Definitions

• the present invention relates to novel 1 ,3-diphenyl ureas which are specifically trifluoromethyl and halogen substituted in the phenyl rings, to pharmaceutical compositions containing them and to their use in the treatment and/or prevention of bacterial infections.
• novel 1 ,3-diphenyl ureas with a distinct halogen/thfluromethyl substitution pattern are specifically active against bacteria and exhibit virtually no activity against fungi and that these novel 1 ,3-diphenyl ureas are very potent against a broad range of aerobic and anaerobic Gram-positive pathogens including, among others, multi-drug resistant staphylococci, e.g., S. aureus and S. epidermidis, enterococci, e.g., E. faecalis, streptococci, e.g., S. pneumoniae, S. pyogenes and S. viridans.
• multi-drug resistant staphylococci e.g., S. aureus and S. epidermidis
• enterococci e.g., E. faecalis
• streptococci e.g., S. pneumoniae, S. pyogenes and S. viridans.
• Preferred applications for the compounds of the present invention are those related to the topical/localized treatment of infections in humans and in animals and to the decolonization and/or prevention of colonization of any site which is needed to be rendered sterile from bacteria or in which the bacterial load has to be decreased to prevent spread of bacteria to other sites and to cause infections.
• Examples of these applications are treatment of skin, mucosal, ocular, dental, gastro-intestinal and upper respiratory-tract infection, decolonization and/or prevention of bacterial colonization of, among others, skin, eyes, nares, mouth, mucosa, gastro-intestinal tract, upper respiratory tract, prosthetic devices and surfaces in general where bacteria can survive and eventually replicate e.g., before surgical practice and/or in general in any instance in which decolonization and/or prevention of spread of bacteria to other sites, which bacteria can infect or colonize, is required.
• R 1 and R 2 represents independently chlorine and bromine
• X represents oxygen or sulfur; and pharmaceutically acceptable salts thereof.
• compositions ⁇ (S-Chloro- ⁇ -trifluoromethyl-phenylJ-S-C ⁇ chloro-S-trifluoromethyl-phenyO-urea, 1-(3-Bromo-5-trifluoromethyl-phenyl)-3-(4-chloro-3-thfluoromethyl-phenyl)-urea, and pharmaceutically acceptable salts thereof.
• pharmaceutically acceptable salts encompasses salts with a strong base like an alkali or earth alkali base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide etc., or e.g. choline etc.
• compounds of this invention can be used for the treatment of human and animal diseases which are typically associated with one or more of such type of pathogens and/or in the decolonization of and/or in the prevention of colonization by one or more of such type of bacteria. This makes compounds of this invention valuable antibacterial agents.
• the described compounds can be administered by all means known in the art such as, among others, orally, intravenously, topically, rectally, vaginally, sublingually, by inhalation or by any means of local delivery depending on the site were bacteria are localized as colonizers or as infecting agents.
• Examples of applications are capsules, tablets, orally administered suspensions or solutions, suppositories, injections, eye-drops, ointments, aerosols/nebulizers or topical/localy administered forms.
• Examples of topical forms and of forms suitable for local delivery can be, among others, gels, creams, ointments, pastes, lotions, solutions, sprays, lozenges, tablets, capsules, sachet, suspension, suppositories, ovules, lacquers, cements, etc.
• colonisation e.g., skin, mucosa, eye, ear, mouth, nares, parts of the gastro-intestinal tract or of the upper-respiratory tract, prosthetic devices.
• the described compounds can be also incorporated in the cement and/or in parts of a prosthetic device from which they are released in order to prevent its colonization.
• Preferred applications are oraly, topicaly as well as eye drops.
• the dosage used depends upon the type of the specific active ingredient, the use in animal or human, the kind of administration and in case of application in man, the age and the requirements of the patient. Generally, dosages of 0.01 - 50 mg / kg body weight per day either as a single or subdivided in 2 to 4 doses per day are considered. For liquid or semi-solid formulations, e.g. solutions, ointments, gels or creams anvile amount of a formulation with a ratio between the active ingredient and the excipients in a range between 0.01 % to 5 % are considered. These dosage should be administered preferably in 1 to 4 doses per day which are of equal amounts. As usual children should receive lower doses which are adapted to body weight and age.
• compositions with compounds of formula I can contain inert excipients or also excipients with antibacterial activity.
• Tablets or granules, for example, could contain a number of binding agents, filling excipients, carrier substances or diluents.
• compositions outlined above may be administered in enteral, oral form or in topical form e.g. as tablets, dragees, gelatine capsules, emulsions, solutions, creams, ointment or suspensions, in intranasal form like sprays or rectally in form of suppositories.
• enteral, oral form or in topical form e.g. as tablets, dragees, gelatine capsules, emulsions, solutions, creams, ointment or suspensions, in intranasal form like sprays or rectally in form of suppositories.
• These compounds may also be administered parenteral, in intramuscular or intraveneous form, e.g. in form of injectable solutions.
• compositions may contain the compounds of formula I as well as their pharmaceutically acceptable salts in combination with inorganic and/or organic excipients which are usual in the pharmaceutical industry like lactose, maize or derivatives thereof, talcum, stearinic acid or salts of these materials.
• vegetable oils, waxes, fats, liquid or half-liquid polyols etc. may be used.
• solutions and syrups e.g. water, polyols, saccharose, glucose etc. are used.
• injectables are prepared by using e.g. water, polyols, alcohols, glycerin, vegetable oils, lecithin, liposomes etc.
• Suppositories are prepared by using natural or hydrogenated oils, waxes, fatty acids (fats), liquid or half-liquid polyols etc.
• creams, gels, ointments etc. for topical and/or local applications e.g. polyols, oils, detergents, penetration enhancer, fillers etc. are used which are known to someone skilled in the art.
• compositions may contain in addition preservatives, stabilisation improving substances, viscosity improving or regulating substances, solubility improving substances, sweeteners, dyes, taste improving compounds, salts to change the osmotic pressure, buffer, antioxidants etc.
• the compounds of formula I may also be used in co-therapy with one or more other therapeutics, for example with other classes of anti-infective agents to increase/ complement their anti-infective spectrum of action, e.g. penicillins and cephalosporins; glycopeptides; quinolones; tetracyclines; aminoglycosides; macrolides, sulfonamides etc. or antifungals, antiprotozals etc.
• other therapeutics e.g. penicillins and cephalosporins; glycopeptides; quinolones; tetracyclines; aminoglycosides; macrolides, sulfonamides etc. or antifungals, antiprotozals etc.
• Compounds of this invention can be also incorporated in cleaning and/or cleansing solutions and/or dressings and/or coatings and/or lacquers and/or cements and/or parts of a prosthetic device for decolonization and/or prevention of bacterial colonization of sites in which bacteria can survive and eventually replicate causing potential risk for infections.
• Clinical and Laboratory Standards Institute (CLSI; formerly NCCLS): Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard - Seventh Edition (2006). Clinical and Laboratory Standards Institute document M7-A7.
• Streptococci S. pneumoniae, S. pyogenes, S. viridans
• CLSI National Committee for Clinical Laboratory Standards
• MIC Minimum Inhibitory Concentration
• MIC Minimum Inhibitory Concentration
• MIC Minimum Inhibitory Concentration
• MIC Minimum Inhibitory Concentration

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• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2006
  • 2006-12-08 EP EP06829406A patent/EP1993997A2/de not_active Withdrawn

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