CZ2001151A3 - Phosphorous organic compounds and their use - Google Patents

Abstract

Phosphorous compounds of formula (I) wherein B is either an ether group of formula (II) or a keto group of formula (III) or a five- and / or six-membered cyclic compound, a their use for the manufacture of medicaments for therapeutic and prophylactic use treatment of infections caused by viruses, bacteria, fungi and parasites in humans or animals, and their use as such fungicide, bactericide and herbicide in sortlin.

Description

Phosphororganic compounds and their use

Technical field

The invention relates to phosphororganic compounds, their salts, esters and amides, as well as their use for the manufacture of medicaments for the therapeutic and prophylactic treatment of infections caused by viruses, bacteria, fungi and parasites in humans and animals and their use as fungicide, bactericide and herbicide. in plants. Phosphoric compounds of the invention include phosphinoyl derivatives, phosphinic acid derivatives and phosphonic acid derivatives.

BACKGROUND OF THE INVENTION

Phosphonic acid derivatives are already known. Thus, for example, the antimicrobial activity of aminohydrocarbylphosphonic acid derivatives is described in Curr. Chemoter. Infect. Dis., Why. Int. Congr. Chemoter., 11 ^th ; 1980, Vol. 1; pp. 355-8, DE 27 33 658, filed February 9, 1978, EP-A-0 009 686 filed April 16, 1980, Antimicrobial Agents and Chemotherapy, Bd. 19, Nr. 6, pp. 1013-1023 and in Antimicrobial Agents and Chemotherapy, Bd. 22, Nr. 4, pp. 560-563. Furthermore, aminohydrocarbylphosphonic acid derivatives have been described as herbicides in Chemical Abstracts Vol. 105, no. 19, 10 November 1986 and JP 61 106504 A and US-A-4,693,742, September 15, 1987.

From Chemical Abstracts, Vol. 11, No. 11, Sept. 11, 1989 and Bioorg. Khim .; 1989, Vol. 15 (5), pp. 627-33, adenosyl aminooxopropylphosphonic acid as well as aminooxobutylphosphonic acid adenosyl esters are further known as carnosine synthetase inhibitors. J. Org. Chem. St. 61, No. 20, pages 7212-7216 disclose N-hydroxyphosphonformamide as well as its use for inhibiting viruses.

There is a strong demand to enrich human and animal treatments, as well as to provide plant protection products that have not only strong potency but against other drugs, respectively. plant protection agents, they also show less side effects or they cause less exposure to the environment and thus pose less health threat to humans.

* ♦ * *

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION It is an object of the present invention to provide a substance which can be used universally in human, animal, viral, bacterial, fungal and parasitic infections and in plants such as fungicide, bactericide and herbicide and which satisfies the above conditions.

This object was surprisingly solved by a group of substances as defined in backbone claim 1. This group of substances exhibits both anti-infective action against viruses, bacteria, fungi, unicellular and multicellular parasites, as well as fungicidal, bactericidal and herbicidal activity in plants.

The phosphororganic compounds of the invention correspond to the general formula (I):

^{R 1} NB / NB-Ρ-Ή ₃ (I) wherein R 1 and R ₂ are the same 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 radicals, halogen, OX 1 and OX ₂ , wherein Χϊ and X ₂ may be the same or different and are selected from the group which is hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted aralkyl; substituted heterocyclic radical,

B is selected from the group consisting of an ether group (II)

H

- AI - OA _{2 -} (II)

Wherein A ₁ and A ₂ , of which A ₂ may also be omitted, are the same or different and are selected from the group consisting of alkylene, alkenylene and hydroxyalkyl, by keto (III)

-A ₃ -C-A4- (III) wherein A ₃ and A4, one or both of which may be omitted, are the same or different and are selected from the group consisting of alkylene, alkenylene and hydroxyalkyl, and five- and six-membered cyclic, in particular heterocyclic, compounds containing, in addition to carbon, at least one heteroatom as part of the ring, wherein the heteroatom is selected from the group consisting of oxygen and nitrogen, wherein R ₃ and R ₄ are the same or different and selected from it consists of hydrogen, substituted and unsubstituted alkyl of up to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl of up to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl of up to 26 carbon atoms, substituted and unsubstituted alkynyl with up to 26 substituted or unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, OX ₃ or OX ₄ , 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 to substituted and unsubstituted hydroxyalkyl of up to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl of up to 26 carbon atoms, substituted and unsubstituted alkynyl of up to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl of up to 26 carbon atoms substituted and unsubstituted heterocyclic radical, silyl, organic and inorganic base cations, in particular metal of the first, second or third main groups of the periodic system, ammonium, substituted ammonium and ammonium compounds which are derived from ethylenediamine or amino acids, and their pharmaceutically acceptable salts, esters and amides, and ester salts, with the exception of H ₂ N (CH ₂ ) ₂ CO (CH ₂ ) _n P (O) (OH) OH with n = 1 or 0;

H (HO) NCOP (O) (ON) ₂ .

Particularly preferred are compounds which correspond to formula (IV)

wherein R ₂ is selected from the group which consists of acetyl and formyl,

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 if both are present, they may be the same or different.

The chain -A 1 -O-C (ZY) - is preferably composed of one oxygen atom and two or three carbon atoms (substituents not counted), preferably two carbon atoms are preferred.

Particularly preferred ether compounds are those 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) ethenoxyjmethylphosphonic acid, [2- (N-acetyl-N-hydroxylamino) ethenoxyjmethylphosphonic acid disodium salt, [3- (N-formyl-N-hydroxylamino) -2-hydroxypropoxy] methylphosphonic acid disodium salt [3 - (N-acetyl-Nhydroxylamino) -2-hydroxypropoxy] methylphosphonic acid.

Further preferred are compounds corresponding to formula (V)

R ₂

N — A1

-A ₂ P-R3 (v)

0x4 wherein R ₂ is selected from the group which consists of acetyl and formyl ·

hydroxylamino) -1-oxopropylphosphonic, hydroxylamino) -1-oxopropylphosphonic,

3- (N-acetyl-N3- (N-formyl-NAi) is selected from the group consisting of methylene, ethylene, ethenylene, hydroxymethylene, hydroxyethylene, 2-hydroxypropylene,

A _{2 is} not 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 when both are present they may be the same or different.

The chain -A1-CO-A2- is preferably composed of two to four carbon atoms (substituents not counted), with three carbon atoms being particularly preferred.

Among these compounds, the disodium salt of 2- (N-formyl-N-hydroxylamino) -1-oxoethylphosphonic acid, the disodium salt of 2- (N-acetyl-Nhydroxylamino) -1-oxoethylphosphonic acid, the disodium salt of 3- (N-formyl-N-disodium salt of hydroxylamino acid) -1-oxo-2-propenylphosphonic acid, 3- (N-acetyl-Nhydroxylamino) -1-oxo-2-propenylphosphonic acid disodium, 4- (N-disodium salt) -formyl-Nhydroxylamino) -1-oxo-3-hydroxybutylphosphonic acid, 4- (N-acetyl-Nhydroxylamino) -1-oxo-3-hydroxybutylphosphonic acid disodium salt, 3- (N-formyl-Nhydroxylamino) -2- disodium salt oxopropylphosphonic acid, disodium salt of 3- (N-acetyl-Nhydroxylamino) -2-oxopropylphosphonic acid, disodium salt of 4- (N-formyl-Nhydroxylamino) -3-oxo-2-hydroxy-2-methylbutylphosphonic acid, disodium salt of 4- ( Nacetyl-N-hydroxylamino) -3-oxo-2-hydroxy-2-methylpropylphosphonic acid 4- (N-formyl-N-hydroxylamino) -3-oxo-2-hydroxy-2- (hydroxymethyl) -butic acid disodium salt ylphosphonic acid, 4- (N-acetyl-N-hydroxylamino) -3-oxo-2-hydroxy-2- (hydroxymethyl) -propylphosphonic acid disodium salt.

For cyclic compounds, the amino group and the phosphorus atom may be bonded to any of the C-ring atoms. However, compounds in which they are bonded to two C-atoms separated by only one other atom are preferred. In heterocyclic compounds, both carbon atoms are separated from each other most preferably by a heteroatom.

The following compounds are particularly preferred:

• ·

The peculiarities of the above definitions and suitable examples are given in the following:

Acyl is a substituent that is derived from an acid, such as an organic carboxylic acid, carbonic acid, carbamic acid, or an individual of the aforementioned corresponding thio acids or imido acids, or organic sulfonic acids, wherein these acids include the respective aliphatic, aromatic and / or heterocyclic groups in the molecule, as well as carbamoyl or carbamimidoyl. Suitable examples for these acyl groups are given in the following.

Aliphatic acyl groups are those derived from an aliphatic acid, including the following:

alkanoyl (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.);

alkenoyl (e.g., acryloyl, methacryloyl, crotonoyl, etc.);

alkylthioalkanoyl (eg, methylthioacetyl, ethylthioacetyl, etc.);

alkanesulfonyl (e.g., mesyl, ethanesulfonyl, propanesulfonyl, etc.);

alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.);

alkylcarbamoyl (eg, methylcarbamoyl, etc.);

(N-alkyl) -thiocarbamoyl (e.g., (N-methyl) -thiocarbamoyl, etc.); alkylcarbamimidoyl (e.g., methylcarbamimidoyl etc.); oxalo;

alkoxalyl (eg, methoxalyl, ethoxalyl, propoxalyl, etc.).

