CA2356289A1 - Organophosphorous compounds and use thereof - Google Patents

Organophosphorous compounds and use thereof Download PDF

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CA2356289A1
CA2356289A1 CA002356289A CA2356289A CA2356289A1 CA 2356289 A1 CA2356289 A1 CA 2356289A1 CA 002356289 A CA002356289 A CA 002356289A CA 2356289 A CA2356289 A CA 2356289A CA 2356289 A1 CA2356289 A1 CA 2356289A1
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substituted
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unsubstituted
alkyl
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Hassan Jomaa
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Bioagency AG
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Jomaa Pharmaka Gmbh
Hassan Jomaa
Bioagency Ag
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/62—Isoquinoline or hydrogenated isoquinoline ring systems
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
    • A01N57/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds
    • A01N57/24—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds containing heterocyclic radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/5537—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom the heteroring containing the structure -C(=O)-N-C(=O)- (both carbon atoms belong to the heteroring)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
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    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

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Abstract

The invention relates to organo-phosphorus compounds of formula (I), wherein A
is selected from the group consisting of a (C1-9) alkylene radical, -C-O-C-and -C-N-C- or A corresponds to formula (II), wherein one or more carbon atoms selected from the group consisting of C3, C4, C5 and their substituents can also be absent and at least one of the substituents of B1 to B10 is a C3-8-cycloalkyl-(C0-9)-alkyl group in which R1 is selected from the group consisting of five and six membered heterocycles having at least one nitrogen atom in the ring or polycyclic carbon atoms containing one of said heterocycles, wherein at least one of said nitrogen atoms belongs to a hydroxamic acid group or a hydroxamic acid ester group. The invention also relates to the utilization of the above-mentioned compounds in the therapeutic and prophylactic treatment of infections in human beings and animals caused by virus, bacteria, fungi and parasites and as fungicides, bactericides and herbicides in plants.

Description

WO 00/37477 Amendments PCT/EP99/10274 Organophosphorus compounds and use thereof This invention relates to organophosphorus compounds, to the salts, esters and amides thereof and to the use thereof for the therapeutic and prophylactic treatment of infections in humans and animals which are caused by viruses, bacteria, fungi and parasites, to the use thereof as a fungicide, bactericide and herbicide in plants. According to the invention, the organophosphorus compounds comprise phosphinoyl derivatives, phosphinic acid derivatives and phosphonic acid derivatives.
3-Hydroxy-2-oxo-4-dimethylphosphono- and 3-hydroxy-2-oxo-4-diphenylphosphinyl-1,2-dihydroquinolines and the production thereof are described in Tetrahedron Letters, no. 38, 1972, pages 3979-3982.
N-Substituted alkylaminophosphates are described in Chemical Abstracts, vol.
093, no. 19, 10''' November 1989 and Curr. Chemother. Infect. Dis. Proc. Int. Congr.
Chemother., 11 ~';
1980; vol. 1; pages 355-8, in Chemical Abstracts, vol. 105, no. 19, 10'h November 1986 and JP 61 106504 A, in US-A-4206 156, in US-A-4 693 742 and in WO 99 525 15 A.
These compounds are described as suitable for the treatment of bacterial infections.

A furthermore describes the use thereof in viral, fungicidal and parasitic infections.
In order to widen the range of options for treating humans and animals, there is an urgent requirement to provide agents which are not only highly active but, unlike other pharmaceutical preparations, also exhibit reduced side-effects and thus constitute a reduced risk to human health.
The object of the present invention is accordingly to provide a substance which is universally usable in infections by viruses, bacteria, fungi and parasites in humans and animals and which meets the above-stated requirements.
This object is utterly surprisingly achieved by the group of substances defined in claim 1. This group of substances exhibits antiinfective action against viruses, bacteria, fungi and uni- and multicellular parasites. Fungicidal, bactericidal and herbicidal action has also been observed in plants.

WO 00/37477 Amendments PCT/EP99/10274 - la-The organophosphorus compounds according to the invention are of the general formula (I):
O
I I
R1_A_P_R3 C I ) I

wherein A is selected from the group which consists of a (C1_9) alkylene residue, which may comprise one or more double bonds and may be substituted with hydroxy, halogen, amino, oxo groups with branched or unbranched C1_9 alkyl groups and CZ_9 alkenyl groups, wherein the C1_9 alkyl groups and CZ_9 alkenyl groups may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups, -C-O-C- and -C-N-C-, wherein the carbon atoms of -C-O-C-and -C-N-C- may be substituted with an alkyl having up to 7 carbon atoms or hydroxy groups, or in which A is of the following formula (II):
-2-_~ 1_ ~2_ ~3_~ 4_~ 5_ (II) wherein one or more of the carbon atoms selected from the group C3, C4, C;, together with their substituents, may also be absent, and at least one substituent present in the range from B1 to Blo is a C3_g-cycloalkyl-(Co_9)-alkyl group, wherein both the C3_8 cycloalkyl group and the Co_9 alkyl group may comprise one or more double bonds and one or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur atoms, and wherein both the cycloalkyl group and the alkyl group may be substituted with hydroxy, halogen, amino, oxo groups with branched or unbranched C1_9 alkyl groups and Cz_9 alkenyl groups, wherein the C1_9 alkyl groups and Cz_9 alkenyl groups may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups, and the remaining substituents B 1 to B to present are selected from the group which consists of hydrogen, hydroxy, halogen, amino groups, C1_zb alkyl residues, C,_zb alkoxy residues, C1_z6-alkoxy-C1_z6-alkyl residues or both substituents of a C atom together form an oxo group, wherein each C1_z6 alkyl residue and each Cl_z6 alkoxy residue may be branched or unbranched and be saturated or unsaturated with one or more double bonds and may be substituted with hydroxy, amino, halogen and oxo groups, in which R1 is selected from the group which consists of 5- and 6-membered heterocycles with at least one ring nitrogen atom or a polycyclic carbon with at least one of these heterocycles, wherein at least one of these nitrogen atoms belongs to a hydroxamic acid group or a hydroxamic acid ester group, and may be saturated or unsaturated with one or more double or triple bonds and may thus also be aromatic and may be substituted with hydroxy, halogen, amino, oxo groups and with branched or unbranched C1_9 alkyl groups and Cz_9 alkenyl groups, wherein the CI_9 alkyl groups and Cz_9 alkenyl groups may be saturated or unsaturated with one or more double or triple bonds and may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups, wherein the nitrogen atom of the hydroxamic acid group or hydroxamic acid ester group is substituted with OR; and R; is selected from the group which consists of hydrogen, substituted and unsubstituted C1_9 alkyl, substituted and unsubstituted hydroxy-C1_9-alkyl, substituted and unsubstituted C1_9 alkenyl, substituted and unsubstituted C1_9 alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic residue, in which R3 and R4 are identical or different and are selected from the group which consists of hydrogen, substituted and unsubstituted Gl_z6 alkyl, hydroxy-C1_z6-alkyl, substituted and
-3-unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C,_26 alkenyl, substituted and unsubstituted C1_Z6 alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic residue, halogen, OX3 and OXq, wherein X3 and X4 are identical or different and are selected from the group which consists of hydrogen, substituted and unsubstituted CI_26 alkyl, substituted and unsubstituted hydroxy-C1_ 26-alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted Ci_z6 alkenyl, substituted and unsubstituted Cl_26 alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic residue, a silyl, a cation of an organic and inorganic base, in particular a metal of main groups I, II or III of the periodic system, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids, and the pharmaceutically acceptable salts, esters and amides thereof and salts of the esters.
If two or more heteroatoms are present in the heterocycle R1, oxygen and sulfur atoms may be present.
The organophosphorus compounds are preferably of the formula (III) I I
R1-A-P-R3 ( I I I ) I
0Xq wherein R3 is preferably hydrogen, methyl, ethyl, an amide residue or OX3 and X4 is selected from the group which consists of hydrogen, sodium, potassium, methyl, ethyl, wherein X3 is defined as above and particularly preferably of the formula (IV) Ii R1-A-P-OX3 (IV) I
0Xq WO 00/37477 Amendments PCT/EP99/10274
-4-wherein X3 and X4 are identical or different and are selected from the group which consists of hydrogen, a (C1_3) alkyl, a metal of main groups I, II or III of the periodic system, ammonium, substituted ammonium, or ammonium compounds derived from ethylenediamine or amino acids.
X3 and X4 are preferably a metal of main groups I, II or III of the periodic system, ammonium, substituted ammonium or ammonium compounds derived from ethylenediamine or amino acids. In other words, the salt compounds of the organophosphorus compounds are formed with organic or inorganic bases (for example sodium salt, potassium salt, calcium salt, aluminium salt, ammonium salt, magnesium salt, triethylamine salt, ethanolamine salt, dicyclohexylamine salt, ethylenediamine salt. N,N'-dibenzylethylenediamine salts) as well as salts with amino acids (for example arginine salt, aspartic acid salt, glutamic acid salt etc.) and the like.
X3 and X4 are particularly preferably identical or different and are selected from the group which consists of hydrogen, sodium, potassium, methyl, ethyl.
A is preferably selected such that a three-membered linking chain is formed between the phosphorus atom and the nitrogen atom of the heterocycle. A is for example advantageously a methylene, hydroxymethylene, ethylene, ethenylene, hydroxyethylene and may in particular also be substituted with an oxo group.
The carbon chain of A with the formula (II) preferably also links, together with the atoms of the heterocycle, the nitrogen and phosphorus atom via three atoms. If the carbon atom arranged in a position relative to the nitrogen or phosphorus atom is substituted with an oxo group in the linking chain, linking chains having four carbon atoms are also preferred. If both an oxo group is in a position relative to the nitrogen atom and another oxo group is in a position relative to the phosphorus atom in this linking chain, a linking chain with five carbon atoms is also preferred. If the carbon atom arranged in a position relative to the phosphorus atom is substituted with a hydroxy group, linking chains having four carbon atoms are preferred. In this case, methylene groups are also preferred for R3 and R4.
Very particularly preferred groups of compounds are listed below:
-5-O/ Rs ~ Rs ~ Rs I ~ I

s A-P032- A-P03z-I II III
~ Rs ~ Rs / Rs O O
O N O N A-P03z- O N
A-P03z- A-P03a-IV V VI
~ Rs O/ Rs ~ Rs I I O
I
p N A-P032- O N O N
A-P03z- A-P03z VII VIII IX
~ Rs ~ Rs O O
I I
O N O O N O
A-PO32- A-P03z_ X XI
-6-A-P03z-A-PO3z.
O N O N ~ A_P03z- O N J
I
Ow Ow Oo Rs Rs ORs XII XIII
XIV
A-PO z- , A-P032-J~ J
p N O N A_pp3z- O N
O O~ O
\Rs Rs Rs XV XVI XVII
A-P032- A-PO z_ O N O N A_P03z_ O N ~ I
O
O ERs Rs \Rs XIX XX
XVIII
A-P03z-A-PO z-\ ~ A-Pp3z- \
O~ N p N O N
t I
O
\Rs p \Rs O \Rs X~ XXII XXIII
7 PCT/EP99/10274 A-PO a_ / / / , A-P032-I I
O \Rs O \Rs O Rs XXIV XXV XXVI

/ /
O N O N A_p032-t t O \Rs O \Rs XXVII XXVIII
A-P03z-A-PO z.
~ A-P03z-O N O N J O N
O
O \Rs \Rs O \Rs XXIX ~ XXXI

_g_ N - OH N - OH
A ~ A i ~XB XXXIB
N - ORs N - ORs A A PO32 ~V
mcxxt v O O
/ ORs , ORs J N

