3-quinuclidinyl amino-substituted biaryl derivatives

Abstract

Compounds of formula (I) wherein A is N or N + —O − ; n is 0, 1, or 2; Y is O, S, —NH—, and —N-alkyl-; Ar 1 is both 6-membered aromatic rings; Ar 2 is 5- or 6-membered aromatic rings with a —NR 8 R 9 group, as defined herein. The compounds are useful in treating conditions or disorders prevented by or ameliorated by α7 nAChR ligands. Also disclosed are pharmaceutical compositions having compounds of formula (I) and methods for using such compounds and compositions.

1 . A compound of formula (I):  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein: 
 A is N or N + —O −   
 n is 0, 1, or 2;  
 Y is selected form the group consisting of O, S, and —N(R 1 )—,  
 Ar 1  is a group of the formula:  
                     
 Ar 2  is a group of the formula:  
                     
 X 1 , X 2 , X 3 , and X 4  are each independently selected from the group consisting of N and —C(R 2 );  
 one of X 5 , X 6 , X 7 , X 8  and X 9  is —C and the others are each independently selected from the group consisting of N and —C(R 5 ), and group (b) is attached to Ar 1  through one of X 5 , X 6 , X 7 , X 8  and X 9  that is represented by C.  
 one of X 10 , X 11 , X 12 , and X 13  is C and the others are each independently selected from the group consisting of N, —N(R 1 ), O, S and —C(R 5 ) and group (c) is attached to Ar 1  through one of X 10 , X 11 , X 12 , and X 13  that is represented by C,  
 R 1  is hydrogen or alkyl;  
 R 2  at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, —OR 3 , and —NHR 4 ;  
 R 2a  is halogen or alkyl;  
 R 3  and R 4  are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and arylcarbonyl;  
 R 5  is selected from the group consisting of hydrogen, halogen, nitro, alkyl, aryl, alkylcarbonyl, arylcarbonyl, —OR 6  and —NR 8 R 9 ;  
 R 6  is independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and arylcarbonyl; and  
 R 8  and R 9  are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, cycloalkylalkyl, alkylcarbonyl, —N═C(alkyl)(alkoxycarbonyl), alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, and alkylsulfonyl.  
 
   
   
       2 . The compound of  claim 1 , wherein Ar 1  is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
     wherein R 2  is as defined in  claim 1 .  
   
   
       3 . The compound of  claim 1 , wherein Ar 2  is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 2a  is halogen or alkyl;  
 R 5  is selected from the group consisting of hydrogen, halogen, nitro, alkyl, aryl, alkylcarbonyl, arylcarbonyl, —OR 6  and —NR 8 R 9 ;  
 R 6  is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and arylcarbonyl;  
 R 8  and R 9  are each independently selected from the group consisting of hydrogen, alkyl, benzyl, methanesulfonyl, phenyl, 4-methylphenyl, benzyloxycarbonyl, acetyl, cyclohexylmethyl, tert-butyloxycarbonyl and —N═C(methyl)(ethoxycarbonyl).  
 
   
   
       4 . The compound of  claim 3 , wherein R 8  is hydrogen or alkyl; and R 9  is selected from the group consisting of hydrogen, alkyl, benzyl, methanesulfonyl, phenyl, 4-methylphenyl, benzyloxycarbonyl, acetyl, cyclohexylmethyl, tert-butyloxycarbonyl and —N═C(methyl)(ethoxycarbonyl).  
   
