Dihydrobenzofuranyl Alkanamine Derivatives and Methods for Using Same

Abstract

Compounds of Formula 1 or pharmaceutically acceptable salts thereof are provided: which are agonists or partial agonists of the 2C subtype of brain serotonin receptors. The compounds, and compositions containing the compounds, can be used to treat a variety of central nervous system disorders such as schizophrenia.

1 - 32 . (canceled) 
     
     
         33 . A method for treating a patient suffering from schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, L-DOPA-induced psychosis, psychosis associated with Alzheimer's dementia, psychosis associated with Parkinson's disease, psychosis associated with Lewy body disease, dementia, memory deficit, or intellectual deficit disorder associated with Alzheimer's disease comprising administering to the patient a therapeutically effective amount of a compound of Formula 1: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, 
         wherein:
 R and R′ are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or alkylcycloalkyl of 4 to 12 carbon atoms having 3 to 6 carbons in the cycloalkyl ring; 
 alternatively R and R′ can be taken together with the nitrogen to which they are attached to form a ring containing 2-5 carbon atoms, wherein one of the ring carbon atoms is optionally replaced by nitrogen, sulfur or oxygen; 
 R 1  and R 2  are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or perfluoroalkyl of 1 to 6 carbon atoms; 
 R 3a  and R 3b  are, independently, hydrogen, halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms; 
 R 4 , R 5 , R 6 , and R 7  are, independently, hydrogen, halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, aryl of 5 to 10 carbon atoms, aryloxy of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, alkenyl of 2 to 8 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, carboxamido, alkanamido of 2 to 6 carbon atoms, alkanesulfonamido of 1 to 6 carbon atoms, amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms per alkyl moiety, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, wherein the cycloalkyl and heterocycloalkyl groups are saturated or partially saturated; and 
 n is 1, 2 or 3; 
 wherein at least one of R 4 , R 5 , R 6  and R 7  is branched alkyl of 3 to 8 carbon atoms, branched alkenyl of 3 to 8 carbon atoms, or —Y—R 8 , wherein Y is selected from a direct bond, lower alkyl, lower ankenyl, O, and NH and R 8  is aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl; and 
 wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, cyano, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms. 
 
       
     
     
         34 . The method of  claim 33  wherein the patient is suffering from schizophrenia. 
     
     
         35 . A method for treating a patient suffering from bipolar disorders, depressive disorders, mood episodes, anxiety disorders, adjustment disorders, or eating disorders comprising comprising administering to the patient a therapeutically effective amount of a compound of Formula 1: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, 
         wherein:
 R and R′ are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or alkylcycloalkyl of 4 to 12 carbon atoms having 3 to 6 carbons in the cycloalkyl ring; 
 alternatively R and R′ can be taken together with the nitrogen to which they are attached to form a ring containing 2-5 carbon atoms, wherein one of the ring carbon atoms is optionally replaced by nitrogen, sulfur or oxygen; 
 R 1  and R 2  are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or perfluoroalkyl of 1 to 6 carbon atoms; 
 R 3a  and R 3b  are, independently, hydrogen, halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms; 
 R 4 , R 5 , R 6 , and R 7  are, independently, hydrogen, halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, aryl of 5 to 10 carbon atoms, aryloxy of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, alkenyl of 2 to 8 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, carboxamido, alkanamido of 2 to 6 carbon atoms, alkanesulfonamido of 1 to 6 carbon atoms, amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms per alkyl moiety, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, wherein the cycloalkyl and heterocycloalkyl groups are saturated or partially saturated; and 
 n is 1, 2 or 3; 
 wherein at least one of R 4 , R 5 , R 6  and R 7  is branched alkyl of 3 to 8 carbon atoms, branched alkenyl of 3 to 8 carbon atoms, or —Y—R 8 , wherein Y is selected from a direct bond, lower alkyl, lower ankenyl, O, and NH and R 8  is aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl; and 
 wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, cyano, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms. 
 
       
     
     
         36 . The method of  claim 35  wherein the bipolar disorder is bipolar I disorder, bipolar II disorder, or cyclothymic disorder; the depressive disorder is major depressive disorder, dysthymic disorder, or substance-induced mood disorder; the mood episode is major depressive episode, manic episode, mixed episode, or hypomanic episode; the anxiety disorder is panic attack, agoraphobia, panic disorder, specific phobia, social phobia, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, separation anxiety disorder, or substance-induced anxiety disorder. 
     
     
         37 . The method of  claim 36  wherein the condition is depressive disorder, bipolar disorder or mood episode. 
     