A-P03z- ' ~ A-P032- ..
XXXVI XXXVII
ORs I
'N

N
s A-YU3= O
XXXVIII

_g_ and the corresponding phosphinic acid and phosphinoyl derivatives.
Special features of the above definitions and suitable examples thereof are given below:
"Acyl" is a substituent which originates from an acid, such as from an organic carboxylic acid, carbonic acid, carbamic acid or the thio acid or imidic acid corresponding to the above individual acids, or from an organic sulfonic acid, wherein these acids in each case comprise aliphatic, aromatic and/or heterocyclic groups in the molecule together with carbamoyl or carbamimidoyl.
Suitable examples of these acyl groups are given below.
Aliphatic acyl groups are defined as acyl residues originating from an aliphatic acid and include the following:
alkanoyl (for example formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl etc.); alkenoyl (for example acryloyl, methacryloyl, crotonoyl etc.);
alkylthioalkanoyl (for example methylthioacetyl, ethylthioacetyl etc.);
alkanesulfonyl (for example mesyl, ethanesulfonyl, propanesulfonyl etc.); alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl etc.); alkylcarbamoyl (for example methylcarbamoyl etc.); (N-alkyl)thiocarbamoyl (for example (N-methyl)thiocarbamoyl etc.);
alkylcarbamimidoyl (for example methylcarbamimidoyl etc.); oxalo; alkoxalyl (for example methoxalyl, ethoxalyl, propoxalyl etc.).
In the above examples of aliphatic acyl groups, the aliphatic hydrocarbon moiety, in particular the alkyl group or alkane residue, may optionally have one or more suitable substituents, such as amino, halogen (for example fluorine, chlorine, bromine etc.), hydroxy, hydroxyimino, carboxy, alkoxy (for example methoxy, ethoxy, propoxy etc.), alkoxycarbonyl, acylamino (for example benzyloxycarbonylamino etc.), acyloxy (for example acetoxy, benzoyloxy etc.) and the like; preferred aliphatic acyl residues with such substituents which may be mentioned are, for example, alkanoyls substituted with amino, carboxy, amino and carboxy, halogen, acylamino or the like.
Aromatic acyl residues are defined as those acyl residues which originate from an acid with a substituted or unsubstituted aryl group, wherein the aryl group may comprise phenyl, toluyl, xylyl, naphthyl and the like; suitable examples are stated below:
aroyl (for example benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl etc.);
aralkanoyl (for example phenylacetyl etc.); aralkenoyl (for example cinnamoyl etc.);
aryloxyalkanoyl (for example phenoxyacetyl etc.); arylthioalkanoyl (for example phenylthioacetyl etc.);

arylaminoalkanoyl (for example N-phenylglycyl, etc.); arenesulfonyl (for example benzenesulfonyl, tosyl or toluenesulfonyl, naphthalenesulfonyl etc.);
aryloxycarbonyl (for example phenoxycarbonyl, naphthyloxycarbonyl etc.); aralkoxycarbonyl (for example benzyloxycarbonyl etc.); arylcarbamoyl (for example phenylcarbamoyl, naphthylcarbamoyl etc.); arylglyoxyloyl (for example phenylglyoxyloyl etc.).
In the above-stated examples of aromatic acyl residues, the aromatic hydrocarbon moiety (in particular the aryl residue) and/or the aliphatic hydrocarbon moiety (in particular the alkane residue) may optionally have one or more suitable substituents, such as those which have already been stated as suitable substituents for the alkyl group or the alkane residue.
Examples of preferred aromatic acyl residues with specific substituents which may in particular be mentioned are aroyl substituted with halogen and hydroxy or with halogen and acyloxy, and aralkanoyl substituted with hydroxy, hydroxyimino, dihaloalkanoyloxyimino, together with arylthiocarbamoyl (for example phenylthiocarbamoyl etc.);
arylcarbamimidoyl (for example phenylcarbamimidoyl etc.).
A heterocyclic acyl residue is taken to mean an acyl residue which originates from an acid with a heterocyclic group; such residues include:
heterocyclic carbonyl, in which the heterocyclic residue is an aromatic or aliphatic 5- to 6-membered heterocycle with at least one heteroatom from the group nitrogen, oxygen and sulfur (for example thiophenyl, furoyl, pyrrolecarbonyl, nicotinyl etc.);
heterocycle-alkanoyl, in which the heterocyclic residue is 5- to 6-membered and comprises at least one heteroatom from the group nitrogen, oxygen and sulfur (for example thiophenylacetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl etc.) and the like.
In the above Examples of heterocyclic acyl residues, the heterocycle and/or the aliphatic hydrocarbon moiety may optionally comprise one or more suitable substituents, such as the same as were stated to be suitable for alkyl and alkane groups.
"Alkyl" is a linear or branched alkyl residue, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl and the like.
"Hydroxyalkyl" is a linear or branched alkyl residue which comprises at least one hydroxyl group, preferably one or two hydroxyl groups.

"Alkenyl" includes linear or branched alkenyl groups, such as for example vinyl, propenyl (for example 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl, hexenyl.
"Alkynyl" includes linear or branched alkynyl groups.
Cycloalkyl preferably.denotes an optionally substituted C3_8 cycloalkyl;
possible substituents are inter alia alkyl, alkenyl, alkynyl, alkoxy (for example methoxy, ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.), nitro and the like.
Aryl is an aromatic hydrocarbon residue, such as phenyl, naphthyl etc., which may optionally comprise one or more suitable substituents, such as alkyl, alkenyl, alkynyl, alkoxy (for example methoxy, ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.), nitro and the like.
"Aralkyl" includes mono-, di-, triphenylalkyls such as benzoyl, phenethyl, benzhydryl, trityl and the like, wherein the aromatic moiety may optionally comprise one or more suitable substituents, such as alkoxy (for example methoxy, ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.), nitro and the like.
The residues X3 and X4 may preferably be selected such that esters are formed on the phosphino group or phosphono group. Suitable examples of such esters according to the formulae (I), (III) and (IV) include suitable mono- and diesters, and preferred examples of such esters include alkyl esters (for example hexadecanyl ester, octadecanyl ester etc.);
aralkyl esters (benzyl ester, phenethyl ester, benzhydryl ester, trityl ester etc.); aryl esters (for example phenyl ester, tolyl ester, naphthyl ester etc.); aroylalkyl esters (for example phenacyl ester etc.); and silyl esters (for example of trialkylhalosilyl, dialkyldihalosilyl, alkyltrihalosilyl, dialkylarylhalosilyl, trialkoxyhalosilyl, dialkylaralkylhalosilyl, dialkoxydihalosilyl, trialkoxyhalosilyl etc.) and the like.
In the above esters, the alkane and/or arene moiety may optionally comprise at least one suitable substituent, such as halogen, alkoxy, hydroxy, nitro or the like.
The compounds used according to the invention according to the formulae (I), (III) and (IV) may be present in the protonated form thereof 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, malefic acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid etc..

The compounds used according to the invention of the formulae (I), (III) and (IV) permit, for example for groups Rl, R3, R4, X3, X4 or A which contain double bonds or are chiral, the occurrence of steric isomers. The use according to the invention of the compounds includes all steric isomers, both as pure substances and in the form of mixtures.
The organophosphorus compounds are suitable for the therapeutic and prophylactic treatment of infections in humans and animals caused by viruses, bacteria, uni- and multicellular parasites and fungi.
The compounds are active against unicellular parasites (protozoa), in particular against the causative organisms of malaria and sleeping sickness and of Chagas' disease, toxoplasmosis, amoebic dysentery, leishmaniases, trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiosis, sarcocytosis, acanthamoebosis, naeglerosis, coccidiosis, giardiasis and lambliasis.
They are accordingly in particular suitable for the prophylactic treatment of malaria and of sleeping sickness and of Chagas' disease, of toxoplasmosis, amoebic dysentery, leishmaniases, trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiosis, sarcocytosis, acanthamoebosis, naeglerosis, coccidiosis, giardiasis and lambliasis.
The active substances according to the invention may in particular be used against the following bacteria:
bacteria of the family Propionibacteriaceae, in particular of the genus Propionibacterium, in particular the species Propionibacterium acnes, bacteria of the family Actinomycetaceae, in particular of the genus Actinomyces, bacteria of the genus Cornynebacterium, in particular the species Corynebacterium diphtheriae and Corynebacterium pseudotuberculosis, bacteria of the family Mycobacteriaceae, of the genus Mycobacterium, in particular the species Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium, bacteria of the family Chlamydiaceae, in particular the species Chlamydia trachomatis and Chlamydia psittaci, bacteria of the genus Listeria, in particular the species Listeria monocytogenes, bacteria of the species Erysipelthrix rhusiopathiae, bacteria of the genus Clostridium, bacteria of the genus Yersinia, the species Yersinia pestis, Yersinia pseudotuberculosis, Yersinia enterocolitica and Yersinia ruckeri, bacteria of the family Mycoplasmataceae, of the genera Mycoplasma and Ureaplasma, in particular the species Mycoplasma pneumoniae, bacteria of the genus Brucella, bacteria of the genus Bordetella, bacteria of the family Neisseriaceae, in particular of the genera Neisseria and Moraxella, in particular the species Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis, bacteria of the family Vibrionaceae, in particular of the genera Vibrio, Aeromonas, Plesiomonas and Photobacterium, in particular the species Vibrio cholerae, Vibrio anguillarum and Aeromonas salmonicidas, bacteria of the genus Campylobacter, in particular the species Campylobacter jejuni, Campylobacter coli and Campylobacter fetus, bacteria of the genus Helicobacter, in particular the species Helicobacter pylori, bacteria of the families 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, 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, in particular of the genera Pseudomonas and Xanthomonas, bacteria of the family Enterobacteriaceae, in particular of 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, bacteria of the family Streptococcaceae, in particular of the genera Streptococcus and Enterococcus and bacteria of the family Bacillaceae, in particular of the genera Bacillus and Clostridium.
The organophosphorus compounds and the derivatives thereof are consequently suitable for treating diphtheria, acne vulgaris, listerioses, swine erysipelas in animals, gas gangrene in humans and animals, malignant oedema in humans and animals, tuberculosis in humans and animals, leprosy and further mycobacterioses in humans and animals, paratuberculosis in animals, plague, mesenterial lymphadenitis and pseudotuberculosis in humans and animals, cholera, legionnaires' disease, borreliosis in humans and animals, leptospiroses in humans and animals, syphilis, Campylobacter enteritis infections in humans and animals, Moraxella keratoconjunctivitis and serositis in animals, brucellosis of animals and humans, anthrax in humans and animals, actinomycosis in humans and animals, streptotrichoses, psittacosis/ortnithosis in animals, Q fever, ehrlichiosis.
Use is furthermore in particular preferred in the eradication of Helicobacter in ulcers of the gastrointestinal tract.
Combinations with another antibiotic may also be used to treat the above-stated diseases.
Isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, protionamide and dapsone are in particular suitable for combination preparations with other antiinfective agents for the treatment of tuberculosis.
The active substances according to the invention are furthermore in particular usable in infections with the following viruses:

Paxvoviridae: parvoviruses, dependoviruses, densoviruses, Adenoviridae:
adenoviruses, mastadenoviruses, aviadenoviruses, Papovaviridae: papovaviruses, in particular papillomaviruses ("wart" viruses), polyomaviruses, in particular JC virus, BK
virus and miopapovaviruses, Herpesviridae: all herpesviruses, in particular herpes simplex viruses, varicella-zoster viruses, human cytomegalovirus, Epstein-Barr viruses, all human herpesviruses, human herpesvirus 6, human herpesvirus 7, human herpesvirus 8, Poxiviridae: poxviruses, orthopoxviruses, parapoxviruses, molluscum contagiosum virus, aviviruses, capriviruses, leporipoxviruses, all primarily hepatotropic viruses, hepatitisviruses: 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 virus, hepatitis D
viruses, Picornaviridae: picornaviruses, all enteroviruses, all polioviruses, all coxsackie-viruses, all echoviruses, all rhinoviruses, hepatitis A virus, aphthoviruses, Calciviridae:
hepatitis E
viruses, Reoviridae: reoviruses, orbiviruses, rotaviruses, Togaviridae:
togaviruses, alphaviruses, rubiviruses, pestiviruses, rubellavirus, Flaviviridae:
flaviviruses, FSME virus, hepatitis C virus, Orthomyxoviridae: all influenza viruses, Paramyxoviridae:
paramyxoviruses, morbillivirus, pneumovirus, measles virus, mumps virus, Rhabdoviridae:
rhabdoviruses, rabies virus, lyssavirus, vascular stomatitisvirus, Coronaviridae: coronaviruses, Bunyaviridae: bunyaviruses, nairovirus, phlebovirus, uukuvirus, hantavirus, hantaan virus, Arenaviridae: arenaviruses, lymphocytic choriomeningitis virus, Retroviridae:
retroviruses, all HTL viruses, human T-cell leukaemia virus, oncornaviruses, spumaviruses, lentiviruses, all HI viruses, Filoviridae: Marburg and Ebola virus, slow-virus infections, prions, oncoviruses and leukaemia viruses.
The organophosphorus compounds used according to the invention are consequently suitable for combating the following viral infections:
eradication of papillomaviruses to prevent tumours, in particular tumours of the reproductive organs caused by papillomaviruses in humans, eradication of JC viruses and BK
viruses, eradication of herpesviruses, eradication of human herpesvirus 8 to treat Kaposi's sarcoma, eradication of cytomegaloviruses before transplantations, eradication of Epstein-Barr viruses before transplantation and to prevent tumours associated with Epstein-Barr viruses, eradication of hepatitis viruses to treat chronic liver disease and to prevent liver tumours and cirrhosis of the liver, eradication of coxsackie-viruses in cardiomyopathy, eradication of coxsackie-viruses in diabetes mellitus patients, eradication of immunodeficiency viruses in humans and animals, treatment of accompanying infections in AIDS patients, treatment of respiratory tract inflammation of viral causation (laryngeal papilloma, hyperplasia, rhinitis, pharyngitis, bronchitis, pneumonia), of the sensory organs (keratoconjunctivitis), of the nervous system (poliomyelitis, meningoencephalitis, encephalitis, subacute sclerosing panencephalitis, SSPE, progressive multifocal leukoencephalopathy, lymphocytic choriomeningitis), of the gastrointestinal tract (stomatitis, gingivostomatitis, oesophagitis, gastritis, gastroenteritis, diarrhoea), of the liver and gall system (hepatitis, cholangitis, hepatocellular carcinoma), of the lymphatic tissue (mononucleosis, lymphadenitis), of the haemopoietic system, of the reproductive organs (mumps orchitis), of the skin (warts, dermatitis, herpes labialis, herpes febrilis, herpes zoster, shingles), of the mucous membranes (papillomas, conjunctiva) papillomas, hyperplasia, dysplasia), of the cardiovascular system (arteriitis, myocarditis, endocarditis, pericarditis), of the kidney/urinary system, of the reproductive organs (anogenital lesions, warts, genital warts, sharp condylomas, dysplasia, papillomas, cervical dysplasia, condyloma acuminatum, epidermodysplasia verruciformis), of the locomotory organs (myositis, myalgia), treatment of foot-and-mouth disease in cloven-hoofed animals, of Colorado tick fever, Dengue syndrome, of haemorrhagic fever, of early summer meningoencephalitis (FSME) and of yellow fever.
The described compounds, i.e. the organophosphorus compounds of the formulae (I), (III) and (IV) and esters and amides thereof on the phosphino group and salts thereof exhibit strong cytotoxic activity against uni- and multicellular parasites, in particular against the causative organisms of malaria and sleeping sickness. The compounds according to the invention are accordingly usable for the treatment of infective diseases which are caused in humans and animals by viruses, bacteria, parasites and fungi. The compounds are also suitable for the prevention of diseases which are caused by viruses, bacteria, parasites and fungi, in particular for the prophylactic treatment of malaria and of sleeping sickness.
The organophosphorus compounds used according to the invention, which generally include for this purpose pharmaceutically acceptable salts, amides, esters, a salt of such an ester or also compounds which, on administration, provide the compounds used according to the invention as metabolites or breakdown products (also known as "prodrugs"), may be formulated for administration in any suitable manner analogous to known agents having an antiinfective action (mixed with a non-toxic, pharmaceutically acceptable excipient).
Pharmaceutically acceptable salts of the compounds include salts which the compounds of the formulae (I), (III) and (IV) according to the invention form in their protonated form as an ammonium salt of inorganic or organic acids, such as hydrochloric acid, sulfuric acid, citric acid, malefic acid, fiunaric acid, tartaric acid, p-toluenesulfonic acid.
Particularly pharmaceutically suitable salts are also those formed by suitable selection of X3 and X4, 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 determined using a test system. This system is based upon in vitro measurement of the inhibition of growth of bacteria, parasites, viruses, fungi or plants.
Test methods known to the person skilled in the art are in part used for this purpose.
For example, antimalarial activity is determined by measuring the inhibition of the growth of malaria parasites in blood cultures.
Antibacterial activity is determined on the basis of measuring the inhibition of bacterial growth on nutrient media and in liquid cultures.
Antiviral activity is determined on the basis of the formation of viral elements in cell cultures.
Fungicidal activity is determined on the basis of inhibition of fungal growth on nutrient media and in liquid cultures.
Some of the microorganisms which are to be investigated may only be investigated in animal models. In this case, the appropriate models will then be used.
Substances which exhibit activity in in vitro measurement systems are then further investigated in in vivo models. Antiparasitic, antiviral, fungicidal or antibacterial activity is further evaluated in the appropriate animal models.
Screening for herbicidal activity is determined by means of algal systems and measurement of isoprene emissions from plants under standard conditions.
The pharmaceutically active agents may be prepared in dosage units in the form of pharmaceutical preparations. This means that the preparation is in the form of individual components, for example tablets, coated tablets, capsules, pills, suppositories and ampoules, the active substance content of which corresponds to a fraction or multiple of an individual dose. The dosage units may contain, for example 1, 2, 3 or 4 individual doses or 1/2, 1/3 or 1/4 of an individual dose. An individual dose preferably contains the quantity of active substance which is administered at one time and usually corresponds to a whole, half, third or quarter of a daily dose.

Non-toxic, inert, pharmaceutically suitable excipients should be taken to mean solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.
Preferred pharmaceutical preparations which may be mentioned are tablets, coated tablets, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays. Tablets, coated tablets;
capsules, pills and granules may contain the active substances together with conventional excipients, such as (a) fillers and extenders, for example starches, lactose, cane sugar, glucose, mannitol and silica, (b) binders, for example carboxymethylcellulose, alginates, gelatine, polyvinylpyrrolidone, (c) humectants, for example glycerol, (d) suspending agents, for example agar-agar, calcium carbonate and sodium carbonate, (e) dissolution retardants, for example paraffin and (f) resorption accelerators, for example quaternary ammonium compounds, (g) wetting agents, for example cetyl alcohol, glycerol monostearate, (h) adsorbents, for example kaolin and bentonite and (i) lubricants, for example talcum, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances stated in (a) to (i).
The tablets, coated tablets, capsules, pills and granules may be provided with conventional coatings and shells optionally containing opacifying agents and may also be composed such that they release the active substances only with a delay or preferably in a particular part of the intestinal tract, wherein polymeric substances and waxes may, for example, be used as the matrices.
The active substance or substances, optionally together with one or more of the above-stated excipients, may also be present in microencapsulated form.
In addition to the active substance or substances, suppositories may contain conventional water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cocoa butter and higher esters (for example C 14 alcohol with C 16 fatty acid) or mixtures of these substances.
In addition to the active substance or substances, ointments, pastes, creams and gels may contain conventional excipients, for example animal and vegetable fats, waxes, paraffins, starch, gum tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talcum and zinc oxide or mixtures of these substances.
In addition to the active substance or substances, powders and sprays may contain conventional excipients, for example lactose, talcum, silica, aluminium hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays may additionally contain conventional propellants, for example chlorofluorocarbons.
In addition to the active substance or substances, solutions and emulsions may contain conventional excipients, such as solvents, solubilising agents 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, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters or mixtures of these substances.
For paxenteral administration, the solutions and emulsions may also be present in sterile, isotonic form.
In addition to the active substance or substances, suspensions may contain conventional excipients, such as liquid diluents, for example water, ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and gum tragacanth or mixtures of these substances.
The stated formulations may also contain colorants, preservatives and odour-or flavour-enhancing additives, for example peppermint oil and eucalyptus oil, and sweeteners, for example saccharin.
The active substances of the formulae (I), (III) and (IV) should preferably be present in the pharmaceutical preparations listed above in a concentration of approx. 0.1 to 99.5 wt.%, preferably from approx. 0.5 to 95 wt.%, of the complete mixture.
Apart from the compounds of the formulae (I), (III) and (IV), the pharmaceutical preparations may also contain further pharmaceutical active substances.
The compounds may be used together with hitherto described substances having antibacterial, antiviral, antimycotic and antiparasitic properties. Such substances in particular include compounds which have already been used in therapeutic applications or are still used.
Substances which are suitable for this purpose are in particular those listed in the Red List or in Simon/Stille, Antibiokia-Therapie in Klinik and Praxis, 9th edition, 1998, Schatauer Verlag, or on the Internet at htt~://www.customs treas gov/imn-exp/rulin~s/harmoniz/hrml29 html. The derivatives may in particular be present with penicillins, benzylpenicillin (penicillin G), phenoxypenicillins, isoxazolylpenicillins, aminopenicillins, ampicillin, amoxicillin, bacampicillin, carboxypenicillin, ticarcillin, temocillin, acylaminopenicillins, azlocillin, mezlocillin, piperacillin, apalcillin, mecillinam, cephalosporins, cefazolin group, cefuroxime group, cefoxitin group, cefoxitin, cefotetan, cefmetazole, latamoxef, flomoxef, cefotaxime group, cefozidime, ceftazidime group, ceftazidime, cefpirome, cefepime, conventional cephalosporins, cefsulodin, cefoperazone, oral cephalosporins of the cephalexin group, loracarbef, cefprozil, new broad-spectrum oral cephalosporins, cefixime, cefpodoxime-proxetil, cefuroxime-axetil, cefetamet, cefotiam-hexetil, cefdinir, ceftibuten, other 13-lactam antibiotics, carbapenem, imipenem/cilastatin, meropenem, biapenem, aztreonam,13-lactamase inhibitors, clavulanic acid/amoxicillin, clavulanic acid/ticarcillin, sulbactam/ampicillin, tazobactam/piperacillin, tetracyclines, oxytetracycline, rolitetracycline, doxycycline, minocycline, chloramphenicol, aminoglycosides, gentamicin, tobramycin, netilmicin, amikacin, spectinomycin, macrolides, erythromycin, clarithromycin, roxithromycin, azithromycin, dirithromycin, spiramycin, josamycin, lincosamides, clindamycin, fusidic acid, glycopeptide antibiotics, vancomycin, teicoplanin, pristinamycin derivatives, fosfomycin, antimicrobial 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, nitroimidazoles, antimycobacterial agents, isoniazid, rifampicin, rifabutin, ethambutol, pyrazinamide, streptomycin, capreomycin, prothionamide, terizidone, dapsone, clofazimine, topical antibiotics, bacitracin, tyrothricin, polymyxins, neomycin, kanamycin, paromomycin, mupirocin, antiviral agents, acyclovir, ganciclovir, azidothymidine, didanosine, zalcitabine, thiacytidine, stavudine, ribavirin, idoxuridine, trifluridine, foscarnet, amantadine, interferons, tibol derivatives, proteinase inhibitors, antimycotics, polyenes, amphotericin B, nystatin, natamycin, azoles, azoles for septic therapy, miconazole, ketoconazole, itraconazole, fluconazole, UK-109,496, azoles for topical use, clotrimazole, econazole, isoconazole, oxiconazole, bifonazole, flucytosine, griseofulvin, ciclopirox olamine, tolnafnate, naftifme, terbinafine, amorolfme, anthraquinones, betulinic acid, semianthraquinones, xanthones, naphthoquinones, arylamino alcohols, quinine, quinidines, mefloquine, halofantrine, chloroquine, amodiaquine, acridine, benzonaphthyridine, mepacrine, pyronaridine, dapsone, sulfonamides, sulfadoxine, sulfalenes, trimethoprim, proguanil, chlorproguanil, diaminopyrimidines, pyrimethamine, primaquine, aminoquinolines, WR 238,605, tetracycline, doxycycline, clindamycin, norfloxacin, ciprofloxacin, ofloxaein, artemisinin, dihydroartemisinin, lOb artemether, arteether, atresunate, atovaquone, suramin, melarsoprol, nifurtimox, stibogluconate sodium, pentamidine, amphotericin B, metronidazole, clioquinol, mebendazole, niclosamide, praziquantel, pyrantel, tiabendazole, diethylcarbamazine, ivermectin, bithionol, oxamniquine, metrifonate, piperazine, embonate.
The organophosphorus compounds may furthermore be present in the pharmaceutical preparations in combination with sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracyclines, doxycycline, proguanil, metronidazole, praziquantel, niclosamide, mebendazole, pyrantel, tiabendazole, diethylcarbazine, piperazine, pyrivinium, metrifonate, oxamniquine, bithionol or suramin or two or more of these substances.
The above-stated pharmaceutical preparations are produced in the conventional manner using known methods, for example by mixing the active substance or substances with the excipient or excipients.
The stated preparations maybe administered to humans and animals orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally, topically (powders, ointments, drops) and for the treatment of infections in cavities, body cavities. Suitable preparations which may be considered are solutions for injections, solutions and suspensions for oral therapy, gels, infusion formulations, emulsions, ointments or drops. Topical treatment may be performed using ophthalmological and dermatological formulations, silver and other salts, ear drops, eye ointments, powders or solutions. Administration to animals may also be achieved via the feed or drinking water in suitable formulations. Gels, pulverulent formulations, powders, tablets, controlled-release tablets, premixes, concentrates, granules, pellets, tablets, boli, capsules, aerosols, sprays, inhalation formulations may also be used in humans and animals. The compounds according to the invention may also be incorporated into other supports, such as for example plastics (plastic chains for topical treatment), collagen or bone cement.
It has in general proved advantageous in both human and veterinary medicine to administer the active substances of the formula (I), (III) and (IV) in total quantities of approx. 0.05 to approx. 600, preferably of 0.5 to 200 mg/kg body weight per 24 hours, optionally in the form of two or more individual doses in order to achieve the desired results. An individual dose preferably contains the active substance or substances in quantities of approx. 1 to approx.
200, in particular of 1 to 60 mg/kg body weight. It may, however, be necessary to deviate from the stated dosages, in particular as a function of the nature and body weight of the patient to be treated, the nature and severity of the disease, the nature of the preparations and the route of administration of the pharmaceutical preparation and the period of time over which administration is performed.

