Diaryl and arylheteroaryl urea derivatives as modulators of the 5-ht2a serotonin receptor useful for the prophylaxis and treatment of disorders related thereto

Abstract

The present invention also relates to the method of prophylaxis or treatment of 5-HT2A serotonin receptor mediated disorders in combination with a dopamine D2 receptor antagonist such as haloperidol, administered separately or together.

1 .- 54 . (canceled) 
     
     
         55 . A compound of Formula (Im): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is phenyl optionally substituted with R 9 , R 10 , R 11 , R 12 , and R 13  each selected independently from the group consisting of C 1-6  acyl, C 1-6  alkoxy, C 1-6  alkyl, amino, C 1-6  alkylamino, C 2-8  dialkylamino, C 1-6  alkylimino, cyano, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, heterocyclic, hydroxyl, nitro, and phenyl, or two adjacent R 9 , R 10 , R 11 , R 12 , and R 13  together with the atoms to which they are attached form a C 5-7  cycloalkyl group or heterocyclic group each optionally substituted with F; and wherein said C 1-6  alkyl, C 1-6  alkylimino, and heterocyclic are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of C 1-6  alkyl, amino, C 1-6  alkylamino, C 2-8  dialkylamino, and hydroxyl; 
 R 2  is H or C 1-6  alkyl; 
 R 3  is H or halogen; 
 R 5  is C 1-6  alkoxy, or hydroxyl, and wherein said C 1-6  alkoxy group can be optionally substituted with 1 to 5 substituents selected independently from the group consisting of C 1-4  alkoxy, C 1-6  alkylamino, C 2-8  dialkylamino, amino, C 1-4  haloalkoxy, hydroxyl and phenyl, wherein said phenyl is optionally substituted with 1 to 5 halogen atoms; 
 R 6  is H; 
 R 7  is H; 
 R 8  is H; 
 X is O or S; and 
 Q is C 1-3  alkylene optionally substituted with 1 to 4 substituents selected from the group consisting of C 1-3  alkyl, C 1-4  alkoxy, carboxy, cyano, C 1-3  haloalkyl, halogen and oxo; or Q is a bond;
 or a pharmaceutically acceptable salt, hydrate or solvate thereof. 
 
 
       
     
     
         56 . The compound according to  claim 55  wherein the compound is selected from the group consisting of:
 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4-chloro-phenyl)-thiourea; 
 1-Benzoyl-3-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-urea; 
 1-Benzyl-3-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-urea; 
 1-[3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4-trifluoromethyl-phenyl)-thiourea; 
 1-Benzyl-3-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-urea; 
 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-{4-chloro-2-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-urea; 
 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-{4-chloro-2-[(3-dimethylamino-propyl)-methyl-amino]-phenyl}-urea; 
 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-urea; 
 1-(4-Chloro-benzyl)-3-[4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea; 
 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-[4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea; and 
 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-[4-(2-dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea, 
 and pharmaceutically acceptable salts, hydrates or solvates thereof. 
 
     
     
         57 . A pharmaceutical composition comprising a compound according to  claim 55 , or pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier. 
     
     
         58 . A pharmaceutical composition comprising a compound according to  claim 56 , or pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier. 
     
     
         59 . A method for modulating the activity of a 5HT 2A  serotonin receptor by contacting the receptor with a compound of  claim 55 . 
     
     
         60 . A method for prophylaxis or treatment of a sleep disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound of  claim 55 . 
     
     
         61 . The method according to  claim 60  wherein said sleep disorder comprises fragmented sleep architecture. 
     
     
         62 . The method according to  claim 60  wherein said effective amount of the compound promotes sleep consolidation. 
     
     
         63 . The method according to  claim 60  wherein said effective amount of the compound increases delta power. 
     
     
         64 . The method according to  claim 60  wherein said sleep disorder is a dyssomnia. 
     
     
         65 . The method according to  claim 64  wherein said dyssomnia is selected from the group consisting of psychophysiological insomnia, sleep state misperception, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, periodic limb movement disorder, restless leg syndrome, inadequate sleep hygiene, environmental sleep disorder, altitude insomnia, adjustment sleep disorder, insufficient sleep syndrome, limit-setting sleep disorder, sleep-onset association disorder, nocturnal eating or drinking syndrome, hypnotic dependent sleep disorder, stimulant-dependent sleep disorder, alcohol-dependent sleep disorder, toxin-induced sleep disorder, time zone change (jet lag) syndrome, shift work sleep disorder, irregular sleep-wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome and non-24-hour sleep-wake disorder. 
     