     
         38 . A method for treating a patient suffering from epilepsy, sleep disorders, migraines, sexual dysfunction, drug addiction, alcohol addiction, gastrointestinal disorders, or obesity comprising administering to the patient a therapeutically effective amount of a compound of Formula 1: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, 
         wherein:
 R and R′ are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or alkylcycloalkyl of 4 to 12 carbon atoms having 3 to 6 carbons in the cycloalkyl ring; 
 alternatively R and R′ can be taken together with the nitrogen to which they are attached to form a ring containing 2-5 carbon atoms, wherein one of the ring carbon atoms is optionally replaced by nitrogen, sulfur or oxygen; 
 R 3a  and R 3b  are, independently, hydrogen, halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms; 
 R 4 , R 5 , R 6 , and R 7  are, independently, hydrogen, halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, aryl of 5 to 10 carbon atoms, aryloxy of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, alkenyl of 2 to 8 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, carboxamido, alkanamido of 2 to 6 carbon atoms, alkanesulfonamido of 1 to 6 carbon atoms, amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms per alkyl moiety, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, wherein the cycloalkyl and heterocycloalkyl groups are saturated or partially saturated; and 
 n is 1, 2 or 3; 
 wherein at least one of R 4 , R 5 , R 6  and R 7  is branched alkyl of 3 to 8 carbon atoms, branched alkenyl of 3 to 8 carbon atoms, or —Y—R 8 , wherein Y is selected from a direct bond, lower alkyl, lower ankenyl, O, and NH and R 8  is aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl; and 
 wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, cyano, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms. 
 
       
     
     
         39 . A method for treating a patient suffering from a central nervous system deficiency associated with trauma, stroke, or spinal cord injury comprising administering to the patient a therapeutically effective amount of a compound of Formula 1: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, 
         wherein:
 R and R′ are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or alkylcycloalkyl of 4 to 12 carbon atoms having 3 to 6 carbons in the cycloalkyl ring; 
 alternatively R and R′ can be taken together with the nitrogen to which they are attached to form a ring containing 2-5 carbon atoms, wherein one of the ring carbon atoms is optionally replaced by nitrogen, sulfur or oxygen; 
 R 1  and R 2  are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or perfluoroalkyl of 1 to 6 carbon atoms; 
 R 3a  and R 3b  are, independently, hydrogen, halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms; 
 R 4 , R 5 , R 6 , and R 7  are, independently, hydrogen, halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, aryl of 5 to 10 carbon atoms, aryloxy of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, alkenyl of 2 to 8 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, carboxamido, alkanamido of 2 to 6 carbon atoms, alkanesulfonamido of 1 to 6 carbon atoms, amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms per alkyl moiety, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, wherein the cycloalkyl and heterocycloalkyl groups are saturated or partially saturated; and 
 n is 1, 2 or 3; 
 wherein at least one of R 4 , R 5 , R 6  and R 7  is branched alkyl of 3 to 8 carbon atoms, branched alkenyl of 3 to 8 carbon atoms, or —Y—R 8 , wherein Y is selected from a direct bond, lower alkyl, lower ankenyl, O, and NH and R 8  is aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl; and 
 wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, cyano, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms. 
 
       
     
     
         40 . A composition comprising a compound of Formula 1: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, 
         wherein:
 R and R′ are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or alkylcycloalkyl of 4 to 12 carbon atoms having 3 to 6 carbons in the cycloalkyl ring; 
 alternatively R and R′ can be taken together with the nitrogen to which they are attached to form a ring containing 2-5 carbon atoms, wherein one of the ring carbon atoms is optionally replaced by nitrogen, sulfur or oxygen; 
 R 1  and R 2  are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or perfluoroalkyl of 1 to 6 carbon atoms; 
 R 3a  and R 3b  are, independently, hydrogen, halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms; 
 R 4 , R 5 , R 6 , and R 7  are, independently, hydrogen, halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, aryl of 5 to 10 carbon atoms, aryloxy of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, alkenyl of 2 to 8 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, carboxamido, alkanamido of 2 to 6 carbon atoms, alkanesulfonamido of 1 to 6 carbon atoms, amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms per alkyl moiety, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, wherein the cycloalkyl and heterocycloalkyl groups are saturated or partially saturated; and 
 n is 1, 2 or 3; 
 wherein at least one of R 4 , R 5 , R 6  and R 7  is branched alkyl of 3 to 8 carbon atoms, branched alkenyl of 3 to 8 carbon atoms, or —Y—R 8 , wherein Y is selected from a direct bond, lower alkyl, lower ankenyl, O, and NH and R 8  is aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl; and 
 wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, cyano, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms; and 
 one or more pharmaceutically acceptable carriers.