Macrocyclic compounds

Abstract

The present invention relates to macrocyclic compounds which are capable of selective binding to a target saccharide (e.g. glucose), making them particularly well suited for use in saccharide sensing applications. The present invention also relates to processes for the preparation of said compounds, to compositions and devices comprising them, and to their use in the detection of a target saccharide.

1 . A compound of Formula (I), or a salt, hydrate or solvate thereof, as shown below: 
       
         
           
           
               
               
           
         
         wherein: 
       
       bonds b 1  and b 2  are independently selected from a single bond or double bond; R 1a , R 1b , R 2a  and R 2b  are independently selected from hydrogen, carbonyl, (1-8C)alkyl, (3-10C)cycloalkyl, aryl, heteroaryl and heterocyclyl, each of which, other than hydrogen and carbonyl, is optionally substituted by one or more substituent groups selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl, sulfamoyl, mercapto and a hydrophilic substituent group; or 
       R 1a  and R 1b  are linked so as to form a group of the formula: 
       
         
           
           
               
               
           
         
       
       and/or R 2a  and R 2b  are linked so as to form a group of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
    denotes the point of attachment; 
 
       bonds b 1  and b 2  are as described above; 
       Rings A and B are independently selected from aryl, heteroaryl, heterocyclyl, cycloalkyl and cycloalkenyl; 
       R 1  and R 2  are independently selected from (1-6C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-6C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxyl, carboxy, carbamoyl, sulfamoyl and mercapto; 
       a and b are integers independently selected from 0 to 2; 
       m and n are integers independently selected from 0 to 2; 
       Z 1  and Z 2  are independently selected from a hydrophilic substituent group; 
       C and D are independently selected from aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl and a group of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 s, t and v are integers independently selected from 1 or 2; 
    denotes the point of attachment; 
 
       R 3  and R 4  are independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, amino, nitro, (1-4C)alkylamino, (1-4C)dialkylamino, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (2-4C)alkenyl, (2-4C)alkynyl and a group of the formula:
   -L 1 -Y 1 -Q 1    
 wherein: 
 
       L 1  is absent or a (1-5C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl and oxo; 
       Y 1  is absent or selected from a one of the following groups; O, S, SO, SO 2 , N(R a ), C(O), C(O)O, OC(O), C(O)N(R a ), N(R a )C(O), N(R b )C(O)N(R a ), N(R a )C(O)O, OC(O)N(R a ), S(O) 2 N(R a ), and N(R a )SO 2 , wherein R a  and R b  are each independently selected from hydrogen and (1-4C)alkyl; and 
       Q 1  is hydrogen, (1-8C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl and heterocyclyl; wherein Q is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, mercapto, ureido, oxy, NR c R d , OR c , C(O)R d , OC)R c , C(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) y R c , (where y is 0, 1 or 2), SO 2 N(R d )R c , N(R d )SO 2 R c , Si(R e )(R d )R c  and (CH 2 ) z NR d R e  (where z is 1, 2 or 3); wherein R c , R d  and R e  are each independently selected from hydrogen, (1-6C)alkyl and (3-6C)cycloalkyl; and R c  and R d  can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxyl; and wherein two R 3  and/or two R 4  groups taken together may form a group of the formula: 
       
         
           
           
               
               
           
         
       
       wherein: 
       R x  is selected from hydrogen and (1-6C)alkyl optionally substituted by one or more substituent groups selected from halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, hydroxy, sulfamoyl, mercapto, ureido, NR f R g , OR f , C(O)R f , C(O)OR f , OC(O)R f , C(O)N(R g )R f  and N(R g )C(O)R f , wherein R f  and R g  are selected from hydrogen and (1-4C)alkyl; and 
       the dashed lines represent the points of attachment to C and/or D; 
       W 1 , W 2 , W 3  and W 4  are independently selected from CR h R i , wherein R h  and R i  are selected from hydrogen and (1-2C)alkyl; 
       X 1 , X 2 , X 3  and X 4  are independently selected from a group of the formula: 
       
         
           
           
               
               
           
         
       
       wherein: 
          denotes the point of attachment; 
       W x  is selected from O or NH; and 
       Q is selected from O, S and NR j , wherein R j  is selected from hydrogen, (1-4C)alkyl, aryl, heteroaryl and sulfonyl; 
       Z 3  and Z 4  are independently selected from a hydrophilic substituent group; 
       L is absent or a linker, which optionally bears a hydrophilic substituent group Z 5 ; 
       c and d are integers independently selected from 0 to 4; and 
       o and p are integers independently selected from 0 to 2; 
       and wherein:
 iii) the compound of Formula I is optionally attached to a displaceable reporter molecule via one or more of the substituent groups associated with R 1 , R 2 , R 3 , R 4 , Z 1 , Z 2 , Z 3 , Z 4  and/or Z 5 ; and/or 
 iv) the compound of Formula I is optionally attached to a substituent group of Formula A1 shown below at a position associated with one or more of the substituent groups R 1a , R 1b , R 2a , R 2b , R 1 , R 2 , R 3 , R 4 , Z 1 , Z 2 , Z 3 , Z 4  and/or Z 5 :
   X 2a -L 2a -Z 2a    (Formula A1)
 
 
 
       wherein: 
       X 2a  is absent or selected from O, S, SO, SO 2 , N(R x2 ), C(O), C(O)O, OC(O), C(O)N(R x2 ), N(R x2 )C(O), N(R x2 )C(O)N(R x3 ), N(R x2 )C(O)O, OC(O)N(R x2 ), S(O) 2 N(R x2 ) and N(R x2 )SO 2 , wherein R x2  and R x3  are each independently selected from hydrogen and (1-4C)alkyl; 
       L 2a  is absent or selected from (1-20C)alkylene, (1-20C)alkylene oxide, (1-20C)alkenyl and (1-20C)alkynyl, each of which being optionally substituted by one or more substituents selected from (1-2C)alkyl, aryl and oxo; and 
       Z 2a  is selected from carboxy, carbamoyl, sulphamoyl, mercapto, amino, azido, (1-4C)alkenyl, (1-4C)alkynyl, NR xc R xd , OR xc , ONR xc R xd , C(O)X a , C(Q z )OR xf , N═C═O, NR xc C(O)CH 2 X b , C(O)N(R xe )NR Xc R Xd , S(O) y X a  (where y is 0, 1 or 2), SO 2 N(R e )NR xc R xd , Si(R xg )(R xh )R xi , S—S—X c  an amino acid and 
       
         
           
           
               
               
           
         
       
       wherein: 
       X a  is a leaving group (e.g. halo or CF 3 ); 
       X b  is a halo (e.g. iodo); 
       X c  is an aryl or heteroaryl, optionally substituted with one or more substituents selected from halo, cyano and nitro; 
       R xc , R xd  and R xe  are each independently selected from hydrogen and (1-6C)alkyl; 
       R xf  is selected from hydrogen and (1-6C)alkyl, or R xf  is a substituent group that renders C(O)OR x , when taken as a whole, to be an activated ester (e.g a hydroxysuccinimide ester, a hydroxy-3-sulfo-succinimide ester or a pentafluorophenyl ester); 
       Q Z  is selected from 0 or  + NR Q1 R a   2 , where R Q1  and R Q2  are independently selected from hydrogen and methyl; and 
       R xg , R xh  and R xi  are each independently selected from (1-4C)alkyl, hydroxy, halo and (1-4C)alkoxy; 
       with the proviso that the compound of Formula I comprises at least one hydrophilic substituent group (e.g. Z 1 , Z 2 , Z 3 , Z 4  or Z 5 ).