Halogenated Rhodamine Derivatives and Applications Thereof

Abstract

Compounds of formula I: in which one of R1, R2, R3, R4 and (R10)n represents halogen and each of the remaining R1, R2, R3, R4 and R10 groups is independently selected from hydrogen, halogen, amino, acylamino, dialkylamino, cycloalkylamino, azacycloalkyl, alkylcycloalkylamino, aroylamino, diarylamino, arylalkylamino, aralkylamino, alkylaralkylamino, arylaralkylamino, hydroxyl, alkoxy, aryloxy, aralkyloxy, mercapto, alkylthio, arylthio, aralkylthio, carboxyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, hydroxysulfonyl, amidosulfonyl, dialkylamidosulfonyl, arylalkylamido-sulfonyl, formyl, acyl, aroyl, alkyl, alkylene, alkenyl, aryl, aralkyl, vinyl, alkynyl and corresponding substituted groups; m=0-1; n=1-4; A is nil, O or NH; R9 is alkylene, Z is H, amino, dialkylamino or trialkylamino salt; X is an anion; and R5, R6, R7 and R8 are independently selected from H and C 1-6 alkyl, or R1 with R5 or R6, or R2 with R5 or R6, or R3 with R7 or R8 represents alkylene, optionally in association with a pharmaceutically acceptable carrier, which are useful as intermediates, and as bacteriocides, antiviral agents or in treating immunological disorders.

1 . A rhodamine compound selected from the group consisting of:
 2′-(6-dimethylamino-3-dimethylimino-3H-xanthen-9-yl) 4′,5′-dichloro-benzoic acid methyl ester hydrochloride;   4,5-dibromorhodamine 110 2-(2-methoxy ethoxy)ethyl ester hydrobromide;   acetate salt of 2,7-dibromorhodamine B hexyl ester;   acetate salt of 2,7-dibromorhodamine B methyl ester;   4,5-dibromorhodamine 6G hydrobromide;   rhodamine B 3-bromopropyl;   acetate salt of 2,7-dibromo-4′-carboxytetramethylrosamine methyl ester;   4-bromo-5-phenyl rhodamine B methyl ester chloride;   2,7-dibromo-4,5-dimethyl rhodamine B methyl ester bromide;   2-bromo-7-ethynyl rhodamine B methyl ester bromide; and   4,5-dibromo-2,7-di-n-butyl rhodamine B methyl ester bromide.   
   
   
       2 . A pharmaceutical composition comprising a rhodamine compound as claimed in  claim 1 , and a pharmaceutically acceptable carrier. 
   
   
       3 . A method of treating an infection generated by Gram positive and/or by Gram negative bacteria in a subject, said method comprising administering to said subject an effective antibacterial amount of at least one rhodamine compound or salt thereof as defined in  claim 1 . 
   
   
       4 . A method as claimed in  claim 3 , wherein said infection is generated by  Staphylococcus epidermitis.    
   
   
       5 . A method as claimed in  claim 3 , wherein said rhodamine compound is administered in combination with a pharmaceutically acceptable carrier. 
   
   
       6 . A method as claimed in  claim 5 , wherein said pharmaceutically acceptable carrier is selected from the group consisting of 5% mannitol in water and DMSO. 
   
   
       7 . A method of inhibiting bacterial growth, said method comprising administering a bacteriostatic amount of a rhodamine compound as claimed in  claim 1 . 
   
   
       8 . A method as claimed in  claim 7 , for inhibiting bacterial growth of  Escherichia coli  0157:H7 or  Salmonella thyphimurium  LT2 or both, wherein said rhodamine compound is 4,5-dibromo rhodamine 110 2-(2-methoxy ethoxy)ethyl ester. 
   
   
       9 . A method as claimed in  claim 7 , for inhibiting bacterial growth of  Salmonella thyphimurium  LT2, wherein said rhodamine compound is an acetate salt of 2,7-dibromorhodamine B hexyl ester. 
   
   
       10 . A method as claimed in  claim 7 , for inhibiting bacterial growth of  Escherichia coli  0157:H7, wherein said rhodamine compound is 4,5-dibromorhodamine 6G hydrobromide. 
   
   
       11 . A method as claimed in  claim 7 , for inhibiting bacterial growth of  Escherichia coli  0157TH7, wherein said compound is rhodamine B 3-bromopropyl ester. 
   
   
       12 . A method as claimed in claimed in  claim 7 , for inhibiting bacterial growth of at least one bacterium selected from the group consisting of  Escherichia coli  0157TH7,  Salmonella thyphimurium  LT2, and  Pseudomonas aeruginosa , wherein said rhodamine compound is 4,5-dibromorhodamine methyl ester. 
   
   
       13 . A method for treating a liquid contaminated with Gram positive or Gram negative bacteria or both, said method comprising adding to said liquid an effective antibacterial amount of a rhodamine compound or salt thereof as claimed in  claim 1 . 
   
   
       14 . A method as claimed in  claim 13 , wherein said rhodamine compound is administered in combination with a pharmaceutically acceptable carrier. 
   
   
       15 . An intermediate selected from the group consisting of 4,5-dibromo rhodamine B lactone; and 2,7-dibromo rhodamine B lactone.