Modulation of chemosensory receptors and ligands associated therewith

• US 9,181,276 B2
• Filed: 11/12/2013
• Issued: 11/10/2015
• Est. Priority Date: 06/08/2007
• Status: Active Grant

• Current Assignee: Senomyx Inc
• Original Assignee: Senomyx Inc
• Inventors: Tachdjian, Catherine, Karanewsky, Donald S., Tang, Xiao-Qing, Li, Xiaodong, Zhang, Feng, Servant, Guy, Chen, Qing, Darmohusodo, Vincent, Fine, Richard, Fotsing, Joseph R., Hammaker, Jeffrey Robert, Kang, Xinshan, Kimmich, Rachel D. A., Klebansky, Boris, Liu, Haitian, Petrovic, Goran, Rinnova, Marketa, Adamski-Werner, Sara, Yamamoto, Jeffrey, Zhang, Hong, Zlotnik, Albert
• Primary Examiner(s): Gembeh, Shirley V
• Application Number:
  US14/077,749
• Publication Number:
  US 20140235623A1
• Time in Patent Office: 728 Days
• Field of Search: 544/11, 514/222.8
• US Class Current: 1/1
• 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 includes 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, and modifiers capable of modulating chemosensory receptors and their ligands. The present invention also includes modifiers of chemosensory receptors and their ligands having Formula (I), its subgenus, and specific compounds. Furthermore, the present invention includes ingestible compositions comprising the modifiers of chemosensory receptors and their ligands and methods of using the modifiers of chemosensory receptors and their ligands to enhance the sweet taste of an ingestible composition or treat a condition associated with a chemosensory receptor. In addition, the present invention include processes for preparing the modifiers of chemosensory receptors and their ligands.

Claims

1. An ingestible composition comprising a compound having structural Formula (IIIb), or a tautomer, salt, solvate, and/or ester thereof;

and an ingestible carrier;

2. The ingestible composition of claim 1, selected from the group consisting of food or beverage product, non-edible product, a pharmaceutical composition, and combinations thereof.

3. The ingestible composition of claim 2, wherein the food or beverage product is selected from the group consisting of the Soup category;

the Dried Processed Food category;

the Beverage category;

the Ready Meal category;

the Canned or Preserved Food category;

the Frozen Processed Food category;

the Chilled Processed Food category;

the Snack Food category;

the Baked Goods category;

the Confectionary category;

the Dairy Product category;

the Ice Cream category;

the Meal Replacement category;

the Pasta and Noodle category;

the Sauces, Dressings, Condiments category;

the Baby Food category;

the Spreads category;

sweet coatings, frostings, or glazes; and

combinations thereof.

4. The ingestible composition of claim 2, wherein the non-edible product is selected from the group consisting of nutritional products and dietary supplements, over the counter medications, oral care products, and cosmetics.

5. The ingestible composition of claim 1, wherein the compound having structural Formula (IIIb), or a tautomer, salt, solvate, and/or ester thereof, is in a sweet flavor enhancing amount.

6. The ingestible composition of claim 5, wherein the sweet flavor enhancing amount is not a therapeutically effective amount.

7. The ingestible composition of claim 1, comprising from about 0.0001 ppm to about 10 ppm of the compound having structural Formula (IIIb), or a tautomer, salt, solvate, and/or ester thereof.

8. The ingestible composition of claim 1, comprising from about 0.01 ppm to about 100 ppm of the compound having structural Formula (IIIb), or a tautomer, salt, solvate, and/or ester thereof.

9. The ingestible composition of claim 1, comprising from about 10 ppm to about 100,000 ppm of the compound having structural Formula (IIIb), or a tautomer, salt, solvate, and/or ester thereof.

10. The ingestible composition of claim 1, further comprising at least one sweet flavor entity.

11. The ingestible composition of claim 10, wherein the sweet flavor entity is selected from the group consisting of sucrose, fructose, glucose, galactose, mannose, lactose, tagatose, maltose, high fructose corn syrup, D-tryptophan, glycine, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin, maltitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolyzate (HSH), stevioside, rebaudioside A, other sweet Stevia-based glycosides, carrelame, other guanidine-based sweeteners, saccharin, acesulfame-K, cyclamate, sucralose, alitame, mogroside, neotame, aspartame, other aspartame derivatives, and combinations thereof.

