyl-N-hydroxyamino) propylphosphonic acid mono hexadecyl ester 3
3 läßt sich analog zu 2 synthetisieren. 3 can be synthesized analogously to 2.

Claims

Patentansprücheclaims
1. Phosphororganische Verbindungen der allgemeinen Formel (I)1. Organophosphorus compounds of the general formula (I)
Ri 0Ri 0
\ II\ II
N-A-P-R* ( I )NAPR * (I)
/ I/ I
R2 R4 R 2 R 4
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, OXi und OX2 besteht, wobei Xι 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,in which R 1 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, OXi and OX 2 , where Xι and X2 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 un d there is 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 und aus der Gruppe ausgewählt ist, die aus substituiertem und unsubstituiertem Alkyl mit 1 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Hydroxyalkyl mit 1 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem Alkenyl mit 1 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Alkinyl mit 1 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem heterocyclischem Rest, Halogen und OX3 besteht, wobeiR 3 is selected from the group consisting of substituted and unsubstituted alkyl of 1 to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl of 1 to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl with 1 to 26 carbon atoms, substituted and unsubstituted alkynyl with 1 to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen and OX 3 , where
X3 aus Wasserstoff, substituiertem und unsubstituiertem Alkyl mit 1 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Hydroxyalkyl mit 1 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem Alkenyl mit 1 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Alkinyl mit 1 bis 26 Kohlenstoffatomen, 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 R»aus der Gruppe ausgewählt ist, die aus einem substituiertem und unsubstituiertem Alkyl mit 10 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Hydroxyalkyl mit 10 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Alkenyl mit 10 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Alkinyl mit 10 bis 26*Kohlenstoffatomen und OX* besteht, wobei X4 aus der Gruppe ausgewählt ist, die aus einem substituiertem und unsubstituiertem Alkyl mit 10 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Hy- droxylalkyl mit 10 bis 26 Kohlenstoffatomen, substituiertem und unsubstituiertem Alkenyl mit 10 bis 26 Kohlenstoffatomen und einem substituierten und unsubstituierten Alkinyl mit 10 bis 26 Kohlenstoffatomen besteht, und deren pharmazeutisch akzeptablen Salze, Ester und Salze der Ester.X 3 from hydrogen, substituted and unsubstituted alkyl having 1 to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having 1 to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl having 1 to 26 carbon atoms, substituted and unsubstituted alkynyl with 1 to 26 carbon atoms, 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 derived from ethylenediamine or amino acids, and R 'is selected from the group consisting of a substituted and unsubstituted alkyl with 10 to 26 Carbon atoms, substituted and unsubstituted hydroxyalkyl having 10 to 26 carbon atoms, substituted and unsubstituted alkenyl having 10 to 26 carbon atoms, substituted and unsubstituted alkynyl having 10 to 26 * carbon atoms and OX *, where X 4 is selected from the group consisting of a substituted and unsubstituted alkyl with 10 to 26 carbon atoms, substituted and unsubstituted hydroxylalkyl with 10 to 26 carbon atoms, substituted and unsubstituted alkenyl with 10 to 26 carbon atoms and a substituted and unsubstituted alkynyl with 10 to 26 carbon atoms, and their pharm azeutically acceptable salts, esters and salts of the esters.
2. Verbindungen nach Anspruch 1, dadurch gekennzeichnet, daß sie der Formel (II)2. Compounds according to claim 1, characterized in that they have the formula (II)
Figure imgf000022_0001
entsprechen, wobei
Figure imgf000022_0001
correspond with
X\ 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, Rt und A die gleiche Bedeutung wie in Formel (I) haben.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 , Rt and A have the same meaning as in formula (I).
3. Verbindung nach Anspruch 2, dadurch gekennzeichnet, daß R2 ein Acylrest ist,3. A compound according to claim 2, characterized in that R 2 is an acyl radical,
R3 eine Alkyl-, Hydroxyalkyl-, Alkinyl- oder Alkenylgruppe mit 16 oder 18 Kohlenstoffatomen oder OX3 ist. wobei X3 eine Alkyl-, Alkinyl-, Hydroxyalkyl- oder Alkenylgruppe mit 16 oder 18 Kohlenstoffatomen ist, t eine Alkyl-, Alkinyl-, Hydroxyalkyl- oder Alkenylgruppe mit 16 oder 18 Kohlenstoffatomen oder OXt ist, wobei * eine Alkyl-, Alkinyl-, Hydroxyalkyl- oder Alkenylgruppe mit 16 oder 18 Kohlenstoffatomen ist, Xι ein Wasserstoff ist, und A aus der Gruppe ausgewählt ist, die aus Alkylen, Alkenylen oder Hydroxyalkylen besteht. R 3 is an alkyl, hydroxyalkyl, alkynyl or alkenyl group with 16 or 18 carbon atoms or OX3. where X 3 is an alkyl, alkynyl, hydroxyalkyl or alkenyl group with 16 or 18 carbon atoms, t is an alkyl, alkynyl, hydroxyalkyl or alkenyl group with 16 or 18 carbon atoms or OXt, where * is an alkyl, alkynyl , Hydroxyalkyl or alkenyl group having 16 or 18 carbon atoms, Xι is a hydrogen, and A is selected from the group consisting of alkylene, alkenylene or hydroxyalkylene.