In the above examples, for aliphatic acyl groups, the aliphatic hydrocarbon moiety, in particular the alkyl group and the alkyl group, may be aliphatic. alkane residue, exhibit in • · ··

in this case, one or more suitable substituents such as amino, halogen (e.g. fluorine, chlorine, bromine etc.), hydroxy, hydroxyimino, carboxy, dkoxy (e.g. methoxy, ethoxy, propoxy etc.), alkoxycarbonyl, acylamino (e.g. benzyloxycarbonylamino) etc.), acyloxy (acetoxy, benzoyloxy etc.) and the like; preferred aliphatic acyl radicals with such substituents include alkanoyls substituted with e.g. amino, carboxy, amino and carboxy, halogen, acylamino and the like.

Aromatic acyl radicals are those which are derived from an acid with a substituted or unsubstituted aryl group, wherein the aryl group may include phenyl, toluyl, xylyl, naphthyl, and the like; Suitable examples are given in the following:

aroyl (e.g., benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, etc.);

aralkanoyl (eg, phenylacetyl, etc.);

aralkenoyl (e.g. cinnamoyl);

aryloxyalkanoyl (eg, phenoxyacetyl, etc.);

arylthioalkanoyl (eg, phenylthioacetyl, etc.);

arylaminoalkanoyl (e.g., N-phenylglycyl, etc.);

arensulfonyl (e.g. benzenesulfonyl, tosyl and toluenesulfonyl, naphthalenesulfonyl, etc.); aryloxycarbonyl (eg, phenoxycarbonyl, naphthyloxycarbonyl, etc.); aralkoxycarbonyl (e.g. benzyloxycarbonyl, etc.); arylcarbamoyl (eg, phenyl carbamoyl, naphthyl carbamoyl, etc.); arylglyoxyloyl (e.g., phenylglyoxyloyl etc.).

In the above examples for aromatic acyl radicals, the aromatic hydrocarbon moiety (especially the aryl moiety) and / or the aliphatic hydrocarbon moiety (especially the alkane moiety) may optionally have one or more suitable substituents, such as those already mentioned as suitable substituents for the alkyl or alkyl radical. . alkane residue. Particularly and by way of example, preferred aromatic acyl radicals with particular substituents include halogen and hydroxy, or halogen and acyloxy substituted aroyl and hydroxy, hydroxyimino, dihaloalkanoyloxyimino substituted aralkanoyl such as arylthiocarbamoyl (e.g. phenylthiocarbamoyl, etc.);

arylcarbamimidoyl (e.g., phenylcarbamimidoyl, etc.).

As heterocyclic acyl radical is meant an acyl radical which is derived from an acid having a heterocyclic radical; this includes:

heterocyclic carbonyl in which the heterocyclic moiety is an aromatic or aliphatic 5- to 6-membered heterocycle with at least one heteroatom selected from nitrogen, oxygen and sulfur (eg thiophenyl, furoyl, pyrrolocarbonyl, nicotinic, etc.). ); heterocyclic-alkanoyl in which the heterocyclic radical is 5- to 6-membered and has at least one heteroatom selected from nitrogen, oxygen and sulfur (e.g. thiophenylacetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino-4thiazolyl) -2-methoxyiminoacetyl etc.) .) etc.

In the above examples for heterocyclic acyl radicals, the heterocycle and / or the aliphatic hydrocarbon moiety may optionally have one or more suitable substituents, such as those already mentioned as being suitable for alkyl and / or alkyl. alkane groups.

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

Hydroxyalkyl is a straight or branched chain alkyl radical up to 9 carbon atoms which, unless otherwise defined, has at least one hydroxyl group, preferably one or two hydroxy groups.

Alkenyl includes straight or branched chain alkenyl groups of up to 9 carbon atoms such as vinyl, propenyl, (e.g., 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl, hexenyl, unless otherwise defined.

Alkynyl includes straight or branched chain alkynyl groups of up to 9 carbon atoms, unless otherwise defined.

Cycloalkyl is in particular an optionally substituted C ₃ - Cycykloalkyl; suitable substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy (e.g., methoxy, ethoxy, etc.), halogen (e.g., fluorine, chlorine, bromine, etc.), nitro, and the like.

Aryl is an aromatic hydrocarbon residue such as phenyl, naphthyl, etc., which may optionally have one or more substituents such as alkyl, alkenyl, alkynyl, alkoxy (e.g. methoxy, ethoxy, etc.), halogen (e.g. fluorine, chlorine, bromine, etc.). ), nitro and the like.

Aralkyl includes mono-, di-, triphenylalkyls such as benzyl, phenethyl, benzhydryl, trityl and the like, wherein the aromatic moiety may optionally have one or more suitable substituents such as alkoxy (e.g. methoxy, ethoxy, etc.), halogen (e.g. fluorine) , chlorine, bromine, etc.), nitro and the like.

• 9 ·· · ·

Alkylene includes straight or branched chain alkylene groups of up to 9 carbon atoms, which may be represented by the formula - (C _n H _2n ) - in which n is an integer from 1 to 9, such as methylene, ethylene, trimethylene, methylethylene tetramethylene, 1-methyltrimethylene, 2-ethylethylene, pentamethylene, 2-methyltetramethylene, isopropylethylene, hexamethylene and the like; preferred alkylene radicals have up to 4 carbon atoms, and especially 3 radicals such as trimethylene are particularly preferred. Hydrogen atoms can also be replaced by substituents, such as halogen radicals.

Alkenylene includes straight or branched chain alkenyl groups of up to 9 carbon atoms, which may be represented by the formula - (C _n H ₂ n-2) - in which n is an integer from 2 to 9, such as vinylene, propenylene (e.g., 1-propenylene, 2-propenylene), 1-methylpropenylene, 2-methylpropenylene, butenylene, 2-ethylpropenylene, pentenylene, hexenylene and the like; preferably the alkenylene radical may in particular have up to 5 carbon atoms and in particular 3 carbon atoms such as 1-propenylene. Hydrogen atoms can also be replaced by substituents, such as halogen radicals.

Hydroxyalkylene includes straight-chain or branched alkylene groups of up to 9 carbon atoms, wherein at least one selected hydrocarbon atom is substituted with hydroxy; these residues may be represented by the formula - (C _n H 2 _n . z) (OH) _z - in which n is an integer from 1 to 9 and z is an integer to which 1 <z <n. hydroalkylene groups include hydroxymethylene, hydroxyethylene (e.g. 1-hydroxyethylene and 2-hydroxyethylene), hydroxytrimethylene (e.g. 1-hydroxytrimethylene, 2-hydroxytrimethylene and 3-hydroxytrimethylene), hydroxytetramethylene (e.g. 2-hydroxytetramethylene), 2-hydroxy-2-methyltrimethylene, hydroxypentamethylene (eg 2-hydroxypentamethylene), hydroxyhexamethylene (eg 2-hydroxyhexamethylene) and the like. Particularly preferred is a lower hydroxyalkylene of up to 4 carbon atoms and in particular of 3 carbon atoms such as 2-hydroxytrimethylene. Hydrogen atoms can also be replaced by substituents, such as halogen radicals.

The 5- and 6-membered cyclic compounds which may represent B may be aromatic or aliphatic and substituted, for example, with alkyl groups of up to 7 carbon atoms and hydroxy groups.

The five- and six-membered heterocyclic compounds which may represent B and which contain at least one ring heteroatom in addition to carbon may be:

Φ Φ · • * * * * * * * * * * * * *

A saturated and unsaturated. Examples are aziran, diaziran, azirin, diazirin, azolan, diazolan, azole, diazole, oxolane, dioxolene, oxol, dioxol, oxirane, dioxiran, oxirin and dioxirin. They may be aromatic or aliphatic and substituted, for example by alkyl groups up to 7 carbon atoms and hydroxy groups.

The radicals X3 and X4 may preferably be selected by reacting the phosphonous and the phosphonous residues respectively. the phosphine group forms esters. Suitable examples for such esters of formulas (I), (IV) to (IX) include suitable mono- and diesters, and preferred examples for such esters include alkyl esters (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, hexyl ester etc.);

arylesters (benzyl ester, phenethyl ester, benzhydryl ester, trityl ester, etc.); aryl esters (eg, phenyl ester, tolyl ester, naphthyl ester, etc.); aroylalkyl esters (e.g., phenacyl ester, etc.) and silyl esters (e.g., trialkyl halogensilyl ester, dialkyldihalogensilyl ester, alkyltrihalogensilyl ester, dialkylarylhalogensilyl ester, trialkoxyhalogensilyl ester, dialkylaralkylhalogensilyl ester, dialkoxydihalogensilyl ester, etc.).

For the upper esters, the alkane and / or arene moiety may optionally have at least one suitable substituent such as halogen, alkoxy, hydroxy, nitro or the like.

X ₃ and X 4 are preferably a metal of the first, second or third main groups of the periodic system, ammonium, substituted ammonium, and ammonium compounds which are derived from ethylenediamine or amino acids. That is, the salt compounds of phosphororganic compounds are formed with organic and inorganic bases (eg, sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylammonium salt, ethanolamine salt, dicyclohexylamine salt, ethylenediamine salt) , a salt with N, N-dibenzylethylenediamine, etc.) as well as salts with amino acids (eg, salt with arginine, salt with aspartic acid, salt with glutamic acid, etc.) and the like.

The compounds according to the invention of formulas (I) to (IX) may exist in their protonated form as an ammonium salt of organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid. acids, maleic acids, fumaric acids, oxalic acids, tartaric acids, benzoic acids, etc.

