Hydrochloride salts of 8-[{1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one and preparation process therefor

Abstract

Disclosed are hydrochloride and tosylate crystalline salt forms of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one, represented by Formula I and methods of preparing the same.

1 - 39 . (canceled) 
     
     
         40 . A crystalline hydrochloride anhydrous Form I salt form of 8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (Formula I), 
       
         
           
           
               
               
           
         
         characterized by an X-ray powder diffraction pattern having peaks present at diffraction angles (in 2θ±0.2) of: 12.9; 15.4; 17.3; and 20.2. 
       
     
     
         41 . A crystalline hydrochloride anhydrous Form II salt form of 8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (Formula I), 
       
         
           
           
               
               
           
         
       
       characterized by an x-ray powder diffraction pattern having peaks present at diffraction angles (in 2θ±0.2) of: 7.0; 9.0; 12.6; and 20.2. 
     
     
         42 . A pharmaceutical composition comprising the crystalline salt form of  claim 40  and a pharmaceutically acceptable carrier optionally in combination with one or more additional therapeutic agents. 
     
     
         43 . A pharmaceutical composition comprising the crystalline salt form of  claim 41  and a pharmaceutically acceptable carrier optionally in combination with one or more additional therapeutic agents. 
     
     
         44 . A method of treating or delaying the onset of nausea and/or emesis in a mammal which comprises administering to said mammal the crystalline salt form of  claim 40 . 
     
     
         45 . A method of treating or delaying the onset of nausea and/or emesis in a mammal which comprises administering to said mammal the crystalline salt form of  claim 41 . 
     
     
         46 . A method of treating or delaying the onset of chemotherapy-induced nausea and/or chemotherapy induced emesis in a mammal receiving chemotherapy, which comprises administering to said mammal the crystalline salt form of  claim 40 . 
     
     
         47 . The method of  claim 46  further comprising contemporaneous administration of a chemotherapeutic agent. 
     
     
         48 . A method of treating or delaying the onset of chemotherapy-induced nausea and/or chemotherapy induced emesis in a mammal receiving chemotherapy, which comprises administering to said mammal the crystalline salt form of  claim 41 . 
     
     
         49 . The method of  claim 48  further comprising contemporaneous administration of a chemotherapeutic agent. 
     
     
         50 . A process for preparing a crystalline salt form of 8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one 
       
         
           
           
               
               
           
         
         comprising a step of treating Formula 1 with at least one equivalent of an acid selected from hydrochloric acid and 4-toluenesulfonic acid to provide the crystalline salt form of Formula 1. 
       
     
     
         51 . The process of  claim 50 , wherein the acid is hydrochloric acid. 
     
     
         52 . The process of  claim 50 , wherein the acid is 4-toluenesulfonic acid. 
     
     
         53 . The process of  claim 51 , further comprising a step of precipitating from a solvent a crystalline hydrochloride monohydrate form of Formula 1. 
     
     
         54 . The process of  claim 53 , wherein the solvent comprises ethanol and water. 
     
     
         55 . The process of  claim 54 , wherein the crystalline hydrochloride monohydrate form of Formula 1 is a Form I crystalline salt form of 8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one monohydrate hydrochloride. 
     
     
         56 . The process of  claim 55 , wherein the Form I crystalline salt form of 8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one monohydrate hydrochloride is characterized by an X-ray powder diffraction pattern having a diffraction angle (in 2θ) of 21.6±0.2. 
     
     
         57 . The process of  claim 52 , further comprising a step of precipitating from a first solvent a crystalline tosylate form of Formula 1. 
     
     
         58 . The process of  claim 57 , wherein the first solvent comprises ethanol and diethyl ether. 
     
     
         59 . The process of  claim 58 , wherein the crystalline tosylate form of Formula 1 is a Form I crystalline salt form of 8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one tosylate.