Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
• • 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
• • 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
  • A61P33/04—Amoebicides
• • 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 phosphonoformic acid derivatives for the therapeutic and prophylactic treatment of infections in humans and animals which are caused by bacteria, fungi and parasites, and their use as a fungicide, bactericide and herbicide in plants.
• the phosphonoformic acid derivatives comprise the physiologically tolerable salts, esters and amides.
• Phosphonoformic acids are already known for their antiviral properties.
• Pharmaceutical preparations for the treatment of viral infections are already in the US patents
• the object of the present invention is therefore to provide a substance which can be used universally in infections by bacteria, fungi and parasites in humans and animals and as a fungicide, bactericide and herbicide in plants and which fulfills the conditions specified above.
• This object is achieved in a completely surprising manner by the group of substances defined in claim 1.
• This group of substances shows both an anti-infectious effect against bacteria, fungi and single and multicellular parasites as well as a fungicidal, bactericidal and herbicidal effect on plants.
• organophosphorus compounds used according to the invention correspond to the general formula I.
• R ⁇ is selected from the group consisting of d- 2 6-alkyl radicals, C2.26-alkenyl radicals. with 1 to 6 double bonds, C 2 -26-alkynyl radicals with 1 to 6 triple bonds, C 1-26 -acyl radicals, Ar -co-26 alkyl, C3-8 cycloalkyl-Co-6 alkyl radicals -2, C 3-8 heterocycloalkyl-co- 26 alkyl radicals having one or two nitrogen, oxygen or sulfur atoms, halogen and consists OX ⁇ , where all the aforementioned radicals can be substituted with d-9-alkyl, d-9-alkoxy, hydroxyl, amino, halogen or oxo groups, where Xu is selected from the group consisting of hydrogen, d-26- alkyl radicals, C 2 - 2 6- alkenyl group having 1 to 6 double bonds, C2 26 alkynyl radicals having 1 to 6 triple bonds, Ar-Co-26 alkyl
• Ri and R 2 are each independently selected from the group consisting of d-2 alkyl radicals, C 3 . -Cycloalkyl residues, C 3 . -Cycloalkyl-C 1 . 24 -alkyl radicals, d ⁇ -alkoxy radicals, C ⁇ - 24 - alkylthio radicals, C 1-24 -alkoxy-C ⁇ - 24 -alkyl radicals and C 1-24 -alkylthio-C 1 .2 4 -alkyl radicals, acyl radicals, Ar- ( d- 24 ) alkyl, C 3-8 heterocyloalkyl-Co- 24 alkyl, halogen and hydrogen, and each d.
• 24 -alkyl radical and -CC-24-alkoxy radical may be branched or unbranched and saturated or unsaturated with 2 to 6 double bonds and optionally with hydroxyl, amino, mercapto, halogen, oxo groups or d.
• each aralkyl radical, heterocyclic radical, and C ⁇ .2 -alkoxy radical may be branched or unbranched and saturated or unsaturated with 2 to 6 double bonds or triple bonds, or in the R 1 -CH-CH-R 2 part of a form, the optionally substituted with hydroxy, mercapto, amino, halogen, oxo groups or with C ⁇ -24 alkyl groups, C 1 - 24 - alkoxy, d- 2 4-alkylthio, d- 2 4-alkylamino, di- ( C 1 -2 4 -alkyl) amino residues, C 1-24 -alkylcarbon
• 24 -alkyl) amino residues can be substituted, each d.
• 24 -alkyl radical can be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds, and their pharmaceutically acceptable salts, esters and amides and salts of the esters and their optical isomers.
• R t and R 2 can in particular each be independently selected from the group consisting of carboxyl residues, carboxamido residues, aryl residues, aryloxycarbonyl residues, aryl-d- 2 4-alkyl residues, C 1-24 alkoxycarbonyloxy residues, i.e. 24 -alkylaminocarbonyl residues, di- (-C ⁇ .
