SYNTHESIS PROCESS, AND CRYSTALLINE FORM OF 4-{3[CIS-HEXAHYDROCYCLOPENT A[CjPYRROL-2( 1 H)-YLjPROPOXYj BENZAMI DE HYDROCHLORI DE AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT

Abstract

Medicinal products containing the crystalline form I of the compound of formula (I): and/or crystalline form I of the associated free base which are useful in the treatment of disorders of the histaminergic system.

1 . A method of treating disorders of the histaminergic system, in a subject in need thereof, comprising administration of an effective amount of a compound selected from the group consisting of a crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide hydrochloride of formula (I): 
       
         
           
           
               
               
           
         
         having an X-ray powder diffraction diagram exhibiting the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°): 16.97°, 17.84°, 18.90°, 20.32°, 23.87°, 27.10°, 27.86° and 30.34°, and a crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide: 
       
       
         
           
           
               
               
           
         
         having an X-ray powder diffraction diagram exhibiting the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°): 6.25°, 12.55°, 17.74°, 18.19°, 19.43°, 20.72°, 21.00°, 23.50° and 27.00°. 
       
     
     
         2 . The method of  claim 1 , wherein the disorder of the histaminergic system is selected from the group consisting of cognitive and psycho-behavioural disorders associated with cerebral aging and with neurodegenerative diseases, mood disorders, attention-deficit hyperactivity syndrome, obesity and pain. 
     
     
         3 . The method of  claim 2 , wherein the disorder of the histaminergic system is selected from the group consisting of cognitive and psycho-behavioural disorders associated with Alzheimer's disease, Parkinson's disease, Pick's disease, Korsakoffs disease, Lewy body dementias, frontal and subcortical dementias, frontotemporal dementias and vascular dementias. 
     
     
         4 . The method of  claim 1 , wherein the crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide hydrochloride is administered. 
     
     
         5 . The method of  claim 4 , wherein the crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide hydrochloride has the following X-ray powder diffraction diagram, measured using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector, and expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees ±0.2°) and interplanar distance d (expressed in Å): 
       
         
           
                 
                 
                 
               
                     
                 
                     
                   Angle 2-theta 
                   Interplanar 
                 
                   Line no. 
                   (degrees) 
                   distance (Å) 
                 
                     
                 
                   1 
                   16.97 
                   5.219 
                 
                   2 
                   17.84 
                   4.967 
                 
                   3 
                   18.90 
                   4.690 
                 
                   4 
                   20.32 
                   4.366 
                 
                   5 
                   23.87 
                   3.724 
                 
                   6 
                   27.10 
                   3.288 
                 
                   7 
                   27.86 
                   3.200 
                 
                   8 
                   30.34 
                   2.943 
                 
                     
                 
             
                
                
                
                
               
               
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         6 . The method of  claim 4 , wherein the crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide hydrochloride has a Raman spectrum exhibiting a significant peak at the location 1606 cm −1  or 1676 cm −1 . 
     
     
         7 . The method of  claim 4 , wherein the crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide hydrochloride has a Raman spectrum exhibiting significant peaks at the locations 1676 cm −1 , 1606 cm −1 , 1564 cm −1 , 1152 cm −1 , 830 cm −1  and 296 cm −1 . 
     
     
         8 . The method of  claim 1 , wherein the crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide is administered. 
     
     
         9 . The method of  claim 8 , wherein the crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide has the following X-ray powder diffraction diagram, measured using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector, and expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees ±0.2°) and interplanar distance d (expressed in Å): 
       
         
           
                 
                 
                 
               
                     
                 
                     
                   Angle 2-theta 
                   Interplanar 
                 
                   Line no. 
                   (degrees) 
                   distance (Å) 
                 
                     
                 
                     
                 
                 
                 
                 
               
                   1 
                   6.25 
                   14.131 
                 
                   2 
                   12.55 
                   7.049 
                 
                   3 
                   17.74 
                   4.997 
                 
                   4 
                   18.19 
                   4.873 
                 
                   5 
                   19.43 
                   4.565 
                 
                   6 
                   20.72 
                   4.284 
                 
                   7 
                   21.00 
                   4.226 
                 
                   8 
                   23.50 
                   3.782 
                 
                   9 
                   27.00 
                   3.297 
                 
                     
                 
             
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         10 . The method of  claim 8 , wherein the crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide has a Raman spectrum exhibiting a significant peak at the location 1683 cm −1 . 
     
     
         11 . The method of  claim 8 , wherein the crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide has a Raman spectrum exhibiting significant peaks at the locations 292 cm −1 , 618 cm −1 , 1045 cm −1 , 1483 cm −1 , 1568 cm −1 , 1683 cm −1 .