Antibacterial optically pure benzoquinolizine carboxylic acids, processes, compositions and methods of treatment

Abstract

The present invention relates to optically pure S-(−)-benzoquinolizine carboxylic acids, their derivatives, salts, pseudopolymorphs, polymorphs and hydrates thereof, substantially free of their R-(+)-isomers, to processes for preparation of the optically pure S-(−)-benzoquinolizine carboxylic acids, their derivatives, salts, pseudopolymorphs, polymorphs and hydrates thereof substantially free of their R-(+)-isomers, and to pharmaceutical compositions comprising the S(−)-benzoquinolizine carboxylic acids, their derivatives, salts, pseudopolymorphs, polymorphs and hydrates thereof.

1 . A S-(−)-optically pure benzoquinolizine carboxylic acid, its derivatives, its pharmaceutically acceptable salts, derivatives, pseudopolymorphs, polymorphs or hydrates thereof of formula I,  
       
         
           
           
               
               
           
         
       
       wherein 
 X is OR 1 , wherein R 1  is hydrogen, a pharmaceutically acceptable cation, aluminum, ammonium or substituted ammonium salts, choline, an organic amine, a heterocyclic amine or, a basic amino acid;  
 or R 1  is C 1 -C 6  alkyl;  
 or R 1  is —(CH 2 )n-CHR 4 —OOCR 5 , wherein R 4 =H, or CH 3 ; n=0-3 and R 5 =C 2 H 5 , or C(CH 3 ) 3 ;  
 or R 1  is  
                     
 wherein A=CH or N, and when A=CH, Z=NH or NCH 3 , and when A=N, Z=CH, O, N, S, or NCH 3 ; p=0-2; and q=0-2;  
 X is NHR 2 , wherein R 2  is hydrogen or NHR 2  is the residue of one of the 20 naturally occurring amino acids or the optically active isomers thereof, or the racemic mixtures thereof;  
 y denotes an integer from 0 to 3 and any fractional numbers therein depending on the moles of acid added to the basic molecule;  
 z denotes moles of water;  
 HA represents an acid of an acid addition salt;  
 R 3  is hydrogen, C 1 -C 6  alkyl, glycosyl, aralkyl, C 1 -C 6  alkanoyl, or aminoalkanoyl  
 or R 3  is an ester of gluconic acid, a phosphoric acid derivative, or a sulphuric acid derivative;  
 substantially free of their R-(+)-isomers.  
 
     
     
         2 . The compound of  claim 1  wherein the pharmaceutically acceptable cation is selected from lithium, sodium, potassium, magnesium or calcium.  
     
     
         3 . The compound of formula I as defined in  claim 1  wherein the basic amino acid is an optically pure or mixture of racemic isomers of arginine, lysine, histidine or tryptophan.  
     
     
         4 . The compound of formula I as defined in  claim 1  wherein z is O, 0.2, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, or 3.  
     
