MODULATION OF CHEMOSENSORY RECEPTORS AND LIGANDS ASSOCIATED THEREWITH
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Accused Products
Abstract
The present invention 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.
179 Citations
125 Claims
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1-3. -3. (canceled)
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5-8. -8. (canceled)
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10. (canceled)
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23-27. -27. (canceled)
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29-31. -31. (canceled)
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38. (canceled)
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41. A compound of structural Formula (IIIa):
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or a salt, hydrate, solvate or N-oxide thereof wherein; A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, halo, —
CN, —
NO2, —
OR9, —
S(O)cR9, —
NR9R10, —
NOR9, —
NHOR9, —
CONR9R10, —
CO2R9, —
NR9COR10, —
NR9CO2R10, —
NR9CONR10R11, —
NR9CSNR10R11, —
NR9C(═
NH)NR10R11, —
B(OR10)(OR11), —
P(O)(OR10)(OR11) or —
P(O)(R10)(OR11);R17 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or —
CO2R19;B is —
N—
orR12 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —
NR13R14, —
CN, —
OR13, —
S(O)dR13, —
CO2R13 or —
CONR13R14;H is —
C(R35)—
or —
N—
;I is —
C(R36) or —
N—
;J is —
C(R37)—
or —
N—
;K is —
C(R38)—
or —
N—
;R35 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, halo, chloro, fluoro, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, —
CN, —
NO2, —
OR39, —
S(O)iR39, —
OCOR39, —
NR39COR40, —
CONR39R40, —
CO2R39, —
SO2NR39R40, —
NR39SO2R40, —
B(OR39)(OR40), —
P(O)(OR39)(OR40);
orR36 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, halo, chloro, fluoro, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, —
CN, —
NO2, —
OR41, —
S(O)kR41, —
OCOR41, —
NR41COR42, —
NR41R42, —
CONR41R42, —
CO2R41, —
SO2NR41R42, —
NR41SO2R42, —
B(OR41)(OR42), —
P(O)(OR41)(OR42) or —
P(O)(R41)(OR42);R37 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, halo, chloro, fluoro, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl ,—
CN, —
NO2, —
OR43, —
S(O)1R43, —
OCOR43, —
NR43R44, —
CONR43R44, —
CO2R43, —
SO2NR43R44, —
NR43SO2R44, —
B(OR43)(OR44), —
P(O)(OR43)(OR44) or —
P(O)(R43)(OR44);R38 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, halo, chloro, fluoro, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, —
CN, —
NO2, —
OR45, —
S(O)mR45, OCOR45, —
NR45COR46, —
NR45R46, —
CONR45R46, —
CO2R45, SO2NR45R46, —
NR45SO2R46, —
B(OR45)(OR46), —
P(O)(OR45)(OR46) or —
P(O)(R45)(OR46);c, d, j, k, 1 and m are independently 0, 1 or 2; and R9, R13, R14, R19 and R39-R46 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively R13 and R14, R39 and R40, R41 and R42, R43 and R44 and R45 and R46 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; with the proviso that at most, three of H, I, J and K are —
N—
.- View Dependent Claims (42, 43, 44, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 57, 58, 59, 60, 61)
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60. The compound of claim 41 having the structure:
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61. The compound of claim 41 having the structure:
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62-67. -67. (canceled)
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68. A composition comprising
at least a sweet flavor entity; - and
a compound of structural Formula (IIc); or a salt thereof;
wherein;A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, —
CN, —
NO2, —
OR9, —
S(O)cR9, —
NR COR9, —
NHOR9, —
NR9R10, —
NOR9, —
CONR9R10, —
CO2R9, —
NR9CO2R10, —
NR9CONR10R11, —
NR9CSNR10R11, —
NR9C(═
NH)NR10R11;R17 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or —
CO2R19;Y forms a single bond with W and a double bond with Z; W is —
S—
;Y is —
C(R26)—
;Z is —
C(R27)—
;R26 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl —
CN, —
NO2, —
OR31, —
S(O)hR31, —
OCOR31, —
NR31R32, —
CONR31R32, —
CO2R31, —
NR31COR32, —
SO2NR31R32, —
NR31SO2R32;R27 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl —
CN, —
NO2, —
OR33, —
S(O)iR33, —
OCOR33, —
NR33R34, —
CONR33R34, —
CO2R33, —
NR33COR34, —
SO2NR33R34, —
NR33SO2R33;
or alternatively R26 and R27 together with the atoms to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;c, h and i are independently 0 or 1 or 2; R9 to R11, R19 and R31 to R34 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
alternatively R10 and R11, R31 and R32, or R33 and R34 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.- View Dependent Claims (97, 98, 101, 102, 103, 104, 105, 106, 107, 108, 109, 112, 113, 114, 115, 116, 117, 120, 121, 122, 123, 124, 125)
R26 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, —
CN, —
NO2, —
OR31, —
S(O)hR31, —
OCOR31, —
NR31R32, —
CONR31R32 or —
CO2R31.