In some cases, it may accordingly be sufficient to use less than the above-stated quantity of active substance, while in other cases more than the above-stated quantity of active substance must be used. The person skilled in the art will use his/her skill to determine the optimum dosage and route of administration required in each particular case.
The compounds according to the invention may be given to animals in conventional concentrations and preparations together with feed or feed preparations or with drinking water.
The compounds according to the invention are furthermore ideally usable as bactericides, fungicides and herbicides in plants.
If the structure of the compound is known, it is generally possible for the person skilled in the art to develop a production process by analogy with known processes. The production of some compounds according to the invention is stated below by way of example:
Example 1' S-j2-lPhosnhono)ethyl)-N-hvdroxy~vrrolidin 2 one~ll N-Fluorenylmethoxycarbonyl-pvrrolidin-2-vl-methanol Vila A solution of 476 g (1.85 mol) of chloroformic acid 1-(9-fluorenylmethyl) ester (F-MOC) in 1 1 of dioxane is slowly added dropwise with ice cooling to a solution of 182 g (1.8 mol) of pyrrolidin-2-yl-methanol in 1200 ml of dioxane and 1800 ml of a 10% sodium carbonate solution. The mixture is stirred for 4 h at this temperature and for 8 h at room temperature, poured into 1.5 1 of ice water and extracted with diethyl ether. The ice-cooled aqueous phase is weakly acidified with dilute HCI, left to stand overnight at 0°C and the product la is then filtered with good purity and yield.
O-~Methanesulfon l~methyl)-N-fluorenvlmetho~carbon ~~1-~yrrolidine (lb) 470 g (1.4 mol) of la are redissolved in 300 ml of absolute pyridine and combined while cold with 400 g (3.5 mol) of methanesulfonyl chloride. The mixture is stirred under argon initially for 16 h at 0°C and then for a further 3 h at RT. Once the mixture has been poured onto ice, extraction is performed repeatedly with diethyl ether and the organic phase is washed in succession with ice-cold dilute HCI, NaHC03 and water. After drying over M,gS04 and evaporation, lb is obtained, which may be purified by recrystallisation from acetone/petroleum ether.

2-lIodomethvl)-N-fluorenylmethoxycarbon~l-pvrrolidine~l c~
3 equivalents (359.7 g) of NaI in acetone are added to a solution of 331 g (0.8 mol) of lb in acetone. After 12 hours' stirring at RT, the mixture is filtered, the filtrate added to 800 ml of water, which had been combined with sodium thiosulfate. After repeated extraction with diethyl ether, the extracts were combined, washed with water, dried over MgS04 and evaporated under reduced pressure. Leaving the mixture to stand at low temperature initially yields an oil, which may be recrystallised from petroleum ether.
2-f2-lDimethyl__phos~hono)eth~]-~yrrolidine (ld) 190 ml of a 1.6 M solution of n-butyllithium in hexane (corresponding to 0.30 mol) were added dropwise at -78°C under argon to 37.2 g (0.3 mol) of methanephosphonic acid dimethyl ester in 900 ml of dry THF. Stirring is continued for a further 15 minutes at this temperature to permit complete formation of the carbanion.
133.9 g (0.3 mol) of lc in 300 ml of dry THF were added dropwise to this solution at -78°C
with stirring. Once the temperature has risen to room temperature, stirnng is continued for a further 4 h. 85.15 g (1 mol) of piperidine is then added and the mixture stirred overnight. The mixture is filtered, the filtrate is poured into 21 of water, the organic phase separated and the aqueous phase extracted 4 times with 100 ml portions of dichloromethane. Once the combined organic phases have been dried over MgS04, the solvent is removed and the residue fractionally distilled under a vacuum. 2-[2-(Dimethylphosphono)ethyl]-pyrrolidine (ld) is obtained as a colourless oil at yields of 30-40%.
5-f2-(Dimethvlphosphono)ether]pvrrolidinone~le) A solution of 60 mmol of dimethyldioxirane in 120 ml of dry acetone is added dropwise to a solution, cooled to 0°C, of 3.32 g (15 mmol) of ld in 50 ml of dry acetone. The mixture is stirred for 30 min at 0°C and the solvent is then stripped out under a vacuum. The resultant crude product is recrystallised from isopropanol. 5-[2-(Dimethylphosphono)ethyl]pyrrolidinone (le) is obtained in moderate yield as colourless crystals.
Dimethyldioxirane is produced in accordance with a method in Org. Syntheses IX, 288.
5-f2-lPhosphonolethvl]-N-hvdrox~pvrrolidin-2-one (lf~
3.06 g (20 mmol) of trimethylbromosilane are added dropwise to a solution, cooled to 0°C, of 1.19 g (5 mmol) of le in 50 ml of dry acetonitrile. The mixture is stirred for 3 h at RT, then the solvent is stripped out under a vacuum, the residue is redissolved with 20 ml of ice water, the mixture is stirred for 1 h at room temperature, extracted twice with 20 ml portions of ether, a pH value of 4.5 is established with 2 M NaOH and the water is then stripped out in a Rotavapor rotary evaporator at a maximum of 50°C. The solid residue is crystallised from methanol/ethyl acetate. 5-[2-(Phosphono)ethyl]-N-hydroxy-pyrrolidin-2-one (lf7 is obtained in good yield in the form of yellowish microcrystals.
Examble 2: 3-(PhosnhonomethYl)-N-h~rdrox~pvrrolidin-2-one~21 3-Meth(2-trimethylsilvlethoxy)-pvrrolidin-2-one ~2a1 A solution of 120 mmol of sodium ethanolate in 50 ml of absolute ethanol is added dropwise at 0°C with exclusion of moisture to a solution of 20.37 g (120 mmol) of O-(2-trimethylsilyethyl)hydroxylamine hydrochloride in 100 ml of absolute ethanol.
Any precipitated NaCI is filtered out with an argon sintered glass filter. The ethanol is removed from the filtrate under reduced pressure and, once argon has been passed through the residue, the latter is redissolved with absolute toluene. 1 mol% of RhCl3*3 H20, 5 mol%
of DMAP
and, dropwise, 5.01 g (50 mmol) of 2-methylbutyrolactone are added thereto at 0°C. The mixture is allowed to thaw and is stirred overnight while being refluxed on the water separator. After cooling, volatile constituents are stripped out under a vacuum at 50°C in a Rotavapor rotary evaporator, a weakly yellow coloured oil being left behind.
Redissolution in 50 ml of ether, filtration through a short Si02 column and stripping of the solvent gives rise to 3-methyl-N-(2-trimethylsilylethoxy)-pyrrolidin-2-one (2a) in moderate yield as a virtually colourless oil, which is obtained in good purity.
3-Bromometh~N-(2-trimethvlsil lethoxy)~yrrolidin-2-one (2b) 50 mmol of 2a, dissolved in 30 ml of absolute carbon tetrachloride, are combined with 1.2 equivalents of N-bromosuccinimide and refluxed for 12 h. Small quantities of azobisisobutyronitrile (AIBN) are added at hourly intervals. After cooling, the product is filtered from succinimide, the latter is washed with CCl4 and the combined CC14 phases are evaporated under reduced pressure. The resultant oil may be chromatographed on Si02, 2b being obtained in poor yield.
3-(Diethvlnhosphonometh~l-N-f2-trimeth~vlethoxvl pyrrolidin 2 one l2cl 100 mmol (17.3 ml) of triethyl phosphite are combined with 100 mmol of 2b and heated to 150°C for 0.5 h without solvent. After cooling, the mixture is evaporated under reduced pressure and the yellowish brown oil is chromatographed on Si02 with chloroform/methanol in a 25:1 ratio. Once volatile constituents have been stripped out, 2c is obtained in moderate yield as a yellow oil.
3-(Phosphonomethvl~ N-~2-trimeth~i_l lethoxyl pvrrolidin 2 one~2d) 4 equivalents (120 mmol, 15.4 ml) of trimethylbromosilane are added dropwise with ice cooling to 30 mmol of 2c in 50 ml of absoluted acetonitrile, the mixture is stirred for 15 min at the same temperature, then for 2 h at RT, evaporated under reduced pressure until a yellowish oil is obtained, the product is redissolved in 100 ml of water and hydrolysed for 1 h at RT (pH less than 1 ). This solution is extracted twice with CHCl3, back-extracted once with water and the combined aqueous phases are evaporated under reduced pressure at 45°C. The resultant yellow-brown oil is redissolved in water and a pH of 4.5 to 5.0 is established. After washing with ice water, 2d is obtained as a virtually colourless sodium salt at a yield of 50%.
3-fPhosnhonometh~~hvdroxy-pvrrolidin-2-one (2e) 5.3 mmol of BF3 etherate are added to a solution of 2.65 mmol of 2d in absoluted acetonitrile and stirred for 0.5 h at room temperature. Once the solution has been evaporated under reduced pressure, it is redissolved in 40 ml of ethyl acetate, washed with 3%
common salt solution, dried over MgS04, filtered through a membrane filter and the solvent is stripped out under reduced pressure. The crude product may be recrystallised from MeOH/EtOH, the product being obtained in pure form and good yield.
Example 3: 4-lPhos~honomethyll-N-hvdrox~nvrrolidin-2-one (31 4-Methyl-2(5Hl-furanone ~3a1 g of 3-methylglutaric acid monoethyl ester and 31 g of lead tetraacetate dissolved in 400 ml of absolute CC14 are heated to boiling under argon. After 10 minutes' illumination by means of a tungsten daylight lamp, 23.1 g of iodine are added within 45 min while illumination is continued. After cooling, the mixture is filtered, the filtrate washed with aqueous sodium thiosulfate solution, soda solution and water, dried over MgS04 and evaporated under reduced pressure. The gamma-iodine ester 3a' is obtained as a oil which may be further reacted without further purification. 18.4 g of freshly precipitated silver acetate and 24 g of acetic anhydride are heated to 120°C in 82 ml of glacial acetic acid for 1 hour, 19.1 g of the gamma-iodine ester 3a' are added and the mixture refluxed for a further 2 hours.
The mixture is then kept for 15 h at R'r, combined with 300 ml of ether and filtered. Once the filtrate has been washed with water and aqueous soda solution, the aqueous phase is extracted again with ether, the combined organic extracts are dried over MgS04 and evaporated under reduced pressure. Once this oil has been redissolved in 70 ml of 2 N NaOH, 10 ml of EtOH
and 50 ml of water, the mixture is repeatedly extracted with ether, the ether phases being quantitatively discarded. The aqueous phase, acidified with 150 ml of 6 N HC1, is continuously extracted with ether and, after drying over MgS04 and evaporation under reduced pressure, is distilled (102-105°C at 34 Torr). 4.4 g of 4-methyl-2[5H]-furanone (3a) are obtained.

