DE19831639C1 - Identifying antiparasitic agents used to treat or prevent parasitic infections, especially malaria, sleeping sickness and leishmaniosis - Google Patents

Abstract

Identification of agents (A) suitable for treatment of infections caused by mono- or poly-cellular parasites comprises (i) treating a test compound with a protein (I) that is involved in the 1-deoxy-D-xylulose-5-phosphate (dDXP) metabolic pathway (or its derivatives with equivalent activity) and (ii) selecting compounds that inhibit (I) or its derivatives. Independent claims are also included for the following: (a) proteins (II) encoded by approximately 3.8 kb (1b) or 3.7 kb (2b) sequences or by sequences that hybridize to (1b) or (2b), or their fragments that encode the mature protein; (b) proteins (III) encoded by approximately 1.5 kb (1a) or 1.5 kb (2a) sequences or by sequences that hybridize to (1a) or (2a) or their fragments that encode the mature protein; (c) (II), (III) and other proteins (IV) involved in the dDXP metabolic pathway isolated from parasite culture media or lysate by chromatography and electrophoresis; (d) (1a), (1b), (2a) and (2b) and sequences that hybridize with them or that would do so but for the degeneracy of the genetic code; (e) recombinant expression vector containing DNA (V) that encodes (II)-(IV) and expresses them in a transformed microorganism or eukaryotic cell, animal or plant; (f) host cells transformed with (V) and able to express (II)-(IV); (g) antibodies (Ab) raised against (II)-(IV); and (h) (A), or herbicides, identified using (I).

Description

The invention relates to organophosphorus compounds and ih re salts, esters and amides and their use in therapy table and prophylactic treatment of infections 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 phosphinoyl derivatives, Phosphinic acid derivatives and phosphonic acid derivatives.

There is a strong need to enrich the Be action of humans and animals as well as the protection of plants Provide funds that are not just powerful own, but unlike other medicines or pesticides show reduced side effects or cause less environmental pollution and thus a mean less danger to human health.

The object of the present invention is therefore a substance to provide universal for virus infections, Bacteria, fungi and parasites in humans and animals and as Fungicide, bactericide and herbicide can be used in plants and meets the above conditions.  

This task is accomplished in a completely surprising way by the in Claim 1 defined substance group solved. This group of substances shows both an anti-infectious effect against viruses, bacteria s, fungi, single and multicellular parasites as well as a fungi cidal, bactericidal and herbicidal activity in plants.

The organophosphorus compounds according to the invention correspond to the general formula (I):

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, OX ₁ and OX ₂ ,
wherein X ₁ and X _{2 may be the} same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical,
B is selected from the group consisting of ether group (II)

and the keto group (III)

consists,
wherein A ₁ and A ₂ , of which A _{2 can} also be omitted, are the same or different and are selected from the group consisting of alkylene, alkenylene and hydroxyalkylene, and A ₃ and A ₄ , one or both of which are also omitted may be the same or different and are selected from the group consisting of alkylene, alkenylene and hydroxyalkylene,
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 aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, OX ₃ or OX ₄ ,
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 heterocyclic radical, a silyl, a cation of an organic and inorganic base, in particular a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium and ammonium compounds , which are derived from ethylenediamine or amino acids, and their pharmaceutically acceptable salts, esters and amides and salts of the esters.

In particular, the compounds which are of the formula (IV) are preferred

correspond with
R ₂ is selected from the group consisting of acetyl and formyl,
A ₁ is selected from the group consisting of methylene, ethylene, ethenylene, hydroxyethylene, 2-hydroxypropylene, and
X ₃ and X _{4 are the} same or different and are selected from the group consisting of sodium, potassium, methyl, ethyl.

The chain -A ₁ -OC (ZY) preferably consists of an oxygen atom and two or three carbon atoms (not including substituents), particularly preferably two carbon atoms.

Of the ether compounds, the compounds are those from the Are selected from ((N-Formyl-N-hydroxylamino) - methoxy) methylphosphonic acid disodium salt, ((N-acetyl-N- hydroxylamino) methoxy) methylphosphonic acid disodium salt, (2- (N-Formyl-N-hydroxylamino) ethenoxy) methylphosphonic acid di sodium salt, (2- (N-acetyl-N-hydroxylamino) ethenoxy) methyl phosphonic acid disodium salt, (3- (N-formyl-N-hydroxylamino) -2- hydroxypropoxy) methylphosphonic acid disodium salt, (3- (N- Acetyl-N-hydroxylamino) -2-hydroxypropoxy) methylphosphonic acid  disodium salt is particularly preferred.

Also preferred are the compounds of the formula (V)

correspond with
R ₂ is selected from the group consisting of acetyl and formyl,
A ₁ is selected from the group consisting of methylene, ethylene, ethenylene, hydroxymethylene, hydroxyethylene and 2-hydroxypropylene,
A ₂ is eliminated or is methylene, and
X ₃ and X _{4 are the} same or different and are selected from the group consisting of a metal from the first, second or third main group of the periodic table, in particular sodium, potassium, and methyl, ethyl.

The chain -A ₁ -CO-A ₂ - preferably consists of two to four carbon atoms (not including substituents), particularly preferably three carbon atoms.

