WO2000003699A2

WO2000003699A2 - Drugs containing phosphoric acid derivatives as active ingredient and their use

Info

Publication number: WO2000003699A2
Application number: PCT/EP1999/004832
Authority: WO
Inventors: Jomaa Hassan
Original assignee: Jomaa Hassan
Priority date: 1998-07-15
Filing date: 1999-07-09
Publication date: 2000-01-27
Also published as: WO2000003699A3; AU5034899A

Abstract

The invention relates to drugs containing as active ingredient at least one phosphonic acid derivative of general formula (I), wherein B is represented by formula (V), formula (VI) or formula (VII) and their pharmaceutically acceptable salts, esters and amides, as well as salts of said esters. The invention also relates to the use of said compounds in the preparation of drugs for prevention or treatment of infections due to viruses, fungi, bacteria or parasites.

Description

Medicinal products containing phosphonic acid derivatives as

Active ingredient and its use

The invention relates to medicaments containing phosphonic acid derivatives and their salts, esters and amides as active ingredients, and to their use in the manufacture of medicaments for the therapeutic and prophylactic treatment of infections in humans and animals which are caused by viruses, bacteria, fungi and parasites.

There is a strong need to provide, for the enrichment of the treatment of humans and animals, pharmaceuticals for the treatment of infections which not only have a strong efficacy, but also, in contrast to other medicinal products, have reduced side effects and thus represent a lower health risk for humans .

The object of the present invention is therefore to develop a medicament which can be used universally in infections by viruses, bacteria, fungi and parasites in humans and animals 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 as well as bacteria, fungi and single and multicellular parasites.

Furthermore, these compounds have a fungicidal, bactericidal and herbicidal activity in plants.

The phosphonic acid derivatives according to the invention correspond to the general formula (I):

H 0

I II B-Aι-CA ₂ -P-OX ₃ (I)

II OH 0X ₄ wherein Ai and A _{2 can} either be eliminated or one can be the same or different and are selected from the group containing an alkylene radical, an alkenylene radical and a hydroxyalkylene radical, and preferably the carbon chain -Aι-CHOH-A ₂ - from 2 to 5 carbon atoms, particularly preferably consists of 3-4 carbon atoms, B is selected from the group consisting of a radical of the formula

(V)

wherein Ri is selected from the group consisting of hydrogen, OH, 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 and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical and halogen consists of a radical of the formula (VI)

wherein R _{2 /} R ₃ and R _{4 are the} same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen, and a radical of the formula (VII)

where Rsr Rε and R? are the same or different and are selected from the group consisting of hydrogen, OH, 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, where X ₃ or X _{4 may be the} same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted Hydroxylalkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted ized heterocyclic radical, a silyl, a cation of an organic and inorganic base, in particular a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids, and their pharmaceutically acceptable salts , Esters and amides and salts of the esters.

Ri in formula (V) is preferably a methyl group.

In formula (VI), R ₂ and R ₄ are preferably hydrogen and R _{3 is} a methyl group.

In formula (VII), R _{5 is} preferably a methyl group R _{6 is} selected from the group consisting of H, OH and methyl, and R _{7 is} a hydroxy group. In particular, the compounds of the formula are preferred

H 0 OH 0

I II I II HCCCA ₂ -P-OX ₃ (II)

IIIHH OX ₄

correspond with

A _{2 is} an unbranched hydroxyalkylene with 1 to 3 carbon atoms and

X ₃ and X _{4 are the} same or different and are selected from the group consisting of hydrogen, a metal of the first, second or third main group of the periodic table, in particular sodium, potassium, and methyl, ethyl.

Of these compounds, 3, 4-dihydroxy-5-oxo-hexylphosphonic acid disodium salt, 1,2,3, -tetrahydroxy-5-oxo-hexylphosphonic acid disodium salt, 2,3, 4-trihydroxy-5-oxo-hexylphosphonic acid disodium salt, 1, 2 , 3-trihydroxy-4-oxopentylphosphonic acid disodium salt and 2,3-dihydroxy-4-oxopentylphosphonic acid disodium salt are particularly preferred.

In particular, the compounds of the formula are also preferred

H CH ₃ OH 0

I I I II

HO-CC - CA ₂ -P-OX ₃ (III)

I I I I

H OH H OX ₄ , where

A _{2 is} an unbranched hydroxyalkylene with 1 to 3 carbon atoms and

X ₃ and X _{4 are the} same or different and are selected from the group consisting of hydrogen, a metal of the first, second or third main group of the periodic table, in particular sodium, potassium, methyl and ethyl.

Of these compounds, 3, 4, 5-trihydroxy-4-methyl-pentylphosphonic acid disodium salt, 2,3,4, 5-tetrahydroxy- 4-methyl-pentylphosphonic acid disodium salt, 1,3,4, 5-tetra-hydroxy-4-methyl-pentylphosphonic acid disodium salt, 1,2,3,4,5-pentahydroxy-4-methyl-pentylphosphonic acid disodium salt are particularly preferred.

In particular, the compounds of the formula are also preferred

0 CH ₃ OH 0

^ 1 1 II CC CA ₂ -P-OX ₃ (IV)

/ I I I H OH H OX

correspond with

A _{2 is} an unbranched hydroxyalkylene or an unbranched alkylene and consists of 1 to 3 carbon atoms and X ₃ and X _{4 are} identical or different and are selected from the group consisting of hydrogen, a metal of the first, second or third main group of the Periodic table, especially sodium, potassium, and methyl, ethyl.