4. Verbindung nach Anspruch 2, dadurch gekennzeichnet, daß X3 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-Dibenzylethylendiamin und Arginin, besteht.4. A compound according to claim 2, characterized in that X 3 group is selected from 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-dibenzylethylenediamine and arginine.
5. Verbindung nach einem der Ansprüche 2 bis 5, dadurch gekennzeichnet, daß R2 ein Alkanoylrest und A eine Gruppe, die das Phosphoratom und das Stickstoffatom mit einer Kette aus drei Kohlenstoffatomen verbindet, wobei R2 vorzugsweise durch Formyl bzw. Acetyl und A vorzugsweise durch Propylen, Propenylen und Hydroxypropylen gebildet werden.5. A compound according to any one of claims 2 to 5, characterized in that R 2 is an alkanoyl radical and A is a group which connects the phosphorus atom and the nitrogen atom with a chain of three carbon atoms, R 2 preferably by formyl or acetyl and A preferably be formed by propylene, propenylene and hydroxypropylene.
6. Pharmazeutisches Präparat, gekennzeichnet durch einen wirksamen Gehalt an zumindest einer phosphororganischen Verbindung nach einem der Ansprüche 1 bis 5 zusammen mit einem pharmazeutisch akzeptablen Träger.6. Pharmaceutical preparation, characterized by an effective content of at least one organophosphorus compound according to one of claims 1 to 5 together with a pharmaceutically acceptable carrier.
7. Pharmazeutisches Präparat nach Anspruch 6, gekennzeichnet durch mindestens einen weiteren pharmazeutischen Wirkstoff.7. Pharmaceutical preparation according to claim 6, characterized by at least one further pharmaceutical active ingredient.
8. Pharmazeutisches Präparat nach einem der Ansprüche 6 oder 7, gekennzeichnet durch einen oder mehrere Bestandteile der Gruppe, die aus Sulfonamid, Sulfadoxin, Artemisinin, Atovaquon, Chinin, Chloroquin, Hydroxychloroquin, Mefloquin, Halofantrin, Py- rimethamin, Armesin, Tetracycline, Doxycyclin, Proguanil, Metronidazol, Praziquantil, Niclosamid, Mebendazol, Pyrantel, Tiabendazol, Diethylcarbazin, Piperazin, Pyri- vinum, Metrifonat, Oxamniquin, Bithionol und Suramin besteht.8. Pharmaceutical preparation according to one of claims 6 or 7, characterized by 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.
9. Pharmazeutisches Präparat nach Anspruch 7, gekennzeichnet durch einen oder mehrere Bestandteile aus der Substanzgruppe: Penicillin, Benzylpenicillin (Penicillin G), Phenoxypenicillin, Isoxazolylpenicillin, Aminopenicillin, Ampicillin, Amoxicillin, Bacampicillin, Carboxypenicillin, Ticarcillin, Temocillin, Acylaminbpeni- cilline, Azlocillin, Mezlocillin, Piperacillin, Apalcillin, Mecillinam, Cephalosporine, Cefazolin-Gruppe, Cefuroxim-Gruppe, Cefoxitin-Gruppe, Cefoxitin, Cefotetan, Cef- metazol, Latamoxef, Flomoxef, Cefotaxim-Guppe, Cefozidim, Ceftazidim-Gruppe, Ceftazidim, Ce irom, 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- 9. Pharmaceutical preparation according to claim 7, characterized by one or more constituents from the group of substances: penicillin, benzylpenicillin (penicillin G), phenoxypenicillin, isoxazolylpenicillin, aminopenicillin, ampicillin, amoxicillin, bacampicillin, carboxypenicillin, ticarcillin, acaminocillin, temaminopillin, temaminopillin Mezlocillin, piperacillin, apalcillin, mecillinam, cephalosporins, cefazolin group, cefuroxime group, cefoxitin group, cefoxitin, cefotetan, cef-metazol, latamoxef, flomoxef, cefotaxim-ce, cefimidim, cefefidim , other cephalosporins, cefsulodin, cefoperazone, oral cephalosporins from the cefalexin group, loracarbef, cefprozil, new oral cephalosporins with an expanded spectrum, cefixim, cefpodoxime proxetil, cefüroxim axetil, cefetiamidam, cefetiamidam, cefetiamine, other -Antibiotics, carbapenem, imipenem / cilastatin, meropenem, biapenem, aztreonam, ß-lactamase-