Of these compounds, 2- (N-formyl-N-hydroxyl have been found amino) -1-oxoethylphosphonic acid disodium salt, 2- (N-acetyl-N- hydroxylamino) -1-oxoethylphosphonic acid disodium salt, 3- (N- Formyl-N-hydroxylamino) -1-oxopropylphosphonic acid disodium salt, 3- (N-acetyl-N-hydroxylamino) -1-oxopropylphosphonic acid di sodium salt, 3- (N-formyl-N-hydroxylamino) -1-oxo-2-propenyl phosphonic acid disodium salt, 3- (N-acetyl-N-hydroxylamino) -1- oxo-2-propenylphosphonic acid disodium salt, 4- (N-formyl-N- hydroxylamino) -1-oxo-3-hydroxylbutylphosphonic acid disodium salt, 4- (N-acetyl-N-hydroxylamino) -1-oxo-3-hydroxylbutyl  phosphonic acid disodium salt, 3- (N-formyl-N-hydroxylamino) -2- oxopropylphosphonic acid disodium salt, 3- (N-acetyl-N-hydroxyl amino) -2-oxoproylphosphonic acid disodium salt, 4- (N-formyl-N- hydroxylamino) -3-oxo-2-hydroxyl-2-methylbutylphosphonic acid disodium salt, 4- (N-acetyl-N-hydroxylamino) -3-oxo-2-hydroxyl- 2-methylpropylphosphonic acid disodium salt, 4- (N-formyl-N- hydroxylamino) -3-oxo-2-hydroxyl-2- (hydroxymethyl) butyl phosphonic acid disodium salt, 4- (N-acetyl-N-hydroxylamino) -3- oxo-2-hydroxyl-2- (hydroxymethyl) propylphosphonic acid disodium salt as particularly preferred.

Peculiarities of the above definitions and suitable examples for this are given below:

"Acyl" is a substituent derived from an acid, such as of an organic carboxylic acid, carbonic acid, carbamic acid or those corresponding to the individual acids above Thioic acid or imidic acid, or from an organic sulfone acid, these acids each being aliphatic, aromatic and / or heterocyclic groups in the molecule include and Carbamoyl or carbamimidoyl.

Suitable examples of these acyl groups are shown below specified.

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, propoxy carbonyl, 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.);
Oxalo;
Alkoxalyl (e.g. methoxalyl, ethoxalyl, propoxalyl etc.).

In the above examples of aliphatic acyl groups the aliphatic hydrocarbon part, especially the Al kylgruppe or the alkane radical, optionally one or more suitable have substituents such as amino, halogen (e.g. fluorine, Chlorine, bromine etc.), hydroxy, hydroxyimino, carboxy, alkoxy (e.g. methoxy, ethoxy, propoxy etc.), alkoxycarbonyl, acylami no (e.g. benzyloxycarbonylamino etc.), acyloxy (e.g. acetoxy, Benzoyloxy etc.) and the like; as the preferred aliphatic Acyl radicals with such substituents are e.g. B. with amino, car boxy, amino and carboxy, halogen, acylamino or the like to name substituted alkanoyle.

Aromatic acyl radicals are those acyl radicals which derive 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) can optionally have one or more suitable substituents, such as those which are suitable substituents for the alkyl group or the alkane residue has already been given. 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 derived from an acid with a heterocyclic group; to belong:

Heterocyclic carbonyl, in which the heterocyclic radical an aromatic or aliphatic 5 to 6-membered He terocycle with at least one heteroatom from the group Is nitrogen, oxygen and sulfur (e.g. thiophenyl, Fu royl, pyrrole carbonyl, nicotinoyl etc.);

Heterocycle alkanoyl, in which the heterocyclic radical 5- to Is 6-membered and at least one heteroatom from the group Contains nitrogen, oxygen and sulfur (e.g. thiophene yl-acetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetyl etc.) and the same.

In the above examples of heterocyclic acyl residues the heterocycle and / or the aliphatic hydrocarbon some may have one or more suitable substituents sen, like the same ones that are suitable for alkyl and alkane groups were specified.

"Alkyl" is a straight or branched chain alkyl group with up to 9 carbon atoms, such as methyl, ethyl, propyl, isopro pyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like  chen.

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

"Alkenyl" includes straight or branched chain alkenyl groups pen with up to 9 carbon atoms, such as. B. vinyl, propenyl (e.g. 1-propenyl, 2-propenyl), 1-methylpropenyl, 2- Methyl propenyl, butenyl, 2-ethyl propenyl, pentenyl, hexenyl.

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

Cycloalkyl preferably represents an optionally substituted C3- C7 cycloalkyl; as possible substituents are u. a. Alkyl, Al kenyl, alkynyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc.), nitro and the like net.

Aryl is an aromatic hydrocarbon residue, such as phenyl Naphthyl, etc., which optionally one or more suitable substituents can have ducks, 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, the aro Matic part optionally one or more suitable substituents may have such as alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine, etc.), nitro and the like.

"Alkylene" includes straight or branched chain alkylene groups which have up to 9 carbon atoms and are represented by the formula

- (C _n H _2n ) -

can be reproduced in which n is an integer of 1 to 9, such as methylene, ethylene, trimethylene, methylethylene, Tetramethylene, 1-methyltrimethylene, 2-ethylethylene, pentame ethylene, 2-methyltetramethylene, isopropylethylene, hexamethylene, and the same; preferred alkylene radicals have up to 4 Koh lenstoffatome and particularly preferred are residues with 3 Koh lenstoffatomen such as. B. Trimethylene.

"Alkenylene" includes straight or branched chain alkenylene groups with up to 9 carbon atoms, which are represented by the formula

- (C _n H _2n-2 ) -

can be reproduced in which n is an integer of 2 to 9, such as B. vinylene, propenylene (e.g. 1-propenylene, 2- Propenylene), 1-methylpropenylene, 2-methylpropenylene, buteny len, 2-ethylpropenylene, pentenylene, hexenylene and the like; the alkenylene radical can particularly preferably contain up to 5 carbons Have substance atoms and in particular 3 carbon atoms such as e.g. B. 1-propenylene.

"Hydroxyalkylene" may include straight or branched chain alkylene radicals which have up to 9 carbon atoms, where at least one selected carbon atom is substituted by a hydroxy group; these residues can be represented by the formula

- (C _n H _2n-2 ) (OH) _z -

are reproduced in which n is an integer from 1 to 9 and z is an integer to which 1 ≦ z ≦ n applies. Too suitable Examples of such hydroxyalkylene groups include Hy  droxymethylene, hydroxyethylene (e.g. 1-hydroxyethylene and 2- Hydroxyethylene), hydroxytrimethylene (e.g. 1-hydroxy trimethylene, 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 low is particularly preferred res hydroxyalkylene with up to 4 carbon atoms and esp special one with 3 carbon atoms such. B. 2- Hydroxytrimethylene.

