Hydrochloride salts of 8-[1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxymethyl]-8-phenyl-1,7-diazaspiro[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.

What is claimed is: 
     
         1 ) An isolated crystalline Form I monohydrate hydrochloride salt form of the compound (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (Formula I) 
       
         
           
           
               
               
           
         
         which yields an x-ray powder diffraction pattern having characteristic peaks at diffraction angles (in 2 θ) of: 16.1 (M); 18.4 (M); 21.6 (S); and 23.5 (M). 
       
     
     
         2 ) The Form I hydrochloride salt form of  claim 1  yielding an x-ray powder diffraction pattern having additional characteristic peaks present at diffraction angles (in 2 θ) of: 12.9 (S); 15.4 (S); 17.3 (S); 20.2 (S). 
     
     
         3 ) A crystalline anhydrous Form II hydrochloride salt form of (5S,8S)-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 2 θ) of: 7.0 (M); 9.0 (S); 12.6 (VS); and 20.2 (S). 
       
     
     
         4 ) A crystalline Form I tosylate 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 2 θ) of: 9.4 (M); 20.0 (VS); 21.0 (MS); and 25.3 (MS). 
       
     
     
         5 ) A crystalline Form II Tosylate salt form of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy]-methyl}-8-phenyl-1,7-diazaspiro[4.5]decan-2-one characterized by an x-ray powder diffraction pattern having peaks present at diffraction angles (in 2 θ) of: 5.0 (VS); 10.0 (S); 13.6 (M); and 19.7 (VS). 
     
     
         6 ) A crystalline Form III Tosylate salt form of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one which is characterized by an x-ray powder diffraction pattern having peaks present at diffraction angles (in 2 θ) of: 6.3 (M); 9.7 (VS); 20.2 (S); and 22.2 (S). 
     
     
         7 ) A crystalline Form IV Tosylate salt form of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one which is characterized by an x-ray powder diffraction pattern having peaks present at diffraction angles (in 2 θ) of: 6.1 (S); 9.6 (S); 20.9 (S); and 22.0 (S). 
     
     
         8 ) A crystalline Form I hydrochloride monohydrate salt form of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (Formula I) 
       
         
           
           
               
               
           
         
         characterized by the following x-ray powder diffraction pattern expressed in terms of lattice “d” spacing (in angstroms) and relative peak intensities (“RI”, denoted as S=strong, M=medium, and W=weak, each of which may be modified by V=very and D=diffuse, for example, VS=Very Strong, VWD=very weak diffuse): 
       
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   d 
                   relative 
                 
                     
                   spacing 
                   intensity 
                 
                     
                     
                 
                     
                   6.85 
                   WD 
                 
                     
                   5.49 
                   M 
                 
                     
                   4.83 
                   M 
                 
                     
                   4.74 
                   WD 
                 
                     
                   4.48 
                   W 
                 
                     
                   4.11 
                   S 
                 
                     
                   3.89 
                   WD 
                 
                     
                   3.78 
                   M 
                 
                     
                   3.70 
                   WD 
                 
                     
                   3.16 
                   W 
                 
                     
                   2.62 
                   VW 
                 
                     
                   2.56 
                   W 
                 
                     
                     
                 
             
                
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         9 ) A pharmaceutical composition comprising the crystalline salt of  claim 1  and a pharmaceutically acceptable carrier and optionally one or more additional therapeutic agents. 
     
     
         10 ) A combination comprising the composition of  claim 9  and a chemotherapeutic agent. 
     
     
         11 ) The combination of  claim 10  wherein the chemotherapeutic agent is temozolomide. 
     
     
         12 ) A pharmaceutical composition comprising the crystalline salt of  claim 2  and a pharmaceutically acceptable carrier optionally in combination with one or more additional therapeutic agents. 
     
     
         13 ) A pharmaceutical composition comprising the crystalline salt of  claim 3  and a pharmaceutically acceptable carrier optionally in combination with one or more additional therapeutic agents. 
     
     
         14 ) A pharmaceutical composition comprising the crystalline salt of  claim 4  and a pharmaceutically acceptable carrier optionally in combination with one or more additional therapeutic agents. 
     
