WO2001093872A1 - Use of organophosphorous hydroxamic acid derivatives for producing medicaments - Google Patents

Use of organophosphorous hydroxamic acid derivatives for producing medicaments Download PDF

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Publication number
WO2001093872A1
WO2001093872A1 PCT/EP2001/006539 EP0106539W WO0193872A1 WO 2001093872 A1 WO2001093872 A1 WO 2001093872A1 EP 0106539 W EP0106539 W EP 0106539W WO 0193872 A1 WO0193872 A1 WO 0193872A1
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substituted
viruses
genus
unsubstituted
bacteria
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PCT/EP2001/006539
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German (de)
French (fr)
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Hassan Jomaa
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Jomaa Pharmaka Gmbh
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Priority to AU2001279649A priority Critical patent/AU2001279649A1/en
Publication of WO2001093872A1 publication Critical patent/WO2001093872A1/en

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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
    • 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
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • A61P31/10—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
    • C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
    • C07F9/301—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
    • C07F9/3808—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
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • C07F9/5304—Acyclic saturated phosphine oxides or thioxides
    • 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
    • C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
    • 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
    • C07F9/58—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
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
    • 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
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07F9/6533—Six-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
    • C07F9/655—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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the use of organophosphorus hydroxamic acid derivatives and their salts, esters and amides for the therapeutic and prophylactic treatment of infections.
  • the object of the present invention is therefore to provide a substance which can be used universally in infections by viruses, bacteria, fungi and parasites in humans and animals and which fulfills the conditions specified above.
  • Phosphonomethylglycylhydroxamic acid and its salts have already been described as herbicides in European Patent Publication No. 0 039 310.
  • A is selected from the group consisting of -CR 5 Pv6-, -CR 5 R ⁇ ; CH (OH) -, - CRsReCO- and - COCR5R5-, in which Ri is selected from the group consisting of hydrogen , substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted alkylcycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted and unsubstituted heterocyclic radical, substituted and unsubstituted alkyl heterocyclic radical, a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium and ammonium compounds which
  • R t is preferably a hydrogen, a metal of the first, second or third main group of the periodic table, such as Na, K, Ca, Mg, Al, Cu and ammonium, substituted ammonium and ammonium compounds which are derived from ethylenediamine or amino acids.
  • Rg and R are preferably selected independently from the group consisting of hydrogen, methyl, ethyl, OXg and OX, OXg and OX 9 preferably being selected from the group consisting of the first, second or third main group of the periodic table, such as Na , K, Ca, Mg, Al, Cu and ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids.
  • 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, triethylamine salt, ethanolamine salt, dicyclohexylamine salt, ethylene diamine salt, N, N'-dibenzylethylenediamine salt etc.
  • salts with amino acids eg arginine salt, aspartic acid salt, glutamic acid salt etc.
  • 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 each being aliphatic, aromatic and / or heterocyclic Include groups in the molecule as well as carbamoyl or carbamimidoyl.
  • acyl groups are given below.
  • -— 'As aliphatic acyl groups are derived from an aliphatic acid
  • 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 thiocarbamoyl e.g. (N-methyl) thiocarbamoyl etc.
  • Alkyl carbamimidoyl e.g. methyl carbamimidoyl etc.
  • 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, hydroxyl ino , 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, hydroxyl ino , Carboxy, alkoxy (e.g. methoxy
  • 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:
  • Aroyl e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl etc.
  • Aralkanoyl e.g. phenylacetyl etc.
  • Aralkenoyl e.g. cinnamoyl etc.
  • Aryloxyalkanoyl e.g. phenoxyacetyl etc.
  • Arylthioalkanoyl e.g. phenylthioacetyl etc.
  • Arylaminoalkanoyl e.g. N-phenylglycyl, etc.
  • Arenesulfonyl e.g. benzenesulfonyl, tosyl or toluenesulfonyl, naphthalenesulfonyl etc.
  • Aryloxycarbonyl e.g. phenoxycarbonyl, naphthyloxycarbonyl etc.
  • Aralkoxycarbonyl e.g. benzyloxycarbonyl etc.
  • Arylcarbamoyl e.g. phenylcarbamoyl, naphthylcarbamoyl etc.
  • Arylglyoxyloyl e.g. phenylglyoxyloyl etc.
  • aromatic hydrocarbon part in particular the aryl radical
  • aliphatic hydrocarbon part in particular the alkane radical
  • suitable substituents such as those which are suitable substituents for the alkyl group or the alkane radical 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 (e.g. thiophenyl, furoyl, pyrrolocarbonyl, nicotinoyl etc.);
  • 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 thiophene-ylacetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino-4- thiazolyl) -2-methoxyiminoacetyl etc.) and the like.
  • nitrogen, oxygen and sulfur for example thiophene-ylacetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino-4- thiazolyl) -2-methoxyiminoacetyl etc.
  • heterocyclic acyl groups the heterocycle and / or the aliphatic hydrocarbon portion may optionally have one or more suitable substituents, such as the same ones that have been stated to be suitable for alkyl and alkane groups.
  • Alkyl is a straight or branched chain alkyl radical having up to 18 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.
  • Alkenyl includes straight-chain or branched-chain alkenyl groups with up to 18 carbon atoms, such as vinyl, propenyl (eg 1-propenyl, 2-propenyl), 1- Methyl propenyl, 2-methyl propenyl, butenyl, 2-ethyl propenyl, pentenyl, hexenyl.
  • Alkynyl includes straight or branched chain alkynyl groups with up to 18 carbon atoms.
  • Cycloalkyl stands for an optionally substituted C3-C-cycloalkyl or a bi- or tricycloalkyl from C 3 -C 7 rings; Possible substituents include alkyl, alkenyl, alkynyl, alkoxy (eg methoxy, ethoxy etc.), halogen (eg fluorine, chlorine, bromine etc.), nitro and the like.
  • a heterocyclic radical is accordingly a cycloalkyl as defined above in which one, two or more carbon atoms in the ring are independently replaced by oxygen, nitrogen or sulfur atoms.
  • 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 can optionally have one or more suitable substituents such as alkoxy (eg methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc.), nitro and the like.
  • the alkane and / or arene portion can optionally have at least one suitable substituent such as halogen, alkoxy, hydroxy, nitro or the like.
  • the compounds of the formula (I) according to the invention can be 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, Ti enoic 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, Ti enoic acid, etc. are present.
  • the compounds of the formula (I) used according to the invention allow, for example for double-containing or chiral groups R 1 to R 9 , Xi, Xg, X 9 and A, the occurrence of spatial isomers.
  • the use of the compounds according to the invention includes all spatial isomers both as pure substances and in the form of their mixtures.
  • organophosphorus compounds are particularly 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, leishmaniasis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis and sarcomocystosis , Akanthamöbose, Naeglerose, Coccidiosis, Giardiosis and Lambliosis.
  • malaria prophylaxis and as a prophylaxis of sleeping sickness and Chagas disease, toxoplasmosis, amoebic dysentery, Leishmaniasis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcolocystosis, acanthambidosis, cocoonosis, and naeglerosis the Giardiose and the Lam- ⁇ bliose suitable.
  • the active compounds according to the invention can be used in particular against the following bacteria:
  • Bacteria of the Propionibacteriaceae family in particular the Propionibacterium genus, in particular the Propionibacterium acnes species, Actinomycetaceae bacteria, in particular the Actinomyces genus, Corynebacterium bacteria, in particular the Corynebacterium diphteriae and Corynebactercoderobacterium family, pseudoteaculoid bacterium, family of bacteria Genus Mycobacterium, in particular the species Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium, bacteria of the Chlamydiaceae family, in particular the species Chlamydia trachomatis and Chlamydia psittaci, bacteria of the genus Listeria bacteria, in particular the type Lymphia monocytosis Erythipathus, especially the species Logenia, especially the type Logenia tris , Bacteria of the genus Clostridium, bacteria of the
  • Organophosphorus compounds and their derivatives are therefore suitable for the treatment of diphtheria, acne vulgaris, 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, 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 in animals, brucellosis in animals and humans, anthrax in humans and animals, actinomycosis in humans and animals, streptotrichoses, psittacosis / ornithosis in animals, Q fever, Ehrlich
  • 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, pyrazinamide, streptomycin, protionamide and dapsone are particularly suitable for the treatment of tuberculosis for combination preparations with other anti-infectives.
  • the active substances according to the invention can also be used in particular for infections with the following viruses:
  • Parvoviridae parvoviruses, dependoviruses, densoviruses, adenoviridae: adenoviruses, mastadenoviruses, aviadenoviruses, papovaviridae: papovaviruses, in particular papillomaviruses (so-called wart viruses), polyomaviruses, in particular JC virus, herpes virus, and herpes virus, and virus virus virus, 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,
  • Picornaviridae Picornaviruses, all enteroviruses, all polioviruses, all Coxsackieviruses, all echo viruses, all rhino viruses, hepatitis A virus, aphthoviruses, Calciviridae: Hepatitis E virus, Reoviridae: reovirus, Orbi virus, rotavirus, Togaviridae: togaviruses, alphaviruses, rubiviruses, pestiviruses, rubella virus, Flaviviridae: flavivirus, TBE virus , hepatitis C virus, Orthomyxoviridae: All influenza viruses, Paramyxoviridae: paramyxovirus, morbillivirus, pneumovirus, measles virus, mumps virus, Rhabdoviridae: rhabdovirus, rabies virus, Lyssavi- rus, viskuläres stomatitis, Coronaviridae: cor
  • organophosphorus compounds according to the invention are therefore suitable for combating the following viral infections:
  • the compounds described, ie the organophosphorus compounds according to Formula (I) and esters and salts thereof show a strong cytotoxic activity against single and multi-cell parasites, in particular against the pathogens of malaria and sleeping sickness. 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 preventing diseases caused by viruses, bacteria, parasites and fungi, in particular as malaria prophylaxis and as sleeping sickness prophylaxis.
  • unicellular parasites are to be understood as protozoa in accordance with the narrower definition of parasitology.
  • organophosphorus compounds according to the invention generally include pharmaceutically acceptable salts, amides, esters, a salt of such an ester, or compounds which, when applied, provide the compounds according to the invention as metabolites or degradation products, also called “prodrugs", for administration in be prepared 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 form the compounds of the formulas (I) 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.
  • the salts formed by a 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, are also particularly pharmaceutically suitable.
  • 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.
  • Tablets, dragees, capsules, pills, granules, suppositories, 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 carriers, such as (a) fillers and extenders, e.g. B. starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. B.
  • humectants e.g. B. glycerin
  • disintegrant e.g. B. agar-agar, calcium carbonate and
  • 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 carriers.
  • 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. C 14 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. C 14 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 of these substances.
  • 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 of these substances.
  • 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 sesate oil, glycerol, glycerol formate - Contain furfuryl alcohol, 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, dimethylformamide,
  • 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 thereof Contain 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 thereof Contain 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) should be present 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 ,
  • the pharmaceutical preparations can also contain further active pharmaceutical ingredients.
  • organophosphorus compounds in the pharmaceutical compositions can be used in combination with sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracycline, doxycycline, proguanil, metronidazole, nicazamidolebazol, praziquantilil Pyrantel, tia bendazole, diethyl carbazine, piperazine, pyrivinum, metrifonate, oxamniquin, bithionol or suramin or more 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 carrier (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 also be used in humans and animals.
  • 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 formula (I) in a total amount of from about 0.05 to about 600, preferably 0.5 to 200 mg / kg of body weight each 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 amounts 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.
  • N-methyl-N - [(3-pyridyl) phosphonomethyl] glycinamide 2a 2.02 g (10 mmol) l- (N-methylamino) -l- (3-pyridyl) methylphosphonic acid (according to B. Boduszek , JSWieczorek, J. Prakt. Chemie 328, 627 (1986)) are dissolved in 0.8 ml (10 mmol) of sodium hydrogen carbonate in 30 ml of water. After 0.94 g (10 mmol) of 2-chloroacetamide has been introduced, the mixture is stirred overnight and the suspension is then heated under reflux for 1 h. The resulting almost clear solution is filtered hot.
  • the filtrate is concentrated under reduced pressure, the residue is taken up in a little water and with half-conc. aqueous HC1 adjusted a pH of 4-5. The acid amide 2a is precipitated from the solution with acetone and reacted further without a cleaning step.
  • N-Methyl-N - [(3-pyridyl) -phosphonomethyne-glycine hydroxamate (2) 0.50 g of the crude product 2a are dissolved in 5 ml of water with 0.15 g (2.2 mmol) of hydroxylamine hydrochloride. After 5 d at RT, the mixture is diluted with water and the product 2 is purified in poor yield on an anion exchanger.
  • N-phosphonomethylglycine 1.50 g (8.8 mmol) of N-phosphonomethylglycine is concentrated in 80 ml of absolute ethanol with the addition of 3 drops. Sulfuric acid refluxed for 3 h. After cooling, 10 equivalents of an equimolar mixture of N-methylhydroxylamine hydrochloride and NaOH in water, stir for 20 min and then adjust the pH to 13. The resulting precipitate is collected, dissolved in water, adjusted to pH 8 with HCl and purified on an anion exchange column. The desired hydroxamate 7 is obtained in medium yield.
  • Compound 8 is prepared analogously to the preparation of compound 7 by reacting N-phosphonomethylglycine with N-
  • the activity of the substances is determined in a test system. This system is based on the inhibition of the growth of parasites, bacteria, viruses and fungi in vitro.
  • the inhibition of malaria parasite growth in blood cultures is determined to determine antimalaria activity.
  • microorganisms to be examined can only be examined in animal models.
  • the corresponding models are used here.
  • Substances that show an effectiveness in the in vitro measuring systems are further investigated in in vivo models.
  • the antiparasitic, antiviral, fungicidal or antibacterial activity is further evaluated in the corresponding animal models.
  • Escherichia coli DOXP reductoisomerase was expressed as a recombinant protein in E. coli.
  • the oxidation of ADPH was measured in a spectrophotometer at 365 nm.
  • the activity of the DOXP reductoisomerase was measured in the presence of the compounds 1 to 8 in various concentrations between 0.1 and 100 ⁇ mol l "1. The measured values were used to determine the concentration at which the enzyme is inhibited half-maximally (IC 5 o)
  • the results, ie the IC50 Values are listed in Table 1.
  • the antimalarial activity of substances 1 to 8 was determined on in vitro cultures of the malaria pathogen Plasmodium falciparum.
  • the wells of a 96-well microtiter plate were each loaded with 200 ⁇ l of an asynchronous Plasmodium falciparum culture with 0.4% parasitemia and 2% hematocrit.
  • a serial dilution series of the compounds was then prepared in triplicate between concentrations of 100 to 0.14 ⁇ mol 1 "1.
  • the plates were incubated at 37 ° C., 3% CO 2 and 5% O 2 for a period of 48 hours.
  • 30 ⁇ l of medium supplemented with 27 ⁇ Ci ml of “1 [ 3 H] hypoxanthine were added to each well.
  • the parasites were harvested by filtration on glass fiber filters and the incorporated radioactivity was measured. Inhibition of parasite growth was measured as a percentage inhibition of tritium incorporation. The inhibition of parasite growth was expressed as a percentage inhibition of tritium incorporation based on a comparison without substance. The half-maximum inhibitory concentration (IC50) of the substance was determined by extrapolation of the values.

Abstract

The invention relates to the use of compounds of general formula (I), in which A is selected from the group comprised of -CR5R6-, -CR5R6CH(OH)-, -CR5R6CO- and -COCR5R6-. Said compounds are used for producing medicaments for the therapeutic and prophylactic treatment of infections in humans and animals caused by viruses, bacteria, fungi and parasites.