The radicals X ₃ and X ₄ can preferably be chosen such that esters are formed on the phosphono group or phosphino group. Suitable examples of such esters according to formulas (I), (IV) and (V) include suitable mono- and diesters, and preferred examples of such esters include alkyl esters (e.g. methyl esters, ethyl esters, propyl esters, isopropyl esters) , Butyl ester, isobutyl ester, hexyl 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.); and silyl esters (e.g., from trialkylhalosilyl, dialkyldihalosilyl, alkyl trihalosilyl, dialkylarylhalosilyl, trialkoxyhalosilyl, dialkylaralkylhalosilyl, dialkoxydihalosilyl, trialkoxyhalosilyl, etc.) and the like.

In the above ester, the alkane and / or arene part can be optional have at least one suitable substituent such as halo gene, alkoxy, hydroxy, nitro or the like.

X ₃ and X ₄ are preferably a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium, or ammonium compounds which are derived from ethylenediamine or amino acids. That is, the salt compounds of the organophosphorus compounds with organic or inorganic bases (e.g. sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylamine salt, ethanolamine salt, dicyclohexylamine salt, ethylene diamond salt, N, N'-dibenzylethylenediamine salt etc.) as well as salts with amino acids (e.g. arginine salt, aspartic acid salt, glutamic acid salt etc.) and the like.

The compounds used according to the invention according to the formulas (I), (IV) or (V) can in their protonated form as ammo nium salt of organic or inorganic acids, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, methanesul fonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, malein acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc. available.

The compounds of the formulas (I), (II) or (III) used according to the invention allow, for example, ent for double bonds or chiral groups R ₁ , R ₂ , R ₃ , R ₄ , X ₁ , X ₂ , X ₃ , X ₄ , A ₁ , A ₂ , A ₃ or A _{4 increase} the occurrence of spatial isomers. The use of the compounds according to the invention includes all spatial isomers both as pure substances and in the form of their mixtures.

The organophosphorus compounds are particularly suitable for therapeutic and prophylactic treatment of infections suitable for humans and animals that are infected by viruses, bacteria, and causing multicellular parasites and fungi.

The compounds are against unicellular parasites (protozoa) effective, especially against malaria and Sleeping sickness as well as Chagas disease, toxoplasmosis, the amoebic dysentery, the leishmaniasis, the trichomoniasis, the  Pneumocystosis, balantidiosis, cryptosporidiosis, Sarcocystosis, Acanthoma, Naeglerosis, Coccidio se, the Giardiosis and the Lambliosis.

They are therefore especially as malaria prophylaxis and as a pro prevention of sleeping sickness and Chagas disease, the Toxoplasmosis, the amoebic dysentery, the leishmaniasis, the trichomo niasis, pneumocystosis, balantidiosis, cryptospori diose, sarcolocystosis, acanthoma, nail disease, coccidiosis, 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 Propionibacte rium acnes species,
Bacteria of the Actinomycetaceae family, in particular the Actinomyces gate,
Bacteria of the genus Corynebacterium, in particular the species Corynebacterium diphteriae and Corynebacterium pseudotubercu losis,
Bacteria of the family Mycobacteriaceae, of the genus Mycobacte rium, in particular the species Mycobacterium leprae, Mycobacte rium tuberculosis, Mycobacterium bovis and Mycobacterium avi um,
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 Yer sinia ruckeri,
Bacteria of the family Mycoplasmataceae, the genera My coplasma and Ureaplasma, especially the species Mycoplasma pneu moniae,
Bacteria of the genus Brucella,
Bacteria of the genus Bordetella,
Bacteria of the family Neiseriaceae, in particular of the genera Neisseria and Moraxella, in particular the species Neisseria me ningitides, Neisseria gonorrhoeae and Moraxella bovis,
Bacteria of the Vibrionaceae family, in particular of the Vibrio, Aeromonas, Plesiomonas and Photobacterium genera, in particular the Vibrio cholerae, Vibrio anguillarum and Aeromonas salmonicidas species,
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 of the Treponema, Borrelia and Leptospira genera, in particular Borrelia burgdorferi,
Bacteria of the genus Actinobacillus,
Bacteria of the Legionellaceae family, of 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 Pseudomonadaceae family, in particular the Pseudomonas and Xanthomonas species,
Bacteria of the Enterobacteriaceae family, in particular of the genera Escherichia, Klebstella, Proteus, Providencia, Sal monella, Serratia and Shigella,
Bacteria of the Pasteurellaceae family, especially the Gat tung Haemophilus,
Bacteria of the Micrococcaceae family, in particular of the genera Micrococcus and Staphylococcus,
Bacteria of the Streptococcaceae family, especially the Streptococcus and Enterococcus and
Bacteria of the Bacillaceae family, especially the genera Bacillus and Clostridium.

Organophosphorus compounds and their are therefore suitable Derivatives for the treatment of the diphtheria, the acne vulgaris, the Listeriosis, the erysipelas in animals, the gas fire in humans and in animals, para-rage in humans and animals, tuberculosis se in humans and animals, leprosy, and other mycobacteriosis Man and animal, paratuberculosis of animals, plague, mesente rial lymphadenitis and pseudotuberculosis in humans and Animal, cholera, legionnaires' disease, Lyme disease in humans and Animal, leptospirosis in humans and animals, syphilis, campylobac enteritis in humans and animals, Moraxella keratoconjunc tivitis and serositis of animals, brucellosis of animals and Humans, anthrax in humans and animals, actinomycosis in Humans and animals, streptotrichoses, psittacosis / ornithosis Animals, Q fever, Ehrlichiosis.

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

It can also be used in combination with another antibiotic Treatment of the above diseases can be used. Suitable for combination preparations with other anti-infectives in particular isoniazid, rifampicin, ethambutol, pyrazina mid, streptomycin, protionamide and dapsone for the treatment of Tuberculosis.

