5-HT receptor ligands and uses thereof

Abstract

Compounds of Formula (IA) that act as 5-HT receptor ligands and their uses in the treatment of diseases linked to the activation of 5-HT 2 receptors in animals are described herein.

1 - 28 . (cancelled).  
     
     
         29 . A method for treating a 5-HT 2  receptor-mediated disease, condition, or disorder in an animal comprising the step of administering to said animal a therapeutically effective amount of a compound of Formula (IA)  
       
         
           
           
               
               
           
         
       
       wherein 
 Y is nitrogen;  
 X and Z are each independently CR, where R for each occurrence is hydrogen, halogen, (  1 -C 4 )alkyl, amino or (C 1 -C 4 )alkylamino;  
 W is amino, (C 1 -C 4 )alkylamino, or acetylamino;  
 at least one of R 1a , R 1b , R 1d , and R 1e  is independently selected from the group consisting of halogen, nitro, amino. (C 1 -C 4 )alkylamino, cyano, —C(O)NH 2 , (C 1 -C 4 )alkyl, halo-substituted(C 1 -C 4 )alkyl, (C 1 -C 4 ) alkoxy, and halo-substituted(C 1 -C 4 )alkoxy, or R 1a  and R 1b  taken together form a five- or six-membered, aromatic or partially or fully saturated fused ring, or R 1a  taken together with R 2a  or R 2b  forms a five- or six-membered fully saturated fused ring;  
 R 1c  is hydrogen;  
 R 2a  and R 2b  are each independently hydrogen, (C 1 -C 4 )alkyl, partially or fully saturated (C 3 -C 6 )cycloalkyl, or one of which taken together with R 1a  forms a five- or six-membered, fully saturated fused ring;  
 n is 0, 1, or2;  
 R 3a  and R 3b  are each independently hydrogen, halogen, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkyl substituted with hydroxy, fluoro, or (C 1 -C 4 )alkoxy;  
 R 4  is hydrogen, hydroxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl substituted with hydroxy or cyano, (C 1 -C 4 )alkylcarbonyl (C-C 4 )alkoxy, (C 1 -C 4 )alkoxy-carbonyl, or (C 3 -C 4 )alkenyl;  
 a nitrogen oxide thereof, a prodrug of said compound or said nitrogen oxide; a pharmaceutically acceptable salt of said compound, said nitrogen oxide, or said prodrug, or a solvate or hydrate of said compound, said nitrogen oxide, said prodrug, or said salt.  
 
     
     
         30 - 32 . (cancelled).  
     
     
         33 . The method of  claim 29  or, 30, 31 or 32 wherein said 5-HT 2  receptor-mediated disease, condition or disorder is a 5-HT 2c  receptor-mediated disease, condition or disorder.  
     
     
         34 . The method of  claim 29  or  68  wherein said 5-HT 2  receptor-mediated disease, condition, or disorder is selected from the group consisting of weight loss, obesity, bulimia, premenstrual syndrome or late luteal phase syndrome, depression, atypical depression, bipolar disorders, psychoses, schizophrenia, migraine, alcoholism, tobacco abuse, panic disorder, anxiety, post-traumatic syndrome, memory loss, dementia of aging, social phobia, attention deficit hyperactivity disorder, disruptive behavior disorders, impulse control disorders, borderline personality disorder, obsessive compulsive disorder, chronic fatigue syndrome, sexual dysfunction in males, sexual dysfunction in females, anorexia nervosa, disorders of sleep, autism, seizure disorders, epilepsy, mutism, spinal cord injury, damage of the central nervous system, cardiovascular disorders, gastrointestinal disorders, diabetes insipidus, and type II diabetes.  
     