Of these compounds, 3, 4-dihydroxy-4-methyl-5-oxopentylphosphonic acid disodium salt, 2, 3, 4-trihydroxy-4-methyl-5-oxopentylphosphonic acid disodium salt, 1,2, 3-tri-hydroxy-4 -methyl-5-oxopentylphosphonic acid disodium salt, 2-monohydroxy-3-methyl-4-oxo-butylphosphonic acid disodium salt, 1,2-dihydroxy-3-methyl-4-oxo-butylphosphonic acid disodium salt are particularly preferred.

Special features of the above definitions and suitable examples are given below:

"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 in each case aliphatic, aromatic and / or heterocyclic 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) thiocarbamyl (e.g. (N-methyl) thiocarbamoyl etc.); Alkylcarba imidoyl (e.g. methylcarbamimidoyl etc.); Oxalo; Alkoxalyl (e.g. methoxalyl, ethoxalyl, propoxalyl etc.).

In the above examples of aliphatic acyl groups, the aliphatic hydrocarbon part, in particular the alkyl group or the alkane radical, can optionally have one or more suitable substituents, such as amino, halogen (for example fluorine, chlorine, bromine etc.), hydroxy, hydroxyimino, Carboxy, alkoxy (e.g. methoxy, ethoxy, propoxy etc.), alkoxycarbonyl, acylamino (e.g. benzyloxycarbonylamino etc.), acyloxy (e.g. acetoxy, benzoyloxy etc.) and the like; as preferred aliphatic acyl radicals with such substituents are e.g. alkanoyl substituted with amino, carboxy, amino and carboxy, halogen, acylamino or the like.

Aromatic acyl radicals are those acyl radicals which originate from an acid having 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.).

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 as 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, arylanoyl substituted with halogen and hydroxy or with halogen and acyloxy and aralkanoyl substituted with hydroxy, hydroxyimino, dihalogenalkanoyloxyimino are also given

Arylthiocarbamoyl (e.g. phenylthiocarbamoyl etc.); Arylcarbamimidoyl (e.g. phenylcarbamimidoyl etc.).

A heterocyclic acyl radical is understood to mean an acyl radical which comes from an acid with a heterocyclic group; this includes:

Heterocyclic carbonyl, in which the heterocyclic radical is an aromatic or aliphatic 5 to 6-membered heterocycle with at least one heteroatom from the group consisting of nitrogen, oxygen and sulfur (for example thiophenyl, furoyl, pyrrole carbonyl, nicotinoyl etc.); - ö -

Heterocycle alkanoyl, in which the heterocyclic radical is 5- to 6-membered and has at least one heteroatom from the group consisting of nitrogen, oxygen and sulfur (for example thiophenyl-acetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino- 4-thiazolyl) -2-methoxyiminoacetyl etc.) and the like.

In the above examples of heterocyclic acyl radicals, the heterocycle and / or the aliphatic hydrocarbon part may optionally have one or more suitable substituents, such as the same ones that have been indicated as being suitable for alkyl and alkane groups.

"Alkyl" is a straight or branched chain alkyl radical having up to 9 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.

"Hydroxylalkyl" is a straight or branched chain alkyl radical with up to 9 carbons, which has at least one hydroxyl group, preferably one or two hydroxyl groups.

"Alkenyl" includes straight-chain or branched-chain alkenyl groups with up to 9 carbon atoms, such as, for example, vinyl, propenyl (for example 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl, Hexenyl.

"Alkynyl" includes straight or branched chain alkynyl groups with up to 9 carbon atoms.

Cycloalkyl preferably represents 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.

"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.

“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, Ethylene, trimethylene, methylethylene, tetramethylene, 1-methyltrimethylene, 2-ethylethylene, pentamethylene, 2-methyltetramethylene, isopropylethylene, hexamethylene, and the like, preferred alkylene radicals have up to 4 carbon atoms and radicals with 3 carbon atoms such as, for example, are particularly preferred Trimethylene.

"Alkenylene" includes straight or branched chain alkenylene groups with up to 9 carbon atoms, which can be represented by the formula ~ (C _n H _2n -2) -, in which n is an integer from 2 to 9, for example Vinylene, propenylene (eg 1-propenylene, 2-propenylene), 1-methylpropenylene, 2-methylpropenylene, butenylene, 2-ethylpropenylene, pentenylene, hexenylene and the like; particularly preferably the alkenylene radical can have up to 5 carbon atoms and in particular 3 carbon atoms such as 1-propenylene.

"Hydroxyalkylene" can include straight-chain or branched-chain alkylene radicals which have up to 9 carbon atoms, at least one selected carbon atom being substituted by a hydroxy group; these radicals can be represented by the formula - (C _n H _2n _ _z ) (OH) ₂ - in which n is an integer from 1 to 9 and z is an integer to which 1 <z <n. Suitable examples of such hydroxyalkylene groups include hy- droxymethylene, hydroxyethylene (e.g. 1-hydroxyethylene and 2-hydroxyethylene), hydroxytrimethylene (e.g. 1-hydroxytrimethylene, 2-hydroxytrimethylene and 3-hydroxytrimethylene), hydroxytetramethylene (e.g. 2-hydroxytetramethylene), 2-hydroxy-2-methyltrimethylene, hydroxypentamethylene ( eg 2-hydroxypentamethylene), hydroxyhexamethylene (eg 2-hydroxyhexamethylene) 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 radicals X ₃ and X ₄ can preferably be chosen such that esters are formed on the phosphono group. Suitable examples of such esters according to formulas (I), (II), (III) and (IV) include suitable mono- and diesters, and preferred examples of such esters include alkyl esters (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, Butyl esters, isobutyl esters, hexyl esters, 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.); and silyl esters (e.g., trialkylhalosilyl, dialkyldihalosilyl, alkyltrihalosilyl, dialkylarylhalosilyl, trialkoxyhalosilyl, dialkylaralkylhalosilyl, dialkoxydihalosilyl, trialkoxyhalosilyl, etc.) and the like.