The active compounds according to the invention can also be used in particular for infections with the following viruses:
Parvoviridae: Parvoviruses, Dependoviruses, Densoviruses,
Adenoviridae: adenoviruses, mastadenoviruses, aviadenoviruses,
Papovaviridae: papovaviruses, in particular papillomaviruses (so-called wart viruses), polyomaviruses, in particular JC virus, BK virus, and miopapovaviruses,
Herpesviridae: all herpes viruses, in particular 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: smallpox 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 - viruses, hepatitis E viruses, hepatitis F viruses, hepatits G viruses,
Hepadnaviruses: all hepatitis viruses, hepatitis B virus, He patitis D viruses,
Picornaviridae: Picornaviruses, all enteroviruses, all polioviruses, all Coxsackieviruses, all echoviruses, all rhinoviruses, He patitis A virus, aphthoviruses,
Calciviridae: hepatitis E viruses,
Reoviridae: reoviruses, orbiviruses, rotaviruses,
Togaviridae: Togaviruses, Alphaviruses, Rubiviruses, Pestiviruses, 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 leu kemia virus, oncornaviruses, spumaviruses, lentiviruses, all HI viruses,
Filoviridae: Marburg and Ebola viruses,
Slow virus infections, prions,
Onkoviruses, leukemia viruses,

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

Eradication of papilloma viruses to prevent tumors, especially caused by tumors of the genital organs due to papilloma viruses 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 cytomegalovirus before transplantation, eradication of Eppstein-Barr viruses before transplantation and for the prevention of Eppstein-Barr virus-associated tumors, eradication of Hepa titis viruses for the treatment of chronic liver diseases and for the prevention of liver tumors and cirrhosis, Eradi cation of Coxsackieviruses in cardiomyopathies, eradication of Coxsackieviruses in Diabetes Mellitus Patients, Eradikati on immunodeficiency viruses in humans and animals, treatment of Concomitant infections in AIDS patients, treatment of inflammation viral genesis of the respiratory tract (laryngeal papillo me, hyberplasia, rhinitis, pharyngitis, bronchitis, pneumoni en), the sensory organs (keratoconjunctivitis), the nervous system stems (poliomyelitis, meningoencephalitis, encephalitis, suba kute sclerosing panencephalitis, SSPE, progressive multi focal leukoencephalopathy, lymphocytic choriomeningitis), of the gastrointestinal tract (stomatitis, gingivostomatitis, oesopha gitis, gastritis, gastroenteritis, diarrhea), the Liver and biliary system (hepatitis, cholangitis, hepato cellular carcinoma), of the lymphatic tissue (mononucleosis, Lymphadenitis), the hematopoietic system, the sex organs (mumps orchitis), the skin (warts, dermatitis, herpes labialis, cold sores, herpes zoster, shingles), the Mucous membranes (papillomas, conjunctive apapillomas, hyperplasias, Dysplasia), the cardiovascular system (arteritis, myocardi  tis, endocarditis, pericarditis), the kidney-urinary system, of the genital organs (anogenital lesions, warts, genital warts, acute condylomas, dysplasias, papillomas, cervix dysplasia, condylomata acuminata, epidermodysplasia verruci formis), the organs of movement (myositis, myalgia), treatment foot-and-mouth disease of the two-toed ungulates, Colorado Tick fever, dengue syndrome, hemorrhagic fie bers, early summer meningoencephalitis (TBE) and yellow feverish.

The compounds described, i. H. the organophosphorus Compounds of formula (I), (IV) and (V) and esters and amides the same on the phosphono or phosphino group and salts these show a strong cytotoxic activity against about single and multicellular parasites, especially against the pathogens of malaria and sleeping sickness. Accordingly are the compounds of the invention for the treatment of Infectious diseases caused by viruses, bacteria, Parasites and fungi are caused in humans and animals. The Connections are also for use to prevent Er diseases caused by viruses, bacteria, parasites and fungi are provoked, especially as malaria prophylaxis and Suitable as prophylaxis for sleeping sickness.

The organophosphorus compounds according to the invention generally include pharmaceutically acceptable salts, ami de, ester, a salt of such an ester, or compound gene, the compounds of the invention when applied as metabolic products or breakdown products, also called "prodrugs", can be administered in ir in a suitable manner analogous to known anti-infectious active agents (mixed with a non-toxic pharma acceptable carrier).

Pharmaceutically acceptable salts of the compounds include  Salts which the compounds of the formulas (I) according to the invention, (IV) and (V) in their protonated form as an ammonium salt ganic or organic acids, such as hydrochloric acid, sulfuric acid re, citric acid, maleic acid, fumaric acid, tartaric acid, p- Toluenesulfonic acid.

Also particularly pharmaceutically suitable are the salts which are formed by a suitable selection of X ₃ and X ₄ , 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 in the form of pharma deutical preparations in dosage units the. This means that the preparation in the form of individual parts le, z. B. tablets, dragees, capsules, pills, suppositories and ampoules are present, the active ingredient content of which is a fraction or a multiple of a single dose. Thu Sation units can, for. B. 1, 2, 3 or 4 single doses or Contain 1/2, 1/3 or 1/4 of a single dose. A single do sis preferably contains the amount of active ingredient that is present in a Application is administered and usually an entire, a half or a third or a quarter of a day dose corresponds.

Taking non-toxic, inert pharmaceutically acceptable drugs materials are solid, semi-solid or liquid diluents tel, fillers and formulation auxiliaries of all kinds stand.

The preferred pharmaceutical preparations are tablets, Coated tablets, capsules, pills, granules, suppositories, solutions, Suspensions and emulsions, pastes, ointments, gels, creams, lo tion, powder and sprays called. Tablets, coated tablets, capsules,  Pills and granules can be the active ingredient or ingredients in addition to the contain conventional carriers, such as (a) filling and stretching tel, e.g. B. starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. B. Carboxymethyl cellulo se, alginates, gelatin, polyvinylpyrrolidone, (c) damp means, e.g. B. glycerin, (d) disintegrant, e.g. B. agar, Calcium carbonate and sodium carbonate, (e) solution retarders, e.g. B. paraffin and (f) absorption accelerator, e.g. B. quaternary re ammonium compounds, (g) wetting agents, e.g. B. cetyl alcohol, Glycerol monostearate, (h) adsorbent, e.g. B. kaolin and Bentonite and (i) lubricants, e.g. B. talc, calcium and Ma magnesium stearate and solid polyethylene glycols or mixtures of substances listed under (a) to (i).

The tablets, dragees, capsules, pills and granules can with the usual, optionally containing opacifiers tendency coatings and covers and so together be set that they only or be the active ingredients preferably in a certain part of the intestinal tract If necessary, deliver with a delay, with z. B. Polymer substances and waxes can be used.

The active ingredient (s) can optionally be combined with an or several of the above-mentioned carriers also in microver encapsulated form.

Suppositories can besides the active ingredient (s) the usual Chen water-soluble or water-insoluble carriers hold, e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat and higher esters (e.g. C14 alcohol with C16 fatty acid) or Gemi of these substances.

Ointments, pastes, creams and gels can next to the or Active substances contain the usual carriers, e.g. B. tieri vegetable and vegetable fats, waxes, paraffins, starch, tra  gant, cellulose derivatives, polyethylene glycols, silicones, bento nite, silica, talc and zinc oxide or mixtures of these Fabrics.

Powders and sprays can in addition to the active ingredient (s) Lichen carriers included, for. B. milk sugar, talc, Kie silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also be used union blowing agents, e.g. B. chlorofluorocarbons, ent hold.

Solutions and emulsions can be added to the active ingredient (s) the usual carriers such as solvents, solubilizers and emulsifiers, e.g. B. water, ethyl alcohol, isopropyl alcohol, Ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, Pro pylene glycol, 1,3-butylene glycol, dimethylformamide, oils, esp special cottonseed oil, peanut oil, corn oil, olive oil, Castor oil and sesame oil, glycerin, glycerin formal, tetrahydro furfuryl alcohol, polyethylene glycols and fatty acid esters of Contain sorbitans or mixtures of these substances.

The solutions and emulsions can be used for parenteral administration are also available in sterile and blood isotonic form.

Suspensions can besides the active ingredient (s) the usual Chen carriers such as liquid diluents, e.g. B. What water, ethyl alcohol, propylene glycol, suspending agents, e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and Sorbitan esters, microcrystalline cellulose, aluminum metal hydroxide, bentonite, agar and tragacanth or mixtures of these Contain substances.

The formulation forms mentioned can also contain colorants, Preservatives as well as smell and taste-improved Additives, e.g. B. peppermint oil and eucalyptus oil and sweeteners,  e.g. B. saccharin.

The active substances of the formulas (I), (IV) and (V) should be used in the pharmaceutical preparations listed above, preferably in a concentration of about 0.1 to 99.5% by weight, preferably from about 0.5 to 95% by weight of the total mixture his.

In addition to the compounds, the pharmaceutical preparations can gene of formula (I), (IV) and (V) also other pharmaceutical Contain active ingredients.

Furthermore, the organophosphorus compounds in the pharmaceutical agents in combination with sulfonamide, sulfa doxin, artemisinin, atovaquone, quinine, chloroquine, hydroxy chloroquine, mefloquine, halofantrine, pyrimethamine, armesin, Te tracycline, doxycycline, proguanil, metronidazole, praziquantil, Niclosamide, mebendazole, pyrantel, tiabendazole, diethylcarba zin, piperazine, pyrivinum, metrifonate, oxamniquin, bithionol or suramin or more of these substances.

The manufacture of the pharmaceutical accessories listed above Horse riding is done in the usual way according to known methods, e.g. B. by mixing the active ingredient or ingredients with the or Carriers.

The preparations mentioned can be used in humans and animals the oral, rectal, parenteral (intravenous, intramuscular, sub cutaneous), intracisternal, intravaginal, intraperitoneal, local (Powder, ointment, drops) and for the treatment of infections in Cavities, body cavities are applied. As a suitable addition Preparations come with injection solutions, solutions and suspensions NEN for oral therapy, gels, infusion formulations, emul ions, ointments or drops. For local therapy ophthalmic and dermatological formulations,  Silver and other salts, ear drops, eye ointments, powder or solutions are used. In animals, the intake also in suitable form via the feed or drinking water take place. Gels, powders, powders, tablets, Prolonged-release tablets, premixes, concentrates, granules, pellets, Tablets, boluses, capsules, aerosols, sprays, inhalants Humans and animals can be used. Furthermore, the inventions compounds according to the invention in other carrier materials such as Example plastics, (plastic chains for local therapy), Collagen or bone cement can be incorporated.

In general, it has been in both human and of veterinary medicine has been shown to be advantageous Active substances of the formula (I), (IV) and (V) in total amounts of about 0.05 to about 600, preferably 0.5 to 200 mg / kg body weight each 24 hours, possibly in the form of several individual were given to achieve the desired results chen. A single dose contains the active ingredient (s) in preference wise in amounts of about 1 to about 200, in particular 1 to 60 mg / kg body weight. However, it may be necessary from the deviations mentioned doses, depending on on the type and body weight of the patient to be treated the type and severity of the disease, the type of accessories riding and the application of the drug as well as the time space or interval within which the administration follows.

So in some cases it may be sufficient with less than the above amount of active ingredient to get by while in at whose cases exceeded the amount of active ingredient mentioned above must become. The determination of the optima required in each case len dosage and type of application of the active ingredients can by the specialist on the basis of his specialist knowledge.

The compounds of the invention can in the usual Kon  concentrations and preparations in animals together with the Feed or with feed preparations or with drinking water are given.

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

The person skilled in the art knows in principle which synthetic route to use Production of the substances according to the invention has to choose. in the the following are examples of some synthetic routes for verbin of the invention.

