DE19843360A1 - New phosphororganic compounds; useful for treatment of bacterial, viral and parasitic infection, and as herbicides or for treating infections in plants - Google Patents

Abstract

Phosphororganic compounds (I) are new. Phosphororganic compounds and their salts, esters or amides of formula (I) are new. R1, R2 = independently H, halo, OX1 or OX2, or alkyl, hydroxyalkyl, alkenyl, alkynyl, aryl, acyl, cycloalkyl, aralkyl or heterocyclyl (all optionally substituted); X1, X2 = independently H, or alkyl, hydroxyalkyl, alkenyl, alkynyl, aryl, acyl, cycloalkyl, aralkyl or heterocyclyl (all optionally substituted); B = -A1-O-A2-C(Y)(Z), -A3-CO-A4 or a 5- or 6-membered cyclic (preferably heterocyclic) group containing O or N heteroatom(s); A1, A2, A3, A4 = independently alkylene, alkenylene or hydroxyalkylene (one of A1 and A2 or A3 or A4 may also be absent); R3, R4 = independently H, halo, OX3 or OX4, or 1-26C alkyl or hydroxyalkyl, 2-26C alkenyl or alkynyl, or aryl, acyl, cycloalkyl, aralkyl or heterocyclyl (all optionally substituted); X3, X4 = independently H, silyl, an organic or inorganic cation (especially a metal from groups 1, 2 or 3 of the periodic table, ammonium, substituted ammonium or an ammonium compound derived from ethylenediamine or an amino acid) or 1-26C alkyl or hydroxyalkyl, aryl, aralkyl, 2-26C alkenyl or alkynyl, cycloalkyl, or heterocyclyl (all optionally substituted).

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)

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, the keto group (III)

where 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,
and 5- and 6-membered cyclic, in particular heterocyclic, compounds which contain, in addition to carbon, at least one heteroatom as a ring member, the heteroatom being selected from the group consisting of oxygen and nitrogen,
consists,
wherein R ₃ and R _{4 are the} same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl having up to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having up to 26 carbon atoms, substituted and unsubstituted aryl, sub substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl with up to 26 carbon atoms, substituted and unsubstituted alkynyl with up to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, OX ₃ or OX ₄ consists,
wherein X ₃ or X _{4 may be the} same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl having up to 26 carbon atoms, substituted and unsubstituted hydroxylalkyl having up to 26 carbon atoms, substituted and unsubstituted aryl and unsubstituted aralkyl, substituted and unsubstituted alkenyl having up to 26 carbon atoms, substituted and unsubstituted alkynyl having up to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, a silyl, a cation of an organic and inorganic base, in particular a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids,
and 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
X _{1 represents} H,
R ₂ is selected from the group consisting of acetyl and formyl,
Y and Z each represent hydrogen,
A ₁ is selected from the group consisting of methylene, ethylene, ethenylene, hydroxyethylene, 2-hydroxypropylene, and
R ₃ is selected from the group consisting of hydrogen, methyl, ethyl, hexadecanyl, octadecanyl and OX ₃ , and
X ₃ and X ₄ are selected from the group consisting of hydrogen, sodium, potassium, methyl, ethyl, hexadecanyl and octadecanyl and, insofar as they are both present, may be the same or different.

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
X _{1 represents} H,
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,
R ₃ is selected from the group consisting of hydrogen, methyl, ethyl, hexadecanyl, octadecanyl and OX ₃ , and
X ₃ and X ₄ are selected from the group consisting of hydrogen, sodium, potassium, methyl, ethyl, hexadecanyl and octadecanyl and, insofar as they are both present, may be the same or different.

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 hydroxyiamino) -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.

In the cyclic compounds, the amino group and the Phosphorus atom to be bound to any C atoms of the ring. It however, compounds are preferred in which they are attached to two C- Atoms are bound, separated only by another atom are. For the heterocyclic compounds, the two are Carbon atoms preferably by a hetero atom from each other Cut.

The following compounds are 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, isopröpoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.);
Alkyl carbamoyl (e.g. methyl carbamoyl etc.);
(N-alkyl) thiocarbamoyl (e.g. (N-methyl) thiocarbamoyl etc.);
Alkylcatbamimidoyl (e.g. methylcarbamimidoyl 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, aroyl substituted with halogen and hydroxy or with halogen and acyloxy and aralkanoyl substituted with hydroxy, hydroxyimino, dihalogenalkanoyloxyimino are given and
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, unless otherwise defined is like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.

"Hydroxylalkyl" is a straight or branched chain alkyl rest with up to 9 carbons, unless otherwise defined is niert, which has at least one hydroxyl group before adds one or two hydroxyl groups.

"Alkenyl" includes straight or branched chain alkenyl groups pen with up to 9 carbon atoms, unless otherwise stated is financed, such as B. vinyl, propenyl (e.g. 1-propenyl, 2- Propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl; , 2- Ethyl propenyl, pentenyl, hexenyl.