• · · ·

3 · ♦ «·····

I I ···· 99 99 99

The compounds according to the invention of formulas (I), (IV) to (IX) allow the existence of spatial isomers, for example, for double bonds containing or chiral groups R 1, R 2, R 3, R 4, Χ 1, X 2, X 3, X 4 , A ₄ and heterocycles. The use of the compounds of the invention encompasses all the spatial isomers both as pure individuals and in the form of mixtures thereof.

The phosphororganic compounds are useful in humans and animals in particular for the therapeutic and prophylactic treatment of infections caused by viruses, bacteria, unicellular and multicellular parasites and fungi.

The compounds are effective against unicellular parasites (protozoa), in particular against malaria and sleeping sickness agents, as well as Chagas disease, toxoplasmosis, amoebic dysentery, leishmaniosis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcocerosis, acanthamebiosis, acanthamebosis, acanthamebiosis, acanthamebiosis, acanthamebiosis, acanthamebiosis, acanthamebiosis .

They are therefore particularly suitable for the prophylaxis of malaria and for the prophylaxis of sleeping sickness, as well as Chagas disease, toxoplasmosis, amoebic dysentery, leishmaniosis, trichomoniasis, pneumocystoses, balantidiosis, cryptosporidiosis, sarcocystoses, acanthameboses, coccidiosis, coccidiosis and naeglerosis.

The combination preparations are particularly useful against the following bacteria: bacteria of the family Propionibacteriaceae, in particular of the genus Propionibacterium, in particular of the species Propionibacterium acnes, bacteria of the family Actinomycetaceae, especially of the genus Actinomyces, bacteria of the genus Corynebacterium in particular Corynebacterium diphteriae, Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium, Chlamydiaceae species, in particular Chlamydia trachomatis and Chlamydia psittaci, Listeria species in particular Listeria monocytogenes, Erysipelthe risia species, Rrysipinthrix rhusia, pseudotuberculosis, Yersinia entrocolitica and Yersinia ruckeri, 9 · 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 Mycoplasmataceae, Mycoplasma and Ureoplasma, in particular Mycoplasma pneumoniae, Brucella, Bordetella, Neisseriaceae, in particular Neisseria and Moraxella, in particular Neisseria gonorrhoeae and Moraxella bovis, Vibrionaceae, in particular Vibrio, Aeromonas, Plesíomonas and Photobacterium, in particular Vibrio cholerae, Vibrio anguillarum and Aeromonas salmonicidas, Campylobacter, in particular Campylobacter,

Campylobacter coli and Campylobacter fetus, Helicobacter spp., In particular Helicobacter pylori spp., Spirochaetaceae and Leptospiraceae spp., In particular Treponema,

Borrelia and Leptospira, especially Borrelia burgdorferi to Actinobacillus, Legionellaceae, Legionella, Rickettsiaceae, Bartonellaceae, Nocardia and Rhodococcus; in particular the genera Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia and Shigella, bacteria of the family Pasteurellaceae, in particular of the genus Haemophilus, bacteria of the family Micrococcaceae, in particular of the genera Micrococcus and Staphylococcus; Streptococcaceae, especially Streptococcus and Enterococcus; and Bacillaceae, especially Bacillus and Clostridium.

Thus, the phosphororganic compounds and their derivatives are useful in the treatment of diphtheria, Acne vulgaris, listerios, animal robins, gaseous anthroposis in human and animal, human and animal paragonimosis, human and animal tuberculosis, leprosy and other human and animal mycobacteriosis, paratuberculosis animal, swine, mesenteric lymphadenitis and pseudotuberculosis in humans and animals, cholera, legionnaires disease, human and animal borreliosis, human and animal leptospirosis, syphilis, Campylobacter enteritis in human and animal, Moraxella keratoconjunctivitis and serositis · · * * Animals, brucellosis of animals and humans, spleen gangrene in humans and animals, actinomycosis in humans and animal, streptotrichos, psittacosis / ornithoses in animals, Q-fever and Ehrlichiosis.

It is also beneficial to use Helicobacter eradication therapy in gastric and intestinal ulcers.

Combinations with another antibiotic may also be used to treat the above-mentioned diseases. Isoniazide, rifampicin, ethambutol, pyrazinamide, streptomycin, protionamide and dapson are particularly suitable for the treatment of tuberculosis in combination preparations with second antiinfectives.

Further, the active compounds according to the invention can be used in particular in infections with the following viruses:

Parvoviridae: parvoviruses, dependoviruses, densoviruses,

Adenoviridae: adenoviruses, mastadenoviruses, aviadenoviruses,

Papovaviridae: papovaviruses, especially papillomaviruses (so-called wart viruses), polyomaviruses, in particular JC-virus, BK-virus and miopapovaviruses,

Herpesviridae: all herpesviruses, especially Herpes-simplex-viruses, varicela / zosterviruses, human cytomegalovirus, Epstein-Barr viruses, all human herpesviruses, human herpesvirus 6, human herpesvirus 7, human herpesvirus 8,

Poxviridae: poxviruses, orthopox-, parapox-, molluscum-contagiosum-virus, aviviruses, capriviruses, leporipoxviruses; all primary hepatotropic viruses, hepatitis-viruses: hepatitis-A-viruses, hepatitis-B-viruses, hepatitis-C-viruses, hepatitis-D-viruses, hepatitis-E-viruses, hepatitis-F-viruses, hepatitis-G-viruses,

Hepadnaviruses: all hepatitisviruses. Hepatitis-B-viruses, hepatitis-D-viruses,

Picornaviridae: picornaviruses, all enteroviruses, all polioviruses, all coxsackieviruses, all echoviruses, all rhinoviruses, hepatitis-A-virus, aftoviruses, Calciviridae: hepatitis-E-viruses,

Reoviridae: reoviruses, orbiviruses, rotaviruses,

Togaviridae: togaviruses, alphaviruses, rubiviruses, pestiviruses, Rubellavirus,

Flaviridae: flaviviruses, FSME-virus, hepatitis-C-virus,

Orthomyxoviridae: all influenza viruses,

Paramyxoviridae: paramyxoviruses, morbillivirus, pneumovirus, masernvirus, mumpsvirus,

Rhabdoviridae: rhabdoviruses, rabiesvirus, lyssavirus, viscular stomatitisvirus, Coronaviridae: coronaviruses,

Bunyaviridae: bunyaviruses, nairovirus, flebovirus, uukuvirus, hantavirus, hantanvirus, ϊ .......

* · · · · · · · · · · · · · · ·

Arenaviridae: arenaviruses, lymphocytic choriomeningitis-virus,

Retroviridae: retroviruses, all HTL-viruses, human T-cell leukemia virus, oncornaviruses, spumaviruses, lentiviruses, all H1-viruses,

Filoviridae: Marburg- and Ebola-virus, slow virus infections, prions; oncoviruses, leukemia viruses.

The phosphororganic compounds are thus suitable for combating the following viral infections:

eradication of papilloma viruses for the prophylaxis of tumors, particularly genital tumors caused by papillomaviruses in humans. Eradication of JC-viruses and BK-viruses, eradication of herpesviruses, eradication of human herpesviruses 8 for treatment of Kaposi-sarcoma, eradication of cytomegalitic viruses prior to transplantation, eradication of Eppstein Barr viruses before transplantation and for prophylaxis of tumors associated with Eppstein-Barr hepatitis diseases and for the prophylaxis of liver tumors and liver cirrhosis, eradication of coxsackieviruses in cardiomyopathies, eradication of coxsackieviruses in patients with diabetes mellitus, eradication of immunodeficiency viruses in humans and animals, treatment of concomitant infections in patients with AIDS, treatment of inflammations of the respiratory tract , rhinitis, pharyngitis, bronchitis, pneumonia), sensory organs (keratoconjunctivitis), nervous system (poliomyelitis, meningoencephalitis, encephalitis, subacute sclerosing panencephalitis, SSPE, prog. resistent multifocal leukoencephalopathy, lymphocytic choriomeningitis of the stomach and intestinal tract (stomatitis, gingivostomatitis, esophagitis, gastritis, gastroenteritis, diarrhea), liver and bile system (hepatitis, cholangitis, lymphatic system, hepatocellular lymphoma) organs (mumpsorchitis), skin (warts, dermatitis, Herpes labialis, feverish blisters, Herpes zoster, shingles), mucous membranes (papillomas, conjunctivapapilomas, hyperplasia, dysplasia), heart and vascular blood system (arteritis, endocarditis, myocarditis, myocarditis, myocarditis, myocarditis) system of kidneys and urinary tract, genital organs (anogenital lesions, warts, genital warts, pointed condylomas, dysplasia, papillomas, cervical dysplasia, condyloma acuminata, epidermodysplasia verruciformis), locomotive organs (myositis, myalgia), ungulates, Colorado-tick fever, Dengue-syndrome, hemorrhagic fever, early summer meningoencephalitis (FSME) and yellow fever.

· · · · · · · · · · · · · · · · · · · · · · · «« «« «« «·« «« · ·

The disclosed compounds, i.e. the phosphororganic compounds of formulas (I), (IV) to (IX), and their phosphono- or phosphinino-group esters and amides, as well as their salts, exhibit potent cytotoxic activity against bacteria, fungi, viruses, unicellular and multicellular parasites . Accordingly, the compounds of the invention are useful for the treatment of infectious diseases caused by viruses, bacteria, parasites and fungi in humans and animals. The compounds are also useful in the prophylaxis of diseases caused by viruses, bacteria, parasites and fungi, in particular as prophylaxis of malaria, and prophylaxis of sleeping sickness.

