EP1143941A2 - Use of 3-isoxazolidinones and hydroxylamine acids for the treatment of infections - Google Patents

Use of 3-isoxazolidinones and hydroxylamine acids for the treatment of infections

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Publication number
EP1143941A2
EP1143941A2 EP00902582A EP00902582A EP1143941A2 EP 1143941 A2 EP1143941 A2 EP 1143941A2 EP 00902582 A EP00902582 A EP 00902582A EP 00902582 A EP00902582 A EP 00902582A EP 1143941 A2 EP1143941 A2 EP 1143941A2
Authority
EP
European Patent Office
Prior art keywords
methyl
chloro
dimethyl
phenyl
isoxazolidinone
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00902582A
Other languages
German (de)
French (fr)
Other versions
EP1143941A3 (en
Inventor
Hassan Jomaa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jomaa Pharmaka GmbH
Original Assignee
Jomaa Pharmaka GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE19903666A external-priority patent/DE19903666A1/en
Application filed by Jomaa Pharmaka GmbH filed Critical Jomaa Pharmaka GmbH
Publication of EP1143941A2 publication Critical patent/EP1143941A2/en
Publication of EP1143941A3 publication Critical patent/EP1143941A3/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • 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 3-isoxazolidinones and hydroxylamine acids as active ingredient and their salts, esters and salts of the esters for the therapeutic and prophylactic treatment of infections in humans and animals which are caused by bacteria, fungi and parasites.
  • the object of the present invention is therefore to provide a substance which can be used in infections by bacteria, fungi and parasites in humans and animals and which fulfills the conditions specified above.
  • U.S. Patent 4,405,357 discloses 3-isoxazolidinones and hydroxylamic acids as herbicides.
  • R 3 is selected from the group consisting of hydrogen, alkyl groups, alkoxy (Co- 26 ) alkyl groups, C 3 - ⁇ 4 cycloalkyl (C 0. 26 ) alkyl groups, cycloalkoxy (C 0. 26 ) alkyl groups, amino no- (C 0. 2, 6) alkyl, silyl (C 0.
  • alkyl and thio (co- 26) alkyl groups wherein each alkyl radical and each alkoxy group is branched or unbranched and each alkyl radical, each alkoxy radical and each cycloalkyl group may be saturated or unsaturated with one or more double or triple bonds and may be substituted by hydroxyl, amino, halogen, oxo groups and alkoxy radicals and one or two carbon atoms of the cycloalkyl groups by nitrogen, oxygen or or sulfur atoms can be replaced, »Is selected from the group consisting of hydrogen, alkyl radicals, acyl radicals and cycloalkyl- (C 0.
  • each alkyl radical and each acyl radical being branched or unbranched and each alkyl radical
  • each acyl radical and each cycloalkyl group saturated or with one or more double or triple bonds may be unsaturated and may be substituted by hydroxyl, amino, halogen, oxo groups and alkoxy radicals and one or two carbon atoms of the cycloalkyl groups may be replaced by nitrogen, oxygen or sulfur atoms
  • Ri and R 2 are the same or different and are selected from the group consisting of hydrogen, hydroxyl, halogen, amino, alkyl, alkoxy and cycloalkyl (C 0. 26 ) alkyl groups, each alkyl and alkoxy branched or unbranched and any amino radical, alkyl radical, any alkoxy radical and any cycloalkyl group saturated or unsaturated with one or more double or triple bonds and can be substituted by hydroxyl, amino, halogen, oxo groups and alkoxy radicals and one or two carbon atoms of the cycloalkyl groups by nitrogen -, oxygen or sulfur atoms can be replaced,
  • R 5 , R ⁇ and R 7 are the same or different and are selected from the group consisting of hydrogen, hydroxyl, halogen, alkyl groups, cycloalkyl (C 0. 26 ) alkyl groups, cycloalkoxy (C 0 - 26 ) -alkyl groups, alkoxy- (C 0. 26 ) -alkyl groups, amino groups and thio- (C 0.
  • each alkyl radical, each alkoxy radical and each acyl radical being branched or unbranched and each alkyl radical, each alkoxy radical and each Cycloalkyl group saturated or unsaturated with one or more double or triple bonds and can be substituted with hydroxyl, amino, halogen, oxo groups and alkoxy radicals and one or two carbon atoms of the cycloalkyl groups can be replaced by nitrogen, oxygen or sulfur atoms, where R 5 alternatively can also form a ring with Ri, and R 3 and R can have a single carbon-oxygen bond, such that a ring structure is present.
  • the invention also includes the pharmaceutically acceptable salts, esters and salts of the esters.
  • R ⁇ and R 2 are preferably identical or different and selected from the group consisting of substituted and unsubstituted alkyl groups, preferably C 1 -C 4 -alkyl groups.
  • R 3 is preferably selected from the group consisting of hydrogen, substituted and unsubstituted substituted alkyl groups, preferably C 1 -C 4 alkyl groups, substituted and unsubstituted aromatic C 7 -C 4 cycloalkyl groups, a pyranyl group, a t-butyldimethylsilyl group and
  • R 8 is selected from the group consisting of substituted and unsubstituted, preferably halogen-substituted alkyl groups, substituted and unsubstituted cycloalkyl (Co- 26 ) alkyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted Phenoxy groups, substituted and unsubstituted alkylthio groups, substituted and unsubstituted, preferably unsubstituted or substituted with halogen, methyl, methoxy, nitro, amino or CF 3 groups, aromatic cycloalkylthio groups.
  • R 4 is preferably selected from the group consisting of hydrogen, substituted and unsubstituted alkyl radicals, substituted and unsubstituted phenyl radicals and
  • X is selected from the group consisting of hydrogen, halogen, C ⁇ -alkyl radicals and phenyl radicals and Y is selected from the group consisting of hydrogen, halogen, d ⁇ -alkyl radicals, nitro radicals, methoxy radicals, methylenedioxy groups, where n Is 0 or 1.
  • R 7 is preferably selected from the group consisting of hydrogen and halogen, or R 3 and R 7 have a single carbon-oxygen bond, so that there is a ring structure.
  • R] and R 2 are independently selected from the group consisting of methyl and ethyl, is and
  • R 5 and R ⁇ 5 are independently selected from the group consisting of hydrogen, chlorine, bromine and methoxy groups.
  • X is selected from the group consisting of 2-chloro, 2-bromo, 2-fluorine and Y is selected from the group consisting of 4-chloro, 4-bromo, 4-fluorine -, 5-fluorine and 4,5-methylenedioxy groups, where n is 0 or 1.
  • R 1 and R 2 are methyl groups are particularly preferred.
  • R 3 and R 7 are hydrogen or contain a carbon-oxygen bond which form a ring structure.
  • Examples of preferred compounds are 3-chloro-N- (2-chlorophenyl) methyl-N-hydroxy-2,2-dimethylpropanamide, N- (2-chloro-nyl) methyl-N-hydroxy-2,2-dimethylpropanamide, 3- Chlorine-N-hydroxy-N-phenyl-2,2-dimethylpropanamide, N- (2-bromophenyl) methyl-3-chloro-N-hydroxy-2,2-dimethylpropanamide, 3-chloro-N-hydroxy-2, 2-dimethyl-N- (2-methylphenyl) methylpropanamide, 3-chloro-N-hydroxy-2,2-N-trimethylpropanamide, 3-chloro-N-hydroxy-2,2-dimethyl-N- (phenylmethyl) propanamide , 3-chloro-N- (2,4-dichlorophenylmethyl) -N-hydroxy-2,2-dimethylpropanamide, 3-chloro-N- (2-chlorophenyl) methyl-N-
  • Acyl is a substituent derived from an acid, such as 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.
  • Aliphatic acyl groups are acyl radicals derived from an aliphatic acid, which include the following:
  • Alkanoyl e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl etc.
  • Alkenoyl e.g. acryloyl, methacryloyl, crotonoyl etc.
  • Alkylthioalkanoyl e.g. methylthioacetyl, ethylthioacetyl etc.
  • alkanesulfonyl e.g. mesyl, ethanesulfonyl, propanesulfonyl etc.
  • Alkoxycarbonyl e.g.
  • the aliphatic hydrocarbon part in particular the alkyl group or the alkane radical, can optionally have one or more suitable substituents, such as amino, halogen (for example fluorine, chlorine, bromine, etc.), hydroxy, hydroxyimino, Carboxy, alkoxy (e.g. methoxy, ethoxy, propoxy etc.), alkoxycarbonyl, acylamino (e.g. benzyloxycarbonylamino etc.), acyloxy (e.g. acetoxy, benzoyloxy etc.) and the like; as preferred aliphatic acyl radicals with such substituents are e.g. alkanoyl substituted with amino, carboxy, amino and carboxy, halogen, acylamino or the like.
  • suitable substituents such as amino, halogen (for example fluorine, chlorine, bromine, etc.), hydroxy, hydroxyimino, Carboxy, alkoxy (e.g. methoxy,
  • Aromatic acyl radicals are those acyl radicals which originate from an acid with a substituted or unsubstituted aryl group, the aryl group being phenyl, to- luyl, 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.
  • Aryloxycarbonyl e.g. phenoxycarbonyl, naphthyloxycarbonyl etc.
  • Aralkoxycarbonyl e.g. benzyloxycarbonyl etc.
  • Arylcarbamoyl e.g. phenylcarbamoyl, naphthylcarbamoyl 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.
  • 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, pyrrole carbonyl, 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 thiophenyl-acetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino- 4-thiazolyl) -2-methoxyiminoacetyl etc.) and the like.
  • nitrogen, oxygen and sulfur for example thiophenyl-acetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino- 4-thiazolyl) -2-methoxyiminoacetyl etc.
  • heterocyclic acyl 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-chain or branched-chain alkyl radical having up to 26 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, Pentyl, hexyl and the like. It can be substituted, for example, with hydroxy, amino, halogen (for example fluorine, bromine, chlorine), oxo residues and alkoxy residues, such as methoxy, ethoxy residues.
  • halogen for example fluorine, bromine, chlorine
  • alkoxy radical is a straight-chain or branched-chain alkoxy radical having up to 26 carbon atoms, such as a methoxy, ethoxy radicals, etc. It can, for example, contain hydroxyl, amino, halogen, oxo groups and alkoxy radicals, such as methoxy -, Ethoxy radicals, may be substituted.
  • Alkoxy (Co- 26 ) alkyl groups are alkoxy radicals which can also be bonded to the basic structure via an alkyl radical.
  • the alkyl and alkoxy groups are as defined above.
  • “Cycloalkyl- (C 0. 26 ) -alkyl radicals” are cyclic compounds with 3 to 8 carbon atoms, unless otherwise defined, which are bonded to the basic structure directly or via an alkylene radical.
  • the alkylene radical can be branched, unbranched and saturated or with Possible substituents of the cycloalkyl radical include alkoxy radicals, alkyl radicals, hydroxy radicals, halogen radicals, amino radicals, oxo radicals.
  • the cycloalkyl groups can also be aromatic with the corresponding number of double bonds, ie aryl- (Co- 26 ) alkyl radicals (eg phenyl, Pyridyl, naphthyl, etc.)
  • aryl- (Co- 26 ) alkyl radicals eg phenyl, Pyridyl, naphthyl, etc.
  • the aromatic cyclic compounds in particular may also contain substituents such as nitro groups and CF 3 and phenyl radicals.
  • Cycloalkoxy (C 0. 26 ) alkyl groups are cyclic compounds having 3 to 8 carbon atoms which are bonded to the basic structure via an oxygen directly or via an alkylene radical.
  • the alkylene radical can be branched, unbranched and saturated or unsaturated with double bonds.
  • Possible substituents of the cycloalkyl radical include alkoxy radicals (also alkylenedioxy radicals such as methylenedioxy), alkyl radicals, hydroxyl radicals, halogen radicals, amino radicals, oxo radicals.
  • the cycloalkyl groups can also be multiple cycles and aromatic (eg phenoxy, pyridoxy, naphthoxy) etc.
  • the aromatic cyclic compounds can also contain substituents such as nitro groups, CF 3 groups and phenyl radicals.
  • Amino may for example with the above defined alkyl radicals or cycloalkanes alkyl- (C 0 - 26) alkyl substituted.
  • Amino (C 0. 26) -alkyl are amino radicals, which can also be bonded via an alkyl group to the backbone.
  • the alkyl and amino groups are as defined above.
  • silyl groups for example, with the above defined alkyl radicals or cycloalkyl- (C 0 - 26) alkyl substituted.
  • silyl groups "are silyl radicals which can also be bonded to the basic structure via an alkyl radical.
  • the alkyl and silyl groups are as defined above.
  • Thio (C 0. 26 ) alkyl groups can for example be substituted with the alkyl radicals or cycloalkyl (C 0 - 26 ) alkyl radicals as defined above.
  • the (Co- 26 ) alkyl groups are straight or branched chain alkylene radicals such as Methylene, ethylene, propylene, isopropylene, butylene, isobutylene, tert-butylene, pentylene, hexylene, etc. They can contain double or triple bonds and, for example, with hydroxy, amino, halogen (for example fluorine, bromine, chlorine), Oxo radicals and alkoxy radicals, such as methoxy, ethoxy radicals, may be substituted.
  • the compounds of formula (I) according to the invention allow spatial isomers to occur, for example, for double bonds containing or chiral groups R 1 to R 7 .
  • the use of the compounds according to the invention includes all spatial isomers both as pure substances and in the form of their mixtures.
  • the compounds are particularly suitable for the therapeutic and prophylactic treatment of infections in humans and animals which are caused by bacteria, unicellular 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, balantidosis, cryptosporidiosis, and sarcolocystosis , Akanthamöbose, Naeglerose, Coccidiosis, Giardiosis and Lambliosis.
  • malaria prophylaxis and as prophylaxis of sleeping sickness and Chagas disease, toxoplasmosis, amoebic dysentery, Leishmaniasis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcolocystosis, acanthamoebosis, cocoonosis, naeglerosis Giardiosis and Lambliosis.
  • 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 Corynebacterium pseudote family mycobacteria, bacteria the species Mycob acterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium, bacteria of the Chlamydiaceae family, especially the species Chlamydia trachomatis and Chlamydia psittaci, bacteria of the genus Listeria, especially the species Listeria monocytogenes, bacteria of the species Erys Clostridium, bacteria of the genus Yersinia, of the species Yersinia pestis, Yersinia pseudotuberculosis, Yersin
  • the use is also useful in Helicobacter eradication therapy for ulcers of the gastrointestinal tract.
  • Combinations 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.
  • the compounds according to the invention generally include pharmaceutically acceptable salts, esters and a salt of such an ester, or compounds which, when administered, provide the compounds according to the invention as metabolites or degradation products, also called “prodrugs", can be administered 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 formula (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 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.
  • test system The activity of the substances is determined in a test system. This system is based on the measurement of the inhibition of the growth of bacteria, parasites or fungi in vitro. For this purpose, test methods are used which are known to the person skilled in the art.
  • the inhibition of the growth of malaria parasites in blood cultures is determined to determine the antimalarial activity.
  • the determination of the antibacterial activity is based on measuring the inhibition of bacterial growth on nutrient media and in liquid cultures.
  • the determination of the fungicidal activity is based on the inhibition of the growth of fungi on nutrient media and in liquid cultures.
  • microorganisms to be examined can only be examined in animal models.
  • the corresponding models are used here.
  • Substances that show effectiveness in the in vitro measuring systems are in vivo Models examined further.
  • the antiparasitic, fungicidal or antibacterial activity is further evaluated in the corresponding animal models.
  • 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.
  • Solid, semi-solid or liquid diluents are among non-toxic, inert pharmaceutically suitable carriers. Understand fillers and formulation aids of all kinds.
  • Tablets, dragees, capsules, pills, granules, suppositories and solutions are 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.
  • cellulose 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 retarders, e.g. B. paraffin and (f) Reso ⁇ tions accelerator, z. B. quaternary ammonium compounds, (g) wetting agents, e.g. B. cetyl alcohol, glycerol monostearate, (h) adsorbent, z. 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).
  • humectants e.g. B. glycerin
  • disintegrant e.g. B. agar-
  • 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 contain water-insoluble carriers, e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat and higher esters (z. B. C ⁇ 4 alcohol with C 16 fatty acid) or mixtures of these substances.
  • water-soluble carriers e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat and higher esters (z. B. C ⁇ 4 alcohol with C 16 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 sesame oil, glycerol, glycerol formurate - hol, 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, oils, especially cotton
  • solutions and emulsions can also be in sterile and blood-isotonic form.
  • suspensions can contain the usual carriers such as liquid diluents, e.g. B. water, ethyl alcohol, propylene glycol, suspending agents, e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth or mixtures of these substances.
  • liquid diluents e.g. B. water, ethyl alcohol, propylene glycol
  • suspending agents e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth or mixtures of these substances.
  • the formulation forms mentioned can also contain colorants, preservatives and odor and taste-improving additives, e.g. B. peppermint oil and eucalyptus oil and sweeteners, e.g. B. saccharin.
  • the active compounds of the formula (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 other active pharmaceutical ingredients.
  • the compounds can be used with previously described substances with antibacterial, antiviral, antimyctoic and antiparasitic properties. These include in particular compounds that have already been used in therapy or are still being used. Substances are particularly suitable for this purpose, which are listed in the Red List or in Simon / Stille, Antibiotic Therapy in Clinic and Practice, 9th Edition 1998 Schattauer Verlag, or at http: Awww.customs.treas. ov / imp-exp / rulings / liarmoniz / hrm 129. html listed on the Internet.
  • the derivatives can be administered with penicillins, benzylpenicillin (Penicillin G), phenoxypenicillins, isoxazolylpenicillins, aminopenicillins, ampicilins, amoxixillins, bacampicillins, carboxypenicillins, ticarcillins, temocillins, acyalaminopenocillins, azlillins, azlillins.
  • penicillins benzylpenicillin (Penicillin G)
  • phenoxypenicillins isoxazolylpenicillins
  • aminopenicillins aminopenicillins
  • ampicilins amoxixillins
  • bacampicillins carboxypenicillins
  • ticarcillins temocillins
  • acyalaminopenocillins azlillins
  • azlillins azlillins.