"Alkynyl" includes straight or branched chain alkynyl groups pen with up to 9 carbon atoms, unless otherwise stated is finished.

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. The hydrogen atoms can by substituents, such as halogen residues, to be replaced.

"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. The hydrogen atoms can also be sub substituents, such as halogen radicals, may be replaced.  

"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-z ) (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 hydrogen atoms can also pass through Substituents such as halogen radicals can be replaced.

The 5- and 6-membered cyclic compounds for which B can be aromatic or aliphatic and sub be substituted, for example by alkyl groups with up to 7 Carbon atoms and hydroxy groups.

The 5- and 6-membered heterocyclic compounds for which B can stand, and which besides carbon at least one He Teroatoms contained as ring members can be saturated or unsung be satisfied. Examples are azixan, diazixan, azixin, diazi xin, azolane, diazolane, azole, diazole, oxolane, dioxoles, oxole, Dioxol, oxixan, dioxixan, oxixin and dioxixin. You can ali be phatic or aromatic and be substituted at  for example by alkyl groups with up to 7 carbon atoms and hydroxy groups.

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) to (IX) 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, trialkoxyhalogen silyl, dialkylaralkylhalosilyl, dialkoxy dihalosilyl, 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, double bonds containing or ehiral groups R ₁ , R ₂ , R ₃ , R ₄ , X ₁ , X ₂ , X ₃ , X ₄ , A ₁ , A ₂ , A ₃ , A ₄ and the heterocycles 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 particularly as malaria prophylaxis and, as prophylaxis of sleeping sickness and Chagas disease, toxoplasmosis, amoebic dysentery, leishmaniasis, trichomo niasis, pneumocystosis, balantidiosis, cryptosporiosis, sarcomocystosis, acanteglobe 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 Neisseriaceae family, in particular of the Neisseria and Moraxella genus, 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 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 Campylobaeter 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, the genus Legionella,
Bacteria of the family Rickettsiaceae and family Bartonella ceae,
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.

Combinations with another antibiotic can also be used used to treat the above diseases the. For combination products with other anti-infectives especially isoniazid, rifampicin, ethambutol, pyra zinamid, streptomycin, protionamide and dapsone for treatment 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, Ru bellavirus,
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, Hantaanvirus,
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, oncoviruses, leukemia viruses.

The organophosphorus compounds are therefore to be combated 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 (Larynxpäpillo me, hyperplasia, 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) to (IX) and esters and ami de same on the phosphono or phosphino group and Sal These show a strong cytotoxic activity compared to bacteria, fungi, viruses, single and multicellular para sites. Accordingly, the compounds of the invention are for the treatment of infectious diseases useful by Viruses, bacteria, parasites and fungi in humans and animals ver be caused. The connections are also for use Prevention of diseases caused by viruses, bacteria, para sites and fungi, especially as mala riaprophylaxe and suitable as sleep sickness prophylaxis.

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) to (IX) in their protonated form as an ammonium salt organic or organic acids, such as hydrochloric acid, sulfur acid, 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 activity of the substances is in a test system Right. This system is based on the measurement of inhibition the growth of bacteria, parasites, viruses, fungi or Plants in vitro. To this end, test procedures are used in part used, which are known to the expert.

For example, to determine antimalaria activity Inhibition of the growth of malaria parasites in blood cultures certainly.

The determination of the antibacterial activity is based on Mes inhibition of bacteria growth on nutrient media and in Liquid cultures.

The determination of the antiviral activity is based on inhibition the formation of viral elements in cell cultures.

The determination of the fungicidal activity is based on inhibition the growth of fungi on nutrient media and in liquid cultures.

Some of the microorganisms that can be examined can only be examined in animal models. Here we will then apply the appropriate models.

Substances that are effective in in vitro measurement systems show, further investigated in in vivo models. The antiparasitic, antiviral, fungicidal or antibacterial Activity is further evaluated in the corresponding animal models iert.

The screening for herbicidal activity is carried out using Algensy  and measurement of isoprene emissions from plants Standard conditions determined.

The pharmaceutically active agents can be in the form of pharma who prepares 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 accelerators, 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) to (IX) 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) to (IX) also other pharmaceutical  Contain active ingredients.