2. Verwendung nach Anspruch 11 zur Herstellung von Arzneimitteln zur Behandlung von Infektionen, die durch Bakterien aus der folgenden Gruppe hervorgerufen werden: Bakterien der Familie Propionibacteriaceae, insbesondere der Gattung Propionibacterium, insbesondere die Art Propionibacterium acnes, Bakterien der Familie Actinomyce- taceae, 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, Bakterien der Art Er si- pelthrix 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, irisbesondere die Art Mycoplasma pneumoniae, Bakterien der Gattung Brucella, Bakterien der Gattung Bordetella, Bakterien der Familie Neisse- riaceae, insbesondere der Gattungen Neisseria und Moraxella, insbesondere die Arten Neisseria meningitides, Neisseria gonorrhoeae und Moraxella bovis, Bakterien der Familie Vibrionaceae, insbesondere der Gattungen Vibrio, Aeromonas, Plesiomonas und Photobacterium, insbesondere die Arten Vibrio cholerae, Vibrio anguillarurn und Aeromonas salmonicidas, 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 Actinob- acillus, Bakterien der Familie Legionellaceae, der Gattung Legionella, Bakterien der Familie Rickettsiaceae und Familie Bartonellaceae, Bakterien der Gattungen Nocardia und Rhodococcus, Bakterien der Gattung Dermatophilus, Bakterien der Familie Pseu- domonadaceae, insbesondere der Gattungen Pseudomonas und Xanthomonas, Bakterien der Familie Enterobacteriaceae, insbesondere der Gattungen Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia und Shigella, Bakterien der Familie Pasteu- rellaceae, insbesondere der Gattung Haemophilus, Bakterien der Familie Micrococca- ceae, insbesondere der Gattungen Micrococcus und Staphylococcus, Bakterien der Familie Streptococcaceae, insbesondere der Gattungen Streptococcus und Enterococcus und Bakterien der Familie Bacillaceae, insbesondere der Gattungen Bacillus und Clostridium besteht, und bei der Helicobacter-Eradikationstherapie bei Ulcera des Magendarmtraktes. 2. Use according to claim 11 for the manufacture of medicaments for the treatment of infections caused by bacteria from the following group: bacteria of the Propionibacteriaceae family, in particular of the Propionibacterium genus, in particular the Propionibacterium acnes species, bacteria of the Actinomyctaceae family, in particular the Genus Actinomyces, bacteria of the genus Corynebacterium, especially the species Corynebacterium diphteriae and Corynebacterium pseudotuberculosis »Bacteria of the family Mycobacteriaceae, of the genus Mycobacterium, especially the species Mycobacterium leprae, Mycobacterium tuberculiumovisia myeaspecies, Mylamobium myisobacterium myisobacterium myisobacterium myisobacterium and mylamobium myisobacterium myisobacterium av trachomatis and Chlamydia psittaci, bacteria of the genus Listeria, especially the species Listeria monocytogenes, bacteria of the species Ersipelthrix rhusiopathiae, bacteria of the genus Clostridium, bacteria of the genus Yersinia, of Sp Ezies Yersinia pestis, Yersinia pseudotuberculosis, Yersinia enterocolitica and Yersinia ruckeri, bacteria of the family Mycoplasmataceae, of the genera Mycoplasma and Ureaplasma, in particular the species Mycoplasma pneumoniae, bacteria of the genus Brucella, bacteria of the genus Bordetella, especially the genus of the Neisse family, bacteria Neisseria and Moraxella, in particular the species Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis, bacteria of the Vibrionaceae family, in particular the genera Vibrio, Aeromonas, Plesiomonas and Photobacterium, in particular the species Vibrio cholerae, Vibrio anguillarurn and Aeromonas salmonicidas, bacteria of the genus Campatt 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 Leptospir a, in particular Borrelia burgdorferi, bacteria of the genus Actinobacillus, bacteria of the family Legionellaceae, of the genus Legionella, bacteria of the family Rickettsiaceae and family Bartonellaceae, bacteria of the genera Nocardia and Rhodococcus, bacteria of the genus Dermatophilus, bacteria of the family Pseu- domad of the genera Pseudomonas and Xanthomonas, bacteria of the Enterobacteriaceae family, in particular of the genera Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia and Shigella, bacteria of the Pasteurellaceae family, in particular of the genus Haemophilus, bacteria of the family Micrococcaceae, in particular of the genus Micrococcus and Staphylococcus, bacteria of the Streptococcaceae family, in particular the genera Streptococcus and Enterococcus and bacteria of the Bacillaceae family, in particular the genera Bacillus and Clostridium, and in Helicobacter eradication therapy for ulcers of the gastrointestinal tract.
