Modified Azole Compounds As Antifungal and Antibacterial Agents

Abstract

The present invention relates to the compounds of formula (I), their preparation and use as antifungal and/or antibacterial agents. where the values for R 1 , R 2 , R 3 , R 4 , R 5 and A are as defined herein.

1 . A method of treating a skin fungal or bacterial disorder comprising topically administering to a recipient in need of such treatment an effective amount of a compound of the formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1 =—H, alkyl, —C(O)R 6 , —C(O)OR 6  or —S(O) n R 6 ; 
 R 2 , R 3 , R 4  and R 5  independently=—H or alkyl 
 A=an azole; 
 R 6 =alkyl, aryl or heteroaryl; and 
 n=1 or 2, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method according to  claim 1 , wherein R 1  is —H. 
     
     
         3 . The method according to  claim 1 , wherein R 1  is —C(O)R 6 . 
     
     
         4 . The method according to  claim 1 , wherein
 R 2  and R 3 =alkyl and   R 4  and R 5 =—H.   
     
     
         5 . The method according to  claim 4 , wherein R 1  is —H. 
     
     
         6 . The method according to  claim 4 , wherein R 1  is —C(O)R 6 . 
     
     
         7 . The method according to  claim 1  or  claim 4 , wherein the azole is selected from the group consisting of ketoconazole, itraconazole, pramiconazole, miconazole, metronidazole, liarozole, rambazole, benzimidazole, benzothiazole, bifonazole, butaconazole nitrate, climbazole, clotrimazole, croconazole, eberconazole, econazole, albaconazole, elubiol, fenticonazole, fluconazole, flutimazole, isoconazole, lanoconazole, neticonazole, omoconazole, oxiconazole nitrate, sertaconazole, sulconazole, tioconazole, thiazole, terconazole, voriconazole, ravuconazole, posaconazole, luliconazole and pharmaceutically acceptable salts thereof. 
     
     
         8 . A method of treating a skin fungal or bacterial disorder comprising topically administering to a recipient in need of such treatment an effective amount of a compound formed by the combination of di-tert-butyl-4-methylphenol (BHT) with an azole or a pharmaceutically acceptable salt of the compound. 
     
     
         9 . The method according to  claim 8 , wherein the compound is a 1:1 combination of the BHT with the azole. 
     
     
         10 . The method according to  claim 8 , wherein the azole is selected from the group consisting of ketoconazole, itraconazole, pramiconazole, miconazole, metronidazole, liarozole, rambazole, benzimidazole, benzothiazole, bifonazole, butaconazole nitrate, climbazole, clotrimazole, croconazole, eberconazole, econazole, albaconazole, elubiol, fenticonazole, fluconazole, flutimazole, isoconazole, lanoconazole, neticonazole, omoconazole, oxiconazole nitrate, sertaconazole, sulconazole, tioconazole, thiazole, terconazole, voriconazole, ravuconazole, posaconazole, luliconazole and pharmaceutically acceptable salts thereof. 
     
     
         11 . The method according to  claim 1  or  claim 8 , wherein the azole is selected from the group consisting of miconazole, rambazole, itraconazole, ketoconazole and pramiconazole. 
     
     
         12 . The method according to  claim 1  or  claim 8 , wherein the recipient is a human. 
     
     
         13 . The method according to  claim 1  or  claim 8 , wherein the skin fungal disorder is associated with  Trichophyton  spp.,  Candida  spp.,  Pityrosporum  spp. or  Malassezia  spp. 
     
     
         14 . The method according to  claim 13 , wherein the  Candida  spp. is selected from the group consisting of  Candida albicans, Candida tropicalis, Candida glabrata, Candida parapsiliosis, Candida guilliermondi, Candida lusitaniae  and  Candida krusei.    
     
     
         15 . The method according to  claim 13 , wherein the  Trichophyton  spp. is selected from the group consisting of  Trichophyton concentricum, Trichophyton interdigitale, Trichophyton megnini, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton schoenleinii, Trichophyton soudanense, Trichophyton tonsurans, Trichophyton violaceum  and  Trichophyton yaoundei.    
     
     
         16 . The method according to  claim 8 , wherein the bacterial disorder is associated with Staphylococci, Streptococci or  Propionbacterium acnes.    
     
     
         17 . The method according to  claim 1  or  claim 8 , wherein the compound is formulated as a solution, gel, cream or ointment. 
     
     
         18 . A pharmaceutical composition comprising a compound of the formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1 =—H, alkyl, —C(O)OR 6  or —S(O) n R 6 ; 
 R 2 , R 3 , R 4  and R 5  independently=—H or alkyl; 
 A=an azole; 
 R 6 =alkyl, aryl or heteroaryl; and 
 n=1 or 2, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . A pharmaceutical composition comprising a compound formed by the combination of di-tert-butyl-4-methylphenol (BHT) with an azole or a pharmaceutically acceptable salt of the compound. 
     
     
         20 . A method of delivering the pharmaceutical composition according to  claim 18  or  claim 19  for the treatment of a skin fungal or bacterial disorder to a recipient in need of such treatment comprising topically administering an effective amount of the composition to the recipient. 
     
     
         21 . The method according to  claim 20 , wherein the azole is selected from the group consisting of ketoconazole, itraconazole, pramiconazole, miconazole, metronidazole, liarozole, rambazole, benzimidazole, benzothiazole, bifonazole, butaconazole nitrate, climbazole, clotrimazole, croconazole, eberconazole, econazole, albaconazole, elubiol, fenticonazole, fluconazole, flutimazole, isoconazole, lanoconazole, neticonazole, omoconazole, oxiconazole nitrate, sertaconazole, sulconazole, tioconazole, thiazole, terconazole, voriconazole, posaconazole, ravuconazole, luliconazole and pharmaceutically acceptable salts thereof. 
     
     
         22 . The method according to  claim 21 , wherein the azole is selected from the group consisting of miconazole, itraconazole, ketoconazole and pramiconazole. 
     
     
         23 . The method according to  claim 20 , wherein the recipient is a human. 
     
     
         24 . The method according to  claim 20 , wherein the skin fungal disorder is associated with  Trichophyton  spp.,  Candida  spp.,  Pityrosporum  spp. or  Malassezia  spp. 
     
     
         25 . The method according to  claim 23 , wherein the human is suffering from candidiasis. 
     
     
         26 . A method of treating candidiasis comprising administering an effective amount of a pharmaceutical composition according to  claim 18  or  claim 19  to a human in need of such treatment. 
     
     
         27 . The pharmaceutical composition according to  claim 18  or  claim 19 , further comprising an additional therapeutic agent. 
     
     
         28 . The pharmaceutical composition according to  claim 27 , wherein the therapeutic agent is selected from the group consisting of antimicrobial agents, anti-allergic agents, anti-inflammatory agents, anti-proliferating agents, anti-acne agents, anti-pruritic agents and anti-aging agents. 
     
     
         29 . The pharmaceutical composition according to  claim 18  or  claim 19 , wherein the composition is formulated as a solution, gel, cream, ointment, tablet, capsule, an intravenous or other parenteral formulation or a muco-adhesive patch. 
     
     
         30 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1 =—H, alkyl, —C(O)R 6 , —C(O)OR 6  or —S(O) n R 6 ; 
 R 2 , R 3 , R 4  and R 5  independently=—H or alkyl; 
 A=an azole; 
 R 6 =alkyl, aryl or heteroaryl; and 
 
       n=1 or 2, 
       or a pharmaceutically acceptable salt thereof, 
       with the proviso that R 1  is not —H when R 2  and R 3  are tert-butyl, R 4  and R 5  are —H, and A is miconazole. 
     
     
         31 . The compound according to  claim 30 , wherein the azole is selected from the group consisting of ketoconazole, itraconazole, pramiconazole, metronidazole, liarozole, rambazole, benzimidazole, benzothiazole, bifonazole, butaconazole nitrate, climbazole, clotrimazole, croconazole, eberconazole, econazole, albaconazole, elubiol, fenticonazole, fluconazole, flutimazole, isoconazole, lanoconazole, neticonazole, omoconazole, oxiconazole nitrate, sertaconazole, sulconazole, tioconazole, thiazole, terconazole, voriconazole, ravuconazole, posaconazole, luliconazole and pharmaceutically acceptable salts thereof.