EP1095050A1 - Composes organiques de phosphore et leur utilisation - Google Patents

Composes organiques de phosphore et leur utilisation

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Publication number
EP1095050A1
EP1095050A1 EP99936505A EP99936505A EP1095050A1 EP 1095050 A1 EP1095050 A1 EP 1095050A1 EP 99936505 A EP99936505 A EP 99936505A EP 99936505 A EP99936505 A EP 99936505A EP 1095050 A1 EP1095050 A1 EP 1095050A1
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EP
European Patent Office
Prior art keywords
viruses
substituted
group
bacteria
genus
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP99936505A
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German (de)
English (en)
Inventor
Hassan Jomaa
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Bioagency AG
Original Assignee
Bioagency AG
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Filing date
Publication date
Priority claimed from DE19831639A external-priority patent/DE19831639C1/de
Priority claimed from DE19843360A external-priority patent/DE19843360A1/de
Application filed by Bioagency AG filed Critical Bioagency AG
Publication of EP1095050A1 publication Critical patent/EP1095050A1/fr
Withdrawn legal-status Critical Current

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    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • 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
    • 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
    • A61P31/10—Antimycotics
    • 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
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
    • C07F9/383—Cycloaliphatic acids
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
    • C07F9/3886—Acids containing the structure -C(=X)-P(=X)(XH)2 or NC-P(=X)(XH)2, (X = O, S, Se)
    • C07F9/3891—Acids containing the structure -C(=X)-P(=X)(XH)2, (X = O, S, Se)
    • 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 System
    • 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
    • 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 System
    • 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
    • C07F9/59—Hydrogenated pyridine rings
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/44—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from protozoa
    • C07K14/445—Plasmodium
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/52—Genes encoding for enzymes or proenzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/527—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving lyase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere

Definitions

  • the invention relates to phosphorus compounds and their salts, esters and amides and to their use in the manufacture of medicaments for the therapeutic and propnylactic treatment of infections in humans and animals which are caused by viruses, bacteria, fungi and parasites, and their use as Fungicide, bactericide and herbicide in plants.
  • the organophosphorus compounds include phosphmoyldenvate, phosphmate acid derivatives and phosphonic acid derivatives.
  • This task is solved in a completely surprising manner by the group of substances defined in claim 1.
  • This group of substances shows both an anti-infectious effect against viruses, bacteria, fungi, single and multicellular parasites as well as a fungicidal, bactericidal and herbicidal effect on plants.
  • organophosphorus compounds according to the invention correspond to the general formula (I):
  • the Ri and R 2 are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkmyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl , substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen, 0X ⁇ and 0X 2 , where Xi and X 2 may be the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl , substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alienyl, substituted and unsubstituted alkmyl, suostituated and unsubstit
  • Ai and A 2 are the same or different and are selected from the group consisting of alkylene radical, alkenylene radical and hydroxyalkylene radical, the keto group (III)
  • a 3 and A 4 are the same or different, are selected from the group consisting of alkylene radical, alkenylene radical and hydroxyalkylene radical, and 5- and 6-membered cyclic, mso particular neterocy- cical compounds which contain at least one heteroatom as ring member in addition to carbon, the heteroatom being selected from the group consisting of oxygen and nitrogen -, where R 3 and R 4 are the same or different and are selected from the group consisting of from hydrogen, substituted and unsubstituted alkyl with up to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl with up to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl with up to 26 carbon atoms , substituted and unsubstituted alkyl having up
  • R 2 is selected from the group consisting of acetyl and formyl
  • Ai is selected from the group consisting of methylene, ethylene, ethenylene, hydroxyethylene, 2-hydroxypropylene and R is selected from the group consisting of hydrogen, methyl, ethyl, hexadecanyl, octadecanyl and OX 3 , and X 3 and X 4 are selected from the group: consisting of hydrogen, sodium, potassium, methyl, ethyl, hexadecanyl and octadecanyl and, insofar as they are both present, can be the same or different.
  • the chain -A ⁇ -O-C (ZY) - preferably consists of an oxygen atom and two or three carbon atoms (not including substituents), particularly preferably two carbonators.
  • the compounds are selected from the group consisting of ((N-formyl-N-hydroxylamino) - r ⁇ ethoxy) -r ⁇ ethylphosphonic acid disodium salt, ((N-acetyl-N-hydroxylamino) methoxy) methylphosphonic acid disodium salt , (2- (N-Formyl-N-hydroxylamino) ethenoxy) methylphosphonic acid di-natriur ⁇ salt, (2- (N-acetyl-N-hydroxylamino) ethenoxy) methylphosphonic acid disodium salt, (3- (N-formyl -N-hydroxylamino) -2-hydroxypropoxy) methylphosphonic acid disodium salt, (3- (N-acetyl-N-hydroxylamino) -2-hydroxypropoxy) methylphosphonic acid disodium salt, is particularly preferred.
