Compounds including substituted thienopyrimidinone derivatives as ligands for modulating chemosensory receptors
The present invention provides compounds including substituted thienopyrimidinone derivatives of Formula (IIc) as ligands for modulating chemosensory receptors: These compounds are useful as sweet taste enhancers in comestible or medicinal compositions. The present invention also provides screening methods for identifying modifiers of chemosensory receptors and their ligands, e.g., by determining whether a test entity is suitable to interact with one or more interacting sites within the Venus flytrap domains of the chemosensory receptors as well as modifiers capable of modulating chemosensory receptors and their ligands.
1. A comestible composition comprising
at least a sweet flavor entity selected from the group consisting of sucrose, sucralose, and combinations thereof; and
a compound of structural Formula (IIc):
or a pharmaceutically acceptable salt thereof, wherein:
A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, —CN, —OR 9 , —NR 9 COR 10 , —NHOR 9 ,—NR 9 R 10 , —NR 9 CO 2 R 10 , —NR 9 CONR 10 R 11 , —NR 9 CSNR 10 R 11 , or —NR 9 C(═NH)NR 10 R 11 ;
R 17 is hydrogen, alkyl, substituted alkyl;
W is —S—;
Y is —C(R 26 )—;
Z is —C(R 27 )—;
R 26 is hydrogen, alkyl, substituted alkyl, —OR 31 , —CONR 31 R 32 , or —CO 2 R 31 ;
R 27 is hydrogen, alkyl, substituted alkyl, —OR 33 , —CONR 33 R 34 , or —CO 2 R 33 and
R 9 , R 10 , R 11 , R 31 , R 32 , R 33 , and R 34 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; alternatively R 10 and R 11 , R 31 and R 32 , or R 33 and R 34 together with the atoms to which they are bonded form a heterocycloalkyl or substituted heterocycloalkyl ring;
wherein the substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroalkyl, substituted heteroaryl, substituted heteroarylalkyl, and substituted heterocycloalkyl each independently comprises one or more substituent groups selected from the group consisting of —R a , halo, ═O, —OR b , —SR b , ═S, —NR c R c , ═NR b , ═N—OR b , trihalomethyl, —CN, —NO 2 , S(O) 2 R b , —S(O) 2 NR b , —S(O) 2 OR b , —OS(O) 2 R b , —OS(O) 2 OR b , —P(O)(OR b )(OR b ), —C(O)R b , —C(NR b )R b , —C(O)OR b , —C(O)NR c R c , —C(NR b )NR c R c , —OC(O)R b , —OC(O)OR b , —NR b C(O)R b , —NR b C(O)OR b , —NR b C(O)NR c R c , —NR b C(NR b )R b and —NR b C(NR b )NR c R c , where R a is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each R b is independently hydrogen or R a ; and each R c is independently R b or alternatively, the two R c s are taken together with the nitrogen atom to which they are bonded form a 4-, 5-, 6- or 7-membered heterocycloalkyl.
2. The comestible composition of claim 1 , wherein
A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, —CN, —OR 9 , —NR 9 COR 10 , —NHOR 9 , —NR 9 R 10 , —NR 9 CO 2 R 10 , —NR 9 CONR 10 R 11 , —NR 9 CSNR 10 R 11 , or —NR 9 C(═NH)NR 10 R 11 ;
R 17 is hydrogen or alkyl;
R 26 is hydrogen, alkyl, —OR 31 , —CONR 31 R 32 , or —CO 2 R 31 ;and
R 27 is hydrogen, alkyl, —OR 33 , —CONR 33 R 34 , or —CO 2 R 33 .
3. The comestible composition of claim 1 , wherein
A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, —CN, —NR 9 R 10 , or —NR 9 CO 2 R 10 ;
R 17 is hydrogen or alkyl;
R 27 is hydrogen, alkyl, —OR 33 , —CONR 33 R 34 or —CO 2 R 33 ; and
R 26 is hydrogen, alkyl, —OR 31 , —CONR 31 R 32 , or —CO 2 R 31 .
4. The comestible composition of claim 1 , wherein
A is —OR 9 , —NR 9 CONR 10 R 11 , —NR 9 CSNR 10 R 11 or —NR 9 C(═NH)NR 10 R 11 ;
R 17 is hydrogen or alkyl;
R 27 is hydrogen, alkyl, —OR 33 , —CONR 33 R 34 or —CO 2 R 33 ; and
R 26 is hydrogen, alkyl, —OR 31 , —CONR 31 R 32 , or —CO 2 R 31 .
5. The comestible composition of claim 1 , wherein
A is —OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHOCH 3 , —NHC(O)CH 3 , —NHC(O)OCH 3 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHC(NH)NH 2 , —CN, —CH 2 OH, —CH 2 NH 2 , —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , or —CH 2 NHC(O)CH 3 ;
R 17 is hydrogen, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, or benzyl;
R 27 is hydrogen, —CF 3 , methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or t-butyl; and
R 26 is hydrogen, —CF 3 , methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or t-butyl.
6. The comestible composition of claim 5 , wherein
A is —NH 2 ;
R 17 is hydrogen or methyl;
R 27 is hydrogen, —CF 3 , methyl or ethyl; and
R 26 is hydrogen, —CF 3 , methyl or ethyl.
7. The comestible composition of claim 1 , wherein
R 27 is hydrogen, alkyl or substituted alkyl; and
R 26 is hydrogen, alkyl or substituted alkyl.
8. The comestible composition of claim 7 , wherein
A is —NR 9 R 10 ;
R 17 is hydrogen or alkyl;
R 27 is hydrogen or alkyl;
R 26 is hydrogen or alkyl; and
R 9 and R 10 are each independently hydrogen, alkyl, or substituted alkyl.
9. The comestible composition of claim 1 , wherein the compound of structural Formula (IIc) has a structural formula selected from the group consisting of
10. The comestible composition of claim 1 , comprising a hydrochloride salt of the compound of structural Formula (IIc) selected from the group consisting of
11. The comestible composition of claim 1 , comprising between about 0.0001 ppm to about 10 ppm of the compound of structural Formula (IIc).
12. The comestible composition of claim 1 , comprising between about 0.0001 ppm to about 100 ppm of the compound of structural Formula (IIc).
13. The comestible composition of claim 1 , comprising between about 0.01 ppm to about 100 ppm of the compound of structural Formula (IIc).
14. The comestible composition of claim 1 , comprising between about 10 ppm to about 100,000 ppm of the compound of structural Formula (IIc).