Benzoquinolizine-2-carboxylic acid arginine salt tetrahydrate

Abstract

The invention relates to crystalline S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt tetrahydrate, a process for its preparation and pharmaceutical formulations incorporating it as the active ingredient for use in treating microbial infections.

1 - 11 . (canceled)  
   
   
       12 . A composition comprising S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt tetrahydrate of the formula I  
     
       
         
         
             
             
         
       
     
     and a carrier or excipient.  
   
   
       13 . A composition comprising S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt tetrahydrate having the following X-ray powder diffraction data: (2θ): 4.86±0.2, 14.10±0.2, 14.90±0.2, 19.35±0.2, 22.20±0.2, 23.04±0.2, 23.54±0.2, 28.44±0.2, 39.44±0.2 and a carrier or excipient.  
   
   
       14 . A composition comprising S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt tetrahydrate having the following X-ray powder diffraction data: (2θ): 4.86±0.2, 14.10±0.2, 14.90±0.2, 19.35±0.2, 22.20±0.2, 23.04±0.2, 23.54±0.2, 28.44±0.2, 39.44±0.2; a DSC exotherm at 194.93° C. (onset at 189.42° C.) and one endotherm at 87.83° C., 144.03° C. and 251.26° C. and a water content of between 11.0 to 12.5% by weight as determined by titration according to Karl Fischer and a carrier or excipient.  
   
   
       15 . A method for treating a disease caused by a microbial infection in a mammal comprising administering an effective amount of S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt tetrahydrate of the formula I  
     
       
         
         
             
             
         
       
     
     to the mammal in need thereof.  
   
   
       16 . A method for treating a disease caused by a microbial infection in a mammal comprising administering an effective amount of S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt tetrahydrate having the following X-ray powder diffraction data: (2θ): 4.86±0.2, 14.10±0.2, 14.90±0.2, 19.35±0.2, 22.20±0.2, 23.04±0.2, 23.54±0.2, 28.44±0.2, 39.44±0.2 to the mammal in need thereof.  
   
   
       17 . A method for treating a disease caused by a microbial infection in a mammal comprising administering an effective amount of S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt tetrahydrate having the following X-ray powder diffraction data: (2θ): 4.86±0.2, 14.10±0.2, 14.90±0.2, 19.35±0.2, 22.20±0.2, 23.04±0.2, 23.54±0.2, 28.44±0.2, 39.44±0.2; a DSC exotherm at 194.93° C. (onset at 189.42° C.) and one endotherm at 87.83° C., 144.03° C. and 251.26° C. and a water content of between 11.0 to 12.5% by weight as determined by titration according to Karl Fischer to the mammal in need thereof.  
   
   
       18 . A method for preventing a disease caused by a microbial infection in a mammal comprising administering an effective amount of S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt tetrahydrate of the formula I  
     
       
         
         
             
             
         
       
     
     to the mammal at risk of being infected.  
   
   
       19 . A method for preventing a disease caused by a microbial infection in a mammal comprising administering an effective amount of S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt tetrahydrate having the following X-ray powder diffraction data: (2θ): 4.86±0.2, 14.10±0.2, 14.90±0.2, 19.35±0.2, 22.20±0.2, 23.04±0.2, 23.54±0.2, 28.44±0.2, 39.44±0.2 to the mammal at risk of being infected.  
   
   
       20 . A method for preventing a disease caused by a microbial infection in a mammal comprising administering an effective amount of S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt tetrahydrate having the following X-ray powder diffraction data: (2θ): 4.86±0.2, 14.10±0.2, 14.90±0.2, 19.35±0.2, 22.20±0.2, 23.04±0.2, 23.54±0.2, 28.44±0.2, 39.44±0.2; a DSC exotherm at 194.93° C. (onset at 189.42° C.) and one endotherm at 87.83° C., 144.03° C. and 251.26° C. and a water content of between 11.0 to 12.5% by weight as determined by titration according to Karl Fischer to the mammal at risk of being infected.  
   
   
       21 . A method for treating a bacterial infection in a mammal comprising administering an effective amount of S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt tetrahydrate of the formula I  
     
       
         
         
             
             
         
       
     
     to the mammal in need thereof.  
   
   
       22 . A method for treating a bacterial infection in a mammal comprising administering an effective amount of S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt tetrahydrate having the following X-ray powder diffraction data: (2θ): 4.86±0.2, 14.10±0.2, 14.90±0.2, 19.35±0.2, 22.20±0.2, 23.04±0.2, 23.54±0.2, 28.44±0.2, 39.44±0.2 to the mammal in need thereof.  
   
   
       23 . A method for treating a bacterial infection in a mammal comprising administering an effective amount of S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt tetrahydrate having the following X-ray powder diffraction data: (2θ): 4.86±0.2, 14.10±0.2, 14.90±0.2, 19.35±0.2, 22.20±0.2, 23.04±0.2, 23.54±0.2, 28.44±0.2, 39.44±0.2; a DSC exotherm at 194.93° C. (onset at 189.42° C.) and one endotherm at 87.83° C., 144.03° C. and 251.26° C. and a water content of between 11.0 to 12.5% by weight as determined by titration according to Karl Fischer to the mammal in need thereof.  
   
   
       24 . The method according to  claim 15 , wherein the disease is impetigo, pneumonia, bronchitis, pharyngitis, endocarditis, urinary tract infection, gastro-intestinal infection or bacteremia.  
   
   
       25 . The method according to  claim 16 , wherein the disease is impetigo, pneumonia, bronchitis, pharyngitis, endocarditis, urinary tract infection, gastro-intestinal infection or bacteremia.  
   
