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WO2000003699A2 - Medicaments contenant des derives d'acide phosphonique comme principe actif et leur utilisation - Google Patents

Medicaments contenant des derives d'acide phosphonique comme principe actif et leur utilisation Download PDF

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Publication number
WO2000003699A2
WO2000003699A2 PCT/EP1999/004832 EP9904832W WO0003699A2 WO 2000003699 A2 WO2000003699 A2 WO 2000003699A2 EP 9904832 W EP9904832 W EP 9904832W WO 0003699 A2 WO0003699 A2 WO 0003699A2
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viruses
substituted
genus
bacteria
unsubstituted
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WO2000003699A3 (fr
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Jomaa Hassan
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    • 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
    • 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
    • A61P33/00—Antiparasitic agents
    • 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

Definitions

  • the invention relates to medicaments containing phosphonic acid derivatives and their salts, esters and amides as active ingredients, and to their use in the manufacture of medicaments for the therapeutic and prophylactic treatment of infections in humans and animals which are caused by viruses, bacteria, fungi and parasites.
  • the object of the present invention is therefore to develop a medicament which can be used universally in infections by viruses, bacteria, fungi and parasites in humans and animals and which fulfills the conditions specified above.
  • This object is achieved in a completely surprising manner by the group of substances defined in claim 1.
  • This group of substances shows an anti-infectious effect against viruses as well as bacteria, fungi and single and multicellular parasites.
  • these compounds have a fungicidal, bactericidal and herbicidal activity in plants.
  • Ai and A 2 can either be eliminated or one can be the same or different and are selected from the group containing an alkylene radical, an alkenylene radical and a hydroxyalkylene radical, and preferably the carbon chain -A ⁇ -CHOH-A 2 - from 2 to 5 carbon atoms, particularly preferably consists of 3-4 carbon atoms, B is selected from the group consisting of a radical of the formula
  • Ri is selected from the group consisting of hydrogen, OH, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical and halogen consists of a radical of the formula (VI)
  • R 2 / R 3 and R 4 are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen, and a radical of the formula (VII)
  • Rsr R ⁇ and R? are the same or different and are selected from the group consisting of hydrogen, OH, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted Cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen, where X 3 or X 4 may be the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted Hydroxylalkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substitute
  • Ri in formula (V) is preferably a methyl group.
  • R 2 and R 4 are preferably hydrogen and R 3 is a methyl group.
  • R 5 is preferably a methyl group
  • R 6 is selected from the group consisting of H, OH and methyl
  • R 7 is a hydroxy group.
  • the compounds of the formula are preferred
  • a 2 is an unbranched hydroxyalkylene with 1 to 3 carbon atoms and
  • X 3 and X 4 are the same or different and are selected from the group consisting of hydrogen, a metal of the first, second or third main group of the periodic table, in particular sodium, potassium, and methyl, ethyl.
  • a 2 is an unbranched hydroxyalkylene with 1 to 3 carbon atoms and
  • X 3 and X 4 are the same or different and are selected from the group consisting of hydrogen, a metal of the first, second or third main group of the periodic table, in particular sodium, potassium, methyl and ethyl.
  • a 2 is an unbranched hydroxyalkylene or an unbranched alkylene and consists of 1 to 3 carbon atoms and X 3 and X 4 are identical or different and are selected from the group consisting of hydrogen, a metal of the first, second or third main group of the Periodic table, especially sodium, potassium, and methyl, ethyl.
  • Acyl is a substituent derived from an acid, such as from an organic carboxylic acid, carbonic acid, carbamic acid or the thioic acid or imidic acid corresponding to the individual acids above, 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 carbamimidoyl. 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, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.
  • Alkyl carbamoyl e.g. methyl carbamoyl etc.
  • N-alkyl thiocarbamyl e.g. (N-methyl) thiocarbamoyl etc.