The compounds can be used with previously described substances with antibacterial, antiviral, antimyctoic and antipa rasitic properties. These include in particular compounds that have already been used in therapy or are still being used. For this purpose, special substances are particularly suitable, which are listed in the Red List or in Simon / Stille, Antibiotic Therapy in Clinic and Practice, 9th Edition 1998 Schattauer Verlag, or at
http: /www.customs.treas.gov/imp exp / rulings / harmoniz / hrm129.html listed on the Internet.
In particular, the derivatives with penicillins, benzylpenicillin (Penicillin G), phenoxypenicillins, isoxazolylpenicil line, aminopenicillins, ampicillin, amoxixillin, bacampicil lin, carboxypenicillin, ticarcillin, temocillin, acyalaminope nicilline, aplocillinillin, azlocillin, azlocillin, azlocillin Group, cefuroxime group, cefoxitin group, cefoxitin, cefotetan, cefmetazol, latamoxef, flomoxef, cefotaxim group, cefozidim, ceftazidim group, ceftazidim, cefpirom, cefepim, other cephalefinephonine, cefalefalophone phone, cefalefosine, cefalefalophone, cefalefalophone, cefalefinephonine, Loracarbef, Cefprozil, new oral cephalosporins with a broader spectrum, Cefixim, Cefpodoxim-Proxetil, Cefuroxim-Axetil, Cefetamet, Cefotiam-Hexetil, Cefdinir, Ceftibutene, at which β-lactam antibiotics, carbapenem, biapenem, imapenem, imipenamamemapenem, imipenem , β-lactamase inhibitor, clavulanic acid / amoxicillin, clavulanic acid / ticarcillin, Sulbac tam / ampicillin, tazobactam / Pi pera cillin, tetracyclines, tracyclin Oxyte, Rolitetraxyxlin, doxycycline, minocycline, Chloram phenicol, aminoglycosides, gentamicin, tobramycin, netilmicin, amikacin, Spectinomyxin, macrolides, erythromycin, Cla rithromycin, roxithromycin, azithromycin, dirithromycin, Spi ramycin, josamycin, lincosamides, clindamycin, Fusidic acid, glycopeptide antibiotics, vancomycin, tecoplanin, pristi namycin derivatives, fosfomycin, antimicrobial folic acid antagonists, sulfonamides, co-trimoxazole, trimethoprim, other dia minopyrimidine-sulfonamide combinations, nitrofurone (nitrofyronone) , Norfloxacin, ciprofloxacin, ofloxacin, sparfloxacin, enoxacin, fleroxacin, pefloxacin, lomefloxacin, Bay Y3118, nitroimidazole, antimycotic bacterial agents, isoniazid, rifampicin, rifabutin, pyracinididomycin, thiomycinamide, ethrazinopinidomycin, tyracinidonomycin Local antibiotics, bacitracin, ty rothricin, polymyxins, neomycin, kanamycin, paromomycin, Mupi rocin, antivirals, acyclovir, ganciclovir, azidothymi din, didanosine, zalcitabine, thiacytidine, stavudine, ribavirin, idoxuridine, trifluridine, foscarnet, amantadine, interferons, tibol derivatives, proteinase inhibitors, polyenase inhibitors, antioxidants, polyenase inhibitors, polyenase inhibitors, antimine drugs, antimirin drugs, antimirin drugs, antimirin drugs Natamycin, Azole, Azole for septic therapy, Miconazole, Ketoconazole, Itraconazole, Fluconazole, UK-109.496, Azole for topical use, Clotrimazöl, Eco nazol, Isoconazole, Oxiconazole, Bifonazole, Flucytosine, Griseo fuloxat, Nolifinfirox, Caminopin Terbinafine, amorolfine, antrachinone, betulinic acid, semianthraquinone, xanthones, naphthoquinone, aryamino alcohols, quinine, quinidines, mefloquine, halotantrine, chloroquine, amodiaquine, acridine, ben zonaphthyridine, mepacrine, pyronaronidone, sulfalene, sulfaphenone, sulfaprone, sulfaprone, sulfaprone, sulfaprone, sulfaprone, sulfaprone, sulfaphenone Chlorprogua nil, diaminopyrimidines, pyrimethamine, primaquine, aminoquinolines, WR 238,605, tetracycline, doxycycline, clindamycin, norflox acin, ciproflox acin, ofloxacin, artemisinin, dihydroartemisi nin, 10b artemether, arteether, atrtesunate, atovaquone, sura min. Melarsoprol, nifurtmox, stibogluconate sodium, pentami din, amphotericin B, metronidazole, clioquinol, mebendazole, niclosamide, praziquantel, pyrantel, tiabendazole, diethylcarbamazine, ivermectin, bithionol, oxamniquin, metrifonate, pipera.

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) to (IX) 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 as bactericides, fungicides and herbicides in plant 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.  

Possible synthetic routes for compounds of appearance

with R = H or Na ⁺
and
X = -CH ₂ - Y = without Y (5-ring) Ex. 1
= -CH ₂ - (6-ring) Ex. 2
-O- = without Y (5-ring) Ex. 3
= -CH ₂ - (6-ring) Ex. 4
-NH- = without Y (5-ring) Ex. 5
= -CH ₂ - (6-ring) Ex. 6

example 1 3-oxo-cyclopentylphosphonic acid diethyl ester 1 (a)