• R 3 and ⁇ are the same or different and are each selected from the group consisting of hydrogen, halogen, C.-4-alkyl radicals, C M alkoxy radicals, formyl, acetyl, pro pionyl, butyryl, formyl, acetyl, propionyl, butyryloxy, C 1- alkoxycarbonyl, which can all be branched or unbranched, or R 3 and t together form an unbranched saturated alkylene chain with 3 to 4 carbon atoms, which is bonded to adjacent positions of the phenyl ring, or R 3 and t together form a methylenedioxy radical, a 1,1-ethylenedioxy radical, a 1,1-ethylenedioxy radical, a 1,1-ethylenedioxy radical or a 1,2-ethylenedioxy radical which are attached to adjacent positions of the phenyl ring.
• R 1 and R 2 are each independently selected from the group consisting of hydrogen, hydroxyl groups, formyl, acetyl and methyl, the methyl radical optionally having a hydroxyl group or mercapto group or having d- 24 alkoxy radicals, C 1- 2 alkylcarbonyloxy radicals. or C1-24 alkylcarbonylthio radicals can be substituted, the d. 24 alkyl groups and the d. 24 - alkoxy groups can be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds.
• Ri is particularly preferably a methyl radical, optionally with a hydroxyl group or mercapto group or with C ⁇ - 24 alkylcarbonyloxy radicals, d-2 4 - alkylthio radicals or d- 24 -alkylcarbonylthio radicals can be substituted, the C1.
• 2 4- alkyl groups and the C ⁇ - 2 4-alkoxy groups can be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds, and R 2 is a hydrogen radical.
• R ⁇ is preferably OH.
• Acyl is a substituent derived from an acid, such as from an organic carboxylic acid, carbonic acid, carbamic acid or the thioic acid or imidic acid corresponding to the individual acids above, or from an organic sulfonic acid, these acids each being aliphatic, aromatic and / or heterocyclic Include groups in the molecule as well as carbamoyl or carbamimidoyl.
• Aliphatic acyl groups are acyl radicals derived from an aliphatic acid, which include the following:
• Alkanoyl e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl etc.
• Alkenoyl e.g. acryloyl, methacryloyl, crotonoyl etc.
• Alkylthioalkanoyl e.g. methylthioacetyl, ethylthioacetyl etc.
• Alkanesulfonyl e.g. mesyl, ethanesulfonyl, propanesulfonyl, etc.
• Alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.
• Alkyl carbamoyl e.g. methyl carbamoyl etc.
• N-alkyl thiocarbamoyl e.g. (N-methyl) thiocarbamoyl etc.
• Alkyl carbamimidoyl e.g. methyl carbamimidoyl etc.
• Alkoxalyl e.g. methoxalyl, ethoxalyl, propoxalyl etc.
• the aliphatic hydrocarbon part in particular the alkyl group or the alkane radical, can optionally have one or more suitable substituents, such as amino, halogen (for example fluorine, chlorine, bromine, etc.), hydroxy, 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 derive from an acid with a substituted or unsubstituted aryl group, where the aryl group can include phenyl, toluyl, xylyl, naphthyl and the like; suitable examples are given below:
• Aroyl e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl etc.
• Aralkanoyl e.g. phenylacetyl etc.
• Aralkenoyl e.g. cinnamoyl etc.
• Aryloxyalkanoyl e.g. phenoxyacetyl etc.
• Arylthioalkanoyl e.g. phenylthioacetyl etc.
• Arylaminoalkanoyl e.g. N-phenylglycyl, etc.
• Arenesulfonyl e.g. benzenesulfonyl, tosyl or toluenesulfonyl, naphthalenesulfonyl etc.
• Aryloxycarbonyl e.g. phenoxycarbonyl, naphthyloxycarbonyl etc.
• Aralkoxycarbonyl e.g. benzyloxycarbonyl etc.
• Arylcarbamoyl e.g. phenylcarbamoyl, naphthylcarbamoyl etc.
• Arylglyoxyloyl e.g. phenylglyoxyloyl etc.
