Quinuclidine derivatives and their use as muscarinic M3 receptor ligands

Abstract

A compound according to formula (I) wherein: © is a phenyl ring, a C 4 to C 9 heteroaromatic compound containing one or more heteroatoms, or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group; which shows high affinity for muscarinic M 3 receptors (Hm3).

What is claimed is: 
     
       1. A compound according to formula (I) 
       
         
           
           
               
               
           
         
       
       wherein:
 © is a phenyl ring, a C 4  to C 9  heteroaromatic group containing one or more heteroatoms or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group; 
 R 1 , R 2  and R 3  each independently represent a hydrogen atom or halogen atom, or a hydroxy group, or a phenyl, —OR 4 , —SR 4 , —NR 4 R 5 , —NHCOR 4 , —CONR 4 R 5 , —CN, —NO 2 , —COOR 4  or —CF 3  group, or a straight or branched lower C 1  to C 4  alkyl group which may optionally be substituted, for example, with a hydroxy or alkoxy group, wherein R 4  and R 5  each independently represent a hydrogen atom, straight or branched lower C 1  to C 4  alkyl group or together form an alicyclic ring; or R 1  and R 2  together form an aromatic, alicyclic or heterocyclic ring, 
 n is an integer from 0 to 4; 
 A represents a —CH 2 —, —CH═CR 6 —, —CR 6 ═CH—, —CR 6 R 7 —, —CO—, —O—, —S—, —S(O)—, SO 2  or —NR 6 — group, wherein R 6  and R 7  each independently represent a hydrogen atom, straight or branched lower C 1  to C 4  alkyl group or R 6  and R 7  together form an alicyclic ring; 
 m is an integer from 0 to 8; provided that when m=0, A is not —CH 2 —; 
 p is an integer from 1 to 2 and the substitution in the azoniabicyclic ring may be in the 2, 3 or 4 position including all possible configurations of the asymmetric carbons; 
 B represents a group of formula i): 
 
       
         
           
           
               
               
           
         
          wherein R 10  represents a hydrogen atom, a hydroxy or methyl group; and R 8  and R 9  each independently represent 
       
       
         
           
           
               
               
           
         
          wherein R 11  represents a hydrogen or halogen atom or a straight or branched lower C 1  to C 4  alkyl group; and 
         XX −  represents a pharmaceutically acceptable anion of a mono or polyvalent acid. 
       
     
     
       2. A compound according to  claim 1 , wherein any alkyl group present as R 1  to R 7  or R 11  contains from 1 to 4 carbon atoms. 
     
     
       3. A compound according to  claim 1  wherein p=2. 
     
     
       4. A compound according to  claim 1  wherein © represents a phenyl, pyrrolyl, thienyl, furyl, biphenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, imidazolyl or benzothiazolyl group. 
     
     
       5. A compound according to  claim 4 , wherein © represents a phenyl, pyrrolyl or thienyl group. 
     
     
       6. A compound according to  claim 1  wherein R 1 , R 2  and R 3  each independently represent a hydrogen or halogen atom or a hydroxy, methyl, tert-butyl, —CH 2 OH, 3-hydroxypropyl, —OMe, —NMe 2 , —NHCOMe, —CONH 2 , —CN, —NO2 —NO 2 , —COOMe or —CF 3  group. 
     
     
       7. A compound according to  claim 6  wherein R 1 , R 2  and R 3  each independently represent a hydrogen or halogen atom or a hydroxy group. 
     
     
       8. A compound according to  claim 7 , wherein the halogen atom is fluorine. 
     
     
       9. A compound according to  claim 1  wherein A represents a —CH 2 —, —CH═CH—, —CO—, —NH—, —NMe—, —O— or —S— group; n is 0 or 1; and m is an integer from 1 to 6. 
     
     
       10. A compound according to  claim 9 , wherein A represents a —CH 2 —,  13  CH═CH— or —O— group and m is 1, 2 or 3. 
     
     
       11. A compound according to  claim 1  wherein the azoniabicyclo group is substituted on the nitrogen atom with a 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 3-(2-hydroxyphenoxy)propyl, 3-(4-fluorophenoxy)propyl, 2-benzyloxyethyl, 3-pyrrol-1-ylpropyl, 2-thien-2-ylethyl or 3-thien-2-ylpropyl group. 
     