0.52 mmol of trimethylsilyl triflate is added dropwise at 0 ° C. to 11.4 mmol of diethyl phosphite and 12.4 mmol of N, O-bis (trimethylsilyl) acetamide in 5 ml of dichloromethane. After stirring for 30 minutes, 0.52 mmol of 2-cyclopenten-1-one is added dropwise at the same temperature and the mixture is stirred for 1 hour. The enolsilane intermediate is hydrolyzed by stirring with 3 ml of 1N HCl for 3 hours. The organic phase is separated off, dried over magnesium sulfate and concentrated. The crude product can be chromatographed on SiO ₂ and, after concentration of the desired fractions, gives 3- (phosphonic acid diethyl ester) - cyclopentan-1-one (a) with a bp _{0.25 Torr} = 104 ° C. in good yield.
(See I. Mori, Y. Kimura, T. Nakano, S. Matsunaga, G. Iwasaki, A. Ogawa, K. Hayakawa, Tetrahedron Letters 1997, 38, 3543-46, RG Harvey, Tetrahedron 1966, 22, 2561 -73 and E. Öhler, E. Zbiral, Liebigs Ann Chem 1991, 229-36)

3- (phosphonic acid diethyl ester) -cyclopentanone oxime 1 (b)

1.41 mmol of N, O-bis (trimethylsilyl) hydroxylamine, likewise dissolved in THF, are added to a suspension of 150 mg of 35% potassium hydride in mineral oil, cooled to -78 ° C., dissolved in THF. The suspension is stirred at 0 ° C for 30 min. At -78 ° C, 1.34 mmol of 3-oxopentylphosphonic acid diethyl ester (a) - in THF - is added dropwise. The reaction mixture is stirred for 90 min at room temperature, then added to 40 ml of ice-cooled aqueous 10% ammonium chloride solution and extracted three times with 30 ml each time with methylene chloride. The combined organic phases are dried over MgSO ₄ and the solvent is removed under reduced pressure. The oxime 1 can be implemented without further cleaning.
(See RV Hoffman, GA Buntain, Synthesis 1987, 9, 831-33 or for an alternative representation: T. Kawada, T. Tsushima, Heterocycles, 1989, 28, 573-578)

3-N- (hydroxylamine) -cyclopentylphosphonic acid diethyl ester 1 (c)

Sodium cyanohydride borate (NaBH ₃ CN) is used without further purification. 4 mmol of oxime 1 (b) dissolved in a little methanol are mixed with 2 drops of bromcresol green and 6 N KOH are added dropwise until a color change from yellow to green is observed. 3 mmol NaBH ₃ CN are added, the mixture is stirred at room temperature for 3 h and quenched dropwise with methanol / HCl until a color change from green to yellow is observed. The reaction mixture is poured into 10 ml of water and adjusted to pH <10 with 6N KOH. After saturation of the aqueous phase with NaCl, the solution is extracted 5 times with 10 ml of chloroform, dried over MgSO ₄ and removed under reduced pressure. The yellow to red colored raw product can be chromatographed on SiO ₂ .
(See RF Borch, MD Bernstein, HD Durst, J Am Chem Soc 1971, 93, 2897-904)

3-N- (hydroxylamine) cyclopentylphosphonic acid 1 (d)

130 ml of conc. To 0.06 mol of ester 1 (c) are cooled with ice. HCl added and heated with vigorous stirring under reflux for 6 h. After cooling, the yellow-brown colored solution is concentrated under reduced pressure, taken up in approx. 30 ml of water and treated with activated carbon until an almost colorless solution is formed. This is again concentrated under reduced pressure, taken up with about 30 ml of water and a pH of 4-5 is set with NaHCO ₃ . The beige precipitate is filtered off and can be washed with water / ethanol. 0.037 mol of product are formed, which corresponds to a yield of 61%. Recrystallization is not necessary.

3- (N-formyl-N-hydroxylamino) -cyclopentylphosphonic acid mono Na trium salt 1 (e)

4 ml of acetic anhydride are added dropwise at 0 ° C. within 5-10 min 2 ml formic acid, leaves 10 min at the same temperature and Stir for 15 min at room temperature and cool the solution again to 0 ° C. 0.02 mol of 3-N- (hydroxylamine) cyclopentyl phosphonic acid (d) are heated to 40-50 ° C in about 6 ml of formic acid dissolved and added dropwise at 0 ° C to the above solution and stirred for 1 h at ambient temperature. Then under redu decorated pressure to an oil, this in water taken and concentrated under reduced pressure. This procedure Ren is carried out three times. In aqueous solution with 1 n NaOH adjusted a pH of 4.5-5. The resulting oil is boiled out several times in isopropanol, discarding the Alcohol phase. The residue is taken up in methanol - bis everything dissolves in the heat - and with the help of ethanol Product likes. After filtration of the raw product, this can be recrystallized again from methanol / ethanol.

Example 2 3-oxo-cyclohexylphosphonic acid diethyl ester 2 (a)

0.52 mmol of trimethylsilyl triflate is added dropwise at 0 ° C. to 11.4 mmol of diethyl phosphite and 12.4 mmol of N, O-bis (trimethylsilyl) acetamide in 5 ml of dichloromethane. After stirring for 30 minutes, 0.52 mmol of 2-cyclohexen-1-one is added dropwise at the same temperature and the mixture is stirred for 1 hour. The enolsilane intermediate is hydrolyzed by stirring with 3 ml of 1N HCl for 3 hours. The organic phase is separated off, dried over magnesium sulfate and concentrated. The crude product can be chromatographed on SiO ₂ and, after concentration of the desired fractions, gives 3-oxocyclohexylphosphonic acid diethyl ester 2 (a) in 95% yield.
(See I. Mori, Y. Kimura, T. Nakano, S. Matsunaga, G. Iwasaki, A. Ogawa, K. Hayakawa, Tetrahedron Letters 1997, 38, 3543-46)

3- (phosphonic acid diethyl ester) cyclohexanone oxime 2 (b)

2 (b) can be synthesized analogously to 1 (b).