  • Spectinomyxin macrolides, erythromycin, charithromycin, roxithromycin, azithromycin, dirithromycin, spiramycin, josamycin, linosamide, clindamycin, fusidic acid.
  • Glycopeptide antibiotics vancomycin, tecoplanin, pristinamycin derivatives, fosfomycin, antimicrobial folic acid antagonists, sulfonamides, co-trimoxazole, trimethoprim, other diaminopyrimidine-sulfonamide combinations, nitrofurane, nitrofurantoin, nitrofacurinone, nitrofacurinone, nitrofacurinone , Ciprofloxacin, ofloxacin, sparfloxacin, enoxacin.
  • the compounds according to the invention can be used in the pharmaceutical compositions in combination with sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracyclines, doxycycline, proguanil, metronidazole, prazamidantebend, praziquantilil, Pyrantel, tiabendazole, 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 treatment 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.
  • Substance 4 Experiments show that the action of the compounds is based on an inhibition of the 1-deoxy-D-xylulose-5-phosphate (DOXP) pathway, which can be detected in bacteria, parasites and fungi, but not for humans.
  • DOXP 1-deoxy-D-xylulose-5-phosphate
  • Escherichia coli DOXP reductoisomerase was expressed as a recombinant protein in E. coli.
  • the oxidation of NADPH was measured in a spectrophotometer at 365 nm.
  • the activity of the DOXP reductoisomerase was measured in the presence of the compounds 1 to 4 in various concentrations between 0.1 and 100 ⁇ mol 1-1.
  • the concentration at which the enzyme is inhibited half-maximally (ICs) was determined from the measured values. The results, ie the IC50 values, are shown in the table.
  • the antimalarial activity of substances 1 to 4 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 half-maximum inhibitory concentration (IC50) of the substance was determined by extrapolation of the values. The results, ie the IC50 values, are shown in the table below:

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Abstract

The invention relates to medicaments containing at least one compound of the formula (I) and to their use for the therapeutic and prophylactic treatment of bacterial, fungal and parasitic infections in humans and animals.

Description

Verwendung von 3-Isoxazolidinonen und Hydroxylaminsäuren zur Behandlung von InfektionenUse of 3-isoxazolidinones and hydroxylamic acids to treat infections
Die Erfindung betrifft die Verwendung von 3-Isoxazolidinonen und Hydroxylaminsäuren als Wirkstoff sowie ihrer Salze, Ester und Salze der Ester zur therapeutischen und prophylaktischen Behandlung von Infektionen bei Mensch und Tier, die durch Bakterien, Pilze und Parasiten hervorgerufen werden.The invention relates to the use of 3-isoxazolidinones and hydroxylamine acids as active ingredient and their salts, esters and salts of the esters for the therapeutic and prophylactic treatment of infections in humans and animals which are caused by bacteria, fungi and parasites.
Es besteht ein starker Bedarf, für die Bereicherung der Behandlung von Mensch und Tier Arzneimittel bereitzustellen, die eine starke Wirksamkeit gegen Infektionen besitzen.There is a strong need to provide medicines that are potent against infections for the enrichment of human and animal treatment.
Aufgabe der vorliegenden Erfindung ist es daher, eine Substanz bereitzustellen, die bei Infektionen durch 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 in infections by bacteria, fungi and parasites in humans and animals and which fulfills the conditions specified above.
In der US-Patenschrift 4 405 357 sind 3-Isoxazolidinone und Hydroxylaminsäuren als Herbizide offenbart.U.S. Patent 4,405,357 discloses 3-isoxazolidinones and hydroxylamic acids as herbicides.
Überraschend hat sich nun herausgestellt, daß 3-Isoxazolidinone und Hydroxylaminsäuren die oben angegebene Aufgabe lösen. Diese Stoffgruppe zeigt eine antiinfektiöse Wirkung gegen Bakterien, Pilze, ein- und mehrzellige Parasiten. Unter einzelligen Parasiten sind erfindungsg Demäß Protozoen zu verstehen.Surprisingly, it has now been found that 3-isoxazolidinones and hydroxylamine acids solve the problem stated above. This group of substances shows an anti-infectious effect against bacteria, fungi, single and multicellular parasites. According to the invention, unicellular parasites are to be understood as protozoa.
Die erfindungsgemäß in den Arzneimitteln enthaltenen Verbindungen entsprechen der allgemeinen Formel (I):The compounds contained in the medicaments according to the invention correspond to the general formula (I):
Ri 0 1 IIRi 0 1 II
Re ■ - C - C - C - - f N-0-R3 ( I ) 1 1 R2 Re ■ - C - C - C - - f N-0-R 3 (I) 1 1 R 2
wobei R3 aus der Gruppe ausgewählt ist, die aus Wasserstoff, Alkylgruppen, Alkoxy-(Co-26)- alkylgruppen, C3-ι4-Cycloalkyl-(C0.26)-alkylgruppen, Cycloalkoxy-(C0.26)-alkylgruppen, Ami- no-(C0.26)-alkylgruppen, Silyl-(C0.26)-alkylgruppen und Thio-(Co-26)-alkyl-gruppen besteht, wobei jeder Alkylrest und jeder Alkoxyrest verzweigt oder unverzweigt und jeder Alkylrest, jeder Alkoxyrest und jede Cycloalkylgruppe gesättigt oder mit ein oder mehreren Doppeloder Dreifachbindungen ungesättigt und mit Hydroxy-, Amino-, Halogen-, Oxogruppen und Alkoxyresten substituiert sein kann und ein oder zwei Kohlenstoffatome der Cycloalkylgrup- pen durch Stickstoff-, Sauerstoff- oder Schwefelatome ersetzt sein können, » aus der Gruppe ausgewählt ist, die aus Wasserstoff, Alkylresten, Acylresten und Cycloal- kyl-(C0.26)-alkylgruppen besteht, wobei jeder Alkylrest und jeder Acylrest verzweigt oder unverzweigt und jeder Alkylrest, jeder Acylrest und jede Cycloalkylgruppe gesättigt oder mit ein oder mehreren Doppel- oder Dreifachbindungen ungesättigt und mit Hydroxy-, Amino-, Halogen-, Oxogruppen und Alkoxyresten substituiert sein kann und ein oder zwei Kohlenstoffatome der Cycloalkylgruppen durch Stickstoff-, Sauerstoff- oder Schwefelatome ersetzt sein können,wherein R 3 is selected from the group consisting of hydrogen, alkyl groups, alkoxy (Co- 26 ) alkyl groups, C 3 -ι 4 cycloalkyl (C 0. 26 ) alkyl groups, cycloalkoxy (C 0. 26 ) alkyl groups, amino no- (C 0. 2, 6) alkyl, silyl (C 0. 26,) alkyl and thio (co- 26) alkyl groups wherein each alkyl radical and each alkoxy group is branched or unbranched and each alkyl radical, each alkoxy radical and each cycloalkyl group may be saturated or unsaturated with one or more double or triple bonds and may be substituted by hydroxyl, amino, halogen, oxo groups and alkoxy radicals and one or two carbon atoms of the cycloalkyl groups by nitrogen, oxygen or or sulfur atoms can be replaced, »Is selected from the group consisting of hydrogen, alkyl radicals, acyl radicals and cycloalkyl- (C 0. 26 ) -alkyl groups, each alkyl radical and each acyl radical being branched or unbranched and each alkyl radical, each acyl radical and each cycloalkyl group saturated or with one or more double or triple bonds may be unsaturated and may be substituted by hydroxyl, amino, halogen, oxo groups and alkoxy radicals and one or two carbon atoms of the cycloalkyl groups may be replaced by nitrogen, oxygen or sulfur atoms,
Ri und R2 gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, Hydroxy-, Halogen-, Aminoresten, Alkylresten, Alkoxyresten und Cycloalkyl-(C0.26)- alkylgruppen besteht, wobei jeder Alkylrest und jeder Alkoxyrest verzweigt oder unverzweigt und jeder Aminorest, Alkylrest, jeder Alkoxyrest und jede Cycloalkylgruppe gesättigt oder mit ein oder mehreren Doppel- oder Dreifachbindungen ungesättigt und mit Hydroxy-, Amino-, Halogen-, Oxogruppen und Alkoxyresten substituiert sein kann und ein oder zwei Kohlenstoffatome der Cycloalkylgruppen durch Stickstoff-, Sauerstoff- oder Schwefelatome ersetzt sein können,Ri and R 2 are the same or different and are selected from the group consisting of hydrogen, hydroxyl, halogen, amino, alkyl, alkoxy and cycloalkyl (C 0. 26 ) alkyl groups, each alkyl and alkoxy branched or unbranched and any amino radical, alkyl radical, any alkoxy radical and any cycloalkyl group saturated or unsaturated with one or more double or triple bonds and can be substituted by hydroxyl, amino, halogen, oxo groups and alkoxy radicals and one or two carbon atoms of the cycloalkyl groups by nitrogen -, oxygen or sulfur atoms can be replaced,
R5, RÖ und R7 gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, Hydroxy-, Halogen-, Alkylgruppen, Cycloalkyl-(C0.26)-alkylgruppen, Cycloalkoxy- (C0-26)-alkylgruppen, Alkoxy-(C0.26)-alkylgruppen, Aminogruppen und Thio-(C0.26)- alkylgruppen und Acylresten besteht, wobei jeder Alkylrest, jeder Alkoxyrest und jeder Acylrest verzweigt oder unverzweigt und jeder Alkylrest, jeder Alkoxyrest und jede Cycloalkylgruppe gesättigt oder mit ein oder mehreren Doppel- oder Dreifachbindungen ungesättigt und mit Hydroxy-, Amino-, Halogen-, Oxogruppen und Alkoxyresten substituiert sein kann und ein oder zwei Kohlenstoffatome der Cycloalkylgruppen durch Stickstoff-, Sauerstoff- oder Schwefelatome ersetzt sein können, wobei R5 alternativ mit Ri auch einen Ring bilden kann, und R3 und R eine Kohlenstoff-Sauerstoff-Einfachbindung aufweisen können, derart daß eine Ringstruktur vorliegt.R 5 , R Ö and R 7 are the same or different and are selected from the group consisting of hydrogen, hydroxyl, halogen, alkyl groups, cycloalkyl (C 0. 26 ) alkyl groups, cycloalkoxy (C 0 - 26 ) -alkyl groups, alkoxy- (C 0. 26 ) -alkyl groups, amino groups and thio- (C 0. 26 ) - alkyl groups and acyl radicals, each alkyl radical, each alkoxy radical and each acyl radical being branched or unbranched and each alkyl radical, each alkoxy radical and each Cycloalkyl group saturated or unsaturated with one or more double or triple bonds and can be substituted with hydroxyl, amino, halogen, oxo groups and alkoxy radicals and one or two carbon atoms of the cycloalkyl groups can be replaced by nitrogen, oxygen or sulfur atoms, where R 5 alternatively can also form a ring with Ri, and R 3 and R can have a single carbon-oxygen bond, such that a ring structure is present.
Die Erfindung enthält ebenfalls die pharmazeutisch akzeptablen Salze, Ester und Salze der Ester.The invention also includes the pharmaceutically acceptable salts, esters and salts of the esters.
Bevorzugt sind R\ und R2 gleich oder verschieden und aus der Gruppe ausgewählt, die aus substituierten und unsubstituierten Alkylgruppen, bevorzugt Cι-C4- Alkylgruppen, besteht.R \ and R 2 are preferably identical or different and selected from the group consisting of substituted and unsubstituted alkyl groups, preferably C 1 -C 4 -alkyl groups.
Bevorzugt ist R3 aus der Gruppe ausgewählt, die aus Wasserstoff, substituierten und unsub- stituierten Alkylgruppen, bevorzugt Cι-C4- Alkylgruppen, substituierten und unsubstituierten aromatischen C7-Cι4-Cycloalkylgruppen, einer Pyranylgruppe, einer t-Butyldimethylsilyl- gruppe undR 3 is preferably selected from the group consisting of hydrogen, substituted and unsubstituted substituted alkyl groups, preferably C 1 -C 4 alkyl groups, substituted and unsubstituted aromatic C 7 -C 4 cycloalkyl groups, a pyranyl group, a t-butyldimethylsilyl group and
OO
II -C- R8 II -C- R 8
besteht, wobei R8 aus der Gruppe ausgewählt ist, die aus substituierten und unsubstituierten, bevorzugt mit Halogen substituierten Alkylgruppen, substituierten und unsubstituierten Cy- loalkyl(Co-26)-alkylgruppen, substituierten und unsubstituierten Aminogruppen, substituierten und unsubstituierten Alkoxygruppen, substituierten und unsubstituierten Phenoxygruppen, substituierten und unsubstituierten Alkylthiogruppen, substituierten und unsubstituierten, bevorzugt unsubstituierten oder mit Halogen-, Methyl-, Methoxy-, Nitro-, Amino- oder CF3- Gruppen substituierten, aromatischen Cycloalkylthiogruppen.consists, wherein R 8 is selected from the group consisting of substituted and unsubstituted, preferably halogen-substituted alkyl groups, substituted and unsubstituted cycloalkyl (Co- 26 ) alkyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted Phenoxy groups, substituted and unsubstituted alkylthio groups, substituted and unsubstituted, preferably unsubstituted or substituted with halogen, methyl, methoxy, nitro, amino or CF 3 groups, aromatic cycloalkylthio groups.
R4 ist bevorzugt aus der Gruppe ausgewählt, die aus Wasserstoff, substituierten und unsubstituierten Alkylresten, substituierten und unsubstituierten Phenylresten undR 4 is preferably selected from the group consisting of hydrogen, substituted and unsubstituted alkyl radicals, substituted and unsubstituted phenyl radicals and
besteht, wobei X aus der Gruppe ausgewählt ist, die aus Wasserstoff, Halogen, Cμ- Alkylresten und Phenylresten besteht und Y aus der Gruppe ausgewählt ist, die aus Wasserstoff, Halogen, d ^-Alkylresten, Nitroresten, Methoxyresten, Methylendioxygruppen besteht, wobei n 0 oder 1 ist.consists in which X is selected from the group consisting of hydrogen, halogen, Cμ-alkyl radicals and phenyl radicals and Y is selected from the group consisting of hydrogen, halogen, d ^ -alkyl radicals, nitro radicals, methoxy radicals, methylenedioxy groups, where n Is 0 or 1.
R7 ist bevorzugt aus der Gruppe ausgewählt, die aus Wasserstoff und Halogen besteht, oder R3 und R7 weisen eine Kohlenstoff-Sauerstoff-Einfachbindung auf, derart daß eine Ringstruktur vorliegt.R 7 is preferably selected from the group consisting of hydrogen and halogen, or R 3 and R 7 have a single carbon-oxygen bond, so that there is a ring structure.
Besonders bevorzugt sind Verbindungen, in denen R] und R2 unabhängig aus der Gruppe ausgewählt sind, die aus Methyl und Ethyl besteht, ist, undParticularly preferred are compounds in which R] and R 2 are independently selected from the group consisting of methyl and ethyl, is and
R5 und R<5 unabhängig aus der Gruppe ausgewählt sind, die aus Wasserstoff, Chlor, Brom und Methoxygruppen besteht.R 5 and R <5 are independently selected from the group consisting of hydrogen, chlorine, bromine and methoxy groups.
Insbesondere sind Verbindungen in denen R*In particular, compounds in which R *
ist, bevorzugt, wobei X aus der Gruppe ausgewählt ist, die aus 2-Chlor, 2-Brom, 2-Fluor besteht, und Y aus der Gruppe ausgewählt ist, die aus 4-Chlor-, 4-Brom-, 4-Fluor-, 5-Fluor- und 4,5-Methylendioxygruppen besteht, wobei n 0 oder 1 ist.is preferred, wherein X is selected from the group consisting of 2-chloro, 2-bromo, 2-fluorine and Y is selected from the group consisting of 4-chloro, 4-bromo, 4-fluorine -, 5-fluorine and 4,5-methylenedioxy groups, where n is 0 or 1.
Ganz besonders sind Verbindungen bevorzugt, in denen Ri und R2 Methylgruppen sind. R3 und R7 Wasserstoff sind oder eine Kohlenstoff-Sauerstoff-Bindung enthalten, die eine Ringstruktur bilden.Compounds in which R 1 and R 2 are methyl groups are particularly preferred. R 3 and R 7 are hydrogen or contain a carbon-oxygen bond which form a ring structure.