Example 1a: Preparation of the compounds HC (= O) -N (OH) -X-PO (OR) ₂ with R = H or Na ⁺ and X = -CH ₂ -CH ₂ -C (= O) - 3-chloropropionylphosphonic acid dimethyl ester

0.5 mol of 3-chloropropionic acid chloride is added dropwise at 5 ° C. Equivalent trimethyl phosphite, then leaves at ambient temperature Warm the door and stir for a further 2 h. The product originates in good yields and can be distilled in an oil pump vacuum. (in analogy to Ref .: R. Karaman, A. Goldblum, E. Breuer, J. Chem Soc Perkin Trans I, 1989, 765-774; to represent β- Chloropropionic acid chloride see: T. Bruylants, Bull. Soc. Chim. Belg. 1949, 58, 319)

3- (N-hydroxyamino) propionylphosphonic acid dimethyl ester

0.8 ml of sodium hydroxide, dissolved in 75 ml of water, then 75 ml of methanol and finally 0.1 mol of 3-chloropropionylphosphonic acid dimethyl ester are added dropwise to a solution of 0.8 mol of hydroxylamine hydrochloride in 100 ml of water with ice cooling. After stirring for 3 hours at a temperature of 40 ° C, methanol was removed under reduced pressure, the resulting aqueous solution saturated with NaHCO ₃ , by-products removed by washing with toluene and the product shaken with methylene chloride, dried over magnesium sulfate, filtered and at room temperature under reduced pressure. What remains is 3- (N-hydroxyamine) propionylphosphonic acid dimethyl ester.

3- (N-hydroxyamino) propionylphosphonic acid

0.2 mol of trimethylsilyl bromide slowly become a solution of 0.1 mol of 3- (N-hydroxyamino) propionyl phosphonic acid Dimethylester given in 100 ml of absolute Acetorfitril. After 3- the solution is stirred for one hour at room temperature concentrated and taken up in 50 ml of methanol. After 30 minutes of stirring ren is concentrated again. 3- (N-hydroxyamino) propionyl phosphonic acid can be reacted further without purification. (in analogy to Ref .: R. Karaman, A. Goldblum, E. Breuer, J. Chem.Soc.Perkin Trans. I, 1989, 765-774)

3- (N-formyl-N-hydroxyamino) propionylphosphonic acid mono natri salting over

2 ml of formic acid are added dropwise to 4 ml of acetic anhydride at 0 ° C. leaves 10 min at the same temperature and 15 min at room temperature stir temperature, cool to 0 ° C again and drip 0.02 mol 3- (N-hydroxyamino) propionylphosphonic acid, dissolved in formic acid re at 0 ° C. After stirring for 1 hour at room temperature the solution is concentrated under reduced pressure, the oil in 50 ml of methanol dissolved, heated to 60 ° C and with a mixture added from ethanol / isopropanol. A white solid falls from which is redissolved in methanol and from ethanol, under further addition of isopropanol, are recrystallized can.

Alternatively, the following synthetic route can be followed: The acid chloride of β-alanine is converted to 3- with triethyl phosphite Aminopropionyl-phosphonic acid diethyl ester implemented (cf. B. A. Arbuzov, M.V. Zolotova, Bull.Acad.Sci.USSR Div. Chem. Sci  (Engl. Transl.) 1964, 1701-04). Then it is formylated to do that resulting secondary amine with dimethyldioxirane to the N-formyl Oxidize N-hydroxyamino-phosphonic acid ester. The hydrolysis can then be performed as described above

Example 1b Preparation of the compounds HC (= O) -N (OH) -X-PO (OR) ₂ with R = H or Na ⁺ and X = -CH ₂ -CH (OH) -C (= O) -

Instead of 3-chloropropionyl chloride, acrylic acid is used exposes it to the acid chloride, epoxidizes with a Peracid and opens the epoxy radically to obtain 3-chloro-2-hydroxy-propionyl chloride. This can be done as under game 1a can be implemented.

Example 1c Preparation of the compounds HC (= O) -N (OH) -X-PO (OR) ₂ with R = H or Na ⁺ and X = -CH ₂ -CH ₂ -O-CH ₂ - (2-chloroethoxy) methylphosphonic acid diethyl ester

1-chloro-2-chloromethoxyethane (for illustration see: B. Castro, Bull. Soc. Chim. 1967, 1533-40) is triethyl phosphite in a Michael Arbuzov reaction under reflux to the (2-chlorine ethoxy) methylphosphonic acid diethyl ester implemented.

(2-Azido-ethoxy) methylphosphonic acid diethyl ester

0.02 mol (2-chloroethoxy) methylphosphonic acid diethyl ester, 3 mmol of tetrabutylammonium bromide and 2.5 g of sodium azide are in 50 ml of toluene boiled under reflux for 4 h. After cooling is washed three times with 25 ml of water. The aqueous phase can be extracted with toluene. The united toluene Phases are dried over sodium sulfate and the solution removed in a vacuum. What remains is a yellow oil. (cf. Lit .: K. Eger, E. M. Klünder, M. Schmidt, J. Med. Chem. 1994, 37, 3057-61; see. also: A. Holy, I. Rosenberg, Col  lect.Czech. Chem. Commun. 1989, 2190-210)

(2-Amino-ethoxy) methyl-phosphonic acid diethyl ester

The oil obtained above (24 mmol), dissolved in 5 ml of toluene, is added dropwise to a solution of 36 mmol of triphenylphosphine in 35 ml of toluene within 30 min. After stirring for one hour at room temperature, 50 ml of water are added, the mixture is stirred vigorously for 15 minutes and the phases are separated. The aqueous phase is washed several times with ether and concentrated. Traces of water are dragged out with the help of methanol. What remains is a yellow oil.
(see Lit .: K. Eger, EM Klünder, M. Schmidt, J. Med. Chem. 1994, 37, 3057-61)

[2- (N-hydroxyamino) ethoxy] methylphosphonic acid diethyl ester

(2-Amino-ethoxy) methyl-phosphonic acid diethyl ester can in ge wrestle yields with Oxidmitmit known in the literature be converted into the corresponding hydroxylamine (e.g. Dimethyldioxirane or benzoyl peroxide).