3-N- (hydroxylamine) -cyclohexylphosphonic acid diethyl ester 2 (c)

Sodium cyanohydride borate (NaBH ₃ CN) is used without further purification. 4 mmol of oxime 2 (b) dissolved in a little methanol are mixed with 2 drops of bromcresol green and 6 N KOH are added dropwise until a color change from yellow to green is observed. 3 mmol NaBH ₃ CN are added, the mixture is stirred at room temperature for 3 h and quenched dropwise with methanol / HCl until a color change from green to yellow is observed. The reaction mixture is poured into 10 ml of water and adjusted to pH <10 with 6N KOH. After saturation of the aqueous phase with NaCl, the solution is extracted 5 times with 10 ml of chloroform, dried over MgSO ₄ and removed under reduced pressure. The yellow to red colored raw product can be chromatographed on SiO ₂ .

3-N- (hydroxylamine) cyclohexylphosphonic acid 2 (d)

2 (d) is analogous to the hydrolysis of 1 (c) with koriz HCl in obtained a yield of over 50%.

3- (N-formyl-N-hydroxyamino) cyclohexylphosphonic acid mono Na trium salt 2 (e)

For the representation of 2 (e), see 1 (e).

Example 3 2,5-dichloro-tetrahydrofuran 3 (a)

At a temperature of -35 ° C, condensed to 72 g absolute THF in 80 ml carbon tetrachloride 142 g chlorine, which is diluted with nitrogen. Then it is exposed for 8-9 h with stirring using a UV lamp. When the reaction is complete, CCl _{4 is} removed under reduced pressure. The products are first condensed in a high vacuum into a template which is at -50 ° C, before being fractionated in a water jet vacuum. It is kept 60 g of 2,5-dichloro-tetrahydrofuran with a bp _{12 Torr} = 61-64 ° C.
(See H. Gross, Chem Ber 1962, 95, 83-90)

5-chloro-tetrahydrofuryl-2- (phosphonic acid di-tert-butyl ester) 3 (b)

31 g (160 mmol) of di-tert-butyl phosphite - dissolved in 90 ml of THF - are added dropwise to a suspension of 5.0 g of 80% NaH (in mineral oil) in 60 ml of absolute THF. After stirring for 30 minutes at 0 ° C., 135 mmol of 2,5-dichlorotetrahydrofuran - dissolved in 120 ml of absolute THF - are added dropwise at the same temperature. The reaction solution is refluxed for 20 hours and then concentrated under reduced pressure. An oil is formed which is contaminated, inter alia, by decomposition products of the educt 2,5-dichlorotetrahydrofuran, which can be separated off by chromatography on SiO ₂ .
(See K. Baczko, WQ. Liu, BP Roques, C. Garbay-Jauregiuiberry, Tetrahedron 1996, 52, 2021-30)

5-chloro-tetrahydrofuryl-2-phosphonic acid 3 (c)

0.9 mmol of tert-butyl ester 3 (b), 10 ml of trifluoroacetic acid, 4.5 mmol of anisole and 10 ml of methylene chloride are stirred at room temperature for 1 h. Then 10 ml of water are added dropwise and evaporated to dryness. The resulting oil can be recrystallized from methanol and chloroform.
(See TR Burke Jr., ZH.Li, JB Bolen, VE Marquez, J Med Chem 1991, 34, 1577-81)

The hydrolysis of the tert-butyl ester 3 (b) can also be carried out by Er warm under reflux in benzene with the addition of trifluores Acetic acid take place (cf. Chem Ber 1975, 108, 1732-44) or also in pure trifluoroacetic acid at room temperature (see Pospho rus, sulfur and silicon and related elements 1991, 61, 183-84).

Formohydroxamic acid 3 (d)

Is represented by a method by Bernhard et al. J Am Chem Soc 1964, 86, 4406 from hydroylamine hydrochloride, potassium chloride and potassium hydroxide, all without further purification were used. Formo-hydroxamic acid: mp: 74-77 ° C.

O-trimethylsilylformohydroxamic acid 3 (e)

1 equivalent of formohydroxamic acid, dissolved in THF, is added to Zu administration of triethylamine with 1 equivalent of trimethylchlorosilane 2 Stirred days at room temperature. O-trimethylsilyl Formohydroxamic acid is produced in low yields and can be purified by column chromatography.

5- (N-formyl-N-hydroxylamino) tetrahydrofuryl-2-phosphonic acid 3 (f)

5-chloro-tetrahydrofuryl-2-phosphonic acid is with a 2-fold Excess O-trimethylsilyl-formo-hydroxamic acid in absolute Dimethylformamide stirred for 4 h at room temperature. After quenching with water is concentrated under reduced pressure, in water added, concentrated again and the oil on cellulose chroma tographed.

Example 4 2,6-dichlorotetrahydropyran 4 (a)

1 kg of 25% aqueous glutaraldehyde solution is extracted with methylene chloride, the organic phase is dried over Na ₂ SO ₄ , concentrated and glutaraldehyde is distilled in vacuo (bp. _{13 torr} = 74-75 ° C.).

In a solution of 200 g of glutaraldehyde dissolved in 700 ml of absolute methylene chloride, dry hydrogen chloride is passed in at -25 ° C. with vigorous stirring, the temperature being kept below -15 ° C. The mixture is left to stand at -40 ° C. for 8 hours, then warmed to 0 ° C. and separated from the water. The organic phase is dried over Na ₂ SO ₄ , volatile constituents are removed under reduced pressure and finally 2,6-dichlorotetrapyran (a) is distilled (bp. _0.01 = 37-39 ° C.).
(See K. Dimroth, W. Kinzebach, M. Soyka, Chem Ber 1966, 99, 2351-60)

6- (N-formyl-N-hydroxylamino) tetrahydropyryl-2-phosphonic acid 4 (f)

Pyran derivative 4 can be started from 2,6-dichloro represent tetrahydropyran as described under 3.

Example 5 5- (Oxo-pyrrolidin-2-yl) -phosphonic acid diethyl ester 5 (a)

The 5-oxo-pyrrolidine derivative 5 (a) can be according to a pre written by J. Oleksyszyn, E. Gruszecka, P. Kafafarski, P. Mastalerz, Monthly Chem 1982, 113, 59-72 by the following Syn thesis sequence obtained: triethyl phosphite is Chlorocarbonyl-propionic acid methyl ester for 4- (diethoxy phosphoryl) -4-oxo-butyric acid methyl ester implemented. This one the 4-oxo position is converted to the amine via the oxime. 4- Amino-4- (diethoxyphosphoryl) butyric acid methyl ester cycli by heating for 30 minutes to the starting compound 5- (Oxo-pyrrolidin-2-yl) -phosphonic acid diethyl ester 5 (a).  

5-Thion-pyrrolidine-2-phosphonic acid diethyl ester 5 (b)

10 mmol of the oxo compound 5 (a) is converted into the thio compound 5 (b) by heating with P ₄ S ₁₀ in xylene. After the reaction has ended, the still hot xylene layer is decanted and the product is chromatographed on silica gel.

5-Pyrrolidone-oxime-2-phosphonic acid diethyl ester 5 (c)

From 4.5 g of hydroxylamine hydrochloride, suspended in 20 ml of methanol, ₃ hydroxylamine is released by adding 5.5 g of NaHCO, to which 5 g of 5-thionopyrrolidine 5 (b) dissolved in methanol are added. The solution is heated until the H ₂ S evolution has ended (approx. 12 h). Then methanol is distilled off and the residue is reacted without further purification.
(See H. Behringer, H. Meier, Liebigs Ann. Chem 1957, 607, 67-91)

5- (N-hydroxylamino) pyrrolidine-2-phosphonic acid diethyl ester 5 (d)

Oxime 5 (c) is reduced to hydroxylamine 5 (d) in Based on the representation of 1 (c). The raw product shows a red color obtained by filtration over activated carbon Methanol can be removed as a solvent.

5- (N-hydroxyamino) pyrrolidine-2-phosphonic acid 5 (e)

Phosphonic acid diethyl ester 5 (d) can be hydrolyzed in amounts of up to 2 g of phosphodiesterase drawn on carboxymethyl cellulose.
(See IA Natchev, Liebigs Ann Chem 1988, 861-867 and IA Natchev, Tetrahedron 1988, 44, 1511-22)

5- (N-formyl-N-hydroxylamino) pyrrolidine-2-phosphonic acid 5 (f)

The regiospecific formylation on hydroxylamine nitrogen Atom to N-formyl-N-hydroxylamine 5 (e) also leads to bis- Formylation. 1,3,5-  Triformylhexahydro-1,3,5-triazine (shown from 1,3,5,7- Tetraaza adamantane and formic acid; see. E. N. Gate, M. D. Threadgill, M.F.G. Stevens, D. Chubb, L.M. Vickers, J Med Chem 1986, 29, 1046-52), N-formylimidazole or also formic acid / Acetic anhydride used. Chromatographically 5 (e) so far not be isolated in substance.

Example 6 Piperidin-2-one-6-diethyl phosphonate (a)

6 (a) can be represented analogously to 5 (a). If you heat 5- Amino-5- (diethoxy-phosphoryl) pentanoic acid so it cyclizes to 6 (a).

