# US 8,148,544 B2 · Compounds that inhibit (block) bitter taste in composition and methods of making same

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- Number: US 8,148,544 B2
- Document ID: US8148544B2
- Status: Granted
- Kind: B2
- Application number: 13/051,052
- Filed: 2011-03-18
- Published: 2011-08-25
- Granted: 2012-04-03
- Earliest claimed: 2007-08-21
- Assignees: Senomyx, Inc.
- Inventors: Xiaodong Li; Andrew Patron; Catherine Tachdjian; Hong Xu; Qing Li; Alexey Pronin; Guy Servant; Lan Zhang; Thomas Brady; Vincent Darmohusodo; Melissa Arellano; Victor Selchau; Brett Weylan Ching; Donald S. Karanewsky; Paul Brust; Jing Ling; Wen Zhao; Chad Priest
- Web page: https://patentgrep.com/patent/US8148544B2

## CPC

- C07C 311/17: to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- A23L 27/86: {Addition of bitterness inhibitors}
- A61K 8/46: containing sulfur (A61K8/44 takes precedence)
- A61K 8/466: {containing sulfonic acid derivatives; Salts}
- A61K 8/4933: {having sulfur as an exocyclic substituent, e.g. pyridinethione}
- A61K 8/494: {with more than one nitrogen as the only hetero atom}
- A61K 8/4973: {with oxygen as the only hetero atom}
- A61K 8/498: {having 6-membered rings or their condensed derivatives, e.g. coumarin}
- A61K 8/4986: {with sulfur as the only hetero atom}
- A61K 31/135: having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)}
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61K 31/60: Salicylic acid; Derivatives thereof
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/00: Drugs for disorders of the senses
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61Q 11/00: Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
- C07C 233/73: of a carbon skeleton containing six-membered aromatic rings
- C07C 311/04: to acyclic carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
- C07C 311/13: the carbon skeleton containing six-membered aromatic rings
- C07C 311/16: having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C 311/18: to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
- C07C 311/19: to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C 311/20: having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C 311/21: having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C 311/29: having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C 311/46: Y being a hydrogen or a carbon atom
- C07C 323/49: to sulfur atoms
- C07C 335/16: having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C 335/18: being further substituted by singly-bound oxygen atoms
- C07D 213/42: having hetero atoms attached to the substituent nitrogen atom (nitro radicals C07D213/26)
- C07D 213/71: to which a second hetero atom is attached
- C07D 217/08: with a hetero atom directly attached to the ring nitrogen atom
- C07D 223/18: Dibenzazepines; Hydrogenated dibenzazepines
- C07D 307/14: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- C07D 307/52: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- C07D 317/58: Radicals substituted by nitrogen atoms (nitro radicals C07D317/52)
- C07D 333/20: by nitrogen atoms (nitro, nitroso radicals C07D333/12)
- C07D 333/34: Sulfur atoms
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A23L: FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF (preservation thereof A23B)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61Q: SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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.

## Claims

### Claim 1

A method of making a compound of the formula A:
or a salt or N-oxide thereof,
wherein Alk is an alkyl group;
R51 and R52 are, the same or different independently one from the other, H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl alkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted arylalkylamidoalkyl, substituted or unsubstituted heteroarylamidoalkyl, substituted or unsubstituted heteroarylalkylamidoalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, haloalkyl, or
R51 and R52, together with the carbon atom to which they are attached, form a substituted or unsubstituted alkenyl group;
M1 is N or CR49, wherein R49 is H or substituted or unsubstituted alkyl;
M2 is N or CR50, wherein R50 is H or substituted or unsubstituted alkyl;
R38 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl alkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted heteroarylamidoalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or haloalkyl;
R47 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or halo; and
R48 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or halo;
wherein the method comprises converting a compound of the formula B:
or a salt or N-oxide thereof;
into a compound of the formula C:
or a salt or N-oxide thereof;
wherein R47, R48, Alk, M1, and M2 are defined above; and
reacting the compound of formula C with a compound of the formula D:
or a salt thereof;
wherein J3 is a leaving group and R38, R51, and R52 are defined above, to give a compound of formula A or a salt or N-oxide thereof.

### Claim 2 (depends on 1)

The method of claim 1, where the compound of formula B, or a salt or N-oxide thereof, is converted into a compound of formula C, or a salt or N-oxide thereof, by heating the compound of formula B, or a salt or N-oxide thereof.

### Claim 3

A compound of the formula B:
or a salt or N-oxide thereof,
wherein Alk is an alkyl group;
M1 is N or CR49, wherein R49 is H or substituted or unsubstituted alkyl;
M2 is N or CR50, wherein R50 is H or substituted or unsubstituted alkyl;
R47 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or halo; and
R48 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or halo.

### Claim 4 (depends on 3)

The compound of claim 3, or a salt or N-oxide thereof, wherein:
M1 is CR49, wherein R49 is H or substituted or unsubstituted alkyl;
M2 is CR50, wherein R50 is H or substituted or unsubstituted alkyl;
R47 is substituted or unsubstituted alkyl; and
R48 substituted or unsubstituted alkyl.

### Claim 5 (depends on 3)

The compound of claim 3, or a salt or N-oxide thereof, wherein the compound of formula B has the formula:

### Claim 6

A compound of the formula C:
or a salt or N-oxide thereof,
wherein Alk is an alkyl group;
M1 is N or CR49, wherein R49 is H or substituted or unsubstituted alkyl;
M2 is N or CR50, wherein R50 is H or substituted or unsubstituted alkyl;
R47 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or halo; and
R48 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or halo.

### Claim 7 (depends on 6)

The compound of claim 6, or a salt or N-oxide thereof, wherein:
M1 is CR49, wherein R49 is H or substituted or unsubstituted alkyl;
M2 is CR50, wherein R50 is H or substituted or unsubstituted alkyl;
R47 is substituted or unsubstituted alkyl; and
R48 substituted or unsubstituted alkyl.

### Claim 8 (depends on 6)

The compound of claim 6, or a salt or N-oxide thereof, wherein the compound of formula C has the formula:
or a salt or N-oxide thereof.

### Claim 9

A method of making a compound of the formula A:
or a salt or N-oxide thereof,
wherein Alk is an alkyl group;
R51 and R52 are, the same or different independently one from the other, H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl alkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted arylalkylamidoalkyl, substituted or unsubstituted heteroarylamidoalkyl, substituted or unsubstituted heteroarylalkylamidoalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, haloalkyl, or R51 and R52, together with the carbon atom to which they are attached, form a substituted or unsubstituted alkenyl group;
M1 is N or CR49, wherein R49 is H or substituted or unsubstituted alkyl;
M2 is N or CR50, wherein R50 is H or substituted or unsubstituted alkyl;
R38 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl alkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamidoalkyl, substituted or unsubstituted heteroarylamidoalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or haloalkyl;
R47 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or halo; and
R48 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or halo;
wherein the method comprises reacting a compound of the formula B:
or a salt or N-oxide thereof;
wherein R47, R48, Alk, M1, and M2 are defined above;
with a compound of formula D:
or a salt thereof;
wherein J3 is a leaving group and R38, R51, and R52 are defined above, to give a compound of formula A or a salt or N-oxide thereof.