13. Verwendung nach Anspruch 11 zur Herstellung von Arzneimitteln zur Behandlung von Infektionen, die durch Viren aus folgenden der Gruppe hervorgerufen werden: Viren der Gattung Parvoviridae, insbesondere Parvoviren, Dependoviren, Densoviren, Viren der Gattung Adenoviridae, insbesondere Adenoviren, Mastadenoviren, 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-Narizellen/Zoster- Viren, menschlicher Zytomegalievirus, Epstein-Barr- Viren, humanes Herpesvirus 6, humanes Herpesvirus 7, humanes Herpesvirus 8, Viren der Gattung Poxviridae, insbesondere Pockenviren, Orthopox- Parapox-, Molluscum- Contagiosum- Virus, Aviviren, Capriviren, Leporipoxviren, primär hepatotropen Viren, a insbesondere Hepatitisviren, wie Hepatitis-A- Viren, Hepatitis-B-Viren, Hepatitis-C- Viren, Hepatitis-D-Viren, Hepatitis-E-Viren, Hepatitis-F- Viren, Hepatits-G- Viren, He- padnaviren, 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, Pestiviren, Rubellavirus, Viren der Gattung Flaviviridae, insbesondere Flaviviren, FSME- Virus, Hepatitis-C- Virus, Viren der Gattung Orthomyxoviridae, insbesondere Influenzaviren, Viren der Gattung Paramyxoviridae, insbesondere Paramyxoviren, Morbillivirus, Pneumovirus, Masernvirus, Mumpsvirus, Viren der Gattung Rhabdoviridae, insbesondere Rhabdovi- ren, Rabiesvirus, Lyssavirus, viskuläres Stomatitisvirus, Viren der Gattung Coronaviri- dae, insbesondere Coronaviren, Viren der Gattung Bunyaviridae, insbesondere Bunya- viren, Nairovirus, Phlebovirus, Uukuvirus, Hantavirus, Hantaanvirus, 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, Onkovi- ren und Leukämieviren besteht.13. Use according to claim 11 for the manufacture of medicaments for the treatment of infections caused by viruses from the following from the group: viruses of the genus Parvoviridae, in particular parvoviruses, dependoviruses, densoviruses, viruses of the genus Adenoviridae, in particular adenoviruses, mastadenoviruses, aviadenoviruses, viruses 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 narizellen / zoster virus, 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, capriviruses, leporipox viruses in particular, primary viruses 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 Picornaviridae genus, 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, in particular reoviruses, red viruses, orbiviruses, orbir viruses Viruses of the genus Togaviridae, in particular Togaviruses, Alphaviruses, Rubiviruses, Pestiviruses, 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 Paramyx Paramyx, Paroviruses Paramyxx, Morbillivirus, pneumovirus, measles virus, mumps virus, viruses of the genus Rhabdoviridae, in particular Rhabdoviruses, Rabies virus, Lyssavirus, viscous stomatitis virus, viruses of the G Attung 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, lymphocytic chirviridae virus, especially virus virus HTL viruses, human T-cell leukemia virus, oncornaviruses, spuma viruses, lentiviruses, all HI viruses, viruses of the genus Filoviridae, in particular Marburg and Ebola viruses, slow viruses, prions, oncoviruses and leukemia viruses.
14. Verwendung nach Anspruch 11 zur Herstellung von Arzneimitteln zur Vorbeugung und Behandlung von Infektionen verursacht durch einzellige Parasiten aus der folgenden Gruppe: Erregern der Malaria, der Schlafkrankheit, der Chagas-Krankheit, der Toxoplasmose, der Amöbenruhr, der Leishmaniosen, der Trichomoniasis, der Pneumozystose, der Balantidiose, der Kryptosporidiose, der Sarkozystose, der Akantha-möbose, der Naeglerose, der Kokzidiose, der Giardiose und der Lambliose. 14. Use according to claim 11 for the manufacture of medicaments for the prevention and treatment of infections caused by unicellular parasites from the following group: pathogens of malaria, sleeping sickness, Chagas disease, toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis Pneumocystosis, Balantidiosis, Cryptosporidiosis, Sarcocystosis, Akantha-Mobose, Naeglerosis, Coccidiosis, Giardiosis and Lambliosis.
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