The further steps are also analogous to the illustration of 5- (N-formyl-N-hydroxylamino) pyrrolidine-2-phosphonic acid 5 (e). 6- (N-formyl-N-hydroxylamino) piperidine-2-phosphonic acid 6 So far, it cannot be summarized.

Example 7a

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 dimethyl ester in 100 ml of absolute acetonitrile. 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 reacted with triethyl phosphite to give 3-aminopropionylphosphonic acid diethyl ester (cf. BA Arbuzov, MV Zolotova, Bull.Acad.Sci.USSR Div. Chem. Sci (Engl. Transl.) 1964, 1701-04 ). It is then formylated to oxidize the resulting secondary amine with dimethyldioxirane to the N-formyl-N-hydroxyamino-phosphonic acid ester. The hydrolysis can then be carried out as described above.

Example 7b

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 7a can be implemented.

Example 7c

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 implemented ethoxy) methylphosphonic acid diethyl ester.  

(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 boiled under reflux in 50 ml of toluene for 4 h. After cooling, it is washed three times with 25 ml of water each time. The aqueous phase can be extracted with toluene. The combined toluene phases are dried over sodium sulfate and the solvent is removed in vacuo. What remains is a yellow oil.
(See Lit .: K. Eger, EM 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 exploited wrestle with oxidation mites 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 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 7a are carried out.

Example 7d

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 (17)