Description

VERWENDUNG VON PHOSPHORORGANISCHEN HYDROXAMSAUREDERIVATEN ZUR HERSTELLUNG VON ARZNEIMITTELN USE OF PHOSPHORORGANIC HYDROXAMIC ACID DERIVATIVES FOR THE PRODUCTION OF MEDICINAL PRODUCTS
Die Erfindung betrifft die Verwendung von phosphororganischen Hydroxamsäurede- rivaten und ihren Salzen, Estern und Amiden zur therapeutischen und prophylaktischen Behandlung von Infektionen.The invention relates to the use of organophosphorus hydroxamic acid derivatives and their salts, esters and amides for the therapeutic and prophylactic treatment of infections.
Es besteht ein starker Bedarf, für die Bereicherung der Behandlung von Mensch und Tier Mittel bereitzustellen, die nicht nur eine starke Wirksamkeit besitzen, sondern auch im Gegensatz zu anderen Arzneimitteln verringerte Nebenwirkungen zeigen und damit eine geringere Gesundheitsgefahr für den Menschen bedeuten.There is a strong need to provide means for the enrichment of the treatment of humans and animals which are not only highly effective but also, in contrast to other medicinal products, have reduced side effects and thus represent a lower health risk for humans.
Aufgabe der vorliegenden Erfindung ist es daher, eine Substanz bereitzustellen, die universell bei Infektionen durch Viren, Bakterien, Pilze und Parasiten bei Menschen und Tieren einsetzbar ist und die oben angegebenen Bedingungen erfüllt.The object of the present invention is therefore to provide a substance which can be used universally in infections by viruses, bacteria, fungi and parasites in humans and animals and which fulfills the conditions specified above.
Phosphonomethylglycylhydroxamsäure und ihre Salze sind bereits in dem Europäischen Patent mit der Veröffentlichungsnummer 0 039 310 als Herbizide beschrieben worden.Phosphonomethylglycylhydroxamic acid and its salts have already been described as herbicides in European Patent Publication No. 0 039 310.
Überraschend zeigt sich nun, daß Phosphonomethylglycylhydroxamsäure und ihre Derivate eine ausgezeichnete antiinfektiöse Wirkung gegen Viren, Bakterien, Pilze, ein- und mehrzellige Parasiten zeigt. Die Aufgabe wird somit durch in Anspruch 1 definierten Verbindungen gelöst. Weiterbildungen der Erfindung sind durch die Unteransprüche gekennzeichnet.Surprisingly, it has now been shown that phosphonomethylglycylhydroxamic acid and its derivatives have an excellent anti-infectious effect against viruses, bacteria, fungi, single and multi-cell parasites. The object is thus achieved by connections defined in claim 1. Developments of the invention are characterized by the subclaims.
Die Verbindungen entsprechen der allgemeinen Formel (I):The compounds correspond to the general formula (I):
Figure imgf000003_0001
Figure imgf000003_0001
in der A aus der Gruppe ausgewählt ist, die aus -CR5Pv6-, -CR5R<;CH(OH)-, - CRsReCO- und - COCR5R5- besteht, in der Ri aus der Gruppe ausgewählt ist, die aus Wasserstoff, substituiertem und un- substituiertem Alkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und unsub- stituiertem Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Alkyl-Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen Rest, substituiertem und unsubstituiertem Alkyl- heterocyclischem Rest, einem Metall der ersten, zweiten oder dritten Hauptgruppe des Periodensystems, Ammonium, substituiertem Ammonium und Ammoniumverbindungen, die sich von Ethylendiamin oder Aminosäuren ableiten, besteht, in der R2, R3, R4, R5, Rβ und R7 gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Alkyl-Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen Rest, substituiertem und unsubstituiertem Alkyl-heterocyclischem Rest und Benzolsulfonyl besteht, in der Rg und R9 gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Alkyl-Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen Rest, substituiertem und unsubstituiertem Alkyl-heterocyclischem Rest, OX3 oder OXj besteht, wobei Xs oder X9 gleich oder verschieden sein können und aus der Gruppe ausgewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Alkyl-Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen Rest, substituiertem und unsubstituiertem Alkyl-heterocyclischem Rest, einem Metall der ersten, zweiten oder dritten Hauptgruppe des Periodensystems, Ammonium, substituiertem Ammonium und Ammoniumverbindungen, die sich von Ethylendiamin oder Aminosäuren ableiten, besteht, wobei sämtliche Gruppen mit Phenylgruppen, Hydroxy-, Oxo-, Halogen-, CN-, (C0- 9)(C0-9)-Amino-, C1- - Alkyl-, Cι-9-Alkoxyguppen und die cyclischen Reste auch mit Nitro- gruppen und R2 auch mit einer Carboxygruppe substituiert sein können, und deren Salze, Ester und Amide und Salze der Ester.in which A is selected from the group consisting of -CR 5 Pv6-, -CR 5 R < ; CH (OH) -, - CRsReCO- and - COCR5R5-, in which Ri is selected from the group consisting of hydrogen , substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted alkylcycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted and unsubstituted heterocyclic radical, substituted and unsubstituted alkyl heterocyclic radical, a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium and ammonium compounds which are derived from ethylenediamine or amino acids, in which R 2 , R 3 , R 4 , R 5 , Rβ and R 7 are the same or different and from the group are selected from hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted alkyl-cycloalkyl, substituted and unsubstituted aryl and unsubstituted heterocyclic residue, substituted and unsubstituted alkyl heterocyclic residue and benzenesulfonyl in which Rg and R 9 are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted Alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted alkyl-cycloalkyl, substituted and us substituted aralkyl, substituted and unsubstituted heterocyclic residue, substituted and unsubstituted alkyl heterocyclic residue, OX 3 or OXj, where Xs or X 9 may be the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted alkylcycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkyl heterocyclic radical, substituted and unsubstituted heterocyclocyclic radical, substituted and unsubstituted a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids, where all groups m it phenyl groups, hydroxyl, oxo, halogen, CN, (C 0- 9 ) (C 0- 9) amino, C 1- - alkyl, Cι -9 alkoxy groups and the cyclic radicals also with nitro - Groups and R 2 can also be substituted with a carboxy group, and their salts, esters and amides and salts of the esters.
Bevorzugt ist Rt ein Wasserstoff, ein Metall der ersten, zweiten oder dritten Hauptgruppe des Periodensystems, wie Na, K, Ca, Mg, AI, Cu sowie Ammonium, substituiertem Ammonium und Ammoniumverbindungen, die sich von Ethylendiamin oder Aminosäuren ableiten.R t is preferably a hydrogen, a metal of the first, second or third main group of the periodic table, such as Na, K, Ca, Mg, Al, Cu and ammonium, substituted ammonium and ammonium compounds which are derived from ethylenediamine or amino acids.
Bevorzugt sind Rg und R unabhängig aus der Gruppe ausgewählt, die aus Wasserstoff, Methyl, Ethyl, OXg und OX besteht, wobei OXg und OX9 bevorzugt aus der Gruppe ausgewählt sind, die aus der ersten, zweiten oder dritten Hauptgruppe des Periodensystems, wie Na, K, Ca, Mg, AI, Cu sowie Ammonium, substituiertem Ammonium und Ammoniumverbindungen, die sich von Ethylendiamin oder Aminosäuren ableiten, besteht. D.h. es werden die Salzverbindungen der phosphororganischen Verbindungen mit organischen oder anorganischen Basen (z.B. Natriumsalz, Kaliumsalz, Calciumsalz, Aluminiumsalz, Ammonium- salz, Magnesiumsalz, Triethylaminsalz, Ethanolaminsalz, Dicyclohexylaminsalz, Ethylen- diaminsalz, N,N'-Dibenzylethylendiaminsalz etc.) sowie Salze mit Aminosäuren (z.B. Argi- ninsalz, Asparaginsäuresalz, Glutaminsäuresalz etc.) und dergleichen gebildet.Rg and R are preferably selected independently from the group consisting of hydrogen, methyl, ethyl, OXg and OX, OXg and OX 9 preferably being selected from the group consisting of the first, second or third main group of the periodic table, such as Na , K, Ca, Mg, Al, Cu and ammonium, substituted ammonium and ammonium compounds 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, triethylamine salt, ethanolamine salt, dicyclohexylamine salt, ethylene diamine salt, N, N'-dibenzylethylenediamine salt etc.) and salts with amino acids (eg arginine salt, aspartic acid salt, glutamic acid salt etc.) and the like.
Besonderheiten der obigen Definitionen und geeignete Beispiele dafür werden nachfolgend angegeben:Special features of the above definitions and suitable examples are given below:
„Acyl" ist ein Substituent, der von einer Säure stammt, wie von einer organischen Carbonsäure, Kohlensäure, Carbaminsäure oder der den einzelnen vorstehenden Säuren entsprechenden Thiosäure oder Imidsäure, oder von einer organischen Sulfonsäure, wobei diese Säuren jeweils aliphatische, aromatische und/oder heterocyclische Gruppen im Molekül umfassen sowie Carbamoyl oder Carbamimidoyl."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 each being aliphatic, aromatic and / or heterocyclic Include groups in the molecule as well as carbamoyl or carbamimidoyl.
Geeignete Beispiele für diese Acylgruppen werden nachfolgend angegeben. -— ' Als aliphatische Acylgruppen werden von einer aliphatischen Säure stammendeSuitable examples of these acyl groups are given below. -— 'As aliphatic acyl groups are derived from an aliphatic acid
Acylreste bezeichnet, zu denen die folgenden gehören:Designated acyl residues, which include the following:
Alkanoyl (z.B. Formyl, Acetyl, Propionyl, Butyryl, Isobutyryl, Valeryl, Isovaleryl, Pivaloyl etc.);Alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl etc.);
Alkenoyl (z. B. Acryloyl, Methacryloyl, Crotonoyl etc.);Alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl etc.);
Alkylthioalkanoyl (z.B. Methylthioacetyl, Ethylthioacetyl etc.);Alkylthioalkanoyl (e.g. methylthioacetyl, ethylthioacetyl etc.);
Alkansulfonyl (z.B. Mesyl, Ethansulfonyl, Propansulfonyl etc.);Alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, etc.);
Alkoxycarbonyl (z.B. Methoxycarbonyl, Ethoxycarbonyl, Propoxycarbonyl, Isopro- poxycarbonyl, Butoxycarbonyl, Isobutoxycarbonyl etc.);Alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.);
Alkylcarbamoyl (z.B. Methylcarbamoyl etc.);Alkyl carbamoyl (e.g. methyl carbamoyl etc.);
(N-Alkyl)-thiocarbamoyl (z.B. (N-Methyl)-thiocarbamoyl etc.);(N-alkyl) thiocarbamoyl (e.g. (N-methyl) thiocarbamoyl etc.);
Alkylcarbamimidoyl (z.B. Methylcarbamimidoyl etc.);Alkyl carbamimidoyl (e.g. methyl carbamimidoyl etc.);
Oxalo;oxalo;
Alkoxalyl (z.B. Methoxalyl, Ethoxalyl, Propoxalyl etc.).Alkoxalyl (e.g. methoxalyl, ethoxalyl, propoxalyl etc.).
Bei den obigen Beispielen für aliphatische Acylgruppen kann der aliphatische Kohlenwasserstoffteil, insbesondere die Alkylgruppe bzw. der Alkanrest, ggf. einen oder mehrere geeignete Substituenten aufweisen, wie Amino, Halogen (z.B. Fluor, Chlor, Brom etc.), Hy- droxy, Hydroxyi ino, Carboxy, Alkoxy (z.B. Methoxy, Ethoxy, Propoxy etc.), Alkoxycarbonyl, Acylamino (z.B. Benzyloxycarbonylamino etc.), Acyloxy (z.B. Acetoxy, Benzoyloxy etc.) und dergleichen; als bevorzugte aliphatische Acylreste mit solchen Substituenten sind z.B. mit Amino, Carboxy, Amino und Carboxy, Halogen, Acylamino oder dergleichen substituierte Alkanoyle zu nennen.In the above examples of aliphatic acyl groups, 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, hydroxyl ino , 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.
Als aromatische Acylreste werden solche Acylreste bezeichnet, die von einer Säure mit substituierter oder nicht substituierter Arylgruppe stammen, wobei die Arylgruppe Phe- nyl, Toluyl, Xylyl, Naphthyl und dergleichen umfassen kann; geeignete Beispiele werden nachfolgend angegeben: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:
Aroyl (z.B. Benzoyl, Toluoyl, Xyloyl, Naphthoyl, Phthaloyl etc.);Aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl etc.);
Aralkanoyl (z.B. Phenylacetyl etc.); Aralkenoyl (z.B. Cinnamoyl etc.);Aralkanoyl (e.g. phenylacetyl etc.); Aralkenoyl (e.g. cinnamoyl etc.);
Aryloxyalkanoyl (z.B. Phenoxyacetyl etc.);Aryloxyalkanoyl (e.g. phenoxyacetyl etc.);
Arylthioalkanoyl (z.B. Phenylthioacetyl etc.);Arylthioalkanoyl (e.g. phenylthioacetyl etc.);
Arylaminoalkanoyl (z.B. N-Phenylglycyl, etc.);Arylaminoalkanoyl (e.g. N-phenylglycyl, etc.);
Arensulfonyl (z.B.Benzolsulfonyl, Tosyl bzw. Toluolsulfonyl, Naphthalinsulfonyl etc.);Arenesulfonyl (e.g. benzenesulfonyl, tosyl or toluenesulfonyl, naphthalenesulfonyl etc.);
Aryloxycarbonyl (z.B. Phenoxycarbonyl, Naphthyl-oxycarbonyl etc.);Aryloxycarbonyl (e.g. phenoxycarbonyl, naphthyloxycarbonyl etc.);
Aralkoxycarbonyl (z.B. Benzyloxycarbonyl etc.);Aralkoxycarbonyl (e.g. benzyloxycarbonyl etc.);
Arylcarbamoyl (z.B. Phenylcarbamoyl, Naphthylcarbamoyl etc.);Arylcarbamoyl (e.g. phenylcarbamoyl, naphthylcarbamoyl etc.);
Arylglyoxyloyl (z.B. Phenylglyoxyloyl etc.).Arylglyoxyloyl (e.g. phenylglyoxyloyl etc.).
Bei den vorstehenden Beispielen für aromatische Acylreste kann der aromatische Kohlenwasserstoffteil (insbesondere der Arylrest) und/oder der aliphatische Kohlenwasserstoffteil (insbesondere der Alkanrest) ggf. ein oder mehrere geeignete Substituenten aufweisen, wie solche, die als geeignete Substituenten für die Alkylgruppe bzw. den Alkanrest bereits angegeben wurden. Insbesondere und als Beispiel für bevorzugte aromatische Acylreste mit besonderen Substituenten werden mit Halogen und Hydroxy oder mit Halogen und Acyloxy substituiertes Aroyl und mit Hydroxy, Hydroxyimino, Dihalogenalkanoyloxyimino substituiertes Aralkanoyl angegeben sowieIn the above examples of aromatic acyl radicals, the aromatic hydrocarbon part (in particular the aryl radical) and / or the aliphatic hydrocarbon part (in particular the alkane radical) may optionally have one or more suitable substituents, such as those which are suitable substituents for the alkyl group or the alkane radical have already been specified. In particular and as an example of preferred aromatic acyl radicals with special substituents, arylanoyl substituted with halogen and hydroxy or with halogen and acyloxy and aralkanoyl substituted with hydroxy, hydroxyimino, dihalogenalkanoyloxyimino are also given
Arylthiocarbamoyl (z.B. Phenylthiocarbamoyl etc.);Arylthiocarbamoyl (e.g. phenylthiocarbamoyl etc.);
Arylcarbamimidoyl (z.B. Phenylcarbamimidoyl etc.).Arylcarbamimidoyl (e.g. phenylcarbamimidoyl etc.).
