Fluorescent substrates for monoamine transporters as optical false neurotransmitters

Abstract

The present invention relates to compounds of the general structure: wherein Y is O, X is O, bond α is absent and bond β is present, or Y is H, X is CH, bond α is present, and bond β is absent; atom Z is a carbon and bonds χ, δ and γ are present, or is a nitrogen and bonds χ, δ and γ are absent; R 1 is —H, —OH, —O—R 7 , —N(H)—R 8 , —N(H)—(CH 2 ) n —NH 2 , —N(R 9 )(R 10 ), or a piperazine cation; R 2 is either covalently bound to R 9 , or is —H, or is covalently bound to R 3 so as to form a substituted or unsubstituted pyrrole or R 2 is covalently bound to R 9 or R 8 or R 7 ; or R 1 and R 2 are covalently joined to form an aromatic ring; R 3 is either covalently bound to R 2 so as to form a pyrrole, or is, inter alia, —H, —OH, alkyl, or when Z is nitrogen R 3 is ═O; R 4 is, inter alia, —H, —OH, or —R 11 NH 2 ; R 5 is, inter alia, —H, —OH, or —R 12 NH 2 , and R 6 is either is covalently bound to R 10 or is —H, or R 6 is covalently bound to R 10 or R 8 or R 7 . This invention also provides processes for making the compounds as well as methods for monitoring activity of monoamine transporters or treating monoamine transporter-associated diseases by employing the compounds.

1 . A compound having the following structure: 
       
         
           
           
               
               
           
         
         wherein 
         Y is O, X is O, bond α is absent and bond β is present, or 
         Y is H, X is CH, bond α is present, and bond β is absent; 
         atom Z is a carbon and bonds χ, δ and γ are present; 
         R 1  is —H, —OH, —O—R 7 , —N(H)—R 8 , —N(R 34 )—(CH 2 ) n —N(R 34 ) 2 , —N(R 34 )alkyl, —N(R 34 ) 2 , —N(R 9 )(R 10 ), or a piperazine cation,
 wherein n is an integer, 
 wherein R 7  and R 8  are, independently, alkyl, alkenyl or alkynyl, or R 8  is alkyl and is covalently bound to Z, 
 wherein R 9  and R 10  are, independently, alkyl, alkenyl or alkynyl, 
 where each occurrence of R 34  is, independently, —H, —CH 3  or —C 2 H 5 ; 
 
         R 2  is —H, or is covalently bound to R 3  so as to form a substituted or unsubstituted pyrrole, 
         or R 1  and R 2  are covalently joined to form an unsubstituted or substituted aromatic ring or a saturated ring; 
         R 3  is either covalently bound to R 2  so as to form a substituted or unsubstituted pyrrole, or is —H, —OH, alkyl, alkenyl, alkynyl, or halo; 
         R 4  is —H, —OH, halo, alkyl, alkenyl, alkynyl, —R 11 N(R 35 ) 2 , —N(R 35 )R 17 N(R 35 ) 2 , —R 17 N(H)R 18 , —R 11 NR 13 R 14 , —N(R 35 )alkyl, —N(R 35 ) 2  or a piperazine group,
 wherein R 11  is a straight or a branched chain alkylene, alkenylene or alkynylene, and wherein the (R 35 ) 2  group may be attached to any carbon atom of the R 11  group, 
 wherein R 13  or R 14  or both are, independently, methyl or ethyl, 
 wherein R 17  is a straight or a branched chain alkylene, alkenylene or alkynylene, 
 wherein R 18  is a straight or a branched chain alkyl, alkenyl or alkynyl, 
 where each occurrence of R 35  is, independently, —H, —CH 3  or —C 2 H 5 ; 
 
         R 5  is —H, —OH, halo, alkyl, alkenyl, alkynyl, —R 12 N(R 36 ) 2 , R 11 NR 15 R 16 , —N(R 36 )alkyl, —N(R 36 ) 2 , a piperazine group, a mono-substituted heterocyclyl or —R 19 W,
 wherein R 12  is a straight or a branched chain alkylene, alkenylene or alkynylene, and wherein the NH 2  group may be attached to any carbon atom of the R 12  group, 
 wherein N 15  or R 16  or both are, independently, methyl or ethyl, 
 wherein R 19  is a straight or a branched chain alkylene, alkenylene or alkynylene, 
 wherein W is a mono- or di-substituted heterocyclyl group or a mono-substituted heterocyclyl cation, where each occurrence of R 36  is, independently, —H, —CH 3  or —C 2 H 5 ; and 
 
         R 6  is —H, or is absent; 
         wherein the compound contains an N(R x ) or N(R x ) 2  group wherein each occurrence of R x  is, independently, —H, —CH 3 , or —C 2 H 5 , 
         or a salt of the compound. 
       
