Aza-bridged bicyclic amine derivatives for use as novel cholinergic receptor ligands

Abstract

The present invention discloses novel cholinergic receptor ligands. The present invention also relates to the synthesis of substituted derivatives of aza-bridged bicyclic amines for use as muscarinic receptor ligands as well as methods of regulating function of certain cholinergic receptors, and hence acting as antagonists, agonists and partial agonists at certain specific cholinergic receptor subtypes. The present invention also relates to methods for treating disorders associated with cholinergic receptors.

1 - 18 . (canceled)  
     
     
         19 . A compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is selected from the group consisting of oxygen, hydroxy, alkoxy, amino, hydrazino and oxime, unsubstituted or substituted;  
 R 2  is selected from the group consisting of hydrogen, carbonyl, aldehyde, amide, aryl, ester and heteroaryl, unsubstituted or substituted;  
 R 3 , R 5  and R 7  are selected from the group consisting of hydrogen, alkyl, allyl, alkenyl, alkynyl alkylaryl, arylalkyl, phenyl, alkenes, alkynes, aryls, amines, halides and alkylhalides, alkyloxyalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, halo, haloalkyl, amino, alkylamino, dialkylamino, cyclic dialkylamino, amidine, cyclic amidine and their N-alkyl derivatives, unsubstituted or substituted;  
 R 4 , R 6  and R 8  are selected from the group consisting of hydrogen, alkyl, allyl, alkenyl, alkynyl alkylaryl, arylalkyl, phenyl, alkenes, alkynes, aryls, amines, halides and alkylhalides, alkyloxyalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, halo, haloalkyl, amino, alkylamino, dialkylamino, cyclic dialkylamino, amidine, cyclic amidine and their N-alkyl derivatives, unsubstituted or substituted;  
 R 9  is selected from the group consisting of hydrogen, alkyl and alkylaryl, unsubstituted or substituted; and  
 wherein at least one of R 3 , R 5 , R 7 , R 4 , R 6  and R 8  are not hydrogen; and  
 wherein the dashed line represents an optional double bond.  
 
     
     
         20 . The compound of  claim 19 , wherein the dashed line is a double bond.  
     
     
         21 . The compound of  claim 19 , wherein the dashed line is a single bond.  
     
     
         22 . The compound of  claim 19 , wherein the R 4 , R 6 , or R 8  moiety exists as an exo isomer.  
     
     
         23 . The compound of  claim 19 , wherein the R 1  moiety is further selected from the group consisting of alkyl, alkenyl, alkynyl, acyl, alkylaryl, arylalkyl, thio, nitro and ester, substituted or unsubstituted.  
     
     
         24 . The compound of  claim 19 , wherein the R 2  moiety is further selected from the group consisting of alkyl, allyl, aryl, alkenyl, alkynyl, alkylaryl, arylalkyl, phenyl, alkenes, alkynes, aryls, halides, alkylhalides, esters and carboxylic acids, substituted or unsubstituted.  
     
     
         25 . The compound of  claim 19 , wherein the R 1 -R 9  groups are an electron withdrawing and/or electron donating group.  
     
     
         26 . The compound of  claim 19 , wherein said compound is selected from the group consisting of C(8) substituted 3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-enes, exo-8-benzyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene, C(8) substituted 1-azabicyclo[3.3.1]non-4-ones, exo-8-Benzyloxymethyl-3-methoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene, exo-8-Benzyloxymethyl-3-allyloxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene, exo-8-Benzyloxymethyl-3-hexyloxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene, exo-8-Benzyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-methyl-1-azabicyclo[3.3.1]non-3-ene iodide, exo-8-Benzyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-ethyl-1-azabicyclo[3.3.1]non-3-ene trifluoromethanesulfonate, exo-8-Hydroxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene, exo-8-Acetoxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene, exo-8-(2′,2′-Diphenyl)propionoxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene, exo-8-Ethylaminocarbonyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene, exo-8-Phenylaminocarbonyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene, exo-8-Benzyloxymethyl-1-azabicyclo[3.3.1]nonan-4-one, exo-8-Benzyloxymethyl-1-azabicyclo[3.3.1]nonan-4-one, O-Methyloxime, and exo-8-Benzyloxymethyl-3-ethoxycarbonyl-4-methoxy-1-azabicyclo[3.3.1]non-3-ene.  
     
     
         27 . A pharmaceutical composition comprising a compound group of formula I  
       
         
           
           
               
               
           
         
       