  • R- is selected from the group consisting of acetyl and formyl
  • Ai is selected from the group consisting of methylene, ethylene, ethenylene, hydroxymethylene, hydroxyethylene and 2-hydroxypropylene, A 2 is eliminated or is methylene,
  • R 3 is selected from the group consisting of hydrogen, methyl, ethyl, hexadecanyl, octadecanyl and OX_, and X 3 and X are selected from the group consisting of hydrogen, sodium, potassium, methyl, ethyl, hexadecanyl and octadecanyl exists and, insofar as they are both available, can be the same or different.
  • the chain preferably consists of -A -CO-A ; - from two dis four carbon atoms (not including substituents, particularly preferably from three carbon atoms.
  • the amino group and the phosphorus atom can be bonded to any C atoms of the ring. However, preference is given to compounds in which they are bonded to two carbon atoms which are only separated by a further atom.
  • the two carbon atoms are preferably separated from one another by a heteroatom.
  • Acyl is a substituent that derives from an acid, such as from an organic carboxylic acid, carbonic acid, caroammic acid or the thiosic acid or imidic acid corresponding to the individual preceding acids, or from an organic sulfonic acid, these acids in each case aliphatic, aromatic and / or heterocyclic groups in the molecule as well as carbamoyl or carbidoyl. Suitable examples of these acyl groups are given below.
  • Aliphatic acyl groups are acyl radicals derived from an aliphatic acid, which include the following:
  • Alkanoyl e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl etc.
  • Alkenoyl e.g. acryloyl, methacryloyl, crotonoyl etc.
  • Alkylthioalkanoyl e.g. methylthioacetyl, ethylthioacetyl etc.
  • Alkanesulfonyl e.g. mesyl, ethanesulfonyl, propanesulfonyl, etc.
  • Alkoxycarbonyl e.g. methoxycarbonyl, ethoxycaroonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.
  • AlkylcarDamoyl e.g. Metnylcarbamoyl etc.
  • N-alkyl thiocarbamoyl e.g. (N-methyl) thiocarbamoyl etc.
  • AlkylcarDami idoyl e.g. methylcarbamimidoyl etc.
  • Oxalo Alkoxalyl (e.g. methoxalyl, ethoxalyl, propoxalyl etc.).
  • the aliphatic hydrocarbon part in particular the alkyl group or the alkane radical, may have one or more suitable substituents, such as ammo, halogen (for example fluorine, chlorine, bromine etc.), hydroxy, hydroxyimino, Carboxy, alkoxy (e.g. methoxy, ethoxy, propoxy etc.), alkoxycarbonyl, acylamino (e.g. benzyloxycarbonylamino etc.), acyloxy (e.g. acetoxy, benzoyloxy etc.) and the like; as preferred aliphatic acyl radicals with such substituents are e.g. alkanoyle substituted with ammo, carboxy, arnino and carboxy, halogen, acylamino or the like.
  • suitable substituents such as ammo, halogen (for example fluorine, chlorine, bromine etc.), hydroxy, hydroxyimino, Carboxy, alkoxy (e.g.
  • Aromatic acyl radicals are those acyl radicals which originate from an acid with a substituted or unsubstituted aryl group, where the aryl group can include phenyl, toluyl, xylyl, naphthyl and the like; suitable examples are given below: O
  • Aroyl e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaioyl etc.
  • Aralkanoyl e.g. phenylacetyl etc.
  • Aralkenoyl e.g. C namoyl etc.
  • Aryloxyalkanoyl e.g. phenoxyacetyl etc.
  • Arylthioalkanoyl e.g. phenylthioacetyl etc.
  • Arylammoalkanoyl e.g. N-phenylglycyl, etc.
  • Arenesulfonyl e.g. benzenesulfonyl, tosyl or toluenesulfonyl,
  • Aryloxycarbonyl e.g. phenoxycarbonyl, naphthyloxycarbonyl, etc.
  • Aralkoxycarbonyl e.g. benzyloxycarbonyl etc.
  • ArylcarDamoyl e.g. phenylcarbamoyl, naphthylcarbamoyl etc.
  • Arylglyoxyloyl e.g. phenylglyoxyloyl etc.
  • aromatic acyl radicals can the aromatic hydrocarbon part (in particular rest of the aryl) and / ooer the aliphatic hydrocarbon part msbe- sondere the alkane residue) may optionally one or more suitable Substi have ⁇ tuenten, such as those described as suitable substituents for the Alkyl group or the alkane radical have already been specified.
  • suitable aromatic acyl radicals with special substituents aroyl uno-substituted with halo and hydroxy or with halogen and acyloxy are indicated with hydroxy, hydroxyimmo, dihalogenal kanoyloxy-imo-substituted aralkanoyl and
  • Arylthiocaramoyl e.g. phenylthiocarbamoyl etc.
  • Arylcarbamimidoyl e.g. phenylcarbamimidoyl etc.