The remaining steps for preparing 3 follow the synthesis sequence described in 2 by the introduction of O-(2-trimethylsilylethyl)-hydroxylamine hydrochloride, NBS, triethyl phosphate and the hydrolyses of phosphonic acid esters by trimethylbromosilane and the liberation of the cyclic hydroxamic acid by BF3 etherate. Reference may also be made to T.Sakamoto, Y.Kikugawa J. Org. Chem. 1994, 59, 929-931 with regard to the synthesis sequence.
Example 4: N-Hvdroxv-3-amino-4-lphosphon-omethyll pvrrolidin 2 one (4) 2-Phenyl-4-(2-acetoxy-1-acetox~ yl-eth laden 1 2 oxazolin 5 one ~4a1_ 0.2 mol of hippuric acid, 0.6 mol of acetic anhydride, 0.24 mol of 1,3-diacetoxyacetone and 0.1 mol of anhydrous lead(II) acetate are initially introduced into 500 ml of THF and refluxed for 16 h under argon. After cooling to RT, inorganic salts are filtered out, the mixture is evaporated under reduced pressure, redissolved in 500 ml of toluene, gaseous hydrogen sulfide is introduced until PbS ceases to precipitate and, after filtration, the mixture is reevaporated. The product is chromatographed on Si02 with hexane/chloroform as the solvent mixture, 4b being obtained at a yield of 73%.
Diacetoxyacetone is synthesised in accordance with a method of A.O.L. Fischer, H.
Mildbrand Ber. Dt, them. Ges. 57, 707, 1924.
2-Amino-3-methox -v butyric acid l4bl A solution of 31.8 mol of 4a in 150 ml of dioxane is combined with 1 g of Pd/C
and hydrogenated at standard pressure until 10 mol of hydrogen have been absorbed (4-6 h). Once the catalyst has been filtered out, the mixture is evaporated to dryness, redissolved in 40 ml of water and 60 ml of coot. HCI, refluxed for 4 h and kept overnight in the refrigerator. The filtered solution is evaporated, redissolved in 50 ml of water and purified on Amberlite IR
120, H+ ion exchanger by elution with 300 ml of aqueous ammonia solution. The mixture is boiled until no ammonia is any longer detectable, reevaporated under reduced pressure and recrystallised.
Aloha-amino-beta-methox~garmsna-butvrolactone (4c) 25 mmol of 4b are stirred for 15 min at RT with 20 ml of 2.5% HCI. The solution is evaporated to dryness and extracted overnight with chloroform in a Soxhlet apparatus. Once the solvent has been stripped out under reduced pressure, the lactone 4c is obtained in virtually quantitative yield.

N.N-Dibenzvla_mino-beta-methox~-gamma butvrolactone ~4d1 0.2 mol of 4c, 72 g of KZC03 and 300 mg of tetrabutylammonium iodide and 500 mg of 18-crown-6 are suspended in 100 ml of ethanol and heated to 40°C. 0.65 mol of benzyl bromide are added dropwise within 15 min, the mixture is stirred for 12 h at RT, the phases are separated, the aqueous phase washed twice with 75 ml portions of ether, the organic phases are combined, washed with saturated NaCI solution and dried over MgS04. After evaporation under reduced pressure, the mixture is chromatographed on a short silica gel column.
N.N-Dibenzylamino-beta~bromomethvll-butyrolactone~4e~
2.23 g (6.18 mmol) of CBr4 are added to a mixture of 4.12 mmol of 4d, 6.18 mmol of PPh3 and 20 ml of absolute acetonitrile. The mixture is stirred for 20 h at RT, the solvent removed under reduced pressure and chromatographed on silica gel with ethyl acetate/n-hexane as solvent. 4e is obtained in variable yield as a yellowish oil.
N.N-Dibenzvlamino-beta-ldimeth~phosphonomethylLutyrolactone (4f1 40 mmol of 4e are refluxed for 0.5 to 1 h with 1 equivalent of trimethyl phosphite in toluene.
After cooling, the mixture is evaporated under reduced pressure and the remaining oil is chromatographed on Si02 with chloroform/methanol as the mobile solvent. Once volatile constituents have been stripped out, 4f is obtained in moderate yield.
N N-Dibenzvlamino-beta~dimet Yl hosnhonometh l~) butvrolactam (4~) A solution of 100 ml of sodium ethanolate in 50 ml of absolute ethanol is added dropwise at 0°C with exclusion of moisture to a solution of 120 mmol of O-benzylhydroxylamine hydrochloride in 100 ml of absolute ethanol. Any precipitated NaCI is filtered out with an argon sintered glass filter. The ethanol is removed from the filtrate under reduced pressure and, once argon has been passed through the residue, the latter is redissolved with absolute toluene. 1 mol% of RhCl3 3 H20, 5 mol% DMAP and, dropwise, 50 mmol of 4f are added thereto at 0°C. The mixture is allowed to thaw and is stirred overnight while being refluxed on the water separator. After cooling, volatile constituents are stripped out under a vacuum at 50°C in a Rotavapor rotary evaporator, an oil being left behind.
Redissolution in 40 ml of ethyl acetate, filtration through a short Si02 column and stripping of the solvent gives rise to (4g) in moderate yield as a yellow oil, which is obtained in good purity.
N-Hvdroxy-3-amino-4-(dimeth~phosphonometh~l ~vrrolidin 2 one (4hl 30 mmol of 4g in 60 ml of methanol and 10 ml of formic acid are hydrogenated with 5 mol%
Pd/C (10-20%) under standard pressure at RT for 13 h. Once the catalyst has been filtered out, the mixture is evaporated under reduced pressure and reacted without further purification.

N-H~xv-3-amino-4~Phosnhonomethyl~pvrrolidin-2-one~4il 35 mmol of trimethylbromosilane are added dropwise with ice cooling to 10 mmol of 4h in 20 ml of absoluted acetonitrile, the mixture is stirred for 15 min at the same temperature, then for 2 h at RT, evaporated under reduced pressure until a yellowish oil is obtained, the product is redissolved in 100 ml of water and hydrolysed for 1 h at RT. This solution is extracted twice with CHC13, back-extracted once with water and the combined aqueous phases are evaporated under reduced pressure at 45°C. The resultant dark oil is redissolved in water and a pH of 6.0 is established. Precipitating 4i is filtered out and washed with ice water. 4i is obtained as the sodium salt in the form of beige crystals at a yield of 35-40%.
Example 5: N.2-Dihvdrox~~2~hosphonoethvl~~vrrole (5) N-Benz~~[2-(dimeth~pho~honoZth~7pvrrolidin-2-one (Sad 20 mmol of 5-[2-(dimethylphosphono)ethyl]pyrrolidinone (le) are stirred overnight at room temperature with 1.2 equivalents of benzyl bromide, 10 mg of tetrabutylammonium iodide and 1.3 equivalents of triethylamine in 30 ml of THF, are then poured into ice water, repeatedly extracted with small quantities of ether, the diethyl ether phase is washed with cold dilute HC1 and with saturated common salt solution, dried over MgS04, evaporated and the crude product chromatographed on silica gel with chloroform/methanol 25:1. Sa is obtained in good yield.
N-Benz~~ henylseleno-5-~2-(dimeth~phos honoleth~l_~pvrrolidin-2-one (5b) 2.0 mmol of Sa, which is dissolved in 1 ml of absolute THF and stirred for 20 min at -78°C, is added at the same temperature to 2.4 mmol of diisopropylamide in 3 ml of THF (LDA, produced from 0.35 ml of diisopropylamine and 1.6 ml of 1.65 M n-BuLi in hexane under argon at -78°C). 2.4 mmol of diphenyl diselenide, dissolved in 1 ml of THF and 1.2 mmol of HMPT, are added at -78°C to the enolate of 5a. The reaction mixture is stirred for 40 min at -78°C and for 1.5 h at -40°C. Quenching with 0.1 N HC1 and subsequent repeated extraction with ether yields, after chromatography on silica gel, a yellowish oil Sb of a characteristic odour.
N-Benz -~ drox~[2-(dimeth~phosphonoleth~~vrrole (Sc) 0.2 mmol of the phenylseleno compound 5b, dissolved in 1 ml of absolute THF, is combined with 30 ~,l of glacial acetic acid, 140 ~l of Perhydrol (30% hydrogen peroxide solution) are added dropwise with ice cooling and the mixture stirred for 30 min at the same temperature.
The solution is poured into cold, saturated aqueous sodium hydrogen carbonate solution, the mixture extracted with ether, dried over MgS04, evaporated under reduced pressure and the crude product chromatographed on silica gel. Sc is obtained in good yield as a yellowish oil.

