MX2008007478A - Diphenyl urea derivatives - Google Patents

Abstract

The invention relates to novel specifically trifluoromethyl and halogen substituted 1,3-diphenyl ureas and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects like the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as anti-infectives.

Description

DERIVATIVES OF DIFENI UREA DESCRIPTION OF THE INVENTION The present invention relates to novel 1,3-diphenyl ureas which are specifically trifluoromethyl and substituted halogen in the phenyl rings, to pharmaceutical compositions which contain them and to their use in the treatment and / or prevention of bacterial infections. In the prior art certain 1,3-diphenyl ureas have been claimed for their insecticidal properties (United States Patent Specification of North America 2 745 874) or by a general biocidal activity to combat infested insects, fungi and herbs (Patent specification of Great Britain 1 326 481). In one case, the possibility has been described that the insecticidal properties of 1,3-diphenyl ureas can be flanked by a bactericidal action, for example against S. aureaus and a fungicidal activity (US Pat. Specification 2,745 874). In addition, certain 1,3-diphenyl ureas have been described as inhibitors of bacterial RNA polymerase and this property is claimed to be frequently translated into antibacterial activity against Gram positive and Gram negative aerobic pathogens, for example, against S. aureaus and E. coli (TolC) Application (WO 01/51456).

Ref..193843 It has been found that a small group of novel 1,3-diphenyl ureas with a different halogen / trifluoromethyl substitution pattern are specifically active against bacteria and exhibit virtually no activity against fungi and that these 1,3-diphenyl ureas Novelties are very potent against a wide range of aerobic and anaerobic Gram-positive pathogens including, among others, multidrug-resistant Staphylococci, for example S. Aureus and S. epidermis, enterococci, for example E. faecalis, streptococci, for example S. pneumoniae, S. pyogenes and S. viridans. These properties make these compounds very useful in the treatment of Gram-positive bacterial infections in humans and animals and / or in the decolonization of sites infested by these pathogens and / or in preventing the colonization of sites from which the bacteria they can then be dispersed and potentially cause bacterial infections. Preferred applications for the compounds of the present invention are those related to topical / localized treatment of infections in humans and animals and to the decolonization and / or prevention of colonization of any site which is necessary to be rendered sterile by bacteria or animals. in which the bacterial load has to be diminished to avoid the dispersion of bacteria to other sites and to cause infections. Examples of these applications are treatment of infection of the skin, mucosa, ocular, dental, gastrointestinal and upper respiratory tract, decolonization and / or prevention of bacterial colonization of, among others, skin, eyes, nose, mouth, mucosa, gastrointestinal tract. intestinal, upper respiratory tract, prosthetic devices and surfaces in general where the bacteria can survive and eventually replicate for example, before the surgical practice and / or in general in any case in which decolonization and / or dispersion prevention is required of bacteria to other sites, which can infect or colonize the bacteria. Therefore, the present invention relates to novel compounds of the general formula I Formula I wherein R represents chlorine or bromine; X represents oxygen or sulfur; And pharmaceutically acceptable salts thereof. Preferred examples are compounds of the formula I wherein R represents chlorine. Compounds where X represents oxygen are also preferred. The most preferred compound of the present invention is: 1- (3-fluoro-5-trifluoromethyl-phenyl) -3- (4-chloro-3-trifluoromethyl-phenyl) -urea and pharmaceutically acceptable salts thereof. The pharmaceutically acceptable salts of expression comprise salts with a strong base such as an alkaline or alkaline earth base, for example sodium hydroxide, potassium hydroxide, calcium hydroxide, etc. or for example, choline, etc. Due to their ability to inhibit aerobic and anaerobic Gram positive bacteria, the compounds of this invention can be used for the treatment of human and animal diseases which are typically associated with one or more such pathogen types and / or in decolonization. of and / or in the prevention of colonization by one or more such types of bacteria. This makes the compounds of this invention valuable antibacterial agents. The disclosed compounds can be administered by any means known in the art such as, inter alia, orally, intravenously, topically, rectally, vaginally, sublingually, by inhalation or by any means of local delivery depending on the site where the bacteria are located as colonizers. or as infectious agents. Examples of applications are capsules, tablets, suspensions or orally administered solutions, suppositories, injections, eye drops, ointments, aerosols / nebulizers or topically / locally administered forms. Examples of topical forms and forms suitable for local delivery may be, among others, gels, creams, ointments, pastes, lotions, solutions, dispersions, pills, tablets, capsules, sachets, suspension, suppositories, ovules, lacquers, cements, etc. depending on the site proposed to treat and / or aims to reach and / or propose to protect from colonization for example, skin, mucosa, eye, ear, mouth, nose, parts of the gastro-intestinal tract or upper respiratory tract , and prosthetic devices. The described compounds can also be incorporated into the cement and / or parts of a prosthetic device from which they are released in order to prevent their colonization. The preferred applications are oral, topically as well as eye drops. The dose used depends on the type of specific active ingredient, the animal or human use, the type of administration and in case of application in man, the age and the requirements of the patient. Generally, doses of 0.01-50 mg / kg of body weight per day are considered either simple or subdivided into 2 to 4 doses per day. For liquid or semi-solid formulations, for example solutions, ointments, gels or creams an appropriate amount of a formulation with a ratio between the active ingredient and the excipients in a range between 0.01% to 5% is considered. These doses should be administered preferably in 1 to 4 doses per day which are equal amounts. As usual, children should receive smaller doses which adapt to body weight and age. Preparations with compounds of Formula I may contain inert excipients or also excipients with antibacterial activity. The tablets or granules, for example, may contain a number of binding agents, filler excipients, carrier substances or diluents. The compositions indicated above can be administered enterally, orally or in topical form for example as tablets, coated tablets, gelatin capsules, emulsions, solutions, creams, ointments or suspensions, in intranasal form as dispersions or rectally in the form of suppositories. These compounds can also be administered parentally, intramuscularly or intravenously, for example in the form of injectable solutions.