  • a heterocyclic acyl radical is understood to mean an acyl radical which comes from an acid with a heterocyclic group; this includes:
  • Heterocyclic carbonyl in which the heterocyclic radical is an aromatic or aliphatic 5-to 6-membered heterocycle with at least one heteroatom from the group consisting of nitrogen, oxygen and sulfur (for example thiophenyl, furoyl, pyrrole carbonyl, nicotmoyl etc.); Heterocycle-alkanoyl, in which the heterocyclic radical is 5- to 6-gl ⁇ edr ⁇ g and has at least one heteroatom from the group consisting of nitrogen, oxygen and sulfur (for example thiophene-yl-acetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino) -4-th ⁇ azolyl) -2-methoxy ⁇ mmoacetyl etc.) and the like.
  • the heterocyclic radical is an aromatic or aliphatic 5-to 6-membered heterocycle with at least one heteroatom from the group consisting of nitrogen, oxygen and sulfur (for example
  • heterocyclic acyl radicals the heterocycle and / or the aliphatic hydrocarbon part may optionally have one or more suitable substituents, such as the same ones which have been indicated as being suitable for alkyl and alkane groups.
  • Alkyl is a straight or branched chain alkyl radical having up to 9 carbon atoms, unless defined otherwise, such as methyl, ethyl, propyl, isopropyl, butyl, isooutyl, tert-butyl, pentyl, hexyl and the like.
  • Hydroxylalkyl is a straight-chain or branched-chain alkyl radical with up to 9 carbons, unless defined otherwise, which has at least one hydroxyl group, preferably one or two hydroxyl groups.
  • Alkenyl includes straight or branched chain alkenyl groups with up to 9 carbon atoms, unless defined otherwise, such as vinyl, propenyl (e.g. 1-propenyl., 2-propenyl), 1-methylpropenyl, 2- Methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl, riexenyl.
  • Alkmyl includes straight-chain or branched-chain alkmyl groups with up to 9 carbon atoms, unless defined otherwise.
  • Cycloalkyl preferably represents an optionally substituted C3-C7-cycloalkyl; Possible substituents include alkyl, alkenyl, alkmyl, alkoxy (eg methoxy, ethoxy etc.), halogen (eg fluorine, chlorine, bromine etc.), nitro and the like.
  • Aryl is an aromatic hydrocarbon radical, such as phenyl naphthyl etc., which may optionally have one or more suitable substituents, such as alkyl, alkenyl, alkmyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc. ), Nitro and the like.
  • Alkyl includes mono-, di-, triphenylalkyls such as benzyl, phenethyl, benzhydryl, t ⁇ tyl and the like, where the aromatic part may have one or more suitable substituents such as alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. Fluorine, chlorine, bromine, etc.), nitro and the like.
  • alkoxy e.g. methoxy, ethoxy etc.
  • halogen e.g. Fluorine, chlorine, bromine, etc.
  • Alkylene includes straight-chain or branched-chain alkylene groups which have up to 9 carbon atoms and can be represented by the formula - (C n H 2n ) -, in which n is an integer from i to 9, such as methylene, Ethylene, trimethylene, methyl ethylene, tetramethylene, 1-methyltmethylene, 2-ethylethylene, pentamethylene, 2-methyltetramethylene, isopropylethylene, hexamethylene, and the like; preferred alkylene radicals have up to 4 carbon atoms and radicals with 3 carbon atoms such as trimethylene are particularly preferred.
  • the hydrogen atoms can also be replaced by substituents, such as halogen radicals.
  • Alkenylene includes straight-chain or branched-chain AlKenylene groups with up to 9 carbon atoms, which can be represented by the formula ⁇ (C n H n - 2 ) -, in which n is an integer from 2 to 9, for example Vmylene, propenylene (eg 1-propenylene, 2-propenylene), 1-methylpropenylene, 2-methylpropenylene, butenylene, 2-ethylpropenylene, pentenylene, hexenylene and the like; particularly preferably the alkenylene radical can have up to 5 carbon atoms and in particular 3 carbon atoms such as 1-propenylene
  • the hydrogen atoms can also be replaced by substituents, such as halogen radicals.
  • hydroxyalkylene groups include hydroxy ethylene, hydroxyethylene (for example 1-hydroxyethylene and 2-hydroxyethylene), hydroxytrimethylene (for example 1-hydroxytrimethylene, 2-hydroxytrimethylene and 3-hydroxytrimethylene), hydroxytetramethylene (for example 2-hydroxytetramethylene), 2-hydroxy-2-methyltrimethylene, hydroxypentamethylene (eg 2-hydroxypentamethylene), hydroxyhexaethylene (eg 2-hydroxyhexamethylene) and the like.
  • a lower hydroxyalkylene with up to 4 carbon atoms and in particular one with 3 carbon atoms such as 2-hydroxytrimethylene is particularly preferred.
  • the hydrogen atoms can also be replaced by substituents, such as halogen radicals.
  • the 5- and 6-membered cyclic compounds which B can represent can be aromatic or aliphatic and substituted, for example by alkyl groups having up to 7 carbon atoms and hydroxyl groups.
  • the 5- and 6-membered heterocyclic compounds which B can represent and which contain at least one heteroatom as the ring member in addition to carbon can be saturated or unsaturated.