- and
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102. The composition of claim 68, wherein
R27 is hydrogen, alkyl or substituted alkyl; - and
R26 is hydrogen, alkyl or substituted alkyl.
- and
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103. The composition of claim 68, wherein
A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, — - CN, —
NO2, —
S(O)cR9, —
NR9R10, —
CONR9R10, —
CO2R9 or —
NR9CO2R10;R17 is hydrogen, alkyl, substituted alkyl, arylalkyl, or substituted arylalkyl; R27 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, —
CN, —
NO2, —
OR33, —
S(O)iR33, —
OCOR33, —
NR33R34, —
CONR33R34 or —
CO2R33; andR26 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, —
CN, —
NO2, —
OR31, —
S(O)hR31, —
OCOR31, —
NR31R32, —
CONR31R32or —
CO2R31.
- CN, —
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104. The composition of claim 68, wherein
A — - OR9, —
NR9CONR10R11, —
NR9CSNR10R11 or —
NR9C(═
NH)NR10R11;R17 is hydrogen, alkyl, substituted alkyl, arylalkyl, or substituted arylalkyl; R27 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, —
CN, —
NO2, —
OR33, —
S(O)iR33, —
OCOR33, —
NR33R34, —
CONR33R34 or —
CO2R33; andR26 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, —
CN, —
NO2, —
OR31, —
S(O)hR31, —
OCOR31, —
NR31R32, —
CONR31R32or —
CO2R31.
- OR9, —
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105. The composition of claim 68, wherein
A is — - OH, —
NH2, —
NHCH3, —
N(CH3)2, —
NHOCH3, —
NOCH3, —
NHC(O)CH3, —
NHC(O)OCH3, —
NHC(O)NH2, —
NHC(S)NH2, —
NHC(NH)NH2, —
CN, —
CH2OH, —
CH2NH2, —
CH2NHCH3, —
CH2N(CH3)2, —
CO2H, —
CONH2, —
CONHCH3 or —
CH2NHC(O)CH3;R17 is hydrogen, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, phenyl or benzyl; R27 is hydrogen, —
CF3, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or t-butyl; andR26 is hydrogen, —
CF3, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or t-butyl.
- OH, —
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106. The composition of claim 68, wherein
A is — - NH2;
R17 is hydrogen or methyl; R27 is hydrogen, —
CF3, methyl or ethyl; andR26 is hydrogen, —
CF3, methyl or ethyl.
- NH2;
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107. The compound of any one of claims 99 to 106, wherein
R25 is hydrogen, alkyl or arylalkyl. -
108. The compound of any one of claims 99 to 106, wherein
R25 is hydrogen, methyl or benzyl. -
109. The compound of anyone of claims 99 to 106, wherein
Z is — - S—
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- S—
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112. The composition of claim 68, wherein the compound of structural Formula (IIc) has a structural formula selected from the group consisting of
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113. The composition of claim 68, comprising a hydrochloride salt of the compound of structural Formula (IIc) selected from the group consisting of
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114. The composition of claim 68, comprising between about 0.0001 ppm to about 10 ppm of the compound of structural Formula (IIc).
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115. The composition of claim 68, comprising between about 0.0001 ppm to about 100 ppm of the compound of structural Formula (IIc).
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116. The composition of claim 68, comprising between about 0.01 ppm to about 100 ppm of the compound of structural Formula (IIc).
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117. The composition of claim 68, comprising between about 10 ppm to about 100,000 ppm of the compound of structural Formula (IIc).
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120. The composition of claim 68 is a food or beverage product.
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121. The composition of claim 120, wherein the food or beverage product is selected from the group consisting of the Wet Soup Category, the Dehydrated and Culinary Food Category, the Beverage Category, the Frozen Food Category, the Snack Food Category, seasonings or seasoning blends, and combinations thereof.
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122. The composition of claim 120, wherein the food or beverage product is selected from the group consisting of carbonated and non-carbonated beverages;
- fruit or vegetable juices;
alcoholic and non-alcoholic beverages;
confectionary products;
cereal and breakfast foods;
canned fruits and fruit sauces;
sweet coatings, frostings, and glazes; and
combinations thereof.
- fruit or vegetable juices;
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123. The composition of claim 68, wherein
A is — - NR9R10;
R17 is hydrogen, alkyl, or substituted alkyl,; R27 is hydrogen, alkyl, or substituted alkyl; R26 is hydrogen, alkyl, or substituted alkyl; and R9 and R10 are each independently hydrogen, alkyl, or substituted alkyl.
- NR9R10;
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124. The composition of claim 68, which is a comestible or medicinal composition.
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125. The medicinal composition of claim 124, comprising a pharmaceutically acceptable vehicle.
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69-71. -71. (canceled)
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99-100. -100. (canceled)
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118-119. -119. (canceled)
Specification