Beispiele für bevorzugte Verbindungen sind 3-Chlor-N-(2-Chlorphenyl)methyl-N-hydroxy- 2,2-dimethylpropanamid, N-(2-Chlo henyl)methyl-N-hydroxy-2,2-Dimethylpropanamid, 3- Chlor-N-hydroxy-N-phenyl-2,2-dimethylpropanamid, N-(2-Bromphenyl)-methyl-3-chlor-N- hydroxy-2,2-dimethylpropanamid, 3-Chlor-N-hydroxy-2,2-dimethyl-N-(2- methylphenyl)methylpropanamid, 3-Chlor-N-hydroxy-2,2-N-trimethylpropanamid, 3-Chlor- N-hydroxy-2,2-dimethyl-N-(phenylmethyl)-propanamid, 3-Chlor-N-(2,4- dichlorphenylmethyl)-N-hydroxy-2,2-dimethylpropanamid, 3-chlor-N-(2- chlorphenyl)methyl-N-methoxy-2,2-dimethylpropan-amid, 3 ,3 -Dichlor-N-(2- chlorpenyl)methyl-N-hydroxy-2,2-dimethylpropanamid, 3-Chlor-N-(2-fluorphenyl)methyl-N- hydroxy-2,2-dimethylpropanamid, 3-Brom-N-(2-chlorphenylmethyl-N-hydroxy-2,2- dimethylpropanamid, N-Benzoyloxy-3-chlor-N-(2-chloφhenyl)methyl-2,2- dimethylpropanamid, N-Acetoxy-3-chlor-N-(2-chlorphenyl)methyl-2,2-dimethylpropanamid, N-(Chloracetoxy)-3-chlor-N-(2-chlorphenyl)methyl-2,2 -dimethylpropanamid, 2-(2- Chloφhenyl)methyl-4,4-dimethyl-3-isoxazolidinon, 4,4-Dimethyl-2-phenyl-3-isoxazolidinon, 2-(2-Bromphenyl)methyl-4,4-dimethyl-3-isoxazolidinon. 4,4-Dimethyl-2-(2-methyl- phenyl)methyl-3-isoxazolidinon, 2,4,-Trimethyl-3-isoxazoli-dinon, 4,4-Dimethyl-2- phenylmethyl-3-isoxazolidinon, 2-(2,4-Dichloφhenyl)methyl-4,4-dimethyl-3-isoxazolidinon, 5-Chlor-2-(2-chloφhenyl)methyl-4,4-dimethyl-3-isoxazolidinon, 2-(2-Chloφhenyl)methyl-5- methoxy-4,4-dimethyl-3 -isoxazoli-dinon, 2-(2-Fluoφhenyl)methyl-4,4-dimethyl-3 - isoxazolidinon, N-[(2-Chlθφhenyl)methyl]-N,3-dihydroxy-2,2-dimethylpropanamid, 3- Chlor-N-[(2-chloφhenyl)methyl]-2,2-dimethyl-N-(methylamino-carbonyloxy)propanamid, 3- Chlor-N-[(2-chlor-phenyl)methyl]N-[(2-tetrahydropyranyl)oxyl-2,2-dimethyl-propanamid, 3- Chlor-N-[(2-chloφhenyl)methyl]-2,2-dimethyl-N-[dimethyl(l,l-dimethyl- ethyl)silyloxypropanamid, 3-Acetoxy-N-[(2-chloφhenoxy)-methyl]-N-hydroxy-2,2- dimethylpropanamid, 2,[(2-Chlor-4-fiuoφhenyl)methyl]-4,4-dimethyl-3-isoxazolidinon, 2- [(2-Chlor-5-fluoφhenyl)methyl]-4,4-dimethyl-3-isoxazolidinon, 2-[(2,4,5- Trichlθφhenyl)methyl]-4,4-dimethyl-3-isoxazolidinon, 2-[(2-Chlor-6-fluoφhenyl)methyl]- 4,4-dimethyl-3 -isoxazoli-dinon, 2-[(2-Chloφhenyl)methyl]-5-ethoxy-4,4-dimethyl-3- isoxazolidinon, 2-[(2-Chlθφhenyl)methyl]-4,4-dimethyl-5-phenylamino-3-isoxazolidinon, 2- [(2-Chlθφhenyl)methyl]-5-hydroxy-4,4-dimethyl-3-isoxazolidinon, 3-Chlor-N-[(2-chlor- phenyl)methyl]-2,2-dimethyl-N-[(phenylamino)carbonyloxy]-propanamid, 3-Chlor-N-[(2- chloφhenyl)methyl]-2,2-dimethyl-N-([(2-chlθφhenyl)methyl]-2,2-dimethyl-N- phenoxycarbonyl-oxy)propanamid, 3-Chlor-N-[(2-chlθφhenyl)methyl]-N-ethoxy- carbonyloxy-2.2-dimethylpropanamid, N-Benzoyloxy-3,3-dichlor-N-[(2- chlθφhenyl)methyl] -2,2-dimethylpropanamid, N-(2-Brom-phenyl)methyl-3 ,3 -dichlor-N- hydroxy-2,2-dimethyl)propanamid, 3-Chlor-N-[(2-chloφhenyl)methyl]-N-(4- nitobenzoyloxy)-2,2-dimethylpropanamid, 3-Chlor-N-[2-chlθφhenylm,ethyl)]-2,2-dimethyl- N-[(2-methylphenyl)carbonyloxy]propanamid, 3-Chlor-N-dichloracetoxy-N-[(2- chloφhenyl)methyl]-2,2-dimethylpropan-amid, 3-Chlor-N-[2-chlθφhenyl)methyl]-2,2- dimethyl-N-[(4-methylphenyl)sulfonyloxy]propanamid, 3-Chlor-N-[2-chlor-phenyl)methyl]- 2,2-dimethyl-N-[(l,l-dimethylethyl)carbonyl-oxy]propanamid, 3-Chlor-N-[2- chloφhenyl)methyl]-2,2-dimethyl-N-(ethylthiocarbonyloxy)propanamid, 3-Chlor-N-[(2,2,2- trichlorethoxy)carbonyloxy)-N-[(2-chloφhenyl)methyl]-2,3-dimethylpropanamid, 3-Chlor-N- [(2-chloφhenyl)aminocarbonyl-oxy-N-[(2-chlθφhenyl)methyl]-2,2-dimethylpropanamid, 3- Chlor-N-[(4-chloφhenyl)aminocarbonyloxy-N-[(2-chloφhenyl)methyl]-2,2- dimethylpropanamid, 3-Chlor-N-[2-chlθφhenyl)methyl]-2,2-dimethyl-N- (phenylmethoxy)propanamid, 3-Chlor-N-[(2,4-dichlor-phenyoxy)acetoxy)-N-[(2- chloφhenyl)methyl]-2,2-dimethyl-propanamid, , 3-Chlor-N-[2-chloφhenyl)methyl]-2,2- dimethyl-N- [(3 -trifluormethyl)benzoyloxypropanamid, 3 -Chlor-N- [2-chlor-phenyl)methyl] - 2,2-dimethyl-N- [(4-methylpheny l)aminocarbonyl-oxy)-propanamid, 3 -Chlor-N- [2- chlθφhenyl)methyl]-N-[(3,4-chloφhenyl)aminocarbonyloxy]-2,2-dimethylpropanamid, 3- Chlor-N-(3-chlor-2,2-dimethyl-l-oxo-propoxy)-N-[(2-chloφhenyl)-methyl]-2,2- dimethylpropanamid, 3-Brom-N-[(2-Bromphenyl)-methyl]-N-hydroxy-2,2- dimethylpropanamid, 3 -Chlor-N- [(2-chlθφhenyl)methyl] -N- [(2- fiuoφhenyl)aminocarbonyloxy] -2,2-dimethylpropanamid,3 -Chlor-N- [(2- chloφhenyl)methyl]-N-[(4-methoxyphenyl)aminocarbonyloxy]-2,2-dimethylpropanamid, 3- Chlor-N-[(2-chloφhenyl)methyl]-N-[(3-trifluormethylphenyl)-aminocarbonyloxy]-2,2- dimethylpropanamid, 3-Brom-N-[(2-chloφhenyl)methyl]-N-(methylaminocarbonyloxy)-2,2- dimethyl-propanamid, 3-Brom-N-(2-chloracetoxy)-N-[(2-chlθφhenyl)-methyl]-2,2- dimethylpropanamid, 3 -Chlor-N- [2,5 -dichlor-(formylamino)-benzoyl]oxy-N- [(2- chloφhenyl)methyl] -2,2-dimethylpropanamid, 3 -Brom-N- [(2-bromphenyl)methyl] -N- chloracetoxy-2,2-dimethylpropanamid, 3-Brom-N-[(2-bromphenyl)-methyl]-N- (methylcarbonyloxy)-2,2-dimethylpropanamid, 3-Brom-N-[(2-bromphenyl)methyl]-N-[(2- chloφhenyl)aminocarbonyloxy]-2.2-dimethylpropanamid, 2-[(2-Chloφhenyl)methyl]-N- hydroxy-2,2-dimethyl-3 -methylthio-propanamid, 3 -Penylcarbonyloxy)-N- [(2-chloφhenyl)- methyl]-N-hydroxy-2,2-dimethylpropanamid, 2-[(4-Chloφhenyl)methyl]-4,4-dimethyl-3- isoxazolidinon, 2-[(3 ,4-Dichloφhenyl)methyl]-4,4-dimethyl-3-isoxazolidinon, 2- [(Chloφhenyl)methyl]-4,4-dimethyl-3-isoxazolidinon-5-ylacetat, 2-[(Chloφhenyl)methyl]- 4,4-dimethyl-3-isoxazoli-dinon-5-ylbenzoat, 2-[(Chloφhenyl)methyl]-4,4-dimethyl-3- isoxazolidinon-5-yldichloracetat, 2-[(Chloφhenyl)methyl]-4,4-dimethyl-3-isoxazolidinon-5- ylphenylcarbamat, 2-[(Chlor-phenyl)methyl]-4,4-dimethyl-3-isoxazolidinon-5-ylmethyl- carbamat, 2-[(2-Chlor-4-cyanophenyl)methyl]-4,4-dimethyl-3-isoxazolidinon, 2-[(2-Chlor-5- methoxyphenyl)methyl]-4,4-dimethyl-3-isoxazolidinon. 2-[(2-Chlor-4-methoxyphenyl)- methyl]-4,4-dimethyl-3-isoxazolidinon, 2-[(2,4-Difluor-phenyl)methyl]-4,4-dimethyl-3- isoxazolidinon, 2-[(4-Brom-2-chloφhenyl)methyl]-4,4-dimethyl-3-isoxazolidinon, 2-[(2- Brom-4-fluoφhenyl)methyl]-4,4-dimethyl-3-isoxazolidinon, 2-[(6-Chlor- 1 ,3-benzdioxol-5- yl)methyl]-4,4-dimethyl-3-isoxazoli-dinon, 2-[(2-Chloφhenyl)methyl]-4,4-dimethyl-5- phenoxy-3 -isoxazolidinon, 2-[(2-Chlθφhenyl)methyl]-4,4-dimethyl-5-(l-methylethoxy)-3- isoxazolidinon, 2-[(2-Chloφhenyl)methyl]-4,4-dimethyl-5-(phenylmethoxy)-3- isoxazolidinon, 2-[(2-Brom-phenyl)methyl]-5-chlor-4,4-dimethyl-3-isoxazolidinon, 2-[(2,5- Dichlθφhenyl)methyl]-4,4-dimethyl~3-isoxazolidinon, 2-[(2-Chloφhenyl)methyl]-4,4- dimethyl-5-propoxy-3-isoxazolidinon, 2-[(2-Chloφhenyl)methyl]-4,4-dimethyl-5-(2- propenyloxy)-3-isoxazolidinon, 2-[(2-Chloφhenyl)methyl]-4,4-dimethyl-5-(2-propinyloxy)- 3-isoxazolidinon, 2-[(2-Chlθφhenyl)methyl]-4,4-dimethyl-5-(2-methoxyethoxy)-3- isoxazolidinon, 2-[(4-Fluor-2-iodphenyl)methyl]-4,4-dimethyl-3-isoxazolidinon, 2-[(2-Chlor- phenyl)methyl] -5-cyclopentoxy-4,4-dimethyl-3 -isoxazolidinon, 2- [(2-Chloφhenyl)methyl] - 4,4-dimethyl-5-(4-nitophenoxy)-3-isoxazolidinon, 2-[(2-Chloφhenyl)methyl]-5-cyclopropyl- methoxy-4,4-dimethyl-3-isoxazolidinon, 2-[(2-Bromphenyl-(methyl)]-4,4-dimethyl-5-(2- propinoxy)-3-isoxazolidinon, 2-[(2-Chlθφhenyl)methyl]-5-(3-butinoxy)-4,4-dimethyl-3- isoxazolidinon, 2-[(2-Chloφhenyl)methyl]-5-(2-butinoxy)-4,4-dimethyl-3-isoxazolidinon, 2- [(2-Chlθφhenyl)methyl]-5-(3-butenoxy)-4,4-dimethyl-3-isoxazolidinon, 2-[(2-Chloφhenyl)- methyl]-5-pentoxy-4,4-dimethyl-3-isoxazolidinon, 2-[(2-Chlor-phenyl)methyl]-5-hexoxy-4,4- dimethyl-3 -isoxazolidinon, 2-[(2-Chlθφhenyl)methyl]-5-(l-methylpropoxy)-4,4-dimethyl-3- isoxazolidinon, 2-[(2-Chloφhenyl)methyl]-5-(3-methyl-3-butenoxy)-4,4-dimethyl-3- isoxazolidinon, 2-[(2-Chloφhenyl)-methyl]-5-butoxy-4,4-dimethyl-3-isoxazolidinon, 2-[(2- Chlor-phenyl)methyl]-4,4-dimethyl-3-isoxazolidinon.Examples of preferred compounds are 3-chloro-N- (2-chlorophenyl) methyl-N-hydroxy-2,2-dimethylpropanamide, N- (2-chloro-nyl) methyl-N-hydroxy-2,2-dimethylpropanamide, 3- Chlorine-N-hydroxy-N-phenyl-2,2-dimethylpropanamide, N- (2-bromophenyl) methyl-3-chloro-N-hydroxy-2,2-dimethylpropanamide, 3-chloro-N-hydroxy-2, 2-dimethyl-N- (2-methylphenyl) methylpropanamide, 3-chloro-N-hydroxy-2,2-N-trimethylpropanamide, 3-chloro-N-hydroxy-2,2-dimethyl-N- (phenylmethyl) propanamide , 3-chloro-N- (2,4-dichlorophenylmethyl) -N-hydroxy-2,2-dimethylpropanamide, 3-chloro-N- (2-chlorophenyl) methyl-N-methoxy-2,2-dimethylpropane amide, 3,3-dichloro-N- (2-chlorophenyl) methyl-N-hydroxy-2,2-dimethylpropanamide, 3-chloro-N- (2-fluorophenyl) methyl-N-hydroxy-2,2-dimethylpropanamide, 3- Bromine-N- (2-chlorophenylmethyl-N-hydroxy-2,2-dimethylpropanamide, N-benzoyloxy-3-chloro-N- (2-chloro-phenyl) methyl-2,2-dimethylpropanamide, N-acetoxy-3-chloro N- (2-chlorophenyl) methyl-2,2-dimethylpropanamide, N- (chloroacetoxy) -3-chloro-N- (2-chlorophenyl) methyl-2,2-dimeth ylpropanamide, 2- (2- Chloφhenyl) methyl-4,4-dimethyl-3-isoxazolidinone, 4,4-dimethyl-2-phenyl-3-isoxazolidinone, 2- (2-bromophenyl) methyl-4,4-dimethyl-3-isoxazolidinone. 4,4-dimethyl-2- (2-methylphenyl) methyl-3-isoxazolidinone, 2,4, -trimethyl-3-isoxazolino-dinone, 4,4-dimethyl-2-phenylmethyl-3-isoxazolidinone, 2- (2,4-dichloro-phenyl) methyl-4,4-dimethyl-3-isoxazolidinone, 5-chloro-2- (2-chloro-phenyl) methyl-4,4-dimethyl-3-isoxazolidinone, 2- (2-chloro-phenyl) methyl -5- methoxy-4,4-dimethyl-3-isoxazolino-dinone, 2- (2-fluoro-phenyl) methyl-4,4-dimethyl-3-isoxazolidinone, N - [(2-chloro-phenyl) methyl] -N, 3rd -dihydroxy-2,2-dimethylpropanamide, 3-chloro-N - [(2-chloro-phenyl) methyl] -2,2-dimethyl-N- (methylamino-carbonyloxy) propanamide, 3-chloro-N - [(2-chloro -phenyl) methyl] N - [(2-tetrahydropyranyl) oxyl-2,2-dimethyl-propanamide, 3-chloro-N - [(2-chloro-phenyl) methyl] -2,2-dimethyl-N- [dimethyl (l , l-dimethyl-ethyl) silyloxypropanamide, 3-acetoxy-N - [(2-chloro-phenoxy) -methyl] -N-hydroxy-2,2-dimethylpropanamide, 2, [(2-chloro-4-fiuoφhenyl) methyl] - 4,4-dimethyl-3-isoxazolidinone, 2- [(2-chloro-5-fluoφhenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2 - [(2,4,5-trichlθφhenyl) methyl] - 4,4-dimethyl-3-isoxazolidinone, 2- [ (2-chloro-6-fluoφhenyl) methyl] - 4,4-dimethyl-3-isoxazolino dinone, 2 - [(2-chloro-phenyl) methyl] -5-ethoxy-4,4-dimethyl-3-isoxazolidinone, 2 - [(2-Chlθφhenyl) methyl] -4,4-dimethyl-5-phenylamino-3-isoxazolidinone, 2- [(2-Chlθφhenyl) methyl] -5-hydroxy-4,4-dimethyl-3-isoxazolidinone, 3 -Chlor-N - [(2-chlorophenyl) methyl] -2,2-dimethyl-N - [(phenylamino) carbonyloxy] propanamide, 3-chloro-N - [(2-chlorophenyl) methyl] -2, 2-dimethyl-N - ([(2-chlθφhenyl) methyl] -2,2-dimethyl-N-phenoxycarbonyl-oxy) propanamide, 3-chloro-N - [(2-chlθφhenyl) methyl] -N-ethoxycarbonyloxy -2,2-dimethylpropanamide, N-benzoyloxy-3,3-dichloro-N - [(2-chloro-phenyl) methyl] -2,2-dimethylpropanamide, N- (2-bromo-phenyl) methyl-3, 3-dichloro-N - Hydroxy-2,2-dimethyl) propanamide, 3-chloro-N - [(2-chloro-phenyl) methyl] -N- (4-nitobenzoyloxy) -2,2-dimethyl-propanamide, 3-chloro-N- [2-chloro-phenylm , ethyl)] - 2,2-dimethyl-N - [(2-methylphenyl) carbonyloxy] propanamide, 3-chloro-N-dichloroacetoxy-N - [(2-chloro-phenyl) methyl] -2,2-dimethylpropane amide, 3-chloro-N- [2-chlθφhenyl) methy l] -2,2-dimethyl-N - [(4-methylphenyl) sulfonyloxy] propanamide, 3-chloro-N- [2-chlorophenyl) methyl] - 2,2-dimethyl-N - [(l, l -dimethylethyl) carbonyl-oxy] propanamide, 3-chloro-N- [2-chloro-phenyl) methyl] -2,2-dimethyl-N- (ethylthiocarbonyloxy) propanamide, 3-chloro-N - [(2,2,2- trichloroethoxy) carbonyloxy) -N - [(2-chloro-phenyl) methyl] -2,3-dimethylpropanamide, 3-chloro-N- [(2-chloro-phenyl) aminocarbonyl-oxy-N - [(2-chloro-phenyl) methyl] -2 , 2-dimethylpropanamide, 3-chloro-N - [(4-chloro-phenyl) aminocarbonyloxy-N - [(2-chloro-phenyl) methyl] -2,2-dimethylpropanamide, 3-chloro-N- [2-chloro-phenyl) methyl] - 2,2-dimethyl-N- (phenylmethoxy) propanamide, 3-chloro-N - [(2,4-dichlorophenyoxy) acetoxy) -N - [(2-chloro-phenyl) methyl] -2,2-dimethyl-propanamide ,, 3-Chloro-N- [2-chloro-phenyl) methyl] -2,2-dimethyl-N- [(3-trifluoromethyl) benzoyloxypropanamide, 3-chloro-N- [2-chlorophenyl) methyl] - 2, 2-dimethyl-N- [(4-methylphenyl) aminocarbonyloxy) propanamide, 3-chloro-N- [2-chloro-phenyl) methyl] -N - [(3,4-chloro-phenyl) aminocarbonyloxy] -2.2 -dimethylpropanamide, 3-chlo r-N- (3-chloro-2,2-dimethyl-l-oxo-propoxy) -N - [(2-chloro-phenyl) -methyl] -2,2- dimethylpropanamide, 3-bromo-N - [(2-bromophenyl) methyl] -N-hydroxy-2,2-dimethylpropanamide, 3-chloro-N- [(2-chlθφhenyl) methyl] -N- [(2-fiuoφhenyl ) aminocarbonyloxy] -2,2-dimethylpropanamide, 3-chloro-N- [(2-chloro-phenyl) methyl] -N - [(4-methoxyphenyl) aminocarbonyloxy] -2,2-dimethylpropanamide, 3-chloro-N - [( 2-chloro-phenyl) methyl] -N - [(3-trifluoromethylphenyl) aminocarbonyloxy] -2,2-dimethylpropanamide, 3-bromo-N - [(2-chloro-phenyl) methyl] -N- (methylaminocarbonyloxy) -2,2- dimethyl-propanamide, 3-bromo-N- (2-chloroacetoxy) -N - [(2-chloro-phenyl) -methyl] -2,2-dimethylpropanamide, 3-chloro-N- [2,5 -dichloro- (formylamino) -benzoyl] oxy-N- [(2-chloro-phenyl) methyl] -2,2-dimethylpropanamide, 3-bromo-N- [(2-bromophenyl) methyl] -N-chloroacetoxy-2,2-dimethylpropanamide, 3-bromo -N - [(2-bromophenyl) methyl] -N- (methylcarbonyloxy) -2,2-dimethylpropanamide, 3-bromo-N - [(2-bromophenyl) methyl] -N - [(2-chlorophenyl) aminocarbonyloxy] -2,2-dimethylpropanamide, 2 - [(2-chloro-phenyl) methyl] -N-hydroxy-2,2-dimethyl-3-methylthio-propanamide, 3 -penylcarbo nyloxy) -N- [(2-chloro-phenyl) methyl] -N-hydroxy-2,2-dimethylpropanamide, 2 - [(4-chloro-phenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2 - [( 3, 4-Dichloφhenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2- [(Chloφhenyl) methyl] -4,4-dimethyl-3-isoxazolidinon-5-ylacetate, 2 - [(Chloφhenyl) methyl] - 4,4-dimethyl-3-isoxazolino-dinon-5-ylbenzoate, 2 - [(Chloφhenyl) methyl] -4,4-dimethyl-3-isoxazolidinon-5-yldichloroacetate, 2 - [(Chloφhenyl) methyl] -4 , 4-dimethyl-3-isoxazolidinon-5-ylphenylcarbamate, 2 - [(chlorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinon-5-ylmethylcarbamate, 2 - [(2-chloro-4- cyanophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2 - [(2-chloro-5-methoxyphenyl) methyl] -4,4-dimethyl-3-isoxazolidinone. 