     
         35 . A method for treating or preventing a 5-HT 2  receptor-mediated disease, condition, or disorder in an animal comprising the step of administering to said animal a therapeutically effective amount of a pharmaceutical composition comprising 
 (1) a compound of Formula (IA)                          wherein    Y is nitrogen;    X and Z are each independently CR, where R for each occurrence is hydrogen, halogen, (C 1 -C 4 )alkyl, amino, or (C 1 -C 4 )alkylamino;    W is amino, (C 1 - 4 )alkylamino, or acetylamino;    at least one of R 1a , R 1b , R 1d , and R 1e  is independently selected from the group consisting of halogen, nitro, amino. (C 1 - 4 )alkylamino, cyano, —C(O)NH 2 . (C 1 -C 4 )alkyl, halo-substituted(C 1 -C 4 )alkyl (C 1 -C 4 ) alkoxy, and halo-substituted(C 1 -C 4 )alkoxy, or R 1a  and R 1b  taken together form a five- or six-membered, aromatic or partially or fully saturated fused ring, or R 1a  taken together with R 2 a or R 2b  forms a five- or six-membered fully saturated fused ring;    R 1c  is hydrogen:    R 2a  and R 2b  are each independently hydrogen, (C 1 -C 4 )alkyl, partially or fully saturated (C 3 -C 6 )cycloalkyl, or one of which taken together with R 1a  forms a five- or six-membered, fully saturated fused ring;    n is 0, 1,or 2;    R 3a  and R 3b  are each independently hydrogen, halogen, (C 1 -C 4 )alkyl, or (C 1 - 4 )alkyl substituted with hydroxy, fluoro, or (C 1 -C 4 )alkoxy;    R 4  is hydrogen, hydroxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl substituted with hydroxy or cyano, (C 1 -C 4 )alkylcarbonyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy-carbonyl, or (C 3 -C 4 )alkenyl;    a nitrogen oxide thereof, a prodrug of said compound or said nitrogen oxide; a pharmaceutically acceptable salt of said compound, said nitrogen oxide,    or said prodrug, or a solvate or hydrate of said compound, said nitrogen oxide, said prodrum, or said salt; and    (2) a pharmaceutically acceptable excipient, diluent, or carrier.    
     
     
         36 . The method of  claim 35  wherein said 5-HT 2  receptor-mediated disease, condition or disorder is a 5-HT 2c  receptor-mediated disease, condition or disorder.  
     
     
         37 . The method of  claim 35  wherein said 5-HT 2  receptor-mediated disease, condition, or disorder is selected from the group consisting of weight loss, obesity, bulimia, premenstrual syndrome or late luteal phase syndrome, depression, atypical depression, bipolar disorders, psychoses, schizophrenia, migraine, alcoholism, tobacco abuse, panic disorder, anxiety, post-traumatic syndrome, memory loss, dementia of aging, social phobia, attention deficit hyperactivity disorder, disruptive behavior disorders, impulse control disorders, borderline personality disorder, obsessive compulsive disorder, chronic fatigue syndrome, sexual dysfunction in males, sexual dysfunction in females, ariorexia nervosa, disorders of sleep, autism, seizure disorders, epilepsy, mutism, spinal cord injury, damage of the central nervous system, cardiovascular disorders, gastrointestinal disorders, diabetes insipidus, and type II diabetes.  
     