   
       5 . The compound of  claim 1 , or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, selected from the group consisting of: 
 4′-(1-azabicyclo[2.2.2]oct-3-yloxy)-1,1′-biphenyl-3-amine;    4′-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]-1,1′-biphenyl-3-amine;    4′-(1-azabicyclo[2.2.2]oct-3-yloxy)-4-methyl-1,1′-biphenyl-3-amine;    4′-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]-4-methyl-1,1′-biphenyl-3-amine;    4′-(1-azabicyclo[2.2.2]oct-3-yloxy)-1,1′-biphenyl-4-amine;    4′-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]-1,1′-biphenyl-4-amine;    4′-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]-1,1′-biphenyl-4-amine;    N-[4′-(1-azabicyclo[2.2.2]oct-3-yloxy)-1,1′-biphenyl-4-yl]-N-methylamine;    N-{4′-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]-1,1′-biphenyl-4-yl}-N,N-dimethylamine;    N-[4′-(1-azabicyclo[2.2.2]oct-3-yloxy)-1,1′-biphenyl-4-yl]methanesulfonamide;    N-[4′-(1-azabicyclo[2.2.2]oct-3-yloxy)-1,1′-biphenyl-4-yl]-N-phenylamine;    3-[6-(1-azabicyclo[2.2.2]oct-3-yloxy)pyridin-3-yl]aniline;    4-[5-(1-azabicyclo[2.2.2]oct-3-yloxy)pyrazin-2-yl]aniline;    4-{5-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrazin-2-yl}aniline;    4-{5-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrazin-2-yl}aniline;    N-{4-[5-(1-azabicyclo[2.2.2]oct-3-yloxy)pyrazin-2-yl]phenyl}-N,N-dimethylamine;    N-{4-[5-(1-azabicyclo[2.2.2]oct-3-yloxy)pyrazin-2-yl]phenyl}acetamide;    4-[2-(1-azabicyclo[2.2.2]oct-3-yloxy)pyrimidin-5-yl]aniline;    4-{2-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}aniline;    3-[2-(1-azabicyclo[2.2.2]oct-3-yloxy)pyrimidin-5-yl]aniline;    3-{2-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}aniline;    3-{2-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}aniline;    5-[2-(1-azabicyclo[2.2.2]oct-3-yloxy)pyrimidin-5-yl]-2-methylaniline;    N-1-azabicyclo[2.2.2]oct-3-yl-1,1′-biphenyl-4,4′-diamine;    4′-(1-oxy-1-aza-bicyclo[2.2.2]oct-3-yloxy)-biphenyl-3-ylamine;    [4′-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-biphenyl-4-yl]-p-tolyl-amine:    [4′-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-biphenyl-4-yl]-cyclohexylmethyl-amine;    2-[4-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-phenyl]-8-iodo-6H,12H-5,11-methano-dibenzo[b,f][1,5]diazocine;    4-{6-[(3R)-1-aza-bicyclo[2.2.2]oct-3-yloxy]-pyridazin-3-yl}-phenylamine;    4-{6-[(3R)-1-aza-bicyclo[2.2.2]oct-3-yloxy]-pyridazin-3-yl}-2-bromo-phenylamine;    4-{6-[(3R)-1-aza-bicyclo[2.2.2]oct-3-yloxy]-pyridazin-3-yl}-2,6-dibromo-phenylamine;    2-({4-{6-[(3R)-1-aza-bicyclo[2.2.2]oct-3-yloxy]-pyridazin-3-yl}-phenyl}-hydrazono)-propionic acid ethyl ester;    (R)—N-{4-[6-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-pyridazin-3-yl]-phenyl}-acetamide;    4-{6-[(3R)-1-aza-bicyclo[2.2.2]oct-3-yloxy]-pyridazin-3-yl}-2-nitro-phenylamine;    4-{6-{(3R)-1-aza-bicyclo[2.2.2]oct-3-yloxy}-pyridazin-3-yl}-benzene-1,2-diamine;    4-{2-[(3R)-1-aza-bicyclo[2.2.2]oct-3-yloxy]-pyrimidin-5-yl}-2-nitro-phenylamine; and    2-amino-4-{2-[(3R)-1-aza-bicyclo[2.2.2]oct-3-yloxy]-pyrimidin-5-yl}-phenol.    
   
   
       6 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  in combination with a pharmaceutically acceptable carrier.  
   
   
       7 . A method of selectively modulating the effects of α7 nicotinic acetylcholine receptors in a mammal comprising administering an effective amount of a compound of  claim 1 .  
   
   
       8 . A method of treating or preventing a condition or disorder selected from the group consisting of attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), mild cognitive impairment, senile dementia, AIDS dementia, Pick's Disease, dementia associated with Lewy bodies, dementia associated with Down's syndrome, amyotrophic lateral sclerosis, Huntington's disease, diminished CNS function associated with traumatic brain injury, acute pain, post-surgical pain, chronic pain, inflammatory pain, neuropathic pain, infertility, need for new blood vessel growth associated with wound healing, need for new blood vessel growth associated with vascularization of skin grafts, and lack of circulation, more particularly circulation around a vascular occlusion, comprising the step of administering a compound of  claim 1 .  
   
   
       9 . The method according to  claim 1 , wherein the condition or disorder is selected from the group consisting of a cognitive disorder, neurodegeneration, and schizophrenia.  
   
   
       10 . The method according to  claim 1 , further comprising administering a compound of  claim 1  in combination with an atypical antipsychotic.