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , wherein W is a mono-substituted heterocyclyl group wherein the heteroatom is nitrogen. 
     
     
         4 . The compound of  claim 1 , wherein W is a di-substituted heterocyclyl group wherein the heteroatoms are each nitrogen. 
     
     
         5 . The compound of  claim 1 , wherein W is a piperazine group. 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . The compound of  claim 1 , wherein R 4  is —H, —CH 2 CH 2 NH 2 , —CH 2 CH 2 NHCH 3 , —CH 2 CH(CH 3 )NH 2 , —NHCH 2 CH 2 NH 2 , —CH 2 NH 2 , or a piperazine group. 
     
     
         10 . The compound of  claim 1 , wherein R 5  is —CH 2 CH 2 NH 2 , a piperazine group, a piperazine cation, a pyrrolidin-2-yl group, a piperidinyl group. 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . The compound of  claim 1  having the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 1  having the following structure: 
       
         
           
           
               
               
           
         
         wherein 
         Y is O, X is O, bond α is absent and bond β is present; 
         atom Z is a carbon and bonds χ, δ and γ are present; 
         R 1  is —H, —OH, —O—R 7 , —N(H)—R 8 , —N(H)—(CH 2 ) n —NH 2 , —N(R 9 )(R 10 ), or a piperazine cation,
 wherein n is an integer, 
 wherein R 7  and R 8  are, independently, alkyl, alkenyl or alkynyl, 
 wherein R 9  and R 10  are, independently, alkyl, alkenyl or alkynyl; 
 
         R 2  is —H; 
         R 3  is —H, —OH, alkyl, alkenyl, alkynyl, or halo; 
         R 4  is —H, —OH, halo, alkyl, alkenyl, alkynyl, or —R 11 NH 2 ,
 wherein R 11  is a straight or a branched chain alkylene, alkenylene or alkynylene, and wherein the NH 2  group may be attached to any carbon atom of the R 11  group; 
 
         R 5  is —H, —OH, halo, alkyl, alkenyl, alkynyl, or —R 12 NH 2 ,
 wherein R 12  is a straight or a branched chain alkylene, alkenylene or alkynylene, and wherein the NH 2  group may be attached to any carbon atom of the R 12  group; and 
 
         R 6  is —H; 
         wherein the compound contains an NH 2  group. 
       
     
     
         18 . (canceled) 
     
     
         19 . The compound of  claim 1  having the following structure: 
       
         
           
           
               
               
           
         
         wherein 
         Y is O, X is O, bond α is absent and bond β is present; 
         Z is a carbon and bonds χ, δ and γ are present; 
         R 1  is —H, —OH, —O—CH 3 , —N(H)—C 2 H 4 —NH 2 , a piperazine cation, or —N(H)—R 8  wherein R 8  is propylene and is covalently bound to Z R 6 ; 
         R 2  is —H; 
         R 3  is —H; 
         R 4  is —H, —OH, —CH 3  or —C 2 H 4 NH 2 ; 
         R 5  is —H, —C 2 H 4 NH 2 , or —CH 2 —CH(CH 3 )—NH 2 ; and 
         R 6  is —H, or is absent; 
         and 
         wherein the compound contains a NH 2  group. 
       
     
     
         20 . (canceled) 
     
     
         21 . The compound of  claim 1  having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         22 .- 145 . (canceled) 
     
     
         146 . The compound of  claim 21 ,
 wherein   R 1  is —N(R 34 ) 2 ,
 wherein each occurrence of R 32  is H, —CH 3  or —CH 2 CH 3 ; 
   R 2 , R 3 , R 5  and R 6  are each —H; and   R 4  is —R 11 N(R 35 ) 2  
 wherein R 11  is a straight or a branched chain 
 alkylene and each R 35  is H or —CH 3 . 
   
     
     
         147 . The compound of  claim 146 ,
 wherein   R 1  is —NH 2 , —N(H)—CH 3 , or —N(—CH 2 CH 3 ) 2 ; and   R 4  is —CH 2 CH 2 NH 2 , —CH 2 CH(CH 3 )NH 2 , —CH 2 C(CH 3 ) 2 NH 2  or —CH 2 CH 2 N(CH 3 ) 2 .   
     