     
         38 . A method for treating or preventing a 5-HT 2  receptor-mediated disease, condition, or disorder in an animal comprising the step of administering to said animal a therapeutically effective amount of a pharmaceutical composition comprising 
 (1) a compound of Formula (IA)                          wherein    Y is nitrogen:    X and Z are each independently CR, or    X is CH and Z is CR,or    X is CR and Z is CH,    where R for each occurrence is halogen, (C 1 -C 4 )alkyl, amino, or (C 1 -C 4 )alkylamino: or    W is oxy or thio:    at least one of R 1a , R 1b , R 1d , and R 1e  is independently selected from the group consisting of halogen, nitro, amino, (C 1 -C 4 )alkylamino, cyano, —C(O)NH 2 , (C 1 -C 4 )alkyl, halo-substituted(C 1 -C 4 )alkyl, (C 1 -C 4 ) alkoxy, and halo-substituted(C 1 -C 4 )alkoxy, or R 1a  and R 1b  taken together form a five- or six-membered, aromatic or partially or fully saturated fused ring, or R 1a  taken together with R 2 a or R 2b  forms a five- or six-membered, fully saturated fused ring;    R 1c  is hydrogen;    R 2 a and R 2b  are each independently hydrogen, (C 1 -C 4 )alkyl, partially or fully saturated (C 3 -C 6 )cycloalkyl, or one of which taken together with R 1a  forms a five- or six-membered, fully saturated fused ring;    n is 0, 1 or2;    R 3a  and R 3b  are each independently hydrogen, halogen, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkyl substituted with hydroxy, fluoro, or (C 1 -C 4 )alkoxy;    R 4  is hydrogen, hydroxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl substituted with hydroxy or cyano, (C 1 -C 4 )alkylcarbonyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy-carbonyl, or (C 3 -C 4 alkenyl;    a nitrogen oxide thereof, a prodrug of said compound or said nitrogen oxide; a pharmaceutically acceptable salt of said compound, said nitrogen oxide, or said prodrug, or a solvate or hydrate of said compound, said nitrogen oxide, said prodrug, or said salt.    
     
     
         39 - 40 . (cancelled).  
     
     
         41 . The method of  claim 38  wherein said 5-HT 2  receptor-mediated disease, condition or disorder is a 5-HT 2c  receptor-mediated disease, condition or disorder.  
     
     
         42 . The method of  claim 38  wherein said 5-HT 2  receptor-mediated disease, condition, or disorder is selected from the group consisting of weight loss, obesity, bulimia, premenstrual syndrome or late luteal phase syndrome, depression, atypical depression, bipolar disorders, psychoses, schizophrenia, migraine, alcoholism, tobacco abuse, panic disorder, anxiety, post-traumatic syndrome, memory loss, dementia of aging, social phobia, attention deficit hyperactivity disorder, disruptive behavior disorders, impulse control disorders, borderline personality disorder, obsessive compulsive disorder, chronic fatigue syndrome, sexual dysfunction in males, sexual dysfunction in females, anorexia nervosa, disorders of sleep, autism, seizure disorders, epilepsy, mutism, spinal cord injury, damage of the central nervous system, cardiovascular disorders, gastrointestinal disorders, diabetes insipidus, and type II diabetes.  
     
     
         43 - 44 . (cancelled).  
     
