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 . (R)-ornidazole and (S)-ornidazole and the racemic mixture of (R)-ornidazole and (S)-ornidazole [rac-ornidazole], or pharmaceutically acceptable salts thereof, for use in the treatment or prophylaxis of disease associated with a dysbiosis of a microbial microbiome with bacteria, protozoa, and fungi in various morphological conformations, including biofilms, wherein the disease is selected from the group consisting of: Gastrointestinal tract disease, skin and soft tissue diseases and infections, Lyme Disease, Glanders and Melioidosis infections, Q-fever infections, systemic & cardiovascular infections, bone & joint infections, central nervous system (CNS) infections & conditions, upper and lower respiratory infections, skin contact/venereal sexually transmitted diseases (STDs), gynecological & genito-urinary/reproductive tract infections and conditions, and dental/periodontal infections. 
     
     
         2 . The compounds for use in  claim 1 , wherein the gastrointestinal tract disease is selected from the group consisting of psuedomembranous colitis,  C. difficile  infection caused by toxigenic strains,  C. difficile  associated diarrhea caused by toxigenic strains, gastroenteritis, chronic gastritis, cholangitis, cholecystitis, pancreatitis, peritonitis, intra-abdominal/bowel/pelvic/liver abscess, Crohn's disease, ulcerative colitis, colo-rectal cancer, gastric cancer, complicated and uncomplicated diverticulitis, and irritable bowel syndrome. 
     
     
         3 . The compounds for use of  claim 1 , wherein the gastrointestinal tract disease is psuedomembranous colitis,  C. difficile  infection caused by toxigenic strains, or  C. difficile  associated diarrhea caused by biofilms and planktonic forms of toxigenic strains. 
     
     
         4 . The compounds for use of  claim 1 , wherein the disease is Crohn's disease, ulcerative colitis, chronic gastritis, gastroenteritis, or irritable bowel disease. 
     
     
         5 . The compounds for use of  claim 1 , wherein the disease is colo-rectal cancer or gastric cancer. 
     
     
         6 . The compounds for use of  claim 1 , wherein the disease is complicated or uncomplicated diverticulitis. 
     
     
         7 . The compounds for use of  claim 1 , wherein the disease is cholangitis, cholecystitis, pancreatitis, peritonitis, or abdominal/intra-abdominal/bowel/pelvic/liver abscess/infections, and irritable bowel syndrome. 
     
     
         8 . The compounds for use of any of  claims 1  to  7 , 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. 
     
     
         9 . The compounds for use of  claim 1 , wherein the bacterial infection is or gives rise to a dermatological condition. 
     
     
         10 . The compounds for use of  claim 1 , wherein the dermatological condition is selected from: rosacea, cellulitis, wound infections (e.g. gangrene), boils, cysts, abscesses, fungating tumors, burns, and decubitus ulcers (bed sores). 
     
     
         11 . The compounds for use of  claim 1 , wherein the dermatological condition is rosacea, for example rosacea associated with  Bacillus oleronius.    
     
     
         12 . The compounds for use of any one of  claims 9  to  11 , wherein the Ornidazole compound is for topical administration. 
     
     
         13 . The compounds for use of  claim 1 , wherein the use in the treatment of Lyme Disease. 
     
     
         14 . The compounds for use of  claim 13 , wherein the Lyme Disease is caused by  Borrelia  spirochetes and at least some of the  Borrelia  spirochetes are present in a biofilm or in a cystic or round hard body form. 
     
     
         15 . The compounds for use of  claims 13 - 14 , wherein the use is for combination with one or more antibiotics, the antibiotics being selected from β-lactam antibiotics, tetracycline antibiotics and macrolide antibiotics. 
     
     
         16 . The compounds for use of  claim 1 , wherein the use is in the treatment of Glanders and Melioidosis infections. 
     
     
         17 . The compound for use of  claim 16 , wherein the Glanders and Melioidosis infections are caused by biofilms of  Burkholderia mallei  or Burholderia  pseudomallei  and at least some of the bacteria are present in an aneroebic configuration. 
     
     
         18 . The compound for use of  claims 16 - 17 , wherein the Ornidazole compounds are for use in combination with one or more antibiotics, the antibiotics being selected from β-lactam antibiotics, tetracycline antibiotics, penem antibiotics, quinolone antibiotics and macrolide antibiotics. 
     
     
         19 . The compounds for use of  claim 1 , wherein the use is in the treatment of Q fever infections. 
     
     
         20 . The compounds for use of  claim 19 , wherein the Q fever infection is caused by  Coxiella burnetii , a bacterium that affects humans and other animals, and at least some of the bacteria are a spore-like small cell variant, and are obligate intracellular pathogens. 
     
     
         21 . The compounds for use of  claims 19 - 20 , wherein the use is in combination with one or more antibiotics, the antibiotics being selected from β-lactam antibiotics, tetracycline antibiotics, penem antibiotics, quinolone antibiotics and macrolide antibiotics. 
     
     
         22 . The compounds for use of  claim 1 , wherein the use in the treatment of a bacterial infection and related conditions selected from the group consisting of systemic and cardiovascular infections, bone and joint infections, CNS infections, upper and lower respiratory infections and lung infections. 
     
     
         23 . The compounds for use of  claim 22 , wherein the infection is selected from: septicemia, septic shock, bacteremia, endocarditis, indwelling catheter or device infections, osteomyelitis, joint infection, septic arthritis, meningitis, encephalitis, autism, brain abscess, sinusitis, tonsillitis, lung abscess, emphysema, pneumonia (including noscomial, aspiration and community acquired pneumonia), bronchitis, and Lemmiere's Syndrome. 
     