  • Alkylcarba imidoyl 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, can optionally have one or more suitable substituents, such as amino, 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. alkanoyl substituted with amino, carboxy, amino and carboxy, halogen, acylamino or the like.
  • suitable substituents such as amino, halogen (for example fluorine, chlorine, bromine etc.), hydroxy, hydroxyimino, Carboxy, alkoxy (e.g. methoxy, eth
  • Aromatic acyl radicals are those acyl radicals which originate from an acid having a substituted or unsubstituted aryl group, where the aryl group can include phenyl, toluyl, xylyl, naphthyl and the like; suitable examples are given below: Aroyl (e.g., benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl etc.);
  • Aralkanoyl e.g. phenylacetyl etc.
  • Aralkenoyl e.g. cinnamoyl etc.
  • Aryloxyalkanoyl e.g. phenoxyacetyl etc.
  • Arylthioalkanoyl e.g. phenylthioacetyl etc.
  • Arylaminoalkanoyl e.g. N-phenylglycyl, etc.
  • Arenesulfonyl e.g. benzenesulfonyl, tosyl or toluenesulfonyl,
  • Aryloxycarbonyl e.g. phenoxycarbonyl, naphthyloxycarbonyl etc.
  • Aralkoxycarbonyl e.g. benzyloxycarbonyl etc.
  • Arylcarbamoyl e.g. phenylcarbamoyl, naphthylcarbamoyl etc.
  • Arylglyoxyloyl e.g. phenylglyoxyloyl etc.
  • aromatic hydrocarbon part in particular the aryl radical
  • aliphatic hydrocarbon part in particular the alkane radical
  • suitable substituents such as those which are suitable as substituents for the alkyl group or the alkane residue have already been specified.
  • arylanoyl substituted with halogen and hydroxy or with halogen and acyloxy and aralkanoyl substituted with hydroxy, hydroxyimino, dihalogenalkanoyloxyimino are also given
  • Arylthiocarbamoyl e.g. phenylthiocarbamoyl etc.
  • Arylcarbamimidoyl e.g. phenylcarbamimidoyl etc.
  • a heterocyclic acyl radical is understood to mean an acyl radical 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, nicotinoyl etc.); - ö -
  • Heterocycle alkanoyl in which the heterocyclic radical is 5- to 6-membered and has at least one heteroatom from the group consisting of nitrogen, oxygen and sulfur (for example thiophenyl-acetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino- 4-thiazolyl) -2-methoxyiminoacetyl etc.) and the like.
  • nitrogen, oxygen and sulfur for example thiophenyl-acetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino- 4-thiazolyl) -2-methoxyiminoacetyl etc.
  • heterocyclic acyl radicals the heterocycle and / or the aliphatic hydrocarbon part may optionally have one or more suitable substituents, such as the same ones that 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, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.
  • Hydroxylalkyl is a straight or branched chain alkyl radical with up to 9 carbons, which has at least one hydroxyl group, preferably one or two hydroxyl groups.
  • Alkenyl includes straight-chain or branched-chain alkenyl groups with up to 9 carbon atoms, such as, for example, vinyl, propenyl (for example 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl, Hexenyl.
  • Alkynyl includes straight or branched chain alkynyl groups with up to 9 carbon atoms.
  • Cycloalkyl preferably represents an optionally substituted C3-C7-cycloalkyl; possible substituents include Alkyl, alkenyl, alkynyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc.), nitro and the like are suitable.
  • Aryl is an aromatic hydrocarbon radical, such as phenyl naphthyl etc., which may optionally have one or more suitable substituents, such as alkyl, alkenyl, alkynyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc.), nitro and the like.
  • suitable substituents such as alkyl, alkenyl, alkynyl, 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, trityl 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 1 to 9, such as methylene, Ethylene, trimethylene, methylethylene, tetramethylene, 1-methyltrimethylene, 2-ethylethylene, pentamethylene, 2-methyltetramethylene, isopropylethylene, hexamethylene, and the like, preferred alkylene radicals have up to 4 carbon atoms and radicals with 3 carbon atoms such as, for example, are particularly preferred Trimethylene.
  • Alkenylene includes straight or branched chain alkenylene groups with up to 9 carbon atoms, which can be represented by the formula ⁇ (C n H 2n -2) -, in which n is an integer from 2 to 9, for example Vinylene, 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.
  • “Hydroxyalkylene” can include straight-chain or branched-chain alkylene radicals which have up to 9 carbon atoms, at least one selected carbon atom being substituted by a hydroxy group; these radicals can be represented by the formula - (C n H 2n _ z ) (OH) 2 - in which n is an integer from 1 to 9 and z is an integer to which 1 ⁇ z ⁇ n.
  • Suitable examples of such hydroxyalkylene groups include hy- droxymethylene, hydroxyethylene (e.g. 1-hydroxyethylene and 2-hydroxyethylene), hydroxytrimethylene (e.g. 1-hydroxytrimethylene, 2-hydroxytrimethylene and 3-hydroxytrimethylene), hydroxytetramethylene (e.g.