  • Examples are azixan, diazixan, azixin, diazixin, azolan, diazolan, azole, diazole, oxolane, dioxoles, oxol, dioxol, oxixane, dioxixane, oxixin and dioxixin. They can be aliphatic or aromatic and substituted, for example by alkyl groups with up to 7 carbon atoms and hydroxyl groups.
  • the radicals X 3 and X 4 can preferably be chosen such that esters are formed on the phosphono group or phosphino group.
  • suitable examples of such esters according to formulas (I), (IV) to (IX) include suitable mono- and diesters, and preferred examples of such esters include alkyl esters (for example methyl esters, ethyl esters, propyl esters, isopropyl esters). ster, butyl ester, isobutyl ester, hexyl ester, etc.); Aralkyl esters (benzyl esters, phenethyl esters, benzhydryl esters, t ⁇ tylesters etc.);
  • Aryl esters e.g. phenyl esters, tolyl esters, naphthyl esters, etc.
  • Aroyl alkyl esters e.g. phenacyl esters etc.
  • silyl esters e.g., from trialkylhalosilyl, dialkyldihalosilyl, alkyltrihalosilyl, dialkyiarylhalosilyl, tnalkoxyhalosilyl, dialkylaralkylhaiogensilyl, dialkoxydihalosilyl, trialkoxyhalosilyl, etc.
  • the alkane and / or ⁇ -arene part can optionally have at least one suitable substituent such as halogen, alkoxy, hydroxy, nitro or the like.
  • Xj and X u are preferably a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium, or ammonium compounds which are derived from ethylenediamine or amino acids. That is, the salt compounds of the organophosphorus compounds with organic or inorganic bases (for example sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylamm salt, ethanol salt, dicyclohexylamm salt, ethylene diamine salt, N, N -dibenzyiethylene diamine salt, etc.) and salts with amino acids (for example argim salt, aspartic acid salt, glutamic acid salt etc.) and the like are formed.
  • organic or inorganic bases for example sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylamm salt, ethanol salt, dicyclohexylamm salt, ethylene diamine salt, N, N -dibenzyiethylene diamine salt, etc
  • the compounds according to the formulas (I) to (IX) according to the invention can, in their protonated form, as the ammonium salt of organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, maleic acid, Mars acid, oxalic acid, tartaric acid, benzoic acid, etc. are present.
  • organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, maleic acid, Mars acid, oxalic acid, tartaric acid, benzoic acid, etc. are present.
  • the compounds according to the formulas (I), (IV) to (IX) according to the invention allow, for example, groups R, R, R 3 , R 4 , Xi, X 2 X J , XA, A 2 , A_, for chiral groups containing double bonds.
  • a 4 and the heterocycles increase the occurrence of spatial isomers.
  • the use of the compounds according to the invention encompasses all spatial isomers both as pure substances and in the form of mers Mixtures.
  • the organophosphorus compounds are particularly suitable for the therapeutic and prophylactic treatment of infections in humans and animals which are caused by viruses, bacteria, em- and multicellular parasites and fungi.
  • the compounds are active against unicellular parasites (protozoa), in particular against pathogens of malaria and sleeping sickness as well as Chagas disease, toxoplasmosis, amoebiasis, leishmaniasis, t ⁇ chomoniasis, pneumocystosis, balantidiosis, cryptosponiosis, sarcolocystosis, or Akanthamobose, Naeglerose, Coccidiosis, Giardiosis and Lambliosis.
  • the substances according to the invention can in particular be used against the following bacteria:
  • Bacteria of the genus Listeria in particular the species Listeria monocytogenes,
  • Bacteria of the genus Brucella, bacteria of the genus Bordetella, Bacteria of the genus Brucella, bacteria of the genus Bordetella,
  • Bacteria of the Neisse ⁇ aceae family in particular of the Neisseria and Moraxella genera, in particular the Neisse ⁇ a menmgitides, Neisseria gonorrhoeae and Moraxella bovis species, bacteria of the Vibrionaceae family, in particular of the Vibrio, Aeromonas, Plesiomonas and Photobacterium species, in particular the Vibrio cholerae and Vibromonasuillarum species, and Vibrioasuillarae salmonicidas,
  • Campylobacter Bacteria of the genus Campylobacter, in particular the species Campylobacter jejuni, Campylobacter coli and Campylobacter feet,
  • Bacteria of the Enterobacte ⁇ aceae family in particular of the genera Esche ⁇ chia, Klebsiella, Proteus, Providencia, Salmonella, Serratia and Shigella, Bacteria of the Pasteurellaceae family, especially of the genus Haemophilus,
  • Bacteria of the Bacillaceae family especially the genera Bacillus and Clostridium.