• aromatic hydrocarbon part in particular the aryl radical
• aliphatic hydrocarbon part "(in particular the alkane radical) may optionally have one or more suitable substituents, such as those which are suitable as substituents for the alkyl group or the In particular and as an example of preferred aromatic acyl radicals with special substituents, arylanoyl substituted with halogen and hydroxyl or with halogen and acyloxy and arroyl substituted with hydroxyl, hydroxyimino, dihalogenalkanoyloxyimino and arylthiocarbamoyl (eg phenylthiocarbamoylimidamidl) (arylcarb) (arylcarb) (arylcarb) (arylcarbamoylimid) Phenylcarbamimidoyl etc.).
• suitable substituents such as those which are suitable as substituents for the alkyl group or the In particular and as an example of preferred aromatic acyl radicals with special substitu
• 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.
• Aryl is an aromatic hydrocarbon radical, such as phenyl, naphthyl etc., which may optionally have one or more suitable substituents, such as alkyl, alkenyl, alkynyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc .), Nitro and the like.
• suitable substituents such as alkyl, alkenyl, alkynyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc .), Nitro and the like.
• Alkyl includes mono-, di-, triphenylalkyls such as benzyl, phenethyl, benzhydryl, trityl and the like, where the aromatic part may have one or more suitable substituents such as alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. Fluorine, chlorine, bromine, etc.), nitro and the like.
• alkoxy e.g. methoxy, ethoxy etc.
• halogen e.g. Fluorine, chlorine, bromine, etc.
• organophosphorus 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 substances 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 Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium, bacteria of the family Chlamydiaceae, in particular the species Chlamydia tracho ⁇ iatis and Chlamydia psittaci, bacteria of the genus Listeria, in particular the species Listeria mondhrixysnixytocytosis , Bacteria of the genus Clostridium, bacteria of the genus Yersinia, of the species Yersinia pestis, Yersini
• Organophosphorus compounds and their derivatives are therefore suitable for the treatment of diphtheria, acne vulgaris, listeriosis, erysipelas in animals, gas burns in humans and animals, para-noise burns in humans and animals, tuberculosis in humans and animals, leprosy and a wide variety of mycobacteriosis in humans and animals, paratuberculosis in animals, plague, mesenteric lymphadenitis and pseudotuberculosis in humans and animals, cholera, legionnaires' disease, Lyme disease in humans and animals, leptospirosis in humans and animals, syphilis, Campylobacter enteritis in humans and animals, Moraxella keratoconjunc -tivitis and serositis of animals, brucellosis of animals and humans, anthrax in humans and animals, actinomycosis in humans and animals, streptotrichoses, psittacosis / ornithosis in animals,
• 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.
• organophosphorus compounds according to the mel I and esters and amides and salts thereof show a strong cytotoxic activity against single and multicellular parasites, especially against the pathogens of malaria and sleeping sickness. Accordingly, the organophosphorus compounds are useful for the treatment of infectious diseases caused by bacteria, parasites and fungi in humans and animals. The compounds are also used for the prevention of diseases caused by bacteria, parasites and fungi.
• organophosphorus compounds these generally include pharmaceutically acceptable salts, amides, esters, a salt of such an ester, or compounds which, when applied, provide the organophosphorus compounds as metabolites or degradation products, also called “prodrugs", for administration in any of them be prepared in a 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, fungi or plants in vitro. For this purpose, test methods are used which are known to the person skilled in the art.
• the inhibition of malaria parasite growth in blood cultures is determined.
• 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. Some of the microorganisms to be examined can only be examined in animal models. The corresponding models are then applied here.
• the antiparasitic, fungicidal or antibacterial activity is further evaluated in the corresponding animal models.
• the screening for herbicidal activity is determined by means of algae systems and measurement of the isoprene emission from plants under standard conditions.
• the pharmaceutically active agents can be prepared in the form of pharmaceutical preparations in dosage units. This means that the preparation in the form of individual parts, e.g. B. tablets, dragees, capsules, pills, suppositories and ampoules are present, the active ingredient content of which corresponds to a fraction or a multiple of a single dose.
