Process for the manufacture of ajoene derivatives

Abstract

The present invention relates to the compound (E,Z)-ajoene of formula (1) for use in treatment of bacterial infections. Another aspect of the present invention is a composition comprising (E,Z)-ajoene of formula (1) and at least one antibiotic. Yet another aspect of the invention relates to a method for manufacturing (E,Z) ajoene of formula (1) wherein the conformation of the internal C═C— bond can be either E or Z or a mixture thereof, said method comprising reacting allicin of formula (3) with an acid in the presence of a solvent to provide (E,Z ajoene) of formula (1) as defined above. Yet another aspect of the invention is (E,Z)-ajoene of formula 1 obtainable by the method described above.

1 . A method of treating an infection of a biofilm forming bacteria comprising providing a composition that comprises an (E,Z)-Ajoene of formula (1): 
       
         
           
           
               
               
           
         
         to a subject in need thereof. 
       
     
     
         2 - 20 . (canceled) 
     
     
         21 . The method of  claim 1 , wherein the bacteria is a gram negative bacteria. 
     
     
         22 . The method of  claim 1 , wherein the bacteria is selected from the group consisting of  Vibrio fischeri, Aeromonas hydrophila, Aeromonas salmonicida, Agrobacterium tumefaciens, Burkholderia cepacia, Chromobacterium violaceum, Enterobacter agglomerans, Erwinia carotovora, Erwinia chrysanthemi, Erwinia Stewartii, Escherichia coli, Pseudomonas aureofaciens, Pseudomonas aeruginosa, Ralstonia solanacearum, Rhizobium etli, Rhizobium leguminosarum, Rhodobacter sphaeroides, Salmonella typhimurium, Serratia liquefaciens, Sinorhizobium meliloti, Vibrio anguillarum, Vibrio harveyi, Yersinia enterocolitica , and  Yersinia pseudotuberculosis.    
     
     
         23 . The method of  claim 1 , wherein the bacteria is  Pseudomonas aeruginosa.    
     
     
         24 . The method of  claim 1 , wherein the bacterial infection is a pulmonary infection. 
     
     
         25 . The method of  claim 1 , wherein the bacterial infection is present in a chronic wound of said subject. 
     
     
         26 . The method of  claim 1 , wherein said subject has an immune deficiency. 
     
     
         27 . The method according to  claim 26 , wherein the immune deficiency is an immuno-compromising disease or said subject is taking an immuno-suppressant medication. 
     
     
         28 . The method according to  claim 26 , wherein the subject is selected from the group consisting of humans, pets and livestock. 
     
     
         29 . The method of  claim 1 , wherein the subject is a mammal having cystic fibrosis. 
     
     
         30 . A composition comprising (E,Z)-ajoene of formula (1): 
       
         
           
           
               
               
           
         
         and at least one antibiotic, wherein the antibiotic is selected from the group consisting of aminoglycosides, ansamycins, carbacephem, carbapenems, cephalosporins, glycopeptides, macrolides, monobactams, penicillins, polypeptides, quinolones, sulfonamides, and tetracyclines. 
       
     
     
         31 . The composition according to  claim 30 , wherein the antibiotic is an aminoglycoside. 
     
     
         32 . The composition according to  claim 30 , wherein the antibiotic is selected from the group consisting of Ampicillin, Bacampicillin, Carbenicillin Indanyl, Mezlocillin, Piperacillin, Ticarcillin, Amoxicillin-Clavulanic Acid, Ampicillin-Sulbactam, Benzylpenicillin, Cloxacillin, Dicloxacillin, Methicillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin Tazobactam, Ticarcillin Clavulanic Acid, Nafcillin, Cefadroxil, Cefazolin, Cephalexin, Cephalothin, Cephapirin, Cephradine, Cefaclor, Cefamandol, Cefonicid, Cefotetan, Cefoxitin, Cefprozil, Ceftmetazole, Cefuroxime, Loracarbef, Cefdinir, Ceftibuten, Cefoperazone, Cefixime, Cefotaxime, Cefpodoxime proxetil, Ceftazidime, Ceftizoxime, Ceftriaxone, Cefepime, Azithromycin, Clarithromycin, Clindamycin, Dirithromycin, Erythromycin, Lincomycin, Troleandomycin, Cinoxacin, Ciprofloxacin, Enoxacin, Gatifloxacin, Grepafloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Sparfloxacin, Trovafloxacin, Oxolinic acid, Gemifloxacin, Perfloxacin, Imipenem-Cilastatin, Meropenem, Aztreonam, Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Streptomycin, Tobramycin, Paromomycin, Teicoplanin, Vancomycin, Demeclocycline, Doxycycline, Methacycline, Minocycline, Oxytetracycline, Tetracycline, Chlortetracycline, Mafenide, Silver Sulfadiazine, Sulfacetamide, Sulfadiazine, Sulfamethoxazole, Sulfasalazine, Sulfisoxazole, Trimethoprim-Sulfamethoxazole, Sulfamethizole, Rifampin, Rifabutin, Rifampin, Rifapentine, Linezolid, Quinopristin Dalfopristin, Bacitracin, Chloramphenicol, Fosfomycin, Isoniazid, Methenamine, Metronidazol, Mupirocin, Nitrofurantoin, Nitrofurazone, Novobiocin, Polymyxin, Spectinomycin, Trimethoprim, Colistin, Cycloserine, Capreomycin, Ethionamide, Pyrazinamide, Para-aminosalicyclic acid, and Erythromycin ethylsuccinate. 
     
     
         33 . The composition according to  claim 30 , wherein the antibiotic is tobramycin. 
     
     
         34 . A method of treating an infection of a biofilm forming bacteria comprising providing the composition of  claim 30  to a subject in need thereof. 
     
     
         35 . The method according to  claim 34 , wherein the bacteria is gram negative bacteria. 
     
     
         36 . The method of  claim 34 , wherein the bacteria is selected from the group consisting of  Vibrio fischeri, Aeromonas hydrophila, Aeromonas salmonicida, Agrobacterium tumefaciens, Burkholderia cepacia, Chromobacterium violaceum, Enterobacter agglomerans, Erwinia carotovora, Erwinia chrysanthemi, Erwinia Stewartii, Escherichia coli, Pseudomonas aureofaciens, Pseudomonas aeruginosa, Ralstonia solanacearum, Rhizobium etli, Rhizobium leguminosarum, Rhodobacter sphaeroides, Salmonella typhimurium, Serratia liquefaciens, Sinorhizobium meliloti, Vibrio anguillarum, Vibrio harveyi, Yersinia enterocolitica , and  Yersinia pseudotuberculosis.    
     
     
         37 . The method of  claim 34 , wherein the bacteria is  Pseudomonas aeruginosa.    
     
     
         38 . The method of  claim 34 , wherein the bacterial infection is a pulmonary infection. 
     
     
         39 . The method of  claim 34 , wherein the bacterial infection is in a chronic wound of said subject.