  • Organophosphorus compounds and their derivatives are therefore suitable for the treatment of diphtheria, acne vulga ⁇ s, listeriosis, erysipelas in animals, gas burns in humans and animals, para-noise burns in humans and animals, tuberculosis in humans and animals, leprosy and other mycobacteriosis in humans and animals, paratuberculosis in animals, plague, es- terial lympnadenitis and pseudotuberculosis in humans and animals, cholera, legionnaires' disease, Lyme disease in humans and animals, leptospirosis in humans and animals, syphilis, campylobacter ducklings in cafeterias and animals , Moraxella keratoconjunctivitis and serositis of animals, brucellosis of animals and humans, anthrax in humans and animals, nude omycosis in humans and animals, streptotrichoses, psittacosis
  • the use is also useful in rielicobacter eradication therapy for ulcers of the gastrointestinal tract.
  • Combinations with another antibiotic can also be used to treat the above-mentioned diseases.
  • Isoniazid, Rifampicm, Ethambutol, Pyrazmamid, Streptomycm, Protionamid and Dapson are particularly suitable for the treatment of tuberculosis for combination preparations with other antimfective agents.
  • the active compounds according to the invention can also be used in particular for infections with the following viruses: Parvovi ⁇ dae: Parvoviruses, Dependoviruses, Densoviruses, Adenovi ⁇ dae: Adenoviruses, Mastadenoviruses, Aviadenoviruses, Papovavi ⁇ dae: Papovaviruses, especially Papillomaviruses (so-called called wart viruses), poly ⁇ ma viruses, especially JC virus, BK
  • Herpesvi ⁇ dae all herpes viruses, in particular herpes simplex viruses, the Va ⁇ zellen / zoster viruses, human cytomegalovirus, Epstem-Barr viruses, all human herpes viruses, human herpes virus 6, human herpes virus 7, human herpes virus 8, Poxvi ⁇ dae: pox viruses, Orthopox, Parapox, Molluscum contagiosum virus, Aviviruses, Cap ⁇ viruses, Leporipoxviruses, all primarily hepatotropic viruses, hepatitis viruses: Hepatitis A viruses, Hepatitis B viruses, Hepatitis C viruses, Hepatitis D viruses, Hepatitis -E viruses, hepatitis F viruses, hepatits G viruses, hepadnaviruses: all hepatitis viruses, hepatitis B virus, hepatitis D viruses,
  • Picornaviridae Picornaviruses, all enteroviruses, all polioviruses, all Coxsackieviruses, all echoviruses, all Rh oviruses, hepatitis A virus, aphthoviruses, Calcivi ⁇ dae: hepatitis E viruses, Reovi ⁇ dae: reoviruses, orbiviruses, red viruses
  • Togaviridae Togaviruses, Alphaviruses, Rubiviruses, Pestiviruses, Rubelavirus,
  • Flaviviridae flaviviruses, TBE virus, hepatitis C virus, Orthomyxoviridae: all influenza viruses,
  • Paramyxovi ⁇ dae paramyxoviruses, morbillivirus, pneumovirus, measles virus, mumps virus,
  • Rhabdovirioae Rhabdoviruses, Rabies virus, Lyssavirus, viscous Sto atitisvirus, Coronaviridae: Coronaviruses,
  • Bunyavi ⁇ dae Bunyaviruses, Nairovirus, Phlebovirus, Uukuvirus, Hantavirus, Hantaanvirus,
  • Arenaviridae arenaviruses, ly phocytic chorioma mgitis virus,
  • Retrovi ⁇ dae retroviruses, all HTL viruses, human T-cell leukemia virus, oncornaviruses, spuvaviruses, lentiviruses, all HI viruses,
  • Filoviridae Marburg and Ebola viruses, slow virus infections, prions, onkoviruses, leukemia viruses,
  • organophosphorus compounds are therefore to be combated following viral infections:
  • the connections described, i.e. the organophosphorus compounds of the formulas (I), (IV) to (IX) and esters and amides thereof on the phosphono- or phosphomo group and salts thereof show a strong cytotoxic activity against bacteria, fungi, viruses, single and multicellular parasites. Accordingly, the compounds according to the invention are useful for the treatment of infectious diseases caused by viruses, bacteria, parasites and fungi in humans and animals. The compounds are also suitable for use in the prevention of diseases caused by viruses, bacteria, parasites and fungi, in particular as prophylaxis against malaria and as prophylaxis against sleeping sickness.
  • organophosphorus compounds according to the invention generally include pharmaceutically acceptable salts, amides, esters, a salt of such an ester, or compounds which, when applied, can provide the compounds according to the invention as metabolites or degradation products, also called “prodrugs” for administration in any suitable manner analogous to known anti-infectious agents (mixed with a non-toxic pharmaceutically acceptable carrier).
  • salts of the compounds include salts which contain the compounds of the formulas (I), (IV) to (IX) according to the invention in their protonated form as the ammonium salt of inorganic or organic acids, such as hydrochloric acid, sulfuric acid, citric acid, maleic acid, fumaric acid, tartaric acid , p-toluenesulfonic acid.
  • salts which are formed by a suitable selection of X 3 and X 4 , such as sodium salt, potassium salt, calcium salt, ammonium salt, ethanolamm salt, triethylamm salt, dicyclohexylamm salt and salts of an amino acid such as arg salt, aspartic acid salt, glutammic acid salt .
