Pharmaceutical composition for the treatment of CNS and other disorders

Abstract

The present invention relates to a method of treating disorders of the Central Nervous System (CNS) and other disorders in a mammal, including a human, by administering to the mammal a CNS-penetrant α7 nicotinic receptor agonist. It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier and a CNS-penetrant α7 nicotinic receptor agonist.

1 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 n=1-2;  
 m=1-2;  
 o=1-2;  
 A=O, S or NR 1 ;  
 B=N or CR 2 ;  
 Q=N or CR 3 ;  
 D=N or CR 4 ;  
 E=N or CR 5 ;  
 R 1  is H, a straight chain or branched (C 1 -C 8 )alkyl, C(═O)OR 6 , CH 2 R 6 , C(═O)NR 6 R 7 , C(═O)R 6 , or SO 2 R 6 ;  
 each R 2, R 3, R 4  and R 5  is independently selected from F, Cl, Br, I, nitro, cyano, CF 3 , —NR 6 R 7 , —NR 6 C(═O)R 7 , —NR 6 C(═O)NR 7 R 8 , —NR 6 C(═O)OR 7 , —NR 6 S(═O) 2 R 7 , —NR 6 S(═O) 2 NR 7 R 8 , —OR 6 , —OC(═O)R 6 , —OC(═O)OR 6 , —OC(═O)NR 6 R 7 , —OC(═O)SR 6 , —C(═O)OR 6 , —C(═O)R 6 , —C(═O)N R 6 R 7 , —SR 6 , —S(═O)R 6 , —S(═O) 2 R 6 , —S(═O) 2 NR 6 R 7 , and R 6 ;  
 each R 6 , R 7 , and R 8  is independently selected from H, straight chain or branched (C 1 -C 8 )alkyl, straight chain or branched (C 2 -C 8 )alkenyl, straight chain or branched (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, 3-8 membered heterocycloalkyl, (C 5 -C 11 )bicycloalkyl, (C 7 -C 11 )bicycloalkenyl, 5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkenyl, (C 6 -C 11 ) aryl, and 5-12 membered heteroaryl; wherein each R 6 , R 7 , and R 8  is optionally substituted with from one to six substituents, independently selected from F, Cl, Br, I, nitro, cyano, CF 3 , —NR 9 R 10 , —NR 9 C(═O)R 10 , —NR 9 C(═O)NR 10 R 11 , —NR 9 C(═O)OR 10 , —NR 9 S(═O) 2 R 10 , —NR 9 S(═O) 2 NR 10 R 11 , —OR 9 , —OC(═O)R 9 , —OC(═O)OR 9 , —OC(═O)NR 9 R 10 , —OC(═O)SR 9 , —C(═O)OR 9 , —C(═O)R 9 , —C(═O)NR 9 R 10 , —SR 9 , —S(═O)R 9 , —S(═O) 2 R 9 , —S(═O) 2 NR 9 R 10  and R 9 ;  
 each R 9 , R 10  and R 11  is independently selected from H, straight chain or branched (C 1 -C 8 )alkyl, straight chain or branched (C 2 -C 8 )alkenyl, straight chain or branched (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, 3-8 membered heterocycloalkyl, (C 5 -C 11 )bicycloalkyl, (C 7 -C 11 )bicycloalkenyl, 5-11 membered heterobicycloalkyl, (5-11 membered) heterobicycloalkenyl, (C 6 -C 11 ) aryl or 5-12 membered heteroaryl; wherein each R 9 , R 10  and R 11  is optionally substituted with from one to six substituents independently selected from F, Cl, Br, I, nitro, cyano, CF 3 , —NR  12 R 13 , —NR 12 C(═O)R 13 , —NR 12 C(═O)NR 13  R 14 , —NR 12 C(═O)OR 13 , —NR 12 S(═O) 2 R 13 , —NR 12 S(═O) 2 NR 13 R 14 , —OR 12 , —OC(═O)R 12 , —OC(═O)OR 12 , —OC(═O)NR 12 R 13 , —OC(═O)SR 12 , —C(═O)OR 12 , —C(═O)R 12 , —C(═O)NR 12 R 13 , —SR 12 , S(═O)R 12  —S(═O) 2 R 12 , —S(═O) 2 NR 12 R 13  and R 12 ;  
 each R 12 , R 13 , and R 14  is independently selected from H, straight chain or branched (C 1 -C 8 )alkyl, straight chain or branched (C 2 -C 8 )alkenyl, straight chain or branched (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, 3-8 membered heterocycloalkyl, (C 5 -C 11 )bicycloalkyl, (C 7 -C 11 )bicycloalkenyl, 5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkenyl, (C 6 -C 11 ) aryl and (5-12 membered) heteroaryl;  
 or R 2  and R 3 , or R 3  and R 4 , or R 4  and R 5 , may form another 6-membered aromatic or heteroaromatic ring sharing B and Q, or Q and D, or D and E, respectively, and may be optionally substituted with from one to four substitutuents independently selected from the group of radicals set forth in the definition of R 6 , R 7  and R 8  above;  
 or an enantiomeric, diastereomeric, or tautomeric isomer thereof, or a pharmaceutically acceptable salt of such compound or isomer.  
 
