Thienyl Compounds

Abstract

Compounds of formula I: and pharmaceutically-acceptable salts thereof, wherein Ar and R are as defined in the specification, compositions containing such compounds and the use of such compounds and compositions for use in therapy.

1 . A method of treatment or prophylaxis of human diseases or conditions in which activation of the α 7  nicotinic receptor is beneficial which comprises administering a therapeutically effective amount of a compound of Formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically-acceptable salt thereof, wherein 
 Ar is selected from a 2-, or 3-linked thienyl or benzo-fused thienyl substituted with 0, 1, 2 or 3 substituents independently selected at each occurence from C 1-4  alkyl, C 1-4  alkoxy, C 1-4  halogenated alkyl, C 1-4  oxygenated alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen, —CO 2 R 1 , —C(O)R 1 , —CN, —NO 2 , —NR 1 R 2 ;  
 R 1  and R 2  are independently selected at each occurrence from hydrogen or C 1-4 alkyl;  
 R is a substituent selected from hydrogen, C 1-4 alkyl, C 1-4  halogenated alkyl, C 1-4  oxygenated alkyl, or halogen.  
 
   
   
       2 . The method according to  claim 1 , wherein said compound of Formula I is selected from: 
 (2′R)-5′-(thiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(thiophen-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(benzo[b]thiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(benzo[b]thiophen-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(5-methylthiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(4-methylthiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(5-chlorothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(5-chlorothiophen-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(5-fluorothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(5-fluorothiophen-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(5-bromothiophen-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-4-{spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridin-5′-yl}thiophene-2-carbonitrile, or    (2′R)-5-{spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridin-5′-yl}thiophene-2-carbonitrile.    
   
   
       3 . The method according to  claim 1 , wherein said human disease or condition is a psychotic disorder or an intellectual impairment disorder.  
   
   
       4 . The method according to  claim 3 , wherein said psychotic disorder is Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, Attention Deficit Hyperactivity Disorder Parkinson's disease, Huntington's disease, Tourette's syndrome, a neurodegenerative disorder in which there is loss of cholinergic synapses anxiety, schizophrenia or mania or manic depression.  
   
   
       5 . The method according to  claim 1 , wherein said human disease or condition is jetlag, cessation of smoking, nicotine addiction, craving, pain, or ulcerative colitis.  
   
   
       6 . A pharmaceutical composition comprising a therapeutically-effective amount of a compound a compound of Formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically-acceptable salt thereof, wherein 
 Ar is selected from a 2-, or 3-linked thienyl or benzo-fused thienyl substituted with 0, 1, 2 or 3 substituents independently selected at each occurence from C 1-4  alkyl, C 1-4  alkoxy, C 1-4  halogenated alkyl, C 1-4  oxygenated alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen, —CO 2 R 1 , —C(O)R 1 , —CN, —NO 2 , —NR 1 R 2 ;  
 R 1  and R 2  are independently selected at each occurrence from hydrogen or C 1-4 alkyl;  
 R is a substituent selected from hydrogen, C 1-4 alkyl, C 1-4  halogenated alkyl, C 1-4  oxygenated alkyl, or halogen,  
 together with at least one pharmaceutically-acceptable diluent or carrier.  
 
   
   
       7 . A pharmaceutical composition according to  claim 6 , wherein said compound of Formula I is selected from: 
 (2′R)-5′-(thiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(thiophen-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(benzo[b]thiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(benzo[b]thiophen-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(5-methylthiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(4-methylthiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(5-chlorothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(5-chlorothiophen-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(5-fluorothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(5-fluorothiophen-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-5′-(5-bromothiophen-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    (2′R)-4-{spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridin-5′-yl}thiophene-2-carbonitrile, or    (2′R)-5-{spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridin-5′-yl}thiophene-2-carbonitrile.