2 - [(2-chloro-4-methoxyphenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2 - [(2,4-difluorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone , 2 - [(4-bromo-2-chloro-phenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2 - [(2-bromo-4-fluoro-phenyl) methyl] -4,4-dimethyl-3-isoxazolidinone , 2 - [(6-chloro-1,3-benzdioxol-5-yl) methyl] -4,4-dimethyl-3-isoxazolino-dinone, 2 - [(2-chloro-phenyl) methyl] -4,4-dimethyl -5-phenoxy-3-isoxazolidinone, 2 - [(2-chloro-phenyl) methyl] -4,4-dimethyl-5- (l-methylethoxy) -3-isoxazolidinone, 2 - [(2-chloro-phenyl) methyl] -4 , 4-dimethyl-5- (phenylmethoxy) -3- isoxazolidinone, 2 - [(2-bromophenyl) methyl] -5-chloro-4,4-dimethyl-3-isoxazolidinone, 2 - [(2,5- Dichloro-phenyl) methyl] -4,4-dimethyl ~ 3-isoxazolidinone, 2 - [(2-chloro-phenyl) methyl] -4,4-dimethyl-5-propoxy-3-isoxazolidinone, 2 - [(2-chloro-phenyl) methyl] -4,4-dimethyl-5- (2-propenyloxy) -3-isoxazolidinone, 2 - [(2-chlorophenyl) methyl] -4,4-dimethyl-5- (2-propynyloxy) - 3-isoxazolidinone, 2- [(2-Chlθφhenyl) methyl] -4,4-dimethyl-5- (2-methoxyethoxy) -3- isoxazolidinone, 2 - [(4-fluoro-2- iodophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2 - [(2-chlorophenyl) methyl] -5-cyclopentoxy-4,4-dimethyl-3-isoxazolidinone, 2- [(2-chloro-phenyl) methyl] - 4,4-dimethyl-5- (4-nitophenoxy) -3-isoxazolidinone, 2 - [(2-chlorophenyl) methyl] -5-cyclopropyl-methoxy-4,4-dimethyl-3-isoxazolidinone, 2- [(2-bromophenyl- (methyl)] - 4,4-dimethyl-5- (2-propynoxy) -3-isoxazolidinone, 2 - [(2-chloro-phenyl) methyl] -5- (3-butynoxy) -4, 4-dimethyl-3-isoxazolidinone, 2 - [(2-chloro-phenyl) methyl] -5- (2-butynoxy) -4,4-dimethyl-3-isoxazolidinone, 2- [(2-chloro-phenyl) methyl] -5- (3-butenoxy) -4,4-dimethyl-3-isoxazolidinone, 2 - [(2-chloro-phenyl) - methyl] -5-pentoxy-4,4-dimethyl-3-isoxazolidinone, 2 - [(2-chlorophenyl) methyl] -5-hexoxy-4,4-dimethyl-3-isoxazolidinone, 2 - [(2- Chlθφhenyl) methyl] -5- (l-methylpropoxy) -4,4-dimethyl-3-isoxazolidinone, 2 - [(2-Chloφhenyl) methyl] -5- (3-methyl-3-butenoxy) -4,4- dimethyl-3-isoxazolidinone, 2 - [(2-chlorophenyl) methyl] -5-butoxy-4,4-dimethyl-3-isoxazolidinone, 2 - [(2-chlorophenyl) methyl] -4,4-dimethyl -3-isoxazolidinone.
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 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.Suitable examples of these acyl groups are given below.
Als aliphatische Acylgruppen werden von einer aliphatischen Säure stammende Acylreste bezeichnet, zu denen die folgenden gehören:Aliphatic acyl groups are acyl radicals derived from an aliphatic acid, which include the following:
Alkanoyl (z.B. Formyl, Acetyl, Propionyl, Butyryl, Isobutyryl, Valeryl, Isovaleryl, Pivaloyl etc.); Alkenoyl (z. B. Acryloyl, Methacryloyl, Crotonoyl etc.); Alkylthioalkanoyl (z.B. Me- thylthioacetyl, Ethylthioacetyl etc.) Alkansulfonyl (z.B. Mesyl, Ethansulfonyl, Propansulfonyl etc.); Alkoxycarbonyl (z.B. Methoxycarbonyl, Ethoxycarbonyl, Propoxycarbonyl, Isopro- poxycarbonyl, Butoxycarbonyl, Isobutoxycarbonyl etc.); Alkylcarbamoyl (z.B. Methylcarba- moyl etc.); (N-Alkyl)-thiocarbamoyl (z.B. (N-Methyl)-thiocarbamoyl etc.); Alkylcarbamimi- doyl (z.B. Methylcarbamimidoyl etc.); Oxalo; Alkoxalyl (z.B. Methoxalyl, Ethoxalyl, Pro- poxalyl etc.).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.); Oxalo; 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.), Hydroxy, Hy- droxyimino, Carboxy, Alkoxy (z.B. Methoxy, Ethoxy, Propoxy etc.), Alkoxycarbonyl, Acy- lamino (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, hydroxyimino, Carboxy, alkoxy (e.g. methoxy, ethoxy, propoxy etc.), alkoxycarbonyl, acylamino (e.g. benzyloxycarbonylamino etc.), acyloxy (e.g. acetoxy, benzoyloxy etc.) and the like; as preferred aliphatic acyl radicals with such substituents are e.g. alkanoyl substituted with amino, carboxy, amino and carboxy, halogen, acylamino or the like.
Als aromatische Acylreste werden solche Acylreste bezeichnet, die von einer Säure mit substituierter oder nicht substituierter Arylgruppe stammen, wobei die Arylgruppe Phenyl, To- luyl, 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, the aryl group being phenyl, to- luyl, xylyl, naphthyl and the like; suitable examples are given below:
Aroyl (z.B. Benzoyl, Toluoyl, Xyloyl, Naphthoyl, Phthaloyl etc.); Aralkanoyl (z.B. Phenyla- cetyl etc.); Aralkenoyl (z.B. Cinnamoyl etc.); Aryloxyalkanoyl (z.B. Phenoxyacetyl etc.); Arylthioalkanoyl (z.B. Phenylthioacetyl etc.); Arylaminoalkanoyl (z.B. N-Phenylglycyl, etc.); Arensulfonyl (z.B.Benzolsulfonyl, Tosyl bzw. Toluolsulfonyl, Naphthalinsulfonyl etc.); Aryloxycarbonyl (z.B. Phenoxycarbonyl, Naphthyl-oxycarbonyl etc.); Aralkoxycarbonyl (z.B. Benzyloxycarbonyl etc.); Arylcarbamoyl (z.B. Phenylcarbamoyl, Naphthylcarbamoyl etc.); Arylglyoxyloyl (z.B. Phenylglyoxyloyl etc.).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.).
Bei den vorstehenden Beispielen für aromatische Acylreste kann der aromatische Kohlenwasserstoffteil (insbesondere der Arylrest) und/oder der aliphatische Kohlenwasserstoffteil (insbesondere der Alkanrest) ggf. einen 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 sowie Arylthiocarbamoyl (z.B. Phenylthiocarbamoyl etc.); Arylcarbamimidoyl (z.B. Phenylcarbamimidoyl etc.).In 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) can 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, aroyl substituted with halogen and hydroxy or with halogen and acyloxy and aralkanoyl substituted with hydroxy, hydroxyimino, dihalogenalkanoyloxyimino and arylthiocarbamoyl (e.g. phenylthiocarbamoyl etc.); Arylcarbamimidoyl (e.g. phenylcarbamimidoyl etc.).
Als heterocyclischer Acylrest wird ein Acylrest verstanden, der von einer Säure mit heterocy- clischer 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 aliphati- scher 5 -bis 6-gliedriger Heterocyclus mit zumindest einem Heteroatom aus der Gruppe Stickstoff, Sauerstoff und Schwefel ist (z.B. Thiophenyl, Furoyl, Pyrrolcarbonyl, Nicotinoyl 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, pyrrole carbonyl, 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- yl-acetyl, 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 thiophenyl-acetyl, 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, soweit nicht anders definiert, ein gerad- oder verzweigtkettiger Alkylrest mit bis zu 26 Kohlenstoffatomen, wie Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.-Butyl, Pentyl, Hexyl und dergleichen. Er kann z.B. mit Hydro-xy-, Amino-, Halogen- (z.B. Fluor, Brom, Chlor), Oxoresten und Alkoxyresten, wie Methoxy-, Ethoxyresten, substituiert sein.Unless otherwise defined, "alkyl" is a straight-chain or branched-chain alkyl radical having up to 26 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, Pentyl, hexyl and the like. It can be substituted, for example, with hydroxy, amino, halogen (for example fluorine, bromine, chlorine), oxo residues and alkoxy residues, such as methoxy, ethoxy residues.
„Alkoxyrest" ist, soweit nicht anders definiert, ein gerad- oder verzweigtkettiger Alkoxyrest mit bis zu 26 Kohlenstoffatomen, wie ein Methoxy, Ethoxyreste, etc.. Er kann z.B. mit Hydroxy-, Amino-, Halogen-, Oxogruppen und Alkoxyresten, wie Methoxy-, Ethoxyresten, substituiert sein.Unless otherwise defined, "alkoxy radical" is a straight-chain or branched-chain alkoxy radical having up to 26 carbon atoms, such as a methoxy, ethoxy radicals, etc. It can, for example, contain hydroxyl, amino, halogen, oxo groups and alkoxy radicals, such as methoxy -, Ethoxy radicals, may be substituted.
„Alkoxy-(Co-26)-alkylgruppen" sind Alkoxyreste, die auch über einen Alkylrest an das Grundgerüst gebunden sein können. Die Alkyl- und Alkoxygruppen sind wie oben definiert.“Alkoxy (Co- 26 ) alkyl groups” are alkoxy radicals which can also be bonded to the basic structure via an alkyl radical. The alkyl and alkoxy groups are as defined above.
„Cycloalkyl-(C0.26)-alkylreste" sind cyclische Verbindungen mit 3 bis 8 Kohlenstoffatome, soweit sie nicht anders definiert sind, die direkt oder über einen Alkylenrest gebunden an das Grundgerüst sind. Der Alkylenrest kann verzweigt, unverzweigt und gesättigt oder mit Doppelbindungen ungesättigt sein. Mögliche Substituenten des Cycloalkylrestes sind u.a. Alkoxyreste. Alkylreste, Hydroxyreste, Halogenreste, Aminoreste, Oxoreste. Die Cycloalkylgruppen können mit der entsprechenden Anzahl an Doppelbindungen auch aromatisch sein, d.h. Aryl- (Co-26)-alkylreste (z.B. Phenyl-, Pyridyl-, Naphthyl- etc.) sein. Insbesondere die aromatischen cyclischen Verbindungen können ferner Substituenten, wie Nitrogruppen und CF3 und Phe- nylreste, enthalten.“Cycloalkyl- (C 0. 26 ) -alkyl radicals” are cyclic compounds with 3 to 8 carbon atoms, unless otherwise defined, which are bonded to the basic structure directly or via an alkylene radical. The alkylene radical can be branched, unbranched and saturated or with Possible substituents of the cycloalkyl radical include alkoxy radicals, alkyl radicals, hydroxy radicals, halogen radicals, amino radicals, oxo radicals. The cycloalkyl groups can also be aromatic with the corresponding number of double bonds, ie aryl- (Co- 26 ) alkyl radicals (eg phenyl, Pyridyl, naphthyl, etc.) The aromatic cyclic compounds in particular may also contain substituents such as nitro groups and CF 3 and phenyl radicals.
„Cycloalkoxy-(C0.26)-alkylgruppen" sind cyclische Verbindungen mit 3 bis 8 Kohlenstoffatome, die über ein Sauerstoff direkt oder über einen Alkylenrest gebunden an das Grundgerüst sind. Der Alkylenrest kann verzweigt, unverzweigt und gesättigt oder mit Doppelbindungen ungesättigt sein. Mögliche Substituenten des Cycloalkylrestes sind u.a. Alkoxyreste (auch Alkylendioxyreste, wie Methylendioxy-), Alkylreste, Hydroxyreste, Halogenreste, Aminoreste, Oxoreste. Die Cycloalkylgruppen können mit der entsprechenden Anzahl an Doppelbindungen auch Mehrfachcyclen und aromatisch sein (z.B. Phenoxy-, Pyridoxy-, Naphthoxy- etc). Insbesondere die aromatischen cyclischen Verbindungen können ferner Substituenten, wie Nitrogruppen, CF3-Gruppen und Phenylreste, enthalten."Cycloalkoxy (C 0. 26 ) alkyl groups" are cyclic compounds having 3 to 8 carbon atoms which are bonded to the basic structure via an oxygen directly or via an alkylene radical. The alkylene radical can be branched, unbranched and saturated or unsaturated with double bonds. Possible substituents of the cycloalkyl radical include alkoxy radicals (also alkylenedioxy radicals such as methylenedioxy), alkyl radicals, hydroxyl radicals, halogen radicals, amino radicals, oxo radicals. With the corresponding number of double bonds, the cycloalkyl groups can also be multiple cycles and aromatic (eg phenoxy, pyridoxy, naphthoxy) etc. In particular the aromatic cyclic compounds can also contain substituents such as nitro groups, CF 3 groups and phenyl radicals.
„Aminoreste" können zum Beispiel mit den wie oben definierten Alkylresten oder Cycloal- kyl-(C0-26)-alkylresten substituiert sein."Amino" may for example with the above defined alkyl radicals or cycloalkanes alkyl- (C 0 - 26) alkyl substituted.
„Amino-(C0.26)-alkylgruppen" sind Aminoreste, die auch über einen Alkylrest an das Grundgerüst gebunden sein können. Die Alkyl- und Aminogruppen sind wie oben definiert."Amino (C 0. 26) -alkyl" are amino radicals, which can also be bonded via an alkyl group to the backbone. The alkyl and amino groups are as defined above.
„Silylreste" können zum Beispiel mit den wie oben definierten Alkylresten oder Cycloalkyl- (C0-26)-alkylresten substituiert sein. „Silyl"-(C0.26)-alkylgruppen" sind Silylreste, die auch über einen Alkylrest an das Grundgerüst gebunden sein können. Die Alkyl- und Silylgruppen sind wie oben definiert."Silyl groups", for example, with the above defined alkyl radicals or cycloalkyl- (C 0 - 26) alkyl substituted. "Silyl" - (C 0. 26 ) alkyl groups "are silyl radicals which can also be bonded to the basic structure via an alkyl radical. The alkyl and silyl groups are as defined above.
„Thio-(C0.26)-alkylgruppen" können zum Beispiel mit den wie oben definierten Alkylresten oder Cycloalkyl-(C0-26)-alkylresten substituiert sein. Die (Co-26)-Alkylgruppen sind gerad- oder verzweigtkettige Alkylenreste wie Methylen, Ethylen, Propylen, Isopropylen, Butylen, Isobutylen, tert.-Butylen, Pentylen, Hexylen und dergleichen. Sie können Doppel- oder Dreifachbindungen enthalten und z.B. mit Hydroxy-, Amino-, Halogen- (z.B. Fluor, Brom, Chlor), Oxoresten und Alkoxyresten, wie Methoxy-, Ethoxyresten, substituiert sein."Thio (C 0. 26 ) alkyl groups" can for example be substituted with the alkyl radicals or cycloalkyl (C 0 - 26 ) alkyl radicals as defined above. The (Co- 26 ) alkyl groups are straight or branched chain alkylene radicals such as Methylene, ethylene, propylene, isopropylene, butylene, isobutylene, tert-butylene, pentylene, hexylene, etc. They can contain double or triple bonds and, for example, with hydroxy, amino, halogen (for example fluorine, bromine, chlorine), Oxo radicals and alkoxy radicals, such as methoxy, ethoxy radicals, may be substituted.
Die erfindungsgemäßen Verbindungen der Formel (I) lassen beispielsweise für Doppelbindungen enthaltende oder chirale Gruppen Ri bis R7 das Auftreten räumlicher Isomerer zu. Die erfindungsgemäße Verwendung der Verbindungen umfaßt alle räumlichen Isomere sowohl als Reinstoffe als auch in Form ihrer Mischungen.The compounds of formula (I) according to the invention allow spatial isomers to occur, for example, for double bonds containing or chiral groups R 1 to R 7 . The use of the compounds according to the invention includes all spatial isomers both as pure substances and in the form of their mixtures.
Die Verbindungen sind insbesondere für die therapeutische und prophylaktischen Behandlung von Infektionen bei Mensch und Tier geeignet, die durch Bakterien, ein- und mehrzellige Parasiten und Pilze hervorgerufen werden.The compounds are particularly suitable for the therapeutic and prophylactic treatment of infections in humans and animals which are caused by bacteria, unicellular 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 Pneumozystose, der Balanti- diose, der Kryptosporidiose, der Sarkozystose, der Akanthamöbose, der Naeglerose, 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, balantidosis, cryptosporidiosis, and sarcolocystosis , 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 Lambliose geeignet.They are therefore particularly useful as malaria prophylaxis and as prophylaxis of sleeping sickness and Chagas disease, toxoplasmosis, amoebic dysentery, Leishmaniasis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcolocystosis, acanthamoebosis, cocoonosis, naeglerosis Giardiosis and Lambliosis.
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 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 Mycob- acterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis und Mycobacterium avi- um, 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 Clostridi- um, 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 Nei- sseriaceae, insbesondere der Gattungen Neisseria und Moraxella, insbesondere die Arten Nei- sseria meningitides, Neisseria gonorrhoeae und Moraxella bovis, Bakterien der Familie Vi- brionaceae, insbesondere der Gattungen Vibrio, Aeromonas, Plesiomonas und Photobacteri- um, insbesondere die Arten Vibrio cholerae, Vibrio anguillarum und Aeromonas salmonici- das, Bakterien der Gattung Campylobacter, insbesondere die Arten Campylobacter jejuni, Campylobacter coli und Campylobacter fetus, Bakterien der Gattung Helicobacter, insbesondere die Art Helicobacter pylori, Bakterien der Familien Spirochaetaceae und der Leptospira- ceae, insbesondere der Gattungen Treponema, Borrelia und Leptospira, insbesondere Borrelia burgdorferi, Bakterien der Gattung Actinobacillus, Bakterien der Familie Legionellaceae, der Gattung Legionella, Bakterien der Familie Rickettsiaceae und Familie Bartonellaceae, Bakterien der Gattungen Nocardia und Rhodococcus, Bakterien der Gattung Dermatophilus, Bakterien der Familie Pseudomonadaceae, insbesondere der Gattungen Pseudomonas und Xantho- monas, 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 Micrococca- ceae, 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 Corynebacterium pseudote family mycobacteria, bacteria the species Mycob acterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium, bacteria of the Chlamydiaceae family, especially the species Chlamydia trachomatis and Chlamydia psittaci, bacteria of the genus Listeria, especially the species Listeria monocytogenes, bacteria of the species Erys Clostridium, bacteria 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 Brucungetella, bacteria Bacteria of the Neisseriaceae family, in particular of the Neisseria and Moraxella genera, in particular the Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis species, bacteria of the Vibrionaceae family, in particular of the Vibrio, Aeromonas, Plesiomonas and Photobacterium genera, in particular ere the species Vibrio cholerae, Vibrio anguillarum and Aeromonas salmonici- das, bacteria of the genus Campylobacter, especially the species Campylobacter jejuni, Campylobacter coli and Campylobacter fetus, bacteria of the genus Helicobacter, especially the species Helicobacter pylori, bacteria of the families Spirochaetacirae and Lept ceae, in particular of the genera Treponema, Borrelia and Leptospira, in particular Borrelia burgdorferi, bacteria of the genus Actinobacillus, bacteria of the family Legionellaceae, of the genus Legionella, bacteria of the family Rickettsiaceae and family Bartonellaceae, bacteria of the genera Nocardia and Rhodococungerm, bacteria the family Pseudomonadaceae, especially the genera Pseudomonas and Xanthomonas, bacteria of the family Enterobacteriaceae, especially the genera Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia and Shigella, bacteria of the family Pasteurellaceae, in particular the genus Haemophilus, bacteria of the Micrococceae family, in particular the Micrococcus and Staphylococcus genera, bacteria of the Streptococcaceae family, in particular the Streptococcus and Enterococcus genus and bacteria of the Bacillaceae family, in particular the Bacillus and Clostridium genus.
Damit eignen sich 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 Paratuberkulose der Tiere, Pest, mesenterialen Lymphadenitis und Pseudotuberkulose bei Mensch und Tier, Cholera, Legionärskrankheit, Borreliose bei Mensch und Tier, Leptospirosen bei Mensch und Tier, Syphilis, Campylobac- ter-Enteritiden bei Mensch und Tier, Moraxella-Keratokonjunc-tivitis und Serositis der Tiere, Brucellosen der Tiere und des Menschen, Milzbrand bei Mensch und Tier, Aktinomykose bei Mensch und Tier, Streptotrichosen, Psittakose/Ornithose bei Tieren, Q-Fieber, Ehrlichiose.This makes compounds and their derivatives suitable for the treatment of diphtheria, acne vulgaris, listeriosis, erysipelas in animals, gas burns in humans and animals, para-burns in humans and animals, tuberculosis in humans and animals, leprosy and other mycobacteriosis Humans and animals, paratuberculosis in animals, plague, mesenteric lymphadenitis and pseudotuberculosis in humans and animals, cholera, legionnaires' disease, Lyme disease in humans and animals, leptospirosis in humans and animals, syphilis, campylobacter enteritis in humans and animals, Moraxella Keratoconjunctivitis and serositis of animals, brucellosis of animals and humans, anthrax in humans and animals, actinomycosis in humans and animals, streptotrichoses, psittacosis / ornithosis in animals, Q fever, Ehrlichiosis.
Weiter ist der Einsatz nützlich bei der Helicobacter-Eradikationstherapie bei Ulcera des Magendarmtraktes. Es können auch Kombinationen mit einem weiteren Antibiotikum zur Behandlung der obengenannten Erkrankungen eingesetzt werden. Für Kombinationspräparate mit anderen Antiin- fektiva eignen sich insbesondere Isoniazid, Rifampicin, Ethambutol, Pyrazinamid, Strep- tomycin, Protionamid und Dapson zur Behandlung der Tuberkulose.The use is also useful in Helicobacter eradication therapy for ulcers of the gastrointestinal tract. Combinations with another antibiotic can also be used to treat the above-mentioned diseases. For combination preparations with other anti-infectives, isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, protionamide and dapsone are particularly suitable for the treatment of tuberculosis.
Die erfindungsgemäßen Verbindungen, hierzu gehören im allgemeinen pharmazeutisch verträgliche Salze, Ester und ein Salz eines solchen Esters, oder aber Verbindungen, die bei Applikation die erfindungsgemäßen 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 compounds according to the invention, these generally include pharmaceutically acceptable salts, esters and a salt of such an ester, or compounds which, when administered, provide the compounds according to the invention as metabolites or degradation products, also called "prodrugs", can be administered 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-Toluolsulfonsäure, bilden.Pharmaceutically acceptable salts of the compounds include salts which form the compounds of the formula (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, wie Natriumsalz, Kaliumsalz, Calci- umsalz, Ammoniumsalz, Ethanolaminsalz, Triethylaminsalz, Dicyclohexylaminsalz und Salze einer Aminosäure wie Argininsalz, Asparaginsäuresalz, Glutaminsäuresalz.The salts, 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 Aktivität der Substanzen wird in einem Versuchssystem bestimmt. Dieses System beruht auf die Messung der Inhibition des Wachstums von Bakterien, Parasiten oder Pilzen in vitro. Hierzu werden zum Teil Versuchsverfahren verwendet, die dem Fachmann bekannt sind.The activity of the substances is determined in a test system. This system is based on the measurement of the inhibition of the growth of bacteria, parasites or fungi in vitro. For this purpose, test methods are used which are known to the person skilled in the art.
Zum Beispiel wird zur Bestimmung der Antimalaria- Aktivität die Inhibition des Wachstums von Malaria-Parasiten in Blutkulturen bestimmt.For example, the inhibition of the growth of malaria parasites in blood cultures is determined to determine the antimalarial activity.
Die Bestimmung der antibakteriellen Aktivität beruht auf Messung der Hemmung von Bakterienwachstum auf Nährböden und in Flüssigkulturen.The determination of the antibacterial activity is based on measuring the inhibition of bacterial growth on nutrient media and in liquid cultures.
Die Bestimmung der fungiziden Aktivität beruht auf Inhibition des Wachstums von Pilzen auf Nährböden und in Flüssigkulturen.The determination of the fungicidal activity is based on the inhibition of the growth of fungi on nutrient media and in liquid cultures.
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, fungizide oder antibakterielle Aktivität wird in den entsprechenden Tiermodelle weiter evaluiert.Substances that show effectiveness in the in vitro measuring systems are in vivo Models examined further. The antiparasitic, fungicidal or antibacterial activity is further evaluated in the corresponding animal models.
Die pharmazeutisch wirksamen Mittel können in Form von pharmazeutischen Zubereitungen in Dosierungseinheiten 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.Solid, semi-solid or liquid diluents are among non-toxic, inert pharmaceutically suitable carriers. Understand fillers and formulation aids 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, Polyvinylpyrrolidon, (c) Feuchthaltemittel, z. B. Glycerin, (d) Sprengmittel, z. B. Agar-Agar, Calciumcarbonat und Natriumcarbonat, (e) Lösungsverzögerer, z. B. Paraffin und (f) Resoφtionsbeschleuniger, z. B. quarternäre Ammoniumverbindungen, (g) Netzmittel, z. B. Cetylalkohol, Glycerinmono- stearat, (h) Adsoφtionsmittel, 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 and solutions are preferred pharmaceutical preparations. Suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays called. 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 retarders, e.g. B. paraffin and (f) Resoφtions accelerator, z. B. quaternary ammonium compounds, (g) wetting agents, e.g. B. cetyl alcohol, glycerol monostearate, (h) adsorbent, z. 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. Cι4-Alkohol mit C16-Fettsäure) oder Gemische dieser Stoffe.In addition to the active ingredient (s), suppositories can contain the usual water-soluble or contain water-insoluble carriers, e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat and higher esters (z. B. Cι 4 alcohol with C 16 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, Ethylalkohol, Isopro- pylalkohol, Ethylcarbonat, Ethylacetat, Benzylalkohol, Benzylbenzoat, Propylenglykol, 1,3- Butylenglykol, Dimethylformamid, Öle, insbesondere Baumwollsaatöl, Erdnußöl, Mais- keimöl, Olivenöl, Ricinusöl und Sesamöl, Glycerin, Glycerinformal, Tetrahydrofurfurylalko- hol, 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 sesame oil, glycerol, glycerol formurate - hol, 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 bluti- sotonischer 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 of these substances.
Die genannten Formulierungsformen können auch Färbemittel, Konservierungsstoffe sowie geruchs- und geschmacksverbessernde 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-improving additives, e.g. B. peppermint oil and eucalyptus oil and sweeteners, e.g. B. saccharin.
Die Wirkstoffe der Formel (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 formula (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 other active pharmaceutical ingredients.
Die Verbindungen können mit bisher beschriebenen Substanzen mit antibakterieller, antivi- raler, antimyktoischer und antiparasitärer Eigenschaften verwendet werden. Hierzu gehören insbesondere Verbindungen, die bereits in der Therapie Anwendung gefunden haben oder noch angewendet werden. Hierzu sind insbesondere geeignet Stoffe, die in der in der Roten Liste oder in Simon/Stille, Antibiotika-Therapie in Klinik und Praxis, 9. Auflage 1998 Schat- tauer Verlag, oder unter http : Awww.customs.treas. ov/imp-exp/rulings/liarmoniz/hrm 129. html im Internet mitaufgeführt. Insbesondere können die Derivate mit Penicilline, Benzylpe- nicillin (Penicillin G), Phenoxypenicilline, Isoxazolylpenicilline, Aminopenicilline, Ampicil- lin, Amoxixillin, Bacampicillin, Carboxypenicillin, Ticarcillin, Temocillin, Acyalaminopeni- cilline, Azlocillin, Mezlocillin. Piperacillin, Apalcillin, Mecillinam, Cephalosporine, Cefazo- lin-Gruppe, Cefuroxim-Gruppe, Cefoxitin-Gruppe, Cefoxitin, Cefotetan, Cefmetazol, Lata- moxef, Flomoxef, Cefotaxim-Guppe, Cefozidim, Ceftazidim-Gruppe, Ceftazidim, Cefpirom, Cefepim, übrige Cephalosporine, Cefsulodin, Cefoperazon, Oralcephalosporine der Cefale- xin-Gruppe, Loracarbef, Cefprozil, neue Oralcephalosporine mit erweitertem Spektrum, Cefi- xim, Cefpodoxim-Proxetil, Cefuroxim-Axetil, Cefetamet, Cefotiam-Hexetil, Cefdinir, Cefti- buten, andere ß-Lactam-Antibiotika, Carbapenem, Imipenem /Cilastatin, Meropenem, Biape- nem, Aztreonam, ß-Lactamase-Hemmer, Clavulansäure/Amoxicillin, Clavulansäu- re/Ticarcillin, Sulbactam/Ampicillin, Tazobactam/Piperacillin, Tetracycline, Oxytetracyclin, Rolitetraxyxlin, Doxycyclin, Minocyclin, Chloramphenicol, Aminoglykoside, Gentamicin, Tobramycin, Netilmicin, Amikacin. Spectinomyxin, Makrolide, Erythromycin, Cla- rithromycin, Roxithromycin, Azithromycin, Dirithromycin, Spiramycin, Josamycin, Linco- samide, Clindamycin, Fusidinsäure. Glykopeptid-Antibiotika, Vancomycin, Tecoplanin, Pri- stinamycin-Derivate, Fosfomycin, Antimikrobielle Folsäureantagonisten, Sulfonamide, Co- Trimoxazol, Trimethoprim, andere Diaminopyrimidin-Sulfonamid-Kombinationen, Nitrofu- rane, Nitrofurantoin, Nitrofurazon, Gyrase-Hemmer (Chinolone), Norfloxacin, Ciprofloxacin, Ofloxacin, Sparfloxacin, Enoxacin. Fleroxacin, Pefloxacin, Lomefloxacin, Bay Y3118, Ni- troimidazole, antimykobakterielle Mittel, Isoniazid, Rifampicin, Rifabutin, Ethambutol, Pyra- zinamid, Streptomycin, Capreomycin, Prothionamid, Terizidon, Dapson, Clofazimin, Lokalantibiotika, Bacitracin, Tyrothricin, Polymyxine, Neomycin, Kanamycin, Paromomycin, Mupirocin, antivirale Mittel, Acyclovir, Ganciclovir, Azidothymidin, Didanosin, Zalcitabin, Thiacytidin, Stavudin, Ribavirin, Idoxuridin, Trifluridin, Foscarnet, Amantadin, Interferone, Tibol-Derivate, Proteinase-Inhibitoren, Antimykotika, Polyene, Amphothericin B, Nystatin, Natamycin, Azole, Azole zur septischen Therapie, Miconazol, Ketoconazol, Itraconazol, Flu- conazol, UK- 109.496, Azole für lokale Anwendung, Clotrimazol, Econazol, Isoconazol, Oxi- conazol, Bifonazol, Flucytosin, Griseofulvin, Ciclopiroxolamin, Tolnaftat, Naftifin, Terbina- fin, Amorolfin, Antrachinone, Betulinic acid, Semianthrachinone, Xanthone, Naphtoquinone, Aryaminoalkohole, Chinin, Quinidine, Mefloquin, Halofantrin, Chloroquin, Amodiaquin, Acridin, Benzonaphthyridin, Mepacrin, Pyronaridin, Dapson, Sulfonamide, Sulfadoxin, Sul- falene, Trimethoprim, Proguanil, Chloφroguanil, Diaminopyrimidine, Pyrimethamin, Pri- maquin, Aminoquinoline, WR 238,605, Tetracyclin, Doxycyclin, Clindamycin, Norfloxacin, Ciprofloxacin, Ofloxacin, Artemisinin, Dihydroartemisinin, 10b artemether, Arteether, Atr- tesunat, Atovaquon, Suramin, Melarsoprol, Nifurtmox, Stibogluconat-Natrium, Pentamidin, Amphotericin B, Metronidazol, clioquinol, Mebendazol, Niclosamid, Praziquantel, Pyrantel, Tiabendazol, Diethylcarbamazin, Ivermectin, Bithionol, Oxamniquin, Metrifonat, Piperazin, Embonat.The compounds can be used with previously described substances with antibacterial, antiviral, antimyctoic and antiparasitic properties. These include in particular compounds that have already been used in therapy or are still being used. Substances are particularly suitable for this purpose, which are listed in the Red List or in Simon / Stille, Antibiotic Therapy in Clinic and Practice, 9th Edition 1998 Schattauer Verlag, or at http: Awww.customs.treas. ov / imp-exp / rulings / liarmoniz / hrm 129. html listed on the Internet. In particular, the derivatives can be administered with penicillins, benzylpenicillin (Penicillin G), phenoxypenicillins, isoxazolylpenicillins, aminopenicillins, ampicilins, amoxixillins, bacampicillins, carboxypenicillins, ticarcillins, temocillins, acyalaminopenocillins, azlillins, azlillins. Piperacillin, apalcillin, mecillinam, cephalosporins, Cefazo- lin group, cefuroxime group, cefoxitin group, cefoxitin, cefotetan, cefmetazole, LATA moxef, flomoxef, cefotaxime Guppe, Cefozidim, ceftazidime group, ceftazidime, cefpirome, cefepime, other cephalosporins, cefsulodin, cefoperazone, oral cephalosporins from the cephalexin group, Loracarbef, cefprozil, new oral cephalosporins with an expanded spectrum, cefixim, cefpodoxime proxetil, cefuroxime axetil, cefetiamine, cefetiamine, other ß-lactam antibiotics, carbapenem, imipenem / cilastatin, meropenem, biapenem, aztreonam, ß-lactamase inhibitors, clavulanic acid / amoxicillin, clavulanic acid / ticarcillin, sulbactam / ampicillin, tazobactametracyclic tetraxinxinxitoxin tetraxinoxitropin tetraxinoxitropin Doxycycline, minocycline, chloramphenicol, aminoglycosides, gentamicin, tobramycin, netilmicin, amikacin. Spectinomyxin, macrolides, erythromycin, charithromycin, roxithromycin, azithromycin, dirithromycin, spiramycin, josamycin, linosamide, clindamycin, fusidic acid. Glycopeptide antibiotics, vancomycin, tecoplanin, pristinamycin derivatives, fosfomycin, antimicrobial folic acid antagonists, sulfonamides, co-trimoxazole, trimethoprim, other diaminopyrimidine-sulfonamide combinations, nitrofurane, nitrofurantoin, nitrofacurinone, nitrofacurinone, nitrofacurinone , Ciprofloxacin, ofloxacin, sparfloxacin, enoxacin. Fleroxacin, pefloxacin, lomefloxacin, Bay Y3118, nitroimidazole, antifungal agents, isoniazid, rifampicin, rifabutin, ethambutol, pyrazine amide, streptomycin, capreomycin, nephthionamide, terizidon, dapsonitrain, clinomycinofin, dapsonitrin, clinomycin, dapsonitrin, clinomycin, dapsonitrin, clinomycin, dapsonitrin, clin, antibiotics Kanamycin, Paromomycin, Mupirocin, Antiviral Agents, Acyclovir, Ganciclovir, Azidothymidine, Didanosine, Zalcitabine, Thiacytidine, Stavudine, Ribavirin, Idoxuridine, Trifluridine, Foscarnet, Amantadine, Interferone, Tibol-Deroterin, Polyamine, Antioxidants, Antioxidants, Polyamine, Antioxidants, Antioxidants, Antioxidants, Antioxidants Nystatin, Natamycin, Azole, Azole for septic therapy, Miconazole, Ketoconazole, Itraconazole, Fluconazol, UK-109.496, Azole for topical use, Clotrimazole, Econazole, Isoconazole, Oxiconazole, Bifonazole, Flucytosine, Tolisepiraftol, Griseofopoxin, Griseofuloxin Naftifin, Terbinafin, Amorolfin, Antrachinone, Betulinic acid, Semianthraquinones, Xanthones, Naphtoquinones, Aryamino alcohols, Quinine, Quinidines, Mefl oquin, halofantrine, chloroquine, amodiaquin, Acridine, benzonaphthyridine, mepacrine, pyronaridine, dapsone, sulfonamides, sulfadoxine, sulphene, trimethoprim, proguanil, chlorogroguanil, diaminopyrimidine, pyrimethamine, primimaquin, aminoquinoline, WR 238.605, tetracycline, doxycycline, cloxacloxacin, cloxacinoxin, cloxacinoxin, cloxamoxinacin, cloxacinoxin, cloxacinoxin, cloxamoxinacin, cloxacinoxin, cloxacinoxin, cloxamoxinacin, cloxacinoxin, cloxacinoxin, cloxacinoxin, cloxacinoxin, cloxacinoxin, cloxacinoxin , Dihydroartemisinin, 10b artemether, arteether, arthresunate, atovaquone, suramin, melarsoprol, nifurtmox, stibogluconate sodium, pentamidine, amphotericin B, metronidazole, clioquinol, mebendazole, niclosamide, praziquantel, oxithinolamine, oxioninolamine, pyrantel, tiimantelin, pyrantel, tiimantelin, pyrantel, tiimantelin, pyrantel, tiimantelin, pyrantel, ti-aminominol, dimantel, pyrantel, ti-aminolamine, pyrantel, ti-aminominol, dimantel, pyrantel, ti-aminolamine, pyrantel, ti-aminominol, dimantel, pyrantel, ti-aminolamine, pyrantel, ti-aminolamine, pyrantel, ti-aminominolamine, pyrantel, ti-aminolamine, pyrantel, ti-aminolamine, iodine carbamone , Metrifonate, piperazine, embonate.