N.2-Dihvdroxv-4-[2-(dimethvlphos hono)ethvl]pvrrole (Sdl 0.15 mmol of Sc is placed in 50 ml of absolute EtOH, a spatula-tipfull of 10%
Pd on activated carbon is added and the mixture hydrogenated for 1 h at RT in a standard pressure hydrogenation apparatus with vigorous stirring. Once the catalyst has been filtered out, the mixture is evaporated and the crude product is reacted without further purification.
N.2-Dihydrox ~-~5-J2-phos~honoethL~ll-pyrrole (5e) 4 equivalents (60 mmol, 8 ml) of trimethylbromosilane are added dropwise with ice cooling to 15 mmol of Sd in 50 ml of absoluted acetonitrile, the mixture is stirred for 15 min at the same temperature, then for 2 h at RT, evaporated under reduced pressure until a yellowish oil is obtained, the product is redissolved in 80 ml of water and hydrolysed for 1 h at RT (pH <
1). This solution is extracted twice with CHC13, back-extracted once with water and the combined aqueous phases are evaporated under reduced pressure at a maximum of 45°C. The resultant oil is redissolved in water and a pH of 4.5 to 5.0 is established with NaHC03. Se is removed by suction filtration and, after washing with iced water, 5e is obtained as a virtually colourless sodium salt at a yield of 40%.
Example 6: N-H~xv-3-[2 ~phosnhonolethyl~-1H-~,vridone~61 2-Bromo-3-(bromometh,~lpvridine (6a~
g (58.1 mmol) of 2-bromo-3-methylpyridine and 11.4 g (64 mmol) of [sic] are refluxed for 24 h in 250 ml of CC14. The succinimide is separated by filtration and the organic phase is washed twice with water. After evaporation under reduced pressure, 6a is obtained as a colourless liquid by fractional distillation (bp: 90°C, 1 Torr).
2-Bromo-3-[2-(dimeth~nhosphonoleth~]pyridine fhb) 0.21 mol of MeLi in ether is added dropwise to 100 ml of absolute THF, 0.1 mol of trimethyl phosphite, dissolved in 50 ml of THF, is added dropwise within 15 min in such a manner that the internal temperature slowly reaches 0°C. 0.107 mol of 6a in 20 ml of THF is then added dropwise at a temperature of -78°C, stirring is continued for a further 30 min at the same temperature, the mixture is allowed to thaw and quenched at 0°C by dropwise addition of 80 ml of 3 M HCI. The organic phase is separated, the aqueous phase extracted three times with 40 ml portions of dichloromethane and, after drying over MgS04, the combined organic phases are evaporated. The yellow crude product may be purified in a short column on Si02.

2-Bromo-3-[2-(dimeth~nhos~nhono)ethy~pyridine N-oxide (6c) 100 mmol of 6b in 60 ml of glacial acetic acid are combined with 2 equivalents of a 40%
peracetic acid solution, wherein the temperature should not exceed 50°C. After 5 hours' heating to 50°C and 12 hours' heating to 70°C, the solution is evaporated to half its volume under reduced pressure, poured onto ice and made highly alkaline with 40%
aqueous KOH.
Triple extraction with chloroform yields, after drying over KzC03 and evaporation under reduced pressure, an N-oxide oil 6c, which was reacted without further purification.
N-Hvdroxv-3-f2-~dimethYlphosphonolet_hvl~-1H-pvridone~6d~
6c is heated in a glass autoclave for 3 h to 120°C in absolute MeOH
together with mortar-ground potassium hydroxide, potassium carbonate and tris(3,6-dioxaheptyl)amine. After cooling, the reaction mixture is poured into water, a pH value of 6 is established, the mixture evaporated under a vacuum and, after addition of ethanol, a crude product is obtained which may be recrystallised in moderate yield from ethanol/toluene.
N-H droxv-3-~2~fphos~hono)eth~]-1H-~vridone (6e) 40 mmol of trimethylbromosilane are added dropwise with ice cooling to 10 mmol of 6d in 30 ml of absolute acetonitrile, the mixture is stirred for 15 min at the same temperature, then for 2 h at RT, evaporated under reduced pressure until an oil is obtained, the product is redissolved in 20 ml of water and hydrolysed for 1 h at RT (acidic pH). This solution is extracted twice with CHCl3, back-extracted once with water and the combined aqueous phases are evaporated under reduced pressure at 45°C. The resultant brown oil is redissolved in water, stirred twice with activated carbon, filtered therefrom and a pH of 5 is established.
As a result, 6e precipitates out, is filtered, washed with ice water and may be recrystallised from MeOH/EtOH.
Example 7: N-Hvdroxv-6-(2-lphosphono~ethvl]-1H-pyridone l7~
2-Bromo-6-bromomethvlpyridine ) 10.1 g (58.7 mmol) of 2-bromo-6-methylpyridine, 11.1 g (62.4 mmol) of N-bromosuccinimide (NBS) and 0.1 g (0.6 mmol) of AIBN are heated under argon for 6 h to 110°C in 150 ml of toluene, the mixture simultaneously being illuminated with a tungsten daylight lamp (150 W, >320 nm). After cooling, succinimide is filtered out and the solution evaporated under reduced pressure. Chromatography on silica gel (mobile solvent:
hexane/dichloromethane) at first yields 2-bromo-6-dibromomethylpyridine, while 7a may subsequently be eluted at a yield of up to 45% (mp: 138°C).

2-Bromo-6-[2-(dimeth~pho h~ono_leth~~~ ridine~7b~
0.21 mol of MeLi in ether is added dropwise to 100 ml of absolute THF, 0.1 mol of trimethyl phosphite, dissolved in 50 ml of THF, is added dropwise within 15 min in such a manner that the internal temperature slowly reaches 0°C. 0.107 mol of 7a in 15 ml of THF is then added dropwise at a temperature of -78°C, stirring is continued for a further 30 min at the same temperature, the mixture is allowed to thaw and quenched at 0°C by dropwise addition of 80 ml of 3 M HCI. The organic phase is separated, the aqueous phase extracted repeatedly with 40 ml portions of dichloromethane and, after drying over MgS04, the combined organic phases are evaporated. The yellow crude product may be chromatographically purified on SiOZ, 7b being obtained at a yield of 47%.
2-Bromo-6-(2-(dimethyl hosphonoleth ~~ll~yridine N-oxide~7c~
50 mmol of 7b in 50 ml of glacial acetic acid are combined with 2 equivalents of a 40%
peracetic acid solution, the temperature varying between 25 and 45°C.
After 5 hours' heating to 50°C and 12 hours' heating to 70°C, the solution is poured onto ice and made highly alkaline with 40% aqueous KOH. Triple extraction with chloroform yields, after drying over KZC03 and evaporation under reduced pressure, an N-oxide oil 7c, which may be recrystallised from ether/ethanol.
N-Hvdroxv-6-~~dimethvlphos honoleth l~pyridone (7dl 7c is heated in a glass autoclave for 2.5 h to 100°C in absolute MeOH
together with mortar-ground potassium hydroxide, potassium carbonate and tris(3,6-dioxaheptyl)amine. After cooling, the reaction mixture is poured into water, a pH value of 6 is established, the mixture evaporated under a vacuum and, after addition of ethanol, a crude product is obtained which, similarly to 6d, may be recrystallised in moderate yield.
N-H drox~[2-(~ho~honolet~vl]-1H ~vridone (7el 40 mmol of trimethylbromosilane axe added dropwise with ice cooling to 10 mmol of 7d in 25 ml of absolute acetonitrile, the mixture is stirred for 10 min at the same temperature, then for 2 h at RT, evaporated under reduced pressure at 45°C until an oil is obtained, the product is redissolved in 20 ml of water and hydrolysed for 1 h at RT. This solution is extracted twice with CHCl3, back-extracted once with water and the combined aqueous phases are evaporated under reduced pressure at 45°C. The resultant dark-coloured oil is redissolved in water and a pH of 4.8 is established. As a result, 7e precipitates out as the sodium salt.
After filtration and washing with ice water, 7e is obtained as a crude product, which may be recrystallised from MeOH/toluene.

Example 8: N-Hvdrox~j2-phosphono-2-hvdroxylethvllpvrrolidin-2-one Ll_ N-Benzyl-2-(1.3-dithio lmeth~ly-pYrrolidine (,8a) 100 mmol (12.0 g) of 1,3-dithiane are weighed out under protective gas, 250 ml of absolute THF are added thereto and a 5% excess of n-BuLi in hexane is added dropwise thereto within 3-5 min at ~.0°C. The mixture is stirred for 2 h at -25 to -15°C, the temperature is reduced to -60 to -78°C and 100 mmol of 2-iodomethyl-N-benzyloxy-pyrrolidine are slowly added thereto under protective gas. After 5-6 hours' stirring at -20 to -10°C, the temperature is allowed to rise to 0°C and the reaction mixture is placed in the refrigerator for three days.
After evaporation to approx. 20 ml, the mixture is poured into three times its volume of water, extraction performed three to five times with chloroform, the organic phases are combined, washed in succession with water, 6% KOH and again with water and the chloroform phase is dried over KZC03. The residue obtained after evaporation under reduced pressure is reacted without further purification.
N-Benzyl_2-lformylmethYl)-nvrrolidine~8b) 1.1 g of CaC03 and 2.5 ml of Hg(C104)2 of a 4 M aqueous solution are added to a solution of 9 mmol of 8a in 30 ml of THF and 6 ml of water, stirring is continued for a further 5 to 10 min, 150 ml of ether are added thereto and inorganic salts are filtered out.
Once the solution has been evaporated under reduced pressure, a coloured crude product remains, which is purified by flash chromatography.
N-Benzyl-2-[2-ldiethylphosphono)-2-hvdroxv]pyrrolidine (8c) 20 g (145 mmol) of diethyl phosphonate and 140 mmol of 8b are heated under argon to 80 to 85°C for 8 h. After cooling, the mixture is evaporated under reduced pressure and the product 8c is purified chromatographically on silica gel.
N-Benz[2-(diethyl_phosphonol-2-acetox~lpvrrolidine ~8d) A mixture of 50 mmol of 1-hydroxyphosphonic acid ester 8c, 75 mmol of triethylamine, 75 mmol of acetic anhydride and 4 mmol of dimethylaminopyridine (DMAP) is left to stand for 14 h at RT and, after addition of 100 ml of ether and 2 N HCI, the etheric phase is washed with saturated aqueous NaHC03 solution, dried over MgS04, evaporated and purified on a short ALOX column.
2-f2-(N-Benzyl-2-[8-ldiethylphosphono)-2-acetoxy~pvrrolidine 1,8e) After addition of 400 mg of PtO2, a solution of 40 mmol of 8d in 30 ml of glacial acetic acid is hydrogenated at 70°C for 6 h at standard pressure. Once the catalyst has been filtered out, the mixture is repeatedly extracted with ether in a strongly alkaline medium, the combined ether extracts are dried over MgS04, evaporated and the product 8e, which is obtained in good yield, is directly further reacted.
N-H drox ~-~5-[2-phosnhono-2-h~X)eth~~pvrrolidin-2-one~8f~
A solution of 70 mmol of dimethyldioxirane in 110 ml of dry acetone is added dropwise to a solution, cooled to 0°C, of 20 mmol of 8e in 50 ml of dry acetone. The mixture is stirred for 30 min at 0°C and the solvent is then stripped out under a vacuum. A
yellow oil is obtained, which may be purified on silica gel with a chloroform/methanol mobile solvent mixture.
N-H~~[(2-dieth~phosnhono-2-hvdrox~ -ethyl]~vrrolidin-2 one (~~l The yellow oil 8f is stirred overnight with 5 M aqueous KOH in MeOH at RT, then neutralised, MeOH is removed under reduced pressure and the mixture extracted with ether.
The combined organic phases were dried over MgS04 and evaporated to dryness.
The resultant 8g is used for the subsequent reactions without further purification.
N-H derv-5-[(2-nhosphono-2-h~xl-ethyl~pvrrolidin-2-one ~8h~
80 mmol of trimethylbromosilane are added dropwise to a solution, cooled to 0°C, of 20 mmol of 8g in 50 ml of dry acetonitrile. The mixture is stirred for 3 h at RT, then the solvent is stripped out under a vacuum, the residue is redissolved with 60 ml of iced water, the mixture is stirred for 1 h at room temperature, extracted three times with 60 ml portions of ether, a pH value of 5.5 to 6.0 is established with 2 M NaOH and the water is then stripped out in a Rotavapor rotary evaporator at a maximum of 45°C. The solid residue is crystallised from methanol/ethyl acetate. N-Hydroxy-5-[(2-phosphono-2-hydroxy)-ethyl]pyrrolidin-2-one (8h) is obtained in good yield in the form of yellowish-white microcrystals.
Example 9: 3-(Methvlphosphono)-N-hvdroxv-succinimide~91 3-(Bromomethyl-succinic anh, d~(9a) In a similar manner to the preparation of N-(2-trimethylsilylethoxy)-pyrrolidin-2-one (2b) 50 mmol of 2-methylsuccinic anhydride, dissolved in 30 ml of absoluted carbon tetrachloride, are reacted with 1.2 equivalents of N-bromosuccinimide by refluxing the mixture for 12 h.
Small quantities of azobisisobutyronitrile (AIBN) are added at hourly intervals. After cooling, the product is filtered from succinimide, the latter is washed with CC14 and the combined CC14 phases are evaporated under reduced pressure. The resultant oil may be chromatographed on Si02, 9a being obtained in low yield.

