Antimicrobial drug synthesis and therapeutic compositions

Abstract

This invention relates to the medical use of an antimicrobial agent, racemic Ornidazole, its (R) and (S) enantiomers, or pharmaceutically acceptable salts or esters thereof, and to methods of treatment which involve treating a subject with Ornidazole. The racemic (rac)-ornidazole, its enantiomers, or pharmaceutically acceptable salts or esters thereof, may be used in combination with other actives. The invention also relates to pharmaceutical formulations and compositions comprising (rac)-ornidazole, (R)-ornidazole, (S)-ornidazole, or pharmaceutically acceptable salts or esters thereof, and/or other actives as well as methods to stereoselectively manufacture the enantiomers.

What is claimed is: 
     
         1 . A method for the treatment or prophylaxis of a disease in a human or other animal associated with a dysbiosis of a microbial microbiome with bacteria in various morphological conformations, including biofilms, wherein the disease is irritable bowel syndrome (IBS), the method comprising administering to the human or other animal in need thereof a therapeutically effective amount of (R)-ornidazole, (S)-ornidazole, a racemic mixture thereof, a pharmaceutically acceptable salt of any thereof, or an ester of any thereof. 
     
     
         2 . The method of  claim 1  wherein the irritable bowel syndrome (IBS) is selected from the group consisting of diarrhea predominant IBS (IBS-D), constipation predominant IBS (IBS-C), and alternating diarrhea and constipation predominant IBS (IBS-A). 
     
     
         3 . The method of  claim 2  wherein the irritable bowel syndrome (IBS) is diarrhea predominant IBS (IBS-D). 
     
     
         4 . The method of  claim 2  wherein the irritable bowel syndrome (IBS) is constipation predominant IBS (IBS-C). 
     
     
         5 . The method of  claim 2  wherein the irritable bowel syndrome (IBS) is alternating diarrhea and constipation predominant IBS (IBS-A). 
     
     
         6 . The method of  claim 1 , wherein the infection is caused by biofilms of one or more organisms selected from the group consisting of  Prevotella  species,  Bacteroides  species, toxigenic  Clostridium  species,  Fusobacterium  species,  Peptococcus  species,  Peptostreptococcus  species, and  Helicobacter  species. 
     
     
         7 . The method of  claim 1 , comprising the administration in combination with one or more antibiotics, the antibiotics being selected from β-lactam antibiotics, tetracycline antibiotics, penem antibiotics, quinoline antibiotics, and macrolide antibiotics. 
     
     
         8 . The method of  claim 1 , comprising the administration in combination with one or more antibiotics, the antibiotics being selected from β-lactam antibiotics, tetracycline and macrolide antibiotics. 
     
     
         9 . The method according to  claim 1  for the treatment or prophylaxis of the disease in a human. 
     
     
         10 . The method according to  claim 1  wherein at least some of the bacteria are present in an anaerobic conformation. 
     
     
         11 . The method according to  claim 1  wherein the (R)-ornidazole or the (S)-ornidazole has an enantiomeric purity selected from the group consisting of at least about 50% enantiomeric excess (ee), at least about 60% enantiomeric excess (ee), at least about 70% enantiomeric excess (ee), at least about 80% enantiomeric excess (ee), at least about 90% enantiomeric excess (ee), at least about 95% enantiomeric excess (ee), at least about 96% enantiomeric excess (ee), at least about 97% enantiomeric excess (ee), at least about 98% enantiomeric excess (ee), or at least about 99% enantiomeric excess (ee). 
     
     
         12 . The method according to  claim 1  wherein the (R)-ornidazole or the (S)-ornidazole has an enantiomeric purity of about 50% enantiomeric excess (ee) or greater. 
     
     
         13 . The method of  claim 2 , wherein the infection is caused by biofilms of one or more organisms selected from the group consisting of  Prevotella  species,  Bacteroides  species, toxigenic  Clostridium  species,  Fusobacterium  species,  Peptococcus  species,  Peptostreptococcus  species, and  Helicobacter  species. 
     
     
         14 . The method of  claim 2 , comprising the administration in combination with one or more antibiotics, the antibiotics being selected from β-lactam antibiotics, tetracycline antibiotics, penem antibiotics, quinoline antibiotics, and macrolide antibiotics. 
     
     
         15 . The method of  claim 2 , comprising the administration in combination with one or more antibiotics, the antibiotics being selected from β-lactam antibiotics, tetracycline and macrolide antibiotics. 
     
     
         16 . The method according to  claim 2  for the treatment or prophylaxis of the disease in a human. 
     
     
         17 . The method according to  claim 2  wherein at least some of the bacteria are present in an anaerobic conformation. 
     
     
         18 . The method according to  claim 2  wherein the (R)-ornidazole or the (S)-ornidazole has an enantiomeric purity selected from the group consisting of at least about 50% enantiomeric excess (ee), at least about 60% enantiomeric excess (ee), at least about 70% enantiomeric excess (ee), at least about 80% enantiomeric excess (ee), at least about 90% enantiomeric excess (ee), at least about 95% enantiomeric excess (ee), at least about 96% enantiomeric excess (ee), at least about 97% enantiomeric excess (ee), at least about 98% enantiomeric excess (ee), or at least about 99% enantiomeric excess (ee). 
     
     
         19 . The method according to  claim 2  wherein the (R)-ornidazole or the (S)-ornidazole has an enantiomeric purity of about 50% enantiomeric excess (ee) or greater.