Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulaters of the 5-ht2a serotonin receptor

Abstract

The present invention relates to processes for preparing phenyl-pyrazoles of Formula (I) and salts and pharmaceutical compositions thereof, useful as modulators of 5-HT 2A serotonin receptor activity. The present invention also relates to intermediates used in the processes, and their preparation. The present invention also relates to crystalline forms of 5-HT 2A serotonin receptor modulators, compositions thereof and methods of using the same.

1 - 95 . (canceled) 
     
     
         96 . A method of treating a 5HT 2A -related disorder comprising administering to a patient in need thereof a therapeutically effective amount of a hydrochloride salt or an oxalate salt of a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is C 1 -C 8  alkyl, halo, C 1 -C 8  haloalkyl or C 1 -C 8  alkoxy; 
 X is O, S, NR 2  or CHR 2 ; and 
 R 2  is H, C 1 -C 8  alkyl, C 1 -C 8  acyl, C 1 -C 8  alkenyl, C 1 -C 8  alkynyl, C 3 -C 7  cycloalkyl, C 1 -C 8  haloalkyl, arylalkyl, aryl, heteroaryl or heteroarylalkyl each optionally substituted with C 1 -C 8  alkyl, halo, C 1 -C 8  haloalkyl or C 1 -C 8  alkoxy. 
 
     
     
         97 . The method according to  claim 96 , wherein the salt is the hydrochloride salt of a compound of Formula (I). 
     
     
         98 . The method according to  claim 97 , wherein R 1  is methoxy and X is O. 
     
     
         99 . The method according to  claim 97 , wherein R 1  is fluoro and X is NC(O)CH 3 . 
     
     
         100 . The method according to  claim 96 , wherein the salt is the oxalate salt of a compound of Formula (I). 
     
     
         101 . The method according to  claim 100 , wherein R 1  is methoxy and X is O. 
     
     
         102 . The method according to  claim 100 , wherein R 1  is fluoro and X is NC(O)CH 3 . 
     
     
         103 . The method according to  claim 96 , wherein the 5HT 2A -related disorder is selected from the group consisting of platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, blood clot formation, asthma or symptoms thereof, agitation or a symptom thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, sleep disorders, diabetic-related disorders and progressive multifocal leukoencephalopathy. 
     
     
         104 . The method according to  claim 96 , wherein the 5HT 2A -related disorder is a condition associated with platelet aggregation. 
     
     
         105 . The method according to  claim 97 , wherein the 5HT 2A -related disorder is selected from the group consisting of platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, blood clot formation, asthma or symptoms thereof, agitation or a symptom thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, sleep disorders, diabetic-related disorders and progressive multifocal leukoencephalopathy. 
     
     
         106 . The method according to  claim 97 , wherein the 5HT 2A -related disorder is a condition associated with platelet aggregation. 
     
     
         107 . The method according to  claim 98 , wherein the 5HT 2A -related disorder is selected from the group consisting of platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, blood clot formation, asthma or symptoms thereof, agitation or a symptom thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, sleep disorders, diabetic-related disorders and progressive multifocal leukoencephalopathy. 
     
     
         108 . The method according to  claim 98 , wherein the 5HT 2A -related disorder is a condition associated with platelet aggregation. 
     
     
         109 . The method according to  claim 100 , wherein the 5HT 2A -related disorder is selected from the group consisting of platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, blood clot formation, asthma or symptoms thereof, agitation or a symptom thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, sleep disorders, diabetic-related disorders and progressive multifocal leukoencephalopathy. 
     
     
         110 . The method according to  claim 100 , wherein the 5HT 2A -related disorder is a condition associated with platelet aggregation. 
     
     
         111 . The method according to  claim 102 , wherein the 5HT 2A -related disorder is selected from the group consisting of platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, blood clot formation, asthma or symptoms thereof, agitation or a symptom thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, sleep disorders, diabetic-related disorders and progressive multifocal leukoencephalopathy. 
     
     
         112 . The method according to  claim 102 , wherein the 5HT 2A -related disorder is a condition associated with platelet aggregation.