The phosphororganic compounds of the invention, which generally include pharmaceutically acceptable salts, amides, esters, salts of such esters, or even compounds which upon administration provide compounds of the invention as metabolic or degradation products, also called precursors, can be prepared for administration by any suitable means. in a manner analogous to known antiinfective agents (mixed with a non-toxic, pharmaceutically acceptable carrier).

Pharmaceutically acceptable salts of the compounds include those which the compounds of the formulas (I), (IV) to (IX) in their protonated form form as the ammonium salt of inorganic or organic acids such as hydrochloric acid, sulfuric acid, citric acid, maleic acid, fumaric acid, tartaric acid, ptoluenesulfonic acid.

Also particularly suitable are the pharmaceutically acceptable salts of X3 and X4 as sodium, potassium, calcium, ammonium, ethanolamine, triethylammonium, dicyclohexylamine, and amino acid salts such as arginine, aspartic acid. , glutamic acid salt.

The activity of the substances is determined by a system of experiments. This system is based on measuring the inhibition of the growth of bacteria, parasites, viruses, fungi or plants in vitro. Experimental procedures which are well known to those skilled in the art are used in part.

For example, inhibition of malaria parasite growth in blood cultures is determined to determine antimalarial activity.

The determination of antibacterial activity is based on the measurement of bacterial growth inhibition on nutrient media or in liquid cultures.

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

The determination of fungicidal activity is based on the inhibition of fungal growth on the culture medium or in liquid cultures.

• ·

Some micro-organisms to be investigated can only be studied in animal models. Then we will use the corresponding models here.

Substances exhibiting efficacy in in vitro measurement systems are studied further in in vivo models. Antiparasitic, antiviral, fungicidal or antibacterial activity is further evaluated in animal models.

Screening for herbicidal activity is determined using an algae system and measuring plant isoprene emissions under standard conditions.

Pharmaceutically active compositions may be prepared in the form of pharmaceutical preparations in dosage units. This means that the preparation is available in the form of individual particles, e.g., coated tablets, capsules, pills, suppositories and ampoules, in which the active substance content corresponds to a fraction or multiple of a single dose. Unit dosages may comprise e.g. 1, 2, 3 or 4 individual doses or 14 _^1/3%, or a single dose. A single dose contains, in particular, the amount of active ingredient to be administered when administered, which generally corresponds to half or a third or a quarter of the daily dose.

Nontoxic, inert, pharmaceutically acceptable carrier materials are solid, semi-solid or liquid diluents, fillers, and formulation aids of any kind.

Tablets, coated tablets, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as pharmaceutical preparations. Tablets, dragees, capsules, pills, and granules may contain the active ingredients in addition to conventional carriers such as (a) fillers and extenders, eg starches, milk sugar, raw sugar, glucose, mannitol and silicic acid, (b) binders, eg carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, (c) humectants such as glycerol, (d) blowing agents such as agar-agar, calcium carbonate, sodium carbonate, (e) dissolution retardants such as paraffin, (f) resorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol, glycerol monostearate, (h) adsorbents such as kaolin and bentonite, and (i) antiadhesives such as talc, calcium and magnesium stearate, and solid polyethylene glycols, or mixtures of the agents of (a) to (i) ).

Tablets, dragees, capsules, pills, and granules may optionally be provided with repeating agents containing coatings and coatings, and may also be formulated so as to deliver the active ingredients only or preferably in a certain part of the intestinal tract,

0 0 0 0 0 0 0 0 0 0 · 0 0

0 · 0 00 0 0 0 0 0

000 00 0 * 0 I

000 0 000 0 I

4-7 0000000004 | <000000 00 0 0 0000 optionally elongated, wherein polymeric substances and waxes may be used as the depositing materials.

Alternatively, the active compounds may also exist in microencapsulated form with one or more of the above-mentioned carriers.

Suppositories may contain, in addition to the active ingredients, customary, water-soluble or water-insoluble carriers such as polyethylene glycols, fats such as cocoa butter and higher esters (e.g. C 14 -alcohol with C 16 -fatty acid) or mixtures thereof.

Ointments, pastes, creams and gels may contain, in addition to the active ingredients, conventional carriers such as animal and vegetable fats, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

The powders and sprays may contain, in addition to the active compounds, conventional carriers, for example, milk sugar, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures thereof. Sprays can additionally contain conventional expellers such as chlorofluorocarbons.

The solutions and emulsions may contain, in addition to the active ingredients, customary carriers such as solvents, solubilizers and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cotton oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters or mixtures thereof.

For parenteral administration, solutions and emulsions may also be available in sterile and blood-isotonic form.

The suspensions may contain, in addition to the active compounds, customary carriers such as liquid diluents, e.g. water, ethanol, propylene glycol, suspending agents, e.g.

Said formulation forms may also contain coloring agents, preservatives, as well as flavor enhancers such as peppermint oil and eucalyptus oil, and sweeteners such as saccharin.

«· · ·

The active compounds of the formulas (I), (IV) to (IX) in the abovementioned pharmaceutical preparations should preferably be in a concentration of from about 0.1 to 99.5% by weight, in particular from about 0.5 to 95% by weight of the total. mixtures.

In addition to the compounds of formula (I), (IV) to (IX), the pharmaceutical preparations may also contain other pharmaceutically active substances.

The compounds may be used with the substances described to date with antibacterial, antiviral, antifungal and antiparasitic properties. These include in particular compounds which have already found use in therapy or are still in use. Particularly suitable for this purpose are the substances listed together in Rota Liste or Simon / Stille, Antibiotics-Therapy in Klinik und Praxis, 9th Ed. 1998, Schattauer Verlag or under http.7www.customs.treas.gov/imp -exp / ruling / harmonize / hrm129.html on the Internet. In particular, they may be penicillin derivatives, benzylpenicillin (penicillin G), phenoxypenicillin, isoxazolylpenicillin, aminopenicillin, ampicillin, amoxixillin, bacampicillin, carboxypenicillin, ticarcillin, temocillin, mesopillillin, cocillin, , cefoxitin, cefoxitin, cefotethane, cefmetazole, latamoxef, flomoxef, cefotaxime, cefozidime, ceftazidime, ceftazidime, cefepime, cefalosporins, cefsulodin, cefoperorphemorce, oral, cefoperazorce, oral , cefpodoxime-proxetil, cefuroxime-axetil, cefetamet, cefotiam-hexetil ,, cefdinir, ceftibuten, other β-lactam antibiotics, carbapenem, imipenem / cilastatin, meropenem, biapenem, aztreonamate, β-lactamactin (beta-lactamactin), (beta-lactamam), ampicillin, tazobactam / piperacillin, te tracyclines, oxytetracycline, rolitetracycline, doxycycline, minocycline, chloramphenicol, aminoglycosides, gentamicin, tobramycin, netilmicin, amikacin, spectinomyxin, macrolides, erythromycin, clarithromycin, clithromycin, spirosin, azithromycin, azithromycin, azithromycin, azithromycin, azithromycin, azithromycin, azithromycin, azithromycin vancomycin, tecopfanine, pristinamycin derivatives, fosfomycin, antimicrobial folic acid antagonists, sulfonamides, Co-trimoxazole, trimethoprim, other combinations of diaminopyridine sulfonamide, nitrofurans, nitrofurantoin, nitrofurazone, gyrasacxacloxacin, quinolloxin, cinininin, cinininin, fleroxacin, pefloxacin, lomefloxacin, Bay Y3118, nitroimidazoles, antimycobacterial agents, isoniazid, rifampicin, rifabutin, ethambutol, pyrazinamide, streptomycin, capreomycin, prothionamide, terizidone, dapson, clofson, clofone

C Β

Β 9 · Β 9 9 Β 999 999 9 9 9 9 Β 9 Β · ((9 * · «

W · * · ΒΒΒΒ ·· *

Antibiotics, bacitracin, tyrothricin, polymyxins, neomycin, kanamycin, paromomycin, mupirocin, antiviral agents, acyclovir, ganciclovir, azidothymidine, didanosine, zalcitabine, idiacuridine, trifacuridine, trifiacuridine, trifacuridine, trifacidine, stavudidine, trifacidine, thudytidine, trifacidine, amantadine, interferons, tibol-derivatives, proteinase inhibitors, antifungals, polyenes, amphothericin B, nystatin, natamycin, azoles, azoles for septic therapy, miconazole, ketoconazole, itraconazole, fluconazole, UK-109.496, topical azoles, clotrimazole, econazole, isoconazole, oxiconazole, bifonazole, flucytosine, griseofulvin, ciclopiroxolamine, tolnaftate, naftifine, terbinafine, amorolfine, anthraquinones, betulinic acid, semianthraquinones, xanthones, naphthoquinones, arylamino amino alcohols, quinine, quinine, quinine, quinine, quinine, quinine, quinine, quinine, quinine, quinine , pyronaridine, dapson, sulfonamides, sulfadoxin, sulfalene, trimethoprim, proguanil, chlorproguanii, diaminopyrimidines , pyrimethamine, primaquine, aminoquinoline, WR 238,605, tetracycline, doxycycline, clindamycin, norfloxacin, ciprofioxacin, ofloxacin, artemisinin, dihydroartemisinin, 10b artemether, arteether, atrtesunate, pentamide, melamine, suramine, melamine, suramine, melamine, suramine, , clioquinol, mebendazole, niclosamide, praziquantel, pyrantel, tiabendazole, diethylcarbamazine, ivermectin, bithionol, oxamnichin, metrifonate, piperazine, embonate.

In addition, phosphororganic compounds can exist in pharmaceutical compositions in combination with sulfonamide, sulfadoxin, artemisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracycline, doxycycline, proguanil, pyronidazolend, metronidazolebem, metronidazoleeb, metronidazoleeb, metronidazoleeb , diethylcarbazine, piperazine, pyrivinum, metrifonate, oxamnichine, bithionol or suramine, or in combination with a plurality of such substances.