     
     
         2 . A compound according to  claim 1  wherein n=1, m=2, and o=1.  
     
     
         3 . A compound according to  claim 1  wherein A=S.  
     
     
         4 . A compound according to  claim 1  wherein A=O.  
     
     
         5 . A compound according to  claim 4  wherein B=CR 2 , Q=CR 3 , D=CR 4 , E=CR 5 .  
     
     
         6 . A compound according to  claim 4  wherein B=N, Q=CR 3 , D=CR 4 , and E=CR 5 .  
     
     
         7 . A compound according to  claim 4  wherein B=CR 2 , Q=N, D=CR 4 , and E=CR 5 .  
     
     
         8 . A compound according to  claim 4  wherein B=CR 2 , Q=CR 3 , D=N, and E=CR 5 .  
     
     
         9 . A compound according to  claim 4  wherein B=CR 2 , Q=CR 3 , D=CR 4 , and E=N.  
     
     
         10 . A pharmaceutical composition for the treatment of schizophrenia in a mammal, comprising an amount of a compound according to  claim 1  that is effective in treating schizophrenia and a pharmaceutically acceptable carrier.  
     
     
         11 . A method of treating schizophrenia in a mammal, comprising administering to said mammal an amount of a compound according to  claim 1  that is effective in treating schizophrenia.  
     
     
         12 . A pharmaceutical composition for the treatment of schizophrenia in a mammal, comprising an α7 nicotinic receptor agonizing amount of a compound according to  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         13 . A method of treating schizophrenia in a mammal, comprising administering to said mammal an α7 nicotinic receptor agonizing amount of a compound according to  claim 1 .  
     
     
         14 . A pharmaceutical composition for treating a disorder or condition selected from inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotropic lateral sclerosis (ALS), cognitive dysfunction, tinnitus, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions (e., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbituates, opioids or cocaine), headache, stroke, traumatic brain injury (TBI), psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, multi-infarct dementia, age related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome in a mammal, comprising an amount of a compound according to  claim 1  that is effective in treating such disorder or condition and a pharmaceutically acceptable carrier.  
     
     
         15 . A method of treating a disorder or condition selected from inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotropic lateral sclerosis (ALS), cognitive dysfunction, tinnitus, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbituates, opioids or cocaine), headache, stroke, traumatic brain injury (TBI), psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, multi-infarct dementia, age related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound according to  claim 1  that is effective in treating such disorder or condition.  
     
     
         16 . A pharmaceutical composition for treating a disorder or condition selected from inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotropic lateral sclerosis (ALS), cognitive dysfunction, tinnitus, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbituates, opioids or cocaine), headache, stroke, traumatic brain injury (TBI), psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, multi-infarct dementia, age related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome in a mammal, comprising an α7 nicotinic receptor agonizing amount of a compound according to  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         17 . A method of treating a disorder or condition selected from inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotropic lateral sclerosis (ALS), cognitive dysfunction, tinnitus, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions (e., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbituates, opioids or cocaine), headache, stroke, traumatic brain injury (TBI), psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, multi-infarct dementia, age related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome in a mammal, comprising administering to a mammal in need of such treatment an α7 nicotinic receptor agonizing amount of a compound according to  claim 1.