  • 2-hydroxytetramethylene 2-hydroxy-2-methyltrimethylene
  • hydroxypentamethylene eg 2-hydroxypentamethylene
  • hydroxyhexamethylene eg 2-hydroxyhexamethylene
  • 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 radicals X 3 and X 4 can preferably be chosen such that esters are formed on the phosphono group.
  • Suitable examples of such esters according to formulas (I), (II), (III) and (IV) include suitable mono- and diesters, and preferred examples of such esters include alkyl esters (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, Butyl esters, isobutyl esters, hexyl esters, etc.);
  • Aralkyl esters (benzyl esters, phenethyl esters, benzhydryl esters, trityl esters, etc.);
  • Aryl esters e.g. phenyl esters, tolyl esters, naphthyl esters, etc.
  • Aroyl alkyl esters e.g. phenacyl esters etc.
  • silyl esters e.g., trialkylhalosilyl, dialkyldihalosilyl, alkyltrihalosilyl, dialkylarylhalosilyl, trialkoxyhalosilyl, dialkylaralkylhalosilyl, dialkoxydihalosilyl, trialkoxyhalosilyl, etc.
  • the alkane and / or arene portion can optionally have at least one suitable substituent such as halogen, alkoxy, hydroxy, nitro or the like.
  • X 3 and X 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 phosphonic acid derivatives with organic or inorganic bases (for example sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylactic min salt, ethanolamine salt, dicyclohexylamine salt, ethylenediamine salt, N, N "-dibenzylethylenediamine salt etc.) and salts with amino acids (for example arginine salt, aspartic acid salt, glutamic acid salt etc.) and the like.
  • organic or inorganic bases for example sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylactic min salt, ethanolamine salt, dicyclohexylamine salt, ethylenediamine salt, N, N "-dibenzylethylenediamine
  • the compounds of the formulas (I), (II), (III) or (IV) according to the invention can be used 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, fumaric 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, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc. are present.
  • the compounds of the formulas (I), (II), (III) or (IV) according to the invention can be used, for example, for double bonds containing or chiral groups R 1, R 2 , R 3 , R, R 5 , R ⁇ , R, X 3 , X or Ai or A 2 the occurrence of spatial isomers.
  • the compounds according to the invention include all spatial isomers both as pure substances and in the form of their mixtures.
  • the phosphonic acid derivatives are suitable for the therapeutic and prophylactic treatment of infections in humans and animals which are caused by viruses, bacteria, single 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, amoebic dysentery, Leishmaniosis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcolocystosis, the Akanthamöbose, Naeglerose, coccidiosis, Giardiose and Lambliose.
  • the active compounds according to the invention can be used in particular 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 Neiseriaceae family in particular of the Neisseria and Moraxella genera, in particular the Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis species, bacteria of the Vibrionaceae family, in particular of the Vibrio, Aeromonas, Plesiomonas and Photobacterium species, in particular the Vibrio cholerum, Vibrio angular species and Aeromonas salmonicidas,
  • Campylobacter Bacteria of the genus Campylobacter, in particular the species Campylobacter jejuni, Campylobacter coli and Campylobacter fe- tus,
  • Bacteria of the Enterobacteriaceae family in particular of the genera Escherichia, Klebsieila, Proteus, Providencia, Salmonella, Serratia and Shigella,
  • Bacteria of the Bacillaceae family especially the genera Bacillus and Clostridium.
  • the organic compounds according to the invention and their derivatives are therefore suitable for the treatment of diphtheria, acne vulgaris, listeriosis, erysipelas in animals, gas fires 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, mesenteric lymphadenitis and pseudotuberculosis in humans and animals, cholera, legionnaires' disease, Lyme disease in humans and animals, leptospirosis in humans and animals, syphilis, Campylobacter enteritis in humans and animals, Moraxella - Keratoconjunctivitis and serositis of animals, brucellosis of animals and humans, anthrax in humans and animals, actinomycosis in humans and animals, streptotrichoses, psittaco- se / ornithosis in animals, and Q
  • the use is also useful in Helicobacter eradication therapy for ulcers of the gastrointestinal tract.
  • a combination with another antibiotic can also be used to treat the above-mentioned diseases.