     
         15 ) A pharmaceutical composition comprising the crystalline salt of  claim 5  and a pharmaceutically acceptable carrier optionally in combination with one or more additional therapeutic agents. 
     
     
         16 ) A pharmaceutical composition comprising the crystalline salt of  claim 6  and a pharmaceutically acceptable carrier optionally in combination with one or more additional therapeutic agents. 
     
     
         17 ) A pharmaceutical composition comprising the crystalline salt of  claim 7  and a pharmaceutically acceptable carrier optionally in combination with one or more additional therapeutic agents. 
     
     
         18 ) A pharmaceutical composition comprising the crystalline salt of  claim 8  and a pharmaceutically acceptable carrier optionally in combination with one or more additional therapeutic agents. 
     
     
         19 ) A method of treating and/or preventing emesis in a mammal which comprises administering to said mammal a medicament comprising a therapeutically effective amount of the crystalline salt of  claim 1 . 
     
     
         20 ) The method of  claim 19  further comprising administering said medicament in combination with a therapeutically effective amount of a chemotherapeutic agent. 
     
     
         21 ) The method of  claim 20  wherein said chemotherapeutic agent is temozolomide. 
     
     
         22 ) A method of treating and/or preventing emesis in a mammal which comprises administering to said mammal a therapeutically effective amount of the crystalline salt of  claim 2  optionally administered in combination with one or more additional therapeutic agents. 
     
     
         23 ) A method of treating and/or preventing emesis in a mammal a therapeutically effective amount of which comprises administering to said mammal the crystalline salt of  claim 3  optionally administered in combination with one or more additional therapeutic agents. 
     
     
         24 ) A method of treating and/or preventing emesis in a mammal which comprises administering to said mammal a therapeutically effective amount of the crystalline salt of  claim 4  optionally administered in combination with one or more additional therapeutic agents. 
     
     
         25 ) A method of treating and/or preventing emesis in a mammal which comprises administering to said mammal a therapeutically effective amount of the crystalline salt of  claim 5  optionally administered in combination with one or more additional therapeutic agents. 
     
     
         26 ) A method of treating and/or preventing emesis in a mammal which comprises administering to said mammal a therapeutically effective amount of the crystalline salt of  claim 6  optionally administered in combination with one or more additional therapeutic agents. 
     
     
         27 ) A method of treating and/or preventing emesis in a mammal which comprises administering to said mammal a therapeutically effective amount of the crystalline salt of  claim 7  optionally administered in combination with one or more additional therapeutic agents. 
     
     
         28 ) A method of treating and/or preventing emesis in a mammal which comprises to administering to said mammal a therapeutically effective amount of the crystalline salt of  claim 8  optionally administered in combination with one or more additional therapeutic agents. 
     
     
         29 ) A salt of the compound (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (Formula I) 
       
         
           
           
               
               
           
         
         prepared by treating an ethanol solution of the compound of Formula I with an acid selected from the group consisting of hydrochloric acid and p-toluene-sulfonic acid. 
       
     
     
         30 ) A method of providing therapy for delayed onset emesis and/or delayed onset nausea along with chemotherapy by administering the combination of  claim 10  to a patient in need of chemotherapy. 
     
     
         31 ) The treatment method of  claim 19  further comprising contemporaneous administration of a chemotherapeutic agent 
     
     
         32 ) The treatment method of  claim 31  wherein the chemotherapeutic agent is temozolomide. 
     
     
         33 ) The treatment method of  claim 22  wherein said salt is administered in combination with a chemotherapeutic agent. 
     
     
         34 ) The treatment method of  claim 23  wherein said salt is administered in combination with a chemotherapeutic agent. 
     
     
         35 ) The treatment method of  claim 24  wherein said salt is administered in combination with a chemotherapeutic agent. 
     
     
         36 ) The treatment method of  claim 25  wherein said salt is administered in combination with a chemotherapeutic agent. 
     
     
         37 ) The treatment method of  claim 26  wherein said salt is administered in combination with a chemotherapeutic agent. 
     
     
         38 ) The treatment method of  claim 27  wherein said salt is administered in combination with a chemotherapeutic agent. 
     
     
         39 ) The treatment method of  claim 28  wherein said salt is administered in combination with a chemotherapeutic agent.