       or an ester or pharmaceutically acceptable salt, solvate, hydrate, or combination thereof, in an amount effective for regulating central nervous system functions, and a pharmaceutically acceptable vehicle, wherein 
 R 1  is selected from the group consisting of oxygen, hydroxy, alkoxy, amino, hydrazino and oxime, unsubstituted or substituted;  
 R 2  is selected from the group consisting of hydrogen, carbonyl, aldehyde, amide, aryl, ester and heteroaryl, unsubstituted or substituted;  
 R 3 , R 5  and R 7  are selected from the group consisting of hydrogen, alkyl, allyl, alkenyl, alkynyl alkylaryl, arylalkyl, phenyl, alkenes, alkynes, aryls, amines, halides and alkylhalides, alkyloxyalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, halo, haloalkyl, amino, alkylamino, dialkylamino, cyclic dialkylamino, amidine, cyclic amidine and their N-alkyl derivatives, unsubstituted or substituted;  
 R 4 , R 6  and R 8  are selected from the group consisting of hydrogen, alkyl, allyl, alkenyl, alkynyl alkylaryl, arylalkyl, phenyl, alkenes, alkynes, aryls, amines, halides and alkylhalides, alkyloxyalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, halo, haloalkyl, amino, alkylamino, dialkylamino, cyclic dialkylamino, amidine, cyclic amidine and their N-alkyl derivatives, unsubstituted or substituted;  
 R 9  is selected from the group consisting of hydrogen, alkyl and alkylaryl, unsubstituted or substituted;  
 wherein at least one of R 3 , R 5 , R 7 , R 4 , R 6  and R 8  are not hydrogen; and  
 wherein the dashed line represents an optional double bond; and  
 wherein said composition is administered in an amount sufficient to regulate a cholinergic receptor.  
 
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein said disorder is a cognitive function disorder, a central nervous system disorder, bronchodilation disorder or a gastrointestinal function disorder.  
     
     
         29 . The pharmaceutical composition of  claim 27 , wherein said compound comprises at least one pharmacophore.  
     
     
         30 . (Canceled).  
     
     
         31 . The pharmaceutical composition of  claim 27 , wherein the R 4 , R 6 , or R 8  moiety exists as an exo isomer.  
     
     
         32 . The pharmaceutical composition of  claim 27 , wherein the cholinergic receptor is selected from the group consisting of nicotinic and muscarinic receptors.  
     
     
         33 . The pharmaceutical composition of  claim 27 , wherein said compound is selected from the group consisting of C(8) substituted 3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-enes, exo-8-benzyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene, C(8) substituted 1-azabicyclo[3.3.1]non-4-ones, exo-8-Benzyloxymethyl-3-methoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene, exo-8-Benzyloxymethyl-3-allyloxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene, exo-8-Benzyloxymethyl-3-hexyloxycarbonyl-4-hydroxy-1-azabicyclo [3.3.1 ]non-3-ene, exo-8-Benzyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-methyl-1-azabicyclo[3.3.1 ]non-3-ene iodide, exo-8-Benzyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-ethyl-1-azabicyclo[3.3.1]non-3-ene trifluoromethanesulfonate, exo-8-Hydroxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1 ]non-3-ene, exo-8-Acetoxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene, exo-8-(2′,2′-Diphenyl)propionoxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1 ]non-3-ene, exo-8-Ethylaminocarbonyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene, exo-8-Phenylaminocarbonyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene, exo-8-Benzyloxymethyl-1-azabicyclo[3.3.1]nonan-4-one, exo-8-Benzyloxymethyl-1-azabicyclo[3.3.1]nonan-4-one, O-Methyloxime, and exo-8-Benzyloxymethyl-3-ethoxycarbonyl-4-methoxy-1-azabicyclo[3.3.1]non-3-ene.  
     
     
         34 . A method of treating a subject with a cognitive function disorder, a central nervous system disorder, an autonomic nervous system disorder, a bronchodilation disorder or a gastrointestinal function disorder comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of a compound of formula I  
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of oxygen, hydroxy, alkoxy, amino, hydrazino and oxime, unsubstituted or substituted;  
         R 2  is selected from the group consisting of hydrogen, carbonyl, aldehyde, amide, aryl, ester and heteroaryl, unsubstituted or substituted;  
         R 3 , R 5  and R 7  are selected from the group consisting of hydrogen, alkyl, allyl, alkenyl, alkynyl alkylaryl, arylalkyl, phenyl, alkenes, alkynes, aryls, amines, halides and alkylhalides, alkyloxyalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, halo, haloalkyl, amino, alkylamino, dialkylamino, cyclic dialkylamino, amidine, cyclic amidine and their N-alkyl derivatives, unsubstituted or substituted;  
         R 4 , R 6  and R 8  are selected from the group consisting of hydrogen, alkyl, allyl, alkenyl, alkynyl alkylaryl, arylalkyl, phenyl, alkenes, alkynes, aryls, amines, halides and alkylhalides, alkyloxyalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, halo, haloalkyl, amino, alkylamino, dialkylamino, cyclic dialkylamino, amidine, cyclic amidine and their N-alkyl derivatives, unsubstituted or substituted;  
         R 9  is selected from the group consisting of hydrogen, alkyl and alkylaryl, unsubstituted or substituted; and  
         wherein at least one of R 3 , R 5 , R 7 , R 4 , R 6  and R 8  are not hydrogen; and  
         wherein the dashed line represents an optional double bond.  
       
     
     
         35 . The method according to  claim 34 , wherein said cognitive function disorder is Alzheimer's disease.  
     
     
         36 . The method according to  claim 34 , wherein said central nervous system disorder is bronchodilation.  
     
     
         37 . The method according to  claim 34 , wherein said gastrointestinal function disorder is selected from the group consisting of Crohn's disease and irritable bowel syndrome.  
     
     
         38 . The method according to  claim 34 , wherein said compound comprises at least one pharmacophore.  
     
     
         39 . (canceled)  
     
     
         40 . The method according to  claim 34 , wherein the R 4 , R 6 , or R 8  moiety exists as an exo isomer.  
     
     
         41 - 54 . (canceled)