Isosorbide derivatives and their use as flavor modifiers, tastants, and taste enhancers

Abstract

The present invention provides isosorbide derivatives having the formula shown below and certain subgenera or species thereof, as flavor or taste modifiers, particularly, savory (“umami”) taste modifiers, savory flavoring agents and savory flavor enhancers in foods, beverages, and other comestible compositions,

1 . A compound having structural formula (I) 
       
         
           
           
               
               
           
         
         or the salt, solvate, ester, or N-oxide thereof, wherein: 
         A is aryl, heteroaryl, or a covalent bond; 
         Y is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkylnyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, substituted heteroarylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, carbocyclyl, substituted carbocyclyl, acyl, halo, —CN, —NO 2 , —OR 1 , —S(O)R 1 , —S(O) 2 R 1 , —OC(O)R 1 , —N(R 1 )C(O)R 2 , —NR 1 R 2 , —C(O)NR 1 R 2 , —C(O)OR 1 , —S(O) 2 NR 1 R 2 , —COR 1 , —N(R 1 )S(O) 2 R 2 , —SR 1 , —C(R 1 R 2 R 6 ), —C(S)—R 1 , —C(═NR 2 )—R 1 , —N(R 1 )—C(═N—OR 2 )R 6 , —N(R 1 )C(S)NR 2 R 6 , —C(═N—OR 1 )R 2 , —C(═NR 1 )—NR 2 R 6 , —N(R 1 )C(═NR 2 )NR 6 R 7 , —N(R 1 )C(S)R 2 , —N(R 1 )—C(O)—C(O)R 2 , —C(S)—NR 1 R 2 , —N(R 1 )C(═NR 2 )OR 6 , —C(═NR 1 )O—NR 2 R 6 , —N(R 1 )N(R 2 )C(O)OR 6 , —N(R 1 )C(O)OR 2 , —N(R 1 )C(O)NR 2 R 6 , —N(R 1 )—C(O)—C(O)—NR 2 R 6 , —C(O)—C(O)—NR 1 R 2 , —P(O)(OR 1 )(OR 2 ), —P(O)(OR 1 )(R 2 ), or —P(O)R 1 R 2 ; 
         X is —O—, —S—, —S(O)—, —S(O) 2 —, —C(R 3 R 4 )—, —C(O)—, —C(S)—, —C(═NR 3 )—, —C(O)O—, —N(R 3 )—, —OC(O)—, —N(R 3 )C(O)—, —C(O)N(R 3 )—, —N(R 3 )—C(═N—OR 4 )—, —C(═N—OR 3 )—, —C(—NR 3 )—NR 4 —, —N(R 3 )C(S)N(R 4 )—R 5 , —N(R 3 )C(O)N(R 4 )—R 5 , —N(R 3 )C(═NR 4 )—, —N(R 3 )C(S)—, —N(R 3 )—C(O)—C(O)—, —C(S)—N(R 3 )—, —N(R 3 )S(O) 2 —, —S(O) 2 —N(R 3 )—, —N(R 3 )C(═NR 4 )O—, —C(═NR 4 )O—N(R 3 )—, —N(R 3 )—C(═NR 4 )—N(R 5 )—, —N(R 3 )N(R 4 )C(O)O—, —N(R 3 )C(O)O—, —N(R 3 )C(O)N(R 4 )—, —N(R 3 )—C(O)—C(O)—NR 4 —, —C(O)—C(O)—NR 4 —, —P(O)(OR 3 )—, or —P(O)R 3 —; 
         Z is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkylnyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, substituted heteroarylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, carbocyclyl, or substituted carbocyclyl; 
         RI, R2, R3, R4, R5, R6, and R7 are each independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkylnyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, carbocyclyl, substituted carbocyclyl, heteroarylalkyl, or substituted heteroarylalkyl; and 
         with the following provisos: 
         (a) when A is triazole or tetrazole; then —X—Z is not —O-alkyl, —O-acyl, or sulfonamido; 
         (b) when A is tetrazole, and Z is cyclohexyl; then X is not -Nli-C(0)-, —NIJ-C(0)-Nfl-; and 
         (c) when A is a covalent bond, then Y is not hydrogen. 
       
     
     
         2 . The compound of  claim 1 , wherein Y is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbocyclyl, or substituted carbocyclyl. 
     
     
         3 . The compound of  claim 1 , wherein A is monocyclic five- or six-membered heteroaryl. 
     