     
         45 . A method for treating or preventing a 5-HT 2  receptor-mediated disease, condition, or disorder comprising administering to an animal in need of such treatment 
 a) a therapeutically effective amount of a compound of Formula (IA)                          wherein    Y is nitrogen;    X and Z are each independently CR, where R for each occurrence is hydrogen, halogen, (C 1 -C 4 alkyl, amino. or (C 1 -C 4 )alkylamino;    W is amino, (C 1 -C 4 )alkylamino, or acetylamino;    at least one of R 1a , R 1b , R 1d , and R 1e  is independently selected from the group consisting of halogen, nitro, amino, (C 1 -C 4 )alkylamino, cyano, —C(O)NH 2 , (C 1 -C 4 )alkyl, halo-substituted(C 1 -C 4 )alkyl, (C 1 -C 4 ) alkoxy, and halo-substituted(C 1 -C 4 )alkoxy, or R 1a  and R 1b  taken together form a five- or six-membered, aromatic or partially or fully saturated fused ring, or R 1a  taken together with R 2a  or R 2b  forms a five- or six-membered fully saturated fused ring;    R 1c  is hydrogen;    R 2a  and R 2b  are each independently hydrogen, (C 1 -C 4 )alkyl, partially or fully saturated (C 3 -C 6 )cycloalkyl, or one of which taken together with R 1a  forms a five- or six-membered, fully saturated fused ring;    n is 0, 1, or 2;    R 3a  and R 3b  are each independently hydrogen, halogen, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkyl substituted with hydroxy, fluoro, or (C 1 -C 4 )alkoxy;    R 4  is hydrogen, hydroxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl substituted with hydroxy or cyano, (C 1 -C 4 )alkylcarbonyl, (C 1 -C 4 )alkoxy, (C 1 -C 4   1 )alkoxy-carbonyl, or (C 3 -C 4 )alkenyl;    a nitrogen oxide thereof, a prodrug of said compound or said nitrogen oxide; a pharmaceutically acceptable salt of said compound, said nitrogen oxide, or said prodrug, or a solvate or hydrate of said compound, said nitrogen oxide, said prodrug, or said salt; and    b) a therapeutically effective amount of at least one additional pharmaceutical agent selected from the group consisting of an apo-B/MTP inhibitor, an MCR-4 agonist, a CCK-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a β 3  adrenergic receptor agonist, a dopamine agonist, a melanocyte-stimulating hormone receptor analog, a cannabinoid 1 receptor antagonist, a melanin concentrating hormone antagonist, leptin, a leptin analog, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, a bombesin agonist, a Neuropeptide-Y antagonist, a thyromimetic agent, dehydroepiandrosterone or an analog thereof, a glucocorticoid receptor agonist or antagonist, an orexin receptor antagonist, a urocortin binding protein antagonist, a glucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor, an AGRP, a ghrelin receptor antagonist, a histamine 3 receptor antagonist or reverse agonist, and a neuromedin U receptor agonist.    
     
     
         46 . The method of  claim 45  or  69  wherein said compound, a nitrogen oxide thereof, a prodrug of said compound or said nitrogen oxide; a pharmaceutically acceptable salt of said compound, said nitrogen oxide, or said prodrug, or a solvate or hydrate of said compound, said nitrogen oxide, said prodrug, or said salt, and said at least one additional pharmaceutical agent is administered simultaneously.  
     
     
         47 . The method of  claim 45  or  69  wherein said compound, a nitrogen oxide thereof, a-prodrug of said compound or said nitrogen oxide; a pharmaceutically acceptable salt of said compound, said nitrogen oxide, or said prodrug, or a solvate or hydrate of said compound, said nitrogen oxide, said prodrug, or said salt, and said at least one additional pharmaceutical agent is administered sequentially.  
     
     
         48 - 51 . (cancelled).  
     
     
         52 . The method of  claim 45  or  69 , wherein said 5-HT 2  receptor-mediated disease, condition or disorder is a 5-HT 2c  receptor-mediated disease, condition or disorder.  
     
     
         53 - 67 . (cancelled)  
     
     
         68 . A method for treating a 5-HT 2  receptor-mediated disease, condition, or disorder in an animal comprising the step of administering to said animal a therapeutically effective amount of a compound of Formula (IA)  
       
         
           
           
               
               
           
         
       
