Nicotinic Acetylcholine Receptor Ligands 101

Abstract

Nicotinic acetylcholine receptor ligands of Formula I wherein X, n, R 1 and R 2 are as described in the specification, diastereoisomers, enantiomers, pharmaceutically-acceptable salts, methods of making, pharmaceutical compositions containing, and methods for using the same.

1 . A compound in accord with Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is independently selected at each occurrence from CH, O, S, N or NH and at least one X is selected from O, S, N or NH and not more than one X is O or S; 
 n is 0, 1, 2, or 3, and 
 R 1  and R 2  are independently selected from hydrogen, —C 1-6 alkyl, —C 3-7 cycloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —CF 3 , —CONR 3 R 4 , —CH 2 NR 3 R 4  or —CH 2 OR 3 ; 
 or, R 1  and R 2  together with the nitrogen to which they are attached form a 5- or 6-membered heteroaromatic ring having as ring atoms 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur, or a 5- or 6-membered heterocyclic ring having as ring atoms 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur; 
 R 3  and R 4  are independently selected at each occurrence from hydrogen or —C 1-4 alkyl, and 
 where any alkyl, cycloalkyl, alkenyl or alkynyl moiety may be substituted with 1, 2, 3 or more halogen, —OH or ═O moieties as chemically feasible, or a 
 stereoisomer, enantiomer, in vivo-hydrolysable precursor or pharmaceutically-acceptable salt thereof. 
 
     
     
         2 . A compound according to  claim 1 , wherein the moiety 
       
         
           
           
               
               
           
         
       
       is selected from moieties of Formulae II, III, IV, V or VI 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, enantiomer, in vivo-hydrolysable precursor or pharmaceutically-acceptable salt thereof. 
     
     
         3 . A compound according to  claim 1 , wherein R 1  and R 2  are independently selected from hydrogen or methyl; or a stereoisomer, enantiomer, in vivo-hydrolysable precursor or pharmaceutically-acceptable salt thereof. 
     
     
         4 . A compound according to  claim 1 , wherein n is 1 or 2; or a stereoisomer, enantiomer, in vivo-hydrolysable precursor or pharmaceutically-acceptable salt thereof. 
     
     
         5 . A compound according to  claim 1 , wherein R 1  and R 2  together with the nitrogen to which they are attached are selected from pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; or a stereoisomer, enantiomer, in vivo-hydrolysable precursor or pharmaceutically-acceptable salt thereof. 
     
     
         6 . A compound according to  claim 1 , wherein the moiety 
       
         
           
           
               
               
           
         
       
       is selected from moieties of Formulae II, III, IV, V or VI, 
       
         
           
           
               
               
           
         
         R 1  and R 2  are independently selected from hydrogen or methyl, and 
         n is 1 or 2; or a stereoisomer, enantiomer, in vivo-hydrolysable precursor or pharmaceutically-acceptable salt thereof. 
       
     
     
         7 . A compound according to  claim 1 , wherein: 
       the moiety 
       
         
           
           
               
               
           
         
       
       is a moiety of Formula II or IV, R 1  and R 2  are independently selected from hydrogen or methyl, and n is 1 or 2. 
     
     
         8 . A compound according to  claim 1 , wherein: 
       the moiety 
       
         
           
           
               
               
           
         
       
       is of Formula II, R 1  and R 2  are independently selected from hydrogen or methyl, and n is 1 or 2. 
     
     
         9 . A compound according to  claim 1 , wherein: 
       the moiety 
       
         
           
           
               
               
           
         
       
       is of Formulae I, R 1  and R 2  are independently selected from hydrogen or methyl, and n is 1 or 2. 
     
     
         10 . A compound selected from the group consisting of
 N,N-dimethyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methenamine;   N,N-dimethyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine;   N,N-dimethyl-1-{4-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methenamine;   N,N-dimethyl-1-{4-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine;   N-methyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]oetane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine;   N-methyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine;   (2R)-5′-[5-(pyrrolidin-1-ylmethyl)-2-furyl]-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3b]pyridine];   (2R)-5′-[5-(morpholin-4-ylmethyl)-2-furyl]-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine];   N,N-dimethyl-1-{4-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine;   (2R)-5′-[5-(pyrrolidin-1-ylmethyl)-3-furyl]-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine];   (2R)-5′-[5-(morpholin-4-ylmethyl)-3-furyl]-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine];   N-methyl-N-({5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methyl)cyclopropanamine;   N-methyl-N-({4-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methyl)cyclopropanamine;   1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine;   1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methenamine, and   1-{4-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine;   or a stereoisomer, enantiomer, in vivo-hydrolysable precursor or pharmaceutically-acceptable salt of any foregoing compound.   
     
     
         11 . A method of treatment or prophylaxis of a disease or condition in which activation of the α7 nicotinic receptor is beneficial which method comprises administering a therapeutically-effective amount of a compound or a pharmaceutically-acceptable salt thereof according to  claim 1  to a subject suffering from said disease or condition. 
     
     
         12 . The method of  claim 11 , wherein said disease or condition is anxiety, schizophrenia, mania or manic depression. 
     
     
         13 . A method of treatment or prophylaxis of neurological disorders, psychotic disorders or intellectual impairment disorders, which comprises administering a therapeutically effective amount of a compound or a pharmaceutically-acceptable salt thereof according to  claim 1 . 
     
     
         14 . The method of  claim 11 , wherein said 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, neurodegenerative disorders in which there is loss of cholinergic synapses, jetlag, nicotine addiction, craving, pain, or ulcerative colitis. 
     
     
         15 . A method for inducing the cessation of smoking comprising administering an effective amount of a compound or a pharmaceutically-acceptable salt thereof according to  claim 1 . 
     
     
         16 . A pharmaceutical composition comprising a compound or a pharmaceutically-acceptable salt thereof according to  claim 1  and at least one pharmaceutically-acceptable diluent, lubricant or carrier. 
     
     
         17 . A method of treatment or prophylaxis of a disease or condition in which activation of the alpha-7 nicotinic receptor is beneficial which method comprises administering a therapeutically-effective amount of a pharmaceutical composition according to  claim 16  to a subject suffering from said disease or condition. 
     
     
         18 . The method of  claim 17 , wherein said disease or condition is anxiety, schizophrenia, mania or manic depression. 
     
     
         19 . A method of treatment or prophylaxis of neurological disorders, psychotic disorders or intellectual impairment disorders, which comprises administering a therapeutically effective amount of a pharmaceutical composition according to  claim 16 . 
     
     
         20 . The method of  claim 18 , wherein said 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, neurodegenerative disorders in which there is loss of cholinergic synapses, jetlag, nicotine addiction, craving, pain, or ulcerative colitis. 
     
     
         21 . A method for inducing the cessation of smoking comprising administering an effective amount of a pharmaceutical composition according to  claim 16 . 
     
     
         22 - 23 . (canceled)