   
       26 . The method according to  claim 17 , wherein the disease is impetigo, pneumonia, bronchitis, pharyngitis, endocarditis, urinary tract infection, gastro-intestinal infection or bacteremia.  
   
   
       27 . The method according to  claim 15 , wherein the disease is caused by bacteria selected from the group consisting of  Staphylococcus aureus,  coagulase negative  Staphylococci,  methicillin-resistant  Staphylococcus aureus,  methicillin-resistant coagulase negative  Staphylococci, Enterococci,  beta-haemolytic  Streptococci,  viridans group of Streptococci, multi-drug resistant  M. Tuberculosis, M. intracellulare, M. avium, Chryseobacterium meningosepticum, Chryseobacterium indologense, E.coli, Klebsiella, Proteus, Serratia, Citrobacter,  and  Pseudomonas.    
   
   
       28 . The method according to  claim 16 , wherein the disease is caused by bacteria selected from the group consisting of  Staphylococcus aureus,  coagulase negative  Staphylococci,  methicillin-resistant  Staphylococcus aureus,  methicillin-resistant coagulase negative  Staphylococci, Enterococci,  beta-haemolytic  Streptococci,  viridans group of  Streptococci,  multi-drug resistant  M. Tuberculosis, M. intracellulare, M. avium, Chryseobacterium meningosepticum, Chryseobacterium indologense, E.coli, Klebsiella, Proteus, Serratia, Citrobacter,  and  Pseudomonas.    
   
   
       29 . The method according to  claim 17 , wherein the disease is caused by bacteria selected from the group consisting of  Staphylococcus aureus,  coagulase negative  Staphylococci,  methicillin-resistant  Staphylococcus aureus,  methicillin-resistant coagulase negative  Staphylococci, Enterococci,  beta-haemolytic  Streptococci,  viridans group of  Streptococci,  multi-drug resistant  M. Tuberculosis, M. intracellulare, M. avium, Chryseobacterium meningosepticum, Chryseobacterium indologense, E.coli, Klebsiella, Proteus, Serratia, Citrobacter,  and  Pseudomonas.    
   
   
       30 . The method according to  claim 21 , wherein the infection is caused by bacteria selected from the group consisting of  Staphylococcus aureus,  coagulase negative  Staphylococci,  methicillin-resistant  Staphylococcus aureus,  methicillin-resistant coagulase negative  Staphylococci, Enterococci,  beta-haemolytic  Streptococci,  viridans group of  Streptococci,  multi-drug resistant  M. Tuberculosis, M. intracellulare, M. avium, Chryseobacterium meningosepticum, Chryseobacterium indologense, E. coli, Klebsiella, Proteus, Serratia, Citrobacter,  and  Pseudomonas.    
   
   
       31 . The method according to  claim 22 , wherein the infection is caused by bacteria selected from the group consisting of  Staphylococcus aureus,  coagulase negative  Staphylococci,  methicillin-resistant  Staphylococcus aureus,  methicillin-resistant coagulase negative  Staphylococci, Enterococci,  beta-haemolytic  Streptococci,  viridans group of  Streptococci,  multi-drug resistant  M. Tuberculosis, M. intracellulare, M. aviurn, Chryseobacterium meningosepticum, Chryseobacterium indologense, E. coli, Klebsiella, Proteus, Serratia, Citrobacter,  and  Pseudomonas.    
   
   
       32 . The method according to  claim 23 , wherein the infection is caused by bacteria selected from the group consisting of  Staphylococcus aureus,  coagulase negative  Staphylococci,  methicillin-resistant  Staphylococcus aureus,  methicillin-resistant coagulase negative  Staphylococci, Enterococci,  beta-haemolytic  Streptococci,  viridans group of  Streptococci,  multi-drug resistant  M. Tuberculosis, M. intracellulare, M. avium, Chryseobacterium meningosepticum, Chryseobacterium indologense, E. coli, Klebsiella, Proteus, Serratia, Citrobacter,  and  Pseudomonas.    
   
   
       33 . A composition according to  claim 12 , which is a solid composition.  
   
   
       34 . A method for treating a bacterial infection in a mammal comprising administering an effective amount of a composition according to  claim 33  to the mammal in need thereof.  
   
   
       35 . A method for treating a disease caused by a bacterial infection in a mammal comprising administering an effective amount of a composition according to  claim 33  to the mammal in need thereof.  
   
   
       36 . The method according to  claim 35 , wherein the disease is impetigo, pneumonia, bronchitis, pharyngitis, endocarditis, urinary tract infection, gastro-intestinal infection or bacteremia.  
   
   
       37 . The method according to  claim 35 , wherein the disease is caused by bacteria selected from the group consisting of  Staphylococcus aureus,  coagulase negative  Staphylococci,  methicillin-resistant  Staphylococcus aureus,  methicillin-resistant coagulase negative  Staphylococci, Enterococci,  beta-haemolytic  Streptococci,  viridans group of  Streptococci,  multi-drug resistant  M. Tuberculosis, M. intracellulare, M. avium, Chryseobacterium meningosepticum, Chryseobacterium indologense, E. coli, Klebsiella, Proteus, Serratia, Citrobacter,  and  Pseudomonas.    
   
   
       38 . The method according to  claim 34 , wherein the infection is caused by bacteria selected from the group consisting of  Staphylococcus aureus,  coagulase negative  Staphylococci,  methicillin-resistant  Staphylococcus aureus,  methicillin-resistant coagulase negative  Staphylococci, Enterococci,  beta-haemolytic  Streptococci,  viridans group of  Streptococci,  multi-drug resistant  M. Tuberculosis, M. intracellulare, M. avium, Chryseobacterium meningosepticum, Chryseobacterium indologense, E. coli, Klebsiella, Proteus, Serratia, Citrobacter,  and  Pseudomonas .