     
         66 . The method according to  claim 60  wherein said sleep disorder is a parasomnia. 
     
     
         67 . The method according to  claim 66  wherein said parasomnia is selected from the group consisting of confusional arousals, sleepwalking and sleep terrors, rhythmic movement disorder, sleep starts, sleep talking and nocturnal leg cramps. 
     
     
         68 . The method according to  claim 67  wherein said sleep disorder is associated with a medical or psychiatric disorder. 
     
     
         69 . A method for treating agitation in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound of  claim 55 . 
     
     
         70 . A method for the treatment of agitation or a symptom thereof in a patient suffering from dementia comprising administering to said patient a therapeutically effective amount of a compound of  claim 55 . 
     
     
         71 . The method of  claim 70 , wherein the dementia is due to a degenerative disease of the nervous system. 
     
     
         72 . The method of  claim 70 , wherein the dementia is selected from the group consisting of Alzheimer's disease, Lewy Body, Parkinson's disease, Huntington's disease, and dementia due to diseases that affect blood vessels, or any combination thereof. 
     
     
         73 . A method of treating agitation or a symptom thereof in a patient in need of such treatment, where the patient is a cognitively intact elderly patient, comprising administering to said patient a therapeutically effective amount of a compound of  claim 55 . 
     
     
         74 . A method for prophylaxis or treatment of platelet aggregation in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to  claim 55 . 
     
     
         75 . A method for prophylaxis or treatment of an indication selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, and atrial fibrillation in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to  claim 55 . 
     
     
         76 . A method for prophylaxis or treatment of reducing the risk of blood clot formation in an angioplasty or coronary bypass surgery individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to  claim 55 . 
     
     
         77 . A method for prophylaxis or treatment of reducing the risk of blood clot formation in an individual suffering from atrial fibrillation, comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to  claim 55 . 
     
     
         78 . A process for preparing a composition comprising admixing a compound according to  claim 55  and pharmaceutically acceptable carrier. 
     
     
         79 . A method for prophylaxis or treatment of diabetic-related disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound of  claim 55 . 
     
     
         80 . The method of  claim 79 , wherein the diabetic-related disorder is diabetic peripheral neuropathy. 
     
     
         81 . The method of  claim 79 , wherein the diabetic-related disorder is diabetic nephropathy. 
     
     
         82 . The method of  claim 79 , wherein the diabetic-related disorder is diabetic retinopathy. 
     
     
         83 . A method for prophylaxis or treatment of an individual suffering from at least one of the indications selected from the group consisting of behavioral disorder, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia and NOS schizophrenia comprising administering to said individual in need thereof a therapeutically effective amount of a dopamine D2 receptor antagonist and a compound of  claim 55 . 
     
     
         84 . The method of  claim 83 , wherein the dopamine D2 receptor antagonist is haloperidol. 
     
     
         85 . A method for prophylaxis or treatment of an individual with infantile autism, Huntington's chorea, or nausea and vomiting from chemotherapy or chemotherapeutic antibodies comprising administering to said individual in need thereof a therapeutically effective amount of a dopamine D2 receptor antagonist and a compound of  claim 55 . 
     
     
         86 . The method of  claim 85 , wherein the dopamine D2 receptor antagonist is haloperidol. 
     
     
         87 . A method for prophylaxis or treatment of alleviating negative symptoms of schizophrenia induced by the administration of haloperidol to an individual suffering from said schizophrenia, comprising administering to said individual in need thereof a therapeutically effective amount of a compound of  claim 55 . 
     
     
         88 . The method of  claim 87 , wherein the haloperidol and the compound of  claim 55  are administered in separate dosage forms. 
     
     
         89 . The method of  claim 87 , wherein the haloperidol and the compound of  claim 55  are administered in a single dosage form. 
     
     
         90 . A method for prophylaxis or treatment of asthma in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound of  claim 55 .