Compounds that inhibit (block) bitter taste in composition and methods of making same

Abstract

The present invention relates to the discovery that specific human taste receptors in the T2R taste receptor family respond to particular bitter compounds present in, e.g., coffee. Also, the invention relates to the discovery of specific compounds and compositions containing that function as bitter taste blockers and the use thereof as bitter taste blockers or flavor modulators in, e.g., coffee and coffee flavored foods, beverages and medicaments. Also, the present invention relates to the discovery of a compound that antagonizes numerous different human T2Rs and the use thereof in assays and as a bitter taste blocker in compositions for ingestion by humans and animals.

1 . A compound of structural Formula (II) shown below: 
       
         
           
           
               
               
           
         
         or a salt, hydrate, solvate or N-oxide thereof wherein: 
         Ar 1 , Ar 2  and Ar 3  are independently a five or six membered aryl, or cycloalkyl ring with the proviso that Ar2-(R2′)n and Ar3-(R3′)p do not simultaneously form phenyl groups when r and t are zero and Y and Z are CR6R7 (where R6 and R7 are each hydrogen); 
         m is 0, or 1; 
         n and p are independently 0, 1, 2, 3 or 4; 
         r and t are independently 0, 1 or 2; 
         Y and Z are independently selected from the group consisting of CR 6 R 7 , C═O, C═S, C═NOR 6 , O, NR 6 , and S(O) b ; 
         R 1  is selected from the group consisting of SO 2 , C═O, C═S, and C═NOR 4 ; 
         X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, CN, NO 2 , —OR 6 , S(O) b R 6 , NR 6 R 7 , CONR 6 R 7 , CO 2 R 6 , NR 6 CO 2 R 7 , NR 6 CONR 7 R 8 , NR 6 CSNR 7 R 8 , NR 6 C(═NH)NR 7 R 8 , SO 2 NR 5 R 6 , NR 5 SO 2 R 6 , NR 5 SO 2 NR 6 R 7 , B(OR 5 )(OR 6 ), P(O)(OR 5 )(OR 6 ), and P(O)(R 5 )(OR 6 );
 each R 1 ′ is independently selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, CN, NO 2 , OR 6 , S(O) b R 6 , NR 6 R 7 , CONR 6 R 7 , CO 2 R 6 , NR 6 CO 2 R 7 , NR 6 CONR 7 R 8 , NR 6 CSNR 7 R 8 , NR 6 C(═NH)NR 7 R 8 , SO 2 NR 5 R 6 , NR 5 SO 2 R 6 , NR 5 SO 2 NR 6 R 7 , B(OR 5 )(OR 6 ), P(O)(OR 5 )(OR 6 ), and P(O)(R 5 )(OR 6 ); 
 each R 2 ′ is independently selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, CN, NO 2 , OR 6 , S(O) b R 6 , NR 6 R 7 , CONR 6 R 7 , CO 2 R 6 , NR 6 CO 2 R 7 , NR 6 CONR 7 R 8 , NR 6 CSNR 7 R 8 , NR 6 C(═NH)NR 7 R 8 , SO 2 NR 5 R 6 , NR 5 SO 2 R 6 , NR 5 SO 2 NR 6 R 7 , B(OR 5 )(OR 6 ), and P(O)(OR 5 )(OR 6 ); 
 each R 3 ′ is independently selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, CN, NO 2 , OR 6 , S(O) b R 6 , NR 6 R 7 , CONR 6 R 7 , CO 2 R 6 , NR 6 CO 2 R 7 , NR 6 CONR 7 R 8 , NR 6 CSNR 7 R 8 , NR 6 C(═NH)NR 7 R 8 , SO 2 NR 5 R 6 , NR 5 SO 2 R 6 , NR 5 SO 2 NR 6 R 7 , B(OR 5 )(OR 6 ), P(O)(OR 5 )(OR 6 ), and P(O)(R 5 )(OR 6 ); 
 
         or alternatively, X and/or at least one of R 1 ′ together with the atoms to which they are bonded form an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring where the ring is optionally fused to another aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         R 4 -R 8  are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R 5  and R 6 , R 6  and R 7 , R 7  and R 8 , together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         b is 0, 1, or 2. 
       
     
     
         2 . The compound of  claim 1 , wherein X is selected from the group consisting of hydrogen, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, CN, S(O) b R 6 , CONR 6 R 7 , —CO 2 R 6 , SO 2 NR 5 R 6 , NR 5 SO 2 R 6 , NR 5 SO 2 NR 6 R 7 , B(OR 5 )(OR 6 ), P(O)(OR 5 )(OR 6 ), and P(O)(R 5 )(OR 6 ). 
     
     
         3 . The compound of  claim 1  having the structure below: 
       
         
           
           
               
               
           
         
         or a salt, hydrate, solvate or N-oxide thereof. 
       
     
     
         4 . A compound having the structure below: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a salt, hydrate, solvate or N-oxide thereof. 
       
     
     
         5 . A compound having the structure below: 
       
         
           
           
               
               
           
         
         or a salt, hydrate, solvate or N-oxide thereof. 
       
     
     
         6 . A compound of the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a salt, hydrate, solvate or N-oxide thereof. 
     
     
         7 . A composition comprising one or more compounds of  claim 1 , or a salt, hydrate, solvate or N oxide thereof, and one or more pharmaceutically acceptable carriers. 
     
     
         8 . The composition of  claim 7 , which is a food, beverage or medicament for human consumption. 
     
     
         9 . A coffee or coffee flavored food or beverage or medicament composition that comprises at least one compound of  claim 1  or a salt, hydrate, solvate or N oxide thereof. 
     
     
         10 . The composition of  claim 9 , which is an instant coffee, ground coffee, or brewed coffee. 
     
     
         11 . The composition of  claim 9 , which is an instant coffee. 
     
     
         12 . A food, beverage, or medicament composition having a bitter taste wherein said bitter taste is alleviated or eliminated by the addition of an effective amount of a compound of  claim 1  or a salt, hydrate, solvate or N oxide thereof. 
     
     
         13 . The composition of  claim 12 , wherein said beverage is an instant coffee beverage, a ground coffee beverage, or a brewed coffee beverage. 
     
     
         14 . The composition of  claim 12 , wherein said beverage is an instant coffee beverage. 
     
     
         15 . An ingestible composition comprising one or more compounds of  claim 1  or a salt, hydrate, solvate or N oxide thereof. 
     
     
         16 . The composition of  claim 15 , wherein said composition is a food or beverage product. 
     
     
         17 . The composition of  claim 16 , wherein the beverage product is a ready-to-drink, soluble and dry coffee beverage, a coffee beverage mix, or a coffee beverage concentrate. 
     
     
         18 . The composition of  claim 16 , wherein the beverage product is a dairy based creamer, a non-dairy based creamer or a whitener for coffee beverages. 
     
     
         19 . The composition of  claim 15 , wherein the composition is a non-comestible product. 
     
     
         20 . The composition of  claim 19 , wherein the non-comestible product is a supplement, nutraceutical, functional food product, pharmaceutical, over the counter medication, oral care product or a cosmetic product. 
     
     
         21 . The composition of  claim 20 , wherein the oral care product is a dentifrice, mouthwash or chewing gum. 
     
     
         22 . The compound of  claim 1  which is a compound of the formula: 
       
         
           
           
               
               
           
         
         or a salt, hydrate, solvate or N oxide thereof.