       wherein 
 Y is nitrogen;  
 X and Z are each independently CR, or  
 X is CH and Z is CR, or  
 X is CR and Z is CH,  
 where R for each occurrence is halogen, (C 1 -C 4 )alkyl, amino, or (C 1 -C 4 )alkylamino; or  
 W is oxy or thio;  
 at least one of R 1a a R 1b , R 1d , and R 1e  is independently selected from the group consisting of halogen, nitro, amino, (C 1 -C 4 )alkylamino, cyano, -C(O)NH 2 , (C 1 -C 4 )alkyl, halo-substituted(C 1 -C 4 )alkyl, (C 1 -C 4 ) alkoxy, and halo-substituted(C 1 -C 4 )alkoxy, or R 1a  and R 1b  taken together form a five- or six-membered, aromatic or partially or fully saturated fused ring, or R 1a  taken together with R 2a  or R 2b  forms a five- or six-membered, fully saturated fused ring;  
 R 1c  is hydrogen;  
 R 2a  and R 2b  are each independently hydrogen, (C 1 -C 4 )alkyl, partially or fully saturated (C 3 -C 6 )cycloalkyl, or one of which taken together with R 1a  forms a five- or six-membered, fully saturated fused ring;  
 n is 0, 1, or 2;  
 R 3a  and R 3b  are each independently hydrogen, halogen, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkyl substituted with hydroxy, fluoro, or (C 1 -C 4 )alkoxy;  
 R 4  is hydrogen, hydroxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl substituted with hydroxy or cyano, (C, -C 4 )alkylcarbonyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy-carbonyl, or (C 3 -C 4 )alkenyl;  
 a nitrogen oxide thereof, a prodrug of said compound or said nitrogen oxide; a pharmaceutically acceptable salt of said compound, said nitrogen oxide, or said prodrug, or a solvate or hydrate of said compound, said nitrogen oxide, said prodrug, or said salt.  
 
     
     
         69 . A method for treating or preventing a 5-HT 2  receptor-mediated disease, condition, or disorder comprising administering to an animal in need of such treatment 
 a) a therapeutically effective amount of a compound of Formula (IA)                          wherein    Y is nitrogen;    X and Z are each independently CR, or    X is CH and Z is CR, or    X is CR and Z is CH,    where R for each occurrence is halogen, (C 1 -C 4 )alkyl, amino, or (C 1 -C 4 )alkylamino; or    W is oxy or thio;    at least one of R 1a , R 1b , R 1d , and R 1e  is independently selected from the group consisting of halogen, nitro, amino, (C 1 -C 4 )alkylamino, cyano, -C(O)NH 2 , (C 1 -C 4 )alkyl, halo-substituted(C 1 -C 4 )alkyl, (C 1 -C 4 ) alkoxy, and halo-substituted(C 1 -C 4 )alkoxy, or R 1a  and R 1b  taken together form a five- or six-membered, aromatic or partially or fully saturated fused ring, or R 1a  taken together with R 2a  or R 2b  forms a five- or six-membered, fully saturated fused ring;    R 1c  is hydrogen;    R 2a  and R 2b  are each independently hydrogen, (C 1 -C 4 )alkyl, partially or fully saturated (C 3 -C 6 )cycloalkyl, or one of which taken together with R 1a  forms a five- or six-membered, fully saturated fused ring;    n is 0, 1, or2;    R 3a  and R 3b  are each independently hydrogen, halogen, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkyl substituted with hydroxy, fluoro, or (C 1 -C 4 )alkoxy;    R 4  is hydrogen, hydroxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl substituted with hydroxy or cyano, (C 1 -C 4 )alkylcarbonyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy-carbonyl, or (C 3 -C 4 )alkenyl;    a nitrogen oxide thereof, a prodrug of said compound or said nitrogen oxide; a pharmaceutically acceptable salt of said compound, said nitrogen oxide, or said prodrug, or a solvate or hydrate of said compound, said nitrogen oxide, said prodrug, or said salt; and    b) a therapeutically effective amount of at least one additional pharmaceutical agent selected from the group consisting of an apo-B/MTP inhibitor, an MCR-4 agonist, a CCK-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a β 3  adrenergic receptor agonist, a dopamine agonist, a melanocyte-stimulating hormone receptor analog, a cannabinoid 1 receptor antagonist, a melanin concentrating hormone antagonist, leptin, a leptin analog, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, a bombesin agonist, a Neuropeptide-Y antagonist, a thyromimetic agent, dehydroepiandrosterone or an analog thereof, a glucocorticoid receptor agonist or antagonist, an orexin receptor antagonist, a urocortin binding protein antagonist, a glucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor, an AGRP, a ghrelin receptor antagonist, a histamine 3 receptor antagonist or reverse agonist, and a neuromedin U receptor agonist.