  • the activity of the substances is determined in a test system. This system is based on the measurement of the inhibition of the growth of bacteria, parasites, viruses, fungi or plants in vitro. For this purpose, test methods are used which are known to the person skilled in the art.
  • the inhibition of malaria parasite growth in blood cultures is determined to determine antimalaria activity.
  • the determination of the antibacterial activity is based on measuring the inhibition of bacteria growth on nutrient media and in liquid cultures.
  • the determination of the antiviral activity is based on innibition of the formation of viral elements in cell cultures.
  • the determination of the fungicidal activity is based on the inhibition of the growth of fungi on nutrient media and in liquid cultures.
  • Substances that show efficacy in m vitro measurement systems are further investigated in vivo models.
  • the antiparasitic, antiviral, fungicidal or antibacterial activity is further evaluated in the corresponding animal models.
  • the screen mg for herbicidal activity is determined by means of algae systems and measurement of the isoprene emission from plants under standard conditions.
  • the pharmaceutically active agents can be prepared in the form of pharmaceutical preparations in dosage units. This means that the preparation in the form of individual parts, e.g. B. tablets, dragees, capsules, pills, suppositories and ampoules are present, the W ⁇ r ⁇ stoff content a fraction or a multiple of a single dose.
  • the dosage units can e.g. B. 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose.
  • An Emzeldo. sis preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.
  • Non-toxic, inert pharmaceutically suitable carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.
  • Tablets, dragees, capsules, pills, granules, supposito ⁇ en, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations.
  • Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carrier substances, such as (a) tulle and extenders, e.g. B. starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. B. carboxymethyl cellulose, Algmate, gelatin, Polyvmylpyrrolidon, (c) humectant, for. B.
  • tulle and extenders e.g. B. starches, milk sugar, cane sugar, glucose, mannitol and silica
  • binders e.g. B. carboxymethyl cellulose, Algmate, gelatin
  • glycerin e.g. B. agar-agar, calcium carbonate and sodium carbonate, (e) solution delay, z. B. paraffin and (f) absorption accelerator, e.g. B. quaternary ammonium compounds, (g) wetting agents, eg. B. cetyl alcohol, glycermmonostearate, (h) adsorbent, e.g. B. kaolin and bentomite and (I) lubricants, e.g. B. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (I).
  • disintegrant e.g. B. agar-agar, calcium carbonate and sodium carbonate
  • e solution delay
  • z. B. paraffin e.g. B. quaternary ammonium compounds
  • wetting agents eg. B. cetyl alcohol, glycermmonostearate
  • adsorbent
  • the tablets, dragées, capsules, pills and granules can be provided with the customary coatings and casings, optionally containing opacifying agents, and can also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, possibly with a delay, where as Embedding compounds e.g. B. polymer substances and waxes can be used.
  • the active ingredient (s) can, if appropriate, also be present in microencapsulated form with one or more of the carrier substances specified above.
  • Supposito ⁇ en can contain the usual water-soluble or water-insoluble carriers, in addition to the active ingredient (s).
  • ointments, pastes, creams and gels can contain the usual carriers, e.g. B. animal and vegetable fats, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.
  • Powder and sprays can contain the usual carrier substances in addition to the active substance or substances, e.g. B. milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances.
  • Sprays can also use the usual blowing agents, e.g. B. chlorofluorocarbons.
  • Solutions and emulsions can in addition to the or ⁇ en active ingredients, the usual carriers such as solvents, solubilizers and emulsifiers, for.
  • solvents such as solvents, solubilizers and emulsifiers
  • ethyl alcohol isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils, especially cottonseedol, peanut oil, corn oil, olive oil, ricinusol and sesamol, glyceryl, alcohol formaldehyde, tetrahydrofuran , Polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.
  • solutions and emulsions can also be in sterile and blood isotonic form.
  • suspensions can contain the usual carriers such as liquid diluents, e.g. B. What- water, ethyl alcohol, propylene glycol, suspending agents, e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth or mixtures of these substances.
  • liquid diluents e.g. B. What- water, ethyl alcohol, propylene glycol
  • suspending agents e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth or mixtures of these substances.
  • the formulation forms mentioned can also contain colorants, preservatives and odor and taste-improved additives, e.g. B. peppermint oil and eucalyptus oil and sweeteners, e.g. B. saccharin.
  • the active compounds of the formulas (I), (IV) to (IX) are present in the abovementioned pharmaceutical preparations, preferably in a concentration of about 0.1 to 99.5 wt .-%, preferably from about 0.5 to ⁇ 95% by weight of the total mixture.
  • the pharmaceutical preparations can also contain further active pharmaceutical ingredients.