[2- (N-hydroxyamino) ethoxy] methylphosphonic acid

Based on K-L. Yu, J.J. Bronson, H. Yang, A. Patick, M. Alam, V. Brankovan, R. Datema, M. J. M. Hitchcock, J. C. Martin, J. Med. Chem. 1992, 35, 2958-2969 0.5 mol [2- (N- hydroxyamino) ethoxy] methylphosphonic acid diethyl ester and 1 mol 2,4,6-collidine in 5 ml absolute methylene chloride at one Temperature of 0 ° C under argon stirred for one hour. After 16 The solution is vacuumed for hours at room temperature concentrated, taken up in aqueous acetone and stirred for 14 hours. After concentration, the mixture is taken up in 1N NaOH and the mixture is stirred for 2 h Heated to 100 ° C. After cooling, the mixture is concentrated and the raw product chromatographically cleaned.

[2- (N-formyl-N-hydroxyamino) ethoxy] methylphosphonic acid mono- Sodium salt

The formylation can be done in analogy to the description below Example 1a are carried out.

Example 1d: Preparation of the compounds HC (= O) -N (OH) -X-PO (OR) ₂ with R = H or Na ⁺ and X = -CH (OH) -CH (OH) -CH (OH) -C (= O)-

The starting point for X can be threonic acid, threose / erythrose or the 2.3.4.4-tetrachlorobutyryl chloride (Cl ₂ C-CHCl-CHCl-COCl) known in the literature.

Claims (10)

