Compounds including substituted thienopyrimidinone derivatives as ligands for modulating chemosensory receptors

• US 7,928,111 B2
• Filed: 08/08/2007
• Issued: 04/19/2011
• Est. Priority Date: 06/08/2007
• Status: Active Grant

• Current Assignee: Senomyx Inc
• Original Assignee: Senomyx Inc
• Inventors: Chen, Qing, Zoller, Mark, Fine, Richard, Werner, Sara, Kang, Xinshan, Tang, Xiao-Qing, Rinnova, Marketa, Liu, Haitian, Klebansky, Boris, Zhang, Feng, Li, Xiaodong, Servant, Guy, Tachdjian, Catherine, Zlotnik, Albert
• Primary Examiner(s): Wilson; James O.
• Assistant Examiner(s): Willis; Douglas M
• Application Number:
  US11/836,074
• Publication Number:
  US 20080306053A1
• Time in Patent Office: 1,350 Days
• Field of Search: 424/452, 424/461, 424/479, 424/493, 514/260.1, 544/278
• US Class Current: 514/260.1
• CPC Class Codes: A23L 2/39 Dry compositions
• CPC Class Codes: A23L 2/60 Sweeteners
• CPC Class Codes: A23L 27/30 Artificial sweetening agents
• CPC Class Codes: A23L 27/31 containing amino acids, nucleotides, peptides or derivatives
• CPC Class Codes: A23L 27/33 containing sugars or derivatives
• CPC Class Codes: A23L 27/34 Sugar alcohols
• CPC Class Codes: A23L 27/88 Taste or flavour enhancing agents
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/06 Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: C07D 215/42 : attached in position 4
• CPC Class Codes: C07D 215/54 : attached in position 3
• CPC Class Codes: C07D 215/56 : with oxygen atoms in position 4
• CPC Class Codes: C07D 239/70 : condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 239/84 : Nitrogen atoms
• CPC Class Codes: C07D 239/94 : Nitrogen atoms
• CPC Class Codes: C07D 239/95 : with hetero atoms directly attached in positions 2 and 4
• CPC Class Codes: C07D 285/16 : Thiadiazines; Hydrogenated thiadiazines
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 491/04 : Ortho-condensed systems
• CPC Class Codes: C07D 491/056 : with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
• CPC Class Codes: C07D 493/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/14 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/20 : Spiro-condensed systems
• CPC Class Codes: G01N 33/566 : using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds

Abstract

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.

Claims

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);

2. The comestible composition of claim 1, wherein

A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, —

CN, —

OR⁹, —

NR⁹COR¹⁰, —

NHOR⁹, —

NR⁹R¹⁰, —

NR⁹CO₂R¹⁰, —

NR⁹CONR¹⁰R¹¹, —

NR⁹CSNR¹⁰R¹¹, or —

NR⁹C(═

NH)NR¹⁰R¹¹;

R¹⁷ is hydrogen or alkyl;

R²⁶ is hydrogen, alkyl, —

OR³¹, —

CONR³¹R³², or —

CO₂R³¹;

and

R²⁷ is hydrogen, alkyl, —

OR³³, —

CONR³³R³⁴, or —

CO₂R³³.

3. The comestible composition of claim 1, wherein

A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, —

CN, —

NR⁹R¹⁰, or —

NR⁹CO₂R¹⁰;

R¹⁷ is hydrogen or alkyl;

R²⁷ is hydrogen, alkyl, —

OR³³, —

CONR³³R³⁴ or —

CO₂R³³; and

R²⁶ is hydrogen, alkyl, —

OR³¹, —

CONR³¹R³², or —

CO₂R³¹.

4. The comestible composition of claim 1, wherein

A is —

OR⁹, —

NR⁹CONR¹⁰R¹¹, —

NR⁹CSNR¹⁰R¹¹ or —

NR⁹C(═

NH)NR¹⁰R¹¹;

R¹⁷ is hydrogen or alkyl;

R²⁷ is hydrogen, alkyl, —

OR³³, —

CONR³³R³⁴ or —

CO₂R³³; and

R²⁶ is hydrogen, alkyl, —

OR³¹, —

CONR³¹R³², or —

CO₂R³¹.

5. The comestible composition of claim 1, wherein

A is —

OH, —

NH₂, —

NHCH₃, —

N(CH₃)₂, —

NHOCH₃, —

NHC(O)CH₃, —

NHC(O)OCH₃, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHC(NH)NH₂, —

CN, —

CH₂OH, —

CH₂NH₂, —

CH₂NHCH₃, —

CH₂N(CH₃)₂, or —

CH₂NHC(O)CH₃;

R¹⁷ is hydrogen, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, or benzyl;

R²⁷ is hydrogen, —

CF₃, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or t-butyl; and

R²⁶ is hydrogen, —

CF₃, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or t-butyl.

6. The comestible composition of claim 5, wherein

A is —

NH₂;

R¹⁷ is hydrogen or methyl;

R²⁷ is hydrogen, —

CF₃, methyl or ethyl; and

R²⁶ is hydrogen, —

CF₃, methyl or ethyl.

7. The comestible composition of claim 1, wherein

R²⁷ is hydrogen, alkyl or substituted alkyl;

and

R²⁶ is hydrogen, alkyl or substituted alkyl.

8. The comestible composition of claim 7, wherein

A is —

NR⁹R¹⁰;

R¹⁷ is hydrogen or alkyl;

R²⁷ is hydrogen or alkyl;

R²⁶ is hydrogen or alkyl; and

R⁹ and R¹⁰ 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).