Ferner können die erfindungsgemäßen Verbindungen in den pharmazeutischen Mitteln in Kombination mit Sulfonamid, Sulfadoxin, Artemisinin, Atovaquon, Chinin, Chloroquin, Hy- droxychloroquin, Mefloquin, Halofantrin, Pyrimethamin, Armesin, Tetracycline, Doxycyclin, Proguanil, Metronidazol, Praziquantil, Niclosamid, Mebendazol, Pyrantel, Tiabendazol, Die- thylcarbazin, Piperazin, Pyrivinum, Metrifonat, Oxamniquin, Bithionol oder Suramin oder mehreren dieser Substanzen vorliegen.In addition, the compounds according to the invention can be used in the pharmaceutical compositions in combination with sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracyclines, doxycycline, proguanil, metronidazole, prazamidantebend, praziquantilil, Pyrantel, tiabendazole, 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, parenteral (intravenös, intramuskulär, subkutan), intracisternal, intravaginal, intraperitoneal, lokal (Puder, Salbe, Tropfen) und zur Therapie von Infektionen in Hohlräumen, Köφerhöhlen 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 treatment 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 Köφergewicht 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 Köφergewicht. Es kann jedoch erforderlich sein, von den genannten Dosierungen abzuweichen, und zwar in Abhängigkeit von der Art und dem Köφergewicht 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. 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 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 administration of the drug, and the period or interval within which the administration takes place. 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.
Dem Fachmann sind die Herstellungsverfahren für die erfindungsgemäßen Stoffe z.B. aus der US-P-4405 357 bekannt.The production processes for the substances according to the invention are e.g. known from US-P-4405 357.
Im folgenden wird die Wirksamkeit einiger erfindungsgemäßer Verbindungen anhand von Beispielen dargestellt:The effectiveness of some compounds according to the invention is illustrated below with the aid of examples:
Es werden die folgenden Substanzen untersucht:The following substances are examined:
Substanz 1:Substance 1:
Substanz 2:Substance 2:
Substanz 3:Substance 3:
Substanz 4: Experimente zeigen, daß die Wirkung der Verbindungen auf einer Inhibierung des 1-Desoxy- D-xylulose-5-phosphat-(DOXP)-Stoffwechselweges beruht, der in Bakterien, Parasiten und Pilzen, nicht jedoch für den Menschen nachgewiesen werden kann. Das folgende Beispiel zeigt demzufolge die Wirkung der erfindungsgemäßen Verbindungen auf die DOXP- Reductoisomerase. Beispiel 1Substance 4: Experiments show that the action of the compounds is based on an inhibition of the 1-deoxy-D-xylulose-5-phosphate (DOXP) pathway, which can be detected in bacteria, parasites and fungi, but not for humans. The following example accordingly shows the effect of the compounds according to the invention on the DOXP reductoisomerase. example 1
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 mM MnCl2, 0,3 mM NADPH und 1 mM DOXP enthielt, bestimmt. Dabei wurde die Oxidation von NADPH in einem Spektrophotometer bei 365 nm gemessen. Zur Durchfuhrung der Inhibitionsstudien wurde die Aktivität der DOXP-Reductoisomerase in Gegenwart der Verbindungen 1 bis 4 in verschiedenen Konzentrationen zwischen 0,1 und 100 μmol 1-1 gemessen. Aus den Meßwerten wurde die Konzentration bestimmt, bei der das Enzym halbmaximal inhibiert wird (ICs ). Die Ergebnisse, d.h. die IC50-Werte, sind in der Tabelle aufgeführt. Beispiel 2Escherichia 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 mM MnCl 2 , 0.3 mM NADPH and 1 mM DOXP. The oxidation of NADPH 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 4 in various concentrations between 0.1 and 100 μmol 1-1. The concentration at which the enzyme is inhibited half-maximally (ICs) was determined from the measured values. The results, ie the IC50 values, are shown in the table. Example 2
Die Antimalaria-Wirksamkeit der Substanzen 1 bis 4 wurde an in-vitro-Kulturen des Malaria- Erregers Plasmodium falciparum bestimmt. Die Vertiefungen einer 96-well- Mikrotiteφlatte 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 incoφorierte Radioaktivität gemessen. Die Inhibition des Parasitenwachstums wurde als prozentuale Inhibition der Tritiumincoφoration gemessen. Die Inhibition des Parasitenwachstums wurde als prozentuale Inhibition der Tritiumincoφoration bezogen auf einen Vergleich ohne Substanz ausgedrückt. Durch Extrapolation der Werte wurde die halbmaximale inhibitorische Konzentration (IC50) der Substanz bestimmt. Die Ergebnisse, d.h. die IC50-Werte, sind in der nachfolgenden Tabelle aufgeführt:The antimalarial activity of substances 1 to 4 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. The inhibition of parasite growth was measured as a percentage inhibition of tritium incooration. The inhibition of parasite growth was expressed as a percentage inhibition of tritium information based on a comparison without substance. The half-maximum inhibitory concentration (IC50) of the substance was determined by extrapolation of the values. The results, ie the IC50 values, are shown in the table below:
Tabelletable

Claims

Patentansprüche claims
1. Verwendung mindestens einer Verbindung der Formel (I)1. Use of at least one compound of the formula (I)
R5 Ri 0 R4 R5 Ri 0 R 4
I I II II I II I
R6 - C - C - C - N-0-R3 ( I )R 6 - C - C - C - N-0-R 3 (I)
I I R7 R2 IIR 7 R 2
R3 aus der Gruppe ausgewählt ist, die aus Wasserstoff, Alkylgruppen, Alkoxy-(C0. 6)- alkylgruppen, C3.14-Cycloalkyl-(Co-26)-alkylgruppen, Cycloalkoxy-(C0.26)-alkylgruppen, Amino-(C0.26)-alkylgruppen, Silyl-(C0.26)-alkylgruppen und Thio-(C0.26)-alkyl-gruppen besteht, wobei jeder Alkylrest und jeder Alkoxyrest verzweigt oder unverzweigt und jeder Alkylrest, jeder Alkoxyrest und jede Cycloalkylgruppe gesättigt oder mit ein oder mehreren Doppel- oder Dreifachbindungen ungesättigt und mit Hydroxy-, Amino-, Halogen-, Oxogruppen und Alkoxyresten substituiert sein kann und ein oder zwei Kohlenstoffatome der Cycloalkylgruppen durch Stickstoff-, Sauerstoff- oder Schwefelatome ersetzt sein können,R 3 is selected from the group consisting of hydrogen, alkyl groups, alkoxy (C 0. 6 ) alkyl groups, C 3 . 14- cycloalkyl (Co-26) alkyl groups, cycloalkoxy (C 0. 26 ) alkyl groups, amino (C 0. 26 ) alkyl groups, silyl (C 0 .2 6 ) alkyl groups and thio- (C 0. 26 ) alkyl groups, each alkyl radical and each alkoxy radical being branched or unbranched and each alkyl radical, each alkoxy radical and each cycloalkyl group being saturated or unsaturated with one or more double or triple bonds and with hydroxy, amino, halogen, Oxo groups and alkoxy radicals can be substituted and one or two carbon atoms of the cycloalkyl groups can be replaced by nitrogen, oxygen or sulfur atoms,
i aus der Gruppe ausgewählt ist, die aus Wasserstoff, Alkylresten, Acylresten und Cy- cloalkyl-(C0.26)-alkylgruppen besteht, wobei jeder Alkylrest und jeder Acylrest verzweigt oder unverzweigt und jeder Alkylrest, jeder Acylrest und jede Cycloalkylgruppe gesättigt oder mit ein oder mehreren Doppel- oder Dreifachbindungen ungesättigt und mit Hydroxy-, Amino-, Halogen-, Oxogruppen und Alkoxyresten substituiert sein kann und ein oder zwei Kohlenstoffatome der Cycloalkylgruppen durch Stickstoff-, Sauerstoff- oder Schwefelatome ersetzt sein können,i is selected from the group consisting of hydrogen, alkyl radicals, acyl radicals and cycloalkyl (C 0. 26 ) alkyl groups, each alkyl radical and each acyl radical being branched or unbranched and each alkyl radical, each acyl radical and each cycloalkyl group saturated or with one or more double or triple bonds may be unsaturated and may be substituted by hydroxyl, amino, halogen, oxo groups and alkoxy radicals and one or two carbon atoms of the cycloalkyl groups may be replaced by nitrogen, oxygen or sulfur atoms,
Ri und R2 gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, Hydroxy-, Halogen-, substituierten und unsubstituierten Aminoresten, substituierten und unsubstituierten Alkylresten, substituierten und unsubstituierten Alkoxyresten und substituierten und unsubstituierten Cycloalkyl-(C0.26)-alkylgruppen besteht, wobei jeder Alkylrest und jeder Alkoxyrest verzweigt oder unverzweigt und jeder Alkylrest, jeder Alkoxyrest und jede Cycloalkylgruppe gesättigt oder mit ein oder mehreren Doppel- oder Dreifachbindungen ungesättigt sein kann und ein oder zwei Kohlenstoffatome der Cycloalkylgruppen durch Stickstoff-, Sauerstoff- oder Schwefelatome ersetzt sein können,Ri and R 2 are the same or different and are selected from the group consisting of hydrogen, hydroxy, halogen, substituted and unsubstituted amino residues, substituted and unsubstituted alkyl residues, substituted and unsubstituted alkoxy residues and substituted and unsubstituted cycloalkyl (C 0. 26 ) -alkyl groups, where each alkyl radical and each alkoxy radical may be branched or unbranched and each alkyl radical, each alkoxy radical and each cycloalkyl group may be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl groups by nitrogen, oxygen or Sulfur atoms can be replaced
R5, Rό und R gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, Hydroxy-, Halogen-, substituierten und unsubstituierten C]-C26- Alkylgruppen, substituierten und unsubstituierten Cycloalkyl-(Co-26)-alkylgruppen, sub- stituierten und unsubstituierten Cycloalkoxy-(C0.26)-alkyl-gruppen, substituierten und unsubstituierten Cycloalkoxy-(C0.26)-alkylgruppen, substituierten und unsubstituierten Aminogruppen und substituierten, unsubstituierten Thio-(C0.26)-alkylgruppen und substituierten oder unsubstituierten Acylresten besteht, wobei jeder Alkylrest, jeder Alkoxyrest und jeder Acylrest verzweigt oder unverzweigt und jeder Alkylrest, jeder Alkoxyrest und jede Cycloalkylgruppe gesättigt oder mit ein oder mehreren Doppel- oder Dreifachbindungen ungesättigt sein kann und ein oder zwei Kohlenstoffatome der Cycloalkylgruppen durch Stickstoff-, Sauerstoff- oder Schwefelatome ersetzt sein können, wobei R5 alternativ mit Rj auch einen Ring bilden kann, und R3 und R7 eine Kohlenstoff-Sauerstoff-Einfachbindung aufweisen können, derart daß eine Ringstruktur vorliegt,R 5 , R ό and R are the same or different and are selected from the group consisting of hydrogen, hydroxy, halogen, substituted and unsubstituted C] -C 26 alkyl groups, substituted and unsubstituted cycloalkyl (Co- 26 ) - alkyl groups substituted and unsubstituted cycloalkoxy (C 0. 26 ) alkyl groups, substituted and unsubstituted cycloalkoxy (C 0. 26 ) alkyl groups, substituted and unsubstituted amino groups and substituted, unsubstituted thio (C 0. 26 ) alkyl groups and substituted or unsubstituted acyl radicals, where every alkyl radical, every alkoxy radical and every acyl radical is branched or unbranched and every alkyl radical, every alkoxy radical and every cycloalkyl group can be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl groups can be substituted by nitrogen, Oxygen or sulfur atoms can be replaced, wherein R 5 can alternatively also form a ring with Rj, and R 3 and R 7 can have a single carbon-oxygen bond, such that a ring structure is present,
oder ihrer pharmazeutisch akzeptablen Salze, Ester und Salze der Ester zur prophylaktischen oder therapeutischen Behandlung von Infektionen, die durch Bakterien, Parasiten oder Pilze hervorgerufen werden.or their pharmaceutically acceptable salts, esters and salts of the esters for the prophylactic or therapeutic treatment of infections caused by bacteria, parasites or fungi.
2. Verwendung nach Anspruch 1, dadurch gekennzeichnet, daß Ri und R2 gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus substituierten und unsubstituierten Alkylgruppen, bevorzugt Cι-C4- Alkylgruppen besteht.2. Use according to claim 1, characterized in that R 1 and R 2 are the same or different and are selected from the group consisting of substituted and unsubstituted alkyl groups, preferably C 1 -C 4 alkyl groups.
