Tartrate salts of (R)-3-N,N-dicyclo-butylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide

Abstract

A new salt (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen tartrate, particularly the (2R,3R)-tartrate thereof, most particularly the (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate, processes for the manufacture of said tartrate salt, the use of the salt in medicine, the use of the tartrate salt in the manufacture of pharmaceutical formulations, and a method for the treatment of CNS disorders by administration of the tartrate salt to a host in need of such treatment.

1 . A salt (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen tartrate.  
     
     
         2 . A salt (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate.  
     
     
         3 . (canceled)  
     
     
         4 . The salt according to  claim 1  or  2  in substantially crystalline form.  
     
     
         5 . A pharmaceutical formulation comprising, as active ingredient, the salt according to  claim 1  or  2  and a suitable diluent, excipient or an inert carrier.  
     
     
         6 . The pharmaceutical formulation according to  claim 5 , wherein the pharmaceutical formulation is an oral dosage form.  
     
     
         7 - 11 . (canceled)  
     
     
         12 . A method for the prevention or the treatment of a condition selected from the group consisting of CNS disorders and related medical disturbances, wherein the method comprises administering, to a host in need of such treatment, an effective amount of the salt according to  claim 1  or  2 .  
     
     
         13 . The method according to  claim 12 , wherein the condition is a 5-HT 1A  receptor antagonist activity related CNS disorder or medical disturbance.  
     
     
         14 . The method according to  claim 13 , wherein the condition is depression.  
     
     
         15 . The method according to  claim 13 , wherein the condition is anxiety.  
     
     
         16 . A process for the manufacture of the salt according to  claim 1  or  2 , wherein the process comprises the following consecutive steps: 
 i) dissolving (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide in an appropriate solvent, optionally by heating,    ii) adding (2R, 3R)-, (2S,3S)- or (2R,3S)-tartaric acid, respectively, dissolved in an appropriate aqueous organic solvent or non-aqueous organic solvent, and    iii) allowing the solution obtained to stand cold to crystallize.    
     
     
         17 . A process for the manufacture of the salt according to  claim 4 , comprising recrystallizing (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-benzopyran-5-carboxamide hydrogen (2R, 3R)-, (2S,3S)- or (2R,3S)-tartrate in an appropriate aqueous organic solvent.  
     
     
         18 . The process according to  claim 16  or  17 , wherein the aqueous organic solvent is aqueous acetone.  
     
     
         19 . The process according to  claim 16  further comprising the step: 
 iv) recrystallizing in an aqueous organic solvent when a non-aqueous solvent is used in step ii).    
     
     
         20 . The method according to  claim 13 , wherein the condition is selected from the group consisting of obsessive-compulsive disorder, anorexia, bulimia, senile dementia, migraine, stroke, Alzheimer's disease, cognitive disorders, schizophrenia, sleep disorders, urinary incontinence, premenstrual syndrome, hypertension, thermoregulatory disturbances, sexual disturbances, disturbances in the cardiovascular system and disturbances in the gastrointestinal system.  
     
     
         21 . The method according to  claim 12 , wherein the condition is Alzheimer's disease.  
     
     
         22 . The method according to  claim 12 , wherein the condition is a cognitive disorder.  
     
     
         23 . The method according to  claim 12 , wherein the condition is urinary incontinence.