     
         148 . The compound of  claim 21 ,
 wherein   R 1  is —N(R 34 ) 2  or —N(H)—R 8 ,
 wherein each occurrence of R 34  is H, —CH 3  or —CH 2 CH 3  and R 8  is substituted alkyl; 
   R 2 , R 3 , R 4  and R 6  are each —H; and   R 5  is —R 12 N(R 36 ) 2 ,
 wherein R 12  is a straight or a branched chain alkylene and each R 36  is H or —CH 3 . 
   
     
     
         149 . The compound of  claim 148 ,
 wherein   R 1  is —N(H)—CH 3 , —N(—CH 2 CH 3 ) 2  or —NHCH 2 CH 2 F; and   R 3  is —CH 2 CH 2 NH 2 , —CH 2 CH(CH 3 )NH 2 , —CH 2 C(CH 3 ) 2 NH 2  or —CH 2 CH 2 N(CH 3 ) 2 .   
     
     
         150 . The compound of  claim 1 ,
 wherein   Y is O, X is O, bond α is absent and bond β is present;   R 1  is —N(H)—R 8 ,
 wherein R 8  is alkyl and is covalently bound to Z; 
   R 2  and R 3  are each —H;   R 4  is H or —R 11 N(R 35 ) 2 ,
 wherein R 11  is a straight chain alkylene and 
 each R 35  is H; 
   R 5  is H or —R 12 N(R 36 ) 2 ,
 wherein R 12  is a straight chain alkylene and 
 each R 36  is H; 
   R 6  is absent.   
     
     
         151 . The compound of  claim 150 ,
 wherein   R 1  is —N(H)—R 8 ,
 wherein R 8  is propylene and is covalently bound to Z; 
   R 4  is —CH 2 CH 2 NH 2 ; and   R 5  is H.   
     
     
         152 . The compound of  claim 21 ,
 wherein   R 1  and R 2  are covalently joined to form a saturated ring;   R 3  is —H;   R 4  is —H or —R 11 N(R 35 ) 2 ,
 wherein R 11  is a straight chain alkylene and each R 35  is H; 
   R 5  is —H or —R 12 N(R 36 ) 2 ,
 wherein R 12  is a straight chain alkylene and each R 36  is H; 
   R 6  is —H.   
     
     
         153 . The compound of  claim 152 ,
 wherein   R 1  and R 2  are covalently joined to form a piperidine ring;   R 4  is —CH 2 CH 2 NH 2 ; and   R 5  is —H.   
     
     
         154 . A compound having the structure: 
       
         
           
           
               
               
           
         
         wherein 
         R 4  is —H, —OH, halo, alkyl, alkenyl, alkynyl, —R 11 N(R 35 ) 2 , —N(R 35 )R 17 N(R 35 ) 2 , —R 17 N(H)R 18 , —R 11 NR 13 R 14 , —N(R 35 )alkyl, —N(R 35 ) 2 , or a piperazine group,
 wherein R 11  is a straight or a branched chain alkylene, alkenylene or alkynylene, and wherein the (R 35 ) 2  group may be attached to any carbon atom of the R 11  group, 
 wherein R 13  or R 14  or both are, independently, methyl or ethyl, 
 wherein R 17  is a straight or a branched chain alkylene, alkenylene or alkynylene, 
 wherein R 18  is a straight or a branched chain alkyl, alkenyl or alkynyl, 
 where each occurrence of R 35  is, independently, —H, —CH 3  or —C 2 H 5 ; 
 
         R 5  is —H, —OH, halo, alkyl, alkenyl, alkynyl, —R 12 N(R 36 ) 2 , R 11 NR 15 R 16 , —N(R 36 )alkyl, —N(R 36 ) 2 , a piperazine group, a mono-substituted heterocyclyl or —R 19 W,
 wherein R 12  is a straight or a branched chain alkylene, alkenylene or alkynylene, and wherein the NH 2  group may be attached to any carbon atom of the R 12  group, 
 wherein R 15  or R 16  or both are, independently, methyl or ethyl, 
 wherein R 19  is a straight or a branched chain alkylene, alkenylene or alkynylene, 
 wherein W is a mono- or di-substituted heterocyclyl group or a mono-substituted heterocyclyl cation, 
 where each occurrence of R 36  is, independently, —H, —CH 3  or —C 2 H 5 ; and 
 
         wherein the compound contains an N(R x ) or N(R x ) 2  group wherein each occurrence of R x  is, independently, —H, —CH 3  or —C 2 H 5 , 
       
       or a salt of the compound. 
     
     
         155 . The compound of  claim 154  having the structure: