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 occurrence 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 occurrence 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];   (2R)-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.