The preparation of the above pharmaceutical preparations is carried out in a conventional manner according to known methods, for example by mixing the active compound (s) with the carrier substance (s).

Said preparations may be used in humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitonally, locally (powders, ointments, drops) and for the treatment of infections in cavities and body cavities. Injectable solutions, solutions and suspensions for oral therapy, gels, poured formulations, emulsions, ointments or drops are suitable preparations. Ophthalmological and • · · ·

9

9 9 · · I · · · · · · ·

Dermatological formulations, silver and other salts, ear drops, eye ointments, powders or solutions. In animals, intake can also take place in suitable formulations in feed or drinking water. Gels, powders, powders, tablets, protracted tablets, premixes, concentrates, granules, pellets, tablets, boluses, capsules, aerosols, sprays, inhalants can also be used in humans and animals. The compounds of the invention may be further incorporated into other carrier materials such as synthetic materials (plastic chains for local therapy), collagen or bone cement.

In general, in both human and veterinary medicine, it has proven advantageous to administer the active compound (s) of formula (I), (IV) to (IX) in total amounts of from about 0.05 to about 600, in particular 0, to achieve the desired results. 5 to 200 mg / kg of body weight for 24 hours, optionally in multiple unit doses. A single dose contains the active compound (s) in particular in amounts of from about 1 to about 200, in particular from 1 to 60 mg / kg of body weight. However, it may be desirable to deviate from the aforementioned dosage, depending on the type and body weight of the subject being treated, the type and severity of the disease, the type of preparation and the drug being administered, as well as the time span and time. the interval within which the administration takes place.

Thus, in some cases it may be sufficient to start with less than the amount of active ingredient given above, while in other cases the amounts of active ingredient must be exceeded. The precise determination of the optimum dosage just required and the method of application of the active compounds can be made by the skilled person on the basis of his expert knowledge.

The compounds of the invention may be administered to animals in the usual concentrations and formulations together with the feed or feed. feedingstuffs or drinking water.

Furthermore, the compounds of the invention can be used excellently as bactericides, fungicides and herbicides in plants.

In principle, one skilled in the art knows which route of synthesis to choose for the preparation of the compounds of the invention. Some synthetic routes for the compounds of the invention are exemplified below.

«« «« «· · · · ·

DETAILED DESCRIPTION OF THE INVENTION

Possible synthetic routes for compounds of the type:

O OH

H-N-CH-X-CH-PO (OR) ₂

Íh ₂ —Y —ihh with R = H or Na ⁺

aX = —Ch ₂ - Y = without Y Y = -CFh- (five-circle) (six, circle) Example 1 Example 2 X = —0— Y = without Y (five-circle) Example 3 Y = -CH2- (six-member circle) Example 4 X = —NH- Y = noY (five-circle) Example 5 Y = —ch ₂ - (six-member circle) Example 6

Example 1

3-Oxo-cyclopentylphosphonic acid diethyl ester 1 (a)

To 11.4 mmol of diethyl phosphite and 12.4 mmol of N, O-bis- (trimethylsilyl) -amide in 5 ml of dichloromethane at 0 ° C was added dropwise 0.52 mmol of trimethylsilyltriflate. After stirring for 30 minutes, cyclopent-2-en-1-one (0.52 mmol) was added dropwise at the same temperature and stirred for 1 h. The enolsilane intermediate was hydrolyzed with 3 ml of 1 N HCl for 3 hours. The organic phase is separated, dried over magnesium sulphate and concentrated. The crude product is chromatographed on SiO 2 and, after concentration of the desired fractions, yields 3-diethylphosphonate-cyclopentan-1-one (a) ob. = 104 ° C / 0.25 torr.

[See I. Sea, Y. Kimura, T. Nakano, S. Matsunaga, G. Iwasaki, A. Ogawa, K. Hayakawa, Tetrahedron, 22, 2561-73 (1966), and E. Ohler, E. Zbiral: Liebigs Ann. Chem. 1991,229-36].

3-Diethylphosphonate cyclopentanone oxime 1 (b)

To a suspension of 150 mg of 35% potassium hydride in a mineral oil dissolved in THF cooled to -78 ° C was added 1.41 mmol of N, O-bis- (trimethylsilyl) 22. • 9 9 9

9 9 9 9 9 9 9 9 hydroxylamine, also dissolved in THF. The suspension was stirred at 0 ° C for 30 minutes. At -78 ° C, 1.34 mmol of 3-oxocyclopentylphosphonic acid diethyl ester (a) in THF was added dropwise. The reaction mixture was stirred at room temperature for 90 min, then poured onto 40 ml of ice-cooled 10% aqueous ammonium chloride solution and extracted with methylene chloride three times for 30 ml each. The combined organic phases were dried over MgSO 4, and the solvent was removed under reduced pressure. Oxime 1 can be reacted without further purification.

[See R. V. Hoffman, G. A. Buntain: Synthesis 9, 831-33 (1987) or for an alternative preparation of T. Kawada, T. Tsuhima: Heterocycles 28, 573-578 (1989)].

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

Sodium cyanoborohydride (NaBH 3 CN) was used without further purification. To 4 mmol of oxime 1 (b) dissolved in little methanol were added 2 drops of bromocresol green and 6 η KOH was added dropwise until a color change from yellow to green was observed. To this was added 3 mmol of NaBH ₃ CN, stirred for 3 h at room temperature, and methanol / HCl was added dropwise until the color change from green to yellow stopped. The reaction mixture is added to 10 ml of water and pH> 10 is adjusted with 6 n KOH. After saturation of the aqueous NaCl phase, the solution is extracted five times with 10 ml of chloroform, then dried over MgSO4 and the solvent is removed under reduced pressure. The yellow to red colored crude product can be chromatographed on SiO ₂ .

[see R.F. Borch, M. D., Bernstein, H. D. Durst: J. Am. Chem. Soc. 93, 2897-904 (1971)].

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

To 0.06 mol of ester 1 was added 130 ml conc. HCl and refluxed for 6 h with vigorous stirring. After cooling, the tan solution was concentrated under reduced pressure, treated with about 30 ml of water and treated with activated carbon until a nearly colorless solution was formed. It was again concentrated under reduced pressure, about 30 ml of water was added thereto, and the pH was adjusted to 4-5 with NaHCO 3. The precipitated beige precipitate is filtered off and can be washed with a water / ethanol mixture. 0.037 mol of product is obtained, which corresponds to a yield of 61%. Recrystallization is not necessary.

9 9 99 9 9999 9 9

9999 99 9 99

999 9,999 9 9

99 9900 99 9

999 * 9 «<9 99 99 999

3- (N-Formyl-N-hydroxylamino) -cyclopentylphosphonic acid monosodium salt 1 (e)

To 4 ml of acetic anhydride, 2 ml of formic acid is added dropwise over 5-10 minutes at 0 ° C, allowed to stir at the same temperature for 10 minutes and at room temperature for 15 minutes and the solution is again cooled to 0 ° C. While warming to 40-50 ° C, 0.02 mol of 3-N- (hydroxylamine) -cyclopentylphosphonic acid 1 (d) is dissolved in about 6 ml of formic acid and added dropwise to the top solution at 0 ° C and stirred for 1 hour at temperature Surroundings. It is then concentrated under reduced pressure to an oil which is mixed with water and concentrated under reduced pressure. This procedure is repeated three times. In aqueous solution, the pH is adjusted to 4.5-5 with 1 n NaOH. The residual oil is boiled several times in isopropyl alcohol, the alcohol phase being discarded. The residue is dissolved in methanol until all of it is dissolved in the hot state and the product precipitates with the aid of ethanol. After filtering off the crude product, it can be recrystallized again from methanol / ethanol.

Example 2

3-Oxo-cyclohexylphosphonic acid diethyl ester 2 (a)

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

3-Diethylphosphonate-cyclohexanone oxime 2 (b) (b) can be synthesized analogously to 1 (b).

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

Sodium cyanoborohydride (NaBHaCN) is used without further purification. 2 drops of bromocresol were added to 4 mmol of oxime 2 (b) dissolved in little methanol

6 n KOH was added dropwise until a color change from yellow to green was observed. To this was added 3 mmol of NaBH ₃ CN, stirred for 3 h at room temperature, and methanol / HCl was added dropwise until the color change from green to yellow stopped. The reaction mixture is added to 10 ml of water and pH> 10 is adjusted with 6 n KOH. After saturation of the aqueous NaCl phase, the solution is extracted five times with 10 ml of chloroform, then dried over MgSO4 and the solvent is removed under reduced pressure. The yellow to red colored crude product can be chromatographed on SiO2.

3-N- (hydroxylamine) -cyclohexylphosphonic acid 2 (d) (d) was analogous to hydrolysis of 1 (c) conc. HCl obtained in a yield of over 50

%.

3- (N-Formyl-N-hydroxylamino) -cyclohexylphosphonic acid monosodium salt 2 (e)

For preparation 2 (e) see 1 (e).

Example 3

2,5-Dichlorotetrahydrofuran 3 (a)

At -35 ° C, 142 g of nitrogen diluted with nitrogen were condensed to 72 g of absolute THF in 80 ml of carbon tetrachloride. It is then irradiated with UFlamp for 8 to 9 hours with stirring. After completion of the reaction, CCl 4 is removed under reduced pressure. The products are first condensed in a high vacuum in a template cooled to -50 ° C to be fractionated in a water pump vacuum. 60 g of 2,5-dichlorotetrahydrofuran are obtained, b.p. = 61-64 ° C / 12torr.