  • the compounds can be used with previously described substances with antibacterial, antiviral, antimvktoischer and antipa ⁇ rasitary properties. These include the ⁇ special compounds which have already found application in ⁇ r therapy or will be applied. To this end, in particular ⁇ are sondere suitable substances in the Red List or in Simon / Stille, antibiotic therapy in hospitals and practices, 9th edition 1998 Schattauer Verlag, or visit http: / www. customs. treas. ov / imb- exp / rulings / harmoniz / hrml29. html listed on the Internet.
  • organophosphorus compounds in the pharmaceutical compositions can be combined with sulfonamide, sulfadox, Artemismm, atovaquone, quinine, chloroqum, hydroxychloroqum, mefloqum, halofantrm, pyrimethamm, armesin, tetracyclme, doxycyclm, proguanil, metronantazil, praziqu Niclosamide, mebendazole, pyrantel, tiabendazole, diethylcarbazm, piperazm, py ⁇ vmum, metrifonate, oxamniqum, bithionol or suramm or several of these substances are present.
  • the preparation of the pharmaceutical preparations listed above is carried out in the usual way by known methods, for. B. by mixing the active substance or substances with the carrier substance or substances.
  • preparations mentioned can be used in humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), mtracisternally, intravaginally, mtraperitoneally, locally (powder, ointment, drops) and for the treatment of infections in cavities, body cavities.
  • Suitable preparations are injection solutions, solutions and suspensions for oral therapy, gels, infusion formulations, emulsions, ointments or drops.
  • ophthalmic and dermatological formulations silver and other salts, ear drops, eye ointments, powder or solutions can be used.
  • suitable formulations can also be ingested through feed or drinking water.
  • gels, powders, powders, tablets, prolonged-release tablets, premixes, concentrates, granules, pellets, tablets, boluses, capsules, aerosols, sprays, inhalants can be added Humans and animals can be used.
  • the compounds according to the invention can be incorporated into other carrier materials such as plastics, (plastic chains for local therapy), collagen or bone cement.
  • the active ingredient (s) of the formulas (I), (IV) to (IX) m total amounts from about 0.05 to about 600, preferably 0, 5 to 200 mg / kg body weight per 24 hours, if necessary in the form of several single doses, to achieve the desired results.
  • a single dose contains the active ingredient (s) preferably in quantities of about 1 to about 200, in particular 1 to 60 mg / kg body weight.
  • the compounds according to the invention can be given in the usual concentrations and preparations in animals together with the feed or with feed preparations or with the drinking water.
  • the compounds according to the invention can be used outstandingly as bactericides, fungicides and herbicides in plants.
  • 3-Oxo-cyclopentylphosphonic acid 1 0.52 mmol of trimethylsilyl triflate is added dropwise at 0 ° C. to 11.4 mmol of diethyl phosphite and 12.4 mmol of N, O-bis (trimethylsilyl) acetamide in 5 ml of dichloromethane. After 30 mm of stirring, 0.52 mmol of 2-cyclopenten-l-one is added dropwise at the same temperature and the mixture is stirred for 1 h. The enolsilane intermediate is hydrolyzed by 3 hours of stirring with 3 ml of 1N HC1. The organic phase is separated off, dried over magnesium sulfate and concentrated.
  • the reaction mixture is stirred 90 mm at room temperature, then to 40 ml of ice-cooled aqueous 10th % ⁇ ge ammonium chloride solution and extracted three times with methylene chloride with e 30 ml.
  • the combined organic phases are dried over MgSO 4 and the solvent is removed under reduced pressure. Oxime 1 can be reacted without further purification.
  • 3-N- (hydroxylamm) -cyclopentylphosphonic acid diethyl ester 1 (c) sodium cyanohydrin borate (NaBH 3 CN) is used without further purification.
  • 4 mmol of oxime 1 (b) dissolved in a little methanol are mixed with 2 drops of bromcresol green and 6 N KOH are added dropwise until a color change from yellow to green is observed.
  • 3 mmol of NaBH 3 CN are added, the mixture is stirred at room temperature for 3 h and quenched dropwise with methanol / HCl until a change in color from green to yellow is observed.
  • the reaction mixture is poured into 10 ml of water and adjusted to pH> 10 with 6N KOH.
  • the solution is extracted 5 times with 10 ml of chloroform, dried over MgSO 4 and removed under reduced pressure.
  • the yellow to red colored crude product can be cranographed on Si0 2 .
  • the pH is adjusted to 4.5-5 with 1N NaOH in aqueous solution.
  • the resulting 01 is boiled out several times in isopropanol, discarding the alkonol phase.
  • the residue is taken up in methanol until everything dissolves in the warmth and the product is precipitated with the help of Ethanoi. After filtration of the crude product, it can be recrystallized again from methanol / ethanol.
  • the hydrolysis of the tert-butyl ester 3 (b) can also be carried out by refluxing in benzene with the addition of trifluoroacetic acid (cf. Chem Ber 1975, 108, 1732-44) or in pure trifluoroacetic acid at room temperature (cf. rus, sulfur and silicon and related elements 1991, ⁇ i, 183-84).
  • Formohydroxamic acid 3 (d) is prepared by a method by Bernhard et al. J Am Chem Soc 1964, 86, 4406 from hydroylamine hydrochloride, potassium chloride and potassium hydroxide, all of which were used without further purification.