     
         4 . The compound of  claim 1 , wherein:
 A is monocyclic five-membered heteroaryl;   Y is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkylnyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, carbocyclyl, substituted carbocyclyl, heteroarylalkyl, or substituted heteroarylalkyl;   X is —O—, —S—, —S(O)—, —S(O) 2 —, —C(R 3 R 4 )—, —C(O)—, —C(S)—, —C(═NR 3 )—, —C(O)O—, —N(R 3 )—, —OC(O)—, —N(R 3 )C(O)—, —C(O)N(R 3 )—, —C(═N—OR 3 )—, —C(═NR 3 )—NR 4 —, —N(R 3 )C(═NR 4 )—, —N(R 3 )C(S)—, —C(S)—N(R 3 )—, —N(R 3 )S(O) 2 —, —S(O) 2 —N(R 3 )—, —N(R 3 )C(—NR 4 )O—, —C(═NR 4 )O—N(R 3 )—, —N(R 3 )—C(═NR 4 )—N(R 5 )—, —N(R 3 )N(R 4 )C(O)O—, —N(R 3 )C(O)O—, —N(R 3 )C(O)N(R 4 )—, —NR 3 —C(O)—C(O)—NR 4 —, —C(O)—C(O)—NR 4 —, —P(O)(OR 3 )—, or —P(O)(R 3 )—;   Z is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkylnyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, carbocyclyl, substituted carbocyclyl, heteroarylalkyl, or substituted heteroarylalkyl; and   R 3 , R 4 , and R 5  are each independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkylnyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, substituted heteroarylalkyl, carbocyclyl, or substituted carbocyclyl.   
     
     
         5 . The compound of  claim 1 , having a structural formula (Ia): 
       
         
           
           
               
               
           
         
         or the salt, solvate, ester, or N-oxide thereof, wherein 
         X a  is —S(O)—, —S(O) 2 —, —C(R 3 R 4 )—, —C(O)—, —C(O)O—, —C(O)N(R 3 )—, —C(═N—OR 3 )—, —C(═NR 3 )—NR 4 —, —C(═NR 3 )—, —C(S)—N(R 3 )—, —C(S)—, —NR 3 —C(O)—C(O)—NR 4 —, —C(O)—C(O)—NR 4 —, or —S(O) 2 —N(R 1 )—; 
         Y is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbocyclyl, or substituted carbocyclyl; 
         Z is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, substituted heteroarylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, carbocyclyl, or substituted carbocyclyl; and 
         R hydrogen, alkyl, or substituted alkyl. 
       
     
     
         6 . The compound of  claim 1 , having a structural formula selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or the salt, solvate, ester, or N-oxide thereof. 
     
     
         7 . The compound of  claim 1  wherein
 A is a covalent bond; 
 Y is —OR 1 , —S(O)R 1 , —S(O) 2 R 1 , —OC(O)R 1 , —N(R 1 )C(O)R 2 , —NR 1 R 2 , —C(O)NR 1 R 2 , —C(O)OR 1 , —S(O) 2 NR 1 R 2 , —N(R 1 )S(O) 2 R 2 , —SR 1 , —C(R 1 R 2 R 6 ), —C(S)—R 1 , —C(═NR 2 )—R 1 , —N(R 1 )—C(═N—OR 2 )R 6 , —C(═N—OR 1 )R 2 , —C(═NR 1 )—NR 2 R 6 , —N(R 1 )C(═NR 2 )R 6 , —N(R 1 )C(S)R 2 , —N(R 1 )—C(O)—C(O)R 2 , —N(R 1 )C(S)N(R 2 )—R 6 , —C(S)—NR 1 R 2 , —N(R 1 )C(═NR 2 )OR 6 , —C(═NR 1 )O—NR 2 R 6 , —N(R 1 )—C(═NR 2 )—N(R 6 )R 7 , —N(R 1 )N(R 2 )C(O)OR 6 , —N(R 1 )C(O)OR 2 , —N(R 1 )C(O)NR 2 R 6 , —N(R 1 )—C(O)—C(O)—NR 2 R 6 , —C(O)—C(O)—NR 1 R 2 , —P(O)(OR 1 )(OR 2 ), —P(O)(OR 1 )(R 2 ), or —P(O)R 1 R 2 ; and 
 R 1 , R 2 , R 6  and R 7  are each independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkylnyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, carbocyclyl, substituted carbocyclyl, heteroarylalkyl, or substituted heteroarylalkyl. 
 
     
     
         8 . The compound of  claim 7  wherein
 Y is —N(R 1 )C(O)R 2 , —NR 1 R 2 , —N(R 1 )S(O) 2 R 2 , —N(R 1 )—C(═N—OR 2 )R 6 , —C(═NR 1 )—NR 2 R 6 , —N(R 1 )C(═NR 2 )R 6 , —N(R 1 )C(S)R 2 , —N(R 1 )—C(O)—C(O)R 2 , —N(R 1 )C(S)N(R 2 )—R 6 , —N(R 1 )C(═NR 2 )OR 6 , —N(R 1 )—C(═NR 2 )—NR 6 R 7 , —N(R 1 )N(R 2 )C(O)OR 6 , —N(R 1 )C(O)OR 2 , —N(R 1 )C(O)NR 2 R 6 , or —N(R 1 )—C(O)—C(O)—NR 2 R 6 ; 
 X is —N(R 3 )C(O)—, —N(R 3 )—, —N(R 3 )S(O) 2 —, —N(R 3 )—C(═N—OR 4 )—, —N(R 3 )C(═NR 4 )—, —N(R 1 )—C(═NR 2 )—N(R 6 )—, —N(R 3 )C(S)—, —N(R 3 )C(S)N(R 4 )—, —N(R 3 )C(O)N(R 4 )—, —N(R 3 )C(═NR 4 )O—, —N(R 3 )—C(═NR 4 )—N(R 5 )—, —N(R 3 )N(R 4 )C(O)O—, —N(R 3 )C(O)O—, or —N(R 3 )C(O)N(R 4 )—; and 
 R 1 , R 2 , R 3 , R 5 , R 6 , and R 7  are each independently alk yl, substituted alkyl, alkenyl, substituted alkenyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heterocyclyl, substituted heterocyclyl, carbocyclyl, or substituted earboeyelyl; and 
 Z is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, carbocyclyl, or substituted carbocyclyl. 
 
     
     
         9 . The compound of  claim 8  wherein Z is carbocyclyl or substituted carbocyclyl. 
     
     
         10 . The compound of  claim 8  wherein Z is alkyl or substituted alkyl. 
     
     
         11 . A compound of formula (Ib): 
       
         
           
           
               
               
           
         
         or a salt, solvate, ester, or N-oxide thereof, wherein 
         M is O or S; and 
         W and Z are each independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkylnyl, alkoxy, alkylamine, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, substituted heteroarylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, carbocyclyl, or substituted carbocyclyl. 
       
     
     
         12 . The compound of  claim 11  wherein
 W and Z are each independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkylamine, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, substituted heteroarylalkyl, carbocyclyl, or substituted carbocyclyl. 
 
     
     
         13 . A composition comprising a compound having structural formula (I), 
       
         
           
           
               
               
           
         
         or the salt, solvate, ester, or N-oxide thereof, wherein: 
         A is aryl, heteroaryl, or a covalent bond; 
         Y is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkylnyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, substituted heteroarylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, carbocyclyl, substituted carbocyclyl, acyl, halo, —CN, —NO 2 , —OR 1 , —S(O)R 1 , —S(O) 2 R 1 , —OC(O)R 1 , —N(R 1 )C(O)R 2 , —NR 1 R 2 , —C(O)NR 1 R 2 , —C(O)OR 1 , —S(O) 2 NR 1 R 2 , —COR 1 , —N(R 1 )S(O) 2 R 2 , —SR 1 , —C(R 1 R 2 R 6 ), —C(S)—R 1 , —C(═NR 2 )—R 1 , —N(R 1 )—C(═N—OR 2 )R 6 , —N(R 1 )C(S)NR 2 —R 6 , —C(═N—OR 1 )R 2 , —C(═NR 1 )—NR 2 R 6 , —N(R 1 )C(═NR 2 )NR 6 R 7 , —N(R 1 )C(S)R 2 , —N(R 1 )—C(O)—C(O)R 2 , —C(S)—NR 1 R 2 , —N(R 1 )C(═NR 2 )OR 6 , —C(═NR 1 )O—NR 2 R 6 , —N(R 1 )N(R 2 )C(O)OR 6 , —N(R 1 )C(O)OR 2 , —N(R 1 )C(O)NR 2 R 6 , —N(R 1 )—C(O)—C(O)—NR 2 R 6 , —C(O)—C(O)—NR 1 R 2 , —P(O)(OR 1 )(OR 2 ), —P(O)(OR 1 )(R 2 ), or —P(O)R 1 R 2 ; 
         X is —O—, —S—, —S(O)—, —S(O) 2 —, —C(R 3 R 4 )—, —C(O)—, —C(S)—, —C(═NR 3 )—, —C(O)O—, —N(R 3 )—, —OC(O)—, —N(R 3 )C(O)—, —C(O)N(R 3 )—, —N(R 3 )—C(═N—OR 4 )—, —C(═N—OR 3 )—, C(═NR 3 )—NR 4 —, —N(R 3 )C(S)N(R 4 )—R 5 , —N(R 3 )C(O)N(R 4 )—R 5 , —N(R 3 )C(═NR 4 )—, —N(R 3 )C(S)—, —N(R 3 )—C(O)—C(O)—, —C(S)—N(R 3 )—, —N(R 3 )S(O) 2 —, —S(O) 2 —N(R 3 )—, —N(R 3 )C(═NR 4 )O—, —C(═NR 4 )O—N(R 3 )—, —N(R 3 )—C(═NR 4 )—N(R 5 )—, —N(R 3 )N(R 4 )C(O)O—, —N(R 3 )C(O)O—, —N(R 3 )C(O)N(R 4 )—, —N(R 3 )—C(O)—C(O)—NR 4 —, —C(O)—C(O)—NR 4 —, P(O)(OR 3 )—, or —P(O)R 3 —; 
         Z is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkylnyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, substituted heteroarylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, carbocyclyl, or substituted carbocyclyl; and 
         R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are each independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkylnyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, carbocyclyl, substituted carbocyclyl, heteroarylalkyl, or substituted heteroarylalkyl. 
       
     
     
         14 . The composition of  claim 13 , which comprises an ingestible composition. 
     
     
         15 . The composition of  claim 13 , which comprises a food or beverage. 
     
     
         16 . A method for modulating the savory taste of a composition comprising combining the composition with at least one compound of formula (I) of  claim 1 .