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.

X ₃ and X are preferably a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium, or ammonium compounds which are derived from ethylenediamine or amino acids. That is, the salt compounds of the phosphonic acid derivatives with organic or inorganic bases (for example sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylactic min salt, ethanolamine salt, dicyclohexylamine salt, ethylenediamine salt, N, N "-dibenzylethylenediamine salt etc.) and salts with amino acids (for example arginine salt, aspartic acid salt, glutamic acid salt etc.) and the like.

The compounds of the formulas (I), (II), (III) or (IV) according to the invention can be used in their protonated form as the ammonium salt of organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, Lactic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc. are present.

The compounds of the formulas (I), (II), (III) or (IV) according to the invention can be used, for example, for double bonds containing or chiral groups R 1, R ₂ , R ₃ , R, R ₅ , Rβ, R, X ₃ , X or Ai or A ₂ the occurrence of spatial isomers. The compounds according to the invention include all spatial isomers both as pure substances and in the form of their mixtures.

The phosphonic acid derivatives are 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, Leishmaniosis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcolocystosis, the Akanthamöbose, Naeglerose, coccidiosis, Giardiose and Lambliose.

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. The active compounds according to the invention can be used in particular against the following bacteria:

Bacteria of the Propionibacteriaceae family, in particular of the Propionibacterium genus, in particular the Propionibacterium acnes species,

Bacteria of the Actinomycetaceae family, especially of the Actinomyces genus,

Bacteria of the genus Corynebacteriu, in particular the species Corynebacterium diphteriae and Corynebacterium pseudotuberculosis,

Bacteria of the family Mycobacteriaceae, of the genus Mycobacterium, in particular the species Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium,

Bacteria of the family Chlamydiaceae, in particular the species Chlamydia trachomatis and Chlamydia psittaci,

Bacteria of the genus Listeria, in particular the species Listeria monocytogenes,

Bacteria of the species Erysipelthrix rhusiopathiae, bacteria of the genus Clostridium,

Bacteria of the genus Yersinia, of the species Yersinia pestis, Yersinia pseudotuberculosis, Yersinia enterocolitica and Yersinia ruckeri,

Bacteria of the family Mycoplasmataceae, of the genera Mycoplasma and Ureaplasma, in particular the species Mycoplasma pneu- moniae,

Bacteria of the genus Brucella, bacteria of the genus Bordetella,

Bacteria of the Neiseriaceae family, in particular of the Neisseria and Moraxella genera, in particular the Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis species, bacteria of the Vibrionaceae family, in particular of the Vibrio, Aeromonas, Plesiomonas and Photobacterium species, in particular the Vibrio cholerum, Vibrio angular species and Aeromonas salmonicidas,

Bacteria of the genus Campylobacter, in particular the species Campylobacter jejuni, Campylobacter coli and Campylobacter fe- tus,

Bacteria of the genus Helicobacter, in particular the species Heli- cobacter pylori,

Bacteria of the Spirochaetaceae and Leptospiraceae families, in particular the Treponema, Borrelia and Leptospira genera, in particular Borrelia burgdorferi, bacteria of the Actinobacillus genus,

Bacteria of the Legionellaceae family, the genus Legionella, bacteria of the Rickettsiaceae family and Bartonella- ceae family,

Bacteria of the genera Nocardia and Rhodococcus, bacteria of the genus Dermatophilus,

Bacteria of the family Pseudomonadaceae, especially of the genera Pseudomonas and Xanthomonas,

Bacteria of the Enterobacteriaceae family, in particular of the genera Escherichia, Klebsieila, Proteus, Providencia, Salmonella, Serratia and Shigella,

Bacteria of the Pasteurellaceae family, especially of the genus Haemophilus,

Bacteria of the Micrococcaceae family, in particular of the Micrococcus and Staphylococcus genera,

Bacteria of the Streptococcaceae family, particularly of the genera Streptococcus and Enterococcus and

Bacteria of the Bacillaceae family, especially the genera Bacillus and Clostridium.

The organic compounds according to the invention 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 - Keratoconjunctivitis and serositis of animals, brucellosis of animals and humans, anthrax in humans and animals, actinomycosis in humans and animals, streptotrichoses, psittaco- se / ornithosis in animals, and Q fever and Ehrlichiosis.

The use is also useful in Helicobacter eradication therapy for ulcers of the gastrointestinal tract.

A combination with another antibiotic can also be used to treat the above-mentioned diseases. Isoniazid, rifampicin, ethambutol, pyrazineid, streptomycin, protionamide and dapsone are particularly suitable for the treatment of tuberculosis for combination preparations with other anti-infectives.