Als heterocyclischer Acylrest wird ein Acylrest verstanden, der von einer Säure mit heterocyclischer Gruppe stammt; dazu gehören:A heterocyclic acyl radical is understood to mean an acyl radical which comes from an acid with a heterocyclic group; this includes:
Heterocyclisches Carbonyl, bei dem der heterocyclische Rest ein aromatischer oder aliphatischer 5-bis 6-gliedriger Heterocyclus mit zumindest einem Heteroatom aus der Gruppe Stickstoff, Sauerstoff und Schwefel ist (z.B. Thiophenyl, Furoyl, Pyrrolcarbonyl, Nicoti- noyl etc.);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 (e.g. thiophenyl, furoyl, pyrrolocarbonyl, nicotinoyl etc.);
Heterocyclus-Alkanoyl, bei dem der heterocyclische Rest 5- bis 6-gliedrig ist und zumindest ein Heteroatom aus der Gruppe Stickstoff, Sauerstoff und Schwefel aufweist (z.B. Thiophen-ylacetyl, Furylacetyl, Imidazolylpropionyl, Tetrazolylacetyl, 2-(2-Amino-4- thiazolyl)-2-methoxyiminoacetyl etc.) und dergleichen.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 thiophene-ylacetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino-4- thiazolyl) -2-methoxyiminoacetyl etc.) and the like.
Bei den obigen Beispielen für heterocyclische Acylreste kann der Heterocyclus und/oder der aliphatische Kohlenwasserstoffteil ggf. einen oder mehrere geeignete Substituenten aufweisen, wie die gleichen, die als geeignet für Alkyl- und Alkangruppen angegeben wurden.In the above examples of heterocyclic acyl groups, the heterocycle and / or the aliphatic hydrocarbon portion may optionally have one or more suitable substituents, such as the same ones that have been stated to be suitable for alkyl and alkane groups.
„Alkyl" ist ein gerad- oder verzweigtkettiger Alkylrest mit bis zu 18 Kohlenstoffatomen, wie Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.-Butyl, Pentyl, Hexyl und dergleichen."Alkyl" is a straight or branched chain alkyl radical having up to 18 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.
Zu „Alkenyl" gehören gerad- oder verzweigtkettige Alkenylgrappen mit bis zu 18 Kohlenstoffatomen, wie z.B. Vinyl, Propenyl (z.B. 1-Propenyl, 2-Propenyl), 1- Methylpropenyl, 2-Methylpropenyl, Butenyl, 2-Ethylpropenyl, Pentenyl, Hexenyl.“Alkenyl” includes straight-chain or branched-chain alkenyl groups with up to 18 carbon atoms, such as vinyl, propenyl (eg 1-propenyl, 2-propenyl), 1- Methyl propenyl, 2-methyl propenyl, butenyl, 2-ethyl propenyl, pentenyl, hexenyl.
Zu „Alkinyl" gehören gerad- oder verzweigtkettige Alkinylgruppen mit bis zu 18 Kohlenstoffatomen."Alkynyl" includes straight or branched chain alkynyl groups with up to 18 carbon atoms.
Cycloalkyl steht für ein ggfs. substituiertes C3-C -Cycloalkyl oder einen Bi- oder Tricycloalkyl aus C3-C7-Ringen; als mögliche Substituenten sind u.a. Alkyl, Alkenyl, Alkinyl, Alkoxy (z.B. Methoxy, Ethoxy etc.), Halogen (z.B. Fluor, Chlor, Brom etc.), Nitro und dergleichen geeignet. Ein heterocyclischer Rest ist entsprechend ein wie oben definiertes Cycloalkyl, bei dem ein, zwei oder mehrere Kohlenstoffatome im Ring unabhängig voneinander durch Sauerstoff-, Stickstoff- oder Schwefelatome ersetzt sind.Cycloalkyl stands for an optionally substituted C3-C-cycloalkyl or a bi- or tricycloalkyl from C 3 -C 7 rings; Possible substituents include alkyl, alkenyl, alkynyl, alkoxy (eg methoxy, ethoxy etc.), halogen (eg fluorine, chlorine, bromine etc.), nitro and the like. A heterocyclic radical is accordingly a cycloalkyl as defined above in which one, two or more carbon atoms in the ring are independently replaced by oxygen, nitrogen or sulfur atoms.
Aryl ist ein aromatischer Kohlenwasserstoffrest, wie Phenyl Naphthyl usw., der ggf. einen oder mehrere geeignete Substituenten aufweisen kann, wie Alkyl, Alkenyl, Alkinyl, Alkoxy (z.B. Methoxy, Ethoxy etc.), Halogen (z.B. Fluor, Chlor, Brom etc.), Nitro und dergleichen.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.
Zu „Aralkyl" gehören Mono-, Di-, Triphenylalkyle wie Benzyl, Phenethyl, Benzhy- dryl, Trityl und dergleichen, wobei der aromatische Teil ggf. ein oder mehrere geeignete Substituenten aufweisen kann wie Alkoxy (z.B. Methoxy, Ethoxy etc.), Halogen (z.B. Fluor, Chlor, Brom etc.), Nitro und dergleichen."Aralkyl" includes mono-, di-, triphenylalkyls such as benzyl, phenethyl, benzhydryl, trityl and the like, where the aromatic part can optionally have one or more suitable substituents such as alkoxy (eg methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc.), nitro and the like.
Beim obigen Ester kann der Alkan- und/oder Arenteil wahlweise zumindest einen geeigneten Substituenten aufweisen wie Halogen, Alkoxy, Hydroxy, Nitro oder dergleichen.In the above ester, the alkane and / or arene portion can optionally have at least one suitable substituent such as halogen, alkoxy, hydroxy, nitro or the like.
Die erfindungsgemäßen Verbindungen gemäß der Formel (I) können in ihrer proto- nierten Form als Ammoniumsalz organischer oder anorganischer Säuren, wie Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Salpetersäure, Methansulfonsäure, p- Toluolsulfonsäure, Essigsäure, Milchsäure, Maleinsäure, Fumarsäure, Oxalsäure, Weinsäure, Ti enzoesäure, etc. vorliegen.The compounds of the formula (I) according to the invention can be 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, Ti enoic acid, etc. are present.
~ ] j Die erfindungsgemäß verwendeten Verbindungen der Formel (I) lassen beispielsweise für Doppelbindungen enthaltende oder chirale Gruppen Ri bis R9, Xi, Xg, X9 und A das Auftreten räumlicher Isomerer zu. Die erfindungsgemäße Verwendung der Verbindungen umfaßt alle räumlichen Isomere sowohl als Reinstoffe als auch in Form ihrer Mischungen. ~ ] j The compounds of the formula (I) used according to the invention allow, for example for double-containing or chiral groups R 1 to R 9 , Xi, Xg, X 9 and A, the occurrence of spatial isomers. The use of the compounds according to the invention includes all spatial isomers both as pure substances and in the form of their mixtures.
Besonders bevorzugt sind Einzelverbindungen, die den nachfolgenden Strukturformeln entsprechen:
Figure imgf000008_0001
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Individual compounds which correspond to the following structural formulas are particularly preferred:
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Die phosphororganischen Verbindungen sind insbesondere für die therapeutische und prophylaktischen Behandlung von Infektionen bei Mensch und Tier geeignet, die durch Viren, Bakterien, ein- und mehrzellige Parasiten und Pilze hervorgerufen werden.
Figure imgf000035_0002
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The organophosphorus compounds are particularly 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.
Die Verbindungen sind gegen einzellige Parasiten (Protozoen) wirksam, insbesondere gegen Erreger der Malaria und der Schlafkrankheit sowie der Chagas-Krankheit, der Toxoplasmose, der Amöbenruhr, der Leishmaniosen, der Trichomoniasis, der Pneumozysto- se, der Balantidiose, der Kryptosporidiose, der Sarkozystose, der Akanthamöbose, der Naeg- lerose, der Kokzidiose, der Giardiose und der Lambliose.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, leishmaniasis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis and sarcomocystosis , Akanthamöbose, Naeglerose, Coccidiosis, Giardiosis and Lambliosis.
Sie sind daher insbesondere als Malariaprophylaxe und als Prophylaxe der Schlafkrankheit sowie der Chagas-Krankheit, der Toxoplasmose, der Amöbenruhr, der Leishmaniosen, der Trichomoniasis, der Pneumozystose, der Balantidiose, der Kryptosporidiose, der Sarkozystose, der Akanthamöbose, der Naeglerose, der Kokzidiose, der Giardiose und der Lam- \ bliose geeignet.They are therefore particularly useful as malaria prophylaxis and as a prophylaxis of sleeping sickness and Chagas disease, toxoplasmosis, amoebic dysentery, Leishmaniasis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcolocystosis, acanthambidosis, cocoonosis, and naeglerosis the Giardiose and the Lam- \ bliose suitable.
Die erfindungsgemäßen Wirkstoffe sind insbesondere gegen die folgenden Bakterien einsetzbar:The active compounds according to the invention can be used in particular against the following bacteria:
Bakterien der Familie Propionibacteriaceae, insbesondere der Gattung Propionibacte- rium, insbesondere die Art Propionibacterium acnes, Bakterien der Familie Actinomyceta- ceae, insbesondere der Gattung Actinomyces, Bakterien der Gattung Corynebacterium, insbesondere die Arten Corynebacterium diphteriae und Corynebacterium pseudotuberculosis, Bakterien der Familie Mycobacteriaceae, der Gattung Mycobacterium, insbesondere die Arten Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis und Mycobacterium avium, Bakterien der Familie Chlamydiaceae, insbesondere die Spezies Chlamydia tra- chomatis und Chlamydia psittaci, Bakterien der Gattung Listeria, insbesondere die Art Listeria monocytogenes, Bakterien der Art Erysipelthrix rhusiopathiae, Bakterien der Gattung Clostridium, Bakterien der Gattung Yersinia, der Spezies Yersinia pestis, Yersinia pseudotuberculosis, Yersinia enterocolitica und Yersinia ruckeri, Bakterien der Familie Mycoplasma- taceae, der Gattungen Mycoplasma und Ureaplasma, insbesondere die Art Mycoplasma pneumoniae, Bakterien der Gattung Brucella, Bakterien der Gattung Bordetella, Bakterien der Familie Neiseriaceae, insbesondere der Gattungen Neisseria und Moraxella, insbesondere die Arten Neisseria meningitides, Neisseria gonorrhoeae und Moraxella bovis, Bakterien der Familie Vibrionaceae, insbesondere der Gattungen Vibrio, Aeromonas, Plesiomonas und Pho- tobacterium, insbesondere die Arten Vibrio cholerae, Vibrio anguillarum und Aeromonas salmonicidas, Bakterien der Gattung Campylobacter, insbesondere die Arten Campylobacter jejuni, Campylobacter coli und Campylobacter fetus, Bakterien der Gattung Helicpbacter, insbesondere die Art Helicobacter pylori, Bakterien der Familien Spirochaetaceae und der Leptospiraceae, insbesondere der Gattungen Treponema, Borrelia und Leptospira, insbesondere Borrelia burgdorferi, Bakterien der Gattung Actinobacillus, Bakterien der Familie Le- gionellaceae, der Gattung Legionella, Bakterien der Familie Rickettsiaceae und Familie Bar- tonellaceae, Bakterien der Gattungen Nocardia und Rhodococcus, Bakterien der Gattung Dermatophilus, Bakterien der Familie Pseudomonadaceae, insbesondere der Gattungen Pseu- domonas und Xanthomonas, Bakterien der Familie Enterobacteriaceae, insbesondere der Gattungen Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia und Shigella, Bakterien der Familie Pasteurellaceae, insbesondere der Gattung Haemophilus, Bakterien der Familie Micrococcaceae, insbesondere der Gattungen Micrococcus und Staphylococcus, Bakterien der Familie Streptococcaceae, insbesondere der Gattungen Streptococcus und Enterococcus und Bakterien der Familie Bacillaceae, insbesondere der Gattungen Bacillus und Clostridium.Bacteria of the Propionibacteriaceae family, in particular the Propionibacterium genus, in particular the Propionibacterium acnes species, Actinomycetaceae bacteria, in particular the Actinomyces genus, Corynebacterium bacteria, in particular the Corynebacterium diphteriae and Corynebactercoderobacterium family, pseudoteaculoid bacterium, family of bacteria Genus Mycobacterium, in particular the species Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium, bacteria of the Chlamydiaceae family, in particular the species Chlamydia trachomatis and Chlamydia psittaci, bacteria of the genus Listeria bacteria, in particular the type Lymphia monocytosis Erythipathus, especially the species Logenia, especially the type Logenia tris , Bacteria of the genus Clostridium, bacteria of the genus Yersinia, of the species Yersinia pestis, Yersinia pseudotuberculosis, Yersinia enterocolitica and Yersinia ruckeri, bacteria of the family Mycoplasma taceae, of the genera Mycoplasm a and ureaplasma, in particular the species Mycoplasma pneumoniae, bacteria of the genus Brucella, bacteria of the genus Bordetella, bacteria of the family Neiseriaceae, in particular of the genera Neisseria and Moraxella, in particular the species Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis, bacteria of the Vibrionaceae family, 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 Helicpbacter, in particular die pylori, bacteria of the Spirochaetaceae and Leptospiraceae families, in particular the Treponema, Borrelia and Leptospira species, in particular Borrelia burgdorferi, bacteria of the Actinobacillus genus, bacteria of the Legionellaceae family, of the Legionella genus, bacteria of the Ri family ckettsiaceae and family bar- tonellaceae, bacteria of the genera Nocardia and Rhodococcus, bacteria of the genus Dermatophilus, bacteria of the family Pseudomonadaceae, in particular of the genera Pseu- domonas and Xanthomonas, bacteria of the family Enterobacteriaceae, in particular of the genera Escherichia, Klebsiella, Proteus, Provellacia, Salidaella, Salmonella, Salmonella Bacteria of the Pasteurellaceae family, in particular of the genus Haemophilus, bacteria of the Micrococcaceae family, in particular of the genera Micrococcus and Staphylococcus, bacteria of the Streptococcaceae family, in particular of the genera Streptococcus and Enterococcus and bacteria of the Bacillaceae family, in particular of the Bacillus and Clostrid genera.
Damit eignen sich phosphororganischen Verbindungen und ihre Derivate zur Behandlung der Diphterie, der Acne vulgaris, der Listeriosen, des Rotlaufs bei Tieren, der Gasbrand beim Mensch und beim Tier, Pararauschbrand bei Mensch und Tier, Tuberkulose bei Mensch und Tier, Lepra, und weitere Mykobacteriosen bei Mensch und Tier, der Paratuber- kulose der Tiere, Pest, mesenterialen Lymphadenitis und Pseudotuberkulose bei Mensch und Tier, Cholera, Legionärskrankheit, Borreliose bei Mensch und Tier, Leptospirosen bei Mensch und Tier, Syphilis, Campylobacter-Enteritiden bei Mensch und Tier, Moraxella- Keratokonjunctivitis und Serositis der Tiere, Brucellosen der Tiere und des Menschen, Milzbrand bei Mensch und Tier, Aktinomykose bei Mensch und Tier, Streptotrichosen, Psittako- se/Ornithose bei Tieren, Q-Fieber, Ehrlichiose.Organophosphorus compounds and their derivatives are therefore suitable for the treatment of diphtheria, acne vulgaris, 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, 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 in animals, brucellosis in animals and humans, anthrax in humans and animals, actinomycosis in humans and animals, streptotrichoses, psittacosis / ornithosis in animals, Q fever, Ehrlichiosis.
Weiter ist der Einsatz nützlich bei der Helicobacter-Eradikationstherapie bei Ulcera des Magendarmtraktes.The use is also useful in Helicobacter eradication therapy for ulcers of the gastrointestinal tract.
Es können auch Kombination mit einem weiteren Antibiotikum zur Behandlung der obengenannten Erkrankungen eingesetzt werden. Für Kombinationspräparate mit anderen Antiinfektiva eignen sich insbesondere Isoniazid, Rifampicin, Ethambutol, Pyrazinamid, Streptomycin, Protionamid und Dapson zur Behandlung der Tuberkulose.A combination with another antibiotic can also be used to treat the above-mentioned diseases. Isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, protionamide and dapsone are particularly suitable for the treatment of tuberculosis for combination preparations with other anti-infectives.