3. Verwendung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß R3 aus der Gruppe ausgewählt, die aus Wasserstoff, substituierten und unsubstituierten Alkylgruppen, bevorzugt Cι-C4- Alkylgruppen, substituierten und unsubstituierten aromatischen C -Cι4-Cycloalkylgruppen, einer Pyranylgruppe und einer t- Butyldimethylsilylgruppe und3. Use according to one of the preceding claims, characterized in that R 3 is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl groups, preferably Cι-C 4 - alkyl groups, substituted and unsubstituted aromatic C 4 -Cι cycloalkyl groups, a pyranyl group and a t-butyldimethylsilyl group and
OO
IIII
-C- R8 -C- R 8
besteht, in der Rg aus der Gruppe ausgewählt ist, die aus substituierten und unsubstituierten, bevorzugt mit Halogen substituierten Alkylgruppen, substituierten und unsubstituierten Cyloalkyl(C0.26)-alkylgruppen, substituierten und unsubstituierten Aminogruppen, substituierten und unsubstituierten Alkoxygruppen, substituierten und unsubstituierten Phenoxygruppen, substituierten und unsubstituierten Alkylthiogruppen, substituierten und unsubstituierten, bevorzugt unsubstituierten oder mit Halogen-, Methyl-, Methoxy-, Nitro-, Amino- oder CF3-Gruppen substituierten, aromatischen Cycloal- kylthiogruppen besteht.there is selected in Rg from the group of substituted and the unsubstituted, preferably halogen-substituted alkyl groups, substituted and unsubstituted cyloalkyl (C 0. 26) -alkyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted phenoxy groups , substituted and unsubstituted alkylthio groups, substituted and unsubstituted, preferably unsubstituted or substituted with halogen, methyl, methoxy, nitro, amino or CF 3 groups, aromatic cycloalkyl thio groups.
4. Verwendung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß Ri aus der Gruppe ausgewählt ist, die aus Wasserstoff, substituierten und unsubstituierten Alkylresten, substituierten und unsubstituierten Phenylresten und4. Use according to any one of the preceding claims, characterized in that Ri is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted phenyl groups and
besteht, wobei X aus der Gruppe ausgewählt ist, die aus Wasserstoff, Halogen, Cμ- Alkylresten, Phenylresten besteht und Y aus der Gruppe ausgewählt ist, die aus Wasserstoff, Halogen, C - Alkylresten, Nitroresten, Methoxyresten, Methylendioxygruppen besteht, wobei n 0 oder 1 ist.exists, where X is selected from the group consisting of hydrogen, halogen, Cμ-alkyl radicals, phenyl radicals and Y is selected from the group consisting of hydrogen, halogen, C-alkyl radicals, nitro radicals, methoxy radicals, methylenedioxy groups, where n 0 or 1.
5. Verwendung nach Anspruch 4, dadurch gekennzeichnet, daß X aus der Gruppe ausgewählt ist, die aus Chlor, Brom, Fluor besteht, und Y aus der Gruppe ausgewählt ist, die aus 4-Chlor-, 4-Brom-, 4-Fluor-, 5-Fluor- und 4,5-Methylendioxygruppen besteht, wobei n 0 oder 1 ist5. Use according to claim 4, characterized in that X is selected from the group consisting of chlorine, bromine, fluorine and Y is selected from the group consisting of 4-chloro, 4-bromo, 4-fluorine -, 5-fluorine and 4,5-methylenedioxy groups, where n is 0 or 1
6. Verwendung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß R7 aus der Gruppe ausgewählt ist, die aus Wasserstoff und Halogen besteht oder R3 und R eine Kohlenstoff-Sauerstoff-Einfachbindung aufweisen, derart daß eine Ringstruktur vorliegt.6. Use according to any one of the preceding claims, characterized in that R 7 is selected from the group consisting of hydrogen and halogen or R 3 and R have a single carbon-oxygen bond, so that there is a ring structure.
7. Verwendung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß R] und R2 unabhängig aus der Gruppe ausgewählt sind, die aus Methyl und Ethyl besteht,7. Use according to one of the preceding claims, characterized in that R] and R 2 are independently selected from the group consisting of methyl and ethyl,
ist und R5 und R4 aus der Gruppe ausgewählt sind, die aus Wasserstoff, Chlor, Brom und Methoxygruppen besteht.and R 5 and R 4 are selected from the group consisting of hydrogen, chlorine, bromine and methoxy groups.
Verwendung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß Ri und R2 Methylgruppen sind, R3 und R Wasserstoff sind oder eine Kohlenstoff- Sauerstoff-Bindung aufweisen, die eine Ringstruktur bildet. Verwendung nach Anspruch 8, dadurch gekennzeichnet, daß es als Wirkstoff mindestens eine Substanz aus der Gruppe enthält, die aus 3-Chlor-N-(2-Chlθφhenyl)methyl- N-hydroxy-2,2-dimethylpropanamid, N-(2-Chlθφhenyl)methyl-N-hydroxy-2,2- Dimethylpropanamid, 3-Chlor-N-hydroxy-N-phenyl-2,2-dimethylpropanamid, N-(2- Bromphenyl)-methyl-3-chlor-N-hydroxy-2,2-dimethylpropanamid, 3-Chlor-N-hydroxy- 2,2-dimethyl-N-(2-methylphenyl)methylpropanamid, 3-Chlor-N-hydroxy-2,2-N- trimethylpropanamid, 3-Chlor-N-hydroxy-2,2-dimethyl-N-(phenylmethyl)-propanamid, 3-Chlor-N-(2,4-dichlθφhenylmethyl)-N-hydroxy-2,2-dimethylpropanamid. 3-chlor-N- (2-chloφhenyl)methyl-N-methoxy-2,2-dimethylpropan-amid, 3 ,3 -Dichlor-N-(2- chlθφenyl)methyl-N-hydroxy-2,2-dimethylpropanamid, 3-Chlor-N-(2- fluoφhenyl)methyl-N-hydroxy-2,2-dimethylpropanamid, 3-Brom-N-(2-chloφhenyl- methyl-N-hydroxy-2,2-dimethylpropanamid, N-Benzoyloxy-3-chlor-N-(2- chloφhenyl)methyl-2,2-dimethylpropanamid, N-Acetoxy-3-chlor-N-(2- chlθφhenyl)methyl-2,2-dimethylpropan-amid, N-(Chlorace-toxy)-3-chlor-N-(2- chloφhenyl)methyl-2,2-dimethylpropanamid, 2-(2-Chloφhenyl)methyl-4,4-dimethyl-3- isoxazolidinon, 4,4-Dimethyl-2-phenyl-3 -isoxazolidinon, 2-(2-Bromphenyl)methyl-4,4- dimethy 1-3 -isoxazolidinon, 4,4-Dimethyl-2-(2-methyl-phenyl)methyl-3-isoxazolidinon, 2,4,-Trimethyl-3-isoxazoli-dinon, 4,4-Dimethyl-2-phenylmethyl-3-isoxazolidinon, 2- (2,4-Dichlor-phenyl)methyl-4,4-dimethyl-3-isoxazolidinon, 5-Chlor-2-(2- chloφhenyl)methyl-4,4-dimethyl-3-isoxazolidinon, 2-(2-Chlθφhenyl)methyl-5- methoxy-4,4-dimethyl-3-isoxazoli-dinon, 2-(2-Fluoφhenyl)methyl-4,4-dimethyl-3- isoxazolidi-non, N-[(2-Chlθφhenyl)methyl]-N,3-dihydroxy-2,2-dimethyl-propanamid, 3-Chlor-N-[(2-chloφhenyl)methyl]-2,2-dimethyl-N-(methylamino- carbonyloxy)propanamid, 3 -Chlor-N- [(2-chlor-phenyl)methyl]N- [(2- tetrahydropyranyl)oxyl-2,2-dimethyl-propanamid, 3-Chlor-N-[(2-chlθφhenyl)methyl]- 2,2-dimethyl-N-[dimethyl(l,l-dimethyl-ethyl)silyloxypropanamid, 3-Acetoxy-N-[(2- chloφhenoxy)-methyl]-N-hydroxy-2,2-dimethylpropanamid, 2,[(2-Chlor-4- fluoφhenyl)methyl]-4,4-dimethyl-3-isoxazolidinon, 2-[(2-Chlor-5-fluoφhenyl)- methyl]-4,4-dimethyl-3-isoxazolidinon, 2-[(2,4,5-Trichlor-phenyl)methyl]-4,4- dimethyl-3 -isoxazolidinon, 2-[(2-Chlor-6-fluoφhenyl)methyl]-4,4-dimethyl-3- isoxazoli-dinon, 2-[(2-Chlθφhenyl)methyl]-5-ethoxy-4,4-dimethyl-3-isoxazoli-dinon, 2-[(2-Chlθφhenyl)methyl]-4,4-dimethyl-5-phenyl-amino-3-isoxazolidinon, 2-[(2- Chloφhenyl)methyl]-5-hydroxy-4,4-dimethyl-3-isoxazolidinon, 3 -Chlor-N- [(2-chlor- phenyl)methyl]-2,2-dimethyl-N-[(phenylamino)carbonyloxy]-propanamid, 3-Chlor-N- [(2-chlθφhenyl)methyl]-2,2-dimethyl-N-([(2-chlθφhenyl)methyl]-2,2-dimethyl-N- phenoxycarbonyl-oxy)propanamid, 3-Chlor-N-[(2-chloφhenyl)methyl]-N-ethoxy- carbonyloxy-2,2-dimethylpropanamid, N-Benzoyloxy-3,3-dichlor-N-[(2- chloφhenyl)methyl]-2,2-dimethylpropanamid, N-(2-Brom-phenyl)methyl-3,3-dichlor- N-hydroxy-2,2-dimethyl)propanamid, 3 -Chlor-N- [(2-chlθφhenyl)methyl] -N-(4- nitobenzoyloxy)-2,2-dimethylpropanamid, 3-Chlor-N-[2-chlθφhenylm,ethyl)]-2,2- dimethyl-N-[(2-methylphenyl)-carbonyloxy]propanamid, 3-Chlor-N-dichloracetoxy-N- [(2-chloφhenyl)methyl]-2,2-dimethylpropan-amid, 3-Chlor-N-[2-chloφhenyl)methyl]- 2,2-dimethyl-N-[(4-methylphenyl)sulfo-nyloxy]propanamid, 3-Chlor-N-[2-chlor- phenyl)methyl]-2,2-dimethyl-N-[(l,l-dimethylethyl)carbonyl-oxy]propanamid, 3- Chlor-N-[2-chloφhenyl)methyl]-2,2-dimethyl-N-(ethylthio-carbonyloxy)propanamid, 3-Chlor-N-[(2,2,2-trichlorethoxy)-carbonyloxy)-N-[(2-chloφhenyl)methyl]-2,3- dimethylpropan-amid, 3-Chlor-N-[(2-chlθφhenyl)aminocarbonyl-oxy-N-[(2- chlθφhenyl)methyl]-2,2-dimethylpropanamid, 3 -Chlor-N-[(4- chloφhenyl)aminocarbonyloxy-N-[(2-chlθφhenyl)methyl]-2,2-dimethylpropanamid, 3- Chlor-N-[2-chloφhenyl)methyl]-2,2-dimethyl-N-(phenylmethoxy)propanamid, 3- Chlor-N-[(2,4-dichlor-phenyoxy)acetoxy)-N-[(2-chlθφhenyl)methyl]-2,2-dimethyl- propanamid, , 3-Chlor-N-[2-chloφhenyl)methyl]-2,2-dimethyl-N-[(3- trifluormethyl)benzoyloxypropanamid, 3-Chlor-N-[2-chlor-phenyl)methyl]-2,2- dimethyl-N-[(4-methyl-phenyl)aminocarbonyl-oxy)-propanamid, 3-Chlor-N-[2- chlθφhenyl)methyl]-N-[(3,4-chlθφhenyl)aminocarbonyloxy]-2,2-dimethylpropanamid, 3-Chlor-N-(3-chlor-2,2-dimethyl-l-oxo-propoxy)-N-[(2-chlθφhenyl)-methyl]-2,2- dimethylpropan-amid, 3-Brom-N-[(2-Bromphenyl)-methyl]-N-hydroxy-2,2- dimethylpropanamid, 3 -Chlor-N- [(2-chloφhenyl)methyl] -N- [(2- fluoφhenyl)aminocarbonyloxy]-2,2-dimethylpropanamid,3-Chlor-N-[(2- chloφhenyl)methyl]-N-[(4-methoxyphenyl)-aminocarbonyloxy]-2,2- dimethy lpropanamid, 3 -Chlor-N- [(2-chlθφhenyl)methy 1] -N- [(3 -trifluormethy lphenyl)- amino-carbonyloxy]-2,2-dimethylpropanamid, 3-Brom-N-[(2-chlor-phenyl)methyl]-N- (methylaminocarbonyloxy)-2,2-dimethyl-propanamid, 3-Brom-N-(2-chloracetoxy)-N- [(2-chloφhenyl)-methyl]-2,2-dimethylpropanamid, 3-Chlor-N-[2,5-dichlor- (formylamino)-benzoy 1] oxy-N- [(2 -chloφhenyl)methyl] -2,2-dimethy lpropanamid, 3 - Brom-N-[(2-bromphenyl)methyl]-N-chloracetoxy-2,2-dimethylpropanamid, 3-Brom-N- [(2-brom-phenyl)-methyl ] -N-(methylcarbonyloxy)-2,2-dimethylpropan-amid, 3 -Brom- N-[(2-bromphenyl)methyl]-N-[(2-chloφhenyl)-aminocarbonyloxy]-2,2- dimethylpropanamid, 2-[(2-Chlor-phenyl)methyl]-N-hydroxy-2,2-dimethyl-3- methylthio-propanamid, 3-Penylcarbonyloxy)-N-[(2-chlθφhenyl)-methyl]-N-hydroxy- 2,2-dimethylpropanamid, 2-[(4-Chloφhenyl)-methyl]-4,4-dimethyl-3-isoxazolidinon, 2- [(3,4-Dichlor-phenyl)methyl]-4,4-dimethyl-3-isoxazolidinon, 2-[(Chlor- phenyl)methy 1] -4,4-dimethyl-3 -isoxazolidinon-5 -ylacetat, 2- [(Chloφhenyl)methyl] -4,4- dimethyl-3-isoxazoli-dinon-5-ylbenzoat, 2-[(Chloφhenyl)methyl]-4,4-dimethyl-3- isoxazo-lidinon-5-yldichloracetat, 2-[(Chlθφhenyl)methyl]-4,4-dimethyl-3- isoxazolidinon-5-ylphenylcarbamat, 2-[(Chlor-phenyl)methyl]-4,4-dimethyl-3- isoxazolidinon-5-ylmethyl-carbamat, 2-[(2-Chlor-4-cyanophenyl)methyl]-4,4-dimethyl- 3 -isoxazolidinon, 2-[(2-Chlor-5-methoxyphenyl)methyl]-4,4-dimethyl-3- isoxazolidinon, 2-[(2-Chlor-4-methoxyphenyl)-methyl]-4,4-dimethyl-3-isoxazolidinon, 2-[(2,4-Difluor-phenyl)methyl]-4,4-dimethyl-3-isoxazolidinon, 2-[(4-Brom-2- chloφhenyl)methyl]-4,4-dimethyl-3-isoxazolidinon, 2-[(2-Brom-4- fluoφhenyl)methyl]-4,4-dimethyl-3-isoxazolidinon, 2-[(6-Chlor- 1 ,3-benzdioxol-5- yl)methyl]-4,4-dimethyl-3-isoxazoli-dinon, 2-[(2-Chloφhenyl)methyl]-4,4-dimethyl-5- phenoxy-3-isoxazolidinon, 2-[(2-Chlθφhenyl)methyl]-4,4-dimethyl-5-(l- methylethoxy)-3 -isoxazolidinon, 2-[(2-Chloφhenyl)methyl]-4,4-dimethyl-5- (phenylmethoxy)-3-isoxazolidinon, 2-[(2-Brom-phenyl)methyl]-5-chlor-4,4-dimethyl-3- isoxazolidinon, 2-[(2,5-Dichloφhenyl)methyl]-4,4-dimethyl— 3-isoxazolidinon, 2-[(2- Chloφhenyl)methyl]-4,4-dimethyl-5-propoxy-3-isoxazolidinon, 2-[(2-Chlor- phenyl)methyl]-4,4-dimethyl-5-(2-propenyloxy)-3-isoxazo-lidinon, 2-[(2- Chloφhenyl)methyl]-4,4-dimethyl-5-(2-propinyloxy)-3-isoxazolidinon, 2-[(2- Chlθφhenyl)methyl]-4,4-dimethyl-5-(2-methoxyethoxy)-3-isoxazolidinon, 2-[(4-Fluor- 2-iodphenyl)methyl]-4,4-dimethyl-3-isoxazolidinon, 2-[(2-Chlor-phenyl)methyl]-5- cyclopentoxy-4,4-dimethyl-3-isoxazolidinon, 2-[(2-Chloφhenyl)methyl]-4,4-dimethyl- 5-(4-nitophenoxy)-3-isoxazolidinon, 2-[(2-Chloφhenyl)-methyl]-5-cyclopropyl- methoxy-4,4-dimethyl-3 -isoxazoli-dinon, 2- [(2-Bromphenyl-(methyl)] -4,4-dimethyl-5 - (2 -propinoxy)-3 -isoxazolidinon, 2-[(2-Chloφhenyl)methyl]-5-(3-butinoxy)-4,4- dimethyl-3 -isoxazolidinon, 2-[(2-Chlor-phenyl)methyl]-5-(2-butinoxy)-4,4-dimethyl-3- isoxazolidi-non, 2-[(2-Chlθφhenyl)methyl]-5-(3-butenoxy)-4,4-dimethyl-3- isoxazolidinon, 2-[(2-Chlθφhenyl)-methyl]-5-pentoxy-4,4-dimethyl-3-isoxazolidinon, 2-[(2-Chlor-phenyl)methyl]-5-hexoxy-4,4-dimethyl-3-isoxazolidinon, 2-[(2- Chloφhenyl)-methyl]-5-( 1 -methylpropoxy)-4,4-dimethyl-3-isoxazolidinon, 2-[(2- Chloφhenyl)methyl]-5-(3-methyl-3-butenoxy)-4,4-dimethyl-3-isoxazolidinon, 2-[(2- Chloφhenyl)-methyl]-5-butoxy-4,4-dimethyl-3-isoxazolidinon und 2-[(2-Chlor- phenyl)methyl]-4,4-dimethyl-3-isoxazolidinon besteht.Use according to one of the preceding claims, characterized in that R 1 and R 2 are methyl groups, R 3 and R are hydrogen or have a carbon-oxygen bond which forms a ring structure. Use according to claim 8, characterized in that it contains at least one substance from the group consisting of 3-chloro-N- (2-chlθφhenyl) methyl-N-hydroxy-2,2-dimethylpropanamide, N- (2- Chlθφhenyl) methyl-N-hydroxy-2,2-dimethylpropanamide, 3-chloro-N-hydroxy-N-phenyl-2,2-dimethylpropanamide, N- (2-bromophenyl) methyl-3-chloro-N-hydroxy- 2,2-dimethylpropanamide, 3-chloro-N-hydroxy-2,2-dimethyl-N- (2-methylphenyl) methylpropanamide, 3-chloro-N-hydroxy-2,2-N-trimethylpropanamide, 3-chloro-N -hydroxy-2,2-dimethyl-N- (phenylmethyl) propanamide, 3-chloro-N- (2,4-dichlorothenylmethyl) -N-hydroxy-2,2-dimethylpropanamide. 3-chloro-N- (2-chloro-phenyl) methyl-N-methoxy-2,2-dimethylpropane amide, 3,3-dichloro-N- (2-chloro-phenyl) methyl-N-hydroxy-2,2-dimethylpropanamide, 3-chloro-N- (2-fluoro-phenyl) methyl-N-hydroxy-2,2-dimethylpropanamide, 3-bromo-N- (2-chloro-phenyl-methyl-N-hydroxy-2,2-dimethylpropanamide, N-benzoyloxy- 3-chloro-N- (2-chloro-phenyl) methyl-2,2-dimethylpropanamide, N-acetoxy-3-chloro-N- (2-chloro-phenyl) methyl-2,2-dimethylpropane amide, N- (chloroacetoxy ) -3-chloro-N- (2-chloro-phenyl) methyl-2,2-dimethylpropanamide, 2- (2-chloro-phenyl) methyl-4,4-dimethyl-3-isoxazolidinone, 4,4-dimethyl-2-phenyl- 3-isoxazolidinone, 2- (2-bromophenyl) methyl-4,4-dimethyl 1-3 -isoxazolidinone, 4,4-dimethyl-2- (2-methyl-phenyl) methyl-3-isoxazolidinone, 2,4, - Trimethyl-3-isoxazolino dinone, 4,4-dimethyl-2-phenylmethyl-3-isoxazolidinone, 2- (2,4-dichlorophenyl) methyl-4,4-dimethyl-3-isoxazolidinone, 5-chloro-2 - (2-chloro-phenyl) methyl-4,4-dimethyl-3-isoxazolidinone, 2- (2-chloro-phenyl) methyl-5-methoxy-4,4-dimethyl-3-isoxazolino-dinone, 2- (2-fluoφhenyl) methyl-4,4- dimethyl-3-isoxazolidi-non, N - [(2-chloro-phenyl) methyl] -N, 3-dihydroxy-2,2-dimethyl-propanamide, 3-chloro-N - [(2-chloro-phenyl) methyl] -2, 2-dimethyl-N- (methylamino-carbonyloxy) propanamide, 3-chloro-N- [(2-chlorophenyl) methyl] N- [(2-tetrahydropyranyl) oxyl-2,2-dimethyl-propanamide, 3-chlorine -N - [(2-chloro-phenyl) methyl] - 2,2-dimethyl-N- [dimethyl (1,1-dimethyl-ethyl) silyloxypropanamide, 3-acetoxy-N - [(2-chloro-phenoxy) methyl] -N -hydroxy-2,2-dimethylpropanamide, 2, [(2-chloro-4-fluoφhenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2 - [(2-chloro-5-fluoφhenyl) - methyl] - 4,4-dimethyl-3-isoxazolidinone, 2 - [(2,4,5-trichlorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2 - [(2-chloro-6-fluoφhenyl) methyl ] -4,4-dimethyl-3-isoxazolino-dinone, 2 - [(2-Chlθφhenyl) methyl] -5-ethoxy-4,4-dimethyl-3-isoxazolino-dinone, 2 - [(2-Chlθφhenyl) methyl ] -4,4-dimethyl-5-phenyl-amino-3-isoxazolidinone, 2 - [(2-chloro-phenyl) methyl] -5-hydroxy-4,4-dimethyl-3-isoxazolidinone, 3-chloro-N- [ (2-chlorophenyl) methyl] -2,2-dimethyl-N - [(phenylamino) carbonylox y] -propanamide, 3-chloro-N- [(2-chlθφhenyl) methyl] -2,2-dimethyl-N - ([(2-chlθφhenyl) methyl] -2,2-dimethyl-N-phenoxycarbonyl-oxy) propanamide, 3-chloro-N - [(2-chloro-phenyl) methyl] -N-ethoxycarbonyloxy-2,2-dimethylpropanamide, N-benzoyloxy-3,3-dichloro-N - [(2-chloro-phenyl) methyl] - 2,2-dimethylpropanamide, N- (2-bromophenyl) methyl-3,3-dichloro- N-hydroxy-2,2-dimethyl) propanamide, 3-chloro-N- [(2-chlθφhenyl) methyl] -N- (4-nitobenzoyloxy) -2,2-dimethylpropanamide, 3-chloro-N- [2- chlθφhenylm, ethyl)] - 2,2-dimethyl-N - [(2-methylphenyl) carbonyloxy] propanamide, 3-chloro-N-dichloroacetoxy-N- [(2-chloφhenyl) methyl] -2,2-dimethylpropane- amide, 3-chloro-N- [2-chloro-phenyl) methyl] - 2,2-dimethyl-N - [(4-methylphenyl) sulfonyloxy] propanamide, 3-chloro-N- [2-chlorophenyl) methyl ] -2,2-dimethyl-N - [(l, l-dimethylethyl) carbonyl-oxy] propanamide, 3-chloro-N- [2-chloro-phenyl) methyl] -2,2-dimethyl-N- (ethylthio-carbonyloxy ) propanamide, 3-chloro-N - [(2,2,2-trichloroethoxy) carbonyloxy) -N - [(2-chloro-phenyl) methyl] -2,3-dimethylpropane amide, 3-chloro-N - [( 2-chlθφhenyl) aminocarbonyl-oxy-N - [(2-chlθφhenyl) methyl] -2,2-dimethylpropanamide, 3-chloro-N - [(4-chloφhenyl) aminocarbonyloxy-N - [(2-chlθφhenyl) methyl] - 2,2-dimethylpropanamide, 3-chloro-N- [2-chlorophenyl) methyl] -2,2-dimethyl-N- (phenylmethoxy) propanamide, 3-chloro-N - [(2,4-dichlorophenyoxy) acetoxy ) -N - [(2-chlθφhenyl) methyl] -2.2 -dimethyl-propanamide,, 3-chloro-N- [2-chloro-phenyl) methyl] -2,2-dimethyl-N - [(3-trifluoromethyl) benzoyloxypropanamide, 3-chloro-N- [2-chlorophenyl) methyl ] -2,2-dimethyl-N - [(4-methylphenyl) aminocarbonyloxy) propanamide, 3-chloro-N- [2-chlθφhenyl) methyl] -N - [(3,4-chlθφhenyl) aminocarbonyloxy ] -2,2-dimethylpropanamide, 3-chloro-N- (3-chloro-2,2-dimethyl-l-oxo-propoxy) -N - [(2-chlθφhenyl) methyl] -2,2-dimethylpropane- amide, 3-bromo-N - [(2-bromophenyl) methyl] -N-hydroxy-2,2-dimethylpropanamide, 3-chloro-N- [(2-chlorophenyl) methyl] -N- [(2-fluoφhenyl ) aminocarbonyloxy] -2,2-dimethylpropanamide, 3-chloro-N - [(2-chlorophenyl) methyl] -N - [(4-methoxyphenyl) aminocarbonyloxy] -2,2-dimethylpropanamide, 3-chloro-N- [(2-chlθφhenyl) methy 1] -N- [(3-trifluoromethylphenyl) - amino-carbonyloxy] -2,2-dimethylpropanamide, 3-bromo-N - [(2-chlorophenyl) methyl] -N- (methylaminocarbonyloxy) -2,2-dimethyl-propanamide, 3-bromo-N- (2-chloroacetoxy) -N- [(2-chloro-phenyl) -methyl] -2,2-dimethylpropanamide, 3-chloro-N- [2 , 5-dichloro- (formylamino) benz oy 1] oxy-N- [(2-chlorophenyl) methyl] -2,2-dimethylpropanamide, 3 - bromo-N - [(2-bromophenyl) methyl] -N-chloroacetoxy-2,2-dimethylpropanamide, 3- Bromine-N- [(2-bromophenyl) methyl] -N- (methylcarbonyloxy) -2,2-dimethylpropane amide, 3-bromo-N - [(2-bromophenyl) methyl] -N - [(2nd -chloφhenyl) aminocarbonyloxy] -2,2-dimethylpropanamide, 2 - [(2-chlorophenyl) methyl] -N-hydroxy-2,2-dimethyl-3-methylthio-propanamide, 3-penylcarbonyloxy) -N- [ (2-chloro-phenyl) methyl] -N-hydroxy-2,2-dimethylpropanamide, 2 - [(4-chloro-phenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2- [(3,4-dichloro -phenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2 - [(chlorophenyl) methyl 1] -4,4-dimethyl-3-isoxazolidinone-5-ylacetate, 2- [(chlorophenyl) methyl] -4,4-dimethyl-3-isoxazolino-dinon-5-ylbenzoate, 2 - [(Chloφhenyl) methyl] -4,4-dimethyl-3-isoxazolidinon-5-yldichloroacetate, 2 - [(Chlθφhenyl) methyl] -4,4-dimethyl-3-isoxazolidinon-5-ylphenylcarbamate, 2 - [(chlorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinon-5-ylmethyl-carbamate, 2 - [(2-chloro- 4-cyanophenyl) methyl ] -4,4-dimethyl- 3-isoxazolidinone, 2 - [(2-chloro-5-methoxyphenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2 - [(2-chloro-4-methoxyphenyl) methyl] -4,4-dimethyl -3-isoxazolidinone, 2 - [(2,4-difluorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2 - [(4-bromo-2-chloro-phenyl) methyl] -4,4-dimethyl -3-isoxazolidinone, 2 - [(2-bromo-4-fluoro-phenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2 - [(6-chloro-1,3-benzodioxol-5-yl) methyl] -4,4-dimethyl-3-isoxazolino dinone, 2 - [(2-chloro-phenyl) methyl] -4,4-dimethyl-5-phenoxy-3-isoxazolidinone, 2 - [(2-chloro-phenyl) methyl] -4 , 4-dimethyl-5- (l-methylethoxy) -3-isoxazolidinone, 2 - [(2-chlorophenyl) methyl] -4,4-dimethyl-5- (phenylmethoxy) -3-isoxazolidinone, 2 - [(2- Bromophenyl) methyl] -5-chloro-4,4-dimethyl-3-isoxazolidinone, 2 - [(2,5-dichlorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2 - [(2- Chloφhenyl) methyl] -4,4-dimethyl-5-propoxy-3-isoxazolidinone, 2 - [(2-chlorophenyl) methyl] -4,4-dimethyl-5- (2-propenyloxy) -3-isoxazo- lidinone, 2 - [(2-chloro-phenyl) methyl] -4,4-dimethyl-5- (2-propynyloxy) -3-isoxazolidinone, 2- [ (2-chloro-phenyl) methyl] -4,4-dimethyl-5- (2-methoxyethoxy) -3-isoxazolidinone, 2 - [(4-fluoro-2-iodophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone , 2 - [(2-chlorophenyl) methyl] -5-cyclopentoxy-4,4-dimethyl-3-isoxazolidinone, 2 - [(2-chlorophenyl) methyl] -4,4-dimethyl-5- (4- nitophenoxy) -3-isoxazolidinone, 2 - [(2-chloro-phenyl) -methyl] -5-cyclopropyl-methoxy-4,4-dimethyl-3-isoxazolino-dinone, 2- [(2-bromophenyl- (methyl)] - 4,4-dimethyl-5 - (2-propinoxy) -3 -isoxazolidinone, 2 - [(2-chlorophenyl) methyl] -5- (3-butynoxy) -4,4-dimethyl-3 -isoxazolidinone, 2- [ (2-chlorophenyl) methyl] -5- (2-butynoxy) -4,4-dimethyl-3-isoxazolidi-non, 2 - [(2-chloro-phenyl) methyl] -5- (3-butenoxy) -4 , 4-dimethyl-3-isoxazolidinone, 2 - [(2-chloro-phenyl) -methyl] -5-pentoxy-4,4-dimethyl-3-isoxazolidinone, 2 - [(2-chlorophenyl) methyl] -5- hexoxy-4,4-dimethyl-3-isoxazolidinone, 2 - [(2-chloro-phenyl) methyl] -5- (1-methylpropoxy) -4,4-dimethyl-3-isoxazolidinone, 2 - [(2-chloro-phenyl) methyl] -5- (3-methyl-3-butenoxy) -4,4-dimethyl-3-isoxazolidinone, 2 - [(2-chloro-phenyl) -methyl l] -5-butoxy-4,4-dimethyl-3-isoxazolidinone and 2 - [(2-chlorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone.
10. Verwendung nach einem der Ansprüche 1 bis 9 zur 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 Pneumozystose, der Balantidiose, der Kryptosporidiose, der Sarkozystose, der Akantha-möbose, der Naeglerose, der Kokzidiose, der Giardiose und der Lambliose.10. Use according to one of claims 1 to 9 for the prevention and treatment of infections caused by unicellular parasites, namely pathogens of malaria, sleeping sickness, Chagas disease, toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis, pneumocystosis, the Balantidiosis, Cryptosporidiosis, Sarcocystosis, Akantha-Möbose, Naeglerose, Coccidiosis, Giardiosis and Lambliosis.
11. Verwendung nach einem der Ansprüche 1 bis 9 zur Vorbeugung und 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 Fami- lie 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 tuberculo- sis, Mycobacterium bovis und Mycobacterium avium, Bakterien der Familie Chlamy- diaceae, insbesondere die Spezies Chlamydia trachomatis 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 Mycoplasmataceae, der Gattungen Mycoplasma und Ureaplasma, insbesondere die Art Mycoplasma pneumoniae, Bakterien der Gattung Brucella, Bakterien der Gattung Bordetella, Bakterien der Familie Neisseriaceae, 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, Plesio- monas und Photobacterium, insbesondere die Arten Vibrio cholerae, Vibrio anguillarum und Aeromonas salmomcidas, Bakterien der Gattung Campylobacter, insbesondere die Arten Campylobacter jejuni, Campylobacter coli und Campylobacter fetus, Bakterien der Gattung Helicobacter, 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 Legionellaceae, der Gattung Legionella, Bakterien der Familie Rickettsiaceae und Familie Bartonellaceae, Bakterien der Gattungen No- cardia und Rhodococcus, Bakterien der Gattung Dermatophilus, Bakterien der Familie Pseudomonadaceae, insbesondere der Gattungen Pseudomonas 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 Ba- cillus und Clostridium besteht, und bei der Helicobacter-Eradikationstherapie bei Ulcera des Magendarmtraktes.11. Use according to any one of claims 1 to 9 for the prevention and 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 of the Family lie Actinomycetaceae, in particular of the genus Actinomyces, bacteria of the genus Corynebacterium, in particular the species Corynebacterium diphteriae and Corynebacterium pseudotuberculosis, bacteria of the family Mycobacteriaceae, of the genus Mycobacterium, in particular the species Mycobacterium lepraium, myobobciumobacterium and Myobobciumobacterium, The Chlamydiaeae family, in particular the species Chlamydia trachomatis and Chlamydia psittaci, bacteria of the genus Listeria, in particular the species Listeria monocytogenes, bacteria of the species Erysipelthrix rhusiopathiae, bacteria of the genus Clostridium, bacteria of the genus Yersinia, of the species Yersinia pseudotersers, Yersinia pseudoters enterocolitica and Yersinia ruckeri, bacteria of the Mycoplasmataceae family, of the genera Mycoplasma and Ureaplasma, in particular the species Mycoplasma pneumoniae, bacteria of the genus Brucella, bacteria of the genus Bordetella, bacteria of the Neisse family riaceae, 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, Plesionomonas and Photobacterium, in particular the species Vibrio cholerae, Vibrio anguillarum and Aeromon , Bacteria of the genus Campylobacter, in particular the species Campylobacter jejuni, Campylobacter coli and Campylobacter fetus, bacteria of the genus Helicobacter, in particular the species Helicobacter pylori, bacteria of the families Spirochaetaceae and the Leptospiraceae, in particular the species Treponema, Borrelia and Leptelia bira, especially Bacteria of the genus Actinobacillus, bacteria of the family Legionellaceae, of the genus Legionella, bacteria of the family Rickettsiaceae and family Bartonellaceae, bacteria of the genera Nocardia and Rhodococcus, bacteria of the genus Dermatophilus, bacteria of the family Pseudo monadaceae, in particular of the genera Pseudomonas and Xanthomonas, bacteria of the Enterobacteriaceae family, in particular of the genera Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia and Shigella, bacteria of the Pasteurellaceae family, in particular of the genus Haemophilus, bacteria of the family Micrococcus genus 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 genera Bacillus and Clostridium, and in Helicobacter eradication therapy for ulcers of the gastrointestinal tract.
12. Verfahren zur Behandlung von infektiösen Erkrankungen, hervorgerufen durch Bakterien, Pilze oder Parasiten, bei dem eine therapeutisch wirksame Menge einer Verbindung nach einem der Ansprüche 1 bis 11 einem an einer durch Bakterien, Pilze oder Parasiten hervorgerufenen Infektion erkrankten Patienten verabreicht wird. 12. A method for the treatment of infectious diseases caused by bacteria, fungi or parasites, in which a therapeutically effective amount of a compound according to any one of claims 1 to 11 is administered to a patient suffering from an infection caused by bacteria, fungi or parasites.
EP00902582A 1999-01-13 2000-01-12 Use of 3-isoxazolidinones and hydroxylamine acids for the treatment of infections Withdrawn EP1143941A3 (en)

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