  • Formo-hydroxamic acid mp: 74-77 ° C.
  • 5-chloro-tetrahydrofuryl-2-phosphonic acid is stirred with a 2-fold excess of O-trimethylsilyl-formo-hydroxamic acid in absolute dimethylformamide for 4 hours at room temperature. After quenching with water, the mixture is concentrated under reduced pressure, taken up in water, concentrated again and the 01 chromatographed on cellulose.
  • Pyran derivative 4 can be prepared starting from 2,6-dichlorotetrahydropyran as described under 3.
  • 5- (Oxo-pyrrolidin-2-yl) -phosphonic acid diethyl ester 5 (a)
  • the 5-oxo-pyrrolidine derivative 5 (a) can be prepared according to a protocol by J. Oleksyszyn, E. Gruszecka, P. Kafafarski, P. Mastalerz , Monthsh Chem 1982, 113, 59-72 obtained by the following synthesis sequence: triethyl phosphite is reacted with methyl 3-chlorocarbonyl-propionate to give 4- (diethoxy-phosphoryl) -4-oxo-butyric acid methyl ester. This one the 4-oxo position is converted to the A m via the oxime.
  • 5-Thione-pyrrolidine-2-phosphonic acid diethyl ester 5 (b) 10 mmol of the oxo compound 5 (a) is converted into the thio compound 5 (b) by heating with PS ⁇ 0 in xylene.
  • the still hot xylene layer is decanted and the product is chromatographed on silica gel.
  • Oxime 5 (c) is reduced to hydroxylamm 5 (d) m
  • Methanol can be removed as a solvent.
  • 5- (N-hydroxyamino) pyrrolidine-2-phosphonic acid 5 phosphonic acid diethyl ester 5 (d) can be hydrolyzed in amounts of up to 2 g of phosphodiesterase, which is grown on carboxymethyl cellulose.
  • Piperidm-2-one-6-phosphonic acid diethyl ester (a) 6 (a) can be prepared analogously to 5 (a). If you heat 5-ammo-5- (diethoxy-phophoryl) pentanoic acid, it cyclizes to 6 (a).
  • 3-chloropropionylchloride instead of acrylic acid, converts it to the acid chloride, epoxidizes it with a peracid and opens the epoxide radically to obtain 3-chloro-2-hydroxy-propionylchloride. This can be implemented as in Example 7a.
  • the formylation can be done in analogy to the description below
  • Example 7a are carried out.
  • the starting point for X can be threonic acid, threose / erythrose or the 2.3.4.4-tetrachlorobutyryl chloride (C1 2 C-CHC1-CHC1-C0C1) known in the literature.

Abstract

L'invention concerne l'utilisation de composés organiques de phosphore de la formule générale (I) dans laquelle B est soit un groupe éther de la formule (II) ou un groupe céto de la formule (III) ou bien un composé cyclique pentagonal ou hexagonal. L'invention concerne également leur utilisation pour la fabrication de médicaments en vue du traitement ou de la prévention d'infections chez l'homme et l'animal, provoquées par des virus, des bactéries, des champignons et des parasites, ainsi que leur utilisation comme fongicide, bactéricide et herbicide chez les végétaux.
EP99936505A 1998-07-15 1999-07-09 Composes organiques de phosphore et leur utilisation Withdrawn EP1095050A1 (fr)

Applications Claiming Priority (5)

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DE19831639 1998-07-15
DE19831639A DE19831639C1 (de) 1998-07-15 1998-07-15 Phosphororganische Verbindungen und ihre Verwendung
DE19843360A DE19843360A1 (de) 1998-09-22 1998-09-22 Phosphororganische Verbindungen und ihre Verwendung
DE19843360 1998-09-22
PCT/EP1999/004827 WO2000004031A1 (fr) 1998-07-15 1999-07-09 Composes organiques de phosphore et leur utilisation

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NO20010200L (no) 2001-03-14
JP2002520419A (ja) 2002-07-09
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KR20010070962A (ko) 2001-07-28
CA2336143A1 (fr) 2000-01-27
US20050075511A1 (en) 2005-04-07
EA200100143A1 (ru) 2001-06-25
IS5784A (is) 2000-12-21
IL140433A0 (en) 2002-02-10
HUP0103481A2 (en) 2002-06-29
AU5158099A (en) 2000-02-07
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TR200100068T2 (tr) 2001-06-21
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AU754165B2 (en) 2002-11-07
US20030045746A1 (en) 2003-03-06
CN1309659A (zh) 2001-08-22
PL345864A1 (en) 2002-01-14
HUP0103481A3 (en) 2003-01-28
NO20010200D0 (no) 2001-01-12
BR9912062A (pt) 2001-04-03
EE200100027A (et) 2002-06-17
US6812224B2 (en) 2004-11-02
WO2000004031A1 (fr) 2000-01-27
AP2001002051A0 (en) 2001-03-31

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