Die erfmdungsgemäßen Wirkstoffe sind ferner insbesondere bei Infektionen mit folgenden Viren einsetzbar:The active substances according to the invention can also be used in particular for infections with the following viruses:
Parvoviridae: Parvoviren, Dependoviren, Densoviren, Adenoviridae: Adenoviren, Mastadenoviren, Aviadenoviren, Papovaviridae: Papovaviren, insbesondere Papillomaviren (sogenannte Warzenviren), Polyomaviren, insbesondere JC-Virus, BK- Virus, und Miopapo- vaviren, Herpesviridae: Alle Herpesviren, insbesondere Herpes-Simplex- Viren, der Varizel- len/Zoster-Viren, menschlicher Zytomegalievirus, Epstein-Barr- Viren, alle humanen Herpesviren, humanes Herpesvirus 6, Humanes Herpesvirus 7, humanes Herpesvirus 8, Poxviri- dae:Pockenviren, Orthopox-, Parapox-, Molluscum-Contagiosum- Virus, Aviviren, Caprivi- ren, Leporipoxviren, alle primär hepatotropen Viren, Hepatitisviren: Hepatitis- A- Viren, He- patitis-B-Viren, Hepatitis-C- Viren, Hepatitis-D-Viren, Hepatitis-E- Viren, Hepatitis-F-Viren, Hepatits-G- Viren, Hepadnaviren: sämtliche Hepatitisviren, Hepatitis-B-Virus, Hepatitis-D- Viren,Parvoviridae: parvoviruses, dependoviruses, densoviruses, adenoviridae: adenoviruses, mastadenoviruses, aviadenoviruses, papovaviridae: papovaviruses, in particular papillomaviruses (so-called wart viruses), polyomaviruses, in particular JC virus, herpes virus, and herpes virus, and virus virus, 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 viruses E viruses, hepatitis F viruses, hepatits G viruses, hepadnaviruses: all hepatitis viruses, hepatitis B virus, hepatitis D viruses,
Picornaviridae: Picornaviren, alle Enteroviren, alle Polioviren, alle Coxsackieviren, alle Echoviren, alle Rhinoviren, Hepatitis- A- Virus, Aphthoviren, Calciviridae: Hepatitis-E- Viren, Reoviridae: Reoviren, Orbiviren, Rotaviren, Togaviridae: Togaviren, Alphaviren, , Rubiviren, Pestiviren, Rubellavirus, Flaviviridae: Flaviviren, FSME- Virus, Hepatitis-C- Virus, Orthomyxoviridae: Alle Influenzaviren, Paramyxoviridae: Paramyxoviren, Morbillivirus, Pneumovirus, Masernvirus, Mumpsvirus, Rhabdoviridae: Rhabdoviren, Rabiesvirus, Lyssavi- rus, viskuläres Stomatitisvirus, Coronaviridae: Coronaviren, Bunyaviridae: Bunyaviren, Nai- rovirus, Phlebovirus, Uukuvirus, Hantavirus, Arenaviridae: Arenaviren, lymphozytäres Cho- riomeningitis- Virus, Retroviridae: Retroviren, alle HTL-Viren, humanes T-cell leukämie- Virus, Oncornaviren, Spumaviren, Lentiviren, Alle HI- Viren, Filoviridae: Marburg- und Ebolavirus, Slow-virus-Infektionen, Prionen, Onkoviren, Leukämie- Viren.Picornaviridae: Picornaviruses, all enteroviruses, all polioviruses, all Coxsackieviruses, all echo viruses, all rhino viruses, hepatitis A virus, aphthoviruses, Calciviridae: Hepatitis E virus, Reoviridae: reovirus, Orbi virus, rotavirus, Togaviridae: togaviruses, alphaviruses, rubiviruses, pestiviruses, rubella virus, Flaviviridae: flavivirus, TBE virus , hepatitis C virus, Orthomyxoviridae: All influenza viruses, Paramyxoviridae: paramyxovirus, morbillivirus, pneumovirus, measles virus, mumps virus, Rhabdoviridae: rhabdovirus, rabies virus, Lyssavi- rus, viskuläres stomatitis, Coronaviridae: coronaviruses, Bunyaviridae: Bunya, NAI rovirus, Phlebovirus , Uukuvirus, hantavirus, arenaviridae: arenaviruses, lymphocytic choriomeningitis virus, retroviridae: retroviruses, all HTL viruses, human T-cell leukemia virus, oncornaviruses, spumaviruses, lentiviruses, all HI viruses, marburg virus and filoviridae , Slow virus infections, prions, oncoviruses, leukemia viruses.
Die erfindungsgemäßen phosphororganischen Verbindungen sind somit zur Bekämpfung folgender viraler Infekte geeignet:The organophosphorus compounds according to the invention are therefore suitable for combating the following viral infections:
Eradikation von Papillomaviren zur Vorbeugung von Tumoren, insbesondere von Tumoren der Geschlechtsorganen verursacht durch Papillomaviren beim Menschen, Eradikation von JC-Viren und BK- Viren, Eradikation von Herpesviren, Eradikation humaner Herpesviren 8 zur Behandlung der Kaposi-Sarkoma, Eradikation von Zytomegalie- Viren vor Transplantationen, Eradikation von Eppstein-Barr- Viren vor Transplantation und zur Vorbeugung von Eppstein-Barr- Viren-assozierten Tumoren, Eradikation von Hepatitisviren zur Behandlung von chronischen Leber-Erkrankungen und zur Vorbeugung von Lebertumoren und Leberzirrhosen, Eradikation von Coxsackieviren bei Kardiomyopatbien, Eradikation von Cox- sackieviren bei Diabetes-mellitus-Patienten, Eradikation von Immunschwäche- Viren in Mensch und Tier, Behandlung von Begleitinfektionen in AIDS-Patienten, Behandlung von Entzündungen viraler Genese des Respirationstraktes (Larynxpapillome, Hyberplasien, Rhi- nitis, Pharyngitis, Bronchitis, Pneumonien), der Sinnesorgane (Keratokonjunktivitis), des Nervensystems (Poliomyelitis, Meningoenzephalitis, Enzephalitis, subakute sklerosierende Panenzephalitis, SSPE, progressive multifokale Leukoenzephalopathie, Lymphozytäre Cho- riomeningitis), des Magen-Darm-Traktes (Stomatitis, Gingivostomatitis, Ösophagitis, Gastritis, Gastroenteritis, Durchfallerkrankungen), der Leber und des Gallensystems (Hepatitis, Cholangitis, hepatozelluläres Karzinom), des lymphatischen Gewebes (Mononukleose, Lymphadenitis), des hämatopoetischen Systems, der Geschlechtsorgane (Mumpsorchitis), der Haut (Warzen, Dermatitis, Herpes labialis, Fieberbläschen, Herpes Zoster, Gürtelrose), der Schleimhäute (Papillome, Konjunktivapapillome, Hyperplasien, Dysplasien), des Herz- Blutgefäß-Systems (Arteriitis, Myokarditis, Endokarditis, Perikarditis), des Nieren-Harnweg- Systems, der Geschlechtsorgane (Anogenitale Läsionen, Warzen, Genitalwarzen, spitzen Kondylome, Dysplasien, Papillome, Zervixdysplasien, Condylomata acuminata, Epidermo- dysplasia verruciformis), der Bewegungsorgane (Myositis, Myalgien), Behandlung der Maul- und Klauenseuche der Paarhufer, des Colorado-Zeckenfiebers, des Dengue-Syndroms, des hämorrhagisches Fiebers, der Frühsommermeningoenzephalitis (FSME) und des Gelbfiebers.Eradication of papillomaviruses for the prevention of tumors, in particular of tumors of the genital organs caused by papillomaviruses in humans, eradication of JC viruses and BK viruses, eradication of herpes viruses, eradication of human herpes viruses 8 for the treatment of Kaposi's sarcoma, eradication of cytomegaloviruses Transplants, eradication of Eppstein-Barr viruses before transplantation and for the prevention of Eppstein-Barr virus-associated tumors, eradication of hepatitis viruses for the treatment of chronic liver diseases and for the prevention of liver tumors and liver cirrhosis, eradication of Coxsackieviruses in cardiomyopatbias, eradication Cox sackieviruses in diabetes mellitus patients, eradication of immunodeficiency viruses in humans and animals, treatment of concomitant infections in AIDS patients, treatment of inflammation of the viral genesis of the respiratory tract (laryngeal papillomas, hyberplasias, rhinitis, pharyngitis, bronchitis, pneumonia) , the senseso rgane (keratoconjunctivitis), of the nervous system (poliomyelitis, meningoencephalitis, encephalitis, subacute sclerosing panencephalitis, SSPE, progressive multifocal leukoencephalopathy, lymphocytic Cho riomeningitis), of the gastrointestinal tract (stomatitis, gingivostomatitis, oesophagitis, gastritis, gastroenteritis, diarrhea), the liver and the biliary system (hepatitis, cholangitis, hepatocellular carcinoma), the lymphatic tissue (mononucleosis, lymphadenitis), the hematopoietic system, the genital organs (mumps orchitis), the skin (warts, dermatitis, herpes labialis, cold sores, herpes zosterosis, herpes zoster , the mucous membranes (papillomas, conjunctival apillomas, hyperplasias, dysplasias), the cardiovascular system (arteritis, myocarditis, endocarditis, pericarditis), the kidney-urinary tract system, the genital organs (anogenital lesions, warts, genital warts, acute condylomas) , Papillomas, cervical dysplasias, condylomata acuminata, E pidermodysplasia verruciformis), the organs of movement (myositis, myalgia), treatment of foot-and-mouth disease of the cloven hoofed animals, Colorado tick fever, dengue syndrome, hemorrhagic fever, early summer meningoencephalitis (TBE) and yellow fever.
Die beschriebenen Verbindungen, d.h. die phosphororganische Verbindungen nach Formel (I) und Ester sowie Salze derselben zeigen eine starke zytotoxische Wirksamkeit gegenüber ein- und mehrzelligen Parasiten, insbesondere gegenüber den Erregern der Malaria und der Schlafkrankheit. Demgemäß sind die erfmdungsgemäßen Verbindungen für die Behandlung von Infektionskrankheiten brauchbar, die durch Viren, Bakterien, Parasiten und Pilze bei Mensch und Tier verursacht werden. Die Verbindungen sind auch für den Einsatz zur Vorbeugung von Erkrankungen, die durch Viren, Bakterien, Parasiten und Pilze hervorgerufen werden, insbesondere als Malariaprophylaxe und als Schlafkrankheitsprophylaxe geeignet. Unter einzelligen Parasiten sind erfindungsgemäß entsprechend der engeren Definition der Parasitologie Protozoen zu verstehen.The compounds described, ie the organophosphorus compounds according to Formula (I) and esters and salts thereof show a strong cytotoxic activity against single and multi-cell parasites, in particular against the pathogens of malaria and sleeping sickness. 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 preventing diseases caused by viruses, bacteria, parasites and fungi, in particular as malaria prophylaxis and as sleeping sickness prophylaxis. According to the invention, unicellular parasites are to be understood as protozoa in accordance with the narrower definition of parasitology.
Die erfindungsgemäßen phosphororganischen Verbindungen, hierzu gehören im allgemeinen pharmazeutisch verträgliche Salze, Amide, Ester, ein Salz eines solchen Esters, oder aber Verbindungen, die bei Applikation die erfmdungsgemäßen Verbindungen als Stoffwechselprodukte oder Abbauprodukte bereitstellen, auch "Prodrugs" genannt, können für die Verabreichung in irgendeiner geeigneten Weise analog zu bekannten antiinfektiös wirkenden Mitteln (gemischt mit einem nicht toxischen pharmazeutisch akzeptablen Träger) zubereitet werden.The organophosphorus compounds according to the invention, these generally include pharmaceutically acceptable salts, amides, esters, a salt of such an ester, or compounds which, when applied, provide the compounds according to the invention as metabolites or degradation products, also called "prodrugs", for administration in be prepared in any suitable manner analogous to known anti-infectious agents (mixed with a non-toxic pharmaceutically acceptable carrier).
Zu pharmazeutisch akzeptablen Salzen der Verbindungen gehören Salze, die die erfindungsgemäßen Verbindungen der Formeln (I) in ihrer protonierten Form als Ammoniumsalz anorganischer oder organischer Säuren, wie Salzsäure, Schwefelsäure, Zitronensäure, Maleinsäure, Fumarsäure, Weinsäure, p-Toluolsu fonsäure, bilden.Pharmaceutically acceptable salts of the compounds include salts which form the compounds of the formulas (I) 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.
Pharmazeutisch besonders geeignet sind auch die Salze, die durch geeignete Auswahl von X3 und X gebildet werden, wie Natriumsalz, Kaliumsalz, Calciumsalz, Ammoni- umsalz, Ethanolaminsalz, Triethylaminsalz, Dicyclohexylaminsalz und Salze einer Aminosäure wie Argininsalz, Asparaginsäuresalz, Glutaminsäuresalz.The salts formed by a 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, are also particularly pharmaceutically suitable.
Die pharmazeutisch wirksamen Mittel können in Form von pharmazeutische Zubereitungen in Dosierangseinheiten zubereitet werden. Dies bedeutet, daß die Zubereitung in Form einzelner Teile, z. B. Tabletten, Dragees, Kapseln, Pillen, Suppositorien und Ampullen vorliegen, deren Wirkstoffgehalt einem Bruchteil oder einem Vielfachen einer Einzeldosis entsprechen. Die Dosierungseinheiten können z. B. 1, 2, 3 oder 4 Einzeldosen oder 1/2, 1/3 oder 1/4 einer Einzeldosis enthalten. Eine Einzeldosis enthält vorzugsweise die Menge Wirkstoff, die bei einer Applikation verabreicht wird und die gewöhnlich einer ganzen, einer halben oder einem Drittel oder einem Viertel einer Tagesdosis entspricht.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.
Unter nicht-toxischen, inerten pharmazeutisch geeigneten Trägerstoffen sind feste, halbfeste oder flüssige Verdünnungsmittel, Füllstoffe und Formulierungshilfsmittel jeder Art zu verstehen.Non-toxic, inert pharmaceutically suitable carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.
Als bevorzugte pharmazeutische Zubereitungen seien Tabletten, Dragees, Kapseln, Pillen, Granulate, Suppositorien, Lösungen, Suspensionen und Emulsionen, Pasten, Salben, Gele, Cremes, Lotions, Puder und Sprays genannt. Tabletten, Dragees, Kapseln, Pillen und Granulate können den oder die Wirkstoffe neben den üblichen Trägerstoffen enthalten, wie (a) Füll- und Streckmittel, z. B. Stärken, Milchzucker, Rohrzucker, Glukose, Mannit und Kieselsäure, (b) Bindemittel, z. B. Carboxymethylcellulose, Alginate, Gelatine, Polyvinylpyrroli- don, (c) Feuchthaltemittel, z. B. Glycerin, (d) Sprengmittel, z. B. Agar-Agar, Calciumcarbo- nat und Natriumcarbonat, (e) Lösungsverzögerer, z. B. Paraffin und (f) Resorptionsbeschleuniger, z. B. quarternäre Ammoniumverbindungen, (g) Netzmittel, z. B. Cetylalkohol, Glyce- rinmonostearat, (h) Adsorptionsmittel, z. B. Kaolin und Bentonit und (i) Gleitmittel, z. B. Talkum, Calcium- und Magnesiumstearat und feste Polyethylenglykole oder Gemische der unter (a) bis (i) aufgeführten Stoffe.Tablets, dragees, capsules, pills, granules, suppositories, 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 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, e.g. B. glycerin, (d) disintegrant, 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, e.g. B. cetyl alcohol, glycerol monostearate, (h) adsorbent, for. B. kaolin and bentonite 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).
Die Tabletten, Dragees, Kapseln, Pillen und Granulate können mit den üblichen, gegebenenfalls Opakisierungsmittel enthaltenden Überzügen und Hüllen versehen sein und auch so zusammengesetzt sein, daß sie den oder die Wirkstoffe nur oder bevorzugt in einem bestimmten Teil des Intestinaltraktes gegebenenfalls verzögert abgeben, wobei als Einbettungsmassen z. B. Polymersubstanzen und Wachse verwendet werden können.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.
Der oder die Wirkstoffe können gegebenenfalls mit einem oder mehreren der oben angegebenen Trägerstoffe auch in mikroverkapselter Form vorliegen.The active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned carriers.
Suppositorien können neben dem oder den Wirkstoffen die üblichen wasserlöslichen oder wasserunlöslichen Trägerstoffe enthalten, z. B. Polyethylenglykole, Fette, z. B. Kakaofett und höhere Ester (z. B. C 14- Alkohol mit C16-Fettsäure) oder Gemische dieser Stoffe.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. C 14 alcohol with C16 fatty acid) or mixtures of these substances.
Salben, Pasten, Cremes und Gele können neben dem oder den Wirkstoffen die üblichen Trägerstoffe enthalten, z. B. tierische und pflanzliche Fette, Wachse, Paraffine, Stärke, Tragant, Cellulosederivate, Polyethylenglykole, Silikone, Bentonite, Kieselsäure, Talkum und Zinkoxid oder Gemische dieser Stoffe.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 of these substances.
Puder und Sprays können neben dem oder den Wirkstoffen die üblichen Trägerstoffe enthalten, z. B. Milchzucker, Talkum, Kieselsäure, Aluminiumhydroxid, Calciumsilikat und Polyamidpulver oder Gemische dieser Stoffe. Sprays können zusätzlich die üblichen Treibmittel, z. B. Chlorfluorkohlenwasserstoffe, enthalten.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.
Lösungen und Emulsionen können neben dem oder den Wirkstoffen die üblichen Trägerstoffe wie Lösungsmittel, Lösungsvermittler und Emulgatoren, z. B. Wasser, Ethylal- kohol, Isopropylalkohol, Ethylcarbonat, Ethylacetat, Benzylalkohol, Benzylbenzoat, Propy- lenglykol, 1,3-Butylenglykol, Dimethylformamid, Öle, insbesondere Baumwollsaatöl, Erdnußöl, Maiskeimöl, Olivenöl, Ricinusöl und Sesatnöl, Glycerin, Glycerinformal, Tetrahydro- furfurylalkohol, Polyethylenglykole und Fettsäureester des Sorbitans oder Gemische dieser Stoffe enthalten.In addition to the active ingredient (s), 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 sesate oil, glycerol, glycerol formate - Contain furfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.
Zur parenteralen Applikation können die Lösungen und Emulsionen auch in steriler und blutisotonischer Form vorliegen.For parenteral administration, the solutions and emulsions can also be in sterile and blood isotonic form.
Suspensionen können neben dem oder den Wirkstoffen die üblichen Trägerstoffe wie flüssige Verdünnungsmittel, z. B. Wasser, Ethylalkohol, Propylenglykol, Suspendiermittel, z. B. ethoxylierte Isostearylalkohole, Polyoxyethylensorbit- und Sorbitan-Ester, mikrokristalline Cellulose, Aluminiummetahydroxid, Bentonit, Agar-Agar und Tragant oder Gemische dieser Stoffe enthalten.In addition to the active ingredient (s), 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 thereof Contain substances.
Die genannten Formulierungsformen können auch Färbemittel, Konservierungsstoffe sowie geruchs- und geschmacksverbesserte Zusätze, z. B. Pfefferminzöl und Eukalyptusöl und Süßmittel, z. B. Saccharin, enthalten.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.
Die Wirkstoffe der Formeln (I) sollen in den oben aufgeführten pharmazeutischen Zubereitungen, vorzugsweise in einer Konzentration von etwa 0,1 bis 99,5 Gew.-%, vorzugsweise von etwa 0,5 bis 95 Gew.-%, der Gesamtmischung vorhanden sein.The active compounds of the formulas (I) should be present 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 ,
Die pharmazeutischen Zubereitungen können außer den Verbindungen der Formel (I) auch weitere pharmazeutische Wirkstoffe enthalten.In addition to the compounds of the formula (I), the pharmaceutical preparations can also contain further active pharmaceutical ingredients.
Ferner können die phosphororganischen Verbindungen in den pharmazeutischen Mitteln in Kombination mit Sulfonamid, Sulfadoxin, Artemisinin, Atovaquon, Chinin, Chlo- roquin, Hydroxychloroquin, Mefloquin, Halofantrin, Pyrimethamin, Armesin, Tetracycline, Doxycyclin, Proguanil, Metronidazol, Praziquantil, Niclosamid, Mebendazol, Pyrantel, Tia- bendazol, Diethylcarbazin, Piperazin, Pyrivinum, Metrifonat, Oxamniquin, Bithionol oder Suramin oder mehreren dieser Substanzen vorliegen.Furthermore, the organophosphorus compounds in the pharmaceutical compositions can be used in combination with sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracycline, doxycycline, proguanil, metronidazole, nicazamidolebazol, praziquantilil Pyrantel, tia bendazole, diethyl carbazine, piperazine, pyrivinum, metrifonate, oxamniquin, bithionol or suramin or more of these substances are present.
Die Herstellung der oben aufgeführten pharmazeutischen Zubereitungen erfolgt in üblicher Weise nach bekannten Methoden, z. B. durch Mischen des oder der Wirkstoffe mit dem oder den Trägerstoffen.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 carrier (s).
Die genannten Zubereitungen können bei Mensch und Tier entweder oral, rektal, pa- renteral (intravenös, intramuskulär, subkutan), intracisternal, intravaginal, intraperitoneal, lokal (Puder, Salbe, Tropfen) und zur Therapie von Infektionen in Hohlräumen, Körperhöhlen angewendet werden. Als geeignete Zubereitungen kommen Injektionslösungen, Lösungen und Suspensionen für die orale Therapie, Gele, Aufgußformulierungen, Emulsionen, Salben oder Tropfen in Frage. Zur lokalen Therapie können ophtalmologische und dermatologische Formulierungen, Silber- und andere Salze, Ohrentropfen, Augensalben, Puder oder Lösungen verwendet werden. Bei Tieren kann die Aufnahme auch über das Futter oder Trinkwasser in geeigneten Formulierungen erfolgen. Ferner können Gele, Pulver, Puder, Tabletten, Retard- Tabletten, Premixe, Konzentrate, Granulate, Pellets, Tabletten, Boli, Kapseln, Aerosole, Sprays, Inhalate bei Mensch und Tier angewendet werden. Ferner können die erfindungsgemäßen Verbindungen in andere Trägermaterialien wie zum Beispiel Kunststoffe, (Kunststoffketten zur lokalen Therapie), Kollagen oder Knochenzement eingearbeitet werden.The 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. For local therapy, ophthalmic and dermatological formulations, silver and other salts, ear drops, eye ointments, powder or solutions can be used. In animals, 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 also be used in humans and animals. Furthermore, 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.
Im allgemeinen hat es sich sowohl in der Human- als auch in der Veterinärmedizin als vorteilhaft erwiesen, den oder die Wirkstoffe der Formel (I) in Gesamtmengen von etwa 0,05 bis etwa 600, vorzugsweise 0,5 bis 200 mg/kg Körpergewicht je 24 Stunden, gegebenenfalls in Form mehrerer Einzelgaben, zur Erzielung der gewünschten Ergebnisse zu verabreichen. Eine Einzelgabe enthält den oder die Wirkstoffe vorzugsweise in Mengen von etwa 1 bis etwa 200, insbesondere 1 bis 60 mg/kg Körpergewicht. Es kann jedoch erforderlich sein, von den genannten Dosierungen abzuweichen, und zwar in Abhängigkeit von der Art und dem Körpergewicht des zu behandelnden Patienten, der Art und der Schwere der Erkrankung, der Art der Zubereitung und der Applikation des Arzneimittels sowie dem Zeitraum bzw. Intervall, innerhalb welchem die Verabreichung erfolgt.In general, it has proven to be advantageous both in human and in veterinary medicine for the active ingredient (s) of the formula (I) in a total amount of from about 0.05 to about 600, preferably 0.5 to 200 mg / kg of body weight each 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 amounts of about 1 to about 200, in particular 1 to 60 mg / kg body weight. However, it may be necessary to deviate from the doses mentioned, depending on the type and body weight of the patient to be treated, the type and severity of the disease, the type of preparation and application of the drug, and the period or interval within which the administration takes place.
So kann es in einigen Fällen ausreichend sein, mit weniger als der obengenannten Menge Wirkstoff auszukommen, während in anderen Fällen die oben angeführte Wirkstoffmenge überschritten werden muß. Die Festlegung der jeweils erforderlichen optimalen Dosierung und Applikationsart der Wirkstoffe kann durch den Fachmann aufgrund seines Fachwissens erfolgen.In some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient has to be exceeded. The person skilled in the art can determine the optimum dosage and type of application of the active ingredients required on the basis of his specialist knowledge.
Die erfindungsgemäßen Verbindungen können in den üblichen Konzentrationen und Zubereitungen bei Tieren zusammen .mit dem Futter bzw. mit Futterzubereitungen oder mit dem Trinkwasser gegeben werden.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.
Grundsätzlich weiß der Fachmann, welchen Syntheseweg er zur Herstellung der erfindungsgemäßen Substanzen zu wählen hat. Im folgenden werden beispielhaft einige Synthesewege für Verbindungen der Erfindung angegeben. i ι Synthesebeispiele: Es werden Beispiele für die folgenden Substanzen angegeben:In principle, the person skilled in the art knows which synthetic route to choose for the preparation of the substances according to the invention. Some synthetic routes for compounds of the invention are given below by way of example. i ι Synthesis examples: Examples are given for the following substances:
HO-NR1-CO-CHR2-NR3-CHR4-P(=O)(OH)2 mit R1 =R2 = Ε? =Εl und R4 = n-Butyl 1 mit R1 = R2 = H, R3 = Methyl und R4 = m-Pyridyl 2 mit R1 = R2 = H, R3 = n-Butyl und R4 = Methyl 3 mit R1 = R2 = R3 = HHO-NR 1 -CO-CHR 2 -NR 3 -CHR 4 -P (= O) (OH) 2 with R 1 = R 2 = Ε? = Εl and R 4 = n-butyl 1 with R 1 = R 2 = H, R 3 = methyl and R 4 = m-pyridyl 2 with R 1 = R 2 = H, R 3 = n-butyl and R 4 = Methyl 3 with R 1 = R 2 = R 3 = H
und R4 = Methyl, Ethyl4 mit R1 = R4 = H, R2 = Methyl und R4 = Methyl 5 mit R1 = H, R2 = R3 = R4 = Methyl 6 mit R* = Methyl, R2 =R3 = R4 = H 7 mit R1 = Isopropyl, R2 = R3 = R4 = H 8and R 4 = methyl, ethyl4 with R 1 = R 4 = H, R 2 = methyl and R 4 = methyl 5 with R 1 = H, R 2 = R 3 = R 4 = methyl 6 with R * = methyl, R 2 = R 3 = R 4 = H 7 with R 1 = isopropyl, R 2 = R 3 = R 4 = H 8
Beispiel 1example 1
N-(l-Phosphono-pentyl)-glvcinhvdroxamat (l)N- (l-phosphonopentyl) glvcin hydroxroxate (l)
Figure imgf000043_0001
N-Pentyliden-glycinmethylester la
Figure imgf000043_0001
N-pentylidene-glycine methyl ester la
2,51 g (20 mmol) Glycinmethylester-hydrochlorid werden mit 2,42 g (24 mmol) Triethylamin sowie 2,58 g (30 mmol) frisch destilliertem Pentanal - und zum Lösen mit dem minimalen Volumen Wasser - versetzt. Man läßt 3 d im Dunkeln bei RT rühren, extrahiert mit Ether, wäscht die vereinten Extrakte mit Wasser und engt unter reduziertem Druck ein. Man erhält Imin la als bräunliches Öl in zufriedenstellender Ausbeute, welches ohne zusätzliche Reinigung weiter umgesetzt wird.2.52 g (20 mmol) of glycine methyl ester hydrochloride are mixed with 2.42 g (24 mmol) of triethylamine and 2.58 g (30 mmol) of freshly distilled pentanal - and to dissolve them with the minimum volume of water. The mixture is stirred for 3 d in the dark at RT, extracted with ether, the combined extracts are washed with water and concentrated under reduced pressure. Imin la is obtained as a brownish oil in a satisfactory yield, which is further reacted without additional purification.
N-(l-Phosphono-pentyl)-glycinmethylester lbN- (l-phosphonopentyl) glycine methyl ester lb
Eine Mischung aus 1,88 g (12 mmol) Imin la und 0,98 g (12 mmol) phosphoriger Säure werden auf 110 °C erhitzt. Nach 10 min bei einer Reaktionstemperatur von 150 °C kühlt man auf 90 °C ab, gibt 10 ml 50%iges wäßriges Ethanol hinzu, wobei das Produkt lb als weißer Feststoff in zufriedenstellender Ausbeute beim weiteren Abkühlen anfällt.A mixture of 1.88 g (12 mmol) Imin la and 0.98 g (12 mmol) phosphorous acid are heated to 110 ° C. After 10 minutes at a reaction temperature of 150 ° C., the mixture is cooled to 90 ° C., 10 ml of 50% strength aqueous ethanol are added, the product lb being obtained as a white solid in a satisfactory yield on further cooling.
N-(l-Phosphono-pentyl)-glycinhydroxamat (l)N- (l-phosphonopentyl) glycine hydroxamate (l)
Die Umsetzung von 1,19 g (5 mmol) Phosphonsäure lb mit 30 mmol freiem Hy- droxylamin in 50 ml wäßrigem Methanol unter Zusatz von 3,8 ml (15 mmol) 4-M-NaOH- Lsg. liefert nach Rühren über Nacht, einengen am Rotationsverdampfer und reinigen an einer Anionentauschersäule Hydroxamsäure 1 als farblosen Feststoff in mäßiger Ausbeute.The reaction of 1.19 g (5 mmol) of phosphonic acid Ib with 30 mmol of free hydroxylamine in 50 ml of aqueous methanol with the addition of 3.8 ml (15 mmol) of 4-M-NaOH solution provides after stirring overnight, concentrate on a rotary evaporator and purify hydroxamic acid 1 as a colorless solid in moderate yield on an anion exchange column.
Beispiel 2Example 2
N-MethvI-N-f(3-pyridvO-phosphonomethyπ"glycinhvdroxamat (2)N-MethvI-N-f (3-pyridvO-phosphonomethyπ "glycine hydroxamate (2)
Figure imgf000044_0001
Figure imgf000044_0001
N-Methyl-N-[(3-pyridyl)-phosphonomethyl]-glycinamid 2a 2,02 g (10 mmol) l-(N-Methylamino)-l-(3-pyridyl)-methylphos- phonsäure (nach B.Boduszek, J.S.Wieczorek, J. prakt. Chemie 328, 627 (1986)) werden mit 0,84 g (10 mmol) Natriumhydrogencarbonat in 30 ml Wasser gelöst. Nach Eintrag von 0,94 g (10 mmol) 2- Chloracetamid läßt man über Nacht rühren und erhitzt die Suspension anschließend 1 h unter Rückfluß. Die entstehende nahezu klare Lösung wird heiß filtriert. Das Filtrat wird unter reduziertem Druck eingeengt, der Rückstand in wenig Wasser aufgenommen und mit halbkonz. wäßriger HC1 ein pH von 4-5 eingestellt. Das Säureamid 2a wird mit Aceton aus der Lösung heraus gefällt und ohne Reinigungsschritt weiter umgesetzt.N-methyl-N - [(3-pyridyl) phosphonomethyl] glycinamide 2a 2.02 g (10 mmol) l- (N-methylamino) -l- (3-pyridyl) methylphosphonic acid (according to B. Boduszek , JSWieczorek, J. Prakt. Chemie 328, 627 (1986)) are dissolved in 0.8 ml (10 mmol) of sodium hydrogen carbonate in 30 ml of water. After 0.94 g (10 mmol) of 2-chloroacetamide has been introduced, the mixture is stirred overnight and the suspension is then heated under reflux for 1 h. The resulting almost clear solution is filtered hot. The filtrate is concentrated under reduced pressure, the residue is taken up in a little water and with half-conc. aqueous HC1 adjusted a pH of 4-5. The acid amide 2a is precipitated from the solution with acetone and reacted further without a cleaning step.
N-Methyl-N-[(3-pyridyl)-phosphonomethyn-glycinhydroxamat (2) 0.50 g des Rohproduktes 2a werden mit 0.15 g (2,2 mmol) Hydroxylaminhydrochlo- rid in 5 ml Wasser gelöst. Nach 5 d bei RT wird mit Wasser verdünnt und das Produkt 2 in schlechter Ausbeute am Anionentauscher gereinigt. Beispiel 3N-Methyl-N - [(3-pyridyl) -phosphonomethyne-glycine hydroxamate (2) 0.50 g of the crude product 2a are dissolved in 5 ml of water with 0.15 g (2.2 mmol) of hydroxylamine hydrochloride. After 5 d at RT, the mixture is diluted with water and the product 2 is purified in poor yield on an anion exchanger. Example 3
Figure imgf000045_0001
π-BuBr
Figure imgf000045_0001
π-BuBr
Figure imgf000045_0002
Figure imgf000045_0002
N-Butyl-N-(l"phosphono-ethvπ-glvcinhvdroxamat (3)N-butyl-N- (1 "phosphono-ethvπ-glvcinhvdroxamat (3)
N-Ethyliden-glycinmethylester 3aN-ethylidene glycine methyl ester 3a
Umsetzung von 6,28 g (50 mmol) Glycinmethylester-hydrochlorid mit 3,30 g (75 mmol) Acetaldehyd analog zu Imin la liefert das Rohimin 3a in guter Ausbeute.Reaction of 6.28 g (50 mmol) of glycine methyl ester hydrochloride with 3.30 g (75 mmol) of acetaldehyde analogously to imine la gives the crude imine 3a in good yield.
N-(l-Phosphono-ethyl)-glycinmethylester 3b -~- "" Umsetzung von 4,37 g (38 mmol) Rohimin 3a mit 3, 12 g (38 mmol) phosphoriger Säure analog zu Verbindung lb liefert die Aminomethanphosphonsäure 3b als fast farblosen Feststoff in mittlerer Ausbeute.N- (l-phosphono-ethyl) -glycine methyl ester 3b - ~ - "" Reaction of 4.37 g (38 mmol) of crude imine 3a with 3, 12 g (38 mmol) of phosphorous acid analogous to compound lb provides the aminomethanephosphonic acid 3b as almost colorless solid in medium yield.
N-Butyl-N-( 1 -phosphono-ethyD-glycinmethylester 3cN-butyl-N- (1 -phosphono-ethyD-glycine methyl ester 3c
3,94 g (20 mmol) 3b werden analog zu Verbindung 6c mit 2,74 g (20 mmol) n- Butylbromid umgesetzt. Als Produkt fällt 3c als Gemisch des Methyl- und Butyl-esters in Form eines gelblichen Pulvers in geringer Ausbeute an.3.94 g (20 mmol) 3b are reacted with 2.74 g (20 mmol) n-butyl bromide analogously to compound 6c. 3c is obtained as a mixture of the methyl and butyl esters in the form of a yellowish powder in low yield.
N-Butyl-N-(l-phosphono-ethyl)-glycinhydroxamat (3)N-butyl-N- (l-phosphono-ethyl) glycine hydroxamate (3)
Eine Suspension von 0,40 g (1,5 mmol) 3c in 15 ml absolutiertem Methanol wird mit 8,0 mmol freiem Hydroxylamin in Methanol und 0,10 g (4,5 mmol) Natrium in 20 ml abs. Methanol versetzt. Nach Rühren über Nacht bei RT engt man ein und wäscht den halbfesten Rückstand mehrmals mit Aceton. Nach Aufnehmen des jetzt festen Rückstands in 5 ml Wasser stellt man mit halbkonz. HC1 einen pH- Wert von 5 bis 6 ein und fällt das Produkt durch Zugabe von Aceton. Hydroxamsäure 3 wird als farbloser Feststoff in mäßiger Ausbeute erhalten.A suspension of 0.40 g (1.5 mmol) of 3c in 15 ml of absolute methanol is mixed with 8.0 mmol of free hydroxylamine in methanol and 0.10 g (4.5 mmol) of sodium in 20 ml of abs. Methanol added. After stirring overnight at RT, the mixture is concentrated and the semi-solid residue is washed several times with acetone. After taking up the now solid residue in 5 ml of water, use half-conc. HC1 has a pH of 5 to 6 and the product falls by adding acetone. Hydroxamic acid 3 is obtained as a colorless solid in moderate yield.
Beispiel 4Example 4
N-(l-Phosphono-l-methylpropyD-L-alaninhvdroxamat (4 \ ~ ~\N- (l-phosphono-l-methylpropyD-L-alanine hydroxamate (4 \ ~ ~ \
Figure imgf000045_0003
Ann. Chem. 1990, 331) werden mit 0,98 g (10 mmol) Chloracetamid zu N-(l-Phosphono-l- methylpropyl)-alaninamid 4a umgesetzt. Nach Fällung aus Wasser/Aceton wird 4a durch Umkristallisieren aus Wasser/Aceton in guter Ausbeute rein erhalten.
Figure imgf000045_0003
Ann. Chem. 1990, 331) are reacted with 0.98 g (10 mmol) of chloroacetamide to give N- (l-phosphono-l-methylpropyl) -alaninamide 4a. After precipitation from water / acetone, 4a is obtained in pure yield by recrystallization from water / acetone.
N-(l-Phosphono-l-methyl-propyl)-L-alaninhydroxamat (4)N- (l-phosphono-l-methyl-propyl) -L-alanine hydroxamate (4)
1,57 g (7.5 mmol) 4a werden mit 0,52 g (7.5 mmol) Hydroxylamin-hydrochlorid in wenig Wasser gelöst. Nach 7 d bei RT wird mit Wasser verdünnt und das Produkt 4 am Anio- nenaustauscher gereinigt. Man erhält N-(l-Phosphono-l-methylpropyl)-L-alaninhydroxamat 4 in mäßiger Ausbeute als schwach-gelben Feststoff.1.57 g (7.5 mmol) 4a are dissolved in 0.52 g (7.5 mmol) hydroxylamine hydrochloride in a little water. After 7 d at RT, the mixture is diluted with water and the product 4 is purified on the anion exchanger. N- (l-Phosphono-l-methylpropyl) -L-alanine hydroxamate 4 is obtained in moderate yield as a pale yellow solid.
Beispiel 5Example 5
N-Methyl-N-phosphonomethvI-L-alaninhydroxamat (5)N-methyl-N-phosphonomethvI-L-alanine hydroxamate (5)
Figure imgf000046_0001
phosphoriger Säure und 10 ml konz. HCl zum Rückfluß erhitzt. Binnen 15 min werden 15 ml 37%ige Formalin-Lsg. zugetropft und eine weitere Stunde unter Rückfluß erhitzt. Nach dem Abkühlen fallen Kristalle aus, die filtriert und mit Isopropanol gewaschen werden. Umkristallisieren aus Wasser Isopropanol liefert farblose Kristalle von 5a in mittlerer Ausbeute.
Figure imgf000046_0001
phosphorous acid and 10 ml conc. HCl heated to reflux. 15 ml of 37% formalin sol. added dropwise and heated under reflux for a further hour. After cooling, crystals precipitate, which are filtered and washed with isopropanol. Recrystallization from water isopropanol gives colorless crystals of 5a in medium yield.
N-Methyl-N-phosphonomethyl-L-alaninhydroxamat (5)N-methyl-N-phosphonomethyl-L-alanine hydroxamate (5)
1, 18 g (6 mmol) 5a werden in 50 ml absolutiertem Ethanol mit einer Spatelspitze p- Toluolsulfonsäure suspendiert. Nach 5-stündigem Erhitzen unter Rückfluß wird die Lösung unter reduziertem Druck eingeengt, der ölige Rückstand in 25 ml absolutem Methanol gelöst und eine Lösung von 30 mmol Hydroxylamin in Methanol dazu getropft [aus 2,08 g (30 mmol) Hydroxylamin-hydrochlorid und Natriummethanolat in äquimolarer Menge]. Zu der resultierenden Suspension gibt man 0,41 g (18 mmol) Natrium in Methanol. Nach Rühren über Nacht zieht man das Lösungsmittel unter reduziertem Druck ab, nimmt in Wasser auf und trennt das Produkt 5 in mäßiger Ausbeute an einem Anionentauscher von anderen Salzen ab.1.18 g (6 mmol) of 5a are suspended in 50 ml of absolute ethanol with a spatula tip of p-toluenesulfonic acid. After refluxing for 5 hours, the solution is concentrated under reduced pressure, the oily residue is dissolved in 25 ml of absolute methanol and a solution of 30 mmol of hydroxylamine in methanol is added dropwise [from 2.08 g (30 mmol) of hydroxylamine hydrochloride and sodium methoxide in equimolar amount]. 0.41 g (18 mmol) of sodium in methanol is added to the resulting suspension. After stirring overnight, the solvent is removed under reduced pressure, taken up in water and the product 5 is separated from other salts in moderate yield on an anion exchanger.
Beispiel 6Example 6
N-Methyl-N-(l-phosphono-ethvπ-L-alaninhvdroxamat (6)
Figure imgf000047_0001
N-methyl-N- (l-phosphono-ethvπ-L-alanine hydroxamate (6)
Figure imgf000047_0001
6a 6b6a 6b
+Mel+ Mel
Figure imgf000047_0002
Figure imgf000047_0002
N-Ethyliden-L-alaninmethylester 6aN-ethylidene-L-alanine methyl ester 6a
Die Umsetzung von 6,98 g (50 mmol) L-Alaninmethylester mit 3,30g (75 mmol) Acetaldehyd nach Vorschrift für Verbindung la liefert das Rohimin 6a in guter Ausbeute.The reaction of 6.98 g (50 mmol) of L-alanine methyl ester with 3.30 g (75 mmol) of acetaldehyde according to the instructions for compound la gives the crude imine 6a in good yield.
N-(l-Phosphonoethyl)-L-alamnmethylester 6bN- (l-phosphonoethyl) -L-methylamine 6b
Die Umsetzung von 4,51 g (35 mmol) Rohimin 6a mit 2,87 g (35 mmol) phosphoriger Säure nach der Vorschrift für la liefert die Aminomethanphosphonsäure lb als farblosen Feststoff in mittlerer Ausbeute.The reaction of 4.51 g (35 mmol) of crude imine 6a with 2.87 g (35 mmol) of phosphorous acid according to the instructions for la gives the aminomethanephosphonic acid lb as a colorless solid in medium yield.
N-Methyl-N-(l-phosphono-ethyl)-L-alaninmethylester 6cN-methyl-N- (l-phosphono-ethyl) -L-alanine methyl ester 6c
3,17 g (15 mmol) 6b werden in 50 ml peroxidfreiem THF suspendiert. Diese Suspension wird nacheinander vesetzt mit 5,0 g wasserfreiem K2CO3, 5 Tropfen 18-Krone-6, 0.5 g Bu4NI und 2,18 g (15 mmol) Mel. Nach Rühren über Nacht bei 30°C kühlt man auf 0°C ab und filtriert. Der Filterrückstand wird in Wasser aufgenommen. Auf Zusatz von Aceton fallt das Produkt aus. 6c wird als gelblicher Feststoff in mäßiger Ausbeute erhalten.3.17 g (15 mmol) 6b are suspended in 50 ml of peroxide-free THF. This suspension is mixed successively with 5.0 g of anhydrous K 2 CO 3 , 5 drops of 18-crown-6, 0.5 g of Bu 4 NI and 2.18 g (15 mmol) of Mel. After stirring overnight at 30 ° C., the mixture is cooled to 0 ° C and filtered. The filter residue is taken up in water. The product precipitates when acetone is added. 6c is obtained as a yellowish solid in moderate yield.
N-Methyl-N-( 1 -phosphono-ethyl)-L-alamnhydroxamat (6)N-methyl-N- (1 -phosphono-ethyl) -L-alamnhydroxamate (6)
Eine Lösung von 0,90 g (4 mmol) 6c in 15 ml Wasser wird mit einer methanolischen Lösung von 20 mmol freiem Hydroxylamin und mit 3,0 ml (12 mmol) 4-M-NaOH versetzt. Nach 1 h wird das Hydroxamat 6 als fast farbloser Feststoff in mittlerer Ausbeute durch Reinigung am Anionenaustauscher isoliert.A solution of 0.90 g (4 mmol) 6c in 15 ml water is mixed with a methanolic solution of 20 mmol free hydroxylamine and with 3.0 ml (12 mmol) 4-M-NaOH. After 1 h the hydroxamate 6 is isolated as an almost colorless solid in medium yield by purification on the anion exchanger.
Beispiel 7Example 7
(N-PhosphonomethylgIvcin)-N-methylhvdroxamat (7)(N-phosphonomethylgvcin) -N-methylhydroxamate (7)
Figure imgf000047_0003
Figure imgf000047_0003
1,50 g (8,8 mmol) N-Phosphonomethylglycin wird in 80 ml absolutem Ethanol unter Zusatz von 3 Tropfen konz. Schwefelsäure 3 h refiuxiert. Nach dem Abkühlen setzt man 10 Äquivalente einer äquimolaren Mischung aus N-Methylhydroxylaminhydrochlorid und NaOH in Wasser zu, rührt 20 min und stellt den pH dann auf 13 ein. Der entstandene Niederschlag wird gesammelt, in Wasser gelöst, mit HCl pH 8 eingestellt und über eine Anionentau- schersäule gereinigt. Man erhält das gewünschte Hydroxamat 7 in mittlerer Ausbeute.1.50 g (8.8 mmol) of N-phosphonomethylglycine is concentrated in 80 ml of absolute ethanol with the addition of 3 drops. Sulfuric acid refluxed for 3 h. After cooling, 10 equivalents of an equimolar mixture of N-methylhydroxylamine hydrochloride and NaOH in water, stir for 20 min and then adjust the pH to 13. The resulting precipitate is collected, dissolved in water, adjusted to pH 8 with HCl and purified on an anion exchange column. The desired hydroxamate 7 is obtained in medium yield.
Beispiel 8Example 8
(N-Phosphonomethv_g.vcm)-N-isopropyIhvdroxamat (8ϊ(N-Phosphonomethv_g.vcm) -N-isopropyIhvdroxamat (8ϊ
OH
Figure imgf000048_0001
OH
Figure imgf000048_0001
Die Darstellung der Verbindung 8 erfolgt analog zu der Herstellung von Verbindung 7 durch Umsetzung von N-Phosphono-methylglycin mit N-Compound 8 is prepared analogously to the preparation of compound 7 by reacting N-phosphonomethylglycine with N-
Isopropylhydroxylaminhydrochlorid. Die Verbindung 8 wird in nur geringer Ausbeute erhalten.Isopropylhydroxylamine. Compound 8 is obtained in a low yield.
Die Aktivität der Substanzen wird in einem Versuchssystem bestimmt. Dieses System beruht auf der Inhibition des Wachstums von Parasiten, Bakterien, Viren und Pilzen in vitro.The activity of the substances is determined in a test system. This system is based on the inhibition of the growth of parasites, bacteria, viruses and fungi in vitro.
Zum Beispiel wird zur Bestimmung der Antimalaria-Aktivität die Inhibition des Wachstums von Malaria-Parasiten in Blutkulturen bestimmt.For example, the inhibition of malaria parasite growth in blood cultures is determined to determine antimalaria activity.
Einige der Mikroorganismen, die untersucht werden sollen, können nur in Tiermodellen untersucht werden. Hier werden die entsprechenden Modelle angewendet.Some of the microorganisms to be examined can only be examined in animal models. The corresponding models are used here.
Substanzen, die eine Wirksamkeit in den in vitro Meßsystemen zeigen, werden in in vivo Modellen weiter untersucht. Die antiparasitäre, antivirale, fungizide oder antibakterielle Aktivität wird in den entsprechenden Tiermodelle weiter evaluiert.Substances that show an effectiveness in the in vitro measuring systems are further investigated in in vivo models. The antiparasitic, antiviral, fungicidal or antibacterial activity is further evaluated in the corresponding animal models.
Beispiele zur WirksamkeitExamples of effectiveness
Experimente zeigen, daß die Wirkung vieler der hier beschriebenen Verbindungen auf einer Inhibition des l-Desoxy-D-xylulose-5-ρhosphat-(pOXP)-Stoffwechselweges beruht, der in Mikroorganismen, nicht jedoch für den Menschen nachgewiesen werden kann. Das folgende Beispiel zeigt demzufolge die Wirkung der erfindungsgemäßen Verbindungen auf die DOXP-Reductoisomerase.Experiments show that the effect of many of the compounds described here is based on an inhibition of the l-deoxy-D-xylulose-5-phosphate (pOXP) pathway, which can be detected in microorganisms, but not for humans. The following example accordingly shows the effect of the compounds according to the invention on the DOXP reductoisomerase.
Beispiel 9Example 9
Die DOXP-Reductoisomerase von Escherichia coli wurde als rekombinantes Protein in E. coli exprimiert. Die Aktivität der DOXP-Reductoisomerase wurde in einem Ansatz, der 100 mM Tris-HCl (pH=7,5), 1 mMMnCl2, 0,3 mMNADPHund ImMDOXP enthielt, bestimmt. Dabei wurde die Oxidation von ADPH in einem Spektrophotometer bei 365 nm gemessen. Zur Durchführung der Inhibitionsstudien wurde die Aktivität der DOXP- Reductoisomerase in Gegenwart der Verbindungen 1 bis 8 in verschiedenen Konzentrationen zwischen 0,1 und 100 μmol l"1 gemessen. Aus den Meßwerten wurde die Konzentration bestimmt, bei der das Enzym halbmaximal inhibiert wird (IC5o). Die Ergebnisse, d.h. die IC50- Werte sind der Tabelle 1 aufgeführt.Escherichia coli DOXP reductoisomerase was expressed as a recombinant protein in E. coli. The activity of the DOXP reductoisomerase was determined in a mixture which contained 100 mM Tris-HCl (pH = 7.5), 1 mMMnCl 2 , 0.3 mMNADPH and ImMDOXP. The oxidation of ADPH was measured in a spectrophotometer at 365 nm. To carry out the inhibition studies, the activity of the DOXP reductoisomerase was measured in the presence of the compounds 1 to 8 in various concentrations between 0.1 and 100 μmol l "1. The measured values were used to determine the concentration at which the enzyme is inhibited half-maximally (IC 5 o) The results, ie the IC50 Values are listed in Table 1.
Beispiel 10Example 10
Die Antimalaria- Wirksamkeit der Substanzen 1 bis 8 wurde an in-vitro-Kulturen des Malaria-Erregers Plasmodium falciparum bestimmt. Die Vertiefungen einer 96-well- Mikro- titerplatte wurden mit je 200 μl einer asynchronen Plasmodium falciparum-Kultur bei 0,4 % Parasitämie und 2 % Hämatokrit beschickt. Dann wurde eine serielle Verdünnungsreihe der Verbindungen in Dreierschritten zwischen Konzentrationen von 100 bis 0,14 μmol l"1 hergestellt. Die Platten wurden bei 37°C, 3 % CO2 und 5 % O2 über einen Zeitraum von 48 Stunden inkubiert. Dann wurden zu jedem well 30 μl Medium supplementiert mit 27 μCi ml"1 [3H]- Hypoxanthin zugefügt. Nach 24-stündiger Inkubation wurden die Parasiten durch Filtration auf Glasfaserfilter geerntet und die incorporierte Radioaktivität gemessen. Die Inhibition des Parasitenwachstums wurde als prozentuale Inhibition der Tritiumincorporation gemessen. Die Inhibition des Parasitenwachstums wurde als prozentuale Inhibition der Tritiumincorporation bezogen auf einen Vergleich ohne Substanz ausgedrückt. Durch Extrapolation der Werte wurde die halbmaximale inhibitorische Konzentration (IC50) der Substanz bestimmt.The antimalarial activity of substances 1 to 8 was determined on in vitro cultures of the malaria pathogen Plasmodium falciparum. The wells of a 96-well microtiter plate were each loaded with 200 μl of an asynchronous Plasmodium falciparum culture with 0.4% parasitemia and 2% hematocrit. A serial dilution series of the compounds was then prepared in triplicate between concentrations of 100 to 0.14 μmol 1 "1. The plates were incubated at 37 ° C., 3% CO 2 and 5% O 2 for a period of 48 hours. Then 30 μl of medium supplemented with 27 μCi ml of “1 [ 3 H] hypoxanthine were added to each well. After 24 hours of incubation, the parasites were harvested by filtration on glass fiber filters and the incorporated radioactivity was measured. Inhibition of parasite growth was measured as a percentage inhibition of tritium incorporation. The inhibition of parasite growth was expressed as a percentage inhibition of tritium incorporation based on a comparison without substance. The half-maximum inhibitory concentration (IC50) of the substance was determined by extrapolation of the values.
Die Ergebnisse, d.h. die IC50- Werte, sind in Tabelle 1 aufgeführt:The results, i.e. the IC50 values are listed in Table 1:
Tabelle 1Table 1
Figure imgf000049_0001
Figure imgf000049_0001

Claims

Patentansprüche claims
Verwendung von Verbindungen der allgemeinen Formel (I):Use of compounds of the general formula (I):
Figure imgf000050_0001
Figure imgf000050_0001
in der A aus der Gruppe ausgewählt ist, die aus -CR5R5-, -CR5R6CH(OH)-, -CR5R5CO- und - COCR5Rδ- besteht, in der Ri aus der Gruppe ausgewählt ist, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem.und unsubstituiertem Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Alkyl-Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen Rest, substituiertem und unsubstituiertem Alkyl-heterocyclischem Rest, einem Metall der ersten, zweiten oder dritten Hauptgruppe des Periodensystems, Ammonium, substituiertem Ammonium und Ammoniumverbindungen, die sich von Ethylendiamin oder Aminosäuren ableiten, besteht in der R2, R3, Rt, R5, R5 und R gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Alkyl- Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen Rest, substituiertem und unsubstituiertem Alkyl- heterocyclischem Rest und Benzolsulfonyl besteht, in der g und R gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Alkyl-Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen Rest, substituiertem und unsubstituiertem Alkyl-heterocyclischem Rest, OX3 oder O i besteht, wobei X8 oder X9 gleich oder verschieden sein können und aus der Gruppe ausgewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Alkyl-Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen Rest, substituiertem und unsubstituiertem Alkyl-heterocyclischem Rest, einem Metall der ersten, zweiten oder dritten Hauptgruppe des Periodensystems, Am¬in which A is selected from the group consisting of -CR 5 R 5 -, -CR 5 R 6 CH (OH) -, -CR 5 R 5 CO- and - COCR 5 Rδ-, in the Ri from the group is selected from hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted . and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted alkyl-cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic residue, substituted and unsubstituted alkyl-heterocyclic residue, second or third main group of the periodic table, ammonium, substituted ammonium and ammonium compounds which are derived from ethylenediamine or amino acids, in which R 2 , R 3 , Rt, R 5 , R 5 and R are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and uns substituted alkyl cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic residue, substituted and unsubstituted alkyl heterocyclic residue and benzenesulfonyl, in which g and R are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted Alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted alkyl-cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkyl-unsubstituted heterocyclic radical heterocyclic radical, OX 3 or O i, where X 8 or X 9 may be the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted alkylcycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, substituted and unsubstituted, substituted and unsubstituted Metal of the first, second or third main group of the periodic table, Am¬
Figure imgf000051_0001
oder Parasiten hervorgerufen werden.
Figure imgf000051_0001
or parasites.
2. Verwendung nach Anspruch 1, dadurch gekennzeichnet, daß Ri aus der Gruppe ausgewählt ist, die aus Wasserstoff, einem Metall der ersten, zweiten oder dritten Hauptgruppe des Periodensystems, wie Na, K, Ca, Mg, AI, Cu sowie Ammonium, substituiertem Ammonium und Ammoniumverbindungen, die sich von Ethylendiamin oder Aminosäuren ableiten, besteht.2. Use according to claim 1, characterized in that Ri is selected from the group consisting of hydrogen, a metal of the first, second or third main group of the periodic table, such as Na, K, Ca, Mg, Al, Cu and ammonium, substituted Ammonium and ammonium compounds derived from ethylenediamine or amino acids.
3. Verwendung nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß Rg und R9 unabhängig aus der Gruppe ausgewählt sind, die aus Wasserstoff, Methyl, Ethyl, OX8 und OX9 besteht.3. Use according to claim 1 or 2, characterized in that Rg and R 9 are independently selected from the group consisting of hydrogen, methyl, ethyl, OX 8 and OX 9 .
4. Verwendung nach Anspruch 3, dadurch gekennzeichnet, daß OXg und OX9 aus der Gruppe ausgewählt sind, die aus der ersten, zweiten oder dritten Hauptgruppe des Periodensystems, wie Na, K, Ca, Mg, AI, Cu sowie Ammonium, substituiertem Ammonium und Ammoniumverbindungen, die sich von Ethylendiamin oder Aminosäuren ableiten, besteht. / i4. Use according to claim 3, characterized in that OXg and OX 9 are selected from the group consisting of the first, second or third main group of the periodic table, such as Na, K, Ca, Mg, Al, Cu and ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids. / i
Verwendung nach Anspruch 1, dadurch gekennzeichnet, daß die Verbindungen aus der Gruppe ausgewählt sind, die aus
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000052_0003
\Use according to claim 1, characterized in that the compounds are selected from the group consisting of
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000052_0003
\
Figure imgf000053_0001
Figure imgf000053_0001
Figure imgf000053_0002
Figure imgf000053_0003
52
Figure imgf000054_0001
Figure imgf000054_0002
Figure imgf000055_0001
Figure imgf000055_0002
Figure imgf000055_0003
Figure imgf000053_0002
Figure imgf000053_0003
52
Figure imgf000054_0001
Figure imgf000054_0002
Figure imgf000055_0001
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Figure imgf000056_0001
Figure imgf000056_0001
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Figure imgf000056_0003
Figure imgf000057_0001
Figure imgf000057_0002
Figure imgf000057_0003
Figure imgf000058_0001
Figure imgf000058_0002
Figure imgf000056_0002
Figure imgf000056_0003
Figure imgf000057_0001
Figure imgf000057_0002
Figure imgf000057_0003
Figure imgf000058_0001
Figure imgf000058_0002
Figure imgf000058_0003
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000060_0002
Figure imgf000061_0002
Figure imgf000058_0003
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000060_0002
Figure imgf000061_0002
Figure imgf000062_0001
Figure imgf000062_0001
Figure imgf000062_0002
Figure imgf000062_0003
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Figure imgf000062_0005
Figure imgf000063_0001
Figure imgf000063_0002
Figure imgf000063_0003
Figure imgf000062_0002
Figure imgf000062_0003
Figure imgf000062_0004
Figure imgf000062_0005
Figure imgf000063_0001
Figure imgf000063_0002
Figure imgf000063_0003
Figure imgf000063_0004
Figure imgf000063_0005
Figure imgf000064_0001
Figure imgf000064_0002
Figure imgf000065_0001
Figure imgf000063_0004
Figure imgf000063_0005
Figure imgf000064_0001
Figure imgf000064_0002
Figure imgf000065_0001
Figure imgf000065_0002
Figure imgf000065_0003
Figure imgf000065_0004
Figure imgf000065_0002
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Figure imgf000065_0004
Figure imgf000066_0001
Figure imgf000066_0002
Figure imgf000066_0003
Figure imgf000066_0004
Figure imgf000066_0005
Figure imgf000066_0001
Figure imgf000066_0002
Figure imgf000066_0003
Figure imgf000066_0004
Figure imgf000066_0005
Figure imgf000067_0001
Figure imgf000067_0002
Figure imgf000067_0003
Figure imgf000067_0004
Figure imgf000067_0005
Figure imgf000068_0001
Figure imgf000068_0002
Figure imgf000068_0003
Figure imgf000069_0001
Figure imgf000069_0002
Figure imgf000069_0003
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000071_0002
Figure imgf000071_0003
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000073_0002
Figure imgf000074_0001
Figure imgf000067_0001
Figure imgf000067_0002
Figure imgf000067_0003
Figure imgf000067_0004
Figure imgf000067_0005
Figure imgf000068_0001
Figure imgf000068_0002
Figure imgf000068_0003
Figure imgf000069_0001
Figure imgf000069_0002
Figure imgf000069_0003
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000071_0002
Figure imgf000071_0003
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000073_0002
Figure imgf000074_0001
Figure imgf000074_0002
Figure imgf000074_0003
Figure imgf000075_0001
Figure imgf000075_0002
Figure imgf000075_0003
Figure imgf000074_0002
Figure imgf000074_0003
Figure imgf000075_0001
Figure imgf000075_0002
Figure imgf000075_0003
Figure imgf000076_0001
Figure imgf000076_0002
Figure imgf000077_0001
Figure imgf000077_0002
76
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000079_0002
Figure imgf000079_0003
Figure imgf000080_0001
Figure imgf000080_0002
besteht. Verwendung nach Anspruch 5, dadurch gekennzeichnet, daß die Verbindungen aus der Gruppe ausgewählt sind, die aus N-(l-Phosphonopentyl)-glycinhydroxamat, N-Methyl- N-[(3-pyridyl)-phosphonomethyl]-glycinhydroxamat, N-Butyl-N-(l-phosphonoethyl)- glycinhydroxamat, N-( 1 -Phosphono- 1 -methylpropyl)-L-alaninhy droxamat, N-Methyl- N-phsphonomethyl-L-alaninhydroxamat, N-Methyl-N-( 1 -phosphonoethyl)-L- alaninhydroxamat, N-Phosphonomethylglycin)-N-methylhydroxamat und (N- Phosphonomethylglycin)-N-isopropylhydroxamat besteht.
Figure imgf000076_0001
Figure imgf000076_0002
Figure imgf000077_0001
Figure imgf000077_0002
76
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000079_0002
Figure imgf000079_0003
Figure imgf000080_0001
Figure imgf000080_0002
consists. Use according to claim 5, characterized in that the compounds are selected from the group consisting of N- (l-phosphonopentyl) glycine hydroxamate, N-methyl-N - [(3-pyridyl) phosphonomethyl] glycine hydroxamate, N-butyl -N- (l-phosphonoethyl) glycine hydroxamate, N- (1-phosphono-1-methylpropyl) -L-alaninhy droxamate, N-methyl-N-phsphonomethyl-L-alanine hydroxamate, N-methyl-N- (1 -phosphonoethyl ) -L-alanine hydroxamate, N-phosphonomethylglycine) -N-methylhydroxamate and (N-phosphonomethylglycine) -N-isopropylhydroxamate.
Verwendung nach einem der Ansprüche 1 bis 6 zur Herstellung von Arzneimitteln für die Behandlung von Infektionen, die durch Bakterien hervorgerufen werden, die aus der Gruppe ausgewählt sind, die aus Bakterien der Familie Propionibacteriaceae, insbesondere der Gattung Propionibacterium, insbesondere die Art Propionibacterium acnes, Bakterien der Familie Actinomycetaceae, insbesondere der Gattung Actinomyces, Bakterien der Gattung Corynebacterium, insbesondere die Arten Corynebacterium diphteriae und Corynebacterium pseudotuberculosis, Bakterien der Familie Mycobacteriaceae, der Gattung Mycobacterium, insbesondere die Arten Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis und Mycobacterium avium, Bakterien der Familie Chlamydiaceae, insbesondere die Spezies Chlamydia trachomatis und Chlamydia psittaci, Bakterien der Gattung Listeria, insbesondere die Art Listeria mo- nocytogenes, Bakterien der Art Erysipelthrix rhusiopathiae, Bakterien der Gattung Clostridium, Bakterien der Gattung Yersinia, der Spezies Yersinia pestis, Yersinia pseudotuberculosis, Yersinia enterocolitica und Yersinia ruckeri, Bakterien der Familie Mycoplasmataceae, der Gattungen Mycoplasma und Ureaplasma, insbesondere die Art Mycoplasma pneumoniae, Bakterien der Gattung Brucella, Bakterien der Gattung Bordetella, Bakterien der Familie Neiseriaceae, insbesondere der Gattungen Neisseria und Moraxella, insbesondere die Arten Neisseria meningitides, Neisseria gonorrhoeae und Moraxella bovis, Bakterien der Familie Vibrionaceae, insbesondere der Gattungen Vibrio, Aeromonas, Plesiomonas und Photobacterium, insbesondere die Arten Vibrio cholerae, Vibrio anguillarum und Aeromonas salmonicidas, Bakterien der Gattung Campylobacter, insbesondere die Arten Campylobacter jejuni, Campylobacter coli und Campylobacter fetus, Bakterien der Gattung Helicobacter, insbesondere die Art Heli- cobacter pylori, Bakterien der Familien Spirochaetaceae und der Leptospiraceae, insbesondere der Gattungen Treponema, Borrelia und Leptospira, insbesondere Borrelia bur- gdorferi, Bakterien der Gattung Actinobacillus, Bakterien der Familie Legionellaceae,Use according to any one of claims 1 to 6 for the manufacture of medicaments for the treatment of infections caused by bacteria selected from the group consisting of bacteria from the Propionibacteriaceae family, in particular the Propionibacterium genus, in particular the Propionibacterium acnes species, bacteria the family Actinomycetaceae, in particular the genus Actinomyces, bacteria of the genus Corynebacterium, in particular the species Corynebacterium diphteriae and Corynebacterium pseudotuberculosis, bacteria of the family Mycobacteriaceae, the genus Mycobacterium, in particular the species Mycobacterium lacterium mycobacterium, myobacterium av 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, Ba cteria of the genus Yersinia, of the species Yersinia pestis, Yersinia pseudotuberculosis, Yersinia enterocolitica and Yersinia ruckeri, bacteria of the family Mycoplasmataceae, of the genera Mycoplasma and Ureaplasma, in particular the species Mycoplasma pneumoniae, bacteria of the genus Brucellaetella, bacteria of the genus Boreae derella, bacteria of the genus , in particular the genera Neisseria and Moraxella, in particular the species Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis, bacteria of the Vibrionaceae family, in particular the genera Vibrio, Aeromonas, Plesiomonas and Photobacterium, in particular the species Vibrio cholerae, Vibrio anguillarum and Aeromonas salmonicidas 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 Spirochaetaceae and Leptospiraceae families, in particular the genera Treponema, Borrelia and Leptospira, in particular Borrelia burdorferi, bacteria of the genus Actinobacillus, bacteria of the Legionellaceae family,
, der Gattung Legionella, Bakterien der Familie Rickettsiaceae und Familie Bartonella- ceae, Bakterien der Gattungen Nocardia und Rhodococcus, Bakterien der Gattung Dermatophilus, Bakterien der Familie Pseudomonadaceae, insbesondere der Gattungen Pseudomonas und Xanthomonas, Bakterien der Familie Enterobacteriaceae, insbesonde- re der Gattungen Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia und Shigella, Bakterien der Familie Pasteurellaceae, insbesondere der Gattung Haemophilus, Bakterien der Familie Micrococcaceae, insbesondere der Gattungen Micrococcus und Staphylococcus, Bakterien der Familie Streptococcaceae, insbesondere der Gattungen Streptococcus und Enterococcus und Bakterien der Familie Bacillaceae, insbesondere der Gattungen Bacillus und Clostridium besteht, und bei der Helicobacter- Eradikationstherapie bei Ulcera des Magendarmtraktes., the genus Legionella, bacteria of the Rickettsiaceae family and Bartonella- ceae family, bacteria of the genera Nocardia and Rhodococcus, bacteria of the genus Dermatophilus, bacteria of the Pseudomonadaceae family, especially of the genera Pseudomonas and Xanthomonas, bacteria of the Enterobacteriaceae family, in particular right of the genera Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia and Shigella, bacteria of the Pasteurellaceae family, especially of the genus Haemophilus, bacteria of the Micrococcaceae family, especially of the genera Micrococcus and Staphylococcus, bacteria of the Streptococccaceaungen and especially Enterptococcus family and bacteria of the family Bacillaceae, in particular of the genera Bacillus and Clostridium, and in Helicobacter eradication therapy for ulcers of the gastrointestinal tract.
Verwendung nach einem der Ansprüche 1 bis 6 zur Herstellung von Arzneimitteln für die Behandlung von Infektionen, die durch Viren hervorgerufen werden, die aus der Gruppe ausgewählt sind, die aus Viren der Gattung Parvoviridae, insbesondere Parvovi- ren, Dependoviren, Densoviren, Viren der Gattung Adenoviridae, insbesondere Adenoviren, Mastadenoviren, Aviadenoviren, Viren der Gattung Papovaviridae, insbesondere Papovaviren, insbesondere Papillomaviren (sogenannte Warzenviren), Polyomaviren, insbesondere JC-Virus, BK- Virus, und Miopapovaviren, Viren der Gattung Herpesviri- dae, insbesondere HerpesτSimplex- Viren, der Varizellen/Zoster- Viren, menschlicher Zytomegahevirus, Epstem-Barr- Viren, humanes Herpesvirus 6, humanes Herpesvirus 7, humanes Herpesvirus 8, Viren der Gattung Poxviridae, insbesondere Pockenviren, Or- thopox- Parapox-, Molluscum-Contagiosum- Virus, Aviviren, Capriviren, Leporipoxvi- ren, primär hepatotropen Viren, insbesondere Hepatitisviren, wie Hepatitis-A- Viren, Hepatitis-B-Viren, Hepatitis-C- Viren, Hepatitis-D- Viren, Hepatitis-E- Viren, Hepatitis- F- Viren, Hepatits-G- Viren, Hepadnaviren, insbesondere sämtliche Hepatitisviren, wie Hepatitis-B-Virus, Hepatitis-D- Viren, Viren der Gattung Picornaviridae, insbeondere Picornaviren, alle Enteroviren, alle Polioviren, alle Coxsackieviren, alle Echoviren, alle Rhinoviren, Hepatitis-A- Virus, Aphthoviren, Viren der Gattung Calciviridae, insbesondere Hepatitis-E- Viren, Viren der Gattung Reoviridae, insbesondere Reoviren, Orbivi- ren, Rotaviren, Viren der Gattung Togaviridae, insbesondere Togaviren, Alphaviren, Rubiviren, Pestiviren, Rubellavirus, Viren der Gattung Flaviviridae, insbesondere Flaviviren, FSME- Virus, Hepatitis-C- Virus, Viren der Gattung Orthomyxoviridae, insbesondere Influenzaviren, Viren der Gattung Paramyxoviridae, insbesondere Paramyxovi- ren, Morbillivirus, Pneumovirus, Masernvirus, Mumpsviras, Viren der Gattung Rhabdoviridae, insbesondere Rhabdoviren, Rabiesvirus, Lyssavirus, viskuläres Stomatitisvi- rus, Viren der Gattung Coronaviridae, insbesondere Coronaviren, Viren der Gattung Bunyaviridae, insbesondere Bunyaviren, Nairovirus, Phlebovirus, Uukuvirus, Hantavi- rus, Viren der Gattung Arenaviridae, insbesondere Arenaviren, lymphozytäres Chorio- meningitis- Virus, Viren der Gattung Retroviridae, insbesondere Retroviren, alle HTL- Viren, humanes T-cell Leukämie- Virus, Oncoraaviren, Spumaviren, Lentiviren, alle HI- Viren, Viren der Gattung Filovjπdae, insbesondere Marburg- und Ebolavirus, Slow- Viren, Prionen, Onkoviren und Leukämie- Viren besteht. Verwendung nach einem der Ansprüche 1 bis 6 zur Herstellung von Arzneimitteln für die Vorbeugung und Behandlung von Infektionen verursacht durch einzellige Parasiten, nämlich Erreger der Malaria, der Schlafkrankheit, der Chagas-Krankheit, der Toxoplasmose, der Amöbenruhr, der Leishmaniosen, der Trichomoniasis, der Pneumo- zystose, der Balantidiose, der Kryptosporidiose, der Sarkozystose, der Akantha-möbose, der Naeglerose, der Kokzidiose, der Giardiose und der Lambliose.Use according to one of claims 1 to 6 for the manufacture of medicaments for the treatment of infections caused by viruses selected from the group consisting of viruses of the genus Parvoviridae, in particular Parvoviruses, Dependoviruses, Densoviruses, viruses of the genus Adenoviridae, in particular adenoviruses, mastadenoviruses, aviadenoviruses, viruses of the genus Papovaviridae, in particular papovaviruses, in particular papillomaviruses (so-called warts viruses), polyomaviruses, in particular JC virus, BK virus, and miopapovaviruses, viruses of the genus Herpesviruses, virus types the varicella / zoster viruses, human cytomegahevirus, Epstem-Barr viruses, human herpes virus 6, human herpes virus 7, human herpes virus 8, viruses of the genus Poxviridae, in particular pox viruses, orthopox parapox, molluscum contagiosum virus, aviv , Capriviruses, leporipoxviruses, primarily hepatotropic viruses, in particular hepatitis viruses, such as hepatitis A virus n, hepatitis B viruses, hepatitis C viruses, hepatitis D viruses, hepatitis E viruses, hepatitis F viruses, hepatits G viruses, hepadnaviruses, in particular all hepatitis viruses, such as hepatitis B virus , Hepatitis D viruses, viruses of the Picornaviridae genus, in particular Picornaviruses, all enteroviruses, all polioviruses, all Coxsackieviruses, all echoviruses, all rhinoviruses, hepatitis A virus, aphthoviruses, viruses of the genus Calciviridae, especially hepatitis E virus, Viruses of the genus Reoviridae, in particular reoviruses, orbiviruses, rotaviruses, viruses of the genus Togaviridae, in particular Togaviruses, alphaviruses, rubiviruses, pestiviruses, rubella virus, viruses of the genus Flaviviridae, in particular flaviviruses, TBE virus, hepatitis C virus, Genus Orthomyxoviridae, in particular influenza viruses, viruses of the genus Paramyxoviridae, in particular Paramyxoviruses, morbillivirus, pneumovirus, measles virus, mumpsviras, viruses of the genus Rhabdoviridae, in particular Rhabdoviruses, Rabies virus, Lyssavir us, viscous stomatitis virus, viruses of the genus Coronaviridae, in particular coronaviruses, viruses of the genus Bunyaviridae, in particular Bunyaviruses, Nairovirus, phlebovirus, uukuvirus, Hantavirus, viruses of the genus Arenaviridae, in particular Arenaviruses virus, virus arenaviruses, lymphoma viruses Genus Retroviridae, especially retroviruses, all HTL viruses, human T-cell leukemia virus, Oncoraaviruses, Spumaviruses, lentiviruses, all HI viruses, viruses of the Filovjπdae genus, especially Marburg and Ebola viruses, slow viruses, prions, oncoviruses and leukemia - Viruses exist. Use according to one of claims 1 to 6 for the manufacture of medicaments for the prevention and treatment of infections caused by unicellular parasites, namely pathogens of malaria, sleeping sickness, Chagas disease, toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis, the Pneumocystosis, balantidiosis, cryptosporidiosis, sarco- cystosis, Akantha-Möbose, Naeglerose, coccidiosis, giardiosis and lambliosis.
Pharmazeutisches Präparat, gekennzeichnet durch einen wirksamen Gehalt an zumindest einer Verbindung nach einem der Ansprüche 1 bis 6 zusammen mit einem pharmazeutisch akzeptablen Träger.Pharmaceutical preparation, characterized by an effective content of at least one compound according to one of claims 1 to 6 together with a pharmaceutically acceptable carrier.
Pharmazeutisches Präparat nach Anspruch 10, gekennzeichnet durch mindestens einen weiteren pharmazeutischen Wirkstoff.Pharmaceutical preparation according to claim 10, characterized by at least one further pharmaceutical active ingredient.
Pharmazeutisches Präparat nach einem der Ansprüche 10 oder 11, gekennzeichnet durch einen oder mehrere Bestandteile der Gruppe, die aus Sulfonamid, Sulfadoxin, Artemisinin, Atovaquon, Chinin, Chloroquin, Hydroxychloroquin, Mefloquin, Halo- fantrin, Pyrimethamin, Armesin, Tetracycline, Doxycyclin, Proguanil, Metronidazol, Praziquantil, Niclosamid, Mebendazol, Pyrantel, Tiabendazol, Diethylcarbazin, Pipera- zin, Pyrivinum, Metrifonat, Oxa niquin, Bithionol und Suramin besteht. Pharmaceutical preparation according to one of claims 10 or 11, characterized by one or more constituents of the group consisting of sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracycline, doxycycline, proguanil , Metronidazole, praziquantil, niclosamide, mebendazole, pyrantel, tiabendazole, diethylcarbazine, piperazine, pyrivinum, metrifonate, oxa niquin, bithionol and suramin.
PCT/EP2001/006539 2000-06-08 2001-06-08 Use of organophosphorous hydroxamic acid derivatives for producing medicaments WO2001093872A1 (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
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US9949988B2 (en) 2014-09-12 2018-04-24 Antibiotx A/S Antibacterial use of halogenated salicylanilides
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WO2010014943A2 (en) * 2008-08-01 2010-02-04 Bioxiness Pharmaceutics, Inc. Methionine analogs and methods of using same
WO2010014943A3 (en) * 2008-08-01 2011-01-13 Bioxiness Pharmaceutics, Inc. Methionine analogs and methods of using same
US8580859B2 (en) 2008-08-01 2013-11-12 Bioxiness Pharmaceuticals, Inc. Methionine analogs and methods of using same
US9695119B2 (en) 2008-08-01 2017-07-04 Bioxiness Pharmaceuticals, Inc. Methionine analogs and methods of using same
AU2016206369B2 (en) * 2009-12-07 2018-01-18 Cardioxyl Pharmaceuticals, Inc. N-acyloxysulfonamide and n-hydroxy-n-acylsulfonamide derivatives
US11285164B2 (en) 2014-09-12 2022-03-29 UNION therapeutics A/S Antibacterial use of halogenated salicylanilides
US10758553B2 (en) 2014-09-12 2020-09-01 UNION therapeutics A/S Antibacterial use of halogenated salicylanilides
US9949988B2 (en) 2014-09-12 2018-04-24 Antibiotx A/S Antibacterial use of halogenated salicylanilides
US11324761B2 (en) 2014-09-12 2022-05-10 UNION therapeutics A/S Antibacterial use of halogenated salicylanilides
US11331327B2 (en) 2014-09-12 2022-05-17 UNION therapeutics A/S Antibacterial use of halogenated salicylanilides
US10463680B2 (en) 2015-05-29 2019-11-05 UNION therapeutics A/S Halogenated salicylanilides for treating clostridium infections
US10857164B2 (en) 2015-05-29 2020-12-08 UNION therapeutics A/S Halogenated salicylanilides for treating Clostridium infections
US11529361B2 (en) 2015-05-29 2022-12-20 UNION therapeutics A/S Halogenated salicylanilides for treating Clostridium infections
US11419834B2 (en) 2019-02-25 2022-08-23 Rhode Island Hospital Methods for treating diseases or infections caused by or associated with H. pylori using a halogenated salicylanilide

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