• the dosage units can e.g. B. 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose.
• a single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.
• Non-toxic, inert pharmaceutically suitable carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.
• Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations.
• Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. B. starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. B.
• humectants e.g. B. glycerin
• disintegrant e.g. B. agar-agar, calcium carbonate and sodium carbonate
• solution retarders e.g. B. paraffin
• absorption accelerator e.g.
• the tablets, dragees, capsules, pills and granules can be provided with the customary coatings and casings, optionally containing opacifying agents, and can also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, possibly with a delay, where as Embedding compounds e.g. B. polymer substances and waxes can be used.
• Embedding compounds e.g. B. polymer substances and waxes can be used.
• the active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned carriers.
• Suppositories can contain the usual water-soluble or water-insoluble excipients in addition to the active ingredient (s), e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat and higher esters (z. B. C 14 alcohol with C16 fatty acid) or mixtures of these substances.
• active ingredient e.g. B. polyethylene glycols
• fats e.g. B. cocoa fat and higher esters (z. B. C 14 alcohol with C16 fatty acid) or mixtures of these substances.
• Ointments, pastes, creams and gels can contain the usual excipients in addition to the active ingredient (s), e.g. B. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.
• active ingredient e.g. B. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.
• Powder and sprays can contain the usual excipients in addition to the active ingredient (s), e.g. B. milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances.
• Sprays can also use the usual blowing agents, e.g. B. chlorofluorocarbons.
• solutions and emulsions can contain the usual carriers such as solvents, solubilizers and emulsifiers, e.g. B. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol, glycerol formaldehyde - 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,
• 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. 12
• 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. 12
• the formulation forms mentioned can also contain colorants, preservatives and odor and taste-improved additives, e.g. B. peppermint oil and eucalyptus oil and sweeteners, e.g. B. saccharin.
• the active compounds of the 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 further active pharmaceutical ingredients.
• the compounds can be used with previously described substances with antibacterial, 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: /www.customs.treas.gov/imp-exp /rulings/harmoniz/hrml29.html listed on the Internet.
• Ce lieoxim group, Cefoxitin group, Cefoxitin, Cefotetan, Cefmetazol, Latamoxef, Flomoxef, Cefaxaxim group, Cefozidim, Ceftazidim group, Ceftazidim, Ce irom, Cefepim, other Cephaloperazalone, Cefaloperazaline, Cefsoperulosaline, Cefoxulosporin the Cefalexin group, Loracar- bef, Cefprozil, new oral cephalo
• organophosphorus compounds in the pharmaceutical compositions can be used in combination with sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine, chloroquine, hydroxylchloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracycline, doxycycline, proguanil, metronidazole, nicazolantil, prazoliquilil, 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 therapy of infections in cavities, body cavities.
• Suitable preparations are injection solutions, solutions and suspensions for oral therapy, gels, pour-on formulations, emulsions, ointments or drops.
• ophthalmic and dermatological formulations silver and other salts, ear drops, eye ointments, powder or solutions can be used.
• suitable formulations can also be ingested through feed or drinking water.
• gels, powders, powders, tablets, slow-release Tablets, premixes, concentrates, granules, pellets, tablets, boluses, capsules, aerosols, sprays, inhalants can be used in humans and animals.
• the compounds used 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 total amounts of about 0.05 to about 2000, preferably 5 to 1000 mg, body weight per 24 hours, optionally in the form multiple doses to achieve the desired results.
• a single dose contains the active ingredient (s) preferably in amounts from about 0.25 to about 2000 mg, e.g. 1 to 4 times a day.
• Liquid preparations can be administered in the form of solutions, syrups, emulsions or suspensions which are suitable for oral applications e.g. Contain 0.1 to 50 wt .-% of active ingredient.
• the active ingredient is preferably between 0.05 and 20% by weight of the preparation.