The active compounds according to the invention can also be used, in particular, for infections with the following viruses: Parvoviridae: Parvoviruses, Dependoviruses, Densoviruses, Adenoviridae: Adenoviruses, Mastadenoviruses, Aviadenoviruses, Papovaviridae: Papovaviruses, in particular Papillomaviruses (so-called Wartsviruses, in particular J virus viruses, Polyvirus viruses, Polyvirus viruses, especially virus viruses, J virus viruses, polyvirus viruses, polyvirus viruses, especially virus viruses, polyvirus viruses, polyvirus viruses, polyvirus viruses, especially virus viruses, poly virus viruses, , and miopapovaviruses,

Herpesviridae: all herpes viruses, especially herpes 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, hepatitis 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 rhinoviruses, hepatitis A virus, aphthoviruses, Calciviridae: hepatitis E viruses, Reoviridae: reoviruses, orbiviruses, rotaviruses

Togaviridae: Togaviren, Alphaviren,, Rubiviren, Pestiviren, Rubellavirus,

Flaviviridae: flaviviruses, TBE virus, hepatitis C virus, Orthomyxoviridae: all influenza viruses, Paramyxoviridae: paramyxoviruses, morbillivirus, pneumovirus, measles virus, mumps virus,

Rhabdoviridae: rhabdoviruses, Rabies virus, Lyssavirus, viscous stomatitis virus, Coronaviridae: Coronaviruses,

Bunyaviridae: Bunyaviren, Nairovirus, Phlebovirus, Uukuvirus, Hantavirus,

Arenaviridae: arenaviruses, lymphocytic choriomeningitis virus,

Retroviridae: retroviruses, all HTL viruses, human T-cell leukemia virus, oncornaviruses, spumaviruses, lentiviruses, all HI viruses,

Filoviridae: Marburg and Ebola viruses, slow virus infections, prions, onkoviruses, leukemia viruses.

The active compounds according to the invention are therefore suitable for combating the following viral infections:

Eradication of papillomaviruses for the prevention of tumors, especially 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 cirrhosis of the liver, eradication of Coxsackieviruses for cardiomyopathies, eradication Coxsackieviruses in diabetes mellitus patients, eradication of immunodeficiency viruses in humans and animals, treatment of concomitant infections in AIDS patients, treatment of inflammation of the viral genesis of the respiratory tract (laryngeal papillomas, hyberplasias, rhinitis, pharyngitis, bronchitis, pneumonia) , the sense organ e (keratoconjunctivitis), the nervous system (poliomyelitis, meningoencephalitis, encephalitis, subacute sclerosing panencephalitis, SSPE, progressive multifocal leukoencephalopathy, lymphocytic choriomeningitis), of the gastrointestinal tract (stomatitis, gingivostomatitis, esophagitis, gastritis, gastroenteritis, diarrheal diseases), the liver and the biliary system (hepatitis, cholangitis, hepatocellular carcinoma), the lymphoid tissue (mononucleosis, lymphadenitis), the hematoma , the genital organs (mumps orchitis), the skin (warts, dermatitis, herpes labialis, cold sores, herpes zoster, shingles), the mucous membranes (papillomas, conjunctive apapillomas, hyperplasias, dysplasias), the cardiovascular system (arteritis, myocarditis, endocarditis Pericarditis), the kidney-urinary system, the genital organs (anogenital lesions, warts, genital warts, pointed condylomas, dysplasias, papillomas, cervical dysplasias, condylomata acuminata, epidermodysplasia verruciformis), the movement organs (myositis treatment, myalgia) Foot-and-mouth disease of cloven hoofed animals, Colorador tick fever, Dengue syndrome, hemorrhagic fever, the Early summer meningoencephalitis (TBE) and yellow fever.

The agents are suitable for combination with other agents with antiviral properties.

The connections described, i.e. the phosphonic acid derivatives according to formulas (I), (II), (III) and (IV) and esters and amides thereof on the phosphono group and salts thereof show a strong cytotoxic activity against single and multicellular parasites, fungi, bacteria and viruses. Accordingly, the compounds of the invention are useful for the treatment of infectious diseases caused by viruses, bacteria, parasites and fungi in humans and animals. The compounds are also suitable for use in preventing diseases caused by viruses, bacteria, parasites and fungi.

The phosphonic acid derivatives according to the invention, these generally include pharmaceutically acceptable salts, amides, esters, a salt of such an ester, or else compounds which, when applied, provide the compounds according to the invention as metabolites or degradation products, also “prodrugs”. can be prepared for administration 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), (II), (III) and (IV) according to the invention in their protonated form as the ammonium salt of inorganic or organic acids, such as hydrochloric acid, sulfuric acid, citric acid, maleic acid, Form fumaric acid, tartaric acid, p-toluenesulfonic acid.

Also particularly pharmaceutically suitable are the salts which are formed by suitable selection of X ₃ and X, such as sodium salt, potassium salt, calcium salt, ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt and salts of an amino acid such as arginine salt, aspartic acid salt, glutamic acid salt.

The pharmaceutically active agents can be prepared in the form of pharmaceutical preparations in dosage units. This means that the preparation in the form of individual parts, e.g. B. tablets, dragees, capsules, pills, suppositories and ampoules are present, the active ingredient content of which corresponds to a fraction or a multiple of a single dose. The dosage units can e.g. B. 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.

Non-toxic, inert pharmaceutically suitable carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.