[See H. Gross: Chem. Ber. 95, 83-90 (1962)]

Di-tert. 5-chloro-tetrahydrofur-2-yl-phosphonic acid butyl ester 3 (b)

To a suspension of 5.0 g of 80% NaH (in mineral oil) in 60 ml of absolute THF at 0 ° C was added dropwise 31 g (160 mmol) of di-tert. butyl phosphite dissolved in 90 mL THF. After stirring at 0 ° C for 30 minutes, 135 mmol of 2,5-dichlorotetrahydrofuran dissolved in 120 ml of absolute THF was added dropwise at the same temperature. The reaction solution was refluxed for 20 h and then concentrated under reduced pressure. An oil is formed which is contaminated, inter alia, by the decomposition products of the starting material, 2,5-tetrahydrofuran, which can be separated by chromatography on SiO2.

[See K. Baczko, W-Q. Liu, Β. Roques, P. Garbay-Jauregiuiberry: Tehtrahedron 52, 2021-30 (1996)].

5-Chloro-tetrahydrofur-2-yl-phosphonic acid 3 (c)

0.9 mmol of tert. of butyl ester 3 (b), 10 mL of trifluoroacetic acid, 4.5 mmol of anisole and 10 mL of methylene chloride was stirred at room temperature for 1 h. 10 ml of water are then added dropwise and evaporated to dryness. The oil formed can be recrystallized from methanol and chloroform.

[See T. R. Burke Jr., Z-H. Li, J.B. Bolen, V. E. Marquez: J. Med. Chem. 34, 1577-81 (1991)].

Hydrolysis target. butyl ester 3 (b) can also be carried out by boiling in benzene with the addition of trifluoroacetic acid [See Chem. Ber. 108, 1732-44 (1975)] or also in pure trifluoroacetic acid at room temperature [See Phosphorus, sulfur and silicium and related elements, 61, 183-84 (1991)].

Formohydroxamic acid 3 (d) was prepared according to the method of Bernhard et al. J. Am. Chem. Soc. 86, 4406 (1964) from hydroxylamine hydrochloride, potassium chloride and potassium hydroxide, all of which were used without further purification. Formohydroxamic acid: mp 7477 ° C.

O-Trimethylsilyl-formohydroxamic acid 3 (e)

The equivalent of formohydroxamic acid dissolved in THF was stirred with 1 equivalent of trimethylchlorosilane at room temperature for 2 days with the addition of triethylamine. O-Trimethylsilyl-formohydroxamic acid is formed in low yields and can be purified by column chromatography.

5- (N-Formyl-N-hydroxylamino) -tetrahydrofur-2-yl-phosphonic acid 3 (f)

5-Chloro-tetrahydrofur-2-yl-phosphonic acid was stirred at room temperature for 4 h with a double excess of O-trimethylsilyl-formohydroxamic acid in absolute dimethylformamide. After quenching with water, it is concentrated under reduced pressure, dissolved in water, concentrated again and the oil chromatographed on cellulose.

9

0

9 9 9 9 9 9

Ζϋ · · · 0 0 0 0 0

Example 4

2,6-Dichlorotetrahydropyran 4 (a) kg of a 25% aqueous glutaraldehyde solution is extracted with methylene chloride, the organic phase is dried over Na 2 SO 4, concentrated and the glutaraldehyde distilled under vacuum (B.v. = 74-75 ° C / 13 torr) .

To a solution of 200 g of glutaraldehyde dissolved in 700 ml of absolute methylene chloride, dry hydrogen chloride was introduced at -25 ° C with vigorous stirring, maintaining the temperature below -15 ° C. Allow to stand at -40 ° C for 8 h, then warm to 0 ° C and separate from water. The organic phase is dried over Na 2 SO 4, the volatiles are removed under reduced pressure and finally 2,6-dichlorotetrahydropyran (a) is distilled (b.p. 3739 ° C / 0.01 torr).

[See K. Dimroth, W. Kinzebach, M. Soyka: Chem. Ber. 99, 2351-60 (1966)]

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

The pyran derivative 4 is prepared from 2,6-dichlorotetrahydropyran as described under 3.

Example 5

5- (Oxopyrrolidin-2-yl-) phosphonic acid diethyl ester 5 (a)

The 5-oxo-pyrrolidine derivative 5 (a) can be obtained as prescribed by J. Oleksyszyn, E. Gruseck, P. Kafafarski, P. Mastalerze: Monatsh. Chem. 113, 59-72 (1982) with the following synthetic sequence: triethylphosphite is reacted with 3-chlorocarbonylpropionic acid methyl ester to give 4 (diethoxyphosphoryl) -4-oxo-butyric acid methyl ester. This is converted to the amine via the oxime at the 4-oxo position. 4-Amino-4- (diethoxyphosphoryl) -4-oxo-butyric acid methyl ester cyclizes to the starting compound 5 (oxopyrrolidin-2-yl) phosphonic acid 5 (a) for 30 minutes by heating.

5-Thione-pyrrolidine-2-phosphonic acid diethyl ester 5 (b) * mmol of oxo compound 5 (a) is converted to thio compound 5 (b) by heating with P ₄ Sw in xylene. After the reaction was completed, the hot xylol layer was decanted and the product chromatographed on silica gel.

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

Hydroxylamine is released from 4.5 g of hydroxylamine hydrochloride suspended in 20 ml of methanol by addition of 5.5 g of NaHCO3, and 5 g of 5-thionpyrrolidine 5 (b) dissolved in methanol are added. Heat the solution until the H ₂ S evolution ceases (about 12 h). Then methanol is distilled off and the residue is further reacted without further purification.

[See H. Behringer, H. Meier: Liebigs Ann. Chem. 607, 67-91 (1957)].

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

The reduction of oxime 5 (c) to hydroxylamine 5 (d) is carried out according to Preparation 1 (c). The crude product shows a red color which can be removed by filtration through activated carbon with methanol as solvent.

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

Phosphonic acid diethyl ester 5 (d) can be hydrolyzed in amounts up to 2 g to phosphodiesterase, which is applied to carboxymethylcellulose.

[See I. A. Natchev: Liebigs Ann. Chem. 1988, 861-867 and I.A. Natchev: Tetrahedron 44, 1511-1522 (1988)].

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

Regiospecific formylation on hydroxylamine nitrogen to N-formyl-N-hydroxylamine 5 (f) also leads to bis-formylation. 1,3,5-Triformylhexahydro-1,3,5-triazine [prepared from 1,3,5,7-tetraazaadamantane and formic acid; see E. N. Gate, M. D. Threadgill, M. F. Stevens, D. Chubb, L. M. Vickers: J. Med. Chem. 29, 1046-52 (1986)], N-formylimidazole or formic acid / acetic anhydride. Until now, 5 (f) could not be isolated in a pure chromatographically pure substance.

Example 6 ······································

Piperidin-2-one-6-phosphonic acid diethyl ester 6 (a) (a) was prepared analogously to 5 (a). When 5-amino (diethoxyphosphoryl) -pentanoic acid is heated, it cyclizes to 6 (a).

The next steps are also analogous to the preparation of 5- (N-formyl-N-hydroxy-amino) -pyrrolidine-2-phosphonic acid 5 (f). To date, 6- (N-formyl-N-hydroxylamino) piperidine-2-phosphonic acid 6 has also not been obtained in the substance.

Example 7a

Preparation of HC (= O) -N (OH) -X-PO (OR) ₂ compounds with R = H or Na ⁺ and X = -CH ₂ -CH ₂ -C (= O) 3-Chloropropionyl-phosphonic acid dimethyl ester

To 0.5 mol of 3-chloropropionic acid chloride was added dropwise at 5 ° C an equivalent of trimethylphosphite, allowed to warm to ambient temperature and stirred for an additional 2 h. [In analogy with: R. Karaman, A. Goldblum, E. Breuer, J. Chem. Soc. Perkin Trans I 1989; 765-774; for the preparation of β-chloropropionic acid chloride, see: T. Bruylants: Bull. Soc. Chim. Belg. 58,319 (1949)].

3- (N-Hydroxylamino) -propionylphosphonic acid dimethyl ester

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

3- (N-hydroxylamino) -propionylphosphonic acid

0.2 mol of trimethylsilyl bromide was slowly added to a solution of 0.1 mol of 3- (N-hydroxylamino) -propionylphosphonic acid dimethyl ester in absolute acetonitrile. After stirring at room temperature for 3 h, the solution was concentrated and taken up to 50 ml

4 4 4 methanol. After stirring for 30 minutes, it was concentrated again. 3- (N-Hydroxylamino) -propionylphosphonic acid can be reacted further without purification). In analogy with: R. Karaman, A. Goldblum, E. Breuer, J. Chem. Soc. Perkin Trans I, 1989, 765774)

3- (N-Formyl-N-hydroxylamino) -propionylphosphonic acid monosodium salt

To 4 ml of acetic anhydride is added dropwise 2 ml of formic acid at 0 ° C, allowed to stir for 10 minutes at the same temperature and 15 minutes at room temperature, cooled again to 0 ° C and 0.02 mol of acid 3 is added dropwise at 0 ° C. - (N-hydroxylamino) -propionylphosphonic acid dissolved in formic acid. After stirring at room temperature for 1 h, the solution is concentrated under reduced pressure, the oil is dissolved in 50 ml of methanol, heated to 60 ° C and mixed with ethanol / isopropyl alcohol. A white solid precipitates which is redissolved in methanol and can be recrystallized from ethanol with further addition of isopropyl alcohol.