  • Isoniazid, rifampicin, ethambutol, pyrazineid, streptomycin, protionamide and dapsone are particularly suitable for the treatment of tuberculosis for combination preparations with other anti-infectives.
  • the active compounds according to the invention can also be used, in particular, for infections with the following viruses: Parvoviridae: Parvoviruses, Dependoviruses, Densoviruses, Adenoviridae: Adenoviruses, Mastadenoviruses, Aviadenoviruses, Papovaviridae: Papovaviruses, in particular Papillomaviruses (so-called Wartsviruses, in particular J virus viruses, Polyvirus viruses, Polyvirus viruses, especially virus viruses, J virus viruses, polyvirus viruses, polyvirus viruses, especially virus viruses, polyvirus viruses, polyvirus viruses, polyvirus viruses, especially virus viruses, poly virus viruses, , and miopapovaviruses,
  • Parvoviridae Parvoviruses, Dependoviruses, Densoviruses
  • Adenoviridae Adenoviruses
  • Mastadenoviruses Aviadenoviruses
  • Papovaviridae Papovaviruses, in particular
  • Herpesviridae all herpes viruses, especially herpes simplex viruses, the varicella / zoster viruses, human cytomegalovirus, Epstein-Barr viruses, all human herpes viruses, human herpes virus 6, human herpes virus 7, human herpes virus 8, Poxviridae: pox viruses, Orthopox, Parapox, Molluscum contagiosum virus, aviviruses, capriviruses, leporipox viruses, all primarily hepatotropic viruses, hepatitis viruses: hepatitis A viruses, hepatitis B viruses, hepatitis C viruses, hepatitis D viruses, hepatitis E viruses -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 rhinoviruses, hepatitis A virus, aphthoviruses, Calciviridae: hepatitis E viruses, Reoviridae: reoviruses, orbiviruses, rotaviruses
  • Togaviridae Togaviren, Alphaviren,, Rubiviren, Pestiviren, Rubellavirus,
  • Flaviviridae flaviviruses, TBE virus, hepatitis C virus, Orthomyxoviridae: all influenza viruses, Paramyxoviridae: paramyxoviruses, morbillivirus, pneumovirus, measles virus, mumps virus,
  • Rhabdoviridae rhabdoviruses, Rabies virus, Lyssavirus, viscous stomatitis virus, Coronaviridae: Coronaviruses,
  • Bunyaviridae Bunyaviren, Nairovirus, Phlebovirus, Uukuvirus, Hantavirus,
  • Arenaviridae arenaviruses, lymphocytic choriomeningitis virus,
  • Retroviridae retroviruses, all HTL viruses, human T-cell leukemia virus, oncornaviruses, spumaviruses, lentiviruses, all HI viruses,
  • Filoviridae Marburg and Ebola viruses, slow virus infections, prions, onkoviruses, leukemia viruses.
  • the active compounds according to the invention are therefore suitable for combating the following viral infections:
  • the agents are suitable for combination with other agents with antiviral properties.
  • connections described i.e. the phosphonic acid derivatives according to formulas (I), (II), (III) and (IV) and esters and amides thereof on the phosphono group and salts thereof show a strong cytotoxic activity against single and multicellular parasites, fungi, bacteria and viruses.
  • the compounds of the invention are useful for the treatment of infectious diseases caused by viruses, bacteria, parasites and fungi in humans and animals.
  • the compounds are also suitable for use in preventing diseases caused by viruses, bacteria, parasites and fungi.
  • the phosphonic acid derivatives according to the invention generally include pharmaceutically acceptable salts, amides, esters, a salt of such an ester, or else compounds which, when applied, provide the compounds according to the invention as metabolites or degradation products, also “prodrugs”.
  • prodrugs can be prepared 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 the compounds of the formulas (I), (II), (III) and (IV) 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, Form fumaric acid, tartaric acid, p-toluenesulfonic acid.
  • inorganic or organic acids such as hydrochloric acid, sulfuric acid, citric acid, maleic acid, Form fumaric acid, tartaric acid, p-toluenesulfonic acid.
  • salts which are formed by suitable selection of X 3 and X, such as sodium salt, potassium salt, calcium salt, ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt and salts of an amino acid such as arginine salt, aspartic acid salt, glutamic acid salt.
  • the pharmaceutically active agents can be 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 active ingredient content of which corresponds to 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.
  • a single dose 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.
  • Preferred pharmaceutical preparations are tablets, dragées, capsules, pills, granules, suppositories, solutions, _ _
  • Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. B. starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. B. carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, (c) humectants, for. B. glycerin, (d) disintegrant, e.g. B.
  • fillers and extenders e.g. B. starches, milk sugar, cane sugar, glucose, mannitol and silica