Preferred pharmaceutical preparations are tablets, dragées, capsules, pills, granules, suppositories, solutions, _ _

Suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays called. 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, for. 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, eg. B. cetyl alcohol, glycerol monostearate, (h) adsorbent, e.g. 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).

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.

The active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned excipients.

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. C14 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 zinc oxide or mixtures thereof Fabrics.

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.

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, glyceryl alcohol, tetra-alcohol, formaldehyde , Polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also be in sterile and blood isotonic form.

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.

The formulation forms mentioned can also contain colorants, preservatives and odor and taste-improved additives, e.g. B. peppermint oil and eucalyptus oil and sweeteners, e.g. B. saccharin.

The active compounds of the formulas (I), (II), (III) and (IV) 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 to be available.

In addition to the compounds of the formulas (I), (II), (III) and (IV), the pharmaceutical preparations can also contain further active pharmaceutical ingredients.

Furthermore, the phosphonic acid derivatives in the pharmaceutical compositions can be used in combination with sulfonamide, sulfadoxine, artisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracyclines, doxycycline, proguanil, metronidazole, nicazamid, praziquantilane, praziquantilane , Tiabendazole, Diethylcarbazin, Piperazin, Pyrivinum, Metrifonat, Oxamniquin, Bithionol 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 excipient (s).

The preparations mentioned can be used in humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally, locally (powder, ointment, drops) and for the therapy of infections in cavities, body cavities. Suitable preparations are injection solutions, solutions and suspensions for oral therapy, gels, pour-on formulations, emulsions, ointments or drops. For local therapy, ophthalmic and dermatological formulations, silver and other salts, ear drops, eye ointments, powder or solutions can be used. In animals, suitable formulations can also be ingested through feed or drinking water. Furthermore, gels, powders, powders, tablets, prolonged-release tablets, premixes, concentrates, granules, pellets, tablets, boluses, capsules, aerosols, sprays, inhalants can be used in humans and animals. Furthermore, the compounds for the medicaments according to the invention can be incorporated into other carrier materials such as plastics, (plastic chains for local therapy), collagen or bone cement. be tested.

In general, it has proven to be advantageous in both human and veterinary medicine to use the active compound (s) of the formula (I), (II), (III) and (IV) in a total amount of from about 0.05 to about 600 , preferably 1 to 200 mg / kg body weight per 24 hours, if necessary in the form of several individual doses, to achieve the desired results. A single dose contains the active ingredient (s) preferably in amounts of about 1 to about 200, in particular 3 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 can determine the optimum dosage and type of application of the active ingredients required on the basis of his specialist knowledge.

The compounds according to the invention can be given in the usual concentrations and preparations in animals together with the feed or with feed preparations or with the drinking water.

Furthermore, the compounds according to the invention can be used outstandingly as bactericides, fungicides and herbicides in plants.

Some synthetic routes for the phosphonic acid derivatives according to the invention are given below by way of example:

Example 1 : Representation of H ₃ CC (= 0) -CH (OH) -CH (OH) -CH (OH) -PO (OR) ₂

1. Preparation of 2,3-di-Q-isopropylidene-4-oxopentanal

25 mmol of 2,3-dihydroxy-4-oxo-pentanal (Lit: Sonntag, Dizdaroglu, Carbohydr. Res. 1977, 58, 21-25) is stirred with an excess of acetone and a few drops of sulfuric acid for 14 h at room temperature. After concentration, it is washed with a little diethyl ether and the crude product is directly converted further. In addition to 2,3-dihydroxy-4-oxo-pentanal, levulinic acid or the analogue to isorhamnonose (cf. Lit: Helferich, Himmen, Ber. Dt. Che. Ges. 1929, 62, 2136) are further possible starting compounds.

2. Production of dimethyl 1-hydroxy-2,3-isopropylidene-4-oxopentylphosphonate

10 mmol of 2,3-di-0-isopropylidene-4-oxo-pentanal are added to 10 mmol of dimethyl phosphite with vigorous stirring and 5 drops of a 10% sodium methoxide solution are added dropwise. The reaction mixture heats up strongly. After cooling, the solution gradually solidifies. The oil is washed several times with diethyl ether, filtered and recrystallized from diethyl ether or acetone.

2. Preparation of 1, 2, 3-trihydroxy-4-oxo-pentylphosphonic acid 2 mmol l-hydroxy-2, 3-isopropylidene-4-oxo-pentylphosphonic acid dimethyl ester are cured at 90 ° C. with 100 mg Levatit S for about 24 h 100 H ⁺ stirred. After cooling, the ion exchanger is filtered off and the mixture is concentrated. An oil remains. A freeze-dried sample is dried over phosphorus pentoxide and crystallized after standing in air for several days at room temperature.

Example 2:

Representation of OHC-C (OH) (CH ₃ ) -CH (OH) -CH (OH) -CH (OH) τPO (OR) ₂

1. Preparation of 1, 2, 3, 4, 5-pentahydroxy-2-methylpentane (a) To 0.2 mol of magnesium shavings in 20 ml of absolute diethyl ether, 0.2 mol of iodomethane, dissolved in 60 ml of the same solvent, is added so that the ether boils easily. After finishing After addition, the mixture is boiled under reflux for a further 30 min, allowed to cool and 0.16 mol of 1, 3, 4, 5-tetrahydroxy-pentan-2-one (D-2-pentulose) is added dropwise (Lit: Fromm, J. Biol. Chem. 1958 , 233, 1049 or Glatthaar, Reichstein, Helv. Chim. Acta 1935, 18, 80) and stir under reflux for 30 min. After cooling to 0 ° C., saturated ammonium chloride solution is added, the ether phase is separated off, the aqueous phase is extracted several times with ether and the combined organic phases are dried over sodium sulfate. The solvent is removed under reduced pressure and perhydroxylated 2-methylpentane is obtained.

2. Preparation of 2, 3, 4-trihydroxy-2-methyl-pentane-l, 5-dialdehyde (b)

A solution of 1.2 g sodium periodate in 30 ml water is added with stirring to a solution of 0.01 mol 1,2,3,4,5-pentahydroxy-2-methylpentane in 25 ml water. After stirring for 2 hours at room temperature, the mixture was filtered off. The filtrate is extracted with methylene chloride, dried over magnesium sulfate and concentrated in vacuo. The bisaldehyde is immediately implemented further.

3. Preparation of a mixture of di-O-isopropylidene-monohydroxy-pentane-1,5-dialdehydes (c)

0.015 mol of 2, 3, 4-trihydroxy-2-methylpentan-l, 5-dialdehyde is added to 40 ml of acetone and a few drops of sulfuric acid, stirred at room temperature for 16 h and then concentrated in vacuo. The remaining oil is washed with a little ether and directly reacted further.

The main product is 2,4-di-0-isopropylidene-3-hydroxy-2-methylpentane-1,5-dialdehyde.

4. Preparation of 1, 3-dihydroxy-2, 4-0-isopropylidene-4-methyl-1-phosphonic acid dimethyl ester (d)

10 mmol of 2,4-di-0-isopropylidene-3-hydroxy-2-methylpentane-1,5-dialdehyde are added to 10 mmol of dimethylphosphite with vigorous stirring, and 5 drops of a 10% sodium methoxide solution are added dropwise. The reaction mixture heats up strongly. After cooling, the reaction product is allowed to solidify, the oil is boiled out several times with ether and filtered as soon as possible the oil can be pulverized.

By-products are the bisphosphonic acid tetramethyl ester and 1, 3-dihydroxy-2, 4-0-isopropylidene-2-methyl-l-phosphonic acid di ethyl ester.

5. Preparation of 1, 2, 3, tetrahydroxy-4-methyl-5-pentanal-1-phosphonic acid (s)

4 mmol of 1-hydroxy-2, 3-isopropylidene-4-oxopentylphosphonic acid dimethyl ester are stirred for about 24 h at 90 ° C. with 200 mg of Levatit S 100 H ⁺ . After cooling, the ion exchanger is filtered off and concentrated. An oil remains. Standing in air for a longer time gives a crystalline solid.

Example 3:

Representation of OHC-C (OH) (CH ₃ ) -CH (OH) -CH (OH) -PO (OR) ₂

1. Preparation of 1, 2, 3-trihydroxy-3-methyl-4-butanal-l-phosphonic acid

Analogously to the synthesis of 1, 2, 3, 4-tetrahydroxy-4-methyl-5-pentanal-1-phosphonic acid, 1, 2, 3-trihydroxy-3-methyl-4-butanal-1-phosphonic acid can be synthesized.

2. Preparation of 1, 2, 3-trihydroxy-3-methyl-4-butanal-l-phosphonic acid

The starting point is 1, 3, 4-trihydroxybutan-2-one, which, as described above, via the Grignard reaction, the oxidation with aqueous sodium periodate solution and the isopropylidene sugar with dimethyl phosphite to give 1-hydroxy-2, 3-0-isopropylidene 3-methyl-4-butanal-1-phosphonic acid methyl ester is reacted, which can be hydrolyzed to the product using an acidic ion exchanger.

Example 4:

Representation of H ₂ C (OH) -CH (OH) -CH (OH) -C (= 0) -PO (OR) ₂ with R = H or Na ⁺

1. Preparation of 2, 4-Q-isopropylidene-3-hydroxybutyraldehyde

(a)

25 mmol of 2, 3, 4-trihydroxybutyraldehyde are catalytic

Amounts of FeCl ₃ in 40-50 ml acetone for 16 h at room temperature stirs. After filtering and concentrating, wash with a little diethyl ether. The raw product can be directly implemented further.

2. Preparation of 2, 4-0-isopropylidene-3-hydroxybutyric acid

U≥l

1.3 equivalents of bromine are added dropwise to 20 mmol of 2,4-0-isopropylidene-3-hydroxybutyraldehyde in water with vigorous stirring. Any hydrogen bromide produced can be partially removed by introducing nitrogen. Repeated concentration of the aqueous solution gives the product, which is washed again with ether.

3. Preparation of 2,4-0-isopropylidene-3-hydroxybutyric acid chloride (c)

The mixture of 18 mmol of 2, 4-0-isopropylidene-3-hydroxybutyric acid and 26 mmol of thionyl chloride is boiled under reflux until the evolution of hydrogen chloride gas and sulfur dioxide has ended. Excess thionyl chloride is removed in vacuo at room temperature. The product can be cleaned by high pressure liquid chromatography.

4. Preparation of 2, 3, 4-trihydroxy-l-oxo-butylphosphonic acid 1dl

One equivalent of trimethyl phosphite is added dropwise to 50 mmol of the acid chloride at 5 ° C., then the mixture is allowed to warm to room temperature and stirred for a further 2 h. The resulting 2, 4-0-isopropylidene-3-hydroxy-1-oxo-butylphosphonic acid dimethyl ester is produced in high yields and is dissolved directly in 5 ml of acetonitrile, mixed with 1.25 equivalents of sodium iodide and boiled under reflux. The complete conversion to the free phosphonic acid can be observed by ¹ H-NMR. Alternatively, the Levatit S 100 H ⁺ ion exchanger provides an identical product.

Claims

claims

Medicaments containing at least one phosphonic acid derivative of the general formula (I):

H 0 I II

B-Aι-CA ₂ -P-OX ₃ (I)

I I

OH OX ₄

wherein Ai and A ₂ both or one of the two may also be omitted, may be the same or different and are selected from the group containing an alkylene radical, an alkenylene radical and a hydroxyalkylene radical, and B is selected from the group consisting of a radical of Formula (V)

wherein Ri is selected from the group consisting of hydrogen, OH, 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 and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical and halogen, a radical of the formula (VI)

where R ₂ , R ₃ and R _{4 are the} same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted ized 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, the halogen consists of Formula (VII)

wherein R ₅ , Rε and R _{7 are the} same or different and are selected from the group consisting of hydrogen, OH, 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, where X ₃ or X _{4 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 aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substi tuiert and unsubstituted heterocyclic radical, a silyl, a cation of an organic and inorganic base, in particular a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium and ammonium compounds, which differ from ethylenediamine or derive amino acids, and their pharmaceutically acceptable salts, esters and

A iden and salts of the esters as active ingredient.

2. Medicament according to claim 1, characterized in that the phosphonic acid derivatives of the formula (II)

H 0 OH 0

I II I II

HCCCA ₂ -P-OX ₃ (II)

I I I

HH OX ₄

correspond with

A _{2 is} an unbranched hydroxyalkylene with 1 to 3 carbon atoms and

X ₃ and X _{4 are the} same or different and are selected from the group consisting of hydrogen, a metal of the first, second or third main group of the periodic table, in particular sodium, potassium, methyl and ethyl '.

3. Medicament according to claim 2, characterized in that the compounds are selected from the group consisting of 3, 4-dihydroxy-5-oxo-hexylphosphonic acid disodium salt, 1,2,3, 4-tetrahydroxy-5-oxohexyl phosphonic acid disodium salt , 2,3, 4-trihydroxy-5-oxohexyl-phosphonic acid disodium salt, 1,2, 3-trihydroxy-4-oxopentyl-phosphonic acid disodium salt and 2, 3-dihydroxy-4-oxopentyl-phosphonic acid disodium salt.

4. Medicament according to claim 1, characterized in that the phosphonic acid derivatives of the formula (III)

H CH ₃ OH 0 III II HO-CC - C-Ar-P-OX ₃ (III)

I I I I

H OH H OX ₄

correspond with

A is an unbranched hydroxyalkylene with 1 to 3 carbon is fatomen and

5. Medicament according to claim 4, characterized in that the compounds are selected from the group consisting of 3, 4, 5-trihydroxy-4-methylpentyl-phosphonic acid disodium salt, 2,3,4, 5-tetrahydroxy-4-methyl-pentylphosphonic acid disodium salt, 1,3,4,5-tetra-hydroxy-4-methyl-pentylphosphonic acid disodium salt and 1,2,3,4,5-pentahydroxy-4-methyl-pentyl-phosphonic acid disodium salt.

6. Medicament according to claim 1, characterized in that the phosphonic acid derivatives of the formula (IV)

0 CH ₃ OH 0

^ 1 1 II

CC - - CA ₂ -P-OX ₃ (IV)

/ 1 1 1

H H H OX4

correspond with

A _{2 is} an unbranched hydroxyalkylene or unbranched alkylene and consists of 1 to 3 carbon atoms and X ₃ and X _{4 are the} same or different and are selected from the group consisting of hydrogen, a metal of the first, second or third main group of the periodic table , in particular sodium, potassium, and methyl, ethyl.

7. Medicament according to claim 6, characterized in that the compounds are selected from the group consisting of 3, 4-dihydroxy-4-methyl-5-oxo-pentylphosphonic acid disodium salt, 2, 3, 4-trihydroxy-4-methyl -5-oxopentylphosphonic acid disodium salt, 1,2,3-trihydroxy-4-methyl-5-oxopentylphosphonic acid disodium salt, 2-monohydroxy-3-methyl-4-oxobutylphosphonic acid disodium salt and 1,2-dihydroxy-3 -methyl- 4-oxo-butylphosphonic acid disodium salt.

Use for the manufacture of a medicament according to one of Claims 1 to 7 for the therapeutic and prophylactic treatment of infections in humans and animals which are caused by fungi, bacteria, viruses and parasites.

