(1s,2s,3s,4r)-3-[(1s)-1-acetylamino-2-ethyl-butyl]-4-uanidino-2-hydroxyl-cyclopentyl-1-carboxylic acid hydrates pharmaceutical uses thereof

Abstract

The present invention relates to (1S,2S,3S,4R)-3-[(1S)-1-acetylamino-2-ethyl-butyl]-4-guanidino-2-hydroxy-cyclopentyl-1-carboxylic acid hydrates compounds, preparing methods thereof, pharmaceutical compositions containing said compounds and preparing methods thereof, and the clinical uses of said compounds as neuramidinase inhibitors for anti-influenza.

1 . (1S,2S,3S,4R)-3-[(1S)-1-acetylamino-2-ethyl-butyl]-4-guanidino-2-hydroxy-cyclopentyl-1-carboxylic acid hydrate of the general formula (I): 
       
         
           
           
               
               
           
         
         wherein X is 2.0 or 3.0. 
       
     
     
         2 . The compound according to  claim 1 , wherein X is 3.0. 
     
     
         3 . A pharmaceutical composition comprising the compound according to  claim 1  or  2  and a pharmaceutically acceptable carrier. 
     
     
         4 . A method for preparing the compound according to  claim 1  or  2 , characterized by comprising the steps of: suspending the (1S,2S,3S,4R)-3-[(1S)-1-acetylamino-2-ethyl-butyl]-4-guanidino-2-hydroxy-cyclopentyl-1-carboxylic acid crude product in water and dissolving by heating to 50-90° C.; standing for a moment and then adding activated carbon to the system; refluxing by heating for 10 minutes and filtering while the system was hot; adding an organic solvent to the system after cooling down by standing to 35-75° C.; or adding crystal seed of the compound of the general formula (I) after the addition of an organic solvent; placing the mixed solution in a sealed vessel, standing, controlling a suitable cooling rate to precipitate a crystal product, and then filtering and collecting the solid product. 
     
     
         5 . The method according to  claim 4 , wherein the organic solvent is one selected from the group consisting of methanol, ethanol, n-butanol, acetone and acetonitrile or a mixture thereof. 
     
     
         6 . The method according to  claim 5 , wherein the organic solvent is one selected from the group consisting of methanol and acetone. 
     
     
         7 . The method according to  claim 4 , wherein the ratio of water to the organic solvent is from 1:5 to 100:1, or is pure water. 
     
     
         8 . The method according to  claim 4 , wherein the cooling rate is from 0.1° C./min to 5° C./min. 
     
     
         9 . The pharmaceutical composition according to  claim 3 , which comprises a pharmaceutically acceptable solvent and from about 50% to about 4000% w/v of the (1S,2S,3S,4R)-3-[(1S)-1-acetylamino-2-ethyl-butyl]-4-guanidino-2-hydroxy-cyclopentyl-1-carboxylic acid hydrate of the general formula (I), wherein the amount of the compound of the general formula (I) is calculated by the amount of (1S,2S,3S,4R)-3-[(1S)-1-acetylamino-2-ethyl-butyl]-4-guanidino-2-hydroxy-cyclopentyl-1-carboxylic acid. 
     
     
         10 . The pharmaceutical composition according to  claim 9  for parenteral administration, wherein the (1S,2S,3S,4R)-3-[(1S)-1-acetylamino-2-ethyl-butyl]-4-guanidino-2-hydroxy-cyclopentyl-1-carboxylic acid hydrate of the general formula (I) is present in an amount of from 300% to 2000% w/v on the basis of the composition. 
     
     
         11 . The pharmaceutical composition according to  claim 9  for parenteral administration, which further comprises at least one ingredient selected from a pH adjusting agent, 0.9% aqueous solution of sodium chloride, a buffer, an antioxidant, a metal ion complexing agent, or any combinations thereof 
     
     
         12 . The pharmaceutical composition according to  claim 11  for parenteral administration, wherein the pH adjusting agent is selected from inorganic acids, and is present in an amount sufficient to adjust the pH value of the composition to about 3-7. 
     
     
         13 . The pharmaceutical composition according to  claim 12  for parenteral administration, wherein the pH adjusting agent is selected from diluted hydrochloric acid, and is present in an amount sufficient to adjust the pH value of the composition to about 3-6. 
     
     
         14 . The pharmaceutical composition according to  claim 9  for parenteral administration, wherein the pharmaceutically acceptable solvent is selected from the group consisting of water, PEG400, propylene glycol, ethanol, glycerin or any combinations thereof 
     
     
         15 . The pharmaceutical composition according to  claim 9  for parenteral administration, wherein the pharmaceutically acceptable solvent is water. 
     
     
         16 . The pharmaceutical composition according to  claim 9  for parenteral administration, which is sterilized at 105-125° C. for 10 to 50 minutes, preferably at 115° C. for 30 minutes. 
     
     
         17 . The pharmaceutical composition according to  claim 9  for parenteral administration, wherein the pharmaceutically acceptable solvent is water, and the (1S,2S,3S,4R)-3-[(1S)-1-acetylamino-2-ethyl-butyl]-4-guanidino-2-hydroxy-cyclopentyl-1-carboxylic acid hydrate of the general formula (I) is present in an amount of from 300 mg/100 ml to 100 mg/5 ml on the basis of the composition which comprises water as solvent. 
     
     
         18 . The pharmaceutical composition according to  claim 17 , wherein the pH value of the composition is adjusted to 4-6 when the (1S,2S,3S,4R)-3-[(1S)-1-acetylamino-2-ethyl-butyl]-4-guanidino-2-hydroxy-cyclopentyl-1-carboxylic acid hydrate is present in an amount of 300 mg/100 ml on the basis of the composition which comprises water as solvent. 
     
     
         19 . The pharmaceutical composition according to  claim 17 , wherein the pH value of the composition is optimally adjusted to 3-5, when the (1S,2S,3S,4R)-3-[(1S)-1-acetylamino-2-ethyl-butyl]-4-guanidino-2-hydroxy-cyclopentyl-1-carboxylic acid hydrate is present in an amount of 100 mg/5 ml on the basis of the composition which comprises water as solvent. 
     
     
         20 . A powder injection preparation comprising the compound according to  claim 1 , characterized by comprising the (1S,2S,3S,4R)-3-[(1S)-1-acetylamino-2-ethyl-butyl]-4-guanidino-2-hydroxy-cyclopentyl-1-carboxylic acid hydrate, which comprises from 0.1 mg to 1 g of the (1S,2S,3S,4R)-3-[(1S)-1-acetylamino-2-ethyl-butyl]-4-guanidino-2-hydroxy-cyclopentyl-1-carboxylic acid hydrate of the general formula (I) per gram of the preparation, or further comprises at least one of the following filling agents: a pH adjusting agent, a buffer, an antioxidant, a metal ion complexing agent, or any combinations thereof. 
     
     
         21 . The powder injection preparation according to  claim 20 , wherein the weight ratio of the (1S,2S,3S,4R)-3-[(1S)-1-acetylamino-2-ethyl-butyl]-4-guanidino-2-hydroxy-cyclopentyl-1-carboxylic acid hydrate to the filling agent in unit dose is 1:0-1:100, and the pH adjusting agent is used in an amount sufficient to assure that, when the preparation is used in unit dose, the solution has a pH ranging from 2.5 to 6.5, preferably ranging from 3.5 to 5.5.