1. Organophosphorus compounds of the general formula (I)
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, OX ₁ and OX ₂ ,
wherein X ₁ and X _{2 may be the} same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl , substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical,
B is selected from the group consisting of an ether group of the general formula (II)
and the keto group (III)
consists
wherein A ₁ and A ₂ , of which A _{2 can} also be omitted, are the same or different and are selected from the group consisting of alkylene, alkenylene and hydroxyalkylene, and
A ₃ and A ₄ , one or both of which can also be omitted, are the same or different, are selected from the group consisting of alkylene radical, alkenylene radical and hydroxyalkylene radical,
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 aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl , substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, OX ₃ or OX ₄ ,
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 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 system, ammonium, substituted ammonium and There are ammonium compounds derived from ethylenediamine or amino acids,
and their pharmaceutically acceptable salts, esters and amides and salts of the esters. 2. Compounds according to claim 1, characterized in that they have the formula (IV)
correspond with
R ₂ is selected from the group consisting of acetyl and formyl,
A ₁ is selected from the group consisting of methylene, ethylene, ethenylene, 2-hydroxypropylene and hydroxyethylene, and
X ₃ and X _{4 are the} same or different and are selected from the group consisting of sodium, potassium, methyl, ethyl be. 3. Compounds according to claim 2, characterized in that they are selected from the group consisting of 2- (N-formyl-N- hydroxylamino) -1-oxoethylphosphonic acid disodium salt, 2- (N- Acetyl-N-hydroxylamino) -1-oxoethylphosphonic acid disodium salt, 3- (N-formyl-N-hydroxylamino) -1-oxopropylphosphone acid disodium salt, 3- (N-acetyl-N-hydroxylamino) -1- oxoproylphosphonic acid disodium salt, 3- (N-formyl-N- hydroxylamino) -1-oxo-2-propenylphosphonic acid disodium salt, 3- (N-acetyl-N-hydroxylamino) -1-oxo-2-propenylphosphonic acid disodium salt, 4- (N-formyl-N-hydroxylamino) -1-oxo-3- hydroxylbutylphosphonic acid disodium salt, 4- (N-acetyl-N- hydroxylamino) -1-oxo-3-hydroxylbutylphosphonic acid disodium salt, 3- (N-formyl-N-hydroxylamino) -2-oxopropylphosphone  acid disodium salt, 3- (N-acetyl-N-hydroxylamino) -2- oxoproylphosphonic acid disodium salt, 4- (N-formyl-N- hydroxylamino) -3-oxo-2-hydroxyl-2-methylbutylphosphon acid disodium salt, 4- (N-acetyl-N-hydroxylamino) -3-oxo-2- hydroxyl-2-methylpropylphosphonic acid disodium salt, 4- (N- Formyl-N-hydroxylamino) -3-oxo-2-hydroxyl-2- (hydroxymethyl) - butylphosphonic acid disodium salt, 4- (N-acetyl-N-hydroxyl amino) -3-oxo-2-hydroxyl-2- (hydroxymethyl) propylphosphon acid disodium salt. 4. Compounds according to claim 1, characterized in that they have the general formula (V)
correspond with
R ₂ is selected from the group consisting of acetyl and formyl,
A ₃ is selected from the group consisting of methylene, ethylene, ethenylene, 2-hydroxypropylene, hydroxymethylene and hydroxyethylene,
A ₄ is eliminated or is methylene, and
X ₃ and X _{4 are the} same or different and are selected from the group consisting of sodium, potassium, methyl, ethyl be. 5. Compounds according to claim 4, characterized in that they are selected from the group consisting of ((N-formyl-N- hydroxylamino) methoxy) methylphosphonic acid disodium salt, ((N-Acetyl-N-hydroxylamino) methoxy) methylphosphonic acid disodium salt, (2- (N-formyl-N-hydroxylamino) ethenoxy) - methylphosphonic acid disodium salt, (2- (N-acetyl-N-hydroxyl  amino) ethenoxy) methylphosphonic acid disodium salt, (3- (N- Formyl-N-hydroxylamino) -2-hydroxypropoxy) methylphosphon acid disodium salt, (3- (N-acetyl-N-hydroxylamino) -2- hydroxypropoxy) methylphosphonic acid disodium salt. 6. Use of organophosphorus compounds according to one of claims 1 to 5 for the treatment of infectious pro eat in humans and animals caused by viruses, bacteria, Fungi or parasites are caused and as a fungicide, Bactericide or herbicide on plants. 7. Use according to claim 6 for the treatment of infections, caused by bacteria, viruses, fungi or one or multicellular parasites. 8. Use according to claim 6 for the treatment of infections, which are caused by bacteria that come from the group pe are selected from bacteria of the Propioni family bacteriaceae, especially of the genus Propionibacterium, especially the species Propionibacterium acnes, bacteria of the Family Actinomycetaceae, especially the genus Acti nomyces, bacteria of the genus Corynebacterium, in particular re the species Corynebacterium diphteriae and Corynebacterium pseudotuberculosis, bacteria of the family Mycobacteriaceae, the genus Mycobacterium, especially the species Mycobac terium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium, family bacteria Chlamydiaceae, especially the species Chlamydia trachoma tis and Chlamydia psittaci, bacteria of the genus Listeria, especially the species Listeria monocytogenes, bacteria of the Type 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, especially the species Mycoplasma pneumoniae, bacteria of the Genus Brucella, bacteria of the genus Bordetella, bacteria of the Neiseriaceae family, especially of the genera Neisseria and Moraxella, especially the Neisseria species meningitides, Neisseria gonorrhoeae and Moraxella bovis, Bacteria of the Vibrionaceae family, especially the Gat Vibrio, Aeromonas, Plesiomonas and Photobacterium, especially the species Vibrio cholerae, Vibrio anguillarum and Aeromonas salmonicidas, bacteria of the Campy genus lobacter, especially the Campylobacter jejuni species, Campylobacter coli and Campylobacter fetus, bacteria of the Genus Helicobacter, in particular the species Helicobacter py lori, bacteria of the Spirochaetaceae and Lep families tospiraceae, especially the genera Treponema, Borrelia and Leptospira, especially Borrelia burgdorferi, bacteri en of the genus Actinobacillus, bacteria of the Legio family nellaceae, of the genus Legionella, bacteria of the family Rickettsiaceae and family Bartonellaceae, bacteria of the Genera Nocardia and Rhodococcus, bacteria of the genus Dermatophilus, bacteria of the family Pseudomonadaceae, ins particular of the genera Pseudomonas and Xanthomonas, bacteria Enterobacteriaceae family, especially the Gat Escherichia, Klebstella, Proteus, Providencia, Sal monella, Serratia and Shigella, bacteria of the Pa family steurellaceae, especially of the genus Haemophilus, Bakte of the Micrococcaceae family, especially of the genera Micrococcus and Staphylococcus, family bacteria Streptococcaceae, especially the genera Streptococcus and Enterococcus and bacteria of the Bacillaceae family, in particular of the genera Bacillus and Clostridium be stands, and in the Helicobacter eradication therapy Ulcers of the gastrointestinal tract.   9. Use according to claim 6 for the treatment of infections, that are caused by viruses that come from the group selected from viruses of the genus Parvoviridae, especially parvoviruses, dependoviruses, densoviruses, viruses of the genus Adenoviridae, especially adenoviruses, mastade noviruses, aviadenoviruses, viruses of the genus Papovaviridae, especially papovaviruses, especially papillomaviruses (see above) wart viruses), polyoma viruses, in particular JC virus, BK virus, and miopapovaviruses, viruses of the genus Herpesviri dae, especially herpes simplex viruses, the varicella len / zoster viruses, human cytomegalovirus, Epstein Barr viruses, human herpes virus 6, human herpes virus 7, human herpes virus 8, viruses of the genus Poxviridae, esp special smallpox viruses, orthopox, parapox, molluscum Contagiosum virus, aviviruses, capriviruses, leporipox viruses, primarily hepatotropic viruses, especially hepatitis viruses such as Hepatitis A viruses, hepatitis B viruses, hepatitis C viruses, Hepatitis D viruses, hepatitis E viruses, hepatitis F viruses, Hepatits G viruses, hepadnaviruses, especially all He patitis viruses, such as hepatitis B virus, hepatitis D viruses, Vi ren of the genus Picornaviridae, especially Picornaviruses, all enteroviruses, all polioviruses, all coxsackieviruses, al le echoviruses, all rhinoviruses, hepatitis A virus, aphthovi ren, viruses of the genus Calciviridae, especially hepati tis-E viruses, viruses of the genus Reoviridae, in particular Reoviruses, orbiviruses, rotaviruses, viruses of the Togaviri genus dae, especially Togaviruses, Alphaviruses, Rubiviruses, Pesti viruses, rubella virus, viruses of the genus Flaviviridae, esp special flaviviruses, TBE virus, hepatitis C virus, viruses of the genus Orthomyxoviridae, especially influenza viruses, Viruses of the genus Paramyxoviridae, especially Paramyxovi ren, morbillivirus, pneumovirus, measles virus, mumps virus, Viruses of the genus Rhabdoviridae, especially rhabdoviruses, Rabies virus, Lyssavirus, viscous stomatitis virus, viruses  the genus Coronaviridae, especially coronaviruses, viruses the genus Bunyaviridae, especially Bunyaviren, Nairovi rus, phlebovirus, uukuvirus, hantavirus, viruses of the genus Arenaviridae, especially arenaviruses, lymphocytic cho riomeningitis virus, viruses of the genus Retroviridae, esp special retroviruses, all HTL viruses, human T-cell Leukä mie virus, oncornaviruses, spuma viruses, lentiviruses, all HI- Viruses, viruses of the genus Filoviridae, especially Marburg and Ebola virus, slow viruses, prions, onkoviruses and Leukä mie viruses exist. 10. Use according to claim 6 for prevention and treatment infections caused by unicellular parasites, näm pathogens of malaria, sleeping sickness, Chagas Disease, toxoplasmosis, amoebic dysentery, leishma niosen, trichomoniasis, pneumocystosis, balanti diose, cryptosporidiosis, sarcomocystosis, acantha Möbose, Naeglerose, Coccidiosis, Giardiosis and the lambliosis.