     
         5 . A compound of formula I as defined in  claim 1  selected from 
 S-(−)-9-fluoro-6,7,-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;    S-(−)-9-fluoro-6,7,-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid 0.2H 2 O;    S-(−)-9-fluoro-6,7,-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid 0.5H 2 O;    S-(−)-9-fluoro-6,7,-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid 0.75 H 2 O;    S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid sodium salt;    S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, sodium salt monohydrate;    S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, potassium salt monohydrate;    S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, arginine salt;    S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, arginine salt 0.25H 2 O;    S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, arginine salt.0.75H 2 O;    S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, lysine salt monohydrate;    S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, histidine salt 0.2H 2 O;    S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, hydroxyethyl pyrrolidine salt;    S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, diethanolamine salt;    S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, choline salt and its hydrates;    Carboxymethyl S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate sodium salt;    Acetoxymethyl S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate;    Propionoxymethyl S-(−)-9-fluoro-6,7-dihydro-8(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate;    Pivaloyloxymethyl S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate;    Pivaloyloxyethyl S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate;    N-methylpiperidin-4-yl S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxy piperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate;    Pyrrolidin-2-yl-ethyl S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxy piperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate;    Piperidin-2-yl-ethyl S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate;    Morpholin-2-yl-ethyl S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxy piperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylate;    9-fluoro-8(4-hydroxypiperidin-1-yl)-(5S)-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-[2(S)-amino-1,5-pentanedioic acid]carboxamide, disodium salt;    9-fluoro-8-{4-hydroxypiperidin-1-yl}-5(S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-[2(S)-amino-3-imidazolylpropionic acid]carboxamide hydrochloride;    S-(−)-9-fluoro-6,7-dihydro-8-(4-methoxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;    S-(−)-9-fluoro-6,7-dihydro-8-(4-[(β-D-tetraacetylglucopyranosyl)oxy]-piperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;    S-(−)-9-fluoro-6,7-dihydro-8-(4-[(β-D-glucopyranosyl)oxy]-piperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid; 
 S-(−)-9-fluoro-6,7-dihydro-8-(4-acetoxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;  
   S-(−)-9-fluoro-6,7-dihydro-8-(4-pivaloyloxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;    S-(−)-9-fluoro-8-[4-(phosphonoxy)-1-piperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;    8-{4-[2(S)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;    8-{4-[2(S)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, hydrochloride;    8-{4-[2(R)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;    8-{4-[2(R)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, acetate;    8-{4-[2(RS)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;    8-{4-[(2S)-amino-propionyl-2S)-aminopropionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid hydrochloride;    8-{4[(2R)-Amino-propionoyl-(2R)-aminopropionyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;    8-{4[(2R)-Amino-propionoyl-(2R)-aminopropionyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid hydrochloride;    8-{4[(2R)-Amino-propionoyl-(2R)-aminopropionyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid acetate;    8-{4[(2S)-Methylamino-propionyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;    8-{4-[(2S)-Methylamino-propionyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and hydrochloride;    8-{4[2(S)-amino-3-carboxypropionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid hydrochloride;    8-{4[2(S)-amino-3-phenylpropionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid hydrochloride;    8-{4[2(R)-amino-3-phenylpropionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid hydrochloride;    8-{4[2(R)-amino-3-phenylpropionyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid acetate;    8-{4[(2S)-Amino-3-methylbutanoyloxy]piperidin-1-yl}-9-fluoro-5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;    8-{4[(2S)-Amino-3-methylbutanoyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and hydrochloride;    8-{4-[2(S)-Amino-4-methylpentanoyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;    8-{4-[2(S)-Amino-4-methylpentanoyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, hydrochloride;    8-{4[(2R)-Amino-4-methylpentanoyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid:    8-{4[(2R)-Amino-4-methylpentanoyloxy]piperidin-1-yl}-9-fluoro-5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and hydrochloride;    8-{4-[2(S),6-Diaminohexanoyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;    8-{4-[2(S),6-Diaminohexanoyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, dihydrochloride;    8-{4[(2S)-Amino-5-nitroguanidino-butanoyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;    8-{4[(2S)-Amino-5-nitroguanidino-butanoyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and hydrochloride;    8-{4[(2S)-Amino-5-guanidino-butanoyloxy]piperidin-1-yl}-9-fluoro-5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;    8-{4[(2S)-Amino-5-guanidino-butanoyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and hydrochloride;    8-{4[(2S)-Amino-5-nitroguanidino-butanoyl(2S)-amino-5-nitroguanidino-butanoyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;    8-(4[(2S)-Amino-5-nitroguanidino-butanoyl-(2S)-amino-5-nitroguanidino-butanoyloxy]piperidin-1-yl)-9-fluoro-5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and hydrochloride;    8-{4[(2S)-Amino-5-guanidino-butanoyl-(2S)-amino-5-guanidino-butanoyloxy]piperidin-1-yl}-9-fluoro-5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2 carboxylic acid or    8-{4[(2S)-Amino-5-guanidino-butanoyl-(2S)-amino-5-guanidino-butanoyloxy]piperidin-1-yl}-9-fluoro-(5S)-methyl-6,7dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and hydrochloride.    
     
     
         6 . A compound of  claim 5  selected from 
 S-(−)-9-fluoro-6,7-dihydro-8(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid 0.2 hydrate;    S-(−)-9-fluoro-6,7-dihydro-8(-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid sodium salt monohydrate;    8-{4-[2(R)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, acetate;    8-{4-[2(S)-Amino-propionyloxy]piperidin-1-yl}-9-fluoro-5(S)-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, hydrochloride;    S-(−)-9-fluoro-6,7-dihydro-8-[4-(hydroxy)-1-piperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt;    S-(−)-9-fluoro-6,7-dihydro-8-[4-(hydroxy)-1-piperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt 0.25H 2 0; or    S-(−)-9-fluoro-6,7-dihydro-8-[4-(hydroxy)-1-piperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt 0.75H 2 0.    
     