These pharmaceutical compositions may contain the compounds of the formula I as well as their pharmaceutically acceptable salts in combination with inorganic and / or organic excipients which are customary in the pharmaceutical industry such as lactose, corn or derivatives thereof, talc, stearic acid, or salts of these materials. Gelatin capsules can be used vegetable oils, waxes, fats or liquid or semi-liquid polyols, etc. For the preparation of solutions and syrups for example, water, polyols, sucrose, glucose, etc. are used. Injectables are prepared by using for example water, polyols, alcohols, glycerin, vegetable oils, lecithin, liposomes, etc. Suppositories are prepared by using natural or hydrogenated oils, waxes, fatty acids (fats), liquid or semi-liquid polyols, etc. For the preparation of creams, gels, ointments, etc. for topical and / or local application for example polyols, oils, detergents, penetration enhancer, fillers, etc. are used which are known to some experts in the art. The compositions may also contain preservatives, stabilizing builder substances, builder substances or viscosity regulators, solubility enhancing substances, sweeteners, dyes, flavor improving compounds, salts for changing the osmotic pressure, buffer, antioxidants, etc. The compounds of the formula I can also be used in co-therapy with one or more different therapeutics, for example with other classes of anti-infective agents to increase / complement their anti-infectious spectrum of action, for example penicillins and cephalosporins; glycopeptides, quinolones, tetracyclines, aminoglycosides; macrolides, sulfonamides, etc. or antifungals, antiprotozoals, etc. The compounds of this invention can also be incorporated in cleaning solutions and / or cleansers and / or bandages 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. The compounds of formula I can generally be synthesized by reacting - as shown in Scheme 1 of subsequent reaction - 4-halo-5- (trifluoromethyl) -phenyl-isocyanate or corresponding phenyl-thioisocyanate of the formula 3-Fluoro-5-trifluoromethyl-aniline Illa (see also the experimental part). Alternatively a 4-halo-5- (trifluoromethyl) -aniline of the formula IIB can be coupled with a 3-fluoro-5- (trifluoromethyl) -phenium-isocyanate or 3-fluoro-5- (trifluoromethyl) -phenyl-thioisocyanate Illb to produce the derivatives of the general formula I Reaction scheme 1 Examples Abbreviations DMF: N, N-dimethylformamide DMSO: dimethyl sulfoxide EtOAc: ethyl acetate MS: mass spectrometry NMR: nuclear magnetic resonance TBME: tert-butyl methyl ether THF: tetrahydrofuran cHexan: cyclohexane Sat: saturated Rt: room temperature R : reaction mixture Example 1 1- (3-Fluoro-5-trifluoromethyl-phenyl) -3- (4-chloro-3-trifluoromethyl-phenyl) -urea It is added to a solution of 3-fluoro-5-trifluoromethyl-aniline (940 mg, 5.25 mmol) , 1.05 equivalents) in dry THF (20 ml) 4-chloro-3- (trifluoromethyl) -phenylisocyanate (1.11 g, 5.0 mmol) in rt and the mixture is stirred overnight. It is then diluted with cHexan (100 ml), washed twice with 2N HCl, once with saturated NaHCO 3 and brine (100 mg each) and adsorbed on Celite in vacuo. Flash chromatography on silica with cHexano / TBME (5: 1 to 3: 1) yields 687 mg of pure product (34%) as a white powder. A-NMRÍDMSO) d 9.41 (s, 2H), 8.09 (d, J = 2.4 Hz, ÍH), 7.6-7.7 (, 4H), 7.25 (d, J = 8.1, ÍH), MS (ES); 398.9. Example 2 1- (3-Fluoro-5-trifluoromethyl-phenyl) -3- (4-bromo-3-trifluoromethyl-phenyl) urea It is added to a solution of 4-bromo-3- (trifluoromethyl) -aniline (132 mg, 0.55 mmole, 1.1 eq.) in dry THF (5 ml) 3-fluoro-5- (trifluoromethyl) -phenylisocyanate (72 μl, 0.5 mmol). After stirring overnight at rt the mixture is diluted with cHexan (20 ml), washed twice with 2N HCl, once with saturated NaHCO 3 and brine (20 ml each) and adsorbed on Celite in vacuo. Flash chromatography on silica with cHexano / TBME (4: 1 to 2: 1) produces 111 mg of product (50%) as a white powder. MS (ES ") 442.9, 444.9 Example 3 1- (3-Fluoro-5-trifluoromethyl-phenyl) -3- (4-chloro-3-trifluoromethyl-phenyl) -thiourea The title compound is synthesized according to the procedure used in example 2 starting with 3-fluoro-5 - (trifluoromethyl) -aniline and 4-chloro-3- (trifluoromethyl) -phenylisothiocyanate. Yield: 98 mg (47%). MS (ES ") 414.9 Example 4 Biological Results The antimicrobial susceptibility test is performed according to the Clinical and Laboratory Standards Institute (CLSI) The Clinical and Laboratory Standards Institute (CLSI, initially NCCLS): Methods for Dilution Antimicrobial Susceptibility Test for Bacteria That Grow Aerobically: Approved Standard - Seventh Edition (2006), Clinical and Laboratory Standars Institute document M7-A7 Streptococci (S. pneumoniae, S. pyrogenes, S. viridans) are tested following the CLSI methodology with the exception that Todd Hewitt Broth Broth without blood is used Anaerobic bacteria (P. acnes, B. dis tasonis) are tested according to the CLSI guidelines (initially NCCLS) except for using dilutions of Wikins Chalgren Broth microcalcium broth National Committee for Clinical Laboratory Standards (NCCLS) Methods for Anti-microbial Susceptibility Testing of anaerobic Bacteria; Approved Standard - Sixth Edition (2004) NCCLS docum ento M11-A6.

A) In vitro antibacterial activity of compounds against representative pathogens for nasal colonization (minimum inhibitory concentration (MIC) in micrograms / ml) B) In vitro antibacterial activity of compounds against representative pathogens for ocular infections (minimum inhibitory concentration (MIC) in micrograms / ml) C) Antibacterial activity in vi tro of compounds against representative pathogens for skin infections (minimum inhibitory concentration (MIC) in micrograms / ml) D) In vitro antibacterial activity of compounds against representative pathogens for gastrointestinal * or dental * infections (minimum inhibitory concentration (MIC) in micrograms / ml) It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (14)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Compounds of the general formula I Formula I characterized in that R represents chlorine or bromine; X represents oxygen or sulfur; and pharmaceutically acceptable salts thereof.
2. 2. The compounds of the formula I according to claim 1, characterized in that R represents chlorine.
3. 3. The compounds according to claim 1 or 2, characterized in that X represents oxygen.
4. 4. The compound according to any of claims 1 to 3, characterized in that it is l- (3-fluoro-5-trifluoromethyl-phenyl) -3- (4-chloro-3-trifluoromethyl-phenyl) -urea, and salts pharmaceutically acceptable thereof.
5. 5. Pharmaceutical compositions for the treatment of infections characterized in that they contain a compound according to any of claims 1 to 4 and customary carrier materials and adjuvants.
6. 6. Pharmaceutical compositions for the treatment of infections caused by Gram-positive aerobic and anaerobic pathogens and anaerobic Gram-negative, characterized in that they contain a compound according to any of claims 1 to 4 and customary carrier materials and adjuvants.
7. The compounds according to any of claims 1 to 4, characterized in that they are for use as medicaments for the treatment of infections.
8. 8. The compounds according to any of claims 1 to 4, characterized in that they are for use as medicaments for the treatment of infections caused by Gram-positive aerobic and anaerobic pathogens and anaerobic Gram-negative.
9. 9. The use of one or more compounds according to any of claims 1 to 4 as active ingredients for the production of pharmaceutical compositions for the treatment of infections.
10. 10. The use of one or more compounds according to any of claims 1 to 4 as active ingredients for the production of pharmaceutical compositions for the treatment of infections caused by Gram-positive aerobic and anaerobic pathogens and anaerobic Gram-negative.
11. 11. The use of one or more compounds according to any of claims 1 to 4 as active ingredients for the production of pharmaceutical compositions for the treatment of bacteria that cause nasal, ocular, dental, gastrointestinal or skin infections.
12. 12. The use of one or more compounds according to any of claims 1 to 4 as active ingredients for the production of pharmaceutical compositions for sterilization, sanitization, antisepsis, disinfection, decolonization or prevention of colonization of the skin, gastrointestinal tract. intestinal or nasal, ocular or dental area or any type of prosthetic device.
13. A process for the manufacture of pharmaceutical compositions for the treatment of infections which contain one or more compounds according to any of claims 1 to 4 as active ingredients, characterized in that it comprises mixing one or more active ingredients with pharmaceutically acceptable excipients in a form known per se.
14. 14. A process for the manufacture of pharmaceutical compositions for the treatment of infections caused by Gram-positive aerobic and anaerobic pathogens and anaerobic Gram-negative which contain one or more compounds according to any of claims 1 to 4 as active ingredients, characterized in that it comprises mixing one or more active ingredients with pharmaceutically acceptable excipients in a manner known per se.