Alternatively, the following synthetic route may be followed: acyl chloride of βalanine is reacted with triethylphosphite to diethyl 3-aminopropionylphosphonic acid ester [see B.A. Arbuzov, Μ. V. Zolotov: Bull. Acad. Sci. USSR Div. Chem.Sci. (Engl. Transl.) 1964, 1701-04]. Then, it is formulated to oxidize the secondary amine formed with dimethydioxiran to the N-formyl-N-hydroxy-aminophosphonic acid ester. The hydrolysis can then be performed as described above.

Example 7b

Preparation of 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, starting from from acrylic acid, which is converted to acyl chloride, epoxidized with a peroxyacid, and the epoxide is radically opened to give 3-chloro-2-hydroxy-propionyl chloride. This can be carried out as described in Example 7a.

♦ · ·· ««

Example 7c

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

1-Chloro-2-chloromethoxyethane (see preparation: B. Castro: Bull. Soc. Chim. Fr. 1967, 1533-40) is subjected to boiling Michael Arbuzov reaction with triethylphosphite to diethyl ester of (2-chloroethoxy) methyl- phosphonic.

(2-Azidoethoxy) methylphosphonic acid diethyl ester

0.02 moles of (2-chloroethoxy) methylphosphonic acid diethyl ester, 3 mmol of tetrabutylammonium bromide and 2.5 g of sodium azide are refluxed in 50 ml of toluene for 4 hours. After cooling, it is washed three times with 25 ml of water. The aqueous phase may be extracted with toluene. The combined toluene phases were dried over sodium sulfate and the solvent was removed in vacuo. Yellow oil remains. [see K. Eger, E.M. Klunder, M. Schmidt: J. Med. Chem. 37, 3057-61 (1994); see also A. Holý, I. Rosenberg: Collect. Czech. Chem. Commun. 1989, 2190-210]

(2-Aminoethoxy) methylphosphonic acid diethyl ester

The above oil (24 mmol) dissolved in 5 mL of toluene was added dropwise to a solution of 36 mmol of triphenylphosphine in 35 mL of toluene over 30 min. After stirring at room temperature for 1 hour, 50 mL of water was added, stirred vigorously for 15 min, and the phases separated. The aqueous phase was washed several times with ether and concentrated. Traces of water were then removed with methanol. A yellow oil remained.

[See K. Eger, E.M. Klunder, M. Schmidt: J. Med. Chem. 37, 3057-61 (1994)].

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

(2-Aminoethoxy) methylphosphonic acid diethyl ester can be converted to the corresponding hydroxylamine (e.g., dimethyldioxirane or benzoyl peroxide) in small extracts from the literature by known oxidizing agents.

9999 99

9 9 9 9 9

9 9 9 9 9 9 9 9 · ·················

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

According to the publication K-L. Yu, J. J. Bronson, H. Ya, A. Patick, M. Alam, V. Brankovan, R. Datema, M. J. M. Hitchcock, J. C. Martin: J. Med. Chem. 35, 29582969 (1992), stirred at 0 ° C for 0.5 hour with 0.5 mol of [2- (N-hydroxylamino) ethoxy] methylphosphonic acid diethyl ester and 1.5 mol of 2,4,6-kollidine in 5 ml of absolute methylene chloride. After 16 hours at room temperature, the solution was concentrated, taken up in aqueous acetone and stirred for 14 hours. After concentration, take up to 1 n NaOH and heat to 100 ° C for 2 h. After cooling, it was concentrated and the crude product was purified by chromatography.

[2- (N-Formyl-N-hydroxylamino) -ethoxy] methylphosphonic acid monosodium salt

Formylation can be carried out analogously to Example 7a.

Example 7d

Preparation of 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 may be threonic acid, threose / erythrosa, or 2,3,4,4-tetrachlorobutyryl chloride (CbCHCI-CHCI-COCI) known from the literature.

Claims (17)