1. Organophosphorus compounds of the general formula (I)
in which R ¹ urad 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)
where 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 radical, alkenylene radical and hydroxyalkylene radical,
the keto group (III)
wherein 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,
and 5- and 6-membered cyclic, in particular heterocyclic, compounds which contain at least one heteroatom as the ring member in addition to carbon, the heteroatom being selected from the group consisting of oxygen and nitrogen,
consists,
R ₃ and R _{4 are} identical or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl having up to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having up to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl having up to 26 carbon atoms, substituted and unsubstituted alkynyl having up to 26 carbon atoms, 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 having up to 26 carbon atoms, substituted and unsubstituted hydroxylalkyl having up to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl having up to 26 carbon atoms, substituted and unsubstituted alkynyl having up to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, a silyl, a cation of an organic and inorganic base, in particular a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids,
and 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
X _{1 represents} H,
R ₂ is selected from the group consisting of acetyl and formyl,
Y and Z each represent hydrogen,
A ₁ is selected from the group consisting of methylene, ethylene, ethenylene, 2-hydroxypropylene and hydroxyethylene,
R ₃ is selected from the group consisting of hydrogen, methyl, ethyl, hexadecanyl, octadecanyl and OX ₃ , and X ₃ and X ₄ are selected from the group consisting of hydrogen, sodium, potassium, methyl, ethyl , Hexadecanyl and Oc tadecanyl exists and, insofar as they are both present, can be the same or different. 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- hydroxylamiho) -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- hydtoxyl-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) propylphosphorus acid disodium salt. 4. Compounds according to claim 1, characterized in that they have the formula (V)
correspond with
X _{1 represents} H,
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
R ₃ is selected from the group consisting of hydrogen, methyl, ethyl, hexadecanyl, octadecanyl and OX ₃ , and
X ₃ and X ₄ are selected from the group consisting of hydrogen, sodium, potassium, methyl, ethyl, hexadecanyl and oc tadecanyl and, insofar as they are both present, may be the same or different. 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) -ethenbxy) - 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. Compounds according to claim 1, characterized in that B is a cyclic compound in which the amino group and the phosphorus atom is bound to two carbon atoms, the only are separated from each other by another atom. 7. Compounds according to claim 6, characterized in that B is a heterocyclic compound in which the amino group and the phosphorus atom are bound to two carbon atoms, which only are separated from each other by a heteroatom. 8. Compounds according to claim 7, characterized in that the organophosphorus compound is selected from the group consisting of compounds of the formulas
where X _{1 is} H,
R ₂ is selected from the group consisting of acetyl and formyl, and
X ₃ and X _{4 are the} same or different and are selected from the group consisting of hydrogen, sodium, potassium, methyl, ethyl, hexadecanyl and octadecanyl. 9. Pharmaceutical preparation, characterized by an effective content of at least one phosphorlorgani together according to one of claims 1 to 8 with a pharmaceutically acceptable carrier. 10. Pharmaceutical preparation according to claim 9, characterized by at least one other active pharmaceutical ingredient. 11. Pharmaceutical preparation according to one of claims 9 or 10, characterized by  one or more components of the group consisting of sulfo namid, sulfadoxine, artemisinin, atovaquone, quinine, chloro quin, hydroxychloroquine, mefloquine, halofantrine, pyrimetha min, armesin, tetracycline, doxycycline, proguanil, metroni dazol, praziquantil, niclosamide, mebendazole, pyrantel, tia bendazole, diethylcarbazine, piperazine, pyrivinum, metrifo nat, oxamniquin, bithionol and suramin. 12. Pharmaceutical preparation according to claim 10, characterized by one or more components of the group consisting of peni cilline, benzylpenicillin (Penicillin G), phenoxypenicilli ne, isoxazolylpenicillins, aminopenicillins, ampicillins, Amoxixillin, bacampicillin, carboxypenicillin, ticärcillin, Temocillin, Acyalaminopenicilline, Azlocillin, Mezlocillin, Piperacillin, Apalcillin, Mecillinam, Cephalosporine, Cefa zolin group, cefuroxime group, cefoxitin group, cefoxi tin, cefotetan, cefmetazole, latamoxef, flomoxef, cefotaxime Guppe, cefozidim, ceftazidim group, ceftazidim, cefpirom, Cefepime, other cephalosporins, cefsulodin, cefoperazone, Oralcephalosporins of the cefalexin group, Loracarbef, Cef prozil, new oral cephalosporins with an expanded spectrum, Cefixime, cefpodoxime proxetil, cefuroxime axetil, cefetamet, Cefotiam hexetil, cefdinir, ceftibutene, other β-lactam Antibiotics, carbapenem, imipenem / cilastatin, meropenem, Biapenem, aztreonam, β-lactamase inhibitor, clavulanic acid right / amoxicillin, clavulanic acid / ticarcillin, Sulbac- tam / ampicillin, tazobactam / piperacillin, tetracycline, Oxytetracycline, rolitetraxyxlin, doxycycline, minocycline, Chloramphenicol, aminoglycosides, gentamicin, tobramycin, Netilmicin, amikacin, spectinomyxin, macrolides, Erythromycin, clarithromycin, roxithromycin, azithromycin, Dirithromycin, Spiramycin, Josamycin, Lincosamide, Clin damycin, fusidic acid, glycopeptide antibiotics, vancomycin, Tecoplanin, pristinamycin derivatives, fosfomycin, antimicro  biological folic acid antagonists, sulfonamides, co-trimoxazole, Trimethoprim, other diaminopyrimidine sulfonamide Combinations, nitrofurans, nitrofurantoin, nitrofurazone, Gyrase inhibitors (quinolones), norfloxacin, ciprofloxacin, Ofloxacin, sparfloxacin, enoxacin, fleroxacin, pefloxacin, Lomefloxacin, Bay Y3118, nitroimidazole, antifungal le agent, isoniazid, rifampicin, rifabutin, ethambutol, Pyrazinamide, streptomycin, capreomycin, prothionamide, teri zidon, dapsone, clofazimin, local antibiotics, bacitracin, Tyrothricin, polymyxins, neomycin, kanamycin, paromomycin, Mupirocin, antiviral, acyclovir, ganciclovir, azi dothymidine, didanosine, zalcitabine, thiacytidine, stavudine, Ribavirin, idoxuridine, trifluridine, foscarnet, amantadine, Interferons, Tibol Derivatives, Proteinase Inhibitors, An timykotika, polyene, amphothericin B, nystatin, natamycin, Azoles, Azoles for septic therapy, Miconazole, Ketocona zol, itraconazole, fluconazole, UK-109,496, azoles for local Application, clotrimazole, econazole, isoconazole, oxiconazole, Bifonazole, flucytosine, griseofulvin, ciclopiroxolamine, Tolnaftat, Naftifin, Terbinafin, Amorolfin, Antrachinone, Betulinic acid, semianthraquinones, xanthones, naphtoquinones, Aryamino alcohols, quinine, quinidines, mefloquine, halofan trin, chloroquine, amodiaquine, acridine, benzonaphthyridine, Mepacrine, pyronaridine, dapsone, sulfonamides, sulfadoxin, Sulfalene, Trimethoprim, Proguanil, Chlorproguanil, Dia minopyrimidines, pyrimethamine, primaquine, aminoquinolines, WR 238,605, tetracycline, doxycycline, clindamycin, norfloxacin, Ciprofloxacin, ofloxacin, artemisinin, dihydroartemisinin, 10b artemether, Arteether, Atrtesunat, Atovaquon, Suramin, Melarsoprol, nifurtmox, stibogluconate sodium, pentamidine, Amphotericin B, metronidazole, clioquinol, mebendazole, Niclosamide, praziquantel, pyrantel, tiabendazole, die thylcarbamazin, ivermectin, bithionol, oxamniquin, metrifo nat, piperazine, embonate.   13. Use of organophosphorus compounds according to one of claims 1 to 8 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. 14. Use according to claim 13 for the treatment of infections, caused by bacteria, viruses, fungi or one or multicellular parasites. 15. Use according to claim 13 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 Neisseriaceae 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, especially the species Helicobäcter 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. 16. Use according to claim 13 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 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, hantaan virus, vi ren of the genus Arenaviridae, especially arenaviruses, lym phocytic choriomeningitis virus, viruses of the retro genus viridae, especially retroviruses, all HTL viruses, human T-cell leukemia virus, oncornaviruses, spuma viruses, lentiviruses, all HI viruses, viruses of the genus Filoviridae, in particular  Marburg and Ebola viruses, slow viruses, prions, oncoviruses and Leukemia viruses exist. 17. Use according to claim 13 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.