Modulation of chemosensory receptors and ligands associated therewith

• US 8,633,186 B2
• Filed: 06/03/2008
• Issued: 01/21/2014
• Est. Priority Date: 06/08/2007
• Status: Active Grant

• Current Assignee: Senomyx Inc (DSM-Firmenich AG)
• Original Assignee: Senomyx Inc (DSM-Firmenich AG)
• 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, Klebansky, Boris, Liu, Haitian, Petrovic, Goran, Rinnova, Marketa, Adamski-Werner, Sara, Yamamoto, Jeffrey, Zhang, Hong, Zlotnik, Albert, Zoller, Mark, Kimmich, Rachel D. A.
• Primary Examiner(s): Habte, Kahsay
• Application Number:
  US12/663,634
• Publication Number:
  US 20110224155A1
• Time in Patent Office: 2,058 Days
• Field of Search: 544/11, 514/222.8
• US Class Current: 514/222.8
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: C07D 239/80 Oxygen atoms
• CPC Class Codes: C07D 239/93 Sulfur atoms
• CPC Class Codes: C07D 239/95 with hetero atoms directly attached in positions 2 and 4
• CPC Class Codes: C07D 239/96 Two oxygen atoms
• CPC Class Codes: C07D 285/15 Six-membered rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• 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 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 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: C07H 17/00 Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
• CPC Class Codes: G01N 2333/726 G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
• CPC Class Codes: G01N 2500/00 : Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 2500/04 : Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• CPC Class Codes: G01N 33/74 : involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
• CPC Class Codes: G16B 15/00 : ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
• CPC Class Codes: G16B 20/00 : ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/30 : Detection of binding sites or motifs
• CPC Class Codes: G16B 20/50 : Mutagenesis

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. A compound having structural Formula (IIIb):

2. The compound of claim 1, wherein

H is —

C(R³⁵)—

;

I is —

C(R³⁶)—

;

J is —

C(R³⁷)—

; and

K is —

C(R³⁸)—

.

15. The compound of claim 1 or 3, having structural formula selected from the group consisting of

3. A compound having structural Formula (IIIb1):

4. The compound of claim 3, wherein

X¹ is —

CH₂—

; and

Y¹ is

5. The compound of claim 3, wherein

X¹ is —

O—

, —

NR⁹—

, or —

S—

;

m is 0 or 1, and

Y¹ is cycloheteroalkyl or substituted cycloheteroalkyl.

6. The compound of claim 3, wherein

X¹ is —

O—

, —

NR⁹—

, or —

S—

;

m is 1, and

Y¹ is

7. The compound of claim 3, wherein

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

8. The compound of claim 3, 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.

9. The compound of claim 3, wherein Y¹ is pyridinyl, substituted pyridinyl, pyrrolyl, substituted pyrrolyl, furanyl, substituted furanyl, pyrazolyl, substituted pyrazolyl, isoxazolyl, substituted isoxazolyl, oxazolyl, and substituted oxazolyl.

10. The compound of claim 3, 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.

11. The compound of claim 3, wherein Y¹ is

12. The compound of claim 3, 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)—

.

13. The compound of claim 3, wherein

A is hydrogen, 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.

14. The compound of claim 3, wherein

A is hydrogen, 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)—

.

16. A process of preparing a compound having structural Formula (e):