Identification of human T2R receptors that respond to bitter compounds that elicit the bitter taste in compositions, and the use thereof in assays to identify compounds that inhibit (block) bitter taste in compositions and use thereof

Patent metadata

Field	Value
Publication number	US-9247759-B2
Application number	US-201313896913-A
Country	US
Kind code	B2
Filing date	May 17, 2013
Priority date	Aug 21, 2007
Publication date	Feb 2, 2016
Grant date	Feb 2, 2016

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.

First claim

The invention claimed is:

1. A compound of the formula:

or a salt, hydrate or N-oxide thereof,
wherein Ar 6 and Ar 7 are, the same or different independently one from the other, a five- or six-membered heteroaryl group;
Alk is an alkyl group, optionally interrupted by a heteroatom;
R 58 is H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl;
R 59 and R 60 are the same or different independently one from the other, H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, with the proviso that when one of R 59 or R 60 is H, then the other of R 59 or R 60 is not H; or
R 59 and R 60 , together with the atom to which they are attached form a cycloalkyl, a substituted cycloalkyl, a cycloheteroalkyl or substituted cycloheteroalkyl ring; or
R 58 and R 60 , together with the atoms to which they are attached, form a five- or six-membered cycloheteroalkyl or substituted cycloheteroalkyl ring.

2. A compound of the formula:

a salt, hydrate or N-oxide thereof,
wherein:
R 61 is H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
R 62 and R 63 are the same or different independently one from the other, H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, with the proviso that when one of R 62 or R 63 is H, then the other of R 62 or R 63 is not H;
or R 62 and R 63 , together with the atoms to which they are attached form a cycloalkyl, a substituted cycloalkyl, a cycloheteroalkyl or substituted cycloheteroalkyl ring; or
R 61 and R 62 , together with the atoms to which they are attached, form a five- or six-membered cycloheteroalkyl or substituted cycloheteroalkyl ring.

3. A compound of the formula:

a salt, hydrate or N-oxide thereof,
wherein:
R 64 and R 65 are the same or different independently one from the other, H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, with the proviso that when one of R 64 or R 65 is H, then the other of R 64 or R 65 is not H;
or R 64 and R 65 , together with the atoms to which they are attached, form a cycloalkyl, a substituted cycloalkyl, a cycloheteroalkyl or substituted cycloheteroalkyl ring;
each R 66 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, F, Cl, —CN, —NO 2 , —OR 67 , —S(O) i R 67 , —NR 67 R 68 , —CONR 67 R 68 , —CO 2 R 67 , —NR 67 CO 2 R 68 , —NR 67 CONR 68 R 69 , —NR 67 CSNR 68 R 69 or —NR 67 C(═NH)NR 68 R 69 , —SO 2 NR 67 R 68 , —NR 67 SO 2 R 68 , —NR 67 SO 2 NR 68 R 69 , —B(OR 67 )(OR 68 ), —P(O)(OR 67 )(OR 68 ), or —P(O)(R 67 )(OR 68 ), wherein R 67 , R 68 , and R 69 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 67 and R 68 or R 68 and R 69 , together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
Ar 10 is an aryl or heteroaryl ring;
g is 0, 1, 2, 3 or 4;
h is 0, 1, 2, 3 or 4; and
i is 0, 1 or 2.

4. A compound of the formula:

a salt, hydrate or N-oxide thereof,
wherein:
each R 70 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, F, Cl, —CN, —NO 2 , —OR 67 , —S(O) i R 67 , —NR 67 R 68 , —CONR 67 R 68 , —CO 2 R 67 , —NR 67 CO 2 R 68 , —NR 67 CONR 68 R 69 , —NR 67 CSNR 68 R 69 or —NR 67 C(═NH)NR 68 R 69 , —SO 2 NR 67 R 68 , —NR 67 SO 2 R 68 , —NR 67 SO 2 NR 68 R 69 , —B(OR 67 )(OR 68 ), —P(O)(OR 67 )(OR 6s ), or —P(O)(R 67 )(OR 68 ), wherein R 67 , R 68 , and R 69 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 67 and R 68 or R 68 and R 69 , together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
j is 0, 1 or 2;
k is 0, 1 or 2; and
l is 0, 1 or 2;
with the proviso that j and k are not simultaneously both 0.

5. The compound of claim 1 having the formula:

or a salt, hydrate or N-oxide thereof.

6. The compound of claim 1 having the formula:

or a salt, hydrate or N-oxide thereof.

7. A method of reducing or alleviating bitter taste comprising adding at least one compound according to claim 1 or an analog thereof to a composition for ingestion by humans or animals at a concentration effective to alleviate or reduce the bitter taste associated with the composition.

8. The method of claim 7 , wherein the concentration of the at least one compound is from about 0.1 ppm to about 100 ppm.

9. The method of claim 7 , wherein the concentration of t

Assignees

• Senomyx Inc

Inventors

• Karanewsky Donald S
• Fotsing Joseph R
• Tachdjian Catherine
• Arellano Melissa

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A23F5/465 Primary

  Flavouring with flavours other than natural coffee flavour or coffee oil · CPC title

• A23L27/2056

  having at least two different hetero atoms, at least one being a nitrogen atom · CPC title

• A23L27/86

  Addition of bitterness inhibitors · CPC title

• A61K31/485

  Morphinan derivatives, e.g. morphine, codeine · CPC title