12. The ingestible composition of claim 10, wherein the sweet entity is selected from the group consisting of a natural sweetener and an artificial or synthesized sweetener.

13. The ingestible composition of claim 12, wherein the natural sweetener is a saccharide sweetener, a natural sugar, or a semi-synthetic “

sugar alcohol”

sweetener.

14. The ingestible composition of claim 13, wherein the natural sweetener is selected from a group consisting of sucrose, fructose, glucose, tagatose, maltose, galactose, mannose, lactose, glycine, corn syrup or other syrups or sweetener concentrates derived from natural fruit and vegetable sources, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin, and mogroside.

15. The ingestible composition of claim 12, wherein the artificial or synthesized sweetener is a non-caloric sweet flavor compound, a reduced caloric sweet flavor compound, or a non-target caloric sweet flavor compound.

16. The ingestible composition of claim 15, wherein the artificial or synthesized sweetener is selected from a group consisting of aspartame, saccharin, acesulfame-K, cyclamate, sucralose, alitame, aspartame, neotame, aspartame derivatives, D-tryptophan, hydroganeted glucose syrup (HGS), hydrogenated starch hydrolyzate (HSH), stevioside, rebaudioside A, sweet Stevia-based glycosides, carrelame, and guanidine-based sweeteners.

17. The ingestible composition of claim 1, wherein A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, —

CN, —

NO₂, —

OR⁹, —

S(O)_cR⁹, —

NR⁹COR¹⁰, —

NHOR⁹, —

NR⁹R¹⁰, —

NOR⁹, —

CONR⁹R¹⁰, —

CO₂R⁹, —

NR⁹CO₂R¹⁰, —

NR⁹CONR¹⁰R¹¹, —

NR⁹CSNR¹⁰R¹¹, or —

NR⁹C(═

NH)NR¹⁰R¹¹.

18. The ingestible composition of claim 1, wherein R¹⁷ is hydrogen, alkyl, or substituted alkyl.

19. The ingestible composition of claim 1, wherein

H is —

C(R³⁵)—

;

I is —

C(R³⁶)—

;

J is —

C(R³⁷)—

; and

K is —

C(R³⁸)—

.

20. The ingestible composition of claim 1, wherein

A is —

NH₂,

R¹⁷ is hydrogen, methyl, ethyl or benzyl; and

R³⁵, R³⁶, R³⁷ and R³⁸ are independently hydrogen, fluoro, chloro, bromo, —

CN, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkanyl, substituted cycloalkanyl, cycloalkenyl, substituted cycloalkenyl, heteroalkanyl, substituted heteroalkanyl, cycloheteroalkyl, substituted cycloheteroalkyl, —

O-alkanyl, —

O-(substituted alkanyl), —

O-alkenyl, —

O-(substituted alkenyl), —

NH-alkanyl, —

NH-(substituted alkanyl), —

NH-alkenyl, —

NH-(substituted alkenyl), —

S-alkanyl, —

S-(substituted alkanyl), —

S-alkenyl, or —

S-(substituted alkenyl).

21. The ingestible composition of claim 1, wherein the compound having structural Formula (IIIb) is represented by structural Formula (IIIb1):

22. The ingestible composition of claim 21, wherein

X¹ is —

CH₂—

; and

Y¹ is

23. The ingestible composition of claim 21, wherein

X¹ is —

O—

, —

NR⁹—

, or —

S—

;

m is 0 or 1, and

Y¹ is cycloheteroalkyl or substituted cycloheteroalkyl.

24. The ingestible composition of claim 21, wherein

X¹ is —

O—

, —

NR⁹—

, or —

S—

;

m is 1, and

Y¹ is

25. The ingestible composition of claim 21, wherein

X² is methylene, ethylene, propylene, iso-propylene, butylene, iso-butylene, sec-butylene, pentylene, hexylene, heptylene, dimethylethylene, methylcyclopropylene, cyclopropylmethylene, ethenylene, propenylene, or butenylene.

26. The ingestible composition of claim 21, wherein Y¹ is piperidinyl, substituted piperidinyl, tetrahydrofuranyl, substituted tetrahydrofuranyl, tetrahydropyranyl, substituted tetrahydropyranyl, dihydrofuranyl, substituted dihydrofuranyl, pyrrolidinyl, substituted pyrrolidinyl, oxetanyl, substituted oxetanyl, saccharide ring or its derivative, substituted saccharide ring or its derivative.