     
       12. A compound according to  claim 1  wherein B represents a group of formula (i) and R 8  and R 9  each independently represent a phenyl, 2-thienyl, 3-thienyl, 2-furyl, or 3-furyl group and R 11  represents a hydrogen atom. 
     
     
       13. A compound according to  claim 1  wherein X X −  represents a bromide, chloride or trifluoroacetate anion. 
     
     
       14. A compound according to  claim 1  wherein the azoniabicyclo group is substituted in the 3-position. 
     
     
       15. A compound according to  claim 14 , wherein the substituent in the 3 position has (R) configuration. 
     
     
       16. A compound according to  claim 15 , wherein R 8  is different from R 9  in group i), and the asymmetric carbon to which R 8  and R 9  are bonded has the (R) configuration. 
     
     
       17. A compound according to  claim 15 , wherein R 8  is different from R 9  in group i), and the asymmetric carbon to which R 8  and R 9  are bonded has the (S) configuration. 
     
     
       18. A compound according to  claim 1  which is a single stereoisomer. 
     
     
       19. A compound according to  claim 1  which is 
       3(R)-Diphenylacetoxy-1-(3-phenoxy-propyl)-1azoniabicyclo[2.2.2]octane; bromide,  
       3(R)-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide,  
       3(R)-(2,2-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide,  
       3(R)-(2-Hydroxy-2-phenyl-2-thien-2-yl-acetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo [2.2.2]octane; bromide,  
       3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenylallyl)-1-azoniabicyclo [2.2.2]octane; bromide,  
       3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo [2.2.2]octane; bromide,  
       3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo [2.2.2]octane; bromide,  
       3(R)-(2,2-Dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide,  
       3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; bromide3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; bromide,  
       3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane; bromide3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane; bromide,  
       3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo[2.2.2]octane; bromide,  
       1-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo [2.2.2]octane; chloride,  
       3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxyphenoxy)propyl]-1-azoniabicyclo [2.2.2]octane; Trifluoroacetate,  
       3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-pyrrol-1-ylpropyl)-1-azonia-bicyclo[2.2.2]octane; trifluoroacetate,  
       3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane; bromide,  
       3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane; bromide,  
       1-(2-Benzyloxyethyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; trifluoroacetate, or  
       3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide. 
     
     
       20. A compound according to  claim 1  characterised in that it has an IC 50  value for muscarinic M 3  receptors (Hm3) of less than 35 nM. 
     
     
       21. A process for the preparation of a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       which comprises reacting an alkylating agent of formula (II) 
       
         
           
           
               
               
           
         
       
       with a compound of formula (III) 
       
         
           
           
               
               
           
         
       
       wherein, in each of formulae I, II and III, R 1 , R 2  R 3 , ©, A, X, B, n, m and p are as defined in any one of  claims 1  to  12  or  13  to  19 . 
     
     
       22. A process according to  claim 21  characterised in that the resulting reaction mixture is purified by solid phase extraction. 
     
     
       23. A pharmaceutical composition comprising a compound according to  claim 1  in admixture with a pharmaceutically acceptable carrier or diluent. 
     
     
       24. A method for treating respiratory, urinary and/or gastrointestinal disease which method comprises administering to a human or animal patient in need of such treatment an effective amount of a compound according to any one of claims claim  1  to  12 ,  13  to  20  or of a pharmaceutical composition according to  claim 23 . 
     
     
       25. A method for treating COPD, chronic bronchitis, asthma and/or ehinitis rhinitis which method comprises administering to a human or animal patient in need of such treatment an effective amount of a compound according to any one of claims claim  1  to  12 ,  13  to  20  or of a pharmaceutical composition according to  claim 23 . 
     
     
       26. A compound chosen from
 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; X −     or   3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; X − ,   wherein X −  represents a pharmaceutically acceptable anion of a mono or polyvalent acid.    
     
     
       27. A compound chosen from
 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; X −     or   3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; X − ,   wherein X −  represents chloride, bromide, iodide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, or p-toluenesulfonate.    
     
     
       28. A compound according to claim 27, wherein X −  represents chloride, bromide, iodide, sulfate, nitrate, acetate, trifluoroacetate, maleate, oxalate, or succinate.  
     
     
       29. A compound according to claim 27, wherein X −  represents chloride, bromide, or trifluoroacetate.  
     
     
       30. A compound chosen from
 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide   or   3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; bromide.