• the compounds used according to the invention can be given in the usual concentrations and preparations in animals together with the feed or with feed preparations or with the drinking water.
• the compounds used according to the invention can be used excellently as bactericides, fungicides and herbicides in plants.
• Substance 1 2 - [(2-ethoxycarbonylphenoxy) carbonyl] - 1, 3, 2-dioxaphospholan-2-oxide
• Substance 2 2 - [(2-ethoxycarbonylphenoxy) carbonyl] -4-dodecanoyloxymethyl-l, 3,2-dioxaphospholan-2-oxide
• Substance 3 2 - [(2-ethoxycarbonylphenoxy) carbonyl] -4-octanoylthiomethyl-l, 3,2-dioxaphospholan-2-oxide
• Substance 4 2 - [(2-ethoxycarbonylphenoxy) carbonyl] -4-dodecanoylthiomethyl-l, 3 * , 2-dioxaphospholan-2-oxide
• Substance 5 2-hydroxyethyl - [(2-ethoxycarbonylphenoxy) carbonyl] sodium phosphonate
• Substance 6 2-dodecanoyloxy-2-hydroxypropyl [(2-ethoxycarbonylphenoxy) carbonyl] sodium phosphonate
• Substance 9 sodium 2-hydroxy-l, 4,2-dioxaphosphorinane-2,3-dioxide
• Substance 10 sodium 2-hydroxy-5-dodecanoyloxymethyl-l, 4,2-dioxaphosphorinane-2,3-dioxide
• Substance 11 Sodium 2-hydroxy-5-octanoylthiomethyl-l, 4,2-dioxaphosphorinane-2,3-dioxide
• Substance 12 Sodium 2-hydroxy-5-dodecanoylthiomethyl-l, 4,2-dioxaphosphorinane-2,3-dioxide
• the antimalarial activity of substances 1 to 12 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 l "1.
• the plates are incubated at 37 ° C., 3% CO 2 and 5% O 2 for a period of 48 hours 30 ⁇ l of medium supplemented with 27 ⁇ Ci ml of “1 [ 3 H] hypoxanthine were added to each well.
• the parasites were harvested by filtration on glass fiber filters and the incorporated radioactivity was measured. Inhibition of parasite growth was measured as a percentage inhibition of tritium corporation. The inhibition of parasite growth was expressed as a percentage inhibition of tritium corporation based on a comparison without substance. The half-maximum inhibitory concentration (IC50) of the substance was determined by extrapolation of the values.

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• 1998
  • 1998-11-25 DE DE19854310A patent/DE19854310A1/de not_active Withdrawn
• 1999
  • 1999-11-20 TR TR2001/01431T patent/TR200101431T2/tr unknown
  • 1999-11-20 CZ CZ20011819A patent/CZ20011819A3/cs unknown
  • 1999-11-20 PL PL99348354A patent/PL348354A1/xx unknown
  • 1999-11-20 EA EA200100585A patent/EA200100585A1/ru unknown
  • 1999-11-20 CA CA002352511A patent/CA2352511A1/en not_active Abandoned
  • 1999-11-20 JP JP2000583536A patent/JP2002530343A/ja active Pending
  • 1999-11-20 AU AU18591/00A patent/AU1859100A/en not_active Abandoned
  • 1999-11-20 OA OA1200100130A patent/OA11718A/en unknown
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  • 1999-11-20 EP EP99962147A patent/EP1133302A2/de not_active Withdrawn
  • 1999-11-20 AP APAP/P/2001/002164A patent/AP2001002164A0/en unknown
  • 1999-11-20 BR BR9915605-9A patent/BR9915605A/pt not_active IP Right Cessation
  • 1999-11-20 CN CN99813747A patent/CN1328464A/zh active Pending
  • 1999-11-20 WO PCT/EP1999/008964 patent/WO2000030653A2/de not_active Application Discontinuation
• 2001
  • 2001-05-23 NO NO20012540A patent/NO20012540L/no not_active Application Discontinuation

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