Use according to claim 8 for the treatment of infections caused by bacteria selected from the group consisting of bacteria from the Propionibacteriaceae family, in particular the Propionibacterium genus, in particular the Propionibacterium acnes species, bacteria of the Actinomycetaceae family, in particular the genus Actonomyces, bacteria of the genus Corynebacterium, in particular the species Corynebacterium diphteriae and Corynebacterium pseudotuberculosis, bacteria of the family Mycobacteriaceae, of the genus Mycobacterium, in particular the species Mycobacterium leprae, Mycobacterium tuberculiacium family, Mycobacterium derlamis, Mycobacteriumobacteria, Mycobacterium deramium, Mycobacteriumobacterium Chlamydia trachomatis and Chlamydia psittaci, bacteria of the genus Listeria, in particular the species Listeria monocytogenes, bacteria of the species Erysipelthrix rhusiopathiae, bacteria of the genus Clostridium, bacteria of the genus Yersinia, of the species Yersinia pesti s, Yersinia pseudotuberculosis, Yersinia * enterocolitica and Yersinia ruckeri, bacteria of the family Mycoplasmataceae, of the genera Mycoplasma and Ureaplasma, in particular the species Mycoplasma pneumoniae, bacteria of the genus Brucella, bacteria of the genus Bordetella, bacteria of the family Neiseriaceae, in particular of the Morse genus and especially of the genus , 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 anguillarum and Aeromonas sal onicidas, bacteria of the genus Campylobacter, in particular the species Campylobacter jejuni, Campylobacter coli and Campylobacter fetus, bacteria of the Genus Helicobacter, in particular the species Helicobacter pyori, bacteria of the Spirochaetaceae and Leptospiraceae families, in particular the Treponema, Borrelia and Leptospira genus, in particular Borrelia burgdorferi, bacteria of the Actinobacillus genus, bacteria of the Legionella family, bacteria of the Legionella family, the genus The Rickettsiaceae family and the Bartonellaceae family, bacteria of the genera Nocardia and Rhodococcus, bacteria of the genus Dermatophilus, bacteria of the family Pseudo onadaceae, in particular the genera Pseudomonas and Xanthomonas, bacteria of the family Enterobacteriaceae, in particular the genera Escherichia, Klebsiella, Proteiella, Proteiella , Serratia and Shigella, bacteria of the Pasturellaceae family, in particular of the genus Haemophilus, bacteria of the Micrococcaceae family, in particular of the genera Micrococcus and Staphylococcus, bacteria of the Streptococcaceae family, in particular of the genera Streptococcus and Enterococ cus and bacteria of the Bacillaceae family, in particular the genera Bacillus and Clostridium, and in Helicobacter eradication therapy for ulcers of the gastrointestinal tract.

10. Use according to claim 8 for the treatment of infections caused by viruses selected from the group consisting of viruses of the genus Parvoviridae, in particular parvoviruses, dependoviruses, densoviruses, viruses of the genus Adenoviridae, in particular adenoviruses, mastadenoviruses, Aviadenoviruses, viruses of the genus Papovaviridae, in particular papovaviruses, in particular papillomaviruses (so-called wart viruses), polyomaviruses, in particular JC virus, BK virus, and miopapovaviruses, viruses of the genus Herpesviridae, in particular herpes simplex virus, the varicella / zoster virus human cytomegalovirus, Epstein-Barr virus, human herpes virus 6, human herpes virus 7, human herpes virus 8, viruses of the genus Poxviridae, in particular Poken virus, Orthopox Parapox virus, Molluscum contagiosum virus, Aviviruses, Caprivärviren virus, Leporipen virus Viruses, in particular hepatitis viruses, such as hepatitis A viruses, hepatitis B viruses, hepatitis C viruses, hepatitis D viruses, Hepatitis E viruses, Hepatitis F viruses, Hepatits G viruses, hepadnaviruses, in particular all hepatitis viruses, such as hepatitis B virus, hepatitis D viruses, viruses of the genus Picornaviridae, in particular Picornaviruses, all enteroviruses, all polio viruses, all coxsackie viruses, all echo viruses, all rhino viruses, hepatitis A virus, aphthoviruses, viruses of the genus Calciviridae, in particular hepatitis e viruses, ^'viruses of the genus Reoviridae, in particular reoviruses, orbiviruses, rotaviruses, viruses of the genus Togaviridae, in particular togaviruses, alphaviruses, rubiviruses, pestiviruses, rubella virus, viruses of the genus Flaviviridae, in particular flaviviruses, FSME virus, hepatitis C virus, viruses of the genus Orthomyxoviridae, in particular influenza viruses, viruses of the genus Paramyxovilliviras, in particular paramy , Pneumovirus, measles virus, mumps virus, viruses of the genus Rhabdoviridae, in particular rhabdoviruses, Rabies virus, Lyssavirus, viscous stomatitis virus, viruses of the genus Coronaviridae, i especially corona viruses, viruses of the genus Bunyaviridae, in particular bunya viruses, nairovirus, phlebo virus, uukuvirus, hantavirus, viruses of the genus Arenaviridae, in particular arena viruses, ly phocytic choriomeningitis virus, viruses of the genus Allevirviridae, in particular retroviridair HTL viruses, human T-cell leukemia virus, oncornaviruses, spuma viruses, lentiviruses, all HI viruses, viruses of the genus Filoviridae, in particular Marburg and Ebolavirus, slow viruses, prions, oncoviruses and leukemia viruses.

11. Use according to claim 8 for the prevention and treatment of infections caused by unicellular parasites, namely pathogens of malaria, sleeping sickness, Chagas disease, toxoplasmosis, amoebic dysentery, leishmaniasis, tricho oniasis, pneumocystosis, balantidiosis Cryptosporidiosis, Sarcocystosis, Acanthoma, Naeglerosis, Coccidiosis, Giardiosis and Lambliosis.

12. Use of the compounds according to one of claims 1 to 10 as a fungicide, bactericide or herbicide in plants.