  • binders e.g. B. carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone
  • agar-agar calcium carbonate and sodium carbonate
  • solution retarders e.g. B. paraffin
  • absorption accelerator e.g. B. quaternary ammonium compounds
  • wetting agents e.g. B. cetyl alcohol, glycerol monostearate
  • adsorbent e.g. B. kaolin and bentonite
  • lubricants e.g. B. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).
  • the tablets, dragees, 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.
  • Embedding compounds e.g. B. polymer substances and waxes can be used.
  • the active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Suppositories can contain the usual water-soluble or water-insoluble excipients in addition to the active ingredient (s), e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat and higher esters (z. B. C14 alcohol with C16 fatty acid) or mixtures of these substances.
  • active ingredient e.g. B. polyethylene glycols
  • fats e.g. B. cocoa fat and higher esters (z. B. C14 alcohol with C16 fatty acid) or mixtures of these substances.
  • Ointments, pastes, creams and gels can contain the usual excipients in addition to the active ingredient (s), e.g. B. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures thereof Fabrics.
  • active ingredient e.g. B. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures thereof Fabrics.
  • Powder and sprays can contain the usual excipients in addition to the active ingredient (s), 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 contain the usual carriers such as solvents, solubilizers and emulsifiers, e.g. B. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol, glyceryl alcohol, tetra-alcohol, formaldehyde , Polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.
  • solvents e.g. B. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, di
  • 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. water, ethyl alcohol, propylene glycol, suspending agents, e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth or mixtures of these substances.
  • liquid diluents e.g. B. water, ethyl alcohol, propylene glycol
  • suspending agents e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, 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), (II), (III) and (IV) should be in the pharmaceutical preparations listed above, preferably in a concentration of about 0.1 to 99.5% by weight, preferably of about 0, 5 to 95% by weight of the total mixture to be available.
  • the pharmaceutical preparations can also contain further active pharmaceutical ingredients.
  • the phosphonic acid derivatives in the pharmaceutical compositions can be used in combination with sulfonamide, sulfadoxine, artisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracyclines, doxycycline, proguanil, metronidazole, nicazamid, praziquantilane, praziquantilane , Tiabendazole, Diethylcarbazin, Piperazin, Pyrivinum, Metrifonat, Oxamniquin, Bithionol or Suramin or several of these substances are present.
  • the pharmaceutical preparations listed above are prepared in a conventional manner by known methods, e.g. B. by mixing the active ingredient (s) with the excipient (s).
  • preparations mentioned can be used in humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally, locally (powder, ointment, drops) and for the therapy of infections in cavities, body cavities.
  • Suitable preparations are injection solutions, solutions and suspensions for oral therapy, gels, pour-on 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 used in humans and animals.
  • the compounds for the medicaments according to the invention can be incorporated into other carrier materials such as plastics, (plastic chains for local therapy), collagen or bone cement. be tested.
  • the active compound (s) of the formula (I), (II), (III) and (IV) in a total amount of from about 0.05 to about 600 , preferably 1 to 200 mg / kg body weight per 24 hours, if necessary in the form of several individual doses, to achieve the desired results.
  • a single dose contains the active ingredient (s) preferably in amounts of about 1 to about 200, in particular 3 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.
  • the main product is 2,4-di-0-isopropylidene-3-hydroxy-2-methylpentane-1,5-dialdehyde.
  • By-products are the bisphosphonic acid tetramethyl ester and 1, 3-dihydroxy-2, 4-0-isopropylidene-2-methyl-l-phosphonic acid di ethyl ester.
  • the starting point is 1, 3, 4-trihydroxybutan-2-one, which, as described above, via the Grignard reaction, the oxidation with aqueous sodium periodate solution and the isopropylidene sugar with dimethyl phosphite to give 1-hydroxy-2, 3-0-isopropylidene 3-methyl-4-butanal-1-phosphonic acid methyl ester is reacted, which can be hydrolyzed to the product using an acidic ion exchanger.