3-[2-(Dimeth~rlhosnhono~ethyl]-succinic anh_ dv ride (2b) 40 mmol of 9a are refluxed for 0.5 to 1 h with 1 equivalent of trimethyl phosphite in toluene.
After cooling, the mixture is evaporated under reduced pressure and the yellowish oil is chromatographed on Si02. Once volatile constituents have been stripped out, 9b is obtained in low yield.
3-[~Dimeth~phosphonolmethvll-N-benzyloxy-succinimide~9c) 1.0 g of benzyloxyamine is heated in a glass autoclave with 1.0 equivalent of 9b to 180°C for 30 min. After cooling, the oil is evaporated under reduced pressure, a poor crude product yield being observed, and 9c is further reacted without purification.
3-[2-(Dimeth~phosphono)meths]-N-h~droxv-succinimide (9dl 9.28 mmol of the benzyloxy compound 9c dissolved in 60 ml of ethanol are combined with 700 mg of Pd/C and hydrogenated at standard pressure for 4 h at RT. Once hydrogen absorption has ceased, the catalyst is filtered out, the mixture evaporated under reduced pressure and recrystallised from ethyl acetate/hexane, 9d being obtained in good yield.
3-(2-Phosnhonomethvl]-N-hydroxy-succinimide ~9e1 110 mmol of trimethylbromosilane are added dropwise to a solution, cooled to 0°C, of 30 mmol of 9g in 70 ml of dry acetonitrile. The mixture is stirred for 3 h at RT, then the solvent is stripped out under a vacuum, the residue is redissolved with 80 ml of iced water, the mixture is stirred for 1 h at room temperature, extracted three times with 50 ml portions of ether, a pH value of 5.5 to 6.0 is established with NaHC03 and the water is then stripped out in a Rotavapor rotary evaporator at a maximum of 45°C. The solid residue is crystallised from methanol/acetone. 9e is obtained in the form of beige crystals in good yield.
Example 10: 1-N-l2-Phosphonoethyll-3-hvdroxy-7-meth~rl-xanthine f101 1-N-(2-Dimethylnhosnhono-eth~,i-7-methylxanthine~l0a) 50 g of 7-methylxanthine (2,6-dihydroxy-7-methylpurine) are dissolved in 1 1 of boiling ethanol and 38 g of 50% potassium hydroxide solution are added thereto. Once the mixture has cooled to 15 to 20°C, the potassium salt of 7-methylxanthine precipitates out, is filtered out and decocted with boiling acetone and boiling absolute ethanol.
A solution of 20 mmol of 2-bromomethylphosphonic acid dimethyl ester and 2 mmol of hexadecyltributyl-phosphonium bromide in 10 ml of toluene is combined with 25 mmol of the potassium salt of 7-methylxanthine and the mixture heated to 100°C for 2 h. Once the reaction mixture has cooled, undissolved fractions are filtered out and the evaporated organic phase is chromatographed on silica gel with ether/chloroform as mobile solvent. In this manner, both the desired 1-N-(2-dimethylphosphono-ethyl)-7-methylxanthine (l0a) and, at lower yield, 3-N-(2-dimethylphosphono-ethyl)-7-methylxanthine (l0a') are obtained.
1-N-f2-Dimeth~phosnhono-ethyll-3-h droxy-7-met~yl-xanthine ~(lObl A solution of 60 mmol of dimethyldioxirane in 120 ml of dry acetone is added dropwise to a solution, cooled to 0°C, of 25 mmol of l0a in 50 ml of dry acetone. The mixture is stirred for 30 min at 0°C and the solvent is then stripped out under reduced pressure. The resultant crude product is chromatographed on silica gel, 1-N-(2-dimethylphosphono-ethyl)-3-hydroxy-7-methyl-xanthine (lOb) being obtained in poor yield.
In a similar manner, 3-N-(2-dimethylphosphonoethyl)-7-methylxanthine (l0a') may be converted into 3-N-(2-dimethylphosphono-ethyl)-1-hydroxy-7-methylxanthine (lOb').
1-N-(2-Phosphono-ethyll-3-hydroxy-7-methyl-xanthine (lOc~
4 equivalents (100 mmol) of trimethylbromosilane are added dropwise with ice cooling to 25 mmol of lOb in 50 ml of absoluted acetonitrile, the mixture is stirred for 15 min at the same temperature, then for 2 h at RT', evaporated under reduced pressure until an oil is obtained, the product is redissolved in 100 ml of water and hydrolysed for 1 h at RT. In order to remove hexamethyldisiloxane, this solution is extracted twice with CHC13, back-extracted once with water and the combined aqueous phases are evaporated under reduced pressure at 45°C. The resultant beige oil is redissolved in water and a pH of 6.5 to 7.0 is established. After washing with iced water, lOc is obtained as a virtually colourless sodium salt at a yield of SS%.
In a similar manner, 3-N-(2-dimethylphosphono-ethyl)-1-hydroxy-7-methyl-xanthine (lOb') is reacted with trimethylbromosilane to yield 3-N-(2-phosphono-ethyl)-1-hydroxy-7-methyl-xanthine (lOc').
Example 11: N-Hvdroxv-1,2,3 4-tetrahvdro-1-oxo-3-~2-nhos~honoethyl)1-iso~uinoline 3-Phenyl-2-amino~ropanol (lla~
3.0 mol of LiAlH4 are suspended in 900 ml of anhydrous tetrahydrofuran in a heat-treated and argon-flooded three-necked flask fitted with a KPG stirrer and 1.5 mol of phenylalanine are added in portions with ice cooling. The mixture is then refluxed for 6 h, allowed to cool and hydrolysed with crushed ice. The mixture is filtered and the solvent removed under a vacuum.
The filtrate is redissolved with CH2Cl2, washed with saturated NaCI solution and dried with Na2S04. Vacuum distillation is then performed. 3-Phenyl-2-aminopropanol lla is obtained at a yield of 76%.
1-Phen,~(tetrahvdro-2-~~,~Xl-2-aminopropane (llb) 2.5 mol of dihydropyran and 5.3 g of p-toluenesulfonic acid are added to 1.4 mol of 3-phenyl-2-aminopropanol 1 and the mixture then stirred for 20 h at RT. The excess dihydropyran is then removed under a vacuum, the residue redissolved with 700 ml of ethyl acetate and washed with 300 ml portions of saturated NaHC03 solution and saturated NaCI
solution. The mixture is then dried with MgS04, filtered and the solvent removed under a vacuum. 1-Phenyl-3-(tetrahydro-2-pyranyloxy)-2-aminopropane (1lb) is obtained at a yield of 63%.
1-Phen,~(tetrahydro-2-pyr~,~~l-2-isocyanopropane fllc) 0.88 mol of 1-phenyl-3-(tetrahydro-2-pyranyloxy)-2-aminopropane llb are added dropwise to a solution of 3.52 mol of phosgene in 1.5 1 of toluene and the mixture then boiled for 3 h at 80°C. The solvent is then removed under a vacuum. The desired product 1-phenyl-3-(tetrahydro-2-pyranyloxy)-2-isocyanopropane llc is obtained at a yield of 83%.
This is used without further purification.
1.2,3~4-Tetrahydro-1-oxo-3-h~droxymeth,1-~quinoline (lld) A solution of 0.72 mol of 1-phenyl-3-(tetrahydro-2-pyranyloxy)-2-isocyanopropane llc in 80 ml of anhydrous acetone is slowly added dropwise to 100 ml of ice-cooled phosphoric acid and stirred for 3 h at RT. Ice water is then added, the mixture stirred for 0.5 h and then extracted with CH2Cl2. The organic phase is washed with water, saturated NaZC03 solution, again with water and with saturated NaCI solution and dried with MgS04. After filtration and removal of the solvent under a vacuum, the product is recrystallised from hexane/benzene, 28% of 1,2,3,4-tetrahydro-1-oxo-3-hydroxymethyl-isoquinoline (lld) being obtained.
1 2,3.4-Tetrahydro-1-oxo-3-bromomethyl-isoquinoline (lle) A solution of 180 mmol of PPh3 in 120 ml of CH2C12 is added to a solution of 150 mmol of 1,2,3,4-tetrahydro-1-oxo-3-hydroxymethyl-isoquinoline llc and 210 mmol of CBr4 in 150 ml of CHZCl2 and stirred for 20 h at RT. The solvent is then removed under a vacuum and the residue repeatedly recrystallised from benzene. The product 1,2,3,4-tetrahydro-1-oxo-3-bromomethyl-isoquinoline lle is obtained at a yield of 31%.
1.2.3.4-Tetrahvdro-1-oxo-3-(2-dieth, l~bhosnhonoeth,~ll-isoauinoline ,llf) 66.2 mmol of solution of n-butyllithium (1.15 M) in hexane are added dropwise at -78°C to a solution of 75 mmol of dimethyl methylphosphonate in 120 ml of absolute THF
under argon and the mixture stirred for 1.5 h at this temperature. 46.5 mmol of 1,2,3,4-tetrahydro-1-oxo-3-bromomethyl-isoquinoline lle in 50 ml of absolute THF are added dropwise to this solution at -78°C, the mixture stirred for a further 1 h at -78°C and then allowed to rise to RT
overnight. 100 ml of water are then added, the aqueous phase separated and extracted 3 times with 50 ml portions of ethyl acetate. The combined organic phases are dried with MgS04, filtered and the solvent removed under a vacuum. The residue is purified chromatographically (silica gel, hexane/ethyl acetate 5:1). 24% of the desired product 1,2,3,4-tetrahydro-1-oxo-3-(2-diethylphosphonoethyl)-isoquinoline llf are obtained.
N-H, d~,~ 2,3.4-tetrah~dro-1-oxo-3-~2-dieth, ly~hosnhonoethy~-isoduinoline~llg) 5.36 mmol of 1,2,3,4-tetrahydro-1-oxo-3-(2-diehtylphosphonoethyl)-isoquinoline 6 are dissolved in 30 ml of absolute acetone and cooled to 0°C. A solution of 17.15 mmol of dimethyldioxirane is then added dropwise and the mixture stirred for 30 min at 0°C. The solvent is removed under a vacuum and the residue purified chromatographically (silica gel, hexane/ethyl acetate 4:1). 33% of the product N-hydroxy-1,2,3,4-tetrahydro-1-oxo-3-(2-diethylphosphonoethyl)-isoquinoline llg are obtained.
N-Hydrox,~.2.3.4-tetrahvdro-1-oxo-3-(2-phosphonoeth_ lv_l-isoduinoline f,llh) 1.77 mmol ofN-hydroxy-1,2,3,4-tetrahydro-1-oxo-3-(2-diethylphosphonoethyl)-isoquinoline llg are dissolved in 15 ml of absolute CHZCl2 under argon and cooled to 0°C. 10 mmol of trimethylbromosilane are then added dropwise from a syringe, the mixture stirred for a further 1 h at 0°C and then overnight at RT. The solvent is then removed under a vacuum, the residue redissolved in 20 ml of water and stirred for 1 h at RT. 15 ml of CHC13 are then added and the organic phase separated. The aqueous phase is extracted twice more with 10 ml portions of CHC13 and the mixture evaporated under a vacuum. The residue is purified chromatographically (silica gel, H20/methanol 1:1). The desired product is obtained at a yield of 54%.
Example 12:
The antimalarial activity of the substances stated in Table I was determined using in vitro cultures of the causative organism of malaria, Plasmodium falciparum. The roman numerals refer to the particularly preferred compounds stated on pages [sic] to [sic].
200 ~l of an asynchronous Plasmodium falciparum culture with a 0.4% blood parasite content and a haematocrit of 2% were loaded into each of the wells of a 96 well microtitre plate. A serial dilution series of the compounds was then prepared in steps of three between concentrations of 100 and 1 ~mol 1-1. The plates are incubated at 37°C, 3% C02 and 5%
02 over a period of 48 hours. 30 pl of medium supplemented with 27 ~Ci ml-1 of [3H]-hypoxanthine were then added to each well. After 24 hours' incubation, the parasites were harvested by filtration through glass fibre filters and the incorporated radioactivity was measured.
Inhibition of parasite growth was measured as the percentage inhibition of tritium incorporation relative to a comparison without the substance. The results for the three different concentrations are stated in Table I.
Ta le I
SubstanceR5 A Form used 100 wM 10 p,M 1 ~.M
inhibitioninhibitioninhibition (%) (%) (%) I H C2H4 Na salt 98 98 98 III H CHZ Na salt 96 98 63 II H CHZ Na salt 98 87 59 I H CH2CHOH Na salt 98 97 78 X H CHZ Na salt 89 80 0 X H CHZ Na salt 98 97 98 III H CHZ Na salt 98 98 82 pyrrole ring is NH2-substituted in osition VII H CZH4 Na salt 98 98 98 ~:XXI H CZH4 Na salt 97 73 53 XXVIII H CZH4 Na salt 98 97 82 ~!:XXVIIIH CZH4 Na salt 92 78 30 N-substituted in osition XXXVI H C2H4 Na salt 95 80 37 in position Example 13 The antibacterial action of the substances stated in Table II was determined.
The roman numerals refer to the particularly preferred compounds stated on pages 5 to 8.
A dilution series comprising the concentrations 500, 100, 50 and 10 ~,mol l~l of the individual compounds in LB medium is introduced into 5 culture microtubes in a volume of 0.5 ml. Each of the microtubes was inoculated with 10 ~1 of an overnight culture of E. coli K12 and shaken overnight at 37°C. Bacterial growth was assessed on the basis of the turbidity of the medium.
The minimum concentration causing inhibition of bacterial growth was determined (minimum inhibition concentration, MIC).
Antibacterial activity with regard to P. aeruginosa was determined in the same manner. The results are shown in Table II.
Table II
SubstanceR5 A Form used E. coli P. aeruginosa MIC (m ) 10 m /1 I H C2H4 Na salt 2.5 5 III H CH2 Na salt 5 5 pyrrole ring is NH2-substituted in osition 3 II H CH2 Na salt 10 5 I H CHZCHOH Na salt 2.5 1.25 X H CH2 Na salt 1.25 1.25 X ~ H CH2 Na salt 10 20 III i H CHz Na salt 1.25 10 VII H CZH4 Na salt 10 40 I~:XXI H C2H4 Na salt 10 1.25 XXVIII H CzH4 Na salt 5 5 XXXVIII H C2H4 Na salt 20 80 N-substituted in osition 5 XXXVI H CZH4 Na salt 40 20 in position

Claims (12)

Claims
1. Organophosphorus compounds of the general formula (I) wherein A is selected from the group which consists of a (C1-9) alkylene residue, which may comprise one or more double bonds and may be substituted with hydroxy, halogen, amino, oxo groups with branched or unbranched C1-9 alkyl groups and C2-9 alkenyl groups, wherein the C1-9 alkyl groups and C2-9 alkenyl groups may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups, -C-O-C- and -C-N-C-, wherein the carbon atoms of -C-O-C- and -C-N-C- may be substituted with an alkyl having up to 7 carbon atoms or hydroxy groups, or in which A is of the following formula (II):

wherein one or more of the carbon atoms selected from the group C3, C4, C5, together with their substituents, may also be absent, and at least one substituent present in the range from B1 to B10 is a C3-8-cycloalkyl-(C0-9)-alkyl group, wherein both the cycloalkyl group and the C0-9 alkyl group may comprise one or more double bonds and one or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur atoms, and wherein both the cycloalkyl group and the alkyl group may be substituted with hydroxy, halogen, amino, oxo groups with branched or unbranched C1-9 alkyl groups and C2-9 alkenyl groups, wherein the C1-9 alkyl groups and C2-9 alkenyl groups may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups, and the remaining substituents B1 to B10 present are selected from the group which consists of hydrogen, hydroxy, halogen, amino groups, C1-26 alkyl residues, C1-26 alkoxy residues, C1-26-alkoxy-C1-26-alkyl residues or both substituents of a C atom together form an oxo group, wherein each C1-26 alkyl residue and each C1-26 alkoxy residue may be branched or unbranched and be saturated or unsaturated with one or more double bonds and may be substituted with hydroxy, amino, halogen and oxo groups, in which R1 is selected from the group which consists of 5- and 6-membered heterocycles with at least one ring nitrogen atom or a polycyclic carbon with at least one of these heterocycles, wherein at least one of these nitrogen atoms belongs to a hydroxamic acid group or a hydroxamic acid ester group, and may be saturated or unsaturated with one or more double or triple bonds and may thus also be aromatic and may be substituted with hydroxy, halogen, amino, oxo groups and with branched or unbranched C1-9 alkyl groups and C2-9 alkenyl groups, wherein the C1-9 alkyl groups and C2-9 alkenyl groups may be saturated or unsaturated with one or more double or triple bonds and may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups, wherein the nitrogen atom of the hydroxamic acid group or hydroxamic acid ester group is substituted with OR5 and R5 is selected from the group which consists of hydrogen, substituted and unsubstituted C1-9 alkyl, substituted and unsubstituted hydroxy-C1-9-alkyl, substituted and unsubstituted C1-9 alkenyl, substituted and unsubstituted C1-9 alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic residue, in which R3 and R4 are identical or different and are selected from the group which consists of hydrogen, substituted and unsubstituted C1-26 alkyl, hydroxy-C1-26-alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C1-26 alkenyl, substituted and unsubstituted C1-26 alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic residue, halogen, OX3 and OX4, wherein X3 and X4 are identical or different and are selected from the group which consists of hydrogen, substituted and unsubstituted C1-26 alkyl, substituted and unsubstituted hydroxy-C1-26-alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted C1-26 alkenyl, substituted and unsubstituted C1-26 alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic residue, a silyl, a canon of an organic and inorganic base, in particular a metal of main groups I, II or III of the periodic system, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids, and the pharmaceutically acceptable salts, esters and amides thereof and salts of the esters.
2. Compound according to claim 1, characterised in that the organophosphorus compounds are of the formula (III) wherein R3 is preferably hydrogen, methyl, ethyl, an amide residue and X4 is selected from the group which consists of hydrogen, sodium, potassium, methyl, ethyl.
3. Compound according to claim 1, characterised in that the organophosphorus compounds are of the formula (IV) wherein X3 and X4 are identical or different and are selected from the group which consists of hydrogen, a (C1-3) alkyl, a metal of main groups I, II or III of the periodic system, ammonium, substituted ammonium, or ammonium compounds derived from ethylenediamine or amino acids.
4. Compound according to claim 3, characterised in that X3 and X4 are identical or different and are selected from the group which consists of hydrogen, sodium, potassium, methyl, ethyl.
5. Compound according to one of the preceding claims, characterised in that A
is selected from the group which consists of alkylene, alkenylene, hydroxyalkylene and oxoalkylene.
6. Compound according to claim 5, characterised in that A is selected such that three atoms are present between the nitrogen atom of the heterocyclic group and the phosphorus atom, wherein A is preferably a methylene, hydroxymethylene, ethylene, ethenylene or hydroxyethylene.
7. Compound according to one of claims 1 to 3, characterised in that the compound is selected from the group of compounds which consists of and the corresponding phosphinic acid and phosphinoyl derivatives, wherein R5 is defined as in claim 1.
Use of a compound according to one of claims 1 to 7 as a fungicide, bactericide or herbicide in plants.
9. Use according to one of claims 1 to 7 for the treatment of infections caused by bacteria, viruses, fungi or uni- or multicellular parasites.
10. Use according to claim 9 for the prevention and treatment of infections caused by unicellular parasites, namely the causative organisms of malaria, sleeping sickness, Chagas' disease, toxoplasmosis, amoebic dysentery, leishmaniases, trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiosis, sarcocytosis, acanthamoebosis, naeglerosis, coccidiosis, giardiasis and lambliasis.
11. Pharmaceutical preparation for the therapeutic and prophylactic treatment of infectious processes, characterised in that the preparation contains an active content of at least one organophosphorus compound according to one of claims 1 to 7 together with a pharmaceutically acceptable excipient.
12. Pharmaceutical preparation according to claim 11, characterised in that the preparation contains another pharmaceutical active substance.
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