Salt of Dimethylaminomethyl-Phenyl-Cyclohexane and Crystalline Forms Thereof

Abstract

Novel 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate compounds corresponding to formula I and processes for preparing these compounds are provided. Pharmaceutical compositions including these compounds and methods of treating or alleviating pain with these compounds are also provided.

1 . A salt of maleic acid and 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol. 
     
     
         2 . The salt of  claim 1 , wherein said salt is a 3-[2-(dimethylamino)-methyl-(cyclohex-1-yl)]-phenol maleate compound corresponding to formula I 
       
         
           
           
               
               
           
         
       
     
     
         3 . The salt of  claim 2 , wherein the 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate compound corresponding to formula I is in the form of a diastereomer or a mixture of enantiomeric diastereomers with transconfiguration of the phenyl ring and of the dimethylaminomethyl group (1R,2R or 1S,2S configuration). 
     
     
         4 . The salt of  claim 2 , wherein the 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate compound corresponding to formula I has the 1R,2R configuration. 
     
     
         5 . A process for preparing a 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate compound corresponding to formula I, comprising:
 combining 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol and maleic acid to form a 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate compound corresponding to formula I   
       
         
           
           
               
               
           
         
       
     
     
         6 . The process of  claim 5 , wherein at least one of the components is present in dissolved or suspended form. 
     
     
         7 . The process of  claim 5 , comprising the steps of:
 a) dissolving 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol in a solvent,   b) mixing the resulting solution with maleic acid or a solution of maleic acid, and   c) isolating a compound corresponding to formula I.   
     
     
         8 . The process of  claim 7 , further comprising preventing the temperature from exceeding 100° C. 
     
     
         9 . A salt of maleic acid and 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol according to  claim 1 , produced by the process comprising:
 combining 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol and maleic acid to form a 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate compound corresponding to formula I   
       
         
           
           
               
               
           
         
       
     
     
         10 . A process for producing a crystalline form of a 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate compound according to  claim 2 , comprising:
 a) treating a pulverulent, solid, amorphous form of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate with a water vapor-containing inert gas to form crystalline 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate; or   b) preparing a suspension of an amorphous form of a 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate compound in a solvent, and stirring the suspension to form crystalline 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate; or   c) dissolving 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate in a solvent and then precipitating the resulting mixture to form crystalline 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate; or   d) combining 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol and maleic acid to form crystalline 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate.   
     
     
         11 . The process of  claim 10 , further comprising preventing the temperature from exceeding 100° C. 
     
     
         12 . A crystalline form of a 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate compound corresponding to formula I 
       
         
           
           
               
               
           
         
       
       according to  claim 2 , produced by the process comprising:
 a) treating a pulverulent, solid, amorphous form of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate with a water vapor-containing inert gas to form crystalline 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate; or 
 b) preparing a suspension of an amorphous form of a 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate compound in a solvent, and stirring the suspension to form crystalline 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate; or 
 c) dissolving 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate in a solvent and then precipitating the resulting mixture to form crystalline 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate; or 
 d) combining 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol and maleic acid to form crystalline 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate. 
 
     
     
         13 . A process for producing a crystalline form of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate comprising the steps of:
 dissolving 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate in a mixture of tetrahydrofuran and water in the volume ratio of 0.8:1.2 to 1.2:0.8, and   removing the solvent mixture (a) at a temperature of at least 80° C., or (b) at room temperature in an open vessel in an open atmosphere in contact with atmospheric humidity to form crystalline 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate, or   stirring a suspension of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate in a solvent as carrier at a temperature of at least 120° C. to form crystalline 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate.   
     
     
         14 . The process of  claim 13 , wherein the resulting crystalline 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate:
 has a characteristic X-ray diffraction pattern in the range from 2° to 35° 2θ with pronounced characteristic lines, expressed in d values (Å): 10.6, 7.5, 7.3, 6.1, 5.29, 4.88, 4.72, 4.47, 4.43, 4.26, 4.24, 3.99, 3.71, 3.52, 3.30, or   has a powder diffractogram comprising one or more of the following reflections: 8.36, 14.5 and 14.83 (in each case ±0.5 in 2θ), or   wherein the powder diffractogram additionally comprises one or more of the following reflections:   11.85, 12.19, 18.16, 22.85, 29.1 and 29.41 (in each case ±0.2 in 2θ), or   has a Raman spectrum comprising one or more of the following bands, in each case expressed in wavenumbers (cm−1): 229 (m), 875 (m) and 2829 (m), or   has a Raman spectrum comprising one or more of the following bands: 229 (m), 307 (w), 372 (w), 605 (vw), 875 (m), 890 (w), 1010 (w), 1197 (m), 1401 (vw), 1480 (vw), 1583 (m), 1703 (s), 2829 (m), 2953 (s), or   exhibits an X-ray diffraction pattern shown in  FIG. 3 , or   exhibits a Raman spectrum as shown in  FIG. 4 .   
     
     
         15 . A crystalline form of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate according to  claim 1 , produced by the process of
 dissolving 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate in a mixture of tetrahydrofuran and water in the volume ratio of 0.8:1.2 to 1.2:0.8, and   removing the solvent mixture (a) at a temperature of at least 80° C., or (b) at room temperature in an open vessel in an open atmosphere in contact with atmospheric humidity to form crystalline 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate, or   stirring a suspension of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate in a solvent as carrier at a temperature of at least 120° C. to form crystalline 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate.   
     
     
         16 . A pharmaceutical composition comprising as an active ingredient a pharmaceutically effective amount of a 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate compound according to  claim 2  and a pharmaceutical excipient or a pharmaceutical diluent. 
     
     
         17 . A composition according to  claim 16 , wherein the compound corresponding to formula I is present as crystalline form A, or crystalline form B, or a mixture of crystalline forms A and B. 
     
     
         18 . The composition of  claim 17 , wherein the compound corresponding to formula I is present as crystalline form A. 
     
     
         19 . A crystalline form of a salt of maleic acid and 3-[2-(dimethylamino)-methyl-(cyclohex-1-yl)]-phenol according to  claim 1 , wherein said crystalline form is crystalline form A. 
     
     
         20 . A crystalline form of a salt of maleic acid and 3-[2-(dimethylamino)-methyl-(cyclohex-1-yl)]-phenol according to  claim 1 , wherein said crystalline form is crystalline form B.