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Abstract

L'invention concerne des médicaments contenant au moins un dérivé d'acide phosphonique de la formule générale (I), dans laquelle B répond à la formule (V), à la formule (VI) ou à la formule (VII), et leurs sels, esters et amides, pharmaceutiquement acceptables, ainsi que les sels de ces esters, comme principe actif. Elle concerne également l'utilisation de ces composés pour la fabrication de médicaments servant à la prévention et au traitement d'infections par des virus, des champignons, des bactéries ou des parasites.
PCT/EP1999/004832 1998-07-15 1999-07-09 Medicaments contenant des derives d'acide phosphonique comme principe actif et leur utilisation Ceased WO2000003699A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU50348/99A AU5034899A (en) 1998-07-15 1999-07-09 Drugs containing phosphoric acid derivatives as active ingredient and their use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19831638.0 1998-07-15
DE19831638 1998-07-15

Publications (2)

Publication Number Publication Date
WO2000003699A2 true WO2000003699A2 (fr) 2000-01-27
WO2000003699A3 WO2000003699A3 (fr) 2000-08-10

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/004832 Ceased WO2000003699A2 (fr) 1998-07-15 1999-07-09 Medicaments contenant des derives d'acide phosphonique comme principe actif et leur utilisation

Country Status (2)

Country Link
AU (1) AU5034899A (fr)
WO (1) WO2000003699A2 (fr)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4206156A (en) * 1976-07-27 1980-06-03 Fujisawa Pharmaceutical Company, Limited Hydroxyaminohydrocarbonphosphonic acids
GB1580899A (en) * 1976-07-27 1980-12-10 Fujisawa Pharmaceutical Co Hydroxyaminohydrocarbonphosphonic acid derivatives and production and use thereof
DE2941384A1 (de) * 1979-10-12 1981-04-23 Bayer Ag, 5090 Leverkusen Phosphono-hydroxy-essigsaeure, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel
US4846872A (en) * 1986-08-11 1989-07-11 Fujisawa Pharmaceutical Co., Ltd. Herbicide

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AU5034899A (en) 2000-02-07

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