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EP1143941A2 - Utilisation de 3-isoxazolidinones et d'hydroxylaminoacides pour le traitement d'infections - Google Patents

Utilisation de 3-isoxazolidinones et d'hydroxylaminoacides pour le traitement d'infections

Info

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Withdrawn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)
English (en)
Other versions
EP1143941A3 (fr
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/de
Application filed by Jomaa Pharmaka GmbH filed Critical Jomaa Pharmaka GmbH
Publication of EP1143941A2 publication Critical patent/EP1143941A2/fr
Publication of EP1143941A3 publication Critical patent/EP1143941A3/fr
Withdrawn legal-status Critical Current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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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des médicaments contenant au moins un composé de formule générale (I), ainsi que leur utilisation pour le traitement thérapeutique et prophylactique d'infections chez l'homme et chez les animaux, provoquées par des bactéries, champignons et parasites.
EP00902582A 1999-01-13 2000-01-12 Utilisation de 3-isoxazolidinones et d'hydroxylaminoacides pour le traitement d'infections Withdrawn EP1143941A3 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE19900907 1999-01-13
DE19900907 1999-01-13
DE19903666A DE19903666A1 (de) 1999-01-13 1999-01-30 Arzneimittel mit einem Gehalt an 3-Isoxazolidinonen und Hydroxylaminsäuren als Wirkstoff und ihre Verwendung
DE19903666 1999-01-30
PCT/EP2000/000165 WO2000041473A2 (fr) 1999-01-13 2000-01-12 Utilisation de 3-isoxazolidinones et d'hydroxylaminoacides pour le traitement d'infections

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EP1143941A2 true EP1143941A2 (fr) 2001-10-17
EP1143941A3 EP1143941A3 (fr) 2002-02-06

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JP (1) JP2002534440A (fr)
CN (1) CN1342078A (fr)
AU (1) AU2436600A (fr)
BR (1) BR0007491A (fr)
CA (1) CA2360366A1 (fr)
CZ (1) CZ20012380A3 (fr)
HU (1) HUP0105412A2 (fr)
IL (1) IL143795A0 (fr)
NO (1) NO20013464L (fr)
PL (1) PL350128A1 (fr)
SK (1) SK9502001A3 (fr)
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GB9928568D0 (en) 1999-12-03 2000-02-02 Zeneca Ltd Chemical compounds
GB0009803D0 (en) 2000-04-25 2000-06-07 Astrazeneca Ab Chemical compounds
JP2005512975A (ja) 2001-10-25 2005-05-12 アストラゼネカ アクチボラグ 抗菌薬として有用なイソキサゾリン誘導体
GB202209172D0 (en) * 2022-06-22 2022-08-10 Syngenta Crop Protection Ag Improvements in or relating to organic compounds

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FR2290442A1 (fr) * 1974-11-06 1976-06-04 Aries Robert Nouvelles rifamycines
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CZ20012380A3 (cs) 2002-01-16
CA2360366A1 (fr) 2000-07-20
AU2436600A (en) 2000-08-01
PL350128A1 (en) 2002-11-04
IL143795A0 (en) 2002-04-21
WO2000041473A2 (fr) 2000-07-20
CN1342078A (zh) 2002-03-27
SK9502001A3 (en) 2002-05-09
NO20013464D0 (no) 2001-07-12
JP2002534440A (ja) 2002-10-15
TR200102019T2 (tr) 2002-04-22
NO20013464L (no) 2001-09-12
BR0007491A (pt) 2001-11-20
WO2000041473A3 (fr) 2001-11-29
HUP0105412A2 (hu) 2002-05-29
EP1143941A3 (fr) 2002-02-06

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