     
         7 . S-(−)-9-fluoro-6,7-dihydro-8(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid.0.2H 2 O, wherein the moisture content varies from 0.9% to 1.1%  
     
     
         8 . A process for the preparation of S(−)-9-Fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid.0.2H 2 O which comprises dissolving S(−)-9-Fluoro-8-(4-hydroxypiperidin-1-yl)-S-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid in a minimum volume of organic solvent, at an elevated temperature, adding an amount of water sufficient to bring about crystallisation after cooling in high yields, filtering and drying the separated crystals at temperatures up to 40-50° C. for 3-6 hours, in vacuo up to 50 mm of Hg to a constant weight.  
     
     
         9 . A process for the preparation of S(−)-9-fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid 0.5 hydrate which comprises dissolving S-(−)-9-fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid in an minimum volume of organic solvent at reflux temperature, adding an amount of water at ambient temperature, sufficient to bring about crystallisation after cooling in high yields, filtering and drying the separated crystals at temperatures up to <40° C. for 3-6 hours.  
     
     
         10 . A process for the preparation of S(−)-9-fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid 0.75 hydrate which comprises suspending S-(−)-9-fluoro-8(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid in water, for formulating into a slurry by stirring with an organic solvent, at 5° C. for 1-2 hours, filtering and drying the product at temperatures <40° C. for 3-6 hours.  
     
     
         11 . A method for treating bacterial infections, mycobacterial infections or nosocomial pathogen infections in humans and animals, which comprises administering to a human or an animal in need of such antiinfective therapy an amount of a compound of the formula I as defined in  claim 1 , or a pharmaceutically acceptable salt, derivative, hydrate, pseudopolymorph or polymorph thereof, substantially free of its R-(+)-enantiomer said amount being sufficient to eradicate said infections.  
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 11  wherein, the compound of formula I, or a pharmaceutically acceptable derivative, salt, pseudopolymorph, polymorph or hydrate thereof is administered by intravenous infusion, transdermal delivery, orally or topically.  
     
     
         13 . The method of  claim 11  wherein the amount administered is from about 200 mg to about 1500 mg per day.  
     
     
         14 . The method of  claim 11  wherein the amount of the compound of formula I, or a pharmaceutically acceptable derivative, pseudopolymorph, polymorph, salt or hydrate thereof is greater than approximately 90% by weight of the total weight of S-(−)-isomer.  
     
     
         15 . The method of  claim 11  wherein the amount of the compound of formula I or a pharmaceutically acceptable derivative, polymorph, pseudopolymorph, salt or hydrate thereof, substantially free of its R-(+)-enantiomer, is administered together with a pharmaceutically acceptable carrier.  
     
     
         16 . An anti-infective composition for the treatment of a human or animal in need of therapy for a systemic or topical antibacterial infection, specially against resistant Gram-positive organism infections, Gram-negative organism infections, mycobacterial infections or nosocomial pathogen infections, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I as defined in  claim 1  or a pharmaceutically acceptable derivative, salt, pseudopolymorph, polymorph or hydrate thereof, substantially free of its R-(+)-enantiomer.  
     
     
         17 . A composition according to  claim 16  comprising:  
       
         
           
                 
                 
               
                     
                     
                 
                     
                     
                 
                     
                   % w/v 
                 
                     
                     
                 
                     
                 
                 
                 
                 
               
                     
                   S-(−)-9-fluoro-8(4-hydroxypiperidin-1-yl)- 
                   Up to 10; 
                 
                     
                   5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo [i,j] 
                 
                     
                   quinolizine-2-carboxylic acid or an optically pure 
                 
                     
                   compound of the invention of formula I. 
                 
                     
                   L-arginine 
                   0.1-10; 
                 
                     
                   Sodium citrate 
                    0-3.5; 
                 
                     
                   Sodium hydroxide to adjust pH between 8.0-9.9 
                   q.s; 
                 
                     
                   Disodium edetate 
                   0-0.5; and 
                 
                     
                   Water for injection 
                   q.s. to 100.