PATENT CLAIMS 1. Phosphoric compounds of formula (I): Ri. NR ₂ O BP-R ₃ R ₄ (I) wherein R 1 and R ₂ are the same 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, 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 an heterocyclic radical, B is selected from the group consisting of an ether group (II) H -Ai-OA ₂ -C- (II) H wherein A ₁ and A ₂ , of which A ₂ may also be omitted, are the same or different and are selected from the group consisting of alkylene, alkenylene and hydroxyalkyl, by keto (III) O -A ₃ -C-A4 (III) 99 »9 9 9 9 9 9 9 9 9 • 999 99 9 · » 9 9 9 9 · 9 9 9 9 98 9 «9 9 9 · 9 9 9 9 9 Wherein A ₃ and A4, one or both of which may be omitted, are the same or different and are selected from the group consisting of alkylene, alkenylene and hydroxyalkyl, and five- and six-membered cyclic, in particular heterocyclic, compounds which: besides carbon, they contain at least one heteroatom as part of the ring, the heteroatom being selected from the group consisting of oxygen and nitrogen, R ₃ and R ₄ are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl of up to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl of up to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted acyl , substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl of up to 26 carbon atoms, substituted and unsubstituted alkynyl of up to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radicals, halogen, OX ₃ or OX4, wherein X ₃ or X 4 may be be the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl of up to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl of up to 26 carbon atoms, substituted and unsubstituted aryl, substi substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl of up to 26 carbon atoms, substituted and unsubstituted alkynyl of up to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, silyl, cation of an organic and inorganic second base, in particular a metal the third main group of the periodic system, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids, and their pharmaceutically acceptable salts, esters and amides and salts of esters, with the exception of H ₂ N (CH 2) 2 CO _(CH2) nP ( O) (OH) OH with n = 1 or 0 a H (OH) NCOP (O) (ONa) ₂ . Compounds according to claim 1, which correspond to formula (IV) HIM. / N-A1 r ₂ ^z H € P — R ₃ i | Η OX4 (IV) 4 4 44 5 4 4 ϊ ϊ Wherein 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, 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, if present, can be the same or different. Compounds according to claim 2, selected from the group consisting of disodium salt of 2- (N-formyl-N-hydroxylamino) -1-oxoethylphosphonic acid, disodium salt of 2- (N-acetyl-N-hydroxylamino) -1 -oxoethyl phosphonic acid, disodium salt of 3- (N-formyl-N-hydroxylamino) -1-oxopropylphosphonic acid, disodium salt of 3- (N-acetyl-N-hydroxyamino) -1-oxopropylphosphonic acid, disodium salt of 3- (N- formyl-Nhydroxylamino) -1-oxo-2-propenylphosphonic acid, 3- (N-acetyl-Nhydroxylamino) -1-oxo-2-propenylphosphonic acid disodium salt, 4- (N-formyl-Nhydroxylamino) -1-oxo disodium salt -3-hydroxybutylphosphonic acid, disodium salt of 4- (N-acetyl-Nhydroxylamino) -1-oxo-3-hydroxybutylphosphonic acid, disodium salt of 3- (N-formyl-Nhydroxylamino) -2-oxopropylphosphonic acid, disodium salt of 3- (N -acetyl-Nhydroxylamino) -2-oxopropylphosphonic acid, 4- (N-formyl-Nhydroxylamino) -3-oxo-2-hydroxy-2-methylbutylphosphonic acid disodium salt, 4- (Nacetyl-N-hydroxylamino) -3- disodium salt oxo-2- hydroxy-2-methylpropylphosphonic acid, 4- (N-formyl-N-hydroxylamino) -3-oxo-2-hydroxy-2- (hydroxymethyl) butylphosphonic acid disodium salt, 4- (N-acetyl-N-hydroxylamino) disodium salt -3-oxo-2-hydroxy-2- (hydroxymethyl) -propylphosphonic acid. Compounds according to claim 1, which correspond to formula (V) HIM N — A1 Rz (V) wherein R ₂ is selected from the group which consists of acetyl and formyl Eno is selected from the group consisting of methylene, ethylene, ethenylene, 2-hydroxypropylene, hydroxymethylene and hydroxyethylene, A ₂ falls off 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, if present, can be the same or different. Compounds according to claim 4, selected from the group consisting of [(N-formyl-N-hydroxylamino) -methoxy] -methylphosphonic acid disodium salt, [(N-acetyl-N-hydroxylamino) -methoxy] -methoxy- methylphosphonic acid, [2- (N-formyl-N-hydroxylamino) -ethenoxy] -methylphosphonic acid, disodium salt [2- (N-acetyl-N-hydroxylamino) -ethenoxy] methylphosphonic acid, disodium salt [3- (N-formyl-N-hydroxylamino) -2-hydroxypropoxy] methylphosphonic acid, [3- (N-acetyl-N-hydroxylamino) -2-hydroxypropoxy] methylphosphonic acid disodium salt. Compounds according to claim 1, wherein B is a cyclic compound in which the amino group and the phosphorus atom are bonded to two C-atoms which are separated by only one other atom. Compounds according to claim 6, wherein B is a heterocyclic compound in which the amino group and the phosphorus atom are bonded to two C-atoms which are separated by only one heteroatom. Compounds according to claim 7, wherein the phosphororganic compound is selected from the group consisting of compounds of formulas Φ φ • · φ · · · φ φ φ φ · · I · 99 ΦΦ φφ 99 where Χι means Η, R ₂ is selected from the group which consists 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. Pharmaceutical preparation characterized by an effective content of at least one phosphororganic compound according to any one of claims 1 to 8 together with a pharmaceutically acceptable carrier. Pharmaceutical preparation according to claim 9, characterized by at least one further pharmaceutically active substance. Pharmaceutical preparation according to either of Claims 9 or 10, characterized by one or more of sulfonamide, sulfadoxin, artemisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mephioquin, halofantrine, pyrimethamine, armesin, tetracyclines, doxycycline, metronazoline, proguidazoline praziquantil, niclosamide, mebendazole, pyrantel, tiabendazole, diethylcarbazine, piperazine, pyrivinum, metrifonate, oxamnichine, bithionol and suramine. Pharmaceutical preparation according to claim 10, characterized by one or more of penicillins, benzylpenicillin (penicillin G), phenoxypenicillin, isoxazolylpenicillin, aminopenicillins, ampicillin, amoxixillin, bacampicillin, carboxypenicillin, ticarcillin, azocopillin, temocillinillin, temocillinillin, temocillinillin, temocillinillin. Ooclocillin, piperacillin, apalcillin, mecillinam, cephalosporin, cefazoline group, cefuroxime group, cefoxitin group, cefoxitin, cefmetethane, cefmetazole, latamoxef, flomoxef, cefotaxime group, cefzidimide, ceftaidta, ceftaidta, other cephalosporins, cefsulodine, cefoperazone, oral cephalosporins of the cefalexin group, loracarbef, cefprozil, new extended spectrum oralcephalosporins, cefixime, cefpodoxime-proxetil, cefuroxime-axetil, cefetamet, cefetamet, cefotiem, , imipenem / cilastatin, meropenem, biapenem, aztreonam, inh β-lactamase ibritors, clavulanic acid / amoxicillin, clavulanic acid / ticarcillin, sulbactam / ampicillin, tazobactam / piperacillin, tetracyclines, oxytetracycline, rolitetracycline, doxycycline, minocycline, amine, nicotinicin, chloramphenicol, chloramphenicol, , clarithromycin, roxithromycin, azithromycin, dirithromycin, spiramycin, josamycin, lincosamides, clindamycin, fusidinic acid, glycopeptide antibiotics, vancomycin, tecoplanin, pristinamycin derivatives, fosfomycin, antimicrobial sulphonamide antagonists, folic acid sulphide, , nitrofurans, nitrofurantoin, nitrofurazone, gyrase inhibitors (quinolones), norfloxacin, ciprofloxacin, ofloxacin, sparfloxacin, enoxacin, fleroxacin, pefloxacin, lomefloxacin, Bay Y3118, nitroimidazoles. anti-mycobacterial agents, isoniazid, rifampicin, rifabutin, ethambutol, pyrazinamide, streptomycin, capreomycin, prothionamide, terizidone, dapson, clofazimin, topical antibiotics, bacitracin, tyrothricin, polymyxins, antivir, mucirin, kanamycin, , azidothymidine, didanosine, zalcitabine, thiacytidine, stavudine, ribavirin, idoxuridine, trifluridine, foscarnet, amantadine, interferons, tibol derivatives, proteinase inhibitors, antifungals, polyenes, amphothericin B, nystatin, natamycin, septic acid, azoles, azoles, azoles, azoles, azoles, azoles ketoconazole, itraconazole, fluconazole, UK-109.496, topical azoles, clotrimazole, econazole, isoconazole, oxiconazole, bifonazole, flucytosine, griseofulvin, ciclopiroxolamine, tolnaftate, naftifine, terbinafine, amorolfine, anthraquinones, xanthoquinones, xanthoquinones, xanthazinones, xanthoquinones, arylaminoalcohols, quinine, quinidine, mefloquine, halofantrine, chloroquine, amodiaquine, acridine , benzonaphthyridine, mepacrine, pyronaridine, dapson, sulfonamides, sulfadoxin, sulfalene, trimethoprim, proguanil, chloroproguanil, diaminopyrimidines, pyrimethamine, primaquine, aminoquinolines, WR 238,605, tetracycline, doxycycline, corfinloxine, clindamloxine, clindamloxine, clindamloxine , arteether, 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 atrtesunat, atovaquon, suramine, melarsoprol, nifurtmox, sodium stibogluconate, pentamidine, amphotericin B, metronidazole, clioquinol, mebendazole, niclosamide, praziquantel, pyrante, thiabendazole, diethylcarbamazine, ivermectin, bithionol, oxamnichine, metrifonate, piperazine, embonate. Use of the phosphororganic compounds according to any one of claims 1 to 8 for the manufacture of medicaments for human and animal in the treatment of infectious processes caused by viruses, bacteria, fungi or parasites and as fungicides, bactericides or herbicides in plants. Use according to claim 13 for the manufacture of medicaments for the treatment of infections caused by bacteria, viruses, fungi or unicellular or multicellular parasites. Use according to claim 13 for the manufacture of medicaments for the treatment of infections caused by bacteria selected from the group consisting of bacteria of the family Propionibacteriaceae, in particular of the genus Propionibacterium, in particular of the species Propionibacterium acnes, bacteria of the family Actinomycetaceae, in particular of the genus Actinomyces. Corynebacterium in particular Corynebacterium diphteriae and Corynebacterium pseudotuberculosis, Mycobacteriaceae, Mycobacterium in particular, Mycobacterium tuberculosis, Lc. Erysipelthrix rhusiopathiae, Clostridium, Yersinia, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia entrocolitica and Yersinia ruckeri, Mycoplasmata ceae, Mycoplasma and Ureoplasma spp., in particular Mycoplasma pneumoniae, Brucella spp., Bordetella spp., Neisseriaceae spp., especially Neisseria and Moraxela spp. , Plesiomonas and Photobacterium, in particular Vibrio cholerae, Vibrio anguillarum and Aeromonas salmonicidas, Campylobacter species, in particular Campylobacter jejuni species, Campylobacter coli and Campylobacter fetus, Helicobacter species, in particular Helicobacter pylori species, • · ··· · »» »· Bacteria of the family Spirochaetaceae and Leptospiraceae, in particular of the genera Treponema, Borrelia and Leptospira, in particular Borrelia burgdorferi, bacteria of the genus Actinobacillus, bacteria of the family Legionellaceae, genus Legionella, bacteria of the family Rickettsiaceae and genus Derecia, matophilus, bacteria of the family Pseudomonadaceae, in particular the genera Pseudomonas and Xanthomonas, bacteria of the family Enterobacteriaceae, in particular the genera Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia and Shigella; Streptococcaceae, especially Streptococcus and Enterococcus; and Bacillaceae, especially Bacillus and Clostridium, and in eradication therapy of gastric ulcers. Use according to claim 13 for the manufacture of medicaments for the treatment of infections caused by viruses selected from the group consisting of Parvoviridae, in particular parvoviruses, dependoviruses, densoviruses, Adenoviridae viruses, in particular adenoviruses, mastadenoviruses, aviadenoviruses, Papovaviridae viruses. especially papovaviruses, especially papillomaviruses (so-called wart viruses), polyomaviruses, in particular JC-virus, BK-virus and miopapovaviruses, viruses of the genus Herpesviridae, in particular Herpes-simplex-viruses, varicela / zoster-viruses, human cytomegalovirus, Epstein-Barr viruses , human herpesvirus 6, human herpesvirus 7, human herpesvirus 8, Poxviridae viruses, especially smallpox viruses, orthopox-, parapox-, molluscum-contagiosum-virus, aviviruses, capriviruses, leporipoxviruses, primary hepatotropic viruses such as hepatitis-virus, especially hepatitis virus viruses, hepatitis-B-viruses, hepatitis-C-viruses, hepatitis-D-viruses, hepatitis-E-viruses, hepatitis-F-viruses, hepatitis-G-viruses, hepadnaviruses, especially all hep atitisviruses, Hepatitis-B-virus, Hepatitis-D-viruses, Picornaviridae viruses, especially picornaviruses, all enteroviruses, all polioviruses, all coxsackieviruses, all echoviruses, all rhinoviruses, Hepatitis-A-virus, aftoviruses, Calciviridae viruses, especially hepatitis -E-viruses, viruses of the genus Reoviridae, in particular reoviruses, orbiviruses, rotaviruses, viruses of the genus Togaviridae, especially togaviruses, alphaviruses, rubiviruses, pestiviruses, Rubellavirus, viruses of the genus Flaviridae, especially flaviviruses, FSME-virus, Hepatitis-C-virus, viruses Orthomyxoviridae, in particular influenza viruses, Paramyxoviridae viruses, in particular paramyxoviruses, Morbillivirus, Pneumovirus, Masernvirus, Mumpsvirus, Rhabdoviridae viruses, in particular rhabdoviruses, rabiesvirus, lyssaviruses, viscous stomatitisoniruses, roduviruses, in particular, roduviruses, corviruses, in particular roduviruses; · 4 · · ♦ 4 4 4 4 ♦ 4 · 4 4 4 · 4 · »9 9 ΛΛ · 45 »··· 4» Bun / 4 4 * 4 4 V 44 * 4 »4 bunyaviruses, nairovirus, flebovirus, uukuvirus, hantavirus, hantaanvirus, Arenaviridae viruses, especially arenaviruses, lymphocytic choriomeningitis virus, Retroviridae viruses, especially retroviruses, all HTL-viruses, human T-cell leukemia virus, oncornaviruses, spumaviruses, lentiviruses, all H1 viruses, Filoviridae viruses, in particular Marburg and Ebola viruses, slow viruses, prions, onkoviruses and leukemia viruses. Use according to claim 13 for the manufacture of medicaments for the prophylaxis and treatment of infections caused by unicellular parasites, namely malaria agents, sleeping sickness, Chagas' disease, toxoplasmosis, amoebic dysentery, leishmaniosis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidosis, acarcantebosis, sarcocystebosis. giardiosis and lamblioses.