27. The ingestible composition of claim 21, wherein Y¹ is pyridinyl, substituted pyridinyl, pyrrolyl, substituted pyrrolyl, furanyl, substituted furanyl, pyrazolyl, substituted pyrazolyl, isoxazolyl, substituted isoxazolyl, oxazolyl, and substituted oxazolyl.

28. The ingestible composition of claim 21, wherein the substituted cycloheteroalkyl comprises one or more substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

OR⁹, —

NO₂, —

S(O)_cR⁹, —

NOR⁹, —

NHOR⁹, —

NR⁹COR¹⁰, —

NR⁹R¹⁰, —

CONR⁹R¹⁰, —

CO₂R⁹, and —

NR⁹CO₂R¹⁰.

29. The ingestible composition of claim 21, wherein Y¹ is

30. The ingestible composition of claim 21, wherein —

X³—

C(X⁴)—

X⁵—

is —

C(O)—

, —

C(O)—

NH—

, —

NH—

C(O)—

, —

NH—

C(O)—

NH—

, —

C(O)—

O—

, —

O—

C(O)—

, —

O—

C(O)—

O—

, —

NH—

C(O)—

O—

, —

O—

C(O)—

NH—

, —

C(NH)—

, —

C(NH)—

NH—

, —

NH—

C(NH)—

, —

NH—

C(NH)—

NH—

, —

C(NH)—

O—

, —

O—

C(NH)—

, —

O—

C(NH)—

O—

, —

NH—

C(NH)—

O—

, —

O—

C(NH)—

NH—

, —

C(N—

OH)—

, or —

C(S)—

.

31. The ingestible composition of claim 21, wherein

A is hydrogen, alkyl, substituted alkyl, or —

NR⁹R¹⁰;

R¹⁷ is hydrogen; and

Y¹ is piperidinyl, substituted piperidinyl, tetrahydrofuranyl, substituted tetrahydrofuranyl, tetrahydropyranyl, substituted tetrahydropyranyl, dihydrofuranyl, substituted dihydrofuranyl, pyrrolidinyl, substituted pyrrolidinyl, oxetanyl, substituted oxetanyl, monosaccharide ring, substituted monosaccharide ring, pyridinyl, substituted pyridinyl, pyrrolyl, substituted pyrrolyl, furanyl, substituted furanyl, pyrazolyl, substituted pyrazolyl, isoxazolyl, substituted isoxazolyl, oxazolyl, or substituted oxazolyl.

32. The ingestible composition of claim 21, wherein

A is hydrogen, alkyl, substituted alkyl, or —

NR⁹R¹⁰;

R¹⁷ is hydrogen;

Y¹ is —

X³—

C(X⁴)—

X⁵—

; and

—

X³—

C(X⁴)_X⁵_is —

C(O)—

, —

C(O)—

NH—

, —

NH—

C(O)—

, —

NH—

C(O)—

NH—

, —

C(O)—

O—

, —

O—

C(O)—

, —

O—

C(O)—

O—

, —

NH—

C(O)—

O—

, —

O—

C(O)—

NH—

, —

C(NH)—

, —

C(NH)—

NH—

, —

NH—

C(NH)—

, —

NH—

C(NH)—

NH—

, —

C(NH)—

O—

, —

O—

C(NH)—

, —

O—

C(NH)—

O—

, —

NH—

C(NH)—

O—

, —

O—

C(NH)—

NH—

, —

S(O)₂—

, —

NH—

S(O)₂—

, —

S(O)₂—

NH—

, —

O—

S(O)₂—

, —

S(O)₂—

O—

, —

C(N—

OH)—

, or —

C(S)—

.

33. The ingestible composition of claim 1, wherein the compound having structural Formula (IIIb) is selected from the group consisting of

34. A liquid or solid concentrate formulation comprising a compound of Formula (IIIb), or a tautomer, salt, solvate, and/or ester thereof;

and an ingestible carrier;

35. A dry powdered beverage mix comprising a compound of Formula (IIIb), or a tautomer, salt, solvate, and/or ester thereof;