Diaryl and arylheteroaryl urea derivatives as modulators of the 5-ht2a serotonin receptor useful for the prophylaxis and treatment of rem sleep behavior disorder

Abstract

The present invention relates to certain pyrazole derivatives of Formula (I) and pharmaceutical compositions thereof that modulate the activity of the 5-HT 2A serotonin receptor and their uses for the treatment of REM sleep behavior disorder.

1 . A method for the prophylaxis and/or treatment of REM sleep behavior disorder, idiopathic REM sleep behavior disorder, or a combination thereof, in a subject in need thereof comprising administering to said subject a therapeutically effective amount nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. 
     
     
         2 .- 4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is from 10 mg to about 160 mg. 
     
     
         6 . The method of  claim 1 , wherein the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is about 10 mg, 20 mg, about 40 mg, 80 mg, or about 160 mg. 
     
     
         7 . The method of  claim 1 , wherein the therapeutically effective amount of nelotanserin is about 10 mg, 20 mg, about 40 mg, 80 mg, or about 160 mg. 
     
     
         8 . The method of  claim 1 , wherein the therapeutically effective amount of nelotanserin is about 10 mg. 
     
     
         9 . The method of  claim 1 , wherein the therapeutically effective amount of nelotanserin is about 20 mg. 
     
     
         10 . The method of  claim 1 , wherein the therapeutically effective amount of nelotanserin is about 40 mg. 
     
     
         11 . The method of  claim 1 , wherein the therapeutically effective amount of nelotanserin is about 80 mg. 
     
     
         12 . The method of  claim 1 , wherein the therapeutically effective amount of nelotanserin is about 160 mg. 
     
     
         13 . The method of  claim 1 , wherein the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is administered once a day, twice a day, three times a day, or four times a day. 
     
     
         14 . The method of  claim 1 , wherein the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is configured for immediate release, for extended release, for delayed release, or any combination thereof. 
     
     
         15 . The method of  claim 1 , wherein the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is in a pharmaceutical composition, and wherein the pharmaceutical composition is formulated for oral administration. 
     
     
         16 . The method of  claim 1 , wherein the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is administered about once daily in the morning, twice daily or once daily about 1 hour prior to the subject's bedtime. 
     
     
         17 . The method of  claim 1 , wherein the subject is a human. 
     
     
         18 . The method of  claim 17 , wherein the human is an adult with a diagnosis of a condition selected from Lewy Body dementia, probable Dementia with Lewy Bodies, Dementia with Lewy Bodies, Parkinson's disease dementia, Parkinson's disease, multiple system atrophy, Alzheimer's disease, vascular dementia, dementia, mild cognitive impairment, Parkinson's disease psychosis, Alzheimer's disease psychosis, a sleep disturbance, insomnia and any combination thereof. 
     
     
         19 . The method of  claim 17 , wherein the human has a concurrent diagnosis of REM Sleep Behavior disorder, idiopathic REM Sleep Behavior disorder, or a combination thereof, and a condition selected from Lewy Body dementia, probable Dementia with Lewy Bodies, Demential with Lewy Bodies, Parkinson's disease dementia, Parkinson's disease, multiple system atrophy, Alzheimer's disease, vascular dementia, dementia, mild cognitive impairment, Parkinson's disease psychosis, Alzheimer's disease psychosis, a sleep disturbance, insomnia and a combination thereof. 
     
     
         20 . The method of  claim 17 , wherein the human has a Mini Mental State Examination score of greater than, or equal to, about 18. 
     
     
         21 . The method of  claim 17 , wherein the human is an adult with a diagnosis of REM sleep behavior disorder associated with Dementia with Lewy Bodies. 
     
     
         22 . The method of  claim 17 , wherein the human is an adult aged 50-85 inclusive. 
     
     
         23 . The method of  claim 17 , wherein the human has experienced frequent episodes of REM sleep behavior disorder. 
     
     
         24 . The method of  claim 17 , wherein the human has experienced episodes of REM sleep behavior disorder. 
     
     
         25 . The method of  claim 17 , wherein the human has experienced episodes of REM sleep behavior disorder on at least three to four days in a week. 
     
     
         26 . The method of  claim 1 , wherein the subject is concurrently receiving a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of melatonin, quetiapine, clonazepam, levodopa, carbidopa, an antiparkinsonian drug, an acetylcholinesterase inhibitor, NMDA receptor antagonist, and a combination thereof. 
     
     
         27 . The method of  claim 26 , wherein the antiparkinsonian drug is selected from an MAO-B inhibitor, a COMT inhibitor, a dopamine agonist or any combination thereof. 
     
     
         28 . The method of  claim 26 , wherein the acetylcholinesterase inhibitor is selected from the group consisting of donepezil, rivastigmine, galantamine, and pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof. 
     
     
         29 . The method of  claim 26 , wherein the acetylcholinesterase inhibitor is donepezil or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. 
     
     
         30 . The method of  claim 26 , wherein the acetylcholinesterase inhibitor is rivastigmine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. 
     
     
         31 . The method of  claim 26 , wherein the acetylcholinesterase inhibitor is galantamine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. 
     
     
         32 . The method of  claim 26 , wherein NMDA receptor antagonist is selected from the group consisting of memantine, amantadine, ketamine, and pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof. 
     
     
         33 . The method of  claim 32 , wherein the NMDA receptor antagonist is memantine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. 
     
     
         34 . The method of  claim 26 , wherein the NMDA receptor antagonist is amantadine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. 
     
     
         35 . The method of  claim 1 , wherein administration of a therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in treatment, and/or prophylaxis of REM sleep behavior disorder, idiopathic REM sleep behavior disorder, or a combination thereof. 
     
     
         36 . The method of  claim 1 , wherein treating or prophylaxis results in a decrease in the frequency, severity, or a combination thereof of REM sleep behavior disorder episodes. 
     
     
         37 . The method of  claim 1 , wherein treating or prophylaxis results in a decrease in the frequency of abnormal vocalizations and motor behavior per sleep period. 
     
     
         38 . The method of  claim 1 , wherein treatment results in a decrease in the amount of nightmare content per sleep period. 
     
     
         39 . The method of  claim 1 , wherein treating or prophylaxis results in a decrease in the potential for injury or injury to said subject during a sleep period. 
     
     
         40 . The method of  claim 1 , wherein treating or prophylaxis results in an increase in quality of partner sleep. 
     
     
         41 . The method of  claim 1 , wherein treating or prophylaxis results in an improvement in subjective sleep quality, objective sleep measures, or a combination thereof. 
     
     
         42 . The method of  claim 1 , wherein treating or prophylaxis results in an improvement in the clinician assessment of global change pertaining to REM sleep behavior disorder. 
     
     
         43 . The method of  claim 1 , wherein treating or prophylaxis results in a decrease in the frequency of REM sleep behavior disorder behaviors. 
     
     
         44 . The method of  claim 43 , wherein REM sleep behavior disorder behaviors are selected from the group consisting of vocalizations, simple and complex motor behaviors, and any combination thereof. 
     
     
         45 . The method of  claim 1 , wherein treating or prophylaxis results in a decrease in the severity of REM sleep behavior disorder behaviors. 
     
     
         46 . The method of  claim 1 , wherein treating or prophylaxis results in a decrease in the number of nights with injurious behaviors to subject or bed partner per week. 
     
     
         47 . The method of  claim 46 , wherein injurious behaviors are selected from a group consisting of vocalizations, simple and complex motor behaviors, and any combination thereof. 
     
     
         48 . The method of  claim 1 , wherein treating or prophylaxis results in a decrease in the number of nightmares per week. 
     
     
         49 . The method of  claim 1 , wherein treating or prophylaxis results in an improvement in the subject's Mini-Mental State Examination score. 
     
     
         50 .- 63 . (canceled) 
     
     
         64 . The method of  claim 17 , wherein the human is an adult with a diagnosis of REM sleep behavior disorder associated with Dementia with Lewy Bodies.