     
         24 . The compounds for use of any of  claims 22  to  23 , wherein the infection is caused by one or more organisms selected from the group consisting of biofilms of  Prevotella  species,  Bacteroides  species,  Peptococcus  species,  Peptostreptococcus  species,  Clostridium , and  Fusobacterium  species. 
     
     
         25 . The compounds for use of  claim 1 , wherein the use is for treatment or prophylaxis/reduction in incidence of a skin contact or venereal/sexually transmitted disease, wherein the disease is selected from the group consisting of syphilis, yaws, and protozoal & bacterial urethritis. 
     
     
         26 . The compounds for use of  claim 25 , wherein the disease is syphilis. 
     
     
         27 . The compounds for use of  claim 25 , wherein the disease is yaws. 
     
     
         28 . The compounds for use of  claim 25 , wherein the disease is bacterial urethritis or trichomonal urethritis. 
     
     
         29 . The compounds for use of  claim 25 , wherein one of the diseases specified cause venerial infection resulting in premature rupture of membrane in pregnancy and preterm labor (PRM/PTL). 
     
     
         30 . The compounds for use of any of  claims 25  to  29 , wherein the infection is caused by one or more organisms selected from the group consisting of biofilms of the spirochete bacterium  Treponema pallidum , subspecies  pallidum  and subspecies  pertenue, Prevotella  species,  Bacteroides  species,  Peptococcus  species,  Peptostreptococcus  species,  Gardnerella vaginalis, Mobiluncus curtisii, Atopobium vaginae , and  Clostridium  species. 
     
     
         31 . The compounds for use of  claim 1 , wherein the use is for the treatment of a gynecological or genitourinary bacterial infection selected from: prostatitis, urosepsis, urinary tract infections, pelvic inflammatory disease (PID), endometritis, endomyometritis, tubo-ovarian abscess, gynecological infection resulting in premature rupture of membrane in pregnancy/preterm labor (PRM/PTL), and postsurgical vaginal cuff infection. 
     
     
         32 . The compounds for use of  claim 31 , wherein the gynecological infection is selected from endometritis, endomyometritis, tubo-ovarian abscess, gynecological infection resulting in premature rupture of membrane in pregnancy (PRM/PTL), and postsurgical vaginal cuff infection. 
     
     
         33 . The compounds for use of  claim 31 , wherein the gynecological or genitourinary infection is caused, at least in part, by an organism selected from biofilms of  Gardnerella vaginalis, Mobiluncus curtisii, Prevotella species, Bacteroides  species,  Atopobium vaginae, Peptococcus  species,  Peptostreptococcus  species, and  Clostridium  species. 
     
     
         34 . The compounds for use of any of  claims 31  to  33 , wherein the genitourinary infection is bacterial urethritis and the use is in the treatment of both women and men who are the sexual partners of women suffering from multibacterial species infections like bacterial Vaginosis and bacterial urethritis. 
     
     
         35 . The compounds for use of  claim 34 , wherein the gynecological, genitourinary or vaginal infection is selected from bacterial vaginosis, vulvovaginitis, vaginal candidiasis (yeast infections), trichomoniasis, endometritis, endomyometritis, tubo-ovarian abscess and pelvic inflammatory disease (PID). 
     
     
         36 . The compounds for use of  claims 31  or  35 , wherein the gynecological or genitourinary infection is caused, at least in part, by an organism selected from biofilms of  Gardnerella vaginalis, Mobiluncus curtisii, Prevotella species, Bacteroides  species,  Atopobium vaginae, Peptococcus  species,  Peptostreptococcus  species, and  Clostridium  species. 
     
     
         37 . The compounds for use of  claim 1 , wherein the use is for the treatment of an odontogenic, dental and periodontal bacterial infection. 
     
     
         38 . The compounds for use of  claim 37 , wherein the infection is selected from: dental carries, peri-apical abscess, periodontal abscess, and acute peri-coronitis of impacted or partially erupted teeth. 
     
     
         39 . The compounds for use of  claims 37  to  38 , wherein the infection is caused by one or more organisms selected from the group consisting of biofilms of:  Bacteroides fragilis, Fusobacterium species, Peptostreptococcus species, Prevotella species, Porphyromonas species , and  Actinomyces  species. 
     
     
         40 . The compounds for use of any of  claims 37  to  39 , wherein the compounds are for systemic administration. 
     
     
         41 . (R)-ornidazole and (S)-ornidazole and the racemic mixture of (R)-ornidazole and (S)-ornidazole [rac-ornidazole], or pharmaceutically acceptable salts thereof, for use in the treatment or prophylaxis of a disease, wherein the disease is or is caused by a protozoal infection. 
     
     
         42 . The compounds for use of  claim 41 , wherein the protozoal infection is selected from trichmoniasis, giardiasis and amoebiasis. 
     
     
         43 . A method of stereoselectively manufacturing (R)-ornidazole and (S)-ornidazole; the method comprising reacting 2-methyl-4(5)-nitroimidazole with (S)-propylene oxide. 
     
     
         44 . The method of  claim 43 , wherein the reaction is performed in the presence of a Lewis acid. 
     
     
         45 . The method of  claim 44 , wherein the Lewis acid is ZnCl 2 .