Composition of a 5-ht2a serotonin receptor modulator useful for the treatment of disorders related thereto

Abstract

The present invention relates to certain compositions of a 5-HT2A serotonin receptor modulator and methods for their preparation. The compositions disclosed herein are useful for increasing slow wave sleep, improving sleep consolidation, improving sleep maintenance and improving sleep quality, and for treating insomnia and related sleep disorders, dyssomnias, parasomnias and nonrestorative sleep and the like. The compositions disclosed herein are further useful for treating platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, thrombosis, asthma or symptoms thereof, agitation or symptoms thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorders, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, diabetic-related disorders and progressive multifocal leukoencephalopathy and the like.

1 - 50 . (canceled) 
     
     
         51 . A method for treating agitation or a symptom thereof in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and an excipient selected from the group consisting of PVP and coPVP. 
     
     
         52 . The method of claim  1 , wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea exhibits a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 165° C. to about 175° C. 
     
     
         53 . The method of claim  1 , wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea exhibits a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 170° C. 
     
     
         54 . The method of claim  1 , wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea exhibits a differential scanning calorimetry thermogram comprising an endotherm with a peak temperature of about 167° C. to about 177° C. 
     
     
         55 . The method of claim  1 , wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea exhibits a differential scanning calorimetry thermogram comprising an endotherm with a peak temperature of about 172° C. 
     
     
         56 . The method of claim  1 , wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea exhibits a differential scanning calorimetry thermogram comprising an endotherm with an associated heat flow of about 59 joules per gram to about 69 joules per gram. 
     
     
         57 . The method of claim  1 , wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea exhibits a differential scanning calorimetry thermogram comprising an endotherm with an associated heat flow of about 64 joules per gram. 
     
     
         58 . The method of claim  1 , wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea exhibits a Raman spectrum comprising peaks at about 1327 cm −1  and about 1657 cm −1 . 
     
     
         59 . The method of claim  1 , wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea exhibits a Raman spectrum comprising peaks at about 1327 cm −1 , about 1622 cm −1  and about 1657 cm −1 . 
     
     
         60 . The method of claim  1 , wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea exhibits a Raman spectrum comprising peaks at about 732 cm −1 , about 1327 cm −1 , about 1573 cm −1 , about 1605 cm −1 , about 1622 cm −1  and about 1657 cm −1 . 
     
     
         61 . The method of claim  1 , wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea exhibits a weight loss of about 2% or less as determined by thermogravimetric analysis at a temperature up to about 150° C. 
     
     
         62 . The method of claim  1 , wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea exhibits a weight loss of about 0.5% or less as determined by thermogravimetric analysis at a temperature up to about 150° C. 
     
     
         63 . The method of claim  1 , wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea exhibits a weight loss of about 0.1% or less as determined by thermogravimetric analysis at a temperature up to about 150° C. 
     
     
         64 . The method of claim  1 , wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea exhibits:
 a. a powder X-ray diffraction pattern comprising peaks expressed in terms of 2θ at about 5.6° and about 21.1°;   b. a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 165° C. to about 175° C.; and   c. a Raman spectrum comprising peaks at about 1327 cm −1  and about 1657 cm −1 .   
     
     
         65 . The method of claim  1 , wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea exhibits:
 a. a powder X-ray diffraction pattern comprising peaks expressed in terms of 2θ at about 7.4° and about 11.2°;   b. a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 170° C.; and   c. a Raman spectrum comprising peaks at about 1327 cm −1 , about 1622 cm −1  and about 1657 cm −1 .   
     
     
         66 . The method of claim  1 , wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea exhibits:
 a. a powder X-ray diffraction pattern comprising peaks expressed in terms of 2θ at about 5.6°, about 7.4°, about 11.2° and about 21.1°;   b. a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 170° C., a peak temperature of about 172° C. and an associated heat flow of about 64 joules per gram;   c. a Raman spectrum comprising peaks at about 732 cm −1 , about 1327 cm −1 , about 1573 cm −1 , about 1605 cm −1 , about 1622 cm −1  and about 1657 cm −1 ; and   d. a weight loss of about 0.5% or less as determined by thermogravimetric analysis at a temperature up to about 150° C.   
     
     
         67 . The method of claim  1  wherein the individual is a cognitively intact elderly patient. 
     
     
         68 . The method of claim  1  wherein the individual in need thereof, is suffering from dementia. 
     
     
         69 . The method of  claim 68 , wherein the dementia is due to a degenerative disease of the nervous system. 
     
     
         70 . The method of  claim 69 , wherein the dementia is selected from the group consisting of Alzheimer's disease, Lewy Body, Parkinson's disease, Huntington's disease, dementia due to diseases that affect